Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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Health-related quality of life with enzalutamide versus flutamide in castration-resistant prostate cancer from the AFTERCAB study.

Uemura H, Kobayashi K, Yokomizo A, Hinotsu S, Horie S, Kakehi Y, Nonomura N, Ogawa O, Oya M, Suzuki K, Saito A, Asakawa K, Uno S, Naito S

International journal of clinical oncology 2022.08

ISSN 1341-9625

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Iliopsoas abscess in patients receiving hemodialysis: a case series and a literature survey

Oshida Takuma, Yoshida Tadashi, Itoh Hiroshi, Oya Mototsugu

RENAL REPLACEMENT THERAPY 8 ( 1 ) 2022.07

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Functional analysis of GCNT3 for cell migration and EMT of castration-resistant prostate cancer cells.

Daiki Yamamoto, Katsumasa Sasaki, Takeo Kosaka, Mototsugu Oya, Toshinori Sato

Glycobiology 2022.07

ISSN 0959-6658

Castration-resistant prostate cancer (CRPC) is a malignant tumor that is resistant to androgen deprivation therapy. Treatments for CRPC are limited, and no diagnostic markers are currently available. O-glycans are known to play an important role in cell proliferation, migration, invasion, and metastasis of cancer cells. However, the differences in the O-glycan expression profiles for normal prostate cancer (PCa) cells compared to CRPC cells have not yet been investigated. In this study, the saccharide primer method was employed to analyze the O-glycans expressed in CRPC cells. Expression levels of core 4-type O-glycans were significantly increased in CRPC cells. Furthermore, the expression level of N-Acetylglucosaminyltransferase 3 (GCNT3), a core 4-type O-glycan synthase gene, was increased in CRPC cells. The expression of core 4-type O-glycans and GCNT3 was presumed to be regulated by androgen deprivation. GCNT3 knockdown induced cell migration and epithelial-mesenchymal transition (EMT). These observations elucidate the mechanism of acquisition of castration resistance in PCa and offer new possibilities for the development of diagnostic markers and therapeutic targets in the treatment of PCa.

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Characterization of aldosterone-producing cell cluster (APCC) at single-cell resolution.

Norifusa Iwahashi, Hironobu Umakoshi, Tsugio Seki, Celso E Gomez-Sanchez, Kuniaki Mukai, Makoto Suematsu, Yuta Umezawa, Mototsugu Oya, Takeo Kosaka, Masahide Seki, Yutaka Suzuki, Yutaka Horiuchi, Yoshihiro Ogawa, Koshiro Nishimoto

The Journal of clinical endocrinology and metabolism 2022.07

ISSN 0021-972X

CONTEXT: The adrenal cortex consists of zona glomerulosa (ZG), fasciculata (ZF), and reticularis. Aldosterone-producing cell clusters that strongly express aldosterone synthase (CYP11B2) are frequently found in adult adrenals and harbor somatic mutations that are also detected in aldosterone-producing adenomas (APAs). Primary aldosteronism is mainly caused by APAs or idiopathic hyperaldosteronism (IHA). We presume that APCCs are causing IHA and are precursors of APAs. However, the gene expression characteristics and especially the development of APCC are not well understood. OBJECTIVE: This study aimed to analyze the transcriptome of APCC at single-cell resolution and infer the developmental trajectory. METHODS: Single-cell RNA sequencing (scRNA-seq) of two adult adrenals was performed. RESULTS: Immunohistochemical analyses confirmed the two adrenals had APCCs. scRNA-seq data of 2,928 adrenal cells were obtained and 1,765 adrenocortical cells were identified based on unsupervised clustering and the marker gene expression. The adrenocortical cells were divided into 6 clusters, of which three clusters (923 cells) were composed of APCC/ZG cells. By further sub-clustering, the APCC/ZG cells were divided into three clusters (clusters C1, C2, and C3), we finally identified APCC-cluster (C3) and ZG-cluster (C1). Cluster C2 seemed to be ZG-to-ZF transitional cells. RNA velocity analysis inferred the developmental direction from cluster ZG-cluster-C1 to APCC-cluster-C3. The scRNA-seq additionally revealed that many CYP11B2-positive cells were positive for CYP11B1 and/or CYP17A1, which were essential for cortisol but not for aldosterone production. CONCLUSIONS: Our results revealed the gene expression characteristics of APCC at single-cell resolution and show that some ZG cells remodel to APCC.

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Salvage focal brachytherapy in castration‐resistant prostate cancer with neuroendocrine differentiation after radiation therapy

Takahiro Komori, Takeo Kosaka, Keitaro Watanabe, Tomoki Tanaka, Yota Yasumizu, Hiroshi Hongo, Shuji Mikami, Toshio Ohashi, Mototsugu Oya

IJU Case Reports (Wiley) 5 ( 4 ) 233 - 236 2022.07

ISSN 2577-171X

Introduction: Treatment strategy for castration-resistant prostate cancer with neuroendocrine differentiation after radiation therapy has not been established. Case presentation: We described a case of castration-resistant prostate cancer with neuroendocrine differentiation after initial external beam radiotherapy followed by salvage androgen deprivation therapy. Magnetic resonance imaging detected recurrence of a suspicious lesion in the left lobe of the prostate, although the prostate-specific antigen level was <0.2 ng/mL. Transperineal prostate saturation needle biopsy detected adenocarcinoma with neuroendocrine differentiation. The patient underwent salvage focal brachytherapy and had a prostate-specific antigen progression-free survival of 20 months with no obvious adverse events. No recurrence has been detected on magnetic resonance imaging for 18 months. Conclusion: Salvage focal brachytherapy for prostate cancer after external beam radiotherapy can be one of the treatment strategies for local recurrence of castration-resistant prostate cancer with neuroendocrine differentiation.

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Hybridisation chain reaction-based visualisation and screening for lncRNA profiles in clear-cell renal-cell carcinoma.

Ryohei Kufukihara, Nobuyuki Tanaka, Kimiharu Takamatsu, Naoya Niwa, Keishiro Fukumoto, Yota Yasumizu, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Eriko Aimono, Hiroshi Nishihara, Ryuichi Mizuno, Mototsugu Oya

British journal of cancer (British Journal of Cancer) 2022.06

ISSN 0007-0920

BACKGROUND: Analysis of long noncoding RNA (lncRNA) localisation at both the tissue and subcellular levels can provide important insights into the cell types that are important for their function. METHODS: By applying new fluorescent in situ hybridisation technique called hybridisation chain reaction (HCR), we achieved a high-throughput lncRNA visualisation and evaluation of clinical samples. RESULTS: Assessing 1728 pairs of 16 lncRNAs and clear-cell renal-cell carcinoma (ccRCC) specimens, three lncRNAs (TUG1, HOTAIR and CDKN2B-AS1) were associated with ccRCC prognosis. Furthermore, we derived a new lncRNA risk group of ccRCC prognosis by combining the expression levels of these three lncRNAs. Examining genomic alterations underlying this classification revealed prominent features of tumours that could serve as potential biomarkers for targeting lncRNAs. We then derived combination of HCR with expansion microscopy and visualised nanoscale-resolution HCR signals in cell nuclei, uncovering intracellular colocalization of three lncRNA (TUG1, HOTAIR and CDKN2B-AS1) signals such as those located intra- or out of the nucleus or nucleolus in cancer cells. CONCLUSION: LncRNAs are expected to be desirable noncoding targets for cancer diagnosis or treatments. HCR involves plural probes consisting of small DNA oligonucleotides, clinically enabling us to detect cancerous lncRNA signals simply and rapidly at a lower cost.

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Influence of response to prior docetaxel on sensitivity to cabazitaxel in prostate cancer patients with PTEN alterations.

Ken Kamisawa, Takeo Kosaka, Kohei Nakamura, Yota Yasumizu, Hiroshi Hongo, Toshikazu Takeda, Kazuhiro Matsumoto, Hiroshi Nishihara, Mototsugu Oya

Cancer science 2022.06

ISSN 1347-9032

The purpose of this study was to investigate factors predicting the sensitivity to cabazitaxel therapy in metastatic castration-resistant prostate cancer (mCRPC) patients with phosphatase and tensin homolog deleted from chromosome 10 (PTEN) alterations. This single-institution, retrospective study included 12 mCRPC patients with PTEN alterations who had received cabazitaxel therapy. Five patients (41%) responded to cabazitaxel therapy with a prostate-specific antigen (PSA) level decline of ≥30% from baseline, and all of them had responded to prior docetaxel therapy with a PSA decline of ≥30%. None of the patients with a poor response to prior docetaxel therapy responded well to cabazitaxel therapy. Of the seven patients who did not respond to cabazitaxel and whose PSA declined from baseline was <30%, five (71%) were also refractory to prior docetaxel therapy. The PSA responses to docetaxel and cabazitaxel were significantly correlated (p = 0.027). Kaplan-Meier analysis revealed that progression-free survival (PFS) for cabazitaxel was significantly shorter for prior docetaxel nonresponders (3.3 versus 9.1 months, p = 0.028). Multivariate analysis revealed that a poor response to prior docetaxel (PSA decline < 30%) (hazard ratio [HR] = 6.382, 95% confidence interval [CI] 1.172-34.750, p = 0.032) and baseline PSA of ≥20 ng/ml (HR = 33.584, 95% CI 2.332-483.671, p = 0.010) were independent prognostic factors for PFS with cabazitaxel therapy. These results demonstrate cross-resistance between docetaxel and cabazitaxel. The response to prior docetaxel therapy can influence the sensitivity to cabazitaxel therapy in mCRPC patients with PTEN alterations.

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A low subcutaneous fat mass is a risk factor for the development of inguinal hernia after radical prostatectomy.

Umeda K, Takeda T, Hakozaki K, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

Langenbeck's archives of surgery 2022.06

ISSN 1435-2443

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A Japanese case of castration-resistant prostate cancer with BRCA2 and RB1 co-loss and TP53 mutation: a case report.

Iwasawa T, Kosaka T, Morita S, Mikami S, Nakamura K, Hongo H, Nishihara H, Oya M

BMC medical genomics 15 ( 1 ) 138 2022.06

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Effectiveness and safety of sorafenib for renal cell, hepatocellular and thyroid carcinoma: pooled analysis in patients with renal impairment.

Oya M, Kaneko S, Imai T, Tsujino T, Sunaya T, Okayama Y

Cancer chemotherapy and pharmacology 89 ( 6 ) 761 - 772 2022.06

ISSN 0344-5704

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Multiple metastases of androgen indifferent prostate cancer in the urinary tract: two case reports and a literature review.

Masuda T, Kosaka T, Nakamura K, Hongo H, Yuge K, Nishihara H, Oya M

BMC medical genomics 15 ( 1 ) 118 2022.05

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特集腹部の最新画像情報2022 症例術後早期に遠隔転移を認めた表在性膀胱小細胞癌の2例

竹下諒, 有田祐起, 秋田大宇, 三上修治, 田中伸之, 奥田茂男, 大家基嗣, 陣崎雅弘

臨床放射線 (金原出版) 67 ( 5 ) 505 - 510 2022.05

ISSN 00099252

Profiling the Biological Characteristics and Transitions through Upper Tract Tumor Origin, Bladder Recurrence, and Muscle-Invasive Bladder Progression in Upper Tract Urothelial Carcinoma.

Shigeta K, Matsumoto K, Tanaka N, Mikami S, Kosaka T, Yasumizu Y, Takeda T, Mizuno R, Kikuchi E, Oya M

International journal of molecular sciences 23 ( 9 ) 2022.05

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Deep Learning Algorithm for Fully Automated Detection of Small (≤4 cm) Renal Cell Carcinoma in Contrast-Enhanced Computed Tomography Using a Multicenter Database.

Toda N, Hashimoto M, Arita Y, Haque H, Akita H, Akashi T, Gobara H, Nishie A, Yakami M, Nakamoto A, Watadani T, Oya M, Jinzaki M

Investigative radiology 57 ( 5 ) 327 - 333 2022.05

ISSN 0020-9996

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Prospective study of tadalafil treatment in patients treated with prostate brachytherapy in Japan.

Hayakawa N., Mizuno R., Shiraishi Y., Tanaka T., Matsumoto K., Kosaka T., Ohashi T., Kikuchi E., Shigematsu N., Oya M.

RADIOTHERAPY AND ONCOLOGY 170 S1618 - S1618 2022.05

ISSN 0167-8140

Utility of radiomics features of diffusion-weighted magnetic resonance imaging for differentiation of fat-poor angiomyolipoma from clear cell renal cell carcinoma: model development and external validation.

Matsumoto S, Arita Y, Yoshida S, Fukushima H, Kimura K, Yamada I, Tanaka H, Yagi F, Yokoyama M, Matsuoka Y, Oya M, Tateishi U, Jinzaki M, Fujii Y

Abdominal radiology (New York) 47 ( 6 ) 2178 - 2186 2022.04

ISSN 2366-004X

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Potential therapeutic effects of adjuvant chemotherapy after neoadjuvant chemotherapy for locally advanced muscle-invasive bladder cancer.

Omura M, Kikuchi E, Shigeta K, Ogihara K, Hakozaki K, Hara S, Shirotake S, Ide H, Yoshimine S, Ohigashi T, Mizuno R, Oya M

Japanese journal of clinical oncology 52 ( 4 ) 388 - 396 2022.04

ISSN 0368-2811

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増刊号特集専門性と多様性を両立させる! 泌尿器科外来ベストNAVI 企画にあたって専門性と多様性を両立させる! 泌尿器科外来ベストNAVI

大家基嗣

臨床泌尿器科 (株式会社医学書院) 76 ( 4 ) 7 - 7 2022.04

ISSN 03852393

Outcomes of sorafenib treatment of advanced renal cell carcinoma according to IMDC risk criteria: analysis of Japanese real-world data from postmarketing all-patient surveillance of sorafenib.

Inamoto T, Azuma H, Adachi M, Okayama Y, Sunaya T, Oya M

Future oncology (London, England) 18 ( 11 ) 1371 - 1380 2022.04

ISSN 1479-6694

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Endoscopic vaporization of benign prostatic hyperplasia using a contact 980 nm diode laser under antithrombotic therapy: A prospective survey.

Sanjo T, Tanaka N, Shinojima T, Yasumizu Y, Takeda T, Matsumoto K, Morita S, Kosaka T, Mizuno R, Asanuma H, Oya M

Asian journal of endoscopic surgery 2022.03

ISSN 1758-5902

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Unique characteristics of tertiary lymphoid structures in kidney clear cell carcinoma: prognostic outcome and comparison with bladder cancer.

Masuda T, Tanaka N, Takamatsu K, Hakozaki K, Takahashi R, Anno T, Kufukihara R, Shojo K, Mikami S, Shinojima T, Kakimi K, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M

Journal for immunotherapy of cancer 10 ( 3 ) 2022.03

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Incidence and location of perioperative deep vein thrombosis in patients with bladder cancer undergoing radical cystectomy.

Yamashita R, Nakamura M, Okayama Y, Kawase M, Muraoka N, Fujita A, Notsu A, Asakura K, Hashizume A, Shinsaka H, Matsuzaki M, Niwakawa M, Oya M

International journal of urology : official journal of the Japanese Urological Association (International Journal of Urology) 29 ( 3 ) 259 - 264 2022.03

ISSN 0919-8172

Objectives: To determine the incidence and location of lower extremity deep vein thrombosis in patients undergoing radical cystectomy. Methods: We performed radical cystectomy in 137 patients with bladder cancer between August 2014 and February 2020. Since 2014, we have had a policy to screen for deep vein thrombosis using lower extremity ultrasonography both before and after radical cystectomy. We determined the incidence and location of deep vein thrombosis and classified it as either proximal or distal type. Furthermore, we explored the incidence of pulmonary embolism within 3 months after radical cystectomy. Results: After excluding six patients with a lack of ultrasonographic data, we evaluated 131 patients. Preoperative deep vein thrombosis (one proximal and 17 distal) was diagnosed in 18 patients (14%) with no symptoms. Postoperative deep vein thrombosis was diagnosed in 41 patients (31%; three proximal and 38 distal), of whom 26 (63%) had new-onset deep vein thrombosis after cystectomy. Three patients, two with proximal and one with distal type deep vein thrombosis, developed nonfatal pulmonary embolism postoperatively. Multivariate analysis showed that preoperative D-dimer levels (odds ratio 5.35, 95% confidence interval 1.74–16.50; P < 0.003), type of urinary diversion (ileal neobladder; odds ratio 11.15, 95% confidence interval 2.16–57.55; P = 0.004), and preoperative deep vein thrombosis (odds ratio 15.93, 95% confidence interval 3.82–66.30; P < 0.001) were significant risk factors for postoperative deep vein thrombosis. Conclusions: Pre- and post-radical cystectomy whole-leg ultrasonography can lead to an early perioperative diagnosis and immediate treatment of proximal deep vein thrombosis, thereby potentially preventing fatal pulmonary embolism.

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An organ-derived extracellular matrix triggers in situ kidney regeneration in a preclinical model.

Tajima K, Yagi H, Morisaku T, Nishi K, Kushige H, Kojima H, Higashi H, Kuroda K, Kitago M, Adachi S, Natsume T, Nishimura K, Oya M, Kitagawa Y

NPJ Regenerative medicine (npj Regenerative Medicine) 7 ( 1 ) 18 2022.02

It has not been considered that nephrons regenerate in adult mammals. We present that an organ-derived extracellular matrix in situ induces nephron regeneration in a preclinical model. A porcine kidney-derived extracellular matrix was sutured onto the surface of partial nephrectomy (PN)-treated kidney. Twenty-eight days after implantation, glomeruli, vessels, and renal tubules, characteristic of nephrons, were histologically observed within the matrix. No fibrillogenesis was observed in the matrix nor the matrix-sutured kidney, although this occurred in a PN kidney without the matrix, indicating the structures were newly induced by the matrix. The expression of renal progenitor markers, including Sall1, Six2, and WT-1, within the matrix supported the induction of nephron regeneration by the matrix. Furthermore, active blood flow was observed inside the matrix using computed tomography. The matrix provides structural and functional foundations for the development of cell-free scaffolds with a remarkably low risk of immune rejection and cancerization.

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PROpel: Phase III trial of olaparib (ola) and abiraterone (abi) versus placebo (pbo) and abi as first-line (1L) therapy for patients (pts) with metastatic castration-resistant prostate cancer (mCRPC).

Saad Fred, Armstrong Andrew J., Thiery-Vuillemin Antoine, Oya Mototsugu, Loredo Eugenia, Procopio Giuseppe, de Menezes Juliana Janoski, Girotto Gustavo Colagiovanni, Arslan Cagatay, Mehra Niven, Parnis Francis, Brown Emma, Schluermann Friederike, Joung Jae Young, Sugimoto Mikio, Poehlein Christian Heinrich, Harrington Elizabeth, Desai Chintu, Kang Jinyu, Clarke Noel

JOURNAL OF CLINICAL ONCOLOGY 40 ( 6 ) 2022.02

ISSN 0732-183X

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Castration-resistant prostate cancer patient presenting with whole genome doubling with CDK-12 mutation.

Baba Y, Kosaka T, Kobayashi H, Nakamura K, Mikami S, Nishihara H, Nakanishi M, Oya M

BMC medical genomics (BMC Medical Genomics) 15 ( 1 ) 32 2022.02

Background: The use of whole-genome sequencing in clinical practice has revealed variable genomic characteristics across cancer types, one of which is whole-genome doubling (WGD), which describes the duplication of a complete set of chromosomes. Yet it is relatively rare in prostate cancer and no such case has ever been reported in Japanese patients. Case presentation: A 54-year-old patient with prostatic adenocarcinoma with bone and lymph node metastases was started on androgen-deprivation therapy. As the prostate cancer turned castration-resistant, multimodal therapies including taxane- and platinum-based chemotherapy, androgen-receptor antagonist inhibitors, radiotherapy and radium-233 were introduced. Good controls of serum prostate-specific antigen (PSA) level and bone metastases were achieved for more than 13 years since after the initial treatment. During the treatment, a metastatic lymph node biopsy was performed to confirm the tumor histology, and spinal decompression surgery were performed for spinal compression due to lumber vertebral metastases. The immunohistochemical analysis identified PSA and androgen receptor positive tumor cells in both metastatic lesions, while no variable cancer cells were detected in the prostate on second biopsy. Whole-genome sequencing was performed on the biopsied metastatic lymph node in search for another possible treatment and it revealed that the tumor had WGD and CDK12 mutation. The WGD-positive tumor cells contained large and polymorphic nucleus, presumably reflecting on the ploidy abnormality of the chromosomes. Conclusions: This report is the first case of a Japanese patient presenting with WGD, who survived more than 13 years with multimodal chemotherapies and radiotherapies.

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Predictors of Survival in Favorable Risk Patients with Metastatic Renal Cell Carcinoma Treated with a Single-Agent First-Line Therapy.

Mizuno R, Takamatsu K, Yasumizu Y, Tanaka N, Takeda T, Morita S, Matsumoto K, Kosaka T, Asanuma H, Mikami S, Oya M

Urologia internationalis (Urologia Internationalis) 1 - 5 2022.02

ISSN 0042-1138

Introduction: The aim of this retrospective study was to elucidate predictors of survival in metastatic renal cell carcinoma (mRCC) patients in an International Metastatic Renal Cell Carcinoma Database Consortium favorable risk group treated with frontline therapy without immune checkpoint inhibitors. Methods: A total of 238 patients with mRCC were reviewed. Among them, 55 patients in favorable risk group treated with single-agent systemic therapy were retrospectively analyzed. Clinical and pathological data were retrieved and analyzed retrospectively. The prognostic effect of each marker on overall survival (OS) was investigated with univariate and multivariate Cox's proportional hazards regression models. Results: After a median follow-up of 46.2 months after first-line treatment initiation, the median progression-free survival (PFS) was 29.3 months, and the median OS has not been reached. The estimated percentage of patients who were alive at 12 and 24 months were 96.1 and 94.1%, respectively. Multivariate analysis revealed that the long-term duration of first-line treatment (hazard ratio [HR]: 0.972, 95% confidence interval [CI]: 0.944-0.997, p = 0.0299) and the metastases limited to lung (HR: 3.852, 95% CI: 1.080-24.502, p = 0.0361) were independent predictors for longer OS in favorable risk mRCC patients. Conclusion: First-line systemic therapy for favorable risk mRCC patients with a single agent resulted in relatively longer PFS and OS. A longer duration of first-line treatment and lung only metastases are correlated with longer OS.

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How to motivate young doctors to start translational research

Oya Mototsugu, Tanaka Nobuyuki, Kosaka Takeo

CANCER SCIENCE 113 1315 - 1315 2022.02

ISSN 1347-9032

Structures and functions of O-glycans expressed in castration resistant prostate cancer cells

Yamamoto Daiki, Kosaka Takeo, Oya Mototsugu, Sato Toshinori

CANCER SCIENCE 113 1285 - 1285 2022.02

ISSN 1347-9032

MUC1 induces neuroendocrine differentiation of prostate cancer

Yasumizu Yota, Kosaka Takeo, Hongo Hiroshi, Oya Mototsugu

CANCER SCIENCE 113 1595 - 1595 2022.02

ISSN 1347-9032

特集尿道狭窄に対する尿道形成術の極意-〈特別付録Web動画〉前部尿道狭窄に対する代用組織を利用した二期的尿道形成術

浅沼宏, 岩佐俊, 高橋遼平, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 76 ( 1 ) 26 - 30 2022.01

ISSN 0385-2393

Optimal surgical treatment for paratesticular leiomyosarcoma: retrospective analysis of 217 reported cases.

Kamitani R, Matsumoto K, Takeda T, Mizuno R, Oya M

BMC cancer (BMC Cancer) 22 ( 1 ) 15 2022.01

Background: Paratesticular leiomyosarcoma (LMS) is a rare tumor. Conventionally, tumor resection by high inguinal orchiectomy is performed as the preferred treatment approach for paratesticular sarcoma. On the other hand, testis-sparing surgery has recently attracted attention as a less-invasive treatment option for paratesticular sarcoma. However, the prognostic predictors and optimal treatment strategy for paratesticular LMS remain unclear because of its rarity. In this study, we systematically reviewed previously reported cases of paratesticular LMS to evaluate the prognostic factors and establish the optimal treatment strategy. Methods: A systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular LMS published between 1971 and 2020 in English. The final cohort included 217 patients in 167 articles. The starting point of this study was the time of definitive surgical treatment, and the end point was the time of local recurrence (LR), distant metastasis (DM), and disease-specific mortality. Results: Patients with cutaneous LMS had a slightly better LR-free survival, DM-free survival, and disease-specific survival than those with subcutaneous LMS (p = 0.745, p = 0.033, and p = 0.126, respectively). Patients with higher grade tumors had a significantly higher risk of DM and disease-specific mortality (Grade 3 vs Grade 1 p < 0.001, and Grade 3 vs Grade 1 p < 0.001, respectively). In addition, those with a microscopic positive margin had a significantly higher risk of LR and DM than those with a negative margin (p < 0.001, and p = 0.018, respectively). Patients who underwent simple tumorectomy had a slightly higher risk of LR than those who underwent high inguinal orchiectomy (p = 0.067). Subgroup analysis of cutaneous LMS demonstrated that the difference in LR between simple tumorectomy and high inguinal orchiectomy was limited (p = 0.212). On the other hand, subgroup analysis of subcutaneous LMS revealed a significant difference in LR (p = 0.039). Conclusions: Our study demonstrated that subcutaneous LMS and high-grade tumors are prognostic factors for paratesticular LMS. For subcutaneous LMS, tumorectomy with high inguinal orchiectomy should be the optimal treatment strategy to achieve a negative surgical margin.

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First successful case of platinum-based chemotherapy for neuroendocrine prostate cancer with BRCA2 and PTEN alterations.

Omura M, Kosaka T, Aimono E, Nakamura K, Hongo H, Mikami S, Nishihara H, Oya M

IJU case reports (IJU Case Reports) 5 ( 1 ) 41 - 44 2022.01

Introduction: Deoxyribonucleic acid repair gene mutations are now being studied in a variety of solid tumors, with the hope of predicting prognosis, pathogenesis, and treatment outcomes. Case presentation: We report the case of a Japanese patient with advanced castration-resistant prostate cancer who exhibited a prominent response to platinum therapy and had coexisting BRCA2 and PTEN mutations according to retrospective multigene panel analysis. Conclusion: Through a review of clinical outcomes and genetic/pathologic profiling, the presented case provides insights into future management strategies based on the tumor genetic status.

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Enzalutamide + androgen deprivation therapy (ADT) versus flutamide + ADT in Japanese men with castration-resistant prostate cancer: AFTERCAB study.

Uemura H, Kobayashi K, Yokomizo A, Hinotsu S, Horie S, Kakehi Y, Naito S, Nonomura N, Ogawa O, Oya M, Suzuki K, Saito A, Uno S, Akaza H

BJUI compass 3 ( 1 ) 26 - 36 2022.01

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Synthetic magnetic resonance imaging for primary prostate cancer evaluation: Diagnostic potential of a non-contrast-enhanced bi-parametric approach enhanced with relaxometry measurements.

Arita Y, Akita H, Fujiwara H, Hashimoto M, Shigeta K, Kwee TC, Yoshida S, Kosaka T, Okuda S, Oya M, Jinzaki M

European journal of radiology open (European Journal of Radiology Open) 9 100403 2022

Purpose: Bi-parametric magnetic resonance imaging (bpMRI) with diffusion-weighted images has wide utility in diagnosing clinically significant prostate cancer (csPCa). However, bpMRI yields more false-negatives for PI-RADS category 3 lesions than multiparametric (mp)MRI with dynamic-contrast-enhanced (DCE)-MRI. We investigated the utility of synthetic MRI with relaxometry maps for bpMRI-based diagnosis of csPCa. Methods: One hundred and five treatment-naïve patients who underwent mpMRI and synthetic MRI before prostate biopsy for suspected PCa between August 2019 and December 2020 were prospectively included. Three experts and three basic prostate radiologists evaluated the diagnostic performance of conventional bpMRI and synthetic bpMRI for csPCa. PI-RADS version 2.1 category 3 lesions were identified by consensus, and relaxometry measurements (T1-value, T2-value, and proton density [PD]) were performed. The diagnostic performance of relaxometry measurements for PI-RADS category 3 lesions in peripheral zone was compared with that of DCE-MRI. Histopathological evaluation results were used as the reference standard. Statistical analysis was performed using the areas under the receiver operating characteristic curve (AUC) and McNemar test. Results: In 102 patients without significant MRI artefacts, the diagnostic performance of conventional bpMRI was not significantly different from that of synthetic bpMRI for all readers (p = 0.11–0.79). The AUCs of the combination of T1-value, T2-value, and PD (T1 + T2 + PD) for csPCa in peripheral zone for PI-RADS category 3 lesions were 0.85 for expert and 0.86 for basic radiologists, with no significant difference between T1 + T2 + PD and DCE-MRI for both expert and basic radiologists (p = 0.29–0.45). Conclusion: Synthetic MRI with relaxometry maps shows promise for contrast media-free evaluation of csPCa.

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MUC1-C integrates type II interferon and chromatin remodeling pathways in immunosuppression of prostate cancer.

Hagiwara M, Fushimi A, Bhattacharya A, Yamashita N, Morimoto Y, Oya M, Withers HG, Hu Q, Liu T, Liu S, Wong KK, Long MD, Kufe D

Oncoimmunology (OncoImmunology) 11 ( 1 ) 2029298 2022

ISSN 2162-4011

The oncogenic MUC1-C protein drives dedifferentiation of castrate resistant prostate cancer (CRPC) cells in association with chromatin remodeling. The present work demonstrates that MUC1-C is necessary for expression of IFNGR1 and activation of the type II interferon-gamma (IFN-γ) pathway. We show that MUC1-C→ARID1A/BAF signaling induces IFNGR1 transcription and that MUC1-C-induced activation of the NuRD complex suppresses FBXW7 in stabilizing the IFNGR1 protein. MUC1-C and NuRD were also necessary for expression of the downstream STAT1 and IRF1 transcription factors. We further demonstrate that MUC1-C and PBRM1/PBAF are necessary for IRF1-induced expression of (i) IDO1, WARS and PTGES, which metabolically suppress the immune tumor microenvironment (TME), and (ii) the ISG15 and SERPINB9 inhibitors of T cell function. Of translational relevance, we show that MUC1 associates with expression of IFNGR1, STAT1 and IRF1, as well as the downstream IDO1, WARS, PTGES, ISG15 and SERPINB9 immunosuppressive effectors in CRPC tumors. Analyses of scRNA-seq data further demonstrate that MUC1 correlates with cancer stem cell (CSC) and IFN gene signatures across CRPC cells. Consistent with these results, MUC1 associates with immune cell-depleted “cold” CRPC TMEs. These findings demonstrate that MUC1-C integrates chronic activation of the type II IFN-γ pathway and induction of chromatin remodeling complexes in linking the CSC state with immune evasion.

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Squamous cell carcinoma of the prostate with SMARCA4 alteration in a Japanese patient

Kaneko Y., Kosaka T., Nakamura K., Mikami S., Nishihara H., Oya M.

IJU Case Reports (IJU Case Reports) 2022

Introduction: Squamous cell carcinoma of the prostate is very rare. Due to difficulty in diagnosis, it is often detected in advanced stages. Effective treatment of squamous cell carcinoma and the genetic profiling has not yet been established. Case presentation: We experienced the case of a 79-year-old man who was diagnosed with primary squamous cell carcinoma of the prostate. He had multiple lymph node metastases, liver metastases, and lung metastases, and he was treated with gemcitabine and carboplatin. However, he had poor patient status: it became difficult to continue after one course, and best supportive care was provided. We also performed targeted next-generation sequencing of 160 cancer-related genes and detected SMARCA4 mutation. Conclusion: This is the first study reporting the genomic profiling of squamous cell carcinoma of prostate in Japan.

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Bullous pemphigoid in patients receiving peritoneal dialysis: a case series and a literature survey.

Kohkichi Morimoto, Tadashi Yoshida, Naoki Washida, Kiyotaka Uchiyama, Takashin Nakayama, Hiroshi Itoh, Mototsugu Oya

Renal failure (Renal Failure) 43 ( 1 ) 651 - 657 2021.12

Research paper (scientific journal), Joint Work, ISSN 0886-022X

Bullous pemphigoid (BP) is an autoimmune subepidermal blistering disease. Although several cases of BP in end-stage renal disease patients receiving peritoneal dialysis (PD) or hemodialysis have been reported, the incidence of BP in these patients remains unknown. We recently experienced three PD patients diagnosed with BP. The skin injury was likely to be a trigger of BP in all the three PD patients. Nifedipine and icodextrin exposures were possible factors directly or indirectly affecting the onset of BP, because they were common in the three cases. We also report that the incidence of BP in PD patients was 3/478.3 person-years in a single-center 10-year study. This case series with a literature survey describes that the skin and tissue injuries are potential triggers responsible for the onset of BP in dialysis patients and that the incidence of BP in these patients seems to be much higher than that in the general population.

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Perimortem changes in clinical parameters in patients undergoing maintenance hemodialysis

Yoshida T., Morimoto K., Nakayama T., Torimitsu T., Kosugi S., Oshida T., Yamaguchi N., Oya M.

Renal Replacement Therapy (Renal Replacement Therapy) 7 ( 1 ) 2021.12

Background: End-of-life medical care for patients receiving maintenance hemodialysis (HD) therapy has become an increasingly important issue worldwide. Thus far, no clear indicators and/or biomarkers exist regarding the timing of HD therapy withdrawal. Methods: To clarify the perimortem circumstances, we examined temporal changes in multiple clinical parameters during the last 10 serial HD sessions of 65 terminal patients with end-stage renal disease who had undergone maintenance HD and died in our hospital. Results: The results showed that, while most of the laboratory data were unaltered, the physical parameters, such as systolic blood pressure and consciousness levels, gradually and significantly deteriorated toward the last HD session prior to death. The frequency of the use of vasopressors and O2 inhalation tended to increase. The accumulation of such severe conditions was observed at the last HD session. Of interest, the accumulation of severe conditions at the last HD session in patients with malignancies was significantly less than those with cardiovascular diseases or infectious diseases. The accumulation of severe conditions at the last HD session did not differ between patients who withdrew HD versus those who continued HD. Conclusion: The results of the present study suggest that predicting the timing of maintenance HD therapy withdrawal is likely to be difficult and that the timing of maintenance HD therapy termination may differ among patient groups with distinct comorbid conditions.

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集中治療にて救命しえた腎移植後COVID-19の1例

森田伸也, 高橋遼平, 浅岡雅人, 山元良, 長田大雅, 本間康一郎, 川田一郎, 吉田理, 石井誠, 浅沼宏, 中川健, 大家基嗣

日本臨床腎移植学会雑誌 ((一社)日本臨床腎移植学会) 9 ( 2 ) 207 - 210 2021.12

ISSN 2187-9907

56歳男性。紫斑病性腎炎による慢性腎不全にてX-19年血液透析導入、同年血液型適合生体腎移植施行。維持免疫抑制剤はシクロスポリン(CyA)、ミコフェノール酸モフェチル(MMF)、プレドニゾロン(PSL)であった。X年に頭重感と微熱を主訴に来院、CTにて肺一部にすりガラス影を認め、鼻咽頭PCRにてSARS-CoV-2陽性となり緊急入院。MMF減量しファビピラビル、セフトリアキソン投与開始した。さらに抗生剤をタゾバクタム/ピペラシリンに、PSLをデキサメタゾンとしMMFを中止した。肺炎増悪したためメチルプレドニゾロン(mPSL)90mg/day投与、抗凝固療法開始しCyA減量した。呼吸状態増悪のため人工呼吸器管理としCyA中止、レムデシビル投与開始、腹臥位療法を施行した。一時血液透析を3回施行。徐々に酸素化は改善しmPSLは漸減とした。細菌性肺炎合併を疑い抗生剤をバンコマイシンとメロペネムとし、肺炎は改善した。下気道PCRにてSARS-CoV-2陰性を2回確認後CyA、MMFを再開し退院となった。(著者抄録)

Vasohibin-1 expression as a biomarker of aggressive nature in ductal adenocarcinoma of the prostate: a retrospective cohort study at two centres in Japan.

Kobayashi H, Kosaka T, Mikami S, Kimura T, Hongo H, Kosugi M, Sato Y, Oya M

BMJ open (BMJ Open) 11 ( 11 ) e056439 2021.11

ISSN 2044-6055

Objectives Vasohibin-1 (VASH1) is an endogenous angiogenesis regulator expressed in activated vascular endothelial cells. We previously reported that high VASH1 expression is a predictor of progression in acinar adenocarcinoma of the prostate. In this study, we evaluated the characteristics of ductal adenocarcinoma of the prostate by comparing the level of VASH1 expression between ductal and acinar adenocarcinoma specimens. Design and setting A retrospective cohort study at two centres in Japan. Participants Among the 1495 patients who underwent radical prostatectomy or transurethral resection for the past 15 years, a total of 14 patients diagnosed with ductal adenocarcinoma and 20 patients diagnosed with acinar adenocarcinoma with a Gleason score of 4+4 were included. Interventions We immunohistochemically examined the CD34 expression as the microvessel density (MVD) and activated endothelial cells as the VASH1 density (vessels per mm2). Primary and secondary outcome measures The primary outcome was the association of MVD and VASH1 density between ductal and acinar adenocarcinoma, and the secondary outcome was their oncological outcomes. Results Nine patients (64.3%) with ductal adenocarcinoma were diagnosed at an advanced clinical stage, and five patients (35.7%) died from cancer during a median follow-up of 56.0 months. The VASH1 densities (mean±SD) in ductal and acinar adenocarcinoma were 45.1±18.5 vs 16.1±21.0 (p<0.001), respectively, while the MVD (mean±SD) in ductal and acinar adenocarcinoma were 65.3±21.9 vs 80.8±60.7 (p=0.666), respectively. The 5-year cancer-specific survival rates for high and low VASH1 expression were 70.0% and 100.0% (p=0.006), respectively. High VASH1 expression and a diagnosis of ductal adenocarcinoma were significant predictors of cancer-specific survival. Conclusions Ductal adenocarcinoma was more aggressive and had higher VASH1 expression than acinar adenocarcinoma, although MVD was equivalent. These results indicate that VASH1 expression may serve as a novel biomarker for the aggressive nature of ductal adenocarcinoma.

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CD8-positive T cells and CD204-positive M2-like macrophages predict postoperative prognosis of very high-risk prostate cancer.

Yanai Y, Kosaka T, Mikami S, Hongo H, Yasumizu Y, Takeda T, Matsumoto K, Miyauchi J, Kitano S, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 22495 2021.11

ISSN 2045-2322

To stratify the heterogeneity of prostate cancer (PCa) with seminal vesicle invasion (SVI) immunologically after radical prostatectomy focusing on the tumor microenvironment. We retrospectively reviewed the clinicopathological data of 71 PCa patients with SVI, which is known as a factor of very high-risk PCa. Preoperative clinical variables and postoperative pathological variables were evaluated as predictors of biochemical recurrence (BCR) with a multivariate logistic regression. Immune cell infiltration including the CD8-positive cell (CD8+ cell) and CD204-positive M2-like macrophage (CD204+ cell) was investigated by immunohistochemistry. The cumulative incidence and risk of BCR were assessed with a Kaplan–Meier analysis and competing risks regression. A higher CD8+ cell count in the SVI area significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). A lower CD204+ cell count in the SVI area also significantly indicated a favorable prognosis for cancers with SVI (p = 0.004). Furthermore, the combination of the CD8+ and CD204+ cell infiltration ratio of the SVI area to the main tumor area was a significant factor for BCR in the patients with the PCa with SVI (p = 0.001). In PCa patients with SVI, the combination of CD8+ and CD204+ cell infiltration is useful to predict the prognosis.

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Topoisomerase II alpha inhibition can overcome taxane-resistant prostate cancer through DNA repair pathways.

Hongo H, Kosaka T, Suzuki Y, Mikami S, Fukada J, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 22284 2021.11

ISSN 2045-2322

Cabazitaxel (CBZ) is approved for the treatment of docetaxel-resistant castration-resistant prostate cancer (CRPC). However, its efficacy against CRPC is limited, and there are no effective treatments for CBZ-resistant CRPC. This study explored the optimal treatment for CRPC in the post-cabazitaxel setting. PC3 (CBZ-sensitive) and PC3CR cells (CBZ-resistant) were used in this study. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of PC3CR cells. The in vivo effect of the drug combination was tested in xenograft mice models. We identified etoposide (VP16) as a promising treatment candidate for CBZ-resistant CRPC. The WST assay revealed that VP16 had a significant antitumor effect on PC3CR cells. PC3CR cells exhibited significantly higher topoisomerase II alpha (TOP2A) expression than PC3 cells. Higher TOP2A expression was a poor prognostic factor in The Cancer Genome Atlas prostate cancer cohort. In the Fred Hutchinson Cancer Research Center dataset, docetaxel-exposed tissues and metastatic tumors had higher TOP2A expression. In addition, VP16 significantly inhibited the growth of tumors generated from both cell lines. Based on these findings, VP16-based chemotherapy may be an optimal treatment for CPRC in the post-CBZ setting.

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Risk factors for haemodynamic instability and its prolongation during laparoscopic adrenalectomy for pheochromocytoma.

Takeda T, Hakozaki K, Yanai Y, Masuda T, Yasumizu Y, Tanaka N, Matsumoto K, Morita S, Kosaka T, Mizuno R, Kurihara I, Asanuma H, Itoh H, Oya M

Clinical endocrinology (Clinical Endocrinology) 95 ( 5 ) 716 - 726 2021.11

ISSN 0300-0664

Objective: Pheochromocytoma is a rare neuroendocrine tumour that secretes catecholamines and originates in the adrenal gland. Although surgical resection is the only curative therapy for pheochromocytoma, it is associated with a risk of haemodynamic instability (HDI), such as extremely high blood pressure and/or post tumour removal hypotension and shock. We investigated the risk factors for HDI during pheochromocytoma surgery. Design and Patients: Eighty-two patients who underwent laparoscopic adrenalectomy for pheochromocytoma between July 2002 and February 2020 were examined. We excluded 3 patients with bilateral disease and 11 without detailed 24 h urinary data. We defined HDI as systolic blood pressure ≥ 200 or <80 mmHg. We investigated the risk factors for HDI during laparoscopic adrenalectomy for pheochromocytoma. Results: There were 29 males and 39 females with a median age of 50.5 years. Tumours were localised on the right adrenal gland in 28 patients and on the left in 40. The median tumour diameter was 37.5 mm and the median pneumoperitoneum time was 93.5 min. Twenty-five out of sixty-eight patients (37%) developed HDI. A multivariate analysis identified diabetes mellitus (DM; odds ratio: 3.834; 95% confidence interval: 1.062–13.83; p =.04) as an independent predictor of HDI. In terms of hormonal data, median 24 h urinary epinephrine levels (p =.04) and metanephrine levels (p =.01) were significantly higher in the HDI group. DM was also considered as a risk factor for prolonged HDI (p =.02). Conclusion: Surgeons and anaesthesiologists need to be aware of the risk of HDI and its prolongation during laparoscopic adrenalectomy for pheochromocytoma for DM patients.

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Does Neoadjuvant Chemotherapy have Therapeutic Benefit for Node-positive Upper Tract Urothelial Carcinoma? Results of a Multi-center Cohort Study.

Shigeta K, Matsumoto K, Oya M

European urology (European Urology) 81 ( 1 ) e20 - e21 2021.10

ISSN 0302-2838

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Urinary pH is an independent predictor of upper tract recurrence in non-muscle-invasive bladder cancer patients with a smoking history.

Ide H, Kikuchi E, Ogihara K, Niwa N, Shigeta K, Masuda T, Baba Y, Mizuno R, Oya M

Scientific reports (Scientific Reports) 11 ( 1 ) 20675 2021.10

ISSN 2045-2322

Limited information is currently available on predictors of upper tract urothelial carcinoma (UTUC) recurrence in non-muscle-invasive bladder cancer (NMIBC) patients according to smoking history, although smoking probably contributes to urothelial carcinogenesis. Therefore, the present study aimed to identify independent predictors of UTUC recurrence in all patients and those with a smoking history. Our study population comprised 1190 NMIBC patients who underwent transurethral resection of bladder tumor. UTUC developed in 43 patients during the follow-up. A history of bacillus Calmette-Guérin (BCG) therapy was independently associated with a lower incidence of UTUC (HR = 0.43; P = 0.011). In a subgroup of NMIBC patients with a smoking history, concomitant carcinoma in situ (CIS) and a lower urinary pH (< 6) were independently associated with a higher incidence of UTUC recurrence (HR = 3.34, P = 0.006 and HR = 3.73, P = 0.008, respectively). Among patients with a longer smoking duration (≥ 20 years) or larger smoking intensity (≥ 20 cigarettes per day), those with lower urinary pH (< 6) had a significantly higher UTUC recurrence rate than their counterparts. These results suggest that BCG instillation may prevent UTUC recurrence in NMIBC patients, while a lower urinary pH and concomitant CIS increase the risk of UTUC recurrence in those with a smoking history.

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A first case of ductal adenocarcinoma of the prostate having characteristics of neuroendocrine phenotype with PTEN, RB1 and TP53 alterations.

Hiroaki Kobayashi, Takeo Kosaka, Kohei Nakamura, Kazunori Shojo, Hiroshi Hongo, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

BMC medical genomics (BMC Medical Genomics) 14 ( 1 ) 245 - 245 2021.10

Research paper (scientific journal), Joint Work

BACKGROUND: Ductal adenocarcinoma and neuroendocrine cancer are rare subtypes of prostate cancer with poor prognosis and limited therapeutic options. We present the first case of ductal adenocarcinoma having a neuroendocrine phenotype. CASE PRESENTATION: A 63-year-old man presented with gross hematuria and urinary retention, and his serum prostate-specific antigen level was 4.58 ng/mL. We performed transurethral resection of the prostate, and the diagnosis was ductal adenocarcinoma with a Gleason score of 5 + 4 for acinar adenocarcinoma. Magnetic resonance imaging showed local invasion of left lobe of the prostate and bone metastasis of the left trochanteric section of the femur. Multidisciplinary treatments such as androgen deprivation therapy, chemoradiation therapy, and surgery for metastatic lesions have led to long-term survival. Since next-generation sequencing revealed PTEN and RB1 co-loss and TP53 mutations, we re-evaluated the immunohistochemistry and he was found to be positive for synaptophysin. CONCLUSIONS: This is the first Japanese case of ductal adenocarcinoma with a neuroendocrine phenotype. Genetic analysis may help not only guide the therapeutic strategies, but also sometimes with the diagnosis.

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The Significance of PARP1 as a biomarker for Predicting the Response to PD-L1 Blockade in Patients with PBRM1-mutated Clear Cell Renal Cell Carcinoma.

Hagiwara M, Fushimi A, Matsumoto K, Oya M

European urology (European Urology) 81 ( 2 ) 145 - 148 2021.10

ISSN 0302-2838

Immune checkpoint inhibitors (ICIs) have become key agents in the management of clear cell renal cell carcinoma (ccRCC), but their benefits are limited and responders remain unidentified. We investigated the significance of PARP1 in ccRCC using RNA sequencing data for 311 tumors from patients enrolled in prospective clinical trials of PD-1 blockade. Among patients treated with nivolumab (n = 181), overall survival (OS) was significantly higher in the PARP1-low group than in the PARP1-high group (p = 0.006), and PARP1 status was significantly associated with OS (hazard ratio [HR] 1.7; p = 0.007). By contrast, for patients treated with everolimus (n = 130) there was no significant difference by PARP1 status for progression-free survival (PFS; p = 0.9) or OS (p = 0.38). In subgroup analysis for PBRM1-mutated ccRCC, PFS (p = 0.016) and OS (p = 0.004) were significantly longer in the group with PARP1-low status and PBRM1 mutation in comparison to the other groups. In addition, PARP1 status was significantly associated with PFS (HR 2.6; p = 0.007) and OS (HR 3.5; p = 0.016) among patients with PBRM1-mutated ccRCC treated with nivolumab. Our study suggests that PARP1 can be used as a biomarker for predicting response to ICI treatment for patients with PBRM1-mutated ccRCC. Patient summary: Immune checkpoint inhibitors (ICIs) are key agents in the treatment of multiple cancers. We found that expression of the PARP1 protein was associated with survival after ICI treatment and with the response to ICI treatment in patients with clear cell kidney cancer who have a mutation of the PBRM1 gene.

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Landscape of prognostic signatures and immunogenomics of the AXL/GAS6 axis in renal cell carcinoma.

Hakozaki K, Tanaka N, Takamatsu K, Takahashi R, Yasumizu Y, Mikami S, Shinojima T, Kakimi K, Kamatani T, Miya F, Tsunoda T, Aimono E, Nishihara H, Mizuno R, Oya M

British journal of cancer (British Journal of Cancer) 125 ( 11 ) 1533 - 1543 2021.10

ISSN 0007-0920

Background: Cabozantinib is an oral tyrosine kinase inhibitor in renal cell carcinoma (RCC), whose targets include oncogenic AXL and unique ligand GAS6. Critical gaps in basic knowledge need to be addressed to devise an exclusive biomarker and candidate when targeting the AXL/GAS6 axis. Methods: To clarify the effects of the AXL/GAS6 axis on RCC, we herein performed a large-scale immunogenomic analysis and single-cell counts including various metastatic organs and histological subtypes of RCC. We further applied genome-wide mutation analyses and methylation arrays. Results: Varying patterns of AXL and GAS6 expression were observed throughout primary RCC tumours and metastases. Scoring individual AXL/GAS6 levels in the tumour centre and invasive margin, namely, the AXL/GAS6 score, showed a good ability to predict the prognosis of clear cell RCC. Metastasis- and histological subtype-specific differences in the AXL/GAS6 score existed since lung metastasis and the papillary subtype were weakly related to the AXL/GAS6 axis. Cell-by-cell immunohistological assessments clarified an immunosuppressive environment in tumours with high AXL/GAS6 scores. Genomic alterations in the PI3K-mTOR pathway and DNA methylation profiling revealed distinct differences with the AXL/GAS6 score in ccRCC. Conclusion: The AXL/GAS6 scoring system could predict the outcome of prognosis and work as a robust biomarker for the immunogenomic state in RCC.

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Diagnostic value of texture analysis of apparent diffusion coefficient maps for differentiating fat-poor angiomyolipoma from non-clear-cell renal cell carcinoma

Yuki Arita, Soichiro Yoshida, Thomas C. Kwee, Hirotaka Akita, Shigeo Okuda, Yuki Iwaita, Kiyoko Mukai, Shunya Matsumoto, Ryo Ueda, Ryota Ishii, Ryuichi Mizuno, Yasuhisa Fujii, Mototsugu Oya, Masahiro Jinzaki

European Journal of Radiology (Elsevier BV) 143 109895 - 109895 2021.10

Research paper (scientific journal), Joint Work, ISSN 0720-048X

Purpose: To investigate the feasibility of texture analysis of apparent diffusion coefficient (ADC) maps for differentiating fat-poor angiomyolipomas (fpAMLs) from non-clear-cell renal cell carcinomas (non-ccRCCs). Methods: In this bi-institutional study, we included two consecutive cohorts from different institutions with pathologically confirmed solid renal masses: 67 patients (fpAML = 46; non-ccRCC = 21) for model development and 39 (fpAML = 24; non-ccRCC = 15) for validation. Patients underwent preoperative magnetic resonance imaging (MRI), including diffusion-weighted imaging. We extracted 45 texture features using a software with volumes of interest on ADC maps. Receiver operating characteristic curve analysis was performed to compare the diagnostic performance between the random forest (RF) model (derived from extracted texture features) and conventional subjective evaluation using computed tomography and MRI by radiologists. Results: RF analysis revealed that grey-level zone length matrix long-zone high grey-level emphasis was the dominant texture feature for diagnosing fpAML. The area under the curve (AUC) of the RF model to distinguish fpAMLs from non-ccRCCs was not significantly different between the validation and development cohorts (p = .19). In the validation cohort, the AUC of the RF model was similar to that of board-certified radiologists (p = .46) and significantly higher than that of radiology residents (p = .03). Conclusions: Texture analysis of ADC maps demonstrated similar diagnostic performance to that of board-certified radiologists for discriminating between fpAMLs and non-ccRCCs. Diagnostic performances in the development and validation cohorts were comparable despite using data from different imaging device manufacturers and institutions.

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Multiplexed single-cell pathology reveals the association of CD8 T-cell heterogeneity with prognostic outcomes in renal cell carcinoma.

Tetsushi Murakami, Nobuyuki Tanaka, Kimiharu Takamatsu, Kyohei Hakozaki, Keishiro Fukumoto, Tsukasa Masuda, Shuji Mikami, Toshiaki Shinojima, Kazuhiro Kakimi, Tatsuhiko Tsunoda, Kazuaki Sawada, Takeshi Imamura, Ryuichi Mizuno, Mototsugu Oya

Cancer immunology, immunotherapy : CII (Cancer Immunology, Immunotherapy) 70 ( 10 ) 3001 - 3013 2021.10

Research paper (scientific journal), Joint Work, ISSN 0340-7004

Despite the high sensitivity of renal cell carcinoma (RCC) to immunotherapy, RCC has been recognized as an unusual disease in which CD8+ T-cell infiltration into the tumor beds is related to a poor prognosis. To approach the inner landscape of immunobiology of RCC, we performed multiplexed seven-color immunohistochemistry (CD8, CD39, PD-1, Foxp3, PD-L1, and pan-cytokeratin AE1/AE3 with DAPI), which revealed the automated single-cell counts and calculations of individual cell-to-cell distances. In total, 186 subjects were included, in which CD39 was used as a marker for distinguishing tumor-specific (CD39+) and bystander (CD39-) T-cells. Our clear cell RCC cohort also revealed a poor prognosis if the tumor showed increased CD8+ T-cell infiltration. Intratumoral CD8+CD39+ T-cells as well as their exhausted CD8+CD39+PD-1+ T-cells in the central tumor areas enabled the subgrouping of patients according to malignancy. Analysis using specimens post-antiangiogenic treatment revealed a dramatic increase in proliferative Treg fraction Foxp3+PD-1+ cells, suggesting a potential mechanism of hyperprogressive disease after uses of anti-PD-1 antibody. Our cell-by-cell study platform provided spatial information on tumors, where bystander CD8+CD39- T-cells were dominant in the invasive margin areas. We uncovered a potential interaction between CD8+CD39+PD-1+ T-cells and Foxp3+PD-1+ Treg cells due to cell-to-cell proximity, forming a spatial niche more specialized in immunosuppression under PD-1 blockade. A paradigm shift to the immunosuppressive environment was more obvious in metastatic lesions; rather the infiltration of Foxp3+ and Foxp3+PD-1+ Treg cells was more pronounced. With this multiplexed single-cell pathology technique, we revealed further insight into the immunobiological standing of RCC.

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Discovery of a new candidate drug to overcome cabazitaxel-resistant gene signature in castration-resistant prostate cancer by in silico screening.

Hongo H, Kosaka T, Suzuki Y, Oya M

Prostate cancer and prostatic diseases (Prostate Cancer and Prostatic Diseases) 2021.09

ISSN 1365-7852

Background: The taxane cabazitaxel (CBZ) is a promising treatment for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, the survival benefit with CBZ for patients with CRPC is limited. This study used screening tests for candidate drugs targeting CBZ-resistant-related gene expression and identified pimozide as a potential candidate for overcoming CBZ resistance in CRPC. Methods: We established CBZ-resistant cell lines, DU145CR and PC3CR by incubating DU145 cells and PC3 cells with gradually increasing concentrations of CBZ. We performed in silico drug screening for candidate drugs that could reprogram the gene expression signature of a CBZ-resistant prostate cancer cells using a Connectivity Map. The in vivo effect of the drug combination was tested in xenograft mice models. Results: We identified pimozide as a promising candidate drug for CBZ-resistant CRPC. Pimozide had a significant antitumor effect on DU145CR cells. Moreover, combination treatment with pimozide and CBZ had a synergic effect for DU145CR cells in vitro and in vivo. Microarray analysis identified AURKB and KIF20A as potential targets of pimozide in CBZ-resistant CRPC. DU145CR had significantly higher AURKB and KIF20A expression compared with a non-CBZ-resistant cell line. Inhibition of AURKB and KIF20A had an antitumor effect in DU145CR xenograft tumors. Higher expression of AURKB and KIF20A was a poor prognostic factor of TGCA prostate cancer cohort. CBZ-resistant prostate cancer tissues in our institution had higher AURKB and KIF20A expression. Conclusions: Pimozide appears to be a promising drug to overcome CBZ resistance in CRPC by targeting AURKB and KIF20A.

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Erratum to: Subgroup analysis of the AFTER I-O study: a retrospective study on the efficacy and safety of subsequent molecular targeted therapy after immune-oncology therapy in Japanese patients with metastatic renal cell carcinoma.

Tomita Y, Kimura G, Fukasawa S, Numakura K, Sugiyama Y, Yamana K, Naito S, Kaneko H, Tajima Y, Oya M

Japanese journal of clinical oncology (Japanese Journal of Clinical Oncology) 51 ( 12 ) 1770 - 1770 2021.09

ISSN 0368-2811

In the originally published article there were errors in the legends to figures 3 and 4. Figure 3 should read: "Figure 3. PFS2 of nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) PFS2 of NIVO, stratified by TT regimens after NIVO, sunitinib, or axitinib. (b) PFS2 of NIVO+IPI, stratified by TT regimens after NIVO+IPI, sunitinib, or axitinib, IMDC all risks." instead of: "Figure 3.OS from first-line therapy of patients treated with nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) OS from first-linetherapy of patients treated with NIVO, stratified by TT regimens after NIVO, sunitinib or axitinib. (b) OS from first-line therapy of patients treated with NIVO+IPI,stratified by TT regimens after NIVO+IPI, sunitinib or axitinib, IMDC all risks.". Figure 4 should read: "Figure 4. OS from first-line therapy of patients treated with nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) OS from first-linetherapy of patients treatedwithNIVO, stratified by TT regimens afterNIVO, sunitinib or axitinib. (b) OS from first-line therapy of patients treated with NIVO+IPI,stratified by TT regimens after NIVO+IPI, sunitinib or axitinib, IMDC all risks." instead of: "Figure 4. PFS2 of nivolumab (NIVO) or nivolumab and ipilimumab combination therapy (NIVO+IPI). (a) PFS2 of NIVO, stratified by TT regimens after NIVO, sunitinib, or axitinib. (b) PFS2 of NIVO+IPI, stratified by TT regimens after NIVO+IPI, sunitinib, or axitinib, IMDC all risks.". These errors have now been corrected online.

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Profiling the inhibitory receptors LAG-3, TIM-3, and TIGIT in renal cell carcinoma reveals malignancy

Kimiharu Takamatsu, Nobuyuki Tanaka, Kyohei Hakozaki, Ryohei Takahashi, Yu Teranishi, Tetsushi Murakami, Ryohei Kufukihara, Naoya Niwa, Shuji Mikami, Toshiaki Shinojima, Takashi Sasaki, Yusuke Sato, Haruki Kume, Seishi Ogawa, Kazuhiro Kakimi, Takashi Kamatani, Fuyuki Miya, Tatsuhiko Tsunoda, Eriko Aimono, Hiroshi Nishihara, Kazuaki Sawada, Takeshi Imamura, Ryuichi Mizuno, Mototsugu Oya

Nature Communications (Springer Science and Business Media LLC) 12 ( 1 ) 5547 2021.09

Research paper (scientific journal), Joint Work

<title>Abstract</title>A cutting edge therapy for future immuno-oncology is targeting a new series of inhibitory receptors (IRs): LAG-3, TIM-3, and TIGIT. Both immunogenomic analyses and diagnostic platforms to distinguish candidates and predict good responders to these IR-related agents are vital in clinical pathology. By applying an automated single-cell count for immunolabelled LAG-3, TIM-3, and TIGIT, we reveal that individual IR levels with exclusive domination in each tumour can serve as valid biomarkers for profiling human renal cell carcinoma (RCC). We uncover the immunogenomic landscape associated with individual IR levels in human RCC tumours with metastases in various organs and histological subtypes. We then externally validate our results and devise a workflow with optimal biomarker cut-offs for discriminating the LAG-3, TIM-3, and TIGIT tumour profiles. The discrimination of LAG-3, TIM-3, and TIGIT profiles in tumours may have a broad impact on investigations of immunotherapy responses after targeting a new series of IRs.

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Negative impact of neoadjuvant hormonal therapy on detecting biochemical recurrence after radical prostatectomy.

Matsumoto K, Niwa N, Kosaka T, Takeda T, Yasumizu Y, Tanaka N, Morita S, Mizuno R, Shinojima T, Asanuma H, Oya M

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 9 ) 1722 - 1728 2021.09

ISSN 1341-9625

Background: Routine use of neoadjuvant hormonal therapy (NHT) before radical prostatectomy (RP) is not recommended, but it is sometimes performed to reduce the prostate size and tumor volume or to prevent tumor progression during the wait times for surgery in clinical practice. On the other hand, the impact of NHT on the pattern of biochemical recurrence (BCR) is unknown. Methods: We retrospectively examined 1749 consecutive patients who underwent RP between 1996 and 2017. Among the patients who met the inclusion criteria, BCR developed in 240 of non-NHT patients and in 120 of NHT patients during the mean follow-up period of 6.9 years. We examined the impact of NHT on the PSA-doubling time (DT) following BCR at different times after RP. Results: The median PSA-DTs in non-NHT patients who experienced BCR in the first year after surgery, between 1 and 2 years, between 2 and 3 years, between 3 and 4 years, between 4 and 5 years, and at > 5 years were 5.5, 8.8, 11.3, 17.7, 18.2, and 18.4 months, respectively. On the other hand, those in NHT patients were 1.4, 4.1, 9.1, 13.4, 27.2, and 19.3 months, respectively. The differences of PSA-DTs in the first year after surgery (p < 0.001) and between 1 and 2 years (p = 0.005) were significant between non-NHT and NHT patients. Conclusion: Patients who received NHT had a higher risk of a rapid PSA increase when they experienced BCR, especially within 2 years after RP. In order to not miss the optimal timing of salvage treatment for BCR, intensive PSA follow-up is necessary.

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Oncological outcomes of dose reductions in cisplatin due to renal dysfunction for patients with metastatic urothelial carcinoma

Tetsushi Murakami, Eiji Kikuchi, Hiroki Ide, Yuta Umezawa, Takayuki Takahashi, Mizuki Izawa, Kyohei Hakozaki, Keisuke Shigeta, Koichiro Ogihara, Hiroaki Kobayashi, Kunimitsu Kanai, Takahiro Maeda, Shunsuke Yoshimine, Ryuichi Mizuno, Koshiro Nishimoto, Mototsugu Oya

BJUI Compass (Wiley) 2 ( 5 ) 322 - 330 2021.09

Research paper (scientific journal), Joint Work, ISSN 2688-4526

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Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): depth of response and efficacy for selected subgroups in the lenvatinib (L) plus pembrolizumab (P) and sunitinib (S) treatment arms

Gruenwald V, Powles T., Kopyltsov E., Kozlov V, Alonso Gordoa T., Eto M., Hutson T., Motzer R., Winquist E., Maroto P., Keam B., Procopio G., Wong S., Melichar B., Rolland F., Oya M., Rodriguez-Lopez K., Saito K., Smith A., Porta C.

ONCOLOGY RESEARCH AND TREATMENT 44 25 - 25 2021.09

ISSN 2296-5270

Correction to: Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma.

Motohide Uemura, Noboru Nakaigawa, Naoto Sassa, Katsunori Tatsugami, Kenichi Harada, Toshinari Yamasaki, Nobuaki Matsubara, Takuya Yoshimoto, Yuki Nakagawa, Tamaki Fukuyama, Mototsugu Oya, Nobuo Shinohara, Hirotsugu Uemura, Toyonori Tsuzuki

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 11 ) 2085 - 2086 2021.08

Joint Work, ISSN 1341-9625

The article Prognostic value of programmed death‑ligand 1 status in Japanese patients with renal cell carcinoma, written by Motohide Uemura, Noboru Nakaigawa, Naoto Sassa, Katsunori Tatsugami, Kenichi Harada, Toshinari Yamasaki, Nobuaki Matsubara, Takuya Yoshimoto, Yuki Nakagawa, Tamaki Fukuyama, Mototsugu Oya, Nobuo Shinohara, Hirotsugu Uemura, and Toyonori Tsuzuki was originally published Online First without Open Access. With the author(s)’ decision to opt for Open Choice the copyright of the article changed on August 18, 2021 to © Author(s) 2021 and the article is forthwith distributed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4.0. The original article has been corrected. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

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Does neoadjuvant chemotherapy have therapeutic benefit for node-positive upper tract urothelial carcinoma? Results of a multi-center cohort study

Keisuke Shigeta, Kazuhiro Matsumoto, Koichiro Ogihara, Tetsushi Murakami, Tadatsugu Anno, Kota Umeda, Mizuki Izawa, Yuto Baba, Tansei Sanjo, Kazunori Shojo, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Yuki Arita, Hirotaka Akita, Masahiro Jinzaki, Eiji Kikuchi, Mototsugu Oya

Urologic Oncology: Seminars and Original Investigations (Elsevier BV) 40 ( 3 ) 105.e19 - 105.e26 2021.08

Research paper (scientific journal), Joint Work, ISSN 1078-1439

Objective: The indications of neoadjuvant chemotherapy (NAC) for lymph node-positive upper tract urothelial carcinoma (UTUC) have not been investigated regarding improved survival outcomes. Our specific aim was to compare the clinical outcomes of clinically node-positive UTUC patients who were treated by NAC followed by radical nephroureterectomy (RNU) or upfront RNU followed by adjuvant chemotherapy (AC). Materials and methods: Among 966 UTUC patients, we identified 89 with clinical nodal involvement who received either NAC before RNU nor AC after upfront RNU. Cox proportional hazard models were employed to evaluate the impact of chemotherapy modality on the oncological outcomes. Results: Of the patient cohort, 36 (40.4%) received NAC followed by RNU, whereas 53 (59.6%) underwent RNU followed by AC. Multivariate analysis revealed that tumor size ≥3 cm, clinical T4, and gemcitabine and cisplatin regimen were independent risk factors for disease recurrence, whereas NAC followed by RNU was an independent factor for favorable RFS. Furthermore, regarding cancer-specific survival (CSS), NAC followed by RNU remained an independent factor for favorable CSS. According to Kaplan-Meier analysis, the 1-year and 2-year RFS were 67.9% and 47.0%, respectively, in the NAC+RNU group, which were significantly higher than those in the RNU+AC group (43.9% and 24.6%, respectively, P = 0.006). Moreover, the 1-year and 2-year CSS were 80.5% and 64.2%, respectively, in the NAC+RNU group, which were higher than those in the RNU+AC group (68.6% and 48.2%, respectively, P = 0.016). Conclusion: For node-positive UTUC patients, NAC followed by RNU was more clinically beneficial than RNU followed by AC.

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Effects of transurethral resection under general anesthesia on tumor recurrence in non-muscle invasive bladder cancer.

Yuto Baba, Eiji Kikuchi, Keisuke Shigeta, Koichiro Ogihara, Masashi Matsushima, Yui Nishimoto, Yasuaki Murata, Hirotaka Asakura, Masafumi Oyama, Ryuichi Mizuno, Mototsugu Oya

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 11 ) 2094 - 2103 2021.08

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: The effects of the type of anesthesia (spinal (SA) vs. general (GA)) used for transurethral resection of bladder tumor (TURBT) on non-muscle invasive bladder cancer (NMIBC) recurrence and progression are controversial and our aim is to investigate their associations. METHODS: We identified 300 NMIBC patients who underwent initial TURBT with SA or GA. Cox's regression analysis was performed to examine the effects of anesthesia on tumor recurrence. RESULTS: Among 300 patients, 153 (51.0%) received GA and 147 (49.0%) SA. The 5-year recurrence-free survival (RFS) rate was 59.9% in the GA group, which was significantly lower than that in the SA group (74.4%, p = 0.029). GA (HR 1.57, p = 0.048), male sex (HR 2.72, p = 0.012), and tumor multiplicity (HR 1.96, p = 0.006) were independently associated with tumor recurrence. In a subgroup of 137 patients with high-risk NMIBC, the 5-year RFS rate was 50.3% in the GA group, which was significantly lower than that in the SA group (77.6%, p = 0.020), and GA remained an independent indicator of tumor recurrence (HR 2.35, p = 0.016). However, no significant differences were observed in the RFS rates of low- to intermediate-risk NMIBC patients between the GA and SA groups. CONCLUSIONS: The RFS rate was lower in NMIBC patients who received GA during TURBT than in those who received SA. Volatile anesthesia may increase tumor recurrence, particularly in high-risk NMIBC patients, which may be due to the inhibition of the immune response system during surgery.

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Subgroup analysis of the AFTER I-O study: a retrospective study on the efficacy and safety of subsequent molecular targeted therapy after immune-oncology therapy in Japanese patients with metastatic renal cell carcinoma

Yoshihiko Tomita, Go Kimura, Satoshi Fukasawa, Kazuyuki Numakura, Yutaka Sugiyama, Kazutoshi Yamana, Sei Naito, Hirokazu Kaneko, Yohei Tajima, Mototsugu Oya

Japanese Journal of Clinical Oncology (Oxford University Press (OUP)) 51 ( 11 ) 1656 - 1664 2021.08

Research paper (scientific journal), Joint Work, ISSN 0368-2811

<title>Abstract</title>
<sec>
<title>Background</title>
We performed subgroup analyses of the AFTER I-O study to clarify the association of time-to-treatment failure (TTF) and discontinuation reason of prior immune-oncology (I-O) therapy, and molecular targeted therapy (TT) regimen with the outcomes of TT after I-O.

</sec>
<sec>
<title>Methods</title>
The data of Japanese metastatic renal cell carcinoma patients treated with TT after nivolumab (NIVO) (CheckMate 025) or NIVO + ipilimumab (IPI) (CheckMate 214) were retrospectively analyzed. The objective response rates (ORRs), progression-free survival (PFS) and overall survival (OS) of TT after I-O were analyzed by subgroups: TTF (&lt;6 or ≥6 months) and discontinuation reason of prior I-O (progression or adverse events), and TT regimen (sunitinib or axitinib). We also analyzed PFS2 of prior I-O and OS from first-line therapy.

</sec>
<sec>
<title>Results</title>
The ORR and median PFS of TT after NIVO and NIVO+IPI among the subgroups was 17–36% and 20–44%, and 7.1–11.6 months and 16.3-not reached (NR), respectively. The median OS of TT after NIVO was longer in patients with longer TTF of NIVO and treated with axitinib. Conversely, median OS of TT after NIVO+IPI was similar among subgroups. The median PFS2 of NIVO and NIVO+IPI was 36.7 and 32.0 months, respectively. The median OS from first-line therapy was 70.5 months for patients treated with NIVO and NR with NIVO+IPI. The safety profile of each TT after each I-O was similar to previous reports.

</sec>
<sec>
<title>Conclusions</title>
The efficacy of TT after NIVO or NIVO+IPI was favorable regardless of the TTF and discontinuation reason of prior I-O, and TT regimen.

</sec>

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On-treatment C-reactive protein control could predict response to subsequent anti-PD-1 treatment in metastatic renal cell carcinoma.

Kimiharu Takamatsu, Ryuichi Mizuno, Yuto Baba, Yota Yasumizu, Nobuyuki Tanaka, Suguru Shirotake, Toshikazu Takeda, Shinya Morita, Kazuhiro Matsumoto, Takeo Kosaka, Hiroshi Asanuma, Masafumi Oyama, Shuji Mikami, Mototsugu Oya

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 8 ) 1500 - 1505 2021.08

Research paper (scientific journal), Joint Work, ISSN 1341-9625

OBJECTIVE: The aim of this study was to evaluate the clinical significance of the on-treatment C-reactive protein (CRP) status during systemic treatment as the predictive marker for the response of subsequent nivolumab monotherapy in patients with refractory metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: A total of 73 mRCC patients treated with nivolumab were retrospectively reviewed. We evaluated the serum CRP levels before and after molecular-targeted treatments. Patients whose CRP did not exceed baseline value were defined as the CRP-control group and the others were defined as the CRP-progression group. The clinical impact of CRP-control on the efficacy of nivolumab was assessed. RESULTS: Twenty-four patients (33%) were categorized into the CRP-control group. The CRP-control group patients (median PFS not reached) had significantly longer PFS than the CRP-progression group (median PFS 11.9 months, 95% confidence interval, CI 4.1-19.8, p = 0.038). The CRP-control group had a tendency of longer OS from nivolumab initiation than the CRP-progression group (p = 0.071). By multivariate analysis, the on-treatment CRP-control was the independent predictive factor for PFS (hazard ratio HR 0.37, 95% CI 0.14-0.99, p = 0.047). CONCLUSION: The on-treatment CRP-control could be the predictive factor for the efficacy of nivolumab in refractory mRCC patients.

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Diagnostic performance of the vesical imaging-reporting and data system for detecting muscle-invasive bladder cancer in real clinical settings: Comparison with diagnostic cystoscopy.

Ryohei Kufukihara, Eiji Kikuchi, Keisuke Shigeta, Koichiro Ogihara, Yuki Arita, Hirotaka Akita, Tatsuya Suzuki, Takayuki Abe, Ryuichi Mizuno, Masahiro Jinzaki, Mototsugu Oya

Urologic oncology (Urologic Oncology: Seminars and Original Investigations) 40 ( 2 ) 61.e1 - 61.e8 2021.07

Research paper (scientific journal), Joint Work, ISSN 1078-1439

PURPOSE: We herein compared the diagnostic performance of Vesical Imaging-Reporting and Data System (VI-RADS) scoring with diagnostic cystoscopy and evaluated diagnostic accuracies based on tumor locations. MATERIALS AND METHODS: Among 112 bladder cancer patients who underwent multiparametric magnetic resonance imaging and diagnostic cystoscopy preoperatively to detect bladder cancer, 61 were analyzed. VI-RADS was categorized into 5 stages by 2 radiologists (R1 and R2). Cut-off values ≥3 indicated muscle-invasive bladder cancer (MIBC). Muscle invasion (MI) was visually evaluated using diagnostic cystoscopy by 2 urologists (U1 and U2). The sensitivity and specificity of VI-RADS scores and diagnostic cystoscopy for diagnosing MI were compared. RESULTS: 16 patients (26.2%) were pathologically diagnosed with MIBC. Regarding MI diagnostic accuracy, the sensitivity/specificity of VI-RADS scores were 93.8/88.9% by R1 and 87.5/86.7% by R2, while those of diagnostic cystoscopy were 56.3/68.9% by U1 and 68.8/84.4% by U2. Therefore, the diagnostic accuracy of VI-RADS was significantly higher than that of cystoscopy, particularly for tumors located on the bladder neck, trigone, dome, and posterior and anterior walls. Over- and under-diagnosis rates were higher with VI-RADS than with diagnostic cystoscopy (25.9% vs. 14.8%) for tumors located on the lateral wall or ureteral orifice. CONCLUSION: VI-RADS had superior diagnostic performance for detecting MI, especially in tumors located at the bladder neck/trigone/dome/posterior and anterior wall. However, VI-RADS was inferior to cystoscopy in terms of MI detection for tumors located on the lateral wall or ureteral orifice. Therefore, a combination of diagnostic tools is recommended for the accurate staging of these tumors.

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Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling.

Arisa Ueki, Kokichi Sugano, Kumiko Misu, Eriko Aimono, Kohei Nakamura, Shigeki Tanishima, Nobuyuki Tanaka, Shuji Mikami, Akira Hirasawa, Miho Ando, Teruhiko Yoshida, Mototsugu Oya, Hiroshi Nishihara, Kenjiro Kosaki

International journal of molecular sciences (International Journal of Molecular Sciences) 22 ( 15 ) 2021.07

Joint Work, ISSN 16616596

Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

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Prognostic value of programmed death-ligand 1 status in Japanese patients with renal cell carcinoma.

International journal of clinical oncology (International Journal of Clinical Oncology) 26 ( 11 ) 2073 - 2084 2021.07

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: Programmed death-ligand 1 (PD-L1) positivity is associated with poor prognosis in renal cell carcinoma (RCC). Because the prognostic impact and effect of confounding factors are less known, we investigated the prognostic significance of PD-L1 expression in Japanese patients with recurrent/metastatic RCC who started systemic therapy in 2010-2015. METHODS: This multicenter, retrospective study recruited patients from 29 Japanese study sites who had prior systemic therapy for RCC (November 2018 to April 2019) and stored formalin-fixed paraffin-embedded primary lesion samples. The primary outcome was overall survival (OS) by PD-L1 expression. Secondary outcomes included OS in subgroups and duration of first- and second-line therapies by PD-L1 expression. OS distributions were estimated using Kaplan-Meier methodology. RESULTS: PD-L1 expression (on immune cells [IC] ≥ 1%) was observed in 315/770 (40.9%) patients. PD-L1 positivity was more prevalent in patients with poor risk per both Memorial Sloan Kettering Cancer Center [MSKCC] and International Metastatic RCC Database Consortium, and high-risk pathological features (higher clinical stage, nuclear grade and sarcomatoid features). Median OS for PD-L1-positive patients was 30.9 months (95% CI 25.5-35.7) versus 37.5 months (95% CI 34.0-42.6) for PD-L1-negative patients (HR 1.04 [90% CI 0.89-1.22, p = 0.65]; stratified by MSKCC risk and liver metastases). Propensity score weight (PSW)-adjusted OS was similar between PD-L1-positive and -negative patients (median 34.4 versus 31.5 months; estimated PSW-adjusted HR 0.986). CONCLUSIONS: This study suggests PD-L1 status was not an independent prognostic factor in recurrent/metastatic RCC during the study period because PD-L1 positivity was associated with poor prognostic factors, especially MSKCC risk status.

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Long-term efficacy and safety of iron-based phosphate binders, ferric citrate hydrate and sucroferric oxyhydroxide, in hemodialysis patients.

Yoshida T, Morimoto K, Kaburagi N, Fujino T, Takemitsu TY, Yamashita N, Oya M

International urology and nephrology (International Urology and Nephrology) 54 ( 4 ) 861 - 872 2021.07

ISSN 0301-1623

Purpose: Iron-based phosphate binders, including ferric citrate hydrate (FCH) and sucroferric oxyhydroxide (SFOH), have been used for the treatment of hyperphosphatemia in end-stage renal disease patients on dialysis. However, the long-term efficacy and safety of these agents have not yet been clearly elucidated. Methods: Laboratory data of 56 hemodialysis patients who had been prescribed either FCH (n = 33) or SFOH (n = 23) were retrospectively examined. Results: We showed that both FCH and SFOH significantly and consistently decreased serum phosphate concentrations in the patients undergoing maintenance hemodialysis during the 36-month observation period. Serum levels of calcium, intact parathyroid hormone, as well as hemoglobin levels were unaltered. No overshoot of parameters of iron metabolism, such as transferrin saturation and serum ferritin levels, was observed, and serum ferritin level remained under 300 ng/mL in most patients. A trend towards decrease in the doses of erythropoiesis-stimulating agents used and frequency of intravenous iron use was observed in both treatment groups. No severe adverse drug reactions were observed in either the patients receiving FCH or SFOH. Conclusion: The results of the present study suggest that the iron-based phosphate binders, FCH and SFOH, decrease serum phosphate concentrations consistently and are safe to use over the long-term in maintenance hemodialysis patients.

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Amiodarone-induced multiple organ damage in an Alström syndrome patient with end-stage renal disease and hepatic cirrhosis.

Torimitsu T, Yoshida T, Makiuchi S, Itoh H, Oya M

CEN case reports (CEN case reports) 11 ( 1 ) 11 - 16 2021.07

ISSN 2192-4449

Alström syndrome (AS) is an extremely rare disease accompanied by blindness, hearing loss, obesity, type 2 diabetes, dilated cardiomyopathy, and progressive hepatic and renal dysfunction. The life span of AS patients rarely exceeds 50 years, and thus there are very few reports describing the implementation of renal replacement therapy for these patients. We here report a case of AS patient who exhibited dilated cardiomyopathy, end-stage renal disease, and hepatic cirrhosis. He underwent hemodialysis therapy more than 3 years. Although he eventually died of amiodarone-induced multiple organ damage in the lungs and liver, the present case suggests that hemodialysis therapy can be a choice of renal replacement therapy for AS patients with end-stage renal disease.

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Genomic characterization of circulating tumor DNA in advanced genitourinary cancer patients SCRUM-Japan MONSTAR SCREEN

Nonomura Norio, Kato Taigo, Fujisawa Takao, Shiota Masaki, Eto Masatoshi, Osawa Takahiro, Abe Takashige, Shinohara Nobuo, Yasumizu Ryota, Tanaka Nobuyuki, Oya Mototsugu, Nishimoto Koshiro, Horasawa Satoshi, Kuramoto Naomi, Nakamura Yoshiaki, Taniguchi Hiroya, Yoshino Takayuki, Matsubara Nobuaki

ANNALS OF ONCOLOGY 32 S284 - S284 2021.07

ISSN 0923-7534

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Prominent response to platinum-based chemotherapy in a patient with BRCA2 mutant-neuroendocrine prostate cancer and MDM2 amplification.

Daimon T, Kosaka T, Hongo H, Aimono E, Nakamura K, Mikami S, Nishihara H, Oya M

IJU case reports (IJU Case Reports) 4 ( 4 ) 216 - 219 2021.07

Introduction: Genomic profiling provides useful information for diagnosis, treatment, and prognosis, and detection of certain defects, such as DNA repair gene aberrations or microsatellite instability, can possibly lead to optimal treatment, but this testing has not been widely used to inform prostate cancer treatment. Case presentation: A 55-year-old man sequentially treated for prostate cancer was diagnosed as neuroendocrine prostate cancer from prostate specimens resected because of urinary retention. Subsequently, he received five cycles of platinum-based chemotherapy in total and responded well. We also performed next-generation sequencing of a sample from the prostate specimen and identified a breast cancer susceptibility gene mutation with Murine Double Minute 2 amplification and loss of heterozygosity in retinoblastoma 1. Conclusion: We report a neuroendocrine prostate cancer patient with Murine Double Minute 2 amplification who experienced an aggressive course and for whom platinum-based chemotherapy was effective, and one of the reasons for the good response might be the breast cancer susceptibility gene mutation.

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MUC1-C activates the PBAF chromatin remodeling complex in integrating redox balance with progression of human prostate cancer stem cells.

Hagiwara M, Fushimi A, Yamashita N, Bhattacharya A, Rajabi H, Long MD, Yasumizu Y, Oya M, Liu S, Kufe D

Oncogene (Oncogene) 40 ( 30 ) 4930 - 4940 2021.07

ISSN 0950-9232

The polybromo-associated PBAF (SWI/SNF) chromatin remodeling complex, which includes PBRM1, ARID2, and BRD7, regulates cell differentiation and genomic integrity. MUC1-C is an oncogenic protein that drives lineage plasticity in prostate cancer (PC) progression. The present work demonstrates that MUC1-C induces PBRM1, ARID2, and BRD7 expression by the previously unrecognized E2F1-mediated activation of their respective promoters. The functional significance of the MUC1-C→PBAF pathway is supported by demonstrating involvement of MUC1-C in associating with nuclear PBAF and driving the NRF2 antioxidant gene transcriptome in PC cells. Mechanistically, MUC1-C forms a complex with NRF2 and PBRM1 on the NRF2 target SLC7A11 gene that encodes the xCT cystine-glutamate antiporter, increases chromatin accessibility and induces SLC7A11/xCT expression. We also show that MUC1-C and PBRM1 are necessary for induction of other NRF2 target genes, including G6PD and PGD that regulate the pentose phosphate pathway. Our results further demonstrate that MUC1-C integrates activation of PBRM1 with the regulation of antioxidant genes, ROS levels, pluripotency factor expression and the cancer stem cell (CSC) state. These findings reveal a role for MUC1-C in regulating PBAF, redox balance and lineage plasticity of PC CSC progression. Our findings also uncover involvement of MUC1-C in integrating the PBAF and BAF pathways in cancer.

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Subtype-specific collaborative transcription factor networks are promoted by OCT4 in the progression of prostate cancer.

Ken-Ichi Takayama, Takeo Kosaka, Takashi Suzuki, Hiroshi Hongo, Mototsugu Oya, Tetsuya Fujimura, Yutaka Suzuki, Satoshi Inoue

Nature communications (Nature Communications) 12 ( 1 ) 3766 - 3766 2021.06

Research paper (scientific journal), Joint Work, ISSN 2041-1723

Interactive networks of transcription factors (TFs) have critical roles in epigenetic and gene regulation for cancer progression. It is required to clarify underlying mechanisms for transcriptional activation through concerted efforts of TFs. Here, we show the essential role of disease phase-specific TF collaboration changes in advanced prostate cancer (PC). Investigation of the transcriptome in castration-resistant PC (CRPC) revealed OCT4 as a key TF in the disease pathology. OCT4 confers epigenetic changes by promoting complex formation with FOXA1 and androgen receptor (AR), the central signals for the progression to CRPC. Meanwhile, OCT4 facilitates a distinctive complex formation with nuclear respiratory factor 1 (NRF1) to gain chemo-resistance in the absence of AR. Mechanistically, we reveal that OCT4 increases large droplet formations with AR/FOXA1 as well as NRF1 in vitro. Disruption of TF collaborations using a nucleoside analogue, ribavirin, inhibited treatment-resistant PC tumor growth. Thus, our findings highlight the formation of TF collaborations as a potent therapeutic target in advanced cancer.

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CD8-positive T cells and CD204-positive M2 macrophages predict postoperative prognosis of very high-risk prostate cancer

Yanai Y., Kosaka T., Mikami S., Yasumizu Y., Takeda T., Matsumoto K., Kitano S., Oya M.

EUROPEAN UROLOGY 79 S1398 - S1399 2021.06

ISSN 0302-2838

Xp11.2転座型腎細胞癌においてInterleukin-6はprogrammed cell death-1 ligand(PDL1)発現を誘導する

高松公晴, 水野隆一, 田中伸之, 浅沼宏, 大家基嗣

日本小児泌尿器科学会雑誌 (日本小児泌尿器科学会) 30 ( 1 ) 17 - 20 2021.06

ISSN 1341-0784

【目的】Xp11.2転座/transcription factor enhancer3融合遺伝子関連腎細胞癌(Xp-RCC)は小児〜AYA世代の腎細胞癌(RCC:renal cell carcinoma)で最多の組織型だが、PDL1発現に関する報告は少ない。本研究ではXp-RCCにおけるPDL1発現と、炎症性サイトカインであるInterleukin-6(IL6)とPDL1発現の関連を評価した。【方法】RCC112検体(Xp-RCC7例、淡明細胞型RCC105例)を対象に免疫染色によりPDL1発現率を評価した。更に各種ヒトRCC細胞株(786-O、Caki2、ACHN)とXp-RCC細胞株(S-TFE)を用いてIL6刺激によるPDL1発現の変化を評価した。【結果】Xp-RCCではPDL1陽性率が57%で、淡明細胞型(25%)よりもPDL1陽性率が高い傾向がみられた(p=0.091)。IL6刺激によりS-TFE(p=0.014)、786O(p=0.011)、Caki2(p=0.016)、ACHN(p=0.002)でPDL1発現が上昇した。IL6+IL6中和抗体付加により、S-TFE(p=0.006)、786O(p=0.026)、Caki2(p=0.025)、ACHN(p=0.021)でIL6によるPDL1発現誘導効果は有意に抑制された。【結論】Xp-RCCでは淡明細胞型RCCと比較してPDL1発現が高い傾向を認めた。Xp-RCC細胞株(S-TFE)ではIL6刺激によりPDL1発現が誘導されることが示唆された。(著者抄録)

Overview of recent progress on steady state operation of all-metal plasma facing wall device QUEST

Hanada K., Yoshida N., Hasegawa M., Oya M., Oya Y., Takagi I, Hatayama A., Shikama T., Idei H., Nagashima Y., Ikezoe R., Onchi T., Kuroda K., Kawasaki S., Higashijima A., Nagata T., Shimabukuro S., Nakamura K., Murakami S., Takase Y., Gao X., Liu H., Qian J.

NUCLEAR MATERIALS AND ENERGY 27 2021.06

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Isocitrate dehydrogenase 2 regulates intracellular metabolic reprogramming in chemoresistant urothelial carcinoma

Shigeta K., Hasegawa M., Kosaka T., Hishiki T., Ryuichi M., Miyajima A., Suematsu M., Kikuchi E., Oya M.

EUROPEAN UROLOGY 79 S632 - S633 2021.06

ISSN 0302-2838

Diagnostic performance of vesical imaging-reporting and data system for detecting muscle-invasive bladder cancer in real clinical setting: Comparison to diagnostic cystoscopy

Shigeta K., Kufukihara R., Ogihara K., Arita Y., Akita H., Suzuki T., Mizuno R., Kikuchi E., Jinzaki M., Oya M.

EUROPEAN UROLOGY 79 S1006 - S1007 2021.06

ISSN 0302-2838

Comparison of clinicopathological characteristics between primary muscle-invasive bladder cancer and secondary muscle invasive bladder recurrence subsequent to upper tract urothelial carcinoma

Shigeta K., Matsumoto K., Yasumizu Y., Tanaka N., Takeda T., Kosaka T., Mizuno R., Kikuchi E., Oya M.

EUROPEAN UROLOGY 79 S1081 - S1082 2021.06

ISSN 0302-2838

Germline BRCA2 mutation in a case of aggressive prostate cancer accompanied by spinal bulbar muscular atrophy.

Hiroshi Hongo, Takeo Kosaka, Hideyuki Hayashi, Kohei Nakamura, Hiroshi Nishihara, Shuji Mikami, Himisha Beltran, Mototsugu Oya

Asian journal of andrology (Asian Journal of Andrology) 24 ( 1 ) 116 - 118 2021.05

Joint Work, ISSN 1008-682X

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Analysis of the CLEAR study in patients (pts) with advanced renal cell carcinoma (RCC): Depth of response and efficacy for selected subgroups in the lenvatinib (LEN) plus pembrolizumab (PEMBRO) and sunitinib (SUN) treatment arms.

Grunwald Viktor, Powles Thomas, Kopyltsov Evgeny, Kozlov Vadim, Gordoa Teresa Alonso, Eto Masatoshi, Hutson Thomas E., Motzer Robert J., Winquist Eric, Maroto-Rey Pablo, Keam Bhumsuk, Procopio Giuseppe, Wong Shirley, Melichar Bohuslav, Rolland Frederic, Oya Mototsugu, Rodriguez-Lopez Karla, Saito Kenichi, Smith Alan D., Porta Camillo

JOURNAL OF CLINICAL ONCOLOGY 39 ( 15 ) 2021.05

ISSN 0732-183X

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Guideline adherence for radical cystectomy significantly affects survival outcomes in non-muscle-invasive bladder cancer patients

Emina Kayama, Keisuke Shigeta, Eiji Kikuchi, Koichiro Ogihara, Kyohei Hakozaki, Tomohiro Iwasawa, Ken Kamisawa, Kunimitsu Kanai, Hiroki Ide, Satoshi Hara, Ryuichi Mizuno, Mototsugu Oya

Japanese Journal of Clinical Oncology (Oxford University Press (OUP)) 51 ( 8 ) 1303 - 1312 2021.05

Research paper (scientific journal), Joint Work, ISSN 0368-2811

<title>Abstract</title>
<sec>
<title>Background</title>
The relationship between guideline adherence for radical cystectomy of non-muscle-invasive bladder cancer and patient prognoses currently remains unclear. We investigated whether guideline adherence at the time of non-muscle-invasive bladder cancer affects the oncological outcomes of bladder cancer patients who underwent radical cystectomy.

</sec>
<sec>
<title>Methods</title>
Among 267 cTa-4N0-2M0 bladder cancer patients, 70 who underwent radical cystectomy under the non-muscle-invasive bladder cancer or muscle-invasive bladder cancer status that progressed from non-muscle-invasive bladder cancer were identified. Patients who followed the guidelines from initial transurethral resection of bladder tumors to radical cystectomy were defined as the guideline adherent group (n = 52), while those who did not were the guideline non-adherent group (n = 18).

</sec>
<sec>
<title>Results</title>
In the guideline non-adherent group, 8 (44.4%) out of 18 were diagnosed with highest risk non-muscle-invasive bladder cancer for Bacillus Calmette Guérin-naïve patients and 7 (38.9%) had a Bacillus Calmette Guérin unresponsive tumor status. Five-year recurrence-free survival and cancer-specific survival rates for the guideline non-adherent group vs guideline adherent group were 38.9% vs 69.8% (P = 0.018) and 52.7% vs 80.1% (P = 0.006), respectively. A multivariate analysis identified guideline non-adherence as one of independent indicators for disease recurrence (hazard ratio = 2.81, P = 0.008) and cancer-specific death (hazard ratio = 4.04, P = 0.003). In a subgroup analysis of 49 patients with cT1 or less non-muscle-invasive bladder cancer at the time of radical cystectomy, guideline non-adherence remained an independent prognostic factor for cancer-specific survival (hazard ratio = 3.46, P = 0.027).

</sec>
<sec>
<title>Conclusions</title>
Guideline adherence during the time course of the non-muscle-invasive bladder cancer stage may result in a favorable prognosis of patients who receive radical cystectomy. Even under non-muscle-invasive bladder cancer status, radical cystectomy needs to be performed with adequate timing under guideline recommendations.

</sec>

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First case of ductal adenocarcinoma of the prostate with MAP3K1 homozygous deletion.

Kazunori Shojo, Takeo Kosaka, Kohei Nakamura, Hiroshi Hongo, Hiroaki Kobayashi, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

IJU case reports (IJU Case Reports) 4 ( 3 ) 176 - 179 2021.05

Joint Work

Introduction: Ductal adenocarcinoma of the prostate is a rare prostate cancer variant and associated with higher stage and greater risk of mortality. Optimal systemic therapy for metastatic ductal adenocarcinoma is not known. Case presentation: A 67-year-old man presented with ductal adenocarcinoma of the prostate accompanied by multiple lung metastases and advanced bone metastases. We performed channel transurethral resection of the prostate and confirmed the diagnosis of ductal adenocarcinoma of the prostate. DNA sequencing identified a TP53 somatic point mutation (p.Gly245Ser) as the pathogenic variant. Furthermore, a homozygous deletion was observed in mitogen-activated protein kinase kinase kinase 1. The patient received enzalutamide but deceased 5 months after presenting to our institution. Conclusion: To our knowledge, this is the first report of ductal adenocarcinoma of the prostate with a mitogen-activated protein kinase kinase kinase 1 homozygous deletion. Accumulation of whole-exome sequencing data is expected to inform future advances in therapy development.

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特集前立腺癌のバイオロジーと最新の治療-いま起こりつつあるパラダイムシフト企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 75 ( 5 ) 273 - 273 2021.04

ISSN 0385-2393

Treatment strategy for neuroendocrine prostate cancer

安水洋太, 小坂威雄, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 75 ( 5 ) 340 - 345 2021.04

ISSN 0385-2393

Utility of prophylactic antibiotics for preventing febrile neutropenia during cabazitaxel therapy for castration-resistant prostate cancer.

Keitaro Watanabe, Takeo Kosaka, Hiroshi Hongo, Mototsugu Oya

Scientific reports (Scientific Reports) 11 ( 1 ) 8367 - 8367 2021.04

Research paper (scientific journal), Joint Work, ISSN 2045-2322

The aim was to investigate the efficacy of prophylactic antibiotics for the prevention of febrile neutropenia (FN) during cabazitaxel therapy for castration-resistant prostate cancer (CRPC) with G-CSF. We retrospectively studied 443 cycles of cabazitaxel therapy given to 56 patients with CRPC at Keio University Hospital between May 2012 and August 2018. Statistical analysis was conducted to determine whether the combination of prophylactic G-CSF and antibiotics was more effective in preventing FN, compared with prophylactic G-CSF alone. Prophylactic PEG-G-CSF or G-CSF was administered in all 443 cycles. Only fluoroquinolones were used as prophylactic antibiotics and were administered in 328 cycles (74.0%). FN occurred in 5 cycles (1.1%). Prophylactic antibiotics were administered in 327 cycles (74.6%) in the FN-negative group and in only 1 cycle (20.0%) in the FN-positive group. Chi-square test indicated the incidence of FN was significantly lower in the group that received prophylactic antibiotics compared with the group that did not receive prophylactic antibiotics (P = 0.017). Compared with prophylactic G-CSF alone, prophylactic G-CSF and antibiotics significantly suppressed the occurrence of FN.

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A long-term survivor of metastatic neuroendocrine prostate cancer treated with multimodal therapy: genetic consideration from next-generation sequencing

Hongo Hiroshi, Kosaka Takeo, Nakatsuka Seishi, Oya Mototsugu

INTERNATIONAL CANCER CONFERENCE JOURNAL 10 ( 3 ) 174 - 180 2021.04

ISSN 2192-3183

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Grading of Multifocal Prostate Cancer Cases in which the Largest Volume and the Highest Grade Do Not Coincide within One Lesion.

Kazuhiro Matsumoto, Minami Omura, Toshikazu Takeda, Takeo Kosaka, Akinori Hashiguchi, Kimiharu Takamatsu, Yota Yasumizu, Nobuyuki Tanaka, Shinya Morita, Ryuichi Mizuno, Hiroshi Asanuma, Mototsugu Oya

The Journal of urology (The Journal of urology) 206 ( 2 ) 101097JU0000000000001765 - 345 2021.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

PURPOSE: In general, the index lesion of prostate cancer has the largest tumor volume, the highest Grade Group (GG), and the highest stage (concordant cases). However, these factors sometimes do not coincide within one lesion (discordant cases). In such discordant cases, the largest tumor may not be of biological significance and the secondary tumor may more greatly impact the prognosis. MATERIALS AND METHODS: We retrospectively reviewed the medical records of patients who underwent radical prostatectomy, and we identified 580 (85.3%) concordant cases and 100 (14.7%) discordant cases. The end point of this study was biochemical recurrence, and median followup was 4.2 years. RESULTS: Among discordant cases in which GGs of the largest tumor and the highest GG tumor differed, the majority (67 patients) had the largest tumor of GG 2, and we set them as the study cohort. On the other hand, we regarded 212 concordant cases with an index tumor of GG 2 as the control cohort. The study cohort comprised 48 (71.6%) patients with a secondary tumor of GG 3 and 19 (28.4%) with a secondary tumor of GG 4/5. Kaplan-Meier curves revealed that the 5-year biochemical recurrence-free survival rates were 76%, and 67%, respectively. The 5-year biochemical recurrence-free survival rate of the control cohort was 91%, which was significantly better than that of the study cohort (p=0.013 and p=0.014, respectively). CONCLUSIONS: Our study suggests that the prognosis of discordant cases is better determined by the secondary cancer lesion with the highest GG instead of the largest lesion.

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増刊号特集泌尿器科当直医マニュアル企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 75 ( 4 ) 7 - 7 2021.04

ISSN 0385-2393

特集内科疾患の診断基準・病型分類・重症度第3章　腎臓腎細胞がん

水野隆一, 大家基嗣

内科 (南江堂) 127 ( 4 ) 643 - 646 2021.04

ISSN 0022-1961

Radiologic features of mixed epithelial and stromal tumors of the kidney: Hyperattenuating on unenhanced computed tomography and T2-hypointensity on magnetic resonance imaging.

Suzuki Tatsuya, Akita Hirotaka, Arita Yuki, Tomiyama Akiko, Hashimoto Masahiro, Okuda Shigeo, Mikami Shuji, Mizuno Ryuichi, Oya Mototsugu, Jinzaki Masahiro

Radiology case reports (Radiology Case Reports) 16 ( 4 ) 858 - 862 2021.04

Research paper (scientific journal), Joint Work

In the 2016 World Health Organization renal tumor classification, the mixed epithelial and stromal tumor family was introduced as a new entity. This family encompasses a spectrum of tumors, ranging from predominantly cystic tumors (adult cystic nephromas) to tumors that are variably solid (mixed epithelial and stromal tumors). The majority of previous studies incorporating "mixed epithelial and stromal tumor" in the titles were actually reports of imaging findings of adult cystic nephroma. Thus, the solid component of mixed epithelial and stromal tumors has not been well evaluated. In this study, we present 2 cases of mixed epithelial and stromal tumors, as defined by the 2016 World Health Organization classification, showing a predominantly solid component. The characteristic findings of the solid component of these tumors were T2-hypointensity on magnetic resonance imaging and hyperattenuation on unenhanced computed tomography. Angiomyolipoma with epithelial cysts and epithelioid angiomyolipoma should be considered in the differential diagnosis of mixed epithelial and stromal tumors.

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ASO Author Reflections: Previous History of Non-urothelial Malignancy May Provide Predictive Information of Worse Clinical Outcome for Initially Diagnosed Non-Muscle Invasive Bladder Cancer.

Ryohei Kufukihara, Eiji Kikuchi, Koichiro Ogihara, Keisuke Shigeta, Mototsugu Oya

Annals of surgical oncology (Annals of Surgical Oncology) 28 ( 9 ) 5360 - 5361 2021.03

Research paper (scientific journal), Joint Work, ISSN 1068-9265

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A first Japanese case of BRCA2 and RB1 co-loss organ-confined prostate cancer successfully treated by radical prostatectomy

Matsumoto Kazuhiro, Kosaka Takeo, Nakamura Kohei, Nishihara Hiroshi, Oya Mototsugu

INTERNATIONAL CANCER CONFERENCE JOURNAL 10 ( 3 ) 170 - 173 2021.03

ISSN 2192-3183

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Role of Previous Malignancy History in Clinical Outcomes in Patients with Initially Diagnosed Non-Muscle Invasive Bladder Cancer.

Ryohei Kufukihara, Eiji Kikuchi, Koichiro Ogihara, Keisuke Shigeta, Yoshinori Yanai, Kimiharu Takamatsu, Hiroki Ide, Masafumi Oyama, Hirotaka Asakura, Ryuichi Mizuno, Mototsugu Oya

Annals of surgical oncology (Annals of Surgical Oncology) 28 ( 9 ) 5349 - 5359 2021.03

Research paper (scientific journal), Joint Work, ISSN 1068-9265

INTRODUCTION: Our aim is to evaluate whether previous non-urothelial malignant history affects the clinical outcomes of patients with non-muscle invasive bladder cancer (NMIBC). PATIENTS AND METHODS: We identified 1097 cases treated by transurethral resection of bladder tumors for initially diagnosed NMIBC at our four institutions between 1999 and 2017. We compared clinical characteristics and outcomes between NMIBC patients with and without previous non-urothelial malignant history and investigated whether smoking status and treatment modality for previous cancer affected NMIBC outcomes. RESULTS: A total of 177 patients (16.1%) had previous non-urothelial malignant history (malignant history group). The 5-year recurrence-free survival rate and the 5-year progression-free survival rate in the malignant history group was 46.4% and 88.3%, respectively, which was significantly lower than that in the counterpart (60.2% p = 0.004, and 94.5% p = 0.002, respectively). A multivariate Cox regression analysis identified previous non-urothelial malignant history as an independent risk factor for tumor recurrence (p = 0.001) and stage progression (p = 0.003). In a subgroup of patients who were current smokers (N = 347), previous non-urothelial malignant history was associated with tumor recurrence and stage progression. In contrast, previous non-urothelial malignant history was not associated with tumor recurrence or stage progression in ex-smokers or non-smokers. In a subgroup analysis of NMIBC patients with previous prostate cancer history, those treated with androgen deprivation therapy had a significantly lower bladder tumor recurrence rate than their counterparts (p = 0.027). CONCLUSIONS: Previous history of non-urothelial malignancy may lead to worse clinical outcome in patients with NMIBC, particularly current smokers.

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Cranial nerve palsy caused by metastasis to the skull base in patients with castration-resistant prostate cancer: Three case reports.

Yota Yasumizu, Takeo Kosaka, Hiroshi Hongo, Ryuichi Mizuno, Mototsugu Oya

IJU case reports 4 ( 2 ) 108 - 111 2021.03

Joint Work

Introduction: Skull base metastasis of prostate cancer associated with cranial nerve palsy is rare. We observed three patients with aggressive prostate cancer who experienced cranial nerve palsy. Case presentation: Case 1 was a 53-year-old patient who was treated with carboplatin and etoposide. He noticed sensory abnormalities on his left mouth edge. Head magnetic resonance imaging revealed skull base metastasis. Case 2 was a 50-year-old patient who received docetaxel. This patient exhibited ptosis of the left eye. Skull base metastasis was detected by magnetic resonance imaging. External beam radiation therapy was performed. Case 3 was a 64-year-old patient who was treated with docetaxel. He experienced ptosis of the right eye and diplopia. He was also treated with external beam radiation therapy. Conclusion: External beam radiation therapy exhibited some efficacy against the symptoms, but skull base metastasis of treatment-resistant prostate cancer has poor prognosis. Three patients died within 3 months after symptoms occurred with or without external beam radiation therapy.

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The clinicopathological characteristics of muscle-invasive bladder recurrence in upper tract urothelial carcinoma.

Keisuke Shigeta, Kazuhiro Matsumoto, Koichiro Ogihara, Tetsushi Murakami, Tadatsugu Anno, Kota Umeda, Mizuki Izawa, Yuto Baba, Tansei Sanjo, Kazunori Shojo, Nobuyuki Tanaka, Toshikazu Takeda, Takeo Kosaka, Ryuichi Mizuno, Shuji Mikami, Eiji Kikuchi, Mototsugu Oya

Cancer science (WILEY) 112 ( 3 ) 1084 - 1094 2021.03

Research paper (scientific journal), Joint Work, ISSN 1347-9032

This study aimed to clarify the clinical characteristics and oncological outcomes of patients with upper tract urothelial carcinoma (UTUC) who developed muscle-invasive bladder cancer (MIBC) after radical nephroureterectomy (RNU). We identified 966 pTa-4N0-2M0 patients with UTUC who underwent RNU and clarified the risk factors for MIBC progression after initial intravesical recurrence (IVR). We also identified 318 patients with primary pT2-4N0-2M0 MIBC to compare the oncological outcomes with those of patients with UTUC who developed or progressed to MIBC. Furthermore, immunohistochemical examination of p53 and FGFR3 expression in tumor specimens was performed to compare UTUC of MIBC origin with primary MIBC. In total, 392 (40.6%) patients developed IVR after RNU and 46 (4.8%) developed MIBC at initial IVR or thereafter. As a result, pT1 stage on the initial IVR specimen, concomitant carcinoma in situ on the initial IVR specimen, and no intravesical adjuvant therapy after IVR were independent factors for MIBC progression. After propensity score matching adjustment, primary UTUC was a favorable indicator for cancer-specific death compared with primary MIBC. Subgroup molecular analysis revealed high FGFR3 expression in non-MIBC and MIBC specimens from primary UTUC, whereas low FGFR3 but high p53 expression was observed in specimens from primary MIBC tissue. In conclusion, our study demonstrated that patients with UTUC who develop MIBC recurrence after RNU exhibited the clinical characteristics of subsequent IVR more than those of primary UTUC. Of note, MIBC subsequent to UTUC may have favorable outcomes, probably due to the different molecular biological background compared with primary MIBC.

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Frequent azoospermia in patients with testicular germ cell cancer and a history of cryptorchidism: a report of nine cases and review of the literature.

Jun Hagiuda, Ken Nakagawa, Mototsugu Oya

Systems biology in reproductive medicine (TAYLOR & FRANCIS INC) 67 ( 3 ) 1 - 4 2021.02

Research paper (scientific journal), Joint Work, ISSN 1939-6368

This study analyzed semen parameters in patients with testicular germ cell cancer and a history of cryptorchidism. Among testicular cancer patients referred for sperm cryopreservation, the semen of 9 patients with a history of cryptorchidism, including three cases of bilateral cryptorchidism and one case of cryptorchidism with bilateral metachronous tumor, was analyzed. Eight patients underwent orchidopexy during childhood. The tumor was observed on the contralateral side of the undescended testis, except in the bilateral metachronous tumor and cryptorchidism cases. Five patients, including the one who developed a metachronous testicular tumor on the undescended testis, showed azoospermia even though in three of them, semen was collected before undergoing orchiectomy. Clinical urologists should recognize that spermatogenesis is severely impaired in these patients and consider cryopreservation before orchiectomy or onco-TESE.

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Efficacy of avelumab plus axitinib (A plus Ax) versus sunitinib (S) by number of IMDC risk factors and tumor sites at baseline in advanced renal cell carcinoma (aRCC): Extended follow-up results from JAVELIN Renal 101.

Tomita Yoshihiko, Motzer Robert J., Choueiri Toni K., Rini Brian I., Miyake Hideaki, Oya Mototsugu, Albiges Laurence, Fujii Yosuke, Umeyama Yoshiko, Wang Jing, Di Pietro Alessandra, Schmidinger Manuela

JOURNAL OF CLINICAL ONCOLOGY 39 ( 6 ) 2021.02

ISSN 0732-183X

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Landscape of genomic alterations of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Project.

Matsubara Nobuaki, Kato Taigo, Fujisawa Takao, Shiota Masaki, Eto Masatoshi, Osawa Takahiro, Abe Takashige, Shinohara Nobuo, Yasumizu Yota, Tanaka Nobuyuki, Oya Mototsugu, Nishimoto Koshiro, Horasawa Satoshi, Kuramoto Naomi, Nakamura Yoshiaki, Taniguchi Hiroya, Yoshino Takayuki, Nonomura Norio

JOURNAL OF CLINICAL ONCOLOGY 39 ( 6 ) 2021.02

ISSN 0732-183X

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Enzalutamide plus androgen deprivation therapy (ADT) versus flutamide plus ADT in men with castration-resistant prostate cancer (CRPC): AFTERCAB

Uemura Hiroji, Kobayashi Kazuki, Yokomizo Akira, Hinotsu Shiro, Horie Shigeo, Kakehi Yoshiyuki, Naito Seiji, Nonomura Norio, Ogawa Osamu, Oya Mototsugu, Suzuki Kazuhiro, Saito Atsushi, Uno Satoshi, Akaza Hideyuki

JOURNAL OF CLINICAL ONCOLOGY 39 ( 6 ) 2021.02

ISSN 0732-183X

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Efficacy and safety of subsequent molecular targeted therapy after immuno-checkpoint therapy, retrospective study of Japanese patients with metastatic renal cell carcinoma (AFTER I-O study).

Yoshihiko Tomita, Go Kimura, Satoshi Fukasawa, Kazuyuki Numakura, Yutaka Sugiyama, Kazutoshi Yamana, Sei Naito, Koki Kabu, Yohei Tajima, Mototsugu Oya

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 6 ) 966 - 975 2021.02

Research paper (scientific journal), Joint Work, ISSN 0368-2811

OBJECTIVES: Guidelines for treatment of mRCC recommend nivolumab monotherapy (NIVO) for treated patients, and nivolumab plus ipilimumab combination therapy (NIVO+IPI) for untreated IMDC intermediate and poor-risk mRCC patients. Although molecular-targeted therapies (TTs) such as VEGFR-TKIs and mTORi are recommended as subsequent therapy after NIVO or NIVO+IPI, their efficacy and safety remain unclear. METHODS: Outcome of Japanese patients with mRCC who received TT after NIVO (CheckMate 025) or NIVO+IPI (CheckMate 214) were retrospectively analyzed. Primary endpoints were investigator-assessed ORR of the first TT after either NIVO or NIVO+IPI. Secondary endpoints included TFS, PFS, OS and safety of TTs. RESULTS: Twenty six patients in CheckMate 025 and 19 patients in CheckMate 214 from 20 centers in Japan were analyzed. As the first subsequent TT after NIVO or NIVO+IPI, axitinib was the most frequently treated regimen for both CheckMate 025 (54%) and CheckMate 214 (47%) patients. The ORRs of TT after NIVO and NIVO+IPI were 27 and 32% (all risks), and median PFSs were 8.9 and 16.3 months, respectively. During the treatment of first TT after either NIVO or NIVO+IPI, 98% of patients experienced treatment-related adverse events, including grade 3-4 events in 51% of patients, and no treatment-related deaths occurred. CONCLUSIONS: TTs have favorable antitumor activity in patients with mRCC after ICI, possibly via changing the mechanism of action. Safety signals of TTs after ICI were similar to previous reports. These results indicate that sequential TTs after ICI may contribute for long survival benefit.

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Site-specific differences in survival among upper and lower tract urothelial carcinoma patients treated with radical surgery.

Tadatsugu Anno, Eiji Kikuchi, Keisuke Shigeta, Koichiro Ogihara, Keitaro Watanabe, Yoshinori Yanai, Kimiharu Takamatsu, Shintaro Hasegawa, Takeshi Masuda, Masafumi Oyama, Ryuichi Mizuno, Mototsugu Oya

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 6 ) 984 - 991 2021.02

Research paper (scientific journal), Joint Work, ISSN 0368-2811

BACKGROUND: It currently remains unclear whether the location of primary tumours affects the clinical outcomes of patients with locally advanced urothelial carcinoma in the urinary tract. The aim of the present study was to compare prognostic differences between bladder urothelial carcinoma and upper tract urothelial carcinoma, particularly pT3 or higher tumours. METHODS: In total, 307 patients with pT3 or higher urothelial carcinoma without distant metastasis who underwent radical cystectomy for bladder urothelial carcinoma (N = 127, 41.4%) or radical nephroureterectomy for upper tract urothelial carcinoma (N = 180, 58.6%) at Keio University Hospital and three affiliated hospitals between 1994 and 2017 were enrolled. Oncological outcomes were compared between bladder urothelial carcinoma and upper tract urothelial carcinoma using Cox regression analysis. RESULTS: Significantly higher rates of male patients, smokers, neoadjuvant chemotherapy, lymph node involvement and lymphovascular invasion were observed in the bladder urothelial carcinoma group. The incidence of regional lymph node or local recurrence was higher in patients with bladder urothelial carcinoma than in those with upper tract urothelial carcinoma, while that of lung metastasis was lower. In all patients, bladder urothelial carcinoma was independently associated with disease recurrence (hazard ratio (HR) 1.504, P = 0.035) in addition to neoadjuvant chemotherapy and lymphovascular invasion. Bladder urothelial carcinoma was also independently associated with cancer death (HR = 1.998, P = 0.002) as well as lymphovascular invasion. Following the exclusion of patients who received neoadjuvant chemotherapy, bladder urothelial carcinoma remained an independent risk factor for disease recurrence and cancer death (HR = 1.702, P = 0.010 and HR = 1.888, P = 0.013, respectively). CONCLUSIONS: Bladder urothelial carcinoma may follow worse prognosis compared to upper tract urothelial carcinoma, particularly that with a high pathological stage.

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In silico screening for identification of novel drugs for overcoming taxane-resistant prostate cancer

本郷周, 本郷周, 小坂威雄, 宮崎保匡, 田中伸之, 大家基嗣

日本癌学会学術総会抄録集(Web) (WILEY) 112 916 - 916 2021.02

Joint Work, ISSN 1347-9032

The Intracellular Metabolic Reprogramming enables Urothelial Carcinoma Cells to Acquire Chemoresistance

茂田啓介, 長谷川政徳, 菊地栄次, 小坂威雄, 水野隆一, 大家基嗣

日本癌学会学術総会抄録集(Web) (WILEY) 112 246 - 246 2021.02

Joint Work, ISSN 1347-9032

21水酸化酵素欠損症に巨大な両側副腎骨髄脂肪腫を合併した一例

松林秀幸, 武田利和, 馬場優人, 桝田司, 安水洋太, 田中伸之, 松本一宏, 森田伸也, 小坂威雄, 水野隆一, 浅沼宏, 大家基嗣

泌尿器外科 (医学図書出版(株)) 34 ( 2 ) 210 - 210 2021.02

Joint Work, ISSN 0914-6180

LONG-TERM FOLLOW-UP COMPARING SALVAGE RADIATION THERAPY AND ANDROGEN DEPRIVATION THERAPY FOR BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY

Kazuhiro Matsumoto, Naoya Niwa, Masayuki Hgiwara, Takeo Kosaka, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Ryuichi Mizuno, Satoshi Hara, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 ( 4 ) E566 - E566 2021.01

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: The salvage treatments for biochemical recurrence (BCR) include local external beam radiation therapy (RT) and systemic androgen-deprivation therapy (ADT). METHODS: We reviewed patients who underwent radical prostatectomy (RP) and developed BCR at three institutions. After excluding patients whose nadir prostate-specific antigen (PSA) was higher than 0.2 ng/mL, those who received neoadjuvant/adjuvant therapy, and those whose BCR was not treated until their PSA exceeded 4.0 ng/mL, the remaining 335 patients comprised the cohort of this study. Salvage RT and ADT were performed for 154 and 181 patients, respectively. After the failure of salvage RT, all patients received subsequent ADT. The starting point of this study was the timing of BCR and the endpoint was the development of castration-resistant prostate cancer (CRPC). RESULTS: During the mean follow-up period of 8.5 years after BCR, CRPC was observed in 13 patients administered RT and 24 patients administered ADT. Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival between the RT and ADT groups (10-year CRPC-free survival 89.9 vs. 86.3%, p = 0.199). On the other hand, we found a significant difference in CRPC-free survival between the RT and ADT groups in 50 high-risk patients with two risk factors of Grade Group ≥ 4 and PSA-doubling time < 6 months (10-year CRPC-free survival 73.4 vs. 40.3%, p = 0.040). CONCLUSION: This study revealed that salvage RT increases the CRPC-free survival rate compared with salvage ADT in high-risk patients with Grade Group ≥ 4 and PSA-doubling time < 6 months.

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Pulmonary metastasis secondary to abiraterone-resistant prostate cancer with homozygous deletions of BRCA2: First Japanese case.

Mizuki Izawa, Takeo Kosaka, Kohei Nakamura, Junna Oba, Tomoyuki Hishida, Hiroshi Hongo, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

IJU case reports (IJU Case Reports) 4 ( 1 ) 14 - 17 2021.01

Joint Work

Introduction: Most metastatic prostate cancers acquire the capacity for androgen-independent growth and become resistant to androgen deprivation therapy. A patient-focused treatment strategy is needed for aggressive castration-resistant prostate cancer. Case presentation: We report the case of a 62-year-old man who presented with prostatic adenocarcinoma who was treated by radiation and combined androgen blockade. After completion of first-line therapy, he was diagnosed with multiple metastatic castration-resistant prostate cancer in the lung. Second-line therapy with abiraterone acetate resulted in partial remission of the lung metastases. Thoracic surgery was performed to remove the single lung metastasis remaining. Next-generation sequencing of the specimens demonstrated homozygous loss of BRCA2. We note in this case a heterogeneous response to abiraterone acetate may be related to the somatic BRCA2 deletions. Conclusions: We present the first Japanese case of a metastatic abiraterone acetate-resistant castration-resistant prostate cancer accompanied by BRCA2 mutation.

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AYA世代で外科的治療を要した先天性腎尿路異常と胎児超音波検査との関連

寺西悠, 浅沼宏, 安水洋太, 田中伸之, 武田利和, 松本一宏, 森田伸也, 小坂威雄, 水野隆一, 大家基嗣

日本腎泌尿器疾患予防医学研究会プログラム・抄録集 (日本腎泌尿器疾患予防医学研究会) 29回 52 - 52 2021.01

Joint Work

Transient hypercalcemia in a patient with SAPHO syndrome

Yoshida T., Oya M.

Journal of General and Family Medicine (Journal of General and Family Medicine) 23 ( 1 ) 44 - 46 2021

ISSN 2189-7948

We here report a case of SAPHO (synovitis-acne-pustulosis-hyperostosis-osteitis) syndrome with hypercalcemia. The patient was diagnosed with SAPHO syndrome at the age of 54, because he exhibited osteitis and hyperostosis around the sternoclavicular joints and the temporomandibular joints bilaterally and had past medical history of palmoplantar pustulosis. At the age of 67, he exhibited appetite loss and nausea. Corrected serum calcium was 13.0 mg/dl. Adequate hydration was recommended, and his calcium levels returned to the normal range without any medical treatment. Although speculative, his hypercalcemia was considered to be caused by an increased bone activity in SAPHO syndrome. This is the first report describing transient hypercalcemia in a patient with SAPHO syndrome.

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Successful Treatment of Anti-MDA5 Antibody-Positive Dermatomyositis-Associated Rapidly Progressive-Interstitial Lung Disease by Plasma Exchange: Two Case Reports.

Rina Takahashi, Tadashi Yoshida, Kohkichi Morimoto, Yasushi Kondo, Jun Kikuchi, Shuntaro Saito, Sho Ishigaki, Yuko Kaneko, Tsutomu Takeuchi, Hiroshi Itoh, Mototsugu Oya

Clinical medicine insights. Case reports (Clinical Medicine Insights: Case Reports) 14 11795476211036322 - 11795476211036322 2021

Joint Work, ISSN 1179-5476

Background: Patients with anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (DM) are frequently accompanied by rapidly progressive-interstitial lung disease (RP-ILD). They are often refractory to intensive immunosuppressive therapy and have poor prognosis. Case presentation: A 73-year-old woman presented with fever, cold symptoms, and skin eruption for a month. She also exhibited muscle weakness on upper extremities slightly. The titer of anti-MDA5 antibody was extremely high, and computed tomography showed ground glass opacity and reticular shadows in the lungs. She was diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD and treated with intensive immunosuppressive therapy. However, the titer of anti-MDA5 antibody did not decrease satisfactorily, and plasma exchange was alternatively initiated. The titer decreased remarkably, and she obtained disease remission. Similarly, a 63-year-old woman presented with stiffness of the neck and hands, fever and cough. She was also diagnosed as anti-MDA5 antibody-positive classical DM-associated RP-ILD, because she had skin eruptions, slight muscle weakness, an elevation in anti-MDA5 antibody, and RP-ILD. She was unresponsive to intensive immunosuppressive therapy, but plasma exchange successfully improved the titer of anti-MDA5 antibody, the symptoms, and the findings of computed tomography. Conclusions: Although anti-MDA5 antibody-positive DM-associated RP-ILD has a high mortality rate, this report suggests the usefulness of plasma exchange to improve the prognosis.

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A Case of New-Onset Systemic Lupus Erythematosus With Serositis in a Maintenance Hemodialysis Patient.

Kosugi S, Yoshida T, Yoshimoto N, Itoh H, Oya M

Clinical medicine insights. Case reports (Clinical Medicine Insights: Case Reports) 14 11795476211056172 2021

ISSN 1179-5476

A 61-year-old woman with a 4-year history of maintenance hemodialysis due to end-stage renal disease of unknown cause was admitted because of a recurrent fever and abdominal pain lasting for 3 months. She had rheumatoid arthritis as a complication and had taken sulfasalazine for over 4 years. Laboratory data revealed thrombocytopenia, hypocomplementemia, a high C-reactive protein level, and positivity for antinuclear antibody and anti-double strand DNA antibody. Gallium scintigraphy showed pericarditis, pleuritis, and peritonitis. Nonscarring alopecia was also noted. She was diagnosed as having systemic lupus erythematosus (SLE). Drug-induced lupus elicited by sulfasalazine was ruled out because the symptoms did not improve even after the discontinuation of the drug upon admission. Oral prednisolone treatment markedly improved her symptoms and laboratory data. However, she later died of sepsis arising from proctitis on day 71 of admission. This report underscores the necessity of considering new-onset SLE in patients with unexplained fever and serositis, including pleuritis, peritonitis, or pericarditis, even if they are receiving maintenance dialysis.

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Role of prior nephrectomy for synchronous metastatic renal cell carcinoma (mRCC) on efficacy in patients treated with avelumab plus axitinib (A plus Ax) or sunitinib (S): Results from JAVELIN Renal 101

Grimm M-O., Oya M., Choueiri T. K., Schmidinger M., Quinn D. I., Mescam G. Gravis, Verzoni E., Van den Eertwegh A. J. M., di Pietro A., Mariani M., Wang J., Thomaidou D., Albiges L.

ANNALS OF ONCOLOGY 32 S690 - S691 2021

ISSN 0923-7534

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Genomic profiling of circulating tumor DNA in advanced genitourinary cancer patients: SCRUM-Japan MONSTAR SCREEN Nationwide Cancer Genome Screening Project

Kato T., Matsubara N., Fujisawa T., Shiota M., Eto M., Osawa T., Abe T., Shinohara N., Yasumizu Y., Tanaka N., Oya M., Nishimoto K., Horasawa S., Kuramoto N., Nakamura Y., Taniguchi H., Yoshino T., Nonomura N.

ANNALS OF ONCOLOGY 32 S656 - S656 2021

ISSN 0923-7534

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MUC1-C Activates the BAF (mSWI/SNF) Complex in Prostate Cancer Stem Cells.

Masayuki Hagiwara, Yota Yasumizu, Nami Yamashita, Hasan Rajabi, Atsushi Fushimi, Mark D Long, Wei Li, Atrayee Bhattacharya, Rehan Ahmad, Mototsugu Oya, Song Liu, Donald Kufe

Cancer research (AMER ASSOC CANCER RESEARCH) 81 ( 4 ) 1111 - 1122 2020.12

Research paper (scientific journal), Joint Work, ISSN 0008-5472

The Brg/Brahma-associated factor (BAF, mSWI/SNF) chromatin remodeling complex is of importance in development and has been linked to prostate oncogenesis. The oncogenic MUC1-C protein promotes lineage plasticity in the progression of neuroendocrine prostate cancer (NEPC), however, there is no known association between MUC1-C and BAF. We report here that MUC1-C binds directly to the E2F1 transcription factor and that the MUC1-C→E2F1 pathway induces expression of embryonic stem cell-specific BAF (esBAF) components BRG1, ARID1A, BAF60a, BAF155, and BAF170 in castrate-resistant prostate cancer (CRPC) and NEPC cells. In concert with this previously unrecognized pathway, MUC1 was associated with increased expression of E2F1 and esBAF components in NEPC tumors as compared with CRPC, supporting involvement of MUC1-C in activating the E2F1→esBAF pathway with progression to NEPC. MUC1-C formed a nuclear complex with BAF and activated cancer stem cell (CSC) gene signatures and the core pluripotency factor gene network. The MUC1-C→E2F1→BAF pathway was necessary for induction of both the NOTCH1 effector of CSC function and the NANOG pluripotency factor, and collectively, this network drove CSC self-renewal. These findings indicate that MUC1-C promotes NEPC progression by integrating activation of E2F1 and esBAF with induction of NOTCH1, NANOG, and stemness. SIGNIFICANCE: These findings show that MUC1-C, which promotes prostate cancer progression, activates a novel pathway that drives the BAF remodeling complex, induces NOTCH1 and NANOG, and promotes self-renewal of prostate cancer stem cells.

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副腎性クッシング症候群における術後ステロイド補充療法の長期化を予測する因子の検討

箱崎恭平, 武田利和, 山田祥岳, 安水洋太, 田中伸之, 松本一宏, 森田伸也, 小坂威雄, 水野隆一, 浅沼宏, 陣崎雅弘, 大家基嗣

日本泌尿器科学会総会 ((一社)日本泌尿器科学会総会事務局) 108回 1140 - 1140 2020.12

Joint Work

脱細胞化臓器骨格を用いた腎臓再生

八木洋, 黒田康平, 田島一樹, 蛭川和也, 水野隆一, 大家基嗣, 北川雄光

日本泌尿器科学会総会 ((一社)日本泌尿器科学会総会事務局) 108回 878 - 878 2020.12

Joint Work

Treatment-free survival after discontinuation of immno-checkpoint therapy, and outcome of subsequent molecular targeted therapy: retrospective study of Japanese metastatic renal cell carcinoma patients(AFTER I-O study)(和訳中)

山名一寿, 大家基嗣, 木村剛, 深沢賢, 沼倉一幸, 杉山豊, 内藤整, 加峰弘毅, 田嶋洋平, 冨田善彦

日本泌尿器科学会総会 ((一社)日本泌尿器科学会総会事務局) 108回 ( 6 ) 675 - 675 2020.12

ISSN 0732-183X

Efficacy and safety of darolutamide in Japanese patients with nonmetastatic castration-resistant prostate cancer: a sub-group analysis of the phase III ARAMIS trial.

Hiroji Uemura, Hisashi Matsushima, Kazuki Kobayashi, Hiroya Mizusawa, Hiroaki Nishimatsu, Karim Fizazi, Matthew Smith, Neal Shore, Teuvo Tammela, Ken-Ichi Tabata, Nobuaki Matsubara, Masahiro Iinuma, Hirotsugu Uemura, Mototsugu Oya, Tetsuo Momma, Mutsushi Kawakita, Satoshi Fukasawa, Tadahiro Kobayashi, Iris Kuss, Marie-Aude Le Berre, Amir Snapir, Toni Sarapohja, Kazuhiro Suzuki

International journal of clinical oncology (SPRINGER JAPAN KK) 26 ( 3 ) 578 - 590 2020.11

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: Darolutamide, an oral androgen receptor inhibitor, has been approved for treating nonmetastatic castration-resistant prostate cancer (nmCRPC), based on significant improvements in metastasis-free survival (MFS) in the ARAMIS clinical trial. Efficacy and safety of darolutamide in Japanese patients are reported here. METHODS: In this randomized, double-blind, placebo-controlled phase III trial, 1509 patients with nmCRPC and prostate-specific antigen (PSA) doubling time ≤ 10 months were randomized 2:1 to darolutamide 600 mg twice daily or matched placebo while continuing androgen deprivation therapy. The primary endpoint was MFS. RESULTS: In Japan, 95 patients were enrolled and randomized to darolutamide (n = 62) or placebo (n = 33). At the primary analysis (cut-off date: September 3, 2018), after 20 primary end-point events had occurred, median MFS was not reached with darolutamide vs. 18.2 months with placebo (HR 0.28, 95% CI 0.11-0.70). Median OS was not reached due to limited numbers of events in both groups but favored darolutamide in the Japanese subgroup. Time to pain progression, time to PSA progression, and PSA response also favored darolutamide. Among Japanese patients randomized to darolutamide vs. placebo, incidences of treatment-emergent adverse events (TEAEs) were 85.5 vs. 63.6%, and incidences of treatment discontinuation due to TEAEs were 8.1 vs. 6.1%. CONCLUSIONS: Efficacy outcomes favored darolutamide in Japanese patients with nmCRPC, supporting the clinical benefit of darolutamide in this patient population. Darolutamide was well tolerated; however, due to the small sample size, it is impossible to conclude with certainty whether differences in the safety profile exist between Japanese and overall ARAMIS populations.

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特集泌尿器科医のためのクリニカル・パール-いま伝えたい箴言・格言・アフォリズム〈下部尿路機能障害/小児・女性・アンドロロジー/結石・感染症/腎不全編〉企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 74 ( 12 ) 903 - 903 2020.11

ISSN 0385-2393

Proton pump inhibitors may hinder hypophosphatemic effect of lanthanum carbonate, but not of ferric citrate hydrate or sucroferric oxyhydroxide, in hemodialysis patients.

Hitoshi Minakuchi, Tadashi Yoshida, Noriko Kaburagi, Teppei Fujino, Sho Endo, Tomoko Yamashita Takemitsu, Norimasa Yamashita, Hiroshi Itoh, Mototsugu Oya

Renal failure (TAYLOR & FRANCIS LTD) 42 ( 1 ) 799 - 806 2020.11

Research paper (scientific journal), Joint Work, ISSN 0886-022X

Because end-stage renal disease patients undergoing hemodialysis frequently take acid suppressants for the treatment or prevention of gastrointestinal diseases, it is important to clarify the drug-interactions between acid suppressants and phosphate binders on the control of serum phosphate levels. In the present study, we examined whether the phosphate-lowering effects of three phosphate binders, lanthanum carbonate (LC), ferric citrate hydrate (FCH), and sucroferric oxyhydroxide (SFOH), were affected by proton pump inhibitors (PPIs) in maintenance hemodialysis patients. Laboratory data for 71 patients who had been newly prescribed one of the three phosphate binders were examined. LC at a dosage of 500 ± 217 mg/day significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 9), while a dosage of 700 ± 230 mg/day only decreased it by -3% in the presence of a PPI (n = 10). Thus, the efficacy of LC in reducing serum phosphate levels was significantly hindered by the presence of PPIs. FCH significantly decreased serum phosphate levels by -18% in the absence of a PPI (n = 7, FCH: 571 ± 189 mg/day) and by -17% in the presence of a PPI (n = 20, FCH: 638 ± 151 mg/day). The decrease in serum phosphate levels by SFOH (393 ± 197 mg/day) was -7% in the absence of a PPI (n = 7), and SFOH at a dosage of 556 ± 316 mg/day significantly decreased serum phosphate levels by -13% in the presence of a PPI (n = 18). These results suggest that the phosphate-lowering effect of LC, but not of FCH or SFOH, is diminished in the presence of PPIs in hemodialysis patients.

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Difficulty in differential diagnosis for renal cancer with microscopic papillary architecture: overlapped pathological features among papillary renal cell carcinoma (RCC), mutinous tubular and spindle cell carcinoma, and unclassified RCC. Lessons from a Japanese multicenter study.

Keiichi Ito, Shuji Mikami, Naoto Kuroda, Yoji Nagashima, Katsunori Tatsugami, Naoya Masumori, Tsunenori Kondo, Toshio Takagi, Shotaro Nakanishi, Masatoshi Eto, Tomomi Kamba, Yoshihiko Tomita, Hideyasu Matsuyama, Tomoyasu Tsushima, Hayakazu Nakazawa, Mototsugu Oya, Go Kimura, Nobuo Shinohara, Tomohiko Asano

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 50 ( 11 ) 1313 - 1320 2020.10

Research paper (scientific journal), Joint Work, ISSN 0368-2811

OBJECTIVES: In our multicenter study evaluating metastatic papillary renal cell carcinoma (PRCC), 29% of tumors diagnosed as PRCC in collaborative institutes were finally diagnosed as other RCCs under central review. In those tumors, mucinous tubular and spindle cell carcinoma (MTSCC) was the leading histology, followed by unclassified RCC (ucRCC). We focused on those patients with MTSCC or ucRCC. METHODS: We reviewed the processes for the pathological diagnoses of nine tumors and reviewed their clinical features. RESULTS: All of the MTSCCs and ucRCCs were positive for AMACR, which is frequently positive in PRCC. Mucin was demonstrated in 80% of the MTSCCs, and its presence is important for their diagnoses. One MTSCC was diagnosed as a mucin-poor variant. The presence of spindle cells with low-grade nuclei was suggestive of MTSCC, but the diagnosis of high-grade MTSCC was difficult. Four tumors were diagnosed as ucRCC by histological and immunohistochemical findings. Three of the four tumors were suspicious of ucRCC in the initial review due to atypical findings as PRCC. Sunitinib and interferon-α were effective for one MTSCC patient who survived for >5 years. Two MTSCC patients who were Memorial Sloan-Kettering Cancer Center poor risk had unfavorable prognoses. One patient with mucin-poor MTSCC had an indolent clinical course. Two of four ucRCC patients showed durable stable disease with targeted agents (TAs) and survived >3 years. CONCLUSION: Some MTSCC metastases progressed very slowly and poor-risk tumors progressed rapidly. Systemic therapies including TAs showed some efficacies. Some patients who have metastatic ucRCC with microscopic papillary architecture can benefit from TAs.

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特集泌尿器科医のためのクリニカル・パール-いま伝えたい箴言・格言・アフォリズム〈腫瘍/処置・救急・当直編〉企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 74 ( 11 ) 815 - 815 2020.10

ISSN 0385-2393

CDK12 and HER2 coamplification in two urothelial carcinomas with rapid and aggressive clinical progression.

Yoshinori Yanai, Takeo Kosaka, Kohei Nakamura, Eriko Aimono, Kazuhiro Matsumoto, Shinya Morita, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Cancer science (WILEY) 111 ( 12 ) 4652 - 4655 2020.10

Research paper (scientific journal), Joint Work, ISSN 1347-9032

Cyclin-dependent kinase 12 (CDK12), one of the key factors associated with DNA damage response pathways, is located on chromosome 17 proximal to Erb-B2 receptor tyrosine kinase 2 (ERBB2). In this report, CDK12 and ERBB2 coamplification was detected by targeted next-generation sequencing in two urothelial carcinomas. The staining intensity of the CDK12 and human epidermal growth factor receptor-2 proteins was associated with the prognosis of each urothelial carcinoma case. Our results suggest that CDK12 coamplification with ERBB2 might be associated with tumor aggressiveness and contribution to cancer pathogenesis. Therapies targeting CDK12 should be developed for these patients.

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Can random bladder biopsies be eliminated after bacillus Calmette-Guérin therapy against carcinoma in situ?

Kimiharu Takamatsu, Kazuhiro Matsumoto, Eiji Kikuchi, Koichiro Ogihara, Nozomi Hayakawa, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Shuji Mikami, Masafumi Oyama, Mototsugu Oya

International urology and nephrology (SPRINGER) 53 ( 3 ) 465 - 469 2020.10

Research paper (scientific journal), Joint Work, ISSN 0301-1623

PURPOSE: Intravesical bacillus Calmette-Guérin (BCG) is the standard of care for bladder carcinoma in situ (CIS). The response to BCG therapy against CIS is generally assessed by random bladder biopsy (RBB). In this study, we examined the necessity of routine RBB after BCG therapy. METHODS: We retrospectively identified 102 patients who were initially diagnosed with CIS with or without papillary tumor and received subsequent 6-8-week BCG therapy. Thereafter, all patients underwent voiding cytology analysis, cystoscopy, and RBB to evaluate the effects of BCG therapy. We evaluated the association between clinical parameters (voiding cytology and cystoscopy findings) and the final pathological results by RBB specimens. RESULTS: According to the pathological results of RBB, 30 (29%) patients had BCG-unresponsive disease (remaining urothelial carcinoma was confirmed pathologically) and 20 were diagnosed with CIS. Positive/suspicious voiding cytology and positive cystoscopy findings were well observed in patients who had BCG-unresponsive disease compared with their counterparts (p = 0.116, and p < 0.001, respectively). The sensitivity (Sen.), specificity (Spe.), positive predictive value (PPV), and negative predictive value (NPV) of voiding cytology were 50%, 68%, 39%, and 77%, respectively. The values for cystoscopy findings were as follows: Sen.: 87%, Spe.: 57%, PPV: 46%, and NPV: 91%. The values for their combination (having either of them) were as follows: Sen.: 100%, Spe.: 44%, PPV: 43%, and NPV: 100%. CONCLUSION: RBB after BCG therapy for patients with negative voiding cytology and negative cystoscopy may be omitted because their risk of BCG-unresponsive disease is significantly low (NPV: 100%).

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Factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy for clinical T1a renal masses.

Toshikazu Takeda, Akari Komatsuda, Yoshinori Yanai, Nobuyuki Tanaka, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Toshiaki Shinojima, Hiroshi Asanuma, Mototsugu Oya

Asian journal of endoscopic surgery (WILEY) 13 ( 4 ) 526 - 531 2020.10

Research paper (scientific journal), Joint Work, ISSN 1758-5902

INTRODUCTION: The goal of partial nephrectomy for renal tumors is complete tumor removal with the preservation of renal function and no complications. Trifecta (total ischemia time < 25 minutes, negative surgical margins, and no surgical complications) is widely used to evaluate success after partial nephrectomy. We investigated factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. METHODS: Sixty-six patients who underwent laparoscopic partial nephrectomy for clinical T1a renal masses between December 2006 and March 2016 were examined. We defined preserved renal function as the preservation of an estimated glomerular filtration rate ≥ 90% 1 year after surgery. We examined factors affecting renal function preservation among patients not achieving trifecta after laparoscopic partial nephrectomy. RESULTS: Thirty out of 66 patients (45%) did not achieve trifecta. In an evaluation of 66 patients, a multivariate analysis identified tumor size (P = .04) as an independent predictor affecting the achievement of trifecta. Tumor size was significantly smaller in the trifecta achievement group (1.9 ± 0.1 cm) than in the non-achievement group (2.2 ± 0.6 cm) (P = .04). We found that renal function was preserved 1 year after surgery in 14 out of the 30 patients not achieving trifecta. In univariate analysis, age (P = .01) was significantly associated with affecting the preservation of renal function among these patients. Patients with preserved renal function were significantly younger (47.8 ± 2.5 years) than those without (58.5 ± 2.9 years) (P = .01). CONCLUSION: Renal function may be preserved in younger patients even if they do not achieve trifecta after partial nephrectomy for small renal masses.

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Significance of tumor microenvironment in acquiring resistance to vascular endothelial growth factor-tyrosine kinase inhibitor and recent advance of systemic treatment of clear cell renal cell carcinoma.

Shuji Mikami, Ryuichi Mizuno, Takeo Kosaka, Nobuyuki Tanaka, Naoto Kuroda, Yoji Nagashima, Yasunori Okada, Mototsugu Oya

Pathology international (WILEY) 70 ( 10 ) 712 - 723 2020.10

Research paper (scientific journal), Joint Work, ISSN 1320-5463

The development of systemic therapies, including vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKI) and mammalian target of rapamycin (mTOR) inhibitors, represents a major breakthrough in the treatment of patients with renal cell carcinoma (RCC). However, inherent resistance is observed in some patients and acquired resistance commonly develops in many patients within several months of the initiation of systemic therapies. Since these treatments rarely cure patients, their aim is to suppress tumor progression and prolong survival. Therefore, the establishment of dependable criteria that predict responses and resistance to systemic therapies is clinically important, and the underlying molecular mechanisms also need to be elucidated for the future development of more effective therapies. We herein review recent advances in research on the molecular mechanisms underlying resistance, with a focus on morphological characteristics, tumor angiogenesis, and the tumor immune microenvironment in RCC and their relationships with VEGF-TKI treatments. Recent therapies using immune checkpoint inhibitors (ICI) and newly developed VEGF-TKI also appear to be effective for advanced RCC, with stable and durable responses to ICI being observed in some RCC patients. These new drugs and their outcomes have been briefly described.

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尿路上皮癌細胞のおける細胞内代謝リプログラミング機構と抗癌剤耐性機序との関連

茂田啓介, 長谷川政徳, 菊地栄次, 小坂威雄, 水野隆一, 大家基嗣

日本癌学会総会記事 ((一社)日本癌学会) 79回 OJ1 - 3 2020.10

Joint Work, ISSN 0546-0476

Prioritising Urological Surgery in the COVID-19 Era: A Global Reflection on Guidelines.

Stavros Gravas, Georges Fournier, Mototsugu Oya, Duncan Summerton, Roberto Mario Scarpa, Piotr Chlosta, Ioannis Gkialas, Li-Ping Xie, Nur Rasyid, Damien Bolton, Reynaldo Gomez, Laurence Klotz, Sanjay Kulkarni, Simon Tanguay, Jean de la Rosette

European urology focus (ELSEVIER) 6 ( 5 ) 1104 - 1110 2020.09

Research paper (scientific journal), Joint Work

BACKGROUND: Determining whether members follow guidelines, including guidelines prepared to help direct practice management during the coronavirus disease 2019 (COVID-19) pandemic, is an important goal for medical associations. OBJECTIVE: To determine whether practice of urologists is in line with guidelines for the management of common urological conditions during the COVID-19 pandemic produced by leading (inter)national urological associations. DESIGN, SETTING, AND PARTICIPANTS: Self-selected urologists completed a voluntary survey available online from March 27 to April 11, 2020 and distributed globally by the Société Internationale d'Urologie. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Responses to two survey questions on the (1) management of 14 common urological procedures and (2) priority scoring of 10 common urological procedures were evaluated by practice setting and geographical region using chi-square and one-way analysis of variance analyses, respectively. RESULTS AND LIMITATIONS: There were 2494 respondents from 76 countries. Oncological conditions were prioritised over benign conditions, and benign conditions were deferred when feasible and safe. Oncological conditions with the greatest malignant potential were prioritised over less aggressive cancers. Respondents from Europe were least likely to postpone and most likely to prioritise conditions identified by guidelines as being of the highest priority. Respondents' priority scoring of urological procedures closely matched the priorities assigned by guidelines. The main limitation of this study is that respondents were self-selected, and access to the survey was limited by language and technology barriers. CONCLUSIONS: Prioritisation and management of urological procedures during the COVID-19 pandemic are in line with current guidelines. The greatest agreement was reported in Europe. Observed differences may be related to limited resources in some settings. PATIENT SUMMARY: When deciding how best to treat patients during the coronavirus disease 2019 (COVID-19) pandemic, urologists are taking into account both expert recommendations and the availability of important local resources.

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Significance of prophylactic urethrectomy at the time of radical cystectomy for bladder cancer.

Kyohei Hakozaki, Eiji Kikuchi, Koichiro Ogihara, Keisuke Shigeta, Takayuki Abe, Yasumasa Miyazaki, Gou Kaneko, Takahiro Maeda, Shunsuke Yoshimine, Kunimitsu Kanai, Hiroki Ide, Suguru Shirotake, Masafumi Oyama, Ryuichi Mizuno, Mototsugu Oya

Japanese journal of clinical oncology (Japanese journal of clinical oncology) 51 ( 2 ) 287 - 295 2020.09

Research paper (scientific journal), Joint Work, ISSN 0368-2811

BACKGROUND: Prophylactic urethrectomy at the time of radical cystectomy is frequently recommended for patients with bladder cancer at a high risk of urethral recurrence without definitive evidence. The present study attempted to clarify the survival benefits of performing prophylactic urethrectomy. METHODS: We identified 214 male patients who were treated by radical cystectomy with an incontinent urinary diversion in our seven institutions between 2004 and 2017. We used propensity score matching and ultimately identified 114 patients, 57 of whom underwent prophylactic urethrectomy (prophylactic urethrectomy group) and 57 who did not (non-prophylactic urethrectomy group). RESULTS: No significant differences were observed in the 5-year overall survival rate between the prophylactic urethrectomy and non-prophylactic urethrectomy groups in the overall. However, the local recurrence rate was significantly lower in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.015). In the subgroup of 58 patients with multiple tumours and/or concomitant carcinoma in situ at the time of transurethral resection of bladder tumour, the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.021). A multivariate analysis revealed that performing prophylactic urethrectomy was the only independent predictor of the overall survival rate (P = 0.016). In those patients who were treated without neoadjuvant chemotherapy (n = 38), the 5-year overall survival rate was significantly higher in the prophylactic urethrectomy group than in the non-prophylactic urethrectomy group (P = 0.007). CONCLUSIONS: Prophylactic urethrectomy at the time of radical cystectomy may have a survival benefit in patients with multiple tumours and/or concomitant carcinoma in situ, particularly those who do not receive neoadjuvant chemotherapy.

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Relationship between radiation doses and erectile function deterioration in patients with localized prostate cancer treated with permanent prostate brachytherapy.

Keisuke Shigeta, Eiji Kikuchi, Masashi Matsushima, Koichiro Ogihara, Takeo Kosaka, Ryuichi Mizuno, Tomoki Tanaka, Naoyuki Shigematsu, Mototsugu Oya

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 12 ) 1087 - 1093 2020.09

Research paper (scientific journal), Joint Work, ISSN 0919-8172

OBJECTIVES: To investigate the relationship between radiation doses in prostate brachytherapy and deterioration of erectile function in patients with localized prostate cancer. METHODS: A longitudinal survey study was carried out among 261 prostate cancer patients who received prostate brachytherapy. A total of 48 patients were potent at baseline and they did not receive any supplemental therapy preoperatively. Dosimetry parameters of the whole prostate gland, prostate apex, urethra and rectum were collected using the VariSeed 8.0 treatment planning system (Varian Medical Systems, Palo Alto, CA, USA). We carried out a logistic regression analysis to clarify the relationship between radiation doses and erectile function deterioration, which was assessed using the International Index of Erectile Function-15 questionnaire. RESULTS: The median patient age was 66 years (range 53-70 years) with a median follow-up time of 44 months (36-71 months). The mean total International Index of Erectile Function-15 score decreased from 49.9 at baseline to 34.7 after 12 months (P < 0.001), but gradually plateaued within 36 months. Erectile function deterioration was noted in 32 (66.7%) patients 36 months after prostate brachytherapy. In an analysis of risk factors for erectile function deterioration after prostate brachytherapy, age ≥70 years (P = 0.029), prostate V100 ≥95% (P = 0.024), apex V100 ≥95% (P = 0.024), apex V150 ≥70% (P = 0.009) and apex D90 ≥150 Gy (P = 0.011) correlated with erectile function deterioration. A multivariate analysis identified an age of ≥70 years (odds ratio 7.91, P = 0.024) and apex V150 ≥70% (odds ratio 7.75, P = 0.007) as independent risk factors for erectile function deterioration after prostate brachytherapy. CONCLUSIONS: An excessive radiation dose, particularly to the prostate apex area, and an advanced age might have a negative impact on the preservation of potency after prostate brachytherapy.

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Influence of chemoradiotherapy on nutritional status in locally advanced rectal cancer: Prospective multicenter study

Yamano Tomoki, Tomita Naohiro, Sato Takeo, Hayakawa Kazushige, Kamikonya Norihiko, Matoba Shuichiro, Uki Akiyoshi, Baba Hideo, Oya Natsuo, Hasegawa Hirotoshi, Shigematsu Naoyuki, Hiraoka Masahiro, Shimada Mitsuo, Noda Masafumi, Sakai Yoshiharu, Sato Hirohiko, Saegusa Makoto, Takeuchi Masahiro, Oguchi Masahiko, Oya Masatoshi, Watanabe Masahiko

NUTRITION 77 2020.09

ISSN 0899-9007

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Three-dimensional single-cell imaging for the analysis of RNA and protein expression in intact tumour biopsies.

Nobuyuki Tanaka, Shigeaki Kanatani, Dagmara Kaczynska, Keishiro Fukumoto, Lauri Louhivuori, Tomohiro Mizutani, Oded Kopper, Pauliina Kronqvist, Stephanie Robertson, Claes Lindh, Lorand Kis, Robin Pronk, Naoya Niwa, Kazuhiro Matsumoto, Mototsugu Oya, Ayako Miyakawa, Anna Falk, Johan Hartman, Cecilia Sahlgren, Hans Clevers, Per Uhlén

Nature biomedical engineering (NATURE PUBLISHING GROUP) 4 ( 9 ) 875 - 888 2020.09

Research paper (scientific journal), Joint Work, ISSN 2157-846X

Microscopy analysis of tumour samples is commonly performed on fixed, thinly sectioned and protein-labelled tissues. However, these examinations do not reveal the intricate three-dimensional structures of tumours, nor enable the detection of aberrant transcripts. Here, we report a method, which we name DIIFCO (for diagnosing in situ immunofluorescence-labelled cleared oncosamples), for the multimodal volumetric imaging of RNAs and proteins in intact tumour volumes and organoids. We used DIIFCO to spatially profile the expression of diverse coding RNAs and non-coding RNAs at the single-cell resolution in a variety of cancer tissues. Quantitative single-cell analysis revealed spatial niches of cancer stem-like cells, and showed that the niches were present at a higher density in triple-negative breast cancer tissue. The improved molecular phenotyping and histopathological diagnosis of cancers may lead to new insights into the biology of tumours of patients.

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Pyometra in a hemodialysis patient with severe constipation.

Kohkichi Morimoto, Tadashi Yoshida, Mototsugu Oya

Clinical and experimental nephrology (SPRINGER) 24 ( 9 ) 849 - 849 2020.09

Research paper (scientific journal), Joint Work, ISSN 1342-1751

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Evaluating the Oncological Outcomes of Pure Laparoscopic Radical Nephroureterectomy Performed for Upper-Tract Urothelial Carcinoma Patients: A Multicenter Cohort Study Adjusted by Propensity Score Matching.

Keisuke Shigeta, Kazuhiro Matsumoto, Toshikazu Takeda, Seiya Hattori, Gou Kaneko, Masashi Matsushima, Takayuki Abe, Nobuyuki Tanaka, Ryuichi Mizuno, Hiroshi Asanuma, Eiji Kikuchi, Mototsugu Oya

Annals of surgical oncology (SPRINGER) 28 ( 1 ) 465 - 473 2020.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 1068-9265

PURPOSE: To evaluate the oncological feasibility of pure laparoscopic radical nephroureterectomy (p-LRNU) for upper tract urothelial carcinoma (UTUC) compared with conventional LRNU (c-LRNU) using a propensity-adjusted multi-institutional collaboration dataset. METHODS: Among the 503 UTUC patients who underwent RNU, we identified 219 who underwent c-LRNU (laparoscopic nephrectomy with open bladder cuff resection) and 72 who underwent p-LRNU (dissecting the kidney, ureter, and bladder cuff under complete laparoscopy). We adopted a propensity score (PS) matching method to achieve homogeneity with respect to patient backgrounds. PS matching-adjusted Cox-regression analysis was performed to evaluate the risk factors that influenced oncological outcomes. RESULTS: Sixty-eight p-LRNU and 68 c-LRNU patients were matched. Overall, 51 (37.0%) developed intravesical recurrence (IVR), 21 (15.4%) had disease recurrence, and 20 (14.7%) died. Patients who underwent p-LRNU had a significantly shorter operation time and less blood loss than those who underwent c-LRNU. Although no significant differences in 3-year recurrence-free survival were found between the two methods, atypical recurrence sites were observed in the p-LRNU group, including the brain, sigmoid colon, vagina, and peritoneum. Regarding IVR, the 3-year IVR-free survival rate was 41.8% in the p-LRNU group, which was significantly lower than that in the c-LRNU group (66.6%, p = 0.004). Multivariate analysis demonstrated that a history of bladder cancer, ureteral cancer, and p-LRNU were independent risk factors for subsequent IVR. CONCLUSION: Although p-LRNU is less invasive, the current technique may increase the incidence of atypical disease recurrence and subsequent IVR due to extravesical and intravesical tumor dissemination.

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Clinical utility of the Vesical Imaging-Reporting and Data System for muscle-invasive bladder cancer between radiologists and urologists based on multiparametric MRI including 3D FSE T2-weighted acquisitions.

Yuki Arita, Keisuke Shigeta, Hirotaka Akita, Tatsuya Suzuki, Ryohei Kufukihara, Thomas C Kwee, Ryota Ishii, Shuji Mikami, Shigeo Okuda, Eiji Kikuchi, Mototsugu Oya, Masahiro Jinzaki

European radiology (SPRINGER) 31 ( 2 ) 875 - 883 2020.08

Research paper (scientific journal), Joint Work, ISSN 0938-7994

OBJECTIVES: To investigate the clinical utility of the Vesical Imaging-Reporting and Data System (VI-RADS) by comparing its diagnostic performance for muscle-invasive bladder cancer (MIBC) between radiologists and urologists based on multiparametric MRI, including three-dimensional (3D) fast spin-echo (FSE) T2-weighted acquisitions. METHODS: This study included 66 treatment-naïve patients (60 men, 6 women; mean age 74.0 years) with pathologically proven bladder cancer who underwent multiparametric MRI, including 3D FSE T2-weighted imaging, before transurethral bladder tumour resection between January 2010 and November 2018. The MRI scans were categorised according to the five-point VI-RADS score by four independent readers (two board-certified radiologists and board-certified urologists each), blinded to the histopathological findings. The VI-RADS scores were compared with the postoperative histopathological diagnosis. Interobserver agreement was assessed using weighted kappa coefficients. ROC analysis and generalised estimating equations were used to evaluate the diagnostic performance. RESULTS: Forty-nine (74.2%) and 17 (25.8%) tumours were confirmed to be non-MIBC and MIBC, respectively, based on pathological examination. The interobserver agreement was good-to-excellent between all pairs of readers (range, 0.73-0.91). The urologists' sensitivity/specificity values for DCE-MRI VI-RADS scores were significantly lower than those of radiologists. No significant differences were observed for the overall VI-RADS score. The AUC for the overall VI-RADS score was 0.94, 0.92, 0.89, and 0.87 for radiologists 1 and 2 and urologists 1 and 2, respectively. CONCLUSIONS: The VI-RADS score, based on multiparametric MRI including 3D FSE T2-weighted acquisitions, can be useful for radiologists and urologists to determine the bladder cancer muscle invasion status preoperatively. KEY POINTS: • VI-RADS (using multiparametric MRI including 3D FSE T2-weighted acquisitions) achieves good to excellent interobserver agreement and has similar diagnostic performance for detecting muscle invasion by both radiologists and urologists. • The diagnostic performance of the overall VI-RADS score is high for both radiologists and urologists, particularly due to the dominant effect of diffusion-weighted imaging on the overall VI-RADS score. • The sensitivity and specificity values of the T2WI VI-RADS scores for four readers in our study (using 3D FSE T2-weighted acquisitions) were similar (with slightly higher specificity values) to previously published results (using 2D FSE T2-weighted acquisitions).

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ASO Author Reflections: Discussing the Oncological Feasibility of Performing Pure Laparoscopic Radical Nephroureterectomy for Upper-Tract Urothelial Carcinoma Patients: Results from a Multi-institution Collaborative Study Adjusted by Propensity Score Matching.

Keisuke Shigeta, Kazuhiro Matsumoto, Mototsugu Oya

Annals of surgical oncology (SPRINGER) 28 ( 1 ) 474 - 475 2020.08

Research paper (scientific journal), Joint Work, ISSN 1068-9265

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Reduced recurrence of low-risk non-muscle-invasive bladder cancer is associated with low urine-specific gravity.

Tomohiro Iwasawa, Naoya Niwa, Kazuhiro Matsumoto, Akari Komatsuda, Hiroki Ide, Mototsugu Oya

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 11 ) 1019 - 1023 2020.08

Research paper (scientific journal), Joint Work, ISSN 0919-8172

OBJECTIVE: To investigate the association between urine-specific gravity and oncological outcomes in patients with non-muscle-invasive bladder cancer. METHODS: We identified 433 primary non-muscle-invasive bladder cancer patients who underwent transurethral resection between 2002 and 2016. The association between urine-specific gravity and tumor recurrence was statistically evaluated. RESULTS: A total of 211 (48.7%) patients received adjuvant bacillus Calmette-Guérin therapy. During the median follow-up period of 60 months, 155 (35.8%) patients experienced at least one tumor recurrence. Of them all, 95 (21.9%) and 338 (78.1%) patients had high (>1.020) and low (≤1.020) urine-specific gravity, respectively. The Kaplan-Meier curve suggested that recurrence-free survival was significantly lower in patients with a high urine-specific gravity; however, the multivariate analysis failed to show that urine-specific gravity is significantly associated with tumor recurrence. In 222 (51.3%) patients who had not received bacillus Calmette-Guérin therapy, the Kaplan-Meier curve also suggested that recurrence-free survival was significantly lower in patients with a high urine-specific gravity. Multivariate analysis showed that age >70 years (hazard ratio 1.69, P = 0.02), grade 3 tumor (hazard ratio 1.81, P = 0.03) and high urine-specific gravity (hazard ratio 1.87, P < 0.01) were independent risk factors for tumor recurrence. CONCLUSION: High urine-specific gravity is an independent risk factor for tumor recurrence in non-muscle-invasive bladder cancer patients who have not received bacillus Calmette-Guérin therapy. Our results suggest that hydration status might have some clinical impacts on bladder tumor recurrence.

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Cabozantinib in advanced renal cell carcinoma: A phase II, open-label, single-arm study of Japanese patients.

Yoshihiko Tomita, Katsunori Tatsugami, Noboru Nakaigawa, Takahiro Osawa, Mototsugu Oya, Hiroomi Kanayama, Chihiro Nakayama Kondoh, Naoto Sassa, Kazuo Nishimura, Masahiro Nozawa, Naoya Masumori, Yasuhide Miyoshi, Shingo Kuroda, Shingo Tanaka, Akiko Kimura, Satoshi Tamada

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 11 ) 952 - 959 2020.08

Research paper (scientific journal), Joint Work, ISSN 0919-8172

OBJECTIVES: To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy. METHODS: This phase II, open-label, single-arm study (ClinicalTrials.gov registration number: NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60 mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8-week stable disease), progression-free survival, overall survival and safety. RESULTS: Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively. The median duration of cabozantinib exposure was 27.0 weeks (range 5.1-43.0 weeks). The objective response rate was 20.0% (90% confidence interval 9.8-34.3%), and the clinical benefit rate was 85.7% (95% confidence interval 69.7-95.2%). The 6-month estimated progression-free survival was 72.3% (95% confidence interval 53.3-84.6%); the median progression-free survival and overall survival were not reached. All patients reported adverse events, which were manageable by supportive treatment or dose modification; two patients (5.7%) discontinued therapy due to adverse events. CONCLUSIONS: The results showed that findings from METEOR can be extrapolated, and that cabozantinib 60 mg/day is a viable treatment option in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.

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Dehydroxymethylepoxyquinomicin, a novel nuclear factor-κB inhibitor, prevents the development of cyclosporine A nephrotoxicity in a rat model.

Shinya Morita, Kazunobu Shinoda, Tadashi Yoshida, Masayuki Shimoda, Yoshihiko Kanno, Ryuichi Mizuno, Hidaka Kono, Hiroshi Asanuma, Ken Nakagawa, Kazuo Umezawa, Mototsugu Oya

BMC pharmacology & toxicology (BMC) 21 ( 1 ) 60 - 60 2020.08

Research paper (scientific journal), Joint Work

BACKGROUND: Cyclosporine A (CsA) is an essential immunosuppressant in organ transplantation. However, its chronic nephrotoxicity is an obstacle to long allograft survival that has not been overcome. Nuclear factor-κB (NF-κB) is activated in the renal tissue in CsA nephropathy. In this study, we aimed to investigate the effect of the specific NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), in a rat model of CsA nephrotoxicity. METHODS: We administered CsA (15 mg/kg) daily for 28 days to Sprague-Dawley rats that underwent 5/6 nephrectomy under a low-salt diet. We administered DHMEQ (8 mg/kg) simultaneously with CsA to the treatment group, daily for 28 days and evaluated its effect on CsA nephrotoxicity. RESULTS: DHMEQ significantly inhibited NF-κB activation and nuclear translocation due to CsA treatment. Elevated serum urea nitrogen and creatinine levels due to repeated CsA administration were significantly decreased by DHMEQ treatment (serum urea nitrogen in CsA + DHMEQ vs CsA vs control, 69 ± 6.4 vs 113.5 ± 8.8 vs 43.1 ± 1.1 mg/dL, respectively, p < 0.0001; serum creatinine in CsA + DHMEQ vs CsA vs control, 0.75 ± 0.02 vs 0.91 ± 0.02 vs 0.49 ± 0.02 mg/dL, respectively, p < 0.0001), and creatinine clearance was restored in the treatment group (CsA + DHMEQ vs CsA vs control, 2.57 ± 0.09 vs 1.94 ± 0.12 vs 4.61 ± 0.18 ml/min/kg, respectively, p < 0.0001). However, DHMEQ treatment did not alter the inhibitory effect of CsA on urinary protein secretion. The development of renal fibrosis due to chronic CsA nephrotoxicity was significantly inhibited by DHMEQ treatment (CsA + DHMEQ vs CsA vs control, 13.4 ± 7.1 vs 35.6 ± 18.4 vs 9.4 ± 5.4%, respectively, p < 0.0001), and these results reflected the results of renal functional assessment. DHMEQ treatment also had an inhibitory effect on the increased expression of chemokines, monocyte chemoattractant protein-1, and chemokine (c-c motif) ligand 5 due to repeated CsA administration, which inhibited the infiltration of macrophages and neutrophils into the renal tissue. CONCLUSIONS: These findings suggest that DHMEQ treatment in combination therapy with CsA-based immunosuppression is beneficial to prevent the development of CsA-induced nephrotoxicity.

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Evaluation of Gleason Grade Group 5 in a Contemporary Prostate Cancer Grading System and Literature Review.

Rei Kamitani, Kazuhiro Matsumoto, Takeo Kosaka, Toshikazu Takeda, Akinori Hashiguchi, Nobuyuki Tanaka, Shinya Morita, Ryuichi Mizuno, Toshiaki Shinojima, Hiroshi Asanuma, Mototsugu Oya

Clinical genitourinary cancer (Clinical Genitourinary Cancer) 19 ( 1 ) 69 - 75.e5 2020.08

Research paper (scientific journal), Joint Work, ISSN 1558-7673

INTRODUCTION: The aim of this study was to validate contemporary grading systems, in particular, the Gleason grade group (GGG) 5. PATIENTS AND METHODS: We retrospectively reviewed the clinicopathologic data of 176 patients who underwent radical prostatectomy and whose pathologic results were GGG 4 or 5. The endpoints were biochemical recurrence (BCR) and castration-resistant prostate cancer (CRPC). RESULTS: The GGG 4 group was composed of 69 patients. The GGG 5 group consisted of 78 patients with GS 4+5 and 29 patients with GS 5+4 or higher. The 5-year BCR-free survival rates for men with GGG 4, GS 4+5, and GS 5+4 or higher were 59%, 54%, and 20%, respectively, and the 5-year CRPC-free survival rates were 98%, 100%, and 88%, respectively. Both the BCR- and CRPC-free survival rates were significantly higher in GS 4+5 than in GS 5+4 or higher (P < .001 and P = .002, respectively), but there were no significant differences between GGG 4 and GS 4+5 (P = .702 and P = .803, respectively). The multivariate analysis demonstrated that GS 5+4 or higher (hazard ratio, 3.4; P = .002) and lymphovascular invasion (hazard ratio, 3.4; P < .001) greatly affected BCR. CONCLUSION: Our follow-up study revealed that men with GS 4+5 and those with GGG 4 had a similar prognosis. However, there was a significant discrepancy in prognosis between GS 4+5 and GS 5+4 or higher. This suggested that GGG 4 and 5 in the contemporary prostate cancer grading system should be reviewed. Furthermore, lymphovascular invasion may be useful to subgroup these pathologically high-risk patients.

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A Japanese patient with ductal carcinoma of the prostate carrying an adenomatosis polyposis coli gene mutation: a case report.

Kota Umeda, Takeo Kosaka, Kohei Nakamura, Toshikazu Takeda, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Diagnostic pathology (BMC) 15 ( 1 ) 102 - 102 2020.08

Research paper (scientific journal), Joint Work

BACKGROUND: Ductal carcinoma of the prostate is a histological subtype with a higher mortality than acinar adenocarcinoma. The number of cases is small and there are no treatment guidelines. We believe that this is the first report of ductal carcinoma of the prostate with an adenomatosis polyposis coli (APC) gene mutation in Japan. CASE PRESENTATION: An 85-year-old man presented with gross hematuria, and a papillary tumor in the prostatic urethra that was diagnosed as ductal carcinoma of the prostate following transurethral resection. Genetic analysis found an APC mutation with loss of heterozygosity. Immunostaining revealed focal nuclear translocation of β-catenin. APC mutations associated with loss of β-catenin degradation in the Wnt signaling pathway and result in over accumulation of β-catenin are thought to increase mortality. In this patient, β-catenin migrated into tumor cell nuclei. CONCLUSION: To the best of our knowledge, this is the first report of ductal carcinoma of the prostate with an APC mutation in Japan. The development of a therapeutic Wnt inhibitor is discussed.

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Real-world use of temsirolimus in Japanese patients with unresectable or metastatic renal cell carcinoma: recent consideration based on the results of a post-marketing, all-case surveillance study.

Shigeru Sugiyama, Kazuo Sato, Yoshiyuki Shibasaki, Yutaka Endo, Taku Uryu, Yasuharu Toyoshima, Mototsugu Oya, Naoto Miyanaga, Nagahiro Saijo, Akihiko Gemma, Hideyuki Akaza

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 50 ( 8 ) 940 - 947 2020.08

Research paper (scientific journal), Joint Work, ISSN 0368-2811

OBJECTIVE: A prospective, observational, post-marketing surveillance was conducted to assess the safety and effectiveness of temsirolimus in patients with renal cell carcinoma in Japan. METHODS: Patients prescribed temsirolimus for advanced renal cell carcinoma were registered and received temsirolimus (25 mg weekly, intravenous infusion for 30-60 minutes) in routine clinical settings (observation period: 96 weeks). RESULTS: Among 1001 patients included in the safety analysis data set (median age, 65.0 years; men, 74.8%; Eastern Cooperative Oncology Group performance status 0 or 1, 69.6%), 778 (77.7%) reported adverse drug reactions. The most common (≥10%) all-grade adverse drug reactions were stomatitis (26.7%), interstitial lung disease (17.3%) and platelet count decreased (11.1%). The incidence rate of grade ≥3 interstitial lung disease was 4.5%. The onset of interstitial lung disease was more frequent after 4-8 weeks of treatment or in patients with lower Eastern Cooperative Oncology Group performance status (21.6% for score 0 vs 8.3% for score 4, P < 0.001). Among 654 patients in the effectiveness analysis data set, the response and clinical benefit rates were 6.7% (95% confidence interval 4.9-8.9) and 53.2% (95% confidence interval 49.3-57.1), respectively. The median progression-free survival was 18.3 weeks (95% confidence interval 16.9-21.1). CONCLUSIONS: The safety and effectiveness profile of temsirolimus observed in this study was similar to that observed in the multinational phase 3 study. The results are generalizable to the real-world scenario at the time of this research, and safety and effectiveness of temsirolimus as a subsequent anticancer therapy for renal cell carcinoma warrants further investigation. (ClinicalTrials.gov identifier NCT01210482, NCT01420601).

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A comparison of laparoendoscopic single-site surgery versus conventional procedures for laparoscopic donor nephrectomy: a Japanese multi-institutional retrospective study.

Takamitsu Inoue, Masayoshi Miura, Masaaki Yanishi, Junya Furukawa, Fuminori Sato, Masahiro Nitta, Koji Yoshimura, Jun Hagiuda, Kazunobu Shinoda, Takashi Kobayashi, Akira Miyajima, Ken Nakagawa, Mototsugu Oya, Osamu Ogawa, Hiromitsu Mimata, Hiro-Omi Kanayama, Masato Fujisawa, Toshiro Terachi, Tadashi Matsuda, Tomonori Habuchi

Surgical endoscopy (SPRINGER) 34 ( 8 ) 3424 - 3434 2020.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0930-2794

PURPOSE: Laparoendoscopic single-site donor nephrectomy (LESSDN) is a feasible and effective procedure because of its non-invasiveness and better cosmetic outcomes. However, there have been few multi-institutional studies conducted by multiple surgeons on LESSDN. We retrospectively compared the clinical data and outcomes between LESSDN and conventional laparoscopic donor nephrectomy (LDN) at multiple institutes in Japan. MATERIALS AND METHODS: From 2009 to 2015, the clinical data of 223 donors who underwent LESSDN and 151 donors who underwent LDN were collected from 10 institutes. All LESSDNs were performed transperitoneally, whereas LDNs were performed transperitoneally (P-LDN) in 75 patients and retroperitoneally (R-LDN) in 76 patients. RESULTS: In the LESSDN group, the single-incision site was pararectal in 155 (69.5%) patients and umbilical in 65 (29.1%) patients. Multiple surgeons (one to eight per institute) performed the LESSDN. No significant differences were observed between the three groups regarding estimated blood loss and warm ischemic time. The operative time was significantly shorter in the LESSDN group than in the R-LDN group (p = 0.018). No significant differences were observed regarding the rates of blood transfusion, open conversion, visceral injuries, and postoperative complications. Furthermore, no significant differences were observed regarding the dose of analgesic and the rate of delayed graft function. One patient required open conversion due to injury to the renal artery. Selection of LESS procedure was not an independent risk factor for the median serum creatinine level of above 1.27 mg/dL in recipients at 1 year after kidney transplantation. CONCLUSION: The results showed the technical feasibility of LESSDN compared with the standard LDNs in a multi-institutional and multi-surgeon setting. A few observed non-negligible complications and the significantly higher levels of serum creatinine in patients who underwent LESSDN indicate that this procedure should be employed cautiously when performed by surgeons without ample experience in performing LESS procedures.

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Sunitinib Versus Sorafenib as Initial Targeted Therapy for mCC-RCC With Favorable/Intermediate Risk: Multicenter Randomized Trial CROSS-J-RCC.

Yoshihiko Tomita, Sei Naito, Naoto Sassa, Atsushi Takahashi, Tsunenori Kondo, Takuya Koie, Wataru Obara, Yasuyuki Kobayashi, Jun Teishima, Masayuki Takahashi, Hideyasu Matsuyama, Takeshi Ueda, Kenya Yamaguchi, Takeshi Kishida, Ryoichi Shiroki, Takashi Saika, Nobuo Shinohara, Mototsugu Oya, Hiro-Omi Kanayama

Clinical genitourinary cancer (CIG MEDIA GROUP, LP) 18 ( 4 ) e374 - e385 2020.08

Research paper (scientific journal), Joint Work, ISSN 1558-7673

PURPOSE: The present study compared the efficacy of sunitinib and sorafenib as first-line treatment of metastatic clear cell renal cell carcinoma (mCC-RCC) with favorable or intermediate Memorial Sloan Kettering Cancer Center (MSKCC) risk. PATIENTS AND METHODS: Treatment-naive patients with mCC-RCC were randomized to receive open-label sunitinib followed by sorafenib (SU/SO) or sorafenib followed by sunitinib (SO/SU). The primary endpoint was first-line progression-free survival (PFS). The secondary endpoints were total PFS and overall survival (OS). RESULTS: Of the 124 patients enrolled at 39 institutions from February 2010 to July 2012, 120 were evaluated. The median first-line PFS duration was 8.7 and 7.0 months in the SU/SO and SO/SU groups, respectively (hazard ratio [HR], 0.67; 95% confidence interval [CI], 0.42-1.08). The total PFS and OS were not significantly different between the SU/SO and SO/SU groups (27.8 and 22.6 months; HR, 0.73; 95% CI, 0.428-1.246; and 38.4 and 30.9 months; HR, 0.934; 95% CI, 0.588-1.485, respectively). The subgroup analysis revealed that the total PFS with SU/SO was superior to the total PFS with SO/SU in the patients with favorable MSKCC risk and those with < 5 metastatic sites). SO/SU was superior to SU/SO for patients without previous nephrectomy. CONCLUSIONS: No statistically significant differences were found in first-line PFS, total PFS, or OS between the 2 treatment arms (ClinicalTrials.gov identifier, NCT01481870).

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Umbilical closure using 2-octyl cyanoacrylate in transumbilical laparoscopic adrenalectomy: A randomized controlled trial.

Keishiro Fukumoto, Akira Miyajima, Kazuhiro Matsumoto, Hiroaki Kobayashi, Naoya Niwa, Hiroshi Hongo, Isao Kurihara, Eiji Kikuchi, Mototsugu Oya

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 8 ) 670 - 675 2020.08

Research paper (scientific journal), Joint Work, ISSN 0919-8172

OBJECTIVES: To evaluate postoperative pain and esthetic outcomes in patients undergoing transumbilical laparoscopic adrenalectomy with wound closure using 2-octyl cyanoacrylate. METHODS: A total of 26 patients who underwent laparoscopic adrenalectomy with the transumbilical approach and agreed to participate in this study were included. Patients were randomly divided into two groups: the 2-octyl cyanoacrylate group (Glue group) or the non-use group (non-Glue group). A single surgeon (AM) carried out all procedures between 2014 and 2017. RESULTS: There were no significant differences in the clinical background of the Glue and non-Glue groups. The number of patients with moderate or high levels of pain in the resting/moving period on postoperative days 1, 2 and 3 was 6/10 (46%/77%), 6/9 (46%/69%) and 3/5 (23%/38%) in the non-Glue group, and 5/7 (38%/54%), 2/7 (15%/54%) and 1/3 (8%/23%) in the Glue group. These differences were not significant. In the subgroup analysis of patients aged <50 years, the numbers were 4/6 (57%/86%), 5/7 (71%/100%) and 3/5 (43%/71%) in the non-Glue group, and 3/4 (33%/44%), 1/4 (11%/44%) and 0/1 (0%/11%) in the Glue group in the resting/moving period. On postoperative days 2 and 3, these differences were significant (P = 0.035 and 0.037 in the resting period, and P = 0.017 and 0.013 in the moving period). CONCLUSIONS: 2-octyl cyanoacrylate can be used safely for laparoscopic adrenalectomy with the transumbilical approach, and might be useful for reducing postoperative pain in patients aged <50 years.

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PROGNOSTIC VALUE OF PD-L1 EXPRESSION ON TUMOR-INFILTRATING IMMUNE CELLS IN RENAL CELL CARCINOMA (ARCHERY STUDY)

Katsunori Tatsugami, Motohide Uemura, Noboru Nakaigawa, Naoto Sassa, Kenichi Harada, Toshinari Yamasaki, Tamaki Fukuyama, Takuya Yoshimoto, Yuki Nakagawa, Nobuaki Matsubara, Mototsugu Oya, Nobuo Shinohara, Hirotsugu Uemura, Toyonori Tsuzuki

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 80 ( 16 ) E1115 - E1115 2020.08

Joint Work, ISSN 0008-5472

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IDENTIFICATION OF FOXO1 AS A TUMOR SUPPRESSOR MODULATED BY ANDROGEN RECEPTOR/ESTROGEN RECEPTOR-beta SIGNALS: IMPLICATIONS FOR BLADDER CANCER PROMOTION AND CHEMORESISTANCE

Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Takuro Goto, Yujiro Nagata, Yuki Teramoto, Mototsugu Oya, George Netto, Hiroshi Miyamoto

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 80 ( 16 ) E230 - E230 2020.08

Joint Work, ISSN 0008-5472

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Optimal treatment strategy for paratesticular liposarcoma: retrospective analysis of 265 reported cases.

Rei Kamitani, Kazuhiro Matsumoto, Toshikazu Takeda, Ryuichi Mizuno, Mototsugu Oya

International journal of clinical oncology (SPRINGER JAPAN KK) 25 ( 12 ) 2099 - 2106 2020.07

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: Liposarcoma is one of the most common subtypes of soft tissue sarcoma. Although the standard treatment for localized liposarcoma is surgical resection with negative margins, a treatment specific to paratesticular liposarcoma has yet to be quantitatively evaluated. METHODS: A systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular liposarcoma published between 1979 and 2018 in English. The final cohort included 265 patients in 183 articles. The starting point was the time of surgical treatment, and the endpoint was the time of recurrence, including local recurrence, or distant metastasis. RESULTS: The median patient age was 62 years and the median tumor size was 9.5 cm. In total, 178 patients underwent high inguinal orchiectomy and 40 underwent simple tumorectomy. Based on the Kaplan-Meier curves, recurrence-free survival rates were significantly higher for those who underwent high inguinal orchiectomy than for those who underwent tumorectomy. Moreover, those with microscopic positive margins had a higher risk of recurrence than those with negative margins, but adjuvant radiation therapy after resection had no statistically significant effect on recurrence-free survival, even in subgroup analysis of patients with positive margins. Regarding the pathological subtypes, dedifferentiated, pleomorphic, and round-cell liposarcoma had a higher risk of recurrence than well-differentiated or myxoid liposarcoma. In the multivariate analysis, high inguinal orchiectomy greatly affected recurrence-free survival. The tumor size and histological subtype were independent risk factors for recurrence. CONCLUSION: Complete resection with high inguinal orchiectomy is the optimal treatment for paratesticular liposarcoma.

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Role of the MUC1-C oncoprotein in the acquisition of cisplatin resistance by urothelial carcinoma.

Keisuke Shigeta, Masanori Hasegawa, Eiji Kikuchi, Yota Yasumizu, Takeo Kosaka, Ryuichi Mizuno, Shuji Mikami, Akira Miyajima, Donald Kufe, Mototsugu Oya

Cancer science (WILEY) 111 ( 10 ) 3639 - 3652 2020.07

Research paper (scientific journal), Joint Work, ISSN 1347-9032

Mucin 1 C-terminal subunit (MUC1-C) has been introduced as a key regulator for acquiring drug resistance in various cancers, but the functional role of MUC1-C in urothelial carcinoma (UC) cells remains unknown. We aimed to elucidate the molecular mechanisms underlying the acquisition of cisplatin (CDDP) resistance through MUC1-C oncoprotein in UC cells. MUC1-C expression was examined immunohistochemically in tumor specimens of 159 UC patients who received CDDP-based perioperative chemotherapy. As a result, moderate to high MUC1-C expression was independently associated with poor survival in UC patients. Using human bladder cancer cell lines and CDDP-resistant (CR) cell lines, we compared the expression levels of MUC1-C, multiple drug resistance 1 (MDR1), the PI3K-AKT-mTOR pathway, and x-cystine/glutamate transporter (xCT) to elucidate the biological mechanisms contributing to the acquisition of chemoresistance. MUC1-C was strongly expressed in CR cell lines, followed with MDR1 expression via activation of the PI3K-AKT-mTOR pathway. MUC1-C also stabilized the expression of xCT, which enhanced antioxidant defenses by increasing intracellular glutathione (GSH) levels. MUC1 down-regulation showed MDR1 inhibition along with PI3K-AKT-mTOR pathway suppression. Moreover, it inhibited xCT stabilization and resulted in significant decreases in intracellular GSH levels and increased reactive oxygen species (ROS) generation. The MUC1-C inhibitor restored sensitivity to CDDP in CR cells and UC murine xenograft models. In conclusion, we found that MUC1-C plays a pivotal role in the acquisition of CDDP resistance in UC cells, and therefore the combined treatment of CDDP with a MUC1-C inhibitor may become a novel therapeutic option in CR UC patients.

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Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: nationwide survey in Japan

Inamoto T., Azuma H., Tatsugami K., Oya M., Adachi M., Okayama Y., Sunaya T., Akaza H.

Expert Review of Anticancer Therapy (Expert Review of Anticancer Therapy) 20 ( 7 ) 615 - 623 2020.07

ISSN 14737140

© 2020 Informa UK Limited, trading as Taylor & Francis Group. Objectives: To assess whether the clinical outcome of advanced/metastatic renal cell carcinoma (mRCC) treated with sorafenib, in real-world conditions, differs in patients with cardiovascular disease (CVD). Methods: mRCC patients (n = 2256 before matching) were matched by propensity score into CVD (n = 560) and non-CVD groups (n = 560), followed by safety and effectiveness analyzes. Results: After matching, patients’ features used for matching were balanced between the CVD and non-CVD groups, except for age (p = 0.0049). Renal comorbidity occurred more frequently in the CVD group. Exposure to sorafenib and objective response rate (25.4% [CVD], 28.5% [non-CVD]) were comparable in both groups. Median progression-free survival (PFS; 7.1 months, 95% CI: 6.4–8.6 [CVD]; 6.7 months, 6.3–8.3 [non-CVD]), and hazard ratios for PFS (0.954, 0.821–1.108) and overall survival (0.889, 0.683–1.156), were similar in the matched population. The incidences of adverse drug reactions (ADR, ≥10%) were generally similar between groups, although hypertension (42.1% vs 34.5%), diarrhea (26.3% vs 19.6%), decreased appetite (11.3% vs 7.5%), and non-serious and serious renal failure/dysfunction (3.6% vs 1.4% and 1.8% vs 0.4%), occurred more frequently in the CVD group. Conclusion: This analyzes suggests that sorafenib has clinical benefit for mRCC patients regardless of baseline CVD. Serious ADRs increased for renal dysfunction. Clinical trial registration: www.clinicaltrials.gov identifier is NCT01411423.

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Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: nationwide survey in Japan

Inamoto Teruo, Azuma Haruhito, Tatsugami Katsunori, Oya Mototsugu, Adachi Masatoshi, Okayama Yutaka, Sunaya Toshiyuki, Akaza Hideyuki

EXPERT REVIEW OF ANTICANCER THERAPY 20 ( 7 ) 615 - 623 2020.07

ISSN 1473-7140

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External validation of the "optimal PSA follow-up schedule after radical prostatectomy" in a new cohort

Yoshinori Yanai, Kazuhiro Matsumoto, Takeo Kosaka, Toshikazu Takeda, Nobuyuki Tanaka, Shinya Morita, Ryuichi Mizuno, Toshiaki Shinojima, Hiroshi Asanuma, Mototsugu Oya

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY (SPRINGER JAPAN KK) 25 ( 7 ) 1393 - 1397 2020.07

Research paper (scientific journal), Joint Work, ISSN 1341-9625

Background Biochemical recurrence (BCR) after radical prostatectomy (RP) is most commonly diagnosed by detecting an increase in asymptomatic prostate-specific antigen (PSA). We previously reported the "optimal PSA follow-up schedule after RP". The aim of this study was to confirm the usefulness and safety of that follow-up schedule in another cohort. Methods We retrospectively reviewed the clinicopathological data of 798 consecutive patients who underwent radical prostatectomy between 2009 and 2017. We examined all PSA values measured during follow-up. Furthermore, we estimated the PSA value when we observed the "optimal PSA follow-up schedule" at each timing in the virtual follow-up. BCR was defined as an elevation of PSA to greater than 0.2 ng/ml, and the ideal PSA range for detection of BCR was regarded to be 0.2-0.4 ng/ml. Results During the mean follow-up period of 5.8 years, BCR occurred in 115 (14.9%) patients and the frequency of virtual follow-up was significantly lower than the actual frequency. However, overlooking of BCR (detecting BCR when PSA exceeded 0.4 ng/ml) was observed in 17 patients, which is higher than the actual frequency of overlooking (12 patients). Therefore, we modified the follow-up schedule, which could achieve the lower follow-up frequency and a limited number of overlooking of BCR (7 patients). Conclusion This external validation study revealed that the "modified optimal PSA follow-up schedule after RP" can reduce the frequency of PSA measurement with a limited risk of overlooking BCR.

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TYPE OF PATIENTS IN WHOM BIOCHEMICAL RECURRENCE AFTER RADICAL PROSTATECTOMY CAN BE OBSERVED WITHOUT SALVAGE THERAPY

Kazuhiro Matsumoto, Naoya Niwa, Masayuki Hagiwara, Takeo Kosaka, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Ryuichi Mizuno, Toshiaki Shinojima, Satoshi Hara, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 7 ) 1749 - 1756 2020.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 0724-4983

PURPOSE: To examine the prognosis after BCR with and without salvage therapy, including radiation and/or androgen deprivation. METHODS: The study population consisted of 431 patients, all of whom underwent radical prostatectomy and developed BCR (PSA > 0.2 ng/mL). According to the two risk factors [Gleason score ≥ 8 and PSA-doubling time (DT) < 6 months], we divided the patients into two groups. The high/intermediate-risk group consisted of patients with both or one risk factor. On the other hand, patients with neither factor were in the low-risk group. We set the starting point at the timing of BCR, and the endpoints were development to castration-resistant prostate cancer (CRPC) and cancer-specific death. RESULTS: During the mean follow-up period of 8.3 years after BCR, CRPC was observed in 49 patients (11.4%), and 21 patients (4.9%) died due to prostate cancer. We first divided the 191 high/intermediate-risk patients according to the PSA level (PSA < 1.0 ng/mL, PSA 1.0-4.0, and PSA > 4.0 or no therapy) at the initiation of salvage therapy, including radiation and/or androgen deprivation. We found that delayed (PSA > 4.0 ng/mL) or no salvage therapy was significantly associated with CRPC and cancer-specific death. In the 240 low-risk patients, Kaplan-Meier curves demonstrated no significant difference in CRPC-free survival or cancer-specific survival within 10 years from the timing of BCR. CONCLUSIONS: Observation after BCR without salvage therapy or delayed administration may be an option for low-risk patients with a Gleason score ≤ 7 and PSA-DT ≥ 6 months when their life expectancy is within 10 years.

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Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: nationwide survey in Japan.

Inamoto T, Azuma H, Tatsugami K, Oya M, Adachi M, Okayama Y, Sunaya T, Akaza H

Expert review of anticancer therapy 20 ( 7 ) 615 - 623 2020.07

ISSN 1473-7140

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Myasthenia gravis with myositis induced by pembrolizumab therapy in a patient with metastatic urothelial carcinoma.

Nozomi Hayakawa, Eiji Kikuchi, Shigeaki Suzuki, Mototsugu Oya

International cancer conference journal (SPRINGER INTERNATIONAL PUBLISHING AG) 9 ( 3 ) 123 - 126 2020.07

Research paper (scientific journal), Joint Work, ISSN 2192-3183

Pembrolizumab is a long-awaited drug for the treatment of metastatic urothelial carcinoma. It is an immune checkpoint inhibitor, which has been shown to trigger new autoimmune disorders. We report a case of pembrolizumab-induced myasthenia gravis that occurred in an 84-year-old Japanese female with metastatic urothelial carcinoma in multiple organs. She developed right ptosis 3 days after the second pembrolizumab treatment. Although prednisolone was administered, her symptoms did not change and dysphagia appeared. She needed the steroid pulse therapy for treatment eventually. On the other hand, 9 weeks after the first pembrolizumab treatment, reductions in the sizes of liver and adrenal metastases was observed. However, unfortunately, the severe immune-related adverse events did not allow her to continue the administration of pembrolizumab for the treatment of multiple metastatic urothelial carcinoma. To our knowledge, this is the first case of myasthenia gravis associated with pembrolizumab treatment against metastatic urothelial carcinoma. In this case, a relationship between immune-related adverse events associated with myasthenia gravis and tumor responses to pembrolizumab was suspected, because marked reductions in the sizes of some metastatic lesions were observed after the administration of only two courses of pembrolizumab.

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特集小児泌尿器科オープンサージャリー-見て学ぶプロフェッショナルの技〈特別付録Web動画〉〈泌尿器科医として習得したい手術〉急性陰囊症-どんな場合に手術が必要か?　どのような手術をすべきか?

浅沼宏, 高橋遼平, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 74 ( 7 ) 472 - 477 2020.06

ISSN 0385-2393

Appropriate timing for a biochemical evaluation after adrenalectomy for unilateral aldosterone-producing adenoma.

Kimiharu Takamatsu, Toshikazu Takeda, Seiya Hattori, Nobuyuki Tanaka, Shinya Morita, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Toshiaki Shinojima, Eiji Kikuchi, Hiroshi Asanuma, Isao Kurihara, Hiroshi Itoh, Mototsugu Oya

Clinical endocrinology (WILEY) 92 ( 6 ) 503 - 508 2020.06

Research paper (scientific journal), Joint Work, ISSN 0300-0664

CONTEXT: The oversecretion of plasma aldosterone by unilateral aldosterone-producing adenoma (APA) can be cured by adrenalectomy. However, the time needed for the endocrine environment to normalize remains unclear. OBJECTIVE: To clarify adequate timing for a biochemical evaluation in unilateral APA patients after adrenalectomy. DESIGN AND PATIENTS: A total of 166 unilateral APA patients were retrospectively reviewed. We evaluated the plasma aldosterone concentration (PAC) (pg/mL), active renin concentration (ARC) (pg/mL), aldosterone-renin ratio (ARR; PAC/ARC), serum potassium concentration and estimated glomerular filtration rate (eGFR) at 1, 3 and 6 postoperation months (POM). RESULTS: PAC was significantly lower at 1POM than at presurgery (presurgery; 407.2, 1 POM; 90.0 pg/mL, P < .001). ARC did not increase from baseline at 1POM, but significantly increased at 3POM (presurgery; 4.43, 1POM; 4.87, 3POM; 11.3 pg/mL, P < .001). ARR significantly decreased at 1POM (presurgery; 146.9, 1 POM; 26.3, P < .001) although ARC did not increase at 1POM. Among the 34 patients who had hypokalaemia presurgery, it was resolved in 28 (82%) at 1POM and in all (100%) at 3POM. The biochemical outcomes at 1POM were 131 (79%) complete, 20 (12%) partial and 15 (9%) absent successes, while at 3POM, 147 (89%) were complete, 9 (5%) partial and 10 (6%) absent. Twenty-three (14%) patients were reclassified into different biochemical outcomes between 1 and 3POM, whereas only 5 (3%) changed between 3 and 6POM. CONCLUSION: The appropriate timing for a biochemical evaluation of unilateral APA patients treated with laparoscopic adrenalectomy appears to be 3 months or more after surgery.

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Safety and efficacy of plasma exchange via direct femoral vein puncture in autoimmune blistering diseases.

Tadashi Yoshida, Hitoshi Minakuchi, Ryohei Takahashi, Shinya Morita, Mototsugu Oya

Journal of clinical apheresis (WILEY) 35 ( 3 ) 172 - 177 2020.06

Research paper (scientific journal), Joint Work, ISSN 0733-2459

Plasma exchange (PE) is performed for patients with autoimmune blistering diseases by using multiple vascular access routes. We retrospectively examined the safety and the efficacy of PE using direct femoral vein puncture (FVP) technique, by comparing with that using double-lumen catheter (DLC). The troubles related to vascular route, such as catheter occlusion, insufficient blood flow and hematoma, were not different between the FVP group (4.6%) and the DLC group (6.7%), whereas access-related infections occurred more frequently in the DLC group (6.7%) than the FVP group (0.4%). Regarding the efficacy, the removal rate of autoantibodies in PE using the FVP technique was similar or lower, as compared with that using the DLC. These results suggest that PE with the FVP technique is able to be performed safely in patients with autoimmune blistering diseases, although the removal of autoantibodies is not superior to that using the DLC.

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The pretreatment neutrophil-to-lymphocyte ratio is a novel biomarker for predicting clinical responses to pembrolizumab in platinum-resistant metastatic urothelial carcinoma patients.

Koichiro Ogihara, Eiji Kikuchi, Keisuke Shigeta, Takashi Okabe, Seiya Hattori, Ryo Yamashita, Shunsuke Yoshimine, Suguru Shirotake, Ryuto Nakazawa, Kazuhiro Matsumoto, Ryuichi Mizuno, Satoshi Hara, Masafumi Oyama, Takeshi Masuda, Masashi Niwakawa, Mototsugu Oya

Urologic oncology (ELSEVIER SCIENCE INC) 38 ( 6 ) 602.e1 - 602.e10 2020.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1078-1439

PURPOSE: We investigated the relationship between pretreatment neutrophil-to-lymphocyte ratio (pre-NLR) levels just before the initiation of treatment with pembrolizumab and clinical outcomes in platinum-resistant metastatic urothelial carcinoma (UC) patients treated with pembrolizumab. METHODS: Our study population comprised 78 patients diagnosed with metastatic UC and treated with pembrolizumab after platinum-based chemotherapy at our institutions between December 2017 and April 2019. We examined the relationships between pre-NLR levels just before pembrolizumab treatment and clinical outcomes. A pre-NLR level of ≥3.35 was defined as elevated according to a calculation by a receiver-operating curve analysis. RESULTS: The high pre-NLR group consisted of 33 patients (42.3%). Overall, 29.5% of patients had a clinical response and the sum of the target lesion longest diameter was decreased in 18.8% of the high pre-NLR group, which was significantly lower than that in the low pre-NLR group (58.1%, P = 0.005). Six-month progression-free survival and cancer-specific survival rates for the high pre-NLR group were 9.1 and 58.0%, which were significantly lower than those for their counterpart (45.9 and 89.1%, P < 0.001 and P = 0.002, respectively). The pre-NLR level was an independent indicator of disease progression and cancer-specific death (P < 0.001 and P = 0.003). Furthermore, patients with a postpembrolizumab NLR level that had decreased ≥25% from the pre-NLR level had significantly lower disease progression and cancer-specific death rates than their counterparts (P = 0.01 and P = 0.022, respectively). CONCLUSIONS: Elevated pre-NLR may be a novel biomarker for identifying poor responders to pembrolizumab among platinum-resistant metastatic UC patients.

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The efficacy of the TachoSil binding suturing technique in laparoscopic partial nephrectomy to prevent the development of pseudoaneurysm.

Keisuke Shigeta, Kazuhiro Matsumoto, Takayuki Abe, Akari Komatsuda, Toshikazu Takeda, Ryuichi Mizuno, Eiji Kikuchi, Hiroshi Asanuma, Yuki Arita, Hirotaka Akita, Masahiro Jinzaki, Akira Miyajima, Mototsugu Oya

Asian journal of surgery (ELSEVIER SINGAPORE PTE LTD) 43 ( 6 ) 668 - 675 2020.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1015-9584

OBJECTIVE: Our specific aim was to introduce the TachoSil binding suturing technique for renal cell carcinoma (RCC) patients when closing the parenchymal defect after tumor excision during laparoscopic partial nephrectomy (LPN), which is a novel technique for reducing the risk of developing subsequent pseudoaneurysm (PA). METHODS: We identified 113 pT1aN0M0 RCC patients who underwent LPN at our institution. Eighty-one (72%) patients underwent the suturing procedure without binding TachoSil, whereas 32 (28%) patients underwent renorraphy with the renal defect closed together with TachoSil. The vascular complications were evaluated by computed tomography or magnetic resonance imaging with enhanced contrast material at the first visit after LPN. We conducted Fischer's exact test to determine risk factors for transcatheter arterial embolization (TAE). RESULTS: The median age was 55 (36-86) years old and the median follow-up time was 65 (12-147) months. In the overall population, there were 11 (11%) patients who underwent TAE because they developed PA. All 11 patients exhibited the imaging findings of PA, and were all from the conventional suturing group. In contrast, no patients for whom the TachoSil binding method was used had any significant findings on imaging (14% vs. 0%). Based on the analysis to determine risk factors for TAE due to PA development, the TachoSil binding suturing technique was one of the significant indicators for reducing the risk of developing PA. CONCLUSIONS: Our study demonstrated that the TachoSil binding suturing technique might reduce the development of PA after LPN. Prospective randomized study and comparison to the standard 2 or 3-layer renorrhaphy is needed to prove its actual value.

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進行性前立腺がんにおける薬剤耐性遺伝子発現ネットワークを標的とした新規リプログラミング療法

小坂威雄, 本郷周, 三上修治, 大家基嗣

臨床薬理の進歩 ((公財)臨床薬理研究振興財団) ( 41 ) 81 - 87 2020.06

ISSN 0914-4366

難治性遺伝子ネットワークを標的とした再プログラム化戦略に基づく、革新的新規治療のための新規薬剤のスクリーニングおよび分子基盤の確立と応用を目指した。まず、コネクティビティマップ解析により約70種類の既存薬を含めた小分子化合物を同定した。これらの化合物は、理論的に、再発・転移遺伝子発現プロファイルを限局がん、初発の遺伝子プロファイルへとリプログラミングし得る候補薬剤として同定された。これら同定された薬剤のうち、臨床で既に使用されている薬剤を中心にリストアップし、in vitroで投与した。高転移能を有するヒト去勢抵抗性前立腺がん(CRPC)細胞であるDU145に対してDER35が濃度依存性に、細胞増殖を有意に抑制した。次に、オス去勢ヌードマウスにDU145を皮下に接種し、皮下腫瘍モデルを作製し、DER35を経口投与して薬剤感受性をin vivoで検討した。皮下腫瘍が150〜200mm3、増大したところでマウスを2群に分け、Control(n=10)、およびDER35 12.5mg/kg/day投与群(17日間連続経口投与、n=10)とした。DER35投与群では、腫瘍の増殖が有意に抑制された。

Pembrolizumab投与後に重症筋無力症を来たした1例

早川望, 菊地栄次, 鈴木重明, 大家基嗣

泌尿器科紀要 (泌尿器科紀要刊行会) 66 ( 6 ) 190 - 190 2020.06

Joint Work, ISSN 0018-1994

A pooled analysis of the efficacy and safety of cabozantinib post immunotherapy in patients with advanced renal cell carcinoma.

Mototsugu Oya, Satoshi Tamada, Katsunori Tatsugami, Noboru Nakaigawa, Takahiro Osawa, Hiro-Omi Kanayama, Chihiro Kondoh, Naoto Sassa, Kazuo Nishimura, Masahiro Nozawa, Naoya Masumori, Yasuhide Miyoshi, Akiko Kimura, Shingo Kuroda, Robert J. Motzer, Toni K. Choueiri, Yoshihiko Tomita

JOURNAL OF CLINICAL ONCOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 15 ) 2020.05

Joint Work, ISSN 0732-183X

Predictors of first line systemic therapy for metastatic renal cell carcinoma in IMDC favorable risk patients.

Ryuichi Mizuno, Kimiharu Takamatsu, Nobuyuki Tanaka, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 15 ) 2020.05

Joint Work, ISSN 0732-183X

The prognostic biomarkers of the patients treated with platinum-based chemotherapy in treatment emergent or related neuroendocrine prostate cancer.

Takeo Kosaka, Hiroshi Hongo, Yota Yasumizu, Kazuhiro Matshumoto, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 15 ) 2020.05

Joint Work, ISSN 0732-183X

The change of serum C-reactive protein levels during molecular-targeted treatments could predict the response to anti-PD-1 treatment in metastatic renal cell carcinoma patients.

Kimiharu Takamatsu, Ryuichi Mizuno, Nozomi Hayakawa, Nobuyuki Tanaka, Takeo Kosaka, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (LIPPINCOTT WILLIAMS & WILKINS) 38 ( 15 ) 2020.05

Joint Work, ISSN 0732-183X

増刊号特集泌尿器科診療の最新スタンダード-平成の常識は令和の非常識企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 74 ( 4 ) 7 - 7 2020.04

ISSN 0385-2393

Successful perinatal management of a dichorionic diamniotic twin pregnancy in an anaemic kidney transplant patient treated with Darbepoetin alfa: a case report.

Satoshi Tamaki, Kazunobu Shinoda, Tadashi Matsumoto, Shinya Morita, Hiroshi Asanuma, Tadashi Yoshida, Mototsugu Oya

Journal of obstetrics and gynaecology : the journal of the Institute of Obstetrics and Gynaecology (TAYLOR & FRANCIS INC) 40 ( 3 ) 427 - 429 2020.04

Research paper (scientific journal), Joint Work, ISSN 0144-3615

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ARE SURVIVAL OUTCOMES AFTER NEOADJUVANT CHEMOTHERAPY SUPERIOR TO THOSE AFTER UPFRONT RADICAL NEPHROURETERECTOMY FOR NODE-POSITIVE UPPER TRACT UROTHELIAL CARCINOMA? RESULTS OF A MULTI-CENTER COHORT STUDY

Keisuke Shigeta, Kazuhiro Matsumoto, Nobuyuki Tanaka, Yota Yasumizu, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E376 - E376 2020.04

Joint Work, ISSN 0022-5347

ANDROGEN DEPRIVATION THERAPY THROUGH THE PERI-RADIATION PERIOD REDUCES THE RISK OF BLADDER HEMORRHAGE IN PROSTATE CANCER PATIENTS UNDERGOING EXTERNAL BEAM RADIOTHERAPY

Yuto Baba, Hiroki Ide, Naoya Niwa, Junichi Fukuda, Hirohiko Nagata, Kazuhiro Matsumoto, Mototsugu Oya, Hiroshi Miyamoto

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E790 - E790 2020.04

Joint Work, ISSN 0022-5347

A SIMPLE/RAPID RNA IMAGING TECHNIQUE QHCR REVEALS MALIGNANCY ASSOCIATED WITH LONG NON-CODING RNA IN CLEAR CELL RENAL CELL CARCINOMA

Ryohei Kufukihara, Nobuyuki Tanaka, Youta Yasumizu, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E113 - E113 2020.04

Joint Work, ISSN 0022-5347

DO ALL CASES OF MAGNETIC RESONANCE IMAGING NEGATIVE HAVE GOOD PROGNOSIS?

Yoshinori Yanai, Takeo Kosaka, Hiroshi Hongo, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E185 - E185 2020.04

Joint Work, ISSN 0022-5347

WHO COULD BE EFFECTIVELY TREATED WITH ADJUVANT CHEMOTHERAPY AMONG PATHOLOGICALLY NODE POSITIVE MUSCLE INVASIVE BLADDER CANCER PATIENTS TREATED WITH RADICAL CYSTECTOMY? : A MULTICENTER COHORT STUDY ADJUSTED BY PROPENSITY SCORE MATCHING

Keitaro Watanabe, Eiji Kikuchi, Kohichiro Ogihara, Takeo Kosaka, Kyohei Hakozaki, Keishiro Fukumoto, Yasumasa Miyazaki, Suguru Shirotake, Kunimitsu Kanai, Satoshi Hara, Masafumi Oyama, Hirohiko Nagata, Tetsuo Monma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E748 - E748 2020.04

Joint Work, ISSN 0022-5347

WHAT TIMING IS APPROPRIATE FOR A BIOCHEMICAL EVALUATION AFTER LAPAROSCOPIC ADRENALECTOMY FOR UNILATERAL ALDOSTERONE-PRODUCING ADENOMA?

Kimiharu Takamatsu, Toshikazu Takeda, Yota Yasumizu, Nobuyuki Tanaka, Shinya Morita, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Isao Kurihara, Hiroshi Itoh, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E630 - E630 2020.04

Joint Work, ISSN 0022-5347

UNCOVERING INTRA-TUMOR AXL EXPRESSION HETEROGENEITY AND OUTCOMES IN CLEAR CELL RENAL CELL CARCINOMA: COMPREHENSIVE ANALYSIS FOR PRIMARY AND METASTATIC LESION

Kyohei Hakozaki, Nobuyuki Tanaka, Kimiharu Takamatsu, Shuji Mikami, Yota Yasumizu, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Hiroshi Asanuma, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E1298 - E1299 2020.04

Joint Work, ISSN 0022-5347

TNFAIP2: A POTENTIAL TARGET IN PLATINUM RESISTANCE UROTHELIAL CARCINOMA

Naoya Niwa, Nobuyuki Tanaka, Hiroshi Hongo, Yasumasa Miyazaki, Kimiharu Takamatsu, Yota Yasumizu, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Eiji Kikuchi, Hiroshi Asanuma, Shuji Mikami, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E1 - E1 2020.04

Joint Work, ISSN 0022-5347

SULFASALAZINE COULD MODULATE THE CD44V9-XCT SYSTEM AND ENHANCE CDDP-INDUCED CYTOTOXIC EFFECTS IN METASTATIC BLADDER CANCER; A NOVEL THERAPEUTIC STRATEGY FOR METASTATIC BLADDER CANCER

Koichiro Ogihara, Eiji Kikuchi, Toshikazu Takeda, Kazuhiro Matsumoto, Hideyuki Saya, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E2 - E2 2020.04

Joint Work, ISSN 0022-5347

ROLE FOR THE ECTONUCLEOTIDASE CD39: OUTCOME AND ASSOCIATION WITH PD-1/PD-L1 BASED CANCER IMMUNITY IN CLEAR CELL RENAL CELL CARCINOMA

Tetsushi Murakami, Nobuyuki Tanaka, Kyohei Hakozaki, Kimiharu Takamatsu, Shuji Mikami, Youta Yasumizu, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Hiroshi Asanmua, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E238 - E239 2020.04

Joint Work, ISSN 0022-5347

PERFORMING TRANSURETHRAL RESECTION UNDER GENERAL ANESTHESIA MAY CONTRIBUTE TO HIGHER RECURRENCE RATES IN HIGH RISK NON-MUSCLE INVASIVE BLADDER CANCER

Yuto Baba, Eiji Kikuchi, Keisuke Shigeta, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E1079 - E1079 2020.04

Joint Work, ISSN 0022-5347

OVERCOMING CABAZITAXEL RESISTANCE BY G2/M REGULATING GENES IN CASTRATION-RESISTANT PROSTATE CANCER

Hiroshi Hongo, Takeo Kosaka, Yoshinori Yanai, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E214 - E214 2020.04

Joint Work, ISSN 0022-5347

OPTIMAL TREATMENT STRATEGY FOR PARATESTICULAR LIPOSARCOMA

Rei Kamitani, Kazuhiro Matsumoto, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E1152 - E1152 2020.04

Joint Work, ISSN 0022-5347

NOVEL PROGNOSTIFICATION MODEL FOR CLEAR CELL RENAL CELL CARCINOMA: PROPOSING THE IMMUNE-BASED CLUSTERING ALGORITHM USING FUTURE IMMUNE-CHECKPOINT TARGETS

Kimiharu Takamatsu, Nobuyuki Tanaka, Ryuichi Mizuno, Kyohei Hakozaki, Ryohei Takahashi, Yota Yasumizu, Toshikazu Takeda, Shinya Morita, Kazuhiro Matsumoto, Takeo Kosaka, Hiroshi Asanuma, Shuji Mikami, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E236 - E236 2020.04

Joint Work, ISSN 0022-5347

NOVEL NUCLEAR FACTOR-kappa B ACTIVATION INHIBITOR, DEHYDROXYMETHYLEPOXYQUINOMICIN, PREVENTS THE DEVELOPMENT OF CHRONIC CYCLOSPORINE NEPHROPATHY

Shinya Morita, Kazunobu Shinoda, Ryohei Takahashi, Satoshi Tamaki, Hidaka Kono, Tadashi Yoshida, Kazuo Umezawa, Ken Nakagawa, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E880 - E880 2020.04

Joint Work, ISSN 0022-5347

INTRAVESICAL BCG INSTILLATION IS STRONGLY ASSOCIATED WITH A DECREASED RISK OF UPPER TRACT UROTHELIAL CARCINOMA RECURRENCE AS WELL AS INTRAVESICAL RECURRENCE IN ELDERLY MALE PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

Hiroki Ide, Naoya Niwa, Yuto Baba, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E1253 - E1254 2020.04

Joint Work, ISSN 0022-5347

IN SILICO SCREENING TARGETING THE REPROGRAMMING OF LINEAGE PLASTICITY IN NEUROENDOCRINE PROSTATE CANCER

Takeo Kosaka, Hiroshi Hongo, Koji Ueda, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E561 - E562 2020.04

Joint Work, ISSN 0022-5347

IN SILICO SCREENING FOR IDENTIFICATION OF NOVEL DRUGS FOR OVERCOMING CABAZITAXEL-RESISTANT PROSTATE CANCER

Hiroshi Hongo, Takeo Kosaka, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E215 - E215 2020.04

Joint Work, ISSN 0022-5347

IMPACT OF PROSTATIC SHAPE ON THE DIFFICULTY OF ROBOT-ASSISTED LAPAROSCOPIC RADICAL PROSTATECTOMY

Ken Kamisawa, Kazuhiro Matsumoto, Toshikazu Takeda, Kimiharu Takamatsu, Yota Yasumizu, Nobuyuki Tanaka, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E902 - E902 2020.04

Joint Work, ISSN 0022-5347

GENOMIC LANDSCAPE AND MOLECULAR CHARACTERIZATION OF RENAL CELL CARCINOMA IN DIALYSIS PATIENTS

Ryohei Takahashi, Nobuyuki Tanaka, Fuyuki Miya, Takashi Kamatani, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Shuji Mikami, Kazuhiro Kakimi, Tatsuhiko Tsunoda, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E108 - E109 2020.04

Joint Work, ISSN 0022-5347

EVALUATING THE DIAGNOSTIC ACCURACY OF VESICAL IMAGING-REPORTING AND DATA SYSTEM FOR DETECTING MUSCLE-INVASIVE BLADDER CANCER IN REAL CLINICAL SETTING

Ryohei Kufukihara, Eiji Kikuchi, Keisuke Shigeta, Youta Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Ryuichi Mizuno, Yuki Arita, Hirotaka Akita, Masahiro Jinzaki, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E524 - E524 2020.04

Joint Work, ISSN 0022-5347

DO ALL PATIENTS WHO HAVE PROSTATE CANCER WITH SEMINAL VESICLE INVASION HAVE POOR PROGNOSIS?

Yoshinori Yanai, Takeo Kosaka, Hiroshi Hongo, Yota Yasumizu, Nobuyuki Tanaka, Toshikazu Takeda, Kazuhiro Matsumoto, Shinya Morita, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 203 E948 - E948 2020.04

Joint Work, ISSN 0022-5347

A case of inguinal cellular angiofibroma.

Rei Kamitani, Kazuhiro Matsumoto, Shinnosuke Fujiwara, Hirotaka Akita, Shuji Mikami, Kaori Kameyama, Masahiro Jinzaki, Mototsugu Oya

IJU case reports 3 ( 2 ) 69 - 71 2020.03

Joint Work

Introduction: Cellular angiofibroma is a benign mesenchymal tumor that is rare and has a good prognosis. However, preoperative distinction of cellular angiofibroma from malignant tumors is difficult. Case presentation: A 77-year-old man complained of a left inguinal mass, which was a solid, painless, mobile tumor measuring approximately 40 mm and contacted with the left spermatic cord. Based on his age, the location and imaging findings, a preoperative diagnosis of myxoid liposarcoma was made. The patient underwent left high inguinal orchiectomy with complete resection of the tumor. Histologically and immunohistochemically, the tumor had no feature of malignancy. A postoperative diagnosis of cellular angiofibroma was made. The patient remains free of disease recurrence 12 months after surgery. Conclusion: Cellular angiofibroma is a benign but rare tumor, which is sometimes difficult to distinguish from malignant neoplasms. Further studies are needed to accurately preoperatively diagnose this tumor.

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Avelumab plus axitinib vs sunitinib for advanced renal cell carcinoma: Japanese subgroup analysis from JAVELIN Renal 101.

Motohide Uemura, Yoshihiko Tomita, Hideaki Miyake, Shingo Hatakeyama, Hiro-Omi Kanayama, Kazuyuki Numakura, Toshio Takagi, Tomoyuki Kato, Masatoshi Eto, Wataru Obara, Hirotsugu Uemura, Toni K Choueiri, Robert J Motzer, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Alessandra di Pietro, Mototsugu Oya

Cancer science (WILEY) 111 ( 3 ) 907 - 923 2020.03

Research paper (scientific journal), Joint Work, Accepted, ISSN 1347-9032

The phase 3 JAVELIN Renal 101 trial of avelumab + axitinib vs sunitinib in patients with treatment-naive advanced renal cell carcinoma (RCC) demonstrated significantly improved progression-free survival (PFS) and higher objective response rate (ORR) with the combination vs sunitinib. Japanese patients enrolled in the study (N = 67) were randomized to receive avelumab + axitinib (N = 33) or sunitinib (N = 34); 67% vs 59% had PD-L1+ tumors (≥1% of immune cells) and 6%/64%/27% vs 6%/82%/12% had International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) favorable/intermediate/poor risk status. In patients who received avelumab + axitinib vs sunitinib, median PFS (95% confidence interval [CI]) was not estimable (8.1 months, not estimable) vs 11.2 months (1.6 months, not estimable) (hazard ratio [HR], 0.49; 95% CI, 0.152, 1.563) in patients with PD-L1+ tumors and 16.6 months (8.1 months, not estimable) vs 11.2 months (4.2 months, not estimable) (HR, 0.66; 95% CI, 0.296, 1.464) in patients irrespective of PD-L1 expression. Median overall survival (OS) has not been reached in either arm in patients with PD-L1+ tumors and irrespective of PD-L1 expression. ORR (95% CI) was 60.6% (42.1%, 77.1%) vs 17.6% (6.8%, 34.5%) in patients irrespective of PD-L1 expression. Common treatment-emergent adverse events (all grade; grade ≥3) in each arm were hand-foot syndrome (64%; 9% vs 71%; 9%), hypertension (55%; 30% vs 44%; 18%), hypothyroidism (55%; 0% vs 24%; 0%), dysgeusia (21%; 0% vs 56%; 0%) and platelet count decreased (3%; 0% vs 65%; 32%). Avelumab + axitinib was efficacious and tolerable in treatment-naive Japanese patients with advanced RCC, which is consistent with results in the overall population.

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Successful Treatment of End-stage Renal Disease in a Patient With Chronic Myeloid Leukemia by Kidney Transplantation and Tyrosine Kinase Inhibitors: A Case Report.

Kazunobu Shinoda, Shinya Morita, Satoshi Tamaki, Ryohei Takahashi, Sotaro Kitaoka, Hiroshi Asanuma, Tadashi Yoshida, Mikio Okayama, Hidenori Kasahara, Shinichiro Okamoto, Mototsugu Oya

Transplantation proceedings (ELSEVIER SCIENCE INC) 52 ( 2 ) 604 - 607 2020.03

Research paper (scientific journal), Joint Work, ISSN 0041-1345

Consensus regarding kidney transplantation feasibility in patients with chronic myeloid leukemia (CML) well controlled by tyrosine kinase inhibitors has not yet been achieved. Here, we report a patient with CML well controlled by tyrosine kinase inhibitors who developed end-stage renal disease during treatment and underwent kidney transplantation. CML activity has been carefully and successfully controlled for 4 years post-transplant. Very cautious dose adjustment and temporary cessation of nilotinib were required because kidney function fluctuated in reference to the doses of nilotinib.

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Editorial Comment to Comparison of single- and multiple-dose cefazolin as prophylaxis for transurethral enucleation of prostate: A multicenter, prospective, randomized controlled trial by the Japanese Research Group for Urinary Tract Infection.

Satoshi Yazawa, Naoki Hasegawa, Mototsugu Oya

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 3 ) 248 - 249 2020.03

Research paper (scientific journal), Joint Work, ISSN 0919-8172

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Physical Parameters, Use of Specific Medical Treatments, Nursing Levels, and Activities of Daily Living Are Potential Indicators for Forgoing Maintenance Hemodialysis

Yamaguchi, Nobuko ; Yoshida, Tadashi ; Oba, Miho ; Nakano, Reiko ; Saito, Miwa ; Hirokawa, Mihoko ; Shinmi, Tazuru ; Urasawa, Chisa ; Oya, Mototsugu

The Keio Journal of Medicine (The Keio Journal of Medicine) 69 ( 1 ) 16 - 25 2020.03

Joint Work, ISSN 0022-9717

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Author Correction: MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer.

Yota Yasumizu, Hasan Rajabi, Caining Jin, Tsuyoshi Hata, Sean Pitroda, Mark D Long, Masayuki Hagiwara, Wei Li, Qiang Hu, Song Liu, Nami Yamashita, Atsushi Fushimi, Ling Kui, Mehmet Samur, Masaaki Yamamoto, Yan Zhang, Ning Zhang, Deli Hong, Takahiro Maeda, Takeo Kosaka, Kwok K Wong, Mototsugu Oya, Donald Kufe

Nature communications (Nature Communications) 11 ( 1 ) 1095 - 1095 2020.02

Research paper (scientific journal), Joint Work

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Treatment-free survival after discontinuation of immuno-checkpoint therapy, and outcome of subsequent molecular targeted therapy: Retrospective study of Japanese metastatic renal cell carcinoma patients (after I-O study)

Tomita Yoshihiko, Kimura Go, Fukasawa Satoshi, Sugiyama Yutaka, Numakura Kazuyuki, Yamana Kazutoshi, Naito Sei, Kabu Koki, Tajima Yohei, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 38 ( 6 ) 675 - 675 2020.02

Joint Work, ISSN 0732-183X

Extensive disease among potential candidates for hemi-ablative focal therapy for prostate cancer.

Toshikazu Takeda, Amy L Tin, Renato B Corradi, Ricardo Alvim, Takeshi Hashimoto, Yujiro Ito, Daniel P Nguyen, Maha Mamoor, Nicola L Robertson, Hebert A Vargas, Nicole E Benfante, Daniel D Sjoberg, James A Eastham, Peter T Scardino, Samson W Fine, Mototsugu Oya, Karim A Touijer

International journal of urology : official journal of the Japanese Urological Association (WILEY) 27 ( 2 ) 179 - 185 2020.02

Research paper (scientific journal), Joint Work, ISSN 0919-8172

OBJECTIVE: To examine a set of proposed eligibility factors for hemi-ablative focal therapy in prostate cancer and to determine the likelihood of residual extensive disease. METHODS: We retrospectively analyzed data from 98 patients with unilateral prostate cancer on biopsy with detailed tumor maps from whole-mount slides and preoperative magnetic resonance imaging data. These patients met the focal therapy consensus meeting inclusion criteria (prostate-specific antigen <15 ng/mL, clinical stage T1c-T2a and Gleason score 3 + 3 or 3 + 4 on needle biopsy), and underwent radical prostatectomy between 2000 and 2014. Extensive disease was defined as having Gleason pattern 4/5 in bilateral lobes, any extraprostatic extension, seminal vesicle invasion or lymph node invasion. Both lobes of the prostate were scored on magnetic resonance imaging. Preoperative characteristics including biopsy and magnetic resonance imaging data were used to predict extensive disease. RESULTS: Among our cohort of 98 patients, 40% (95% CI 30-50%) had extensive disease. A total of 33% (95% CI 24-43%) had Gleason pattern 4/5 in both lobes with a median Gleason pattern 4/5 tumor volume in the biopsy negative lobe of 0.06 cm3 , 17 patients had pathological tumor stage ≥3 and one patient had lymph node invasion. CONCLUSIONS: An important number of patients meeting the focal therapy consensus meeting inclusion criteria can present extensive disease. Further studies using targeted biopsies might provide more accurate information about the selection of focal therapy candidates.

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Nivolumab plus ipilimumab versus sunitinib in previously untreated advanced renal-cell carcinoma: analysis of Japanese patients in CheckMate 214 with extended follow-up.

Yoshihiko Tomita, Tsunenori Kondo, Go Kimura, Takamitsu Inoue, Yoshiaki Wakumoto, Masahiro Yao, Takayuki Sugiyama, Mototsugu Oya, Yasuhisa Fujii, Wataru Obara, Robert J Motzer, Hirotsugu Uemura

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 50 ( 1 ) 12 - 19 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 0368-2811

BACKGROUND: Nivolumab plus ipilimumab (NIVO+IPI) demonstrated superior efficacy over sunitinib (SUN) for previously untreated advanced renal cell carcinoma (aRCC) in CheckMate 214, with a manageable safety profile. We report efficacy and safety with extended follow-up amongst Japanese patients. METHODS: CheckMate 214 patients received NIVO (3 mg/kg) plus IPI (1 mg/kg) every 3 weeks for four doses, then NIVO (3 mg/kg) every 2 weeks; or SUN (50 mg) once daily for 4 weeks (6-week cycle). This subgroup analysis assessed overall survival (OS), objective response rate (ORR) and progression-free survival (PFS) per investigator in International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) intermediate/poor-risk and intent-to-treat (ITT) patients and safety (ITT patients). RESULTS: Of 550 and 546 patients randomized to NIVO+IPI and SUN, 38 and 34, respectively, were Japanese. Of these, 31 (NIVO+IPI) and 29 (SUN) patients were IMDC intermediate/poor-risk. In IMDC intermediate/poor-risk patients with 30 months' minimum follow-up, there was a delayed trend in OS benefit with NIVO+IPI (hazard ratio [HR] 0.56; 95% confidence interval [CI]: 0.19-1.59; P = 0.2670), and 24-month OS probability favoured NIVO+IPI (84%) versus SUN (76%). The ORR was 39% with NIVO+IPI and 31% with SUN (P = 0.6968). PFS was similar in both treatment arms (HR 1.17; 95% CI: 0.62-2.20; P = 0.6220). Efficacy in ITT patients was similar to IMDC intermediate/poor-risk patients. Grade 3-4 treatment-related adverse event incidence was lower with NIVO+IPI versus SUN (58 versus 91%). CONCLUSIONS: Japanese patients with untreated aRCC in the NIVO+IPI arm had a numerically higher ORR and improved safety profile versus patients in the SUN arm. A delayed OS benefit appears to be emerging with NIVO+IPI. Longer follow-up is needed. https://clinicaltrials.gov/ct2/show/NCT02231749?term=NCT02231749&rank=1 identifier: NCT02231749.

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MUC1-C regulates lineage plasticity driving progression to neuroendocrine prostate cancer.

Nature communications (NATURE PUBLISHING GROUP) 11 ( 1 ) 338 - 338 2020.01

Research paper (scientific journal), Joint Work, Accepted, ISSN 2041-1723

Neuroendocrine prostate cancer (NEPC) is an aggressive malignancy with no effective targeted therapies. The oncogenic MUC1-C protein is overexpressed in castration-resistant prostate cancer (CRPC) and NEPC, but its specific role is unknown. Here, we demonstrate that upregulation of MUC1-C in androgen-dependent PC cells suppresses androgen receptor (AR) axis signaling and induces the neural BRN2 transcription factor. MUC1-C activates a MYC→BRN2 pathway in association with induction of MYCN, EZH2 and NE differentiation markers (ASCL1, AURKA and SYP) linked to NEPC progression. Moreover, MUC1-C suppresses the p53 pathway, induces the Yamanaka pluripotency factors (OCT4, SOX2, KLF4 and MYC) and drives stemness. Targeting MUC1-C decreases PC self-renewal capacity and tumorigenicity, suggesting a potential therapeutic approach for CRPC and NEPC. In PC tissues, MUC1 expression associates with suppression of AR signaling and increases in BRN2 expression and NEPC score. These results highlight MUC1-C as a master effector of lineage plasticity driving progression to NEPC.

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Aggressive prostate cancer with somatic loss of the homologous recombination repair gene FANCA: a case report.

Hiroshi Hongo, Takeo Kosaka, Eriko Aimono, Hiroshi Nishihara, Mototsugu Oya

Diagnostic pathology (BMC) 15 ( 1 ) 5 - 5 2020.01

Research paper (scientific journal), Joint Work, Accepted

BACKGROUND: Precision medicine based on genomic analysis of germline or tumor tissue is attracting attention. However, there is no consensus on how to apply the results of genomic analysis to treatment. CASE PRESENTATION: A 59-year-old man diagnosed with metastatic prostate cancer was diagnosed with castration-resistant prostate cancer. Although he was sequentially treated with enzalutamide and abiraterone, bone metastasis progression was identified by skeletal scintigraphy. Therefore, we sequentially performed docetaxel therapy followed by cabazitaxel. After the third cycle of cabazitaxel, his prostate-specific antigen level was stable at < 10 ng/mL, and no radiological progression was detected. The patient's formalin-fixed paraffin-embedded tumor biopsy specimen underwent multiple-gene testing by next-generation sequencing, which identified a FANCA homodeletion. No significant germline mutation was observed. CONCLUSIONS: We describe a case of aggressive, castration-resistant prostate cancer with FANCA homodeletion. Genomic analysis of prostate cancer tissue can be useful to determine optimal treatment of such cancers.

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Acute scrotum in children: Surgical indication and procedures

Asanuma H., Takahashi R., Oya M.

Japanese Journal of Clinical Urology (Japanese Journal of Clinical Urology) 74 ( 7 ) 472 - 477 2020

ISSN 03852393

腎移植におけるエベロリムス併用ステロイド早期離脱プロトコールの検討

香野日高, 中川健, 環聡, 坂巻裕介, 谷川実央, 高橋遼平, 森田伸也, 伊藤祐二郎, 萩生田純, 大家基嗣

Japanese Journal of Transplantation (The Japan Society for Transplantation) 55 ( 0 ) 358_2 - 358_2 2020

ISSN 0578-7947

我々はCNI、MMF、MP、BXLに加えてEVRを術後約2週間で導入しMPを2-3ヶ月で中止するプロトコールを用いている。CNIはトラフで術後1年ではCsAは50ng/ml、FKでは5ng/mlを目標としている。長期の成績を予測するために腎機能、拒絶反応、脈波伝導速度（PWV）、病理組織等について検討した。対象は2012年以降に当院および慶應義塾大学病院にて施行した生体腎移植症例76例(平均48.5歳)である。術後1年のsCrは1.41±0.58mg/dl、術後5年は1.49±0.79mg/dlであった。BPARはABO適合移植では11.5%(6/52例)、ABO不適合移植では33.3%(8/24例)であったが8例中7例がEVR開始前の術後早期の発症であった。ステロイドは68例(89.5％)、術後平均4.0ヶ月で中止できた。中止できなかった8例は全てARによりステロイド継続を余儀なくされた症例であった。baPWV値は、術前は1660±376cm/s、術後1年は1465±308cm/sであり、有意に低下していた（p<0.05）。1年後の病理組織において1時間生検と比較した非増悪が、cvスコアで59例(77.6%)、aahスコアで63例(82.9%)であった。EVRを使用しMPを早期に中止しCNIを減量することで、術後良好な経過が得られた。

Biomarkers Towards New Era of Therapeutics for Metastatic Renal Cell Carcinoma

Mizuno Ryuichi, Oya Mototsugu

KIDNEY CANCER 4 ( 2 ) 61 - 69 2020

ISSN 2468-4562

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膀胱・前立腺/腟・子宮横紋筋肉腫　機能温存と再建術

浅沼宏, 大家基嗣

小児外科 52 1270 - 1275 2020

Splenic cord capillary hemangioma with non-islet cell tumor hypoglycemia: a case report.

Tatsuaki Daimon, Takeo Kosaka, Minoru Horinaga, Junichi Saito, Yoshito Ueyama, Shoji Matsuzaki, Mototsugu Oya

Diagnostic pathology (BMC) 14 ( 1 ) 135 - 135 2019.12

Research paper (scientific journal), Joint Work

BACKGROUND: Splenic cord capillary hemangioma is a rare benign vascular lesion classified as a splenic hamartoma. On the other hand, non-islet cell tumor hypoglycemia (NICTH) is one of the rare causes of spontaneous hypoglycemia and is considered to be one of the paraneoplastic syndromes. To the best of our knowledge, this is the first reported case of a splenic cord capillary hemangioma with NICTH. CASE PRESENTATION: A 25-year-old male was referred to our hospital with hypoglycemia. Except for his low blood sugar, there were no abnormal findings from laboratory tests, which included an endocrinological examination. Enhanced computed tomography confirmed the presence of a solid mass measuring about 6 cm in the retroperitoneum, and a tumorectomy was performed. During this operation, it became clear that the tumor turned out to be a splenic parenchyma, and as a result, a total splenectomy was performed. Microscopically, we diagnosed this as a cord capillary hemangioma, and through immunohistochemistry, we found that some tumor cells were positive for insulin-like growth factor -II. Fortunately, the hypoglycemia-related symptoms disappeared after surgical resection was performed. The patient is still alive and well without evidence of local tumor recurrence 15 years after the operation. CONCLUSIONS: Splenic cord capillary hemangioma, one of the types of splenic hamartomas, is a very rare benign vascular lesion and might be associated with hypoglycemia thought to be NICTH.

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ASO Author Reflections: Could Laparoscopic Surgery Have the Same Long-Term Oncological Outcomes as Open Radical Nephroureterectomy in T3N0M0 Upper Tract Urothelial Carcinoma? A Multicenter Cohort Study Adjusted by Propensity Score Matching.

Keisuke Shigeta, Eiji Kikuchi, Mototsugu Oya

Annals of surgical oncology (SPRINGER) 26 ( Suppl 3 ) 815 - 816 2019.12

Research paper (scientific journal), Joint Work, ISSN 1068-9265

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A first Japanese case of neuroendocrine prostate cancer accompanied by lung and brain metastasis with somatic and germline BRCA2 mutation.

Takeo Kosaka, Hiroshi Hongo, Eriko Aimono, Kazuhiro Matsumoto, Tetsu Hayashida, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Pathology international (WILEY) 69 ( 12 ) 715 - 720 2019.12

Research paper (scientific journal), Joint Work, Accepted, ISSN 1320-5463

Germline mutations and copy number changes in DNA damage repair (DDR) genes such as BRCA2 are associated with aggressive forms of prostate cancer (PCa). Although the prevalence of BRCA2 variants in PCa is increasing in Japan, the genomic and biological implications in Japanese patients are unclear. An 81-year-old male presented with prostatic adenocarcinoma with neuroendocrine differentiation accompanied by metastatic lung nodule and brain metastases. Platinum-based doublet chemotherapy combined with etoposide resulted in partial and complete remissions of brain and lung metastases, respectively. Next-generation sequencing of biopsy and peripheral blood samples demonstrated a somatic BRCA2 mutation at c.7008-2A>C and a germline mutation at p.E2877*. The patient's son had been diagnosed with breast cancer 2.5 years ago and was found to have the same germline BRCA2 mutation. BRCA2 mutation increases the risks of aggressive PCa and other cancer types in Japanese males. These forms may be highly responsive to platinum-based chemotherapy.

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Biopsy-diagnosed renal granuloma after intravesical bacillus Calmette-Guérin therapy for bladder carcinoma: a case series and review of the literature.

Keiichi Narita, Hirotaka Akita, Eiji Kikuchi, Tadaki Nakahara, Shigeo Okuda, Seishi Nakatsuka, Mototsugu Oya, Masahiro Jinzaki

BJR case reports (BRITISH INST RADIOLOGY) 5 ( 4 ) 2019.12

Joint Work, ISSN 2055-7159

Renal granuloma is a rare complication affecting the kidneys after intravesical bacillus Calmette-Guérin (BCG) therapy for bladder carcinoma. Our case series review describes the imaging and histopathological findings of BCG-induced renal granulomas. All three renal granulomas, which were located in the upper pole, had a solitary mass-like appearance. The mean diameter was 31.3 mm. In the two cases, the lesion was homogeneously enhanced on post-contrast CT, and presented homogeneous low signal intensity on T2 weighted imaging (T2WI) and iso-signal intensity on diffusion-weighted imaging (DWI). Both lesions had increased fludeoxyglucose (FDG) uptake. Histological examinations revealed granulomatous inflammation with fibrosis. The third case showed a lesion having heterogeneous enhancement on CT, heterogeneous and slightly high signal intensity on T2WI, and high signal intensity on DWI. This case showed more severe inflammatory cell infiltration and less fibrosis than the former two cases did. It was suggested that the signal intensity on T2WI and DWI depends on the degree of inflammation and fibrosis in renal granuloma. It is currently challenging to distinguish renal granuloma from renal malignancy based on only imaging findings. Biopsies were helpful in confirming the diagnosis and avoiding unnecessary resection. Renal granuloma should be considered as a differential diagnosis when a renal mass is found in a patient with a history of intravesical BCG treatment.

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Classification of solid renal tumor with oncocytic/eosinophilic cytoplasm: is hybrid oncocytic/chromophobe renal tumor a subtype of oncocytoma, chromophobe renal cell carcinoma, or a distinct tumor entity?

Shuji Mikami, Naoto Kuroda, Yoji Nagashima, Chisato Ohe, Hiroyuki Hayashi, Ryuichi Mizuno, Mototsugu Oya, Kaori Kameyama

Annals of translational medicine (AME PUBL CO) 7 ( Suppl 8 ) S350 2019.12

Joint Work, ISSN 2305-5839

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A very-high-energy component deep in the Gamma-ray Burst afterglow

H. Abdalla R. Adam F. Aharonian F. Ait Benkhali E. O. Anguener M. Arakawa, C. Arcaro, C. Armand, H. Ashkar, M. Backes, V. Barbosa Martins, M. Barnard Y. Becherini, D. Berge, K. Bernloehr, E. Bissaldi, R. Blackwell, M. Boettcher, C. Boisson, J. Bolmont, S. Bonnefoy, J. Bregeon, M. Breuhaus, F. Brun, P. Brun, M. Bryan, M. Buechele, T. Bulik, T. Bylund, M. Capasso, S. Caroff, A. Carosi, S. Casanova, M. Cerruti, T. Chand, S. Chandra, A. Chen, S. Colafrancesco, M. Curylo, I. D. Davids, C. Deil, J. Devin, P. deWilt, L. Dirson, A. Djannati-Atai, A. Dmytriiev, A. Donath, V. Doroshenko, J. Dyks, K. Egberts, G. Emery, J. -P. Ernenwein, S. Eschbach, K. Feijen, S. Fegan, A. Fiasson, G. Fontaine, S. Funk, M. Fuessling, S. Gabici, Y. A. Gallant, F. Gate, G. Giavitto, L. Giunti, D. Glawion, J. F. Glicenstein, D. Gottschall, M. -H. Grondin, J. Hahn, M. Haupt, G. Heinzelmann, G. Henri, G. Hermann, J. A. Hinton, W. Hofmann, C. Hoischen, T. L. Holch, M. Holler, D. Horns, D. Huber, H. Iwasaki, M. Jamrozy, D. Jankowsky, F. Jankowsky, A. Jardin-Blicq, I. Jung-Richardt, M. A. Kastendieck, K. Katarzynski, M. Katsuragawa, U. Katz, D. Khangulyan, B. Khelifi, J. King, S. Klepser, W. Kluzniak, N. Komin, K. Kosack, D. Kostunin, M. Kreter, G. Lamanna, A. Lemiere, M. Lemoine-Goumard, J. -P. Lenain, E. Leser, C. Levy, T. Lohse, I. Lypova, J. Mackey, J. Majumdar, D. Malyshev, V. Marandon, A. Marcowith, A. Mares, C. Mariaud, G. Marti-Devesa, R. Marx, G. Maurin, P. J. Meintjes, A. M. W. Mitchell, R. Moderski, M. Mohamed, L. Mohrmann, C. Moore, E. Moulin, J. Muller, T. Murach, S. Nakashima, M. de Naurois, H. Ndiyavala, F. Niederwanger, J. Niemiec, L. Oakes, P. O Brien, H. Odaka, S. Ohm, E. de Ona Wilhelmi, M. Ostrowski, I. Oya, M. Panter, R. D. Parsons, C. Perennes, P. -O. Petrucci, B. Peyaud, Q. Piel, S. Pita, V. Poireau, A. Priyana Noel, D. A. Prokhorov, H. Prokoph, G. Puehlhofer, M. Punch, A. Quirrenbach, S. Raab, R. Rauth, A. Reimer, O. Reimer, Q. Remy, M. Renaud, F. Rieger, L. Rinchiuso, C. Romoli, G. Rowell, B. Rudak, E. Ruiz-Velasco, V. Sahakian, S. Sailer, S. Saito, D. A. Sanchez, A. Santangelo, M. Sasaki, R. Schlickeiser, F. Schuessler, A. Schulz, H. M. Schutte, U. Schwanke, S. Schwemmer, M. Seglar-Arroyo, M. Senniappan, A. S. Seyffert, N. Shafi, K. Shiningayamwe, R. Simoni, A. Sinha, H. Sol, A. Specovius, M. Spir-Jacob, L. Stawarz, R. Steenkamp, C. Stegmann, C. Steppa, T. Takahashi, T. Tavernier, A. M. Taylor, R. Terrier, D. Tiziani, M. Tluczykont, C. Trichard, M. Tsirou, N. Tsuji, R. Tuffs, Y. Uchiyama, D. J. van der Walt, C. van Eldik, C. van Rensburg, B. van Soelen, G. Vasileiadis, J. Veh, C. Venter, P. Vincent, J. Vink, H. J. Voelk, T. Vuillaume, Z. Wadiasingh, S. J. Wagner, R. White, A. Wierzcholska, R. Yang, H. Yoneda, M. Zacharias, R. Zanin, A. A. Zdziarski, A. Zech, A. Ziegler, J. Zorn, N. Zywucka, F. de Palma, M. Axelsson, O. J. Roberts

2019.11

Gamma-ray bursts (GRBs) are brief flashes of gamma rays, considered to be the
most energetic explosive phenomena in the Universe. The emission from GRBs
comprises a short (typically tens of seconds) and bright prompt emission,
followed by a much longer afterglow phase. During the afterglow phase, the
shocked outflow -- produced by the interaction between the ejected matter and
the circumburst medium -- slows down, and a gradual decrease in brightness is
observed. GRBs typically emit most of their energy via gamma-rays with energies
in the kiloelectronvolt-to-megaelectronvolt range, but a few photons with
energies of tens of gigaelectronvolts have been detected by space-based
instruments. However, the origins of such high-energy (above one
gigaelectronvolt) photons and the presence of very-high-energy (more than 100
gigaelectronvolts) emission have remained elussive. Here we report observations
of very-high-energy emission in the bright GRB 180720B deep in the GRB
afterglow -ten hours after the end of the prompt emission phase, when the X-ray
flux had already decayed by four orders of magnitude. Two possible explanations
exist for the observed radiation: inverse Compton emission and synchrotron
emission of ultrarelativistic electrons. Our observations show that the energy
fluxes in the X-ray and gamma-ray range and their photon indices remain
comparable to each other throughout the afterglow. This discovery places
distinct constraints on the GRB environment for both emission mechanisms, with
the inverse Compton explanation alleviating the particle energy requirements
for the emission observed at late times. The late timing of this detection has
consequences for the future observations of GRBs at the highest energies.

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Advances in targeted alpha therapy for prostate cancer

De Vincentis G., Gerritsen W., Gschwend J.E., Hacker M., Lewington V., O'Sullivan J.M., Oya M., Pacilio M., Parker C., Shore N., Sartor O.

Annals of Oncology (Annals of Oncology) 30 ( 11 ) 1728 - 1739 2019.11

ISSN 09237534

© 2019 THE AUTHORS Amongst therapeutic radiopharmaceuticals, targeted alpha therapy (TαT) can deliver potent and local radiation selectively to cancer cells as well as the tumor microenvironment and thereby control cancer while minimizing toxicity. In this review, we discuss the history, progress, and future potential of TαT in the treatment of prostate cancer, including dosimetry-individualized treatment planning, combinations with small-molecule therapies, and conjugation to molecules directed against antigens expressed by prostate cancer cells, such as prostate-specific membrane antigen (PSMA) or components of the tumor microenvironment. A clinical proof of concept that TαT is efficacious in treating bone-metastatic castration-resistant prostate cancer has been demonstrated by radium-223 via improved overall survival and long-term safety/tolerability in the phase III ALSYMPCA trial. Dosimetry calculation and pharmacokinetic measurements of TαT provide the potential for optimization and individualized treatment planning for a precision medicine-based cancer management paradigm. The ability to combine TαTs with other agents, including chemotherapy, androgen receptor-targeting agents, DNA repair inhibitors, and immuno-oncology agents, is under investigation. Currently, TαTs that specifically target prostate cancer cells expressing PSMA represents a promising therapeutic approach. Both PSMA-targeted actinium-225 and thorium-227 conjugates are under investigation. The described clinical benefit, safety and tolerability of radium-223 and the recent progress in TαT trial development suggest that TαT occupies an important new role in prostate cancer treatment. Ongoing studies with newer dosimetry methods, PSMA targeting, and novel approaches to combination therapies should expand the utility of TαT in prostate cancer treatment.

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A NOVEL RISK BASED APPROACH SIMULATING ONCOLOGIC SURVEILLANCE ACCORDING TO SMOKING STATUS AFTER RADICAL NEPHROURETERECTOMY WITH UPPER TRACT UROTHELIAL CARCINOMA

Shigeta Keisuke, Eiji Kikuchi, Masayuki Hagiwara, Takayuki Abe, Koichiro Ogihara, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 30 ( 4 ) E1197 - E1197 2019.11

Joint Work, ISSN 0923-7534

Neutrophil-to-lymphocyte ratio is a useful biomarker for predicting worse clinical outcome in chemo-resistant urothelial carcinoma patients treated with pembrolizumab

Ogihara K., Kikuchi E., Okabe T., Hattori S., Yamashita R., Yoshimine S., Shirotake S., Matsumoto K., Mizuno R., Hara S., Oyama M., Niwakawa M., Oya M.

ANNALS OF ONCOLOGY 30 2019.11

ISSN 0923-7534

TNFAIP2 expression induces epithelial-to-mesenchymal transition and confers platinum resistance in urothelial cancer cells.

Naoya Niwa, Nobuyuki Tanaka, Hiroshi Hongo, Yasumasa Miyazaki, Kimiharu Takamatsu, Ryuichi Mizuno, Eiji Kikuchi, Shuji Mikami, Takeo Kosaka, Mototsugu Oya

Laboratory investigation; a journal of technical methods and pathology (NATURE PUBLISHING GROUP) 99 ( 11 ) 1702 - 1713 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0023-6837

Cisplatin (CDDP)-based chemotherapy is the gold standard treatment for many types of cancer. However, the phenotypic hallmark of tumors often changes after CDDP treatment, with the acquisition of epithelial-to-mesenchymal transition (EMT) and platinum resistance. Furthermore, the mechanisms by which cancer cells acquire EMT under the control of CDDP remain unclear. Following an investigation of urothelial carcinoma (UC) before and after the acquisition of platinum resistance, we offer the new target TNFAIP2, which led to EMT and tumor invasion in platinum-treated UC cells. TNFAIP2 expression in cancer was examined at the protein and transcriptional levels. A potential target for TNFAIP2 during EMT was assessed by microarray. Clinically, upregulated TNFAIP2 expression was identified as a significant predictor of mortality following surgery in three different cohorts of patients with UC (n = 156, n = 119, and n = 54). Knockdown of TNFAIP2 resulted in upregulation of E-cadherin expression and downregulation of TWIST1 expression, which decreased motile function in platinum-resistant UC cells. TNFAIP2 overexpression led to downregulation of E-cadherin expression and upregulation of TWIST1 expression in platinum-naïve UC cells. Clinical investigation of matched pre- and post-CDDP-treated UC sections confirmed upregulation of TNFAIP2 expression in CDDP-treated tumors but downregulation of E-cadherin expression. Global gene expression analysis following TNFAIP2 knockdown identified MTDH as a positive regulator of TNFAIP2-derived EMT acquisition in cancer cells. The present results suggest a relationship between TNFAIP2 and EMT in cancers under the control of CDDP, in which MTDH expression levels in cancer cells are vital for promoting TNFAIP2-derived EMT acquisition.

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Renal Trauma Classification and Management: Validating the Revised Renal Injury Grading Scale

Satoshi Yazawa, Mototsugu Oya, Yosuke Nakajima

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 202 ( 5 ) 1002 - 1002 2019.11

Joint Work, ISSN 0022-5347

Usefulness of contrast-enhanced ultrasonography for diagnosis of renal cell carcinoma in dialysis patients: Comparison with computed tomography.

Masahiro Hashimoto, Kiyoshi Ohkuma, Hirotaka Akita, Yoshitake Yamada, Seishi Nakatsuka, Ryuichi Mizuno, Mototsugu Oya, Masahiro Jinzaki

Medicine (LIPPINCOTT WILLIAMS & WILKINS) 98 ( 47 ) e18053 2019.11

Research paper (scientific journal), Joint Work, Accepted, ISSN 0025-7974

AIMS: To investigate the usefulness of contrast-enhanced ultrasonography for diagnosing renal cell carcinoma (RCC) in dialysis patients. MATERIAL AND METHODS: Of 1301 dialysis patients who underwent abdominal computed tomography (CT) between January 2012 and March 2017, 19 were suspected to have solid renal lesions; of these patients, 18 gave consent for and underwent contrast-enhanced ultrasonography with perflubutane in addition to CT; 13 underwent dynamic contrast-enhanced CT, and 5, who could not be administered iodinated contrast media, underwent unenhanced CT. The final diagnoses were based on histopathological findings or the presence/absence of enlargement of the lesion during follow-up. RESULTS: Of the 19 lesions in 18 patients, 14 were diagnosed as RCC and 5 as benign cysts. CT facilitated accurate diagnosis in 10/19 lesions (52.6%) with obvious enhancement (≥20 Hounsfield units [HU]), while definitive diagnosis by CT was difficult in 9 lesions: 2 lesions showed ambiguous enhancement (10-20 HU), 1 lesion was an inflammatory cyst with obvious enhancement, and 6 lesions were assessed by unenhanced CT. Compared with CT, contrast-enhanced ultrasonography allowed more accurate diagnosis (McNemar test, P = .02) in 17/19 lesions (89.5%, 14 RCC and 3 cysts; including all lesions assessed by unenhanced CT and 2 with ambiguous enhancement on CT), with 1 false-positive (inflammatory cyst with hyper-enhancement) and 1 false-negative result due to deep location of the lesion. CONCLUSIONS: Contrast-enhanced ultrasonography was useful for the diagnosis of RCC in dialysis patients with suspected solid renal lesions especially when contrast enhancement was not obvious on CT or contrast-enhanced CT could not be performed.

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特集希少癌に備える-いざという時のための基礎知識企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 73 ( 11 ) 785 - 785 2019.10

ISSN 0385-2393

特集希少癌に備える-いざという時のための基礎知識前立腺導管癌

小坂威雄, 萩原正幸, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 73 ( 11 ) 846 - 849 2019.10

ISSN 0385-2393

Ductal adenocarcinoma of the prostate

Kosaka T., Hagiwara M., Oya M.

Japanese Journal of Clinical Urology (Japanese Journal of Clinical Urology) 73 ( 11 ) 846 - 849 2019.10

ISSN 03852393

Randomized phase III trial of avelumab plus axitinib vs sunitinib as first-line treatment for advanced renal cell carcinoma: JAVELIN renal 101 Japanese subgroup analysis

Uemura M., Tomita Y., Miyake H., Hatakeyama S., Kanayama H-O., Numakura K., Takagi T., Kato T., Eto M., Obara W., Uemura H., Motzer R. J., Fujii Y., Kamei Y., Oya M.

ANNALS OF ONCOLOGY 30 2019.10

ISSN 0923-7534

Long-Term Oncologic Outcomes of Laparoscopic Versus Open Radical Nephroureterectomy for Patients with T3N0M0 Upper Tract Urothelial Carcinoma: A Multicenter Cohort Study with Adjustment by Propensity Score Matching.

Keisuke Shigeta, Eiji Kikuchi, Takayuki Abe, Masayuki Hagiwara, Koichiro Ogihara, Tadanori Anno, Kota Umeda, Yuto Baba, Tansei Sanjo, Kazunori Shojo, Ryuichi Mizuno, Mototsugu Oya

Annals of surgical oncology (SPRINGER) 26 ( 11 ) 3774 - 3781 2019.10

Research paper (scientific journal), Joint Work, Accepted, ISSN 1068-9265

BACKGROUND: This study aimed to investigate the long-term oncologic outcomes of laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) for patients with clinical and pathologic T3N0M0 upper tract urothelial carcinoma (UTUC). METHODS: Among 375 UTUC patients who underwent radical nephroureterectomy, this study identified 144 pT3N0M0 patients as cohort 1 after propensity score (PS) matching. Among 399 UTUC patients, the study identified 110 cT3N0M0 patients as cohort 2 after PS matching. Oncologic outcomes such as intravesical recurrence-free survival (IVRFS) and cancer-specific survival (CSS) were assessed by multivariate Cox's regression analysis. RESULTS: Cohort 1 of pT3N0M0 UTUC had 3-year CSS and IVRFS rates of 67.9 and 52.7%, respectively, in the LRNU group, which were significantly lower than in the ORNU group (81.4%, p = 0.039 and 71.6%, p = 0.046). The multivariate Cox's regression analysis identified the type of surgical approach (LRNU vs. ORNU) as one of the independent prognostic factors for CSS (hazard rate [HR], 1.88, p = 0.043) and IVRFS (HR, 1.75, p = 0.049). Cohort 2 of cT3N0M0 UTUC had 3-year CSS and IVRFS rates of 48.5 and 41.4%, respectively, in the LRNU group, which were significantly lower than in the ORNU group (65.8%, p = 0.049 and 67.2%, p = 0.047), and the type of surgical approach (LRNU vs. ORNU) remained as one of the independent prognostic factors for CSS and IVRFS. CONCLUSIONS: Based on clinical and pathologic T3N0M0 UTUC populations after PS adjustments, LRNU resulted in poorer CSS and IVRFS than ORNU.

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Japanese Case of Enzalutamide-Resistant Prostate Cancer Harboring a SPOP Mutation With Scattered Allelic Imbalance: Response to Platinum-Based Therapy.

Keitaro Watanabe, Takeo Kosaka, Eriko Aimono, Hiroshi Hongo, Shuji Mikami, Hiroshi Nishihara, Mototsugu Oya

Clinical genitourinary cancer (CIG MEDIA GROUP, LP) 17 ( 5 ) e897 - e902 2019.10

Research paper (scientific journal), Joint Work, ISSN 1558-7673

Genomic analysis of tumor biopsy specimens is critical for precision medicine, but there are no consensus guidelines on treatment plans for specific mutations. Herein we present a case of enzalutamide-resistant prostate cancer (PC) harboring a speckle-type pox virus and zinc finger protein (SPOP) mutation with scattered allelic imbalance successfully treated using platinum-based treatment.A 71-year-old man was diagnosed with castration-resistant PC and bone metastases. He was initial treated using enzalutamide and denosumab, and subsequently administrated radium-223. His prostate-specific antigen level initially decreased during treatment, but eventually began to rise.Magnetic resonance imaging revealed progressive PC invading the bladder, so we performed channeling transurethral resection of bladder tumor. The pathological diagnosis was adenocarcinoma with neuroendocrine differentiation.Carboplatin with etoposide therapy was initiated and no obvious tumor progression was detected thereafter. Genetic sequencing identified a SPOP p.Y87N mutation with scattered allelic imbalance.These findings suggest that enzalutamide-resistant PC with SPOP loss of function might be highly responsive to platinum-based therapy.Mutational analyses might provide useful information for treatment guidance of refractory PC. (C) 2019 Elsevier Inc. All rights reserved.

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Resolving the Crab pulsar wind nebula at teraelectronvolt energies

H. E. S. S. Collaboration, H. Abdalla, F. Aharonian, F. Ait Benkhali, E. O. Angüner, M. Arakawa, C. Arcaro, C. Arm, M. Backes, M. Barnard, Y. Becherini, J. Becker Tjus, D. Berge, K. Bernlöhr, R. Blackwell, M. Böttcher, C. Boisson, J. Bolmont, S. Bonnefoy, P. Bordas, J. Bregeon, F. Brun, P. Brun, M. Bryan, M. Büchele, T. Bulik, T. Bylund, M. Capasso, S. Caroff, A. Carosi, S. Casanova, M. Cerruti, N. Chakraborty, T. Ch, S. Ch, R. C. G. Chaves, A. Chen, S. Colafrancesco, B. Condon, I. D. Davids, C. Deil, J. Devin, P. deWilt, L. Dirson, A. Djannati-Ataï, A. Dmytriiev, A. Donath, V. Doroshenko, L. O'C. Drury, J. Dyks, K. Egberts, G. Emery, J. -P. Ernenwein, S. Eschbach, S. Fegan, A. Fiasson, G. Fontaine, S. Funk, M. Füßling, S. Gabici, Y. A. Gallant, F. Gaté, G. Giavitto, D. Glawion, J. F. Glicenstein, D. Gottschall, M. -H. Grondin, J. Hahn, M. Haupt, G. Heinzelmann, G. Henri, G. Hermann, J. A. Hinton, W. Hofmann, C. Hoischen, T. L. Holch, M. Holler, D. Horns, D. Huber, H. Iwasaki, A. Jacholkowska, M. Jamrozy, D. Jankowsky, F. Jankowsky, L. Jouvin, I. Jung-Richardt, M. A. Kastendieck, K. Katarzyński, M. Katsuragawa, U. Katz, D. Khangulyan, B. Khélifi, J. King, S. Klepser, W. Kluźniak, Nu. Komin, K. Kosack, M. Kraus, G. Lamanna, J. Lau, J. Lefaucheur, A. Lemière, M. Lemoine-Goumard, J. -P. Lenain, E. Leser, T. Lohse, R. López-Coto, I. Lypova, D. Malyshev, V. Mar, A. Marcowith, C. Mariaud, G. Martí-Devesa, R. Marx, G. Maurin, P. J. Meintjes, A. M. W. Mitchell, R. Moderski, M. Mohamed, L. Mohrmann, C. Moore, E. Moulin, T. Murach, S. Nakashima, M. de Naurois, H. Ndiyavala, F. Niederwanger, J. Niemiec, L. Oakes, P. O'Brien, H. Odaka, S. Ohm, M. Ostrowski, I. Oya, M. Panter, R. D. Parsons, C. Perennes, P. -O. Petrucci, B. Peyaud, Q. Piel, S. Pita, V. Poireau, A. Priyana Noel, D. A. Prokhorov, H. Prokoph, G. Pühlhofer, M. Punch, A. Quirrenbach, S. Raab, R. Rauth, A. Reimer, O. Reimer, M. Renaud, F. Rieger, L. Rinchiuso, C. Romoli, G. Rowell, B. Rudak, E. Ruiz-Velasco, V. Sahakian, S. Saito, D. A. Sanchez, A. Santangelo, M. Sasaki, R. Schlickeiser, F. Schüssler, A. Schulz, H. Schutte, U. Schwanke, S. Schwemmer, M. Seglar-Arroyo, M. Senniappan, A. S. Seyffert, N. Shafi, I. Shilon, K. Shiningayamwe, R. Simoni, A. Sinha, H. Sol, A. Specovius, M. Spir-Jacob, Ł. Stawarz, R. Steenkamp, C. Stegmann, C. Steppa, T. Takahashi, J. -P. Tavernet, T. Tavernier, A. M. Taylor, R. Terrier, D. Tiziani, M. Tluczykont, C. Trichard, M. Tsirou, N. Tsuji, R. Tuffs, Y. Uchiyama, D. J. van der Walt, C. van Eldik, C. van Rensburg, B. van Soelen, G. Vasileiadis, J. Veh, C. Venter, P. Vincent, J. Vink, F. Voisin, H. J. Völk, T. Vuillaume, Z. Wadiasingh, S. J. Wagner, R. M. Wagner, R. White, A. Wierzcholska, R. Yang, H. Yoneda, D. Zaborov, M. Zacharias, R. Zanin, A. A. Zdziarski, A. Zech, A. Ziegler, J. Zorn, N. Żywucka

2019.09

The Crab nebula is one of the most studied cosmic particle accelerators,
shining brightly across the entire electromagnetic spectrum up to very
high-energy gamma rays. It is known from radio to gamma-ray observations that
the nebula is powered by a pulsar, which converts most of its rotational energy
losses into a highly relativistic outflow. This outflow powers a pulsar wind
nebula (PWN), a region of up to 10~light-years across, filled with relativistic
electrons and positrons. These particles emit synchrotron photons in the
ambient magnetic field and produce very high-energy gamma rays by Compton
up-scattering of ambient low-energy photons. While the synchrotron morphology
of the nebula is well established, it was up to now not known in which region
the very high-energy gamma rays are emitted. Here we report that the Crab
nebula has an angular extension at gamma-ray energies of 52 arcseconds
(assuming a Gaussian source width), significantly larger than at X-ray
energies. This result closes a gap in the multi-wavelength coverage of the
nebula, revealing the emission region of the highest energy gamma rays. These
gamma rays are a new probe of a previously inaccessible electron and positron
energy range. We find that simulations of the electromagnetic emission
reproduce our new measurement, providing a non-trivial test of our
understanding of particle acceleration in the Crab nebula.

Accidental Hypothermia Treated by Hemodialysis in the Acute Phase: Three Case Reports and a Review of the Literature.

Tetsushi Murakami, Tadashi Yoshida, Arata Kurokochi, Kimiharu Takamatsu, Yu Teranishi, Keisuke Shigeta, Satoshi Tamaki, Shinya Morita, Ryuichi Mizuno, Mototsugu Oya

Internal medicine (Tokyo, Japan) (JAPAN SOC INTERNAL MEDICINE) 58 ( 18 ) 2743 - 2748 2019.09

Research paper (scientific journal), Joint Work, Accepted, ISSN 0918-2918

Accidental hypothermia is defined as a core body temperature <35°C. Even with the use of multiple active rewarming methods, it has a high mortality rate. No standard treatment strategy for moderate or severe hypothermia in the absence of cardiac arrest has yet been established. We herein report three patients with severe or moderate accidental hypothermia who were treated by hemodialysis in the acute phase. This case report with a literature review describes the usefulness of hemodialysis for the treatment of moderate and severe accidental hypothermia without cardiac arrest.

[Risk Classification and Nivolumab plus Ipilimumab Combination Therapy for Treatment of Renal Cell Carcinoma].

Oya M, Tajima Y, Kabu K

Gan to kagaku ryoho. Cancer & chemotherapy 46 ( 9 ) 1397 - 1404 2019.09

Research paper (scientific journal), Joint Work, ISSN 0385-0684

The International Metastatic Renal Cell Carcinoma Database Consortium(IMDC)classification is often used to predict the prognosis of patients treated with molecularly targeted agents. In this review, the authors describe the prognostic value of the neutrophil-lymphocyte ratio and C-reactive protein for Japanese patients with renal cell carcinoma. Both markers may help identify which patients are likely to have a poor prognosis despite molecularly targeted therapy. In these circumstances, the CheckMate 214 trial showed that nivolumab plus ipilimumab combination therapy was superior to sunitinib for the treatment of patients with intermediate/poor prognosis. As a consequence, the combination of nivolumab plus ipilimumab is now positioned as standard first-line treatment for renal cell carcinoma, and the IMDCclassification is recommended as an aid in treatment decisions. Although careful management of immune-related adverse events is necessary, nivolumab plus ipilimumab combination therapy is expected to improve the outcomes of renal cell carcinoma for which the prognosis is otherwise generally poor.

Erectile function recovery at 12 months after radical prostatectomy for prostate cancer is not associated with overall survival.

Toshikazu Takeda, Nicole E Benfante, Melissa Assel, John P Mulhall, Mototsugu Oya, Karim A Touijer

International journal of urology : official journal of the Japanese Urological Association (WILEY) 26 ( 9 ) 934 - 935 2019.09

Research paper (scientific journal), Joint Work, ISSN 0919-8172

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Risk classification and nivolumab plus ipilimumab combination therapy for treatment of renal cell carcinoma

Oya M., Tajima Y., Kabu K.

Japanese Journal of Cancer and Chemotherapy (Japanese Journal of Cancer and Chemotherapy) 46 ( 9 ) 1397 - 1404 2019.09

ISSN 03850684

© 2019 Japanese Journal of Cancer and Chemotherapy Publishers Inc.. All rights reserved. The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) classification is often used to predict the prognosis of patients treated with molecularly targeted agents. In this review, the authors describe the prognostic value of the neutrophil-lymphocyte ratio and C-reactive protein for Japanese patients with renal cell carcinoma. Both markers may help identify which patients are likely to have a poor prognosis despite molecularly targeted therapy. In these circumstances, the CheckMate 214 trial showed that nivolumab plus ipilimumab combination therapy was superior to sunitinib for the treatment of patients with intermediate/poor prognosis. As a consequence, the combination of nivolumab plus ipilimumab is now positioned as standard first-line treatment for renal cell carcinoma, and the IMDC classification is recommended as an aid in treatment decisions. Although careful management of immune-related adverse events is necessary, nivolumab plus ipilimumab combination therapy is expected to improve the outcomes of renal cell carcinoma for which the prognosis is otherwise generally poor.

A Novel Risk-based Approach Simulating Oncological Surveillance After Radical Nephroureterectomy in Patients with Upper Tract Urothelial Carcinoma.

Keisuke Shigeta, Eiji Kikuchi, Takayuki Abe, Masayuki Hagiwara, Koichiro Ogihara, Tadatsugu Anno, Kota Umeda, Yuto Baba, Tansei Sanjo, Kazunori Shojo, Shuji Mikami, Ryuichi Mizuno, Mototsugu Oya

European urology oncology (ELSEVIER) 3 ( 6 ) 756 - 763 2019.08

Research paper (scientific journal), Joint Work, Accepted

BACKGROUND: The current guideline lacks evidence for creating individualized surveillance strategies for upper tract urothelial carcinoma (UTUC) patients after radical nephroureterectomy (RNU). OBJECTIVE: To create a novel risk model and to simulate individualized surveillance duration that dynamically illustrates the changing risk relationship of UTUC-related death and non-UTUC death, considering the impact of cigarette smoking. DESIGN, SETTING, AND PARTICIPANTS: This multicenter cohort study comprised 714 pTa-T4N0M0 UTUC patients, with a median follow-up duration of 65mo. There were 279 (39.1%) nonsmokers, 260 (36.4%) current smokers, and 175 (24.5%) ex-smokers. INTERVENTION: All patients underwent RNU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The risks of UTUC death and non-UTUC death over time were estimated using parametric models for time to failure with Weibull distributions. Age-specific, stage-specific, and smoking status-specific surveillance durations were simulated based upon Weibull estimates. RESULTS AND LIMITATIONS: The hazard rate (HR) of non-UTUC death gradually increased over time in all age groups regardless of the smoking status, whereas that of UTUC-related death decreased markedly according to the pathological T (pT) stage and was affected by the smoking status. Among current smokers, the baseline HR of UTUC-related death in pT3/4 was higher than that of pT ≤2 and remained high even 10yr after RNU. Among heavy smokers, the HR of UTUC-related death in all pT stages was highest at baseline and remained high after RNU, compared with nonsmokers, current smokers, or ex-smokers. We simulated specific time points when the risk of non-UTUC death was greater than that of UTUC-related death. Among patients ≥80yr of with pT3N0M0, the risk of non-UTUC death was greater than that of UTUC-related death 1yr after RNU in nonsmokers, but 7yr for heavy smokers. CONCLUSIONS: Our result revealed that smokers bear a long-term risk burden of UTUC-related death more than the risk of non-UTUC death. For UTUC smokers, longer-term surveillance duration is recommended even in elderly stage. PATIENT SUMMARY: In the present study, we evaluated the risk transition of upper tract urothelial carcinoma (UTUC)-related death and non-cancer-related death over time. We found that smoking weighed a huge impact upon UTUC-related death compared with death from other cause, and therefore, we created a more individualized surveillance duration model.

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Impact of pegfilgrastim as primary prophylaxis for metastatic castration-resistant prostate cancer patients undergoing cabazitaxel treatment: an open-label study in Japan.

Takeo Kosaka, Hiroji Uemura, Makoto Sumitomo, Kenichi Harada, Mikio Sugimoto, Narihiko Hayashi, Kazuhiro Yoshimura, Satoshi Fukasawa, Evelyne Ecstein-Fraisse, Yoshinori Sunaga, Mototsugu Oya

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 49 ( 8 ) 766 - 771 2019.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0368-2811

BACKGROUND: Cabazitaxel is an efficacious treatment for patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel, but febrile neutropenia during the first cycle is a frequent complication. Asian patients are at increased risk of febrile neutropenia. Although primary prophylaxis with granulocyte colony-stimulating factor can reduce the incidence, its efficacy has not been prospectively demonstrated in Japanese patients with cabazitaxel treatment. METHODS: PEGAZUS, a prospective, single-arm study conducted at eight clinical sites in Japan, enrolled 21 heavily pretreated patients with metastatic castration-resistant prostate cancer. Patients received cabazitaxel 25 mg/m2 every 3 weeks, up to 10 cycles. Oral prednisolone 10 mg was taken daily. Pegfilgrastim 3.6 mg was administered at least 24 h after the cabazitaxel infusion. The primary endpoint was the incidence of febrile neutropenia in the first cycle. RESULTS: The median number of treatment cycles was seven. The relative dose intensity of cabazitaxel was 67.4% (range, 53.2-91.3%). Two of 21 patients (9.5%) experienced febrile neutropenia in the first cycle. This rate was lower than the rate (43%) previously observed without prophylactic granulocyte colony-stimulating factor in a similar patient population. Six patients showed a prostate-specific antigen response (28.6%). Three of four patients evaluable for tumor response had stable disease and one had progressive disease. Grade ≥3 diarrhea was not observed. Primary prophylaxis with granulocyte colony-stimulating factor significantly reduced the incidence of febrile neutropenia in this study. CONCLUSIONS: Cabazitaxel plus granulocyte colony-stimulating factor is safe and effective for Japanese patients with metastatic castration-resistant prostate cancer who have previously progressed on docetaxel. Clinical trial registration: ClinicalTrials.gov (NCT02441894).

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Efficacy of systemic therapy for metastatic non clear renal cell carcinoma

Mizuno R., Takamatsu K., Hayakawa N., Tanaka N., Kosaka T., Oya M.

INTERNATIONAL JOURNAL OF UROLOGY 26 192 - 192 2019.08

ISSN 0919-8172

Serum Lactate Dehydrogenase Before Nivolumab Treatment Could Be a Therapeutic Prognostic Biomarker for Patients With Metastatic Clear Cell Renal Cell Carcinoma.

Suguru Shirotake, Kimiharu Takamatsu, Ryuichi Mizuno, G O Kaneko, Koshiro Nishimoto, Mototsugu Oya, Masafumi Oyama

Anticancer research (INT INST ANTICANCER RESEARCH) 39 ( 8 ) 4371 - 4377 2019.08

Research paper (scientific journal), Joint Work, Accepted, ISSN 0250-7005

BACKGROUND/AIM: The purpose of this retrospective study was to identify the predictive biomarkers of response to pretreatment for patients with metastatic renal cell carcinoma (mRCC) treated with nivolumab. MATERIALS AND METHODS: The subjects were 54 patients treated with nivolumab for mRCC with a clear cell component (mccRCC) between September 2016 and February 2018. We analyzed the impact of serum biomarkers (lactate dehydrogenase [LDH], neutrophil-to-lymphocyte ratio, and C-reactive protein) on patients treated with nivolumab. We adopted the International Metastatic Renal Cell Carcinoma Database Consortium prognostic model using six clinical factors (0=favorable, 1 or 2=intermediate, 3 to 6=poor risk groups, respectively). RESULTS: The prognostic risk classification (non-poor vs. poor) and serum LDH levels were correlated with the objective response of nivolumab treatment for mccRCC. Elevated serum LDH levels at baseline were an independent biomarker for progression-free survival (PFS) of mccRCC patients receiving nivolumab [HR=2.268 (95%CI=1.014-5.051), p=0.046]. Notably, high LDH levels were associated with a poorer PFS for patients in the favorable-risk group. CONCLUSION: Serum LDH levels at baseline before nivolumab treatment were associated with the objective response and clinical outcome of nivolumab treatment.

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Prospctive study of tadarafil treatment in patients treated with prostate brachytherapy

Hayakawa N., Mizuno R., Kikuchi E., Takamatsu K., Oya M.

INTERNATIONAL JOURNAL OF UROLOGY 26 76 - 77 2019.08

ISSN 0919-8172

PRETREATMENT ABSOLUTE MONOCYTE COUNT IS A NOVEL BIOMARKER FOR PREDICTING WORSE CLINICAL OUTCOME IN CHEMO-RESISTANT UROTHELIAL CARCINOMA PATIENTS TREATED WITH PEMBROLIZUMAB

Koichiro Ogihara, Eiji Kikuchi, Takashi Okabe, Ryo Yamashita, Shunsuke Yoshimine, Suguru Shirotake, Ryuto Nakazawa, Kazuhiro Matsumoto, Ryuichi Mizuno, Satoshi Hara, Masafumi Oyama, Takeshi Masuda, Masashi Niwakawa, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 26 9 - 10 2019.08

Joint Work, ISSN 0919-8172

限局性前立腺がんに対する腫瘍発生領域の臨床的検討

高松公晴, 松本一宏, 服部盛也, 田中伸之, 武田利和, 森田伸也, 小坂威雄, 水野隆一, 篠島利明, 菊地栄次, 浅沼宏, 大家基嗣

泌尿器外科 (医学図書出版(株)) 32 ( 8 ) 1011 - 1012 2019.08

ISSN 0914-6180

Interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy: a case report.

Yoshinori Yanai, Takeo Kosaka, Hiroshi Hongo, Mototsugu Oya

BMC cancer (BMC) 19 ( 1 ) 720 - 720 2019.07

Research paper (scientific journal), Joint Work, Accepted, ISSN 1471-2407

BACKGROUND: Interstitial pneumonitis is a rare reaction in a previously irradiated area of pulmonary or thoracic lesion after treatment with anticancer drugs such as taxanes. CASE PRESENTATION: A 66-year-old man presented with a fever and dyspnea after treatment with cabazitaxel for castration-resistant prostate cancer. He was treated with an intravenous broad-spectrum antimicrobial agent, however he complained of dyspnea and had a pulse oximetric saturation of 80% while breathing room air. The patients had been treated for bone metastases with 37.5 Gy to the thoracic spine (Th 7) as a local radiotherapy. Radiological images showed pulmonary interstitial opacities in the irradiated field of the both lungs. The steroid pulse therapy was started. The patient's dyspnea disappeared and the interstitial opacities had also improved. CONCLUSIONS: This report is a case of interstitial pneumonitis in a castration-resistant prostate cancer patient receiving cabazitaxel after thoracic radiation therapy.

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特集ハイリスク前立腺癌を深掘りする-その変遷とM0 CRPCの最新治療企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 73 ( 8 ) 509 - 509 2019.07

ISSN 0385-2393

Brachytherapy seeds as a nidus for urethral stone formation: A case report.

Ken Kamisawa, Takeo Kosaka, Hiroshi Hongo, Ryuichi Mizuno, Mototsugu Oya

IJU case reports 2 ( 4 ) 206 - 208 2019.07

Joint Work

Introduction: Iatrogenic foreign bodies can cause urolithiasis. However, iodine seeds used in brachytherapy are not a known cause of stone formation. We report a rare case of urethral stone formation with brachytherapy seeds determined to be the nidus, which occurred 9 years after permanent seed brachytherapy for prostate cancer. Case presentation: An 87-year-old man with a history of prostate cancer treated with brachytherapy presented to our hospital with macroscopic hematuria. He underwent transurethral resection of the mucosa with erythema 4 years after brachytherapy. Cystoscopy revealed urethral stones on the bladder neck. Transurethral lithotripsy was performed and the nidus of stone formation was revealed to be an aggregate of iodine seeds. Conclusion: In the course of the long-term follow-up after brachytherapy for prostate cancer, the possibility of the formation of the urethral stone associated with iodine seeds should be considered when gross hematuria is observed.

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Particle balance investigation with the combination of the hydrogen barrier model and rate equations of hydrogen state in long duration discharges on an all-metal plasma facing wall in QUEST

Hanada K., Yoshida N., Hasegawa M., Hatayama A., Okamoto K., Takagi I, Hirata T., Oya Y., Miyamoto M., Oya M., Shikama T., Kuzmin A., Wang Z. X., Long H., Idei H., Nagashima Y., Nakamura K., Watanabe O., Onchi T., Watanabe H., Tokunaga K., Higashijima A., Kawasaki S., Nagata T., Shimabukuro S., Takase Y., Murakami S., Gao X., Liu H., Qian J., Raman R., Ono M.

NUCLEAR FUSION 59 ( 7 ) 2019.07

ISSN 0029-5515

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Clinically complete response to abiraterone acetate in a patient with metastatic castration-resistant prostate cancer.

Yoshinori Yanai, Takeo Kosaka, Hiroshi Hongo, Mototsugu Oya

IJU case reports 2 ( 4 ) 187 - 189 2019.07

Joint Work

Introduction: Abiraterone acetate in combination with prednisone is now widely used for the treatment of castration-resistant prostate cancer. Case presentation: A 62-year-old patient with a bone metastatic castration-resistant prostate cancer was started on abiraterone acetate at a dose of 1000 mg a day along with 10 mg prednisone. In spite of castrate testosterone level, the laboratory test showed a relatively high level of serum testosterone, which was 21 ng/dL. Within 6 months, the patient achieved a complete prostate-specific antigen response. Follow-up bone scintigraphy demonstrated no area of intense uptake. He had a history of hyperlipidemia and was started on atorvastatin at home just after starting abiraterone acetate. Conclusion: This report is a rare case of a clinically complete response to abiraterone acetate in a patient with metastatic castration-resistant prostate cancer.

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CKD 患者におけるがん化学療法─透析患者を中心に Ⅱ　がん薬物療法の特性　6　分子標的薬-チロシンキナーゼ阻害薬

水野隆一, 大家基嗣

臨床透析 (日本メディカルセンター) 35 ( 7 ) 782 - 789 2019.06

ISSN 0910-5808

Complete response with early introduction of cabazitaxel in a patient with multiple lung metastases of castration-resistant prostate cancer following the early detection of metastases using liquid biopsy: a case report.

Takeo Kosaka, Hiroshi Hongo, Mototsugu Oya

BMC cancer (BMC) 19 ( 1 ) 562 - 562 2019.06

Research paper (scientific journal), Joint Work, Accepted, ISSN 1471-2407

BACKGROUND: Cabazitaxel (CBZ) chemotherapy for metastatic castration-resistant prostate cancer (mCRPC) is believed to be palliative because the radiological response rate is low and a durable response is rare. Here, we describe a rare case of a patient with mCRPC who was treated with CBZ chemotherapy and showed a durable radiological response and a complete biochemical response. CASE PRESENTATION: A 43-year-old man with prostate cancer and metastasis of the pubic bone underwent neoadjuvant androgen deprivation and docetaxel therapy, followed by laparoscopic prostatectomy, extended lymphadenectomy, and metastatectomy in 2014. Pathological examination revealed residual adenocarcinoma in the prostate and pubic bone (pathological T stage 3b, positive surgical margin). Following the operation, he received adjuvant radiation therapy (66 Gy) to the pelvic floor. His serum prostate-specific antigen (PSA) level decreased to < 0.01 ng/mL but gradually increased following docetaxel chemotherapy. Imaging findings indicated five tiny nodules in the bilateral lungs. Biopsy specimens are difficult to obtain and might not reflect the precise extent of the disease owing to heterogeneity in patients with CRPC. Thus, we performed liquid biopsy to isolate circulating tumor cells (CTCs), and overall 156 CTCs were detected per 7.5 mL. Almost all CTCs were androgen receptor-negative in the nucleus. We diagnosed the five nodules as lung metastases from docetaxel-resistant CRPC with few AR-signaling-dependent cancer cells. The patient was initiated on CBZ chemotherapy (25 mg/m2) according to the standard protocol in August 2016, instead of using a second-generation AR-targeting agent. After 2 cycles of CBZ chemotherapy, PSA level decreased to < 0.01 ng/mL and the lung metastases completely disappeared, with a reduced CTC count of < 5. To date, the patient has been receiving intermittent CBZ chemotherapy. CONCLUSIONS: We presented a rare case of a patient with mCRPC who was successfully treated with early CBZ chemotherapy. The early detection of metastasis using liquid biopsy enabled the introduction of early CBZ chemotherapy for docetaxel-resistant mCRPC.

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Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup 3-year follow-up analysis from the Phase III CheckMate 025 study.

Yoshihiko Tomita, Satoshi Fukasawa, Nobuo Shinohara, Hiroshi Kitamura, Mototsugu Oya, Masatoshi Eto, Kazunari Tanabe, Mitsuru Saito, Go Kimura, Junji Yonese, Masahiro Yao, Hirotsugu Uemura

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 49 ( 6 ) 506 - 514 2019.06

Research paper (scientific journal), Joint Work, ISSN 0368-2811

BACKGROUND: Nivolumab treatment resulted in superior efficacy and safety versus everolimus treatment in the 2-year follow-up of the CheckMate 025 Phase III study, with consistent results in the global population and the Japanese population. Here, we report the 3-year follow-up in both groups. METHODS: Patients were randomized 1:1 to nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10 mg orally once daily until progression/intolerable toxicity. The primary endpoint was overall survival (OS). Key secondary endpoints included objective response rate, progression-free survival, safety and patient-reported quality of life. RESULTS: Of 410 and 411 patients randomized to nivolumab and everolimus, 37 and 26 were Japanese, respectively. The median OS for the global population was 25.8 months with nivolumab and 19.7 months with everolimus (hazard ratio 0.74; 95.5% confidence interval [CI]: 0.63-0.88; P = 0.0005); in the Japanese population, median OS was 45.9 months and not reached (hazard ratio 1.08; 95% CI: 0.50-2.34; P = 0.85), respectively. The investigator-assessed objective response rate was 26% versus 5% with nivolumab versus everolimus (odds ratio [OR] 6.19; 95% CI: 3.82-10.06) in the global population and 43% versus 8% in the Japanese population (OR 6.80; 95% CI: 1.60-28.91; P = 0.0035), respectively. The incidence of any-grade treatment-related adverse events was lower with nivolumab versus everolimus in both the global patient population (80% versus 89%) and the Japanese population (81% versus 100%). CONCLUSIONS: At the 3-year follow-up, the efficacy and safety results of CheckMate 025 are generally consistent in the global and the Japanese populations.

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Do you avoid prostate biopsy in patients with negative findings by mpMRI?

Mototsugu Oya

WORLD JOURNAL OF UROLOGY (SPRINGER) 37 ( 6 ) 1226 - 1226 2019.06

Single Work, ISSN 0724-4983

TVT術後の難治性切迫性尿失禁に対して仙骨神経電気刺激療法が有効であった1例

篠島利明, 茂田啓介, 田中伸之, 大家基嗣

日本排尿機能学会誌 ((一社)日本排尿機能学会) 29 ( 2 ) 460 - 463 2019.06

ISSN 1347-6513

症例は53歳女性。尿パッドを1日10枚必要とする尿失禁にて当科紹介。ストレステスト、Qチップテストともに強陽性だが、OABSSは5点と過活動膀胱症状は軽度であった。腹圧性尿失禁を主とする混合性尿失禁に対して保存的治療を行うも有効でなくTVT手術を施行した。術後にストレステストは陰性化したが切迫性尿失禁が顕著となった。メッシュ露出、尿路感染や残尿を認めず、テープによる尿道の屈曲や圧排等の閉塞所見も明らかでなかった。ウロダイナミクス検査では排尿筋過活動、ならびに低尿流率かつ高排尿筋圧の所見を認めた。過活動膀胱治療薬による症状の改善は乏しい上、抗コリン剤は副作用で継続困難であった。OABSSは14点、切迫性尿失禁の回数は1位平均3回以上であった。また膀胱内圧検査では排尿筋過活動の所見を認めた。TVT術後9ヵ月目に仙骨神経電気刺激療法のリード留置術を施行したところ試験刺激により切迫性失禁が消失、刺激装置植え込み術後も有害事象を認めず、本症例では有効な治療法であった。(著者抄録)

Making Valuable Digital Connections a Priority

Mototsugu Oya

WORLD JOURNAL OF UROLOGY (SPRINGER) 37 ( 6 ) 1226 - 1226 2019.06

Single Work, ISSN 0724-4983

Are there any significant impacts of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer?

Takeo Kosaka, Hiroshi Hongo, Ryuichi Mizuno, Nobuyuki Tanaka, Toshikazu Takaeda, Kazuhiro Matshumoto, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 37 ( 15 ) 2019.05

Joint Work, ISSN 0732-183X

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Efficacy of systemic therapy for metastatic renal cell carcinoma in patients over 75 years of age.

Ryuichi Mizuno, Kimiharu Takamatsu, Nozomi Hayakawa, Takeo Kosaka, Nobuyuki Tanaka, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 37 ( 15 ) 2019.05

Joint Work, ISSN 0732-183X

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Physical Parameters, Use of Specific Medical Treatments, Nursing Levels, and Activities of Daily Living Are Potential Indicators for Forgoing Maintenance Hemodialysis.

Yamaguchi N, Yoshida T, Oba M, Nakano R, Saito M, Hirokawa M, Shinmi T, Urasawa C, Oya M

The Keio journal of medicine (KEIO JOURNAL MEDICINE) 69 ( 1 ) 16 - 25 2019.05

Research paper (scientific journal), Joint Work, ISSN 0022-9717

Maintenance hemodialysis (HD) therapy is essential for survival in patients with end-stage renal disease (ESRD); however, HD can also be life-threatening in the final stages of ESRD. Currently, no clear indicators and/or biomarkers exist regarding when HD should be forgone. In the present study, we examined temporal changes in multiple clinical parameters, including biochemical data, physical data, the use of specific medical treatments, nursing care levels, and the activities of daily living (ADL) in 47 ESRD patients who underwent maintenance HD and who died in our hospital. We also investigated the status of informed consents regarding the forgoing of HD in these patients. We found that while biochemical parameters were unaltered, physical parameters such as consciousness levels and blood pressure gradually deteriorated during hospitalization. The use of the following specific medical treatments significantly increased over time: vasopressor use, O2 inhalation, and ventilator use. The need for nursing care increased and the ADL levels decreased toward the time of death. Medical doctors gave information regarding forgoing HD to patients and/or their family/relatives in 55% of cases, obtained agreement to forego HD in 45% of cases, and HD was actually foregone in 38% of cases. Most clinical parameters were not significantly different between the patients whose HD sessions were forgone versus those in whom HD was continued, indicating that HD was foregone in the very last stages of life. The results suggest that physical parameters, the use of specific medical treatments, the levels of nursing care, and ADL are potential indicators for forgoing HD in the final stages of ESRD.

Preserved Kidney Volume, Body Mass Index, and Age Are Significant Preoperative Factors for Predicting Estimated Glomerular Filtration Rate in Living Kidney Donors at 1 Year After Donation.

Kazunobu Shinoda, Shinya Morita, Hirotaka Akita, Fuyuki Washizuka, Satoshi Tamaki, Ryohei Takahashi, Hideyo Oguchi, Kei Sakurabayashi, Toshihide Mizutani, Yusuke Takahashi, Yoji Hyodo, Yoshihiro Itabashi, Masaki Muramatsu, Takeshi Kawamura, Hiroshi Asanuma, Eiji Kikuchi, Masahiro Jinzaki, Nobuyuki Shiraga, Ken Nakagawa, Mototsugu Oya, Seiichiro Shishido, Ken Sakai

Transplantation proceedings (ELSEVIER SCIENCE INC) 51 ( 5 ) 1306 - 1310 2019.05

Research paper (scientific journal), Joint Work, ISSN 0041-1345

BACKGROUND: Securing postdonation renal function in the lifetime of donors is a consequential subject for physicians, and precise prediction of postdonation renal function would be considerably beneficial when judging the feasibility of kidney donation. The aim of this study was to investigate the optimum model for predicting eGFR at 1 year after kidney donation. METHODS: We enrolled 101 living-related kidney donors for the development cohort and 44 for the external validation cohort. All patients in each cohort underwent thin-sliced (1 mm) enhanced computed tomography (CT) scans. We excluded individuals with diabetes, glucose intolerance, or albuminuria from this study. We evaluated preoperative factors including age, sex, hypertension, body mass index (BMI), serum uric acid, baseline eGFR, and body surface area (BSA)-adjusted preserved kidney volume (PKV) by using 3-dimensional reconstruction of thin-sliced enhanced CT images. To detect independent predictors, we performed multivariable regression analysis. RESULTS: The multivariable regression analysis revealed that age, BMI, predonation eGFR, and BSA-adjusted PKV were independent predictors of eGFR at 1 year after kidney donation (correlation coefficient: -0.15, -0.476, 0.521, 0.127, respectively). A strong correlation between predicted eGFR and observed eGFR was obtained in the development cohort (r = 0.839, P < .0001). The significance of this predictive model was also confirmed with the external validation cohort (r = 0.797, P < .0001). CONCLUSIONS: Age, BMI, predonation eGFR, and BSA-adjusted PKV may be useful for precisely predicting eGFR at 1 year after living kidney donation and be helpful to determine the feasibility of kidney donation from marginal donors.

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Sub-classification of patients with intermediate-risk metastatic renal cell carcinoma treated with targeted therapy.

Go Kaneko, Suguru Shirotake, Koshiro Nishimoto, Yasumasa Miyazaki, Keiichi Ito, Yujiro Ito, Masayuki Hagiwara, Kent Kanao, Ken Nakagawa, Tetsuo Momma, Tomohiko Asano, Nobuyuki Tanaka, Ryuichi Mizuno, Mototsugu Oya, Masafumi Oyama

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 49 ( 8 ) 780 - 785 2019.05

Research paper (scientific journal), Joint Work, ISSN 0368-2811

BACKGROUND: International Metastatic Renal Cell Carcinoma Database Consortium model predicts the outcomes of metastatic renal cell carcinoma stratified into favorable, intermediate, and poor risk groups (FG, IG, and PG, respectively), with approximately 50% of patients being classified as IG. We aimed to generate better risk model based on the sub-classification of IG. METHODS: We analyzed records of 213 consecutive patients receiving molecular targeted therapy. Age, gender, histology, type of initial molecular targeted therapy, serum laboratory data, previous nephrectomy and immunotherapy, and metastatic sites were used for IG sub-stratification. Modified and original models were compared using a concordance correlation coefficient analysis. RESULTS: Median follow-up was 17.8 months. Serum albumin, serum C-reactive protein, and bone metastases were independent predictors of overall survival (OS) in IG. IG was sub-classified into low-, middle-, and high-risk IG according to the number of predictors. The following modified model was developed: modified FG (FG & low-risk IG), modified IG (middle-risk IG), and modified PG (PG & high-risk IG). Concordance indices for original and modified models were 0.68 and 0.73, respectively (P < 0.001). OS was significantly longer in modified PG treated with mammalian target of rapamycin inhibitors as second-line therapy than with tyrosine kinase inhibitors, whereas this was not observed in the original model. CONCLUSIONS: We successfully developed modified IMDC model using a two-step process: the original IMDC plus an IG sub-stratification, and demonstrated that it predicts outcomes more accurately than original model.

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Prognostic value of serum C-reactive protein level prior to second-line treatment in intermediate risk metastatic renal cell carcinoma patients.

Takamatsu K, Mizuno R, Tanaka N, Takeda T, Morita S, Matsumoto K, Kosaka T, Shinojima T, Kikuchi E, Asanuma H, Oyama M, Mikami S, Oya M

International journal of clinical oncology (SPRINGER JAPAN KK) 24 ( 9 ) 1069 - 1074 2019.05

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: The later-line treatment of metastatic renal cell carcinoma (mRCC) has been drastically changing by the development of immune-oncology drugs and molecular targeted treatment in recent years. Although the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model is useful for second-line setting, this model has the problem that over 50% patients are classified as intermediate risk group. The aim of this study is to evaluate whether the serum C-reactive protein (CRP) levels prior to second-line treatment could divide intermediate risk group patients. METHODS: We retrospectively reviewed 82 consequent intermediate-risk mRCC patients who received second-line molecular targeted therapy. We classified patients who had serum CRP higher than 0.5 mg/dl in elevated CRP group because the median baseline serum CRP level before second-line treatment was 0.51 mg/dl. We assessed the prognostic impact of serum CRP levels prior to second-line treatment initiation to predict overall survival (OS). RESULTS: Thirty-three out of 82 (40%) patients demonstrated elevated baseline CRP levels. The median OS of elevated and non-elevated CRP group was 11.5 (95% CI 5.4-17.5) and 29.4 (95% CI 25.5-33.5) months, respectively (p = 0.001). The serum CRP elevation could predict prognosis in intermediate risk patients treated with second-line treatment (HR 2.5, 95% CI 1.4-4.2, p = 0.001). CONCLUSIONS: The serum CRP levels after first-line treatment termination could divide intermediate risk group mRCC patients into two prognostic subgroups in second-line targeted treatment setting.

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Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration.

Shigeta K, Kosaka T, Hongo H, Yanai Y, Matsumoto K, Morita S, Mizuno R, Shinojima T, Kikuchi E, Oya M

International journal of clinical oncology (SPRINGER JAPAN KK) 24 ( 5 ) 546 - 553 2019.05

Research paper (scientific journal), Joint Work, ISSN 1341-9625

BACKGROUND: Our specific aim was to investigate the prognostic value of effective duration of first androgen deprivation therapy (ADT) and to evaluate the clinical impact on early docetaxel administration with oncological outcomes in castration-resistant prostate cancer (CRPC) patients treated with docetaxel. METHODS: We identified 148 mCRPC patients who were treated with 75 mg/m2 docetaxel. We defined 16 months as the threshold for the effective duration of ADT, and defined 12 months as the cut-off time for starting docetaxel from the onset of CRPC. Univariate and multivariate analyses were conducted to investigate the prognostic indicators that influenced the survival outcomes. RESULTS: Overall, 81 (54.7%) patients died. The median 1st ADT response was 22.2 months and the median time interval from CRPC onset to docetaxel treatment was 11.7 months. Multivariate analysis indicated that visceral metastasis, bone metastasis extent of disease (EOD) ≥ 2, and effective duration of ADT < 16 months were the independent prognostic indicators for progression-free survival (PFS). Referring to cancer-specific survival (CSS), besides visceral metastasis and effective duration of ADT < 16 months, late docetaxel treatment ≥ 12 months became as the predictors for poor prognosis. Among the ADT poor-responder group (ADT < 16 months), Kaplan-Meier method showed that 1-year and 2-year CSS rates were 96.0% and 80.0% in the patients who introduced docetaxel in early setting (< 12 months), which were significantly higher than those who introduced in late settings (93.6% and 30.8%, respectively, p < 0.001). CONCLUSION: CRPC patients who had poor response during 1st ADT would obtain survival benefit by introducing docetaxel treatment in early stage.

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Correction to: Castration-resistant prostate cancer patients who had poor response on first androgen deprivation therapy would obtain certain clinical benefit from early docetaxel administration.

Shigeta K, Kosaka T, Hongo H, Yanai Y, Matsumoto K, Morita S, Mizuno R, Shinojima T, Kikuchi E, Oya M

International journal of clinical oncology (SPRINGER JAPAN KK) 24 ( 5 ) 554 - 556 2019.05

Research paper (scientific journal), Joint Work, ISSN 1341-9625

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Estimation of fuel particle balance in steady state operation with hydrogen barrier model

Hanada K., Yoshida N., Takagi I, Hirata T., Hatayama A., Okamoto K., Oya Y., Shikama T., Wang Z., Long H., Huang C., Oya M., Idei H., Nagashima Y., Onchi T., Hasegawa M., Nakamura K., Zushi H., Kuroda K., Kawasaki S., Higashijima A., Nagata T., Shimabukuro S., Takase Y., Murakami S., Gao X., Liu H., Qian J., Raman R., Ono M.

NUCLEAR MATERIALS AND ENERGY 19 544 - 549 2019.05

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Clinical significance of programmed death-1 and programmed death-ligand 1 expression in the tumor microenvironment of clear cell renal cell carcinoma.

Mikami S, Mizuno R, Kondo T, Shinohara N, Nonomura N, Ozono S, Eto M, Tatsugami K, Takayama T, Matsuyama H, Kishida T, Oya M, Japanese Society of Renal Cancer

Cancer science (WILEY) 110 ( 6 ) 1820 - 1828 2019.04

Research paper (scientific journal), Joint Work, ISSN 1347-9032

Recently, immunotherapy based on blocking immune checkpoints with programmed death-1 (PD-1) or PD-ligand 1 (PD-L1) Abs has been introduced for the treatment of advanced clear cell renal cell carcinoma (ccRCC), especially tumors resistant to vascular endothelial growth factor-tyrosine kinase inhibitors (VEGF-TKIs), but the significance of their expression in the tumor microenvironment is unclear. We investigated these immune checkpoint markers in tumor cells and tumor-infiltrating immune cells (TIIC) in the tumor microenvironment of 100 untreated and 25 VEGF-TKI-treated primary ccRCC tissues. Upregulated expression of PD-1 and PD-L1 by TIIC, and PD-L1 by tumor cells was associated with the histological grade and unfavorable prognosis of RCC patients. High PD-1 and PD-L1 expression by TIIC was associated with a poorer response to VEGF-TKI, whereas PD-L1 expression by tumor cells did not affect the efficacy of the treatment. Furthermore, increased PD-1-positive TIIC and PD-L1-positive TIIC were observed in tumors treated with VEGF-TKIs compared with those in untreated tumors. Our data suggest that PD-1 and PD-L1 expression by TIIC in the tumor microenvironment is involved in treatment resistance, and that sequential therapy with immune checkpoint inhibitors could be a promising therapeutic strategy for ccRCC resistant to VEGF-TKI treatment.

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The prognostic value of zonal origin and extraprostatic extension of prostate cancer for biochemical recurrence after radical prostatectomy.

Takamatsu K, Matsumoto K, Shojo K, Tanaka N, Takeda T, Morita S, Kosaka T, Mizuno R, Shinojima T, Kikuchi E, Asanuma H, Oya M

Urologic oncology (ELSEVIER SCIENCE INC) 37 ( 9 ) 575.e19 - 575.e25 2019.04

Research paper (scientific journal), Joint Work, ISSN 1078-1439

OBJECTIVE: To investigate the influence of the zonal origin of prostate cancer and extraprostatic extension on biochemical recurrence (BCR). PATIENTS AND METHODS: We included 638 consecutive patients undergoing radical prostatectomy between 2005 and 2015 who did not receive neoadjuvant/adjuvant therapy. The largest lesion was defined as the index tumor. We categorized each patient into the transition zone (TZ) or peripheral zone (PZ) group based on the lesion where the index tumor existed. Differences in the BCR defined as increasing prostate-specific antigen rate between groups were examined by Kaplan-Meier analysis and the Cox proportional hazards model. RESULTS: There were 293 (46%) patients with TZ cancer and 345 (54%) with PZ cancer. TZ cancer was significantly associated with a higher prostate-specific antigen (P = 0.012), lower biopsy positive core rate (P = 0.020), lower pathological Gleason score (P = 0.017), lower pathological stage (P = 0.002), and lower rate of seminal vesicle invasion (P = 0.002). During a median follow-up period of 59 months, 79 patients (12%) developed BCR. In the entire cohort, the PZ origin (hazard ratio: 1.68, P = 0.033) and extraprostatic extension were independent risk factors for BCR. The 3-, 5-, and 7-year BCR-free survival rates of patients with pT3a TZ cancer were 89%, 88%, and 86%, respectively, which were significantly better than those of patients with pT3a PZ cancer (80%, 74%, and 62%, P = 0.012), but were similar to those of the pT2 cancer cohort (92%, 91%, and 90%, P = 0.376). CONCLUSION: TZ cancer had more favorable pathological characteristics and oncological outcome than PZ cancer especially in pT3a cases.

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Small intestinal perforation due to a huge gastrointestinal stromal tumor in a kidney transplant recipient: a case report and literature review.

Ryohei Takahashi, Kazunobu Shinoda, Takashi Ishida, Yasuo Hamamoto, Shinya Morita, Hirotaka Akita, Sotaro Kitaoka, Satoshi Tamaki, Hiroshi Asanuma, Tadashi Yoshida, Masahiro Jinzaki, Kaori Kameyama, Mototsugu Oya

BMC nephrology (BMC) 20 ( 1 ) 120 - 120 2019.04

Research paper (scientific journal), Joint Work, ISSN 1471-2369

BACKGROUND: Gastrointestinal stromal tumors (GISTs) in transplant recipients are very rare and only a handful of cases have been reported to date. Here we present the first known case of a huge GIST in a kidney transplant recipient with perforation of small intestine. CASE PRESENTATION: A 64-year-old male presented at our hospital with right colic pain; he had received an ABO incompatible kidney transplant 6 years earlier and was treated with cyclosporine, mycophenolate mofetil, and methylprednisolone. Radiological evaluation revealed a huge (11 cm in diameter) solitary tumor at the small intestine without distant metastasis. The small intestinal wall at the tumor location was perforated one week after diagnosis and the patient underwent emergency surgery. The pathological findings were compatible with GIST and the tumor consisted of spindle cells with positive staining for KIT, CD34, and DOG1 and negative or weak staining for desmin and S-100 protein. A mutation in exon 11 of the c-kit gene was also detected. Cyclosporine was withdrawn and imatinib mesylate (400 mg daily) was introduced. However, thereafter, we needed to decrease the dose at 300 mg daily due to severe hyponatremia. Reduced imatinib treatment was well tolerated and recurrence was not observed for 18 months after surgery. CONCLUSIONS: The occurrence of GISTs in transplant patients is rare, and huge GISTs should be resected immediately after diagnosis because gastrointestinal tract at the tumor site could be perforated. Imatinib treatment is feasible in transplant recipients under immunosuppression, although immunosuppressive drugs metabolized by CYP3A4 should be used at a reduced dosage or withdrawn.

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Sulfasalazine could modulate the CD44v9-xCT system and enhance cisplatin-induced cytotoxic effects in metastatic bladder cancer.

Koichiro Ogihara, Eiji Kikuchi, Shogo Okazaki, Masayuki Hagiwara, Toshikazu Takeda, Kazuhiro Matsumoto, Takeo Kosaka, Shuji Mikami, Hideyuki Saya, Mototsugu Oya

Cancer science (WILEY) 110 ( 4 ) 1431 - 1441 2019.04

Research paper (scientific journal), Joint Work, ISSN 1347-9032

The prognostic role of CD44v9, a variant isoform of CD44 and a new cell surface marker of cancer stem cells, remains unclear in bladder cancer (BC) patients. Furthermore, limited information is available on the functional role of sulfasalazine (SSZ), which could modulate the CD44v9-xCT system in order to enhance cisplatin (CDDP)-induced cytotoxicity and inhibit the metastatic potential of BC. CD44v9 protein expression was examined immunohistochemically in 63 muscle invasive BC (MIBC) patients who underwent radical cystectomy. CD44v9 expression was independently associated with disease recurrence and cancer-specific death in MIBC. Cytotoxic effects, glutathione levels, and reactive oxygen species production by SSZ and CD44v9 and phospho-p38MAPK protein expression by SSZ with or without CDDP were assessed in MBT-2V cells with highly metastatic potential. Sulfasalazine exerted cytotoxic effects against MBT-2V cells by inhibiting glutathione levels and inducing the production of reactive oxygen species. Sulfasalazine in combination with CDDP appeared to exert strong cytotoxic effects against MBT-2V cells by inhibiting CD44v9 expression and upregulating phospho-p38MAPK expression. The inhibitory effects of SSZ with or without CDDP were also investigated using an MBT-2V lung metastatic model. In the murine lung metastatic BC model, SSZ significantly prolonged animal survival. Furthermore, the combination of SSZ with CDDP exerted stronger inhibitory effects on the establishment of lung tumor nodules than SSZ or CDDP alone. CD44v9 expression could be a clinical biomarker for predicting poor outcomes in MIBC patients. Sulfasalazine in combination with CDDP has potential as a novel therapy against metastatic BC.

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CD44 VARIANT 9 EXPRESSION IS A NOVEL INDICATOR FOR IDENTIFYING POOR SURVIVAL IN PATIENTS WITH INVASIVE UROTHELIAL CARCINOMA

Koichiro Ogihara, Eiji Kikuchi, Masayuki Hagiwara, Kazuhiro Matsumoto, Shuji Mikami, Hideyuki Saya, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E899 - E900 2019.04

Joint Work, ISSN 0022-5347

THE SURVIVAL PREDICTION WITH TIME OF INTRAVESICAL RECURRENCE IN UPPER TRACT UROTHELIAL CARCINOMA

Koichiro Ogihara, Eiji Kikuchi, Keisuke Shigeta, Masayuki Hagiwara, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E716 - E717 2019.04

Joint Work, ISSN 0022-5347

SITE SPECIFIC DIFFERENCES IN SURVIVAL AMONG BLADDER, RENAL PELVIC, AND URETERAL UROTHELIAL CARCINOMA PATIENTS TREATED WITH RADICAL SURGERY

Tadatsugu Anno, Eiji Kikuchi, Koichiro Ogihara, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E720 - E720 2019.04

Joint Work, ISSN 0022-5347

SIMULATING THE SURVEILLANCE DURATION OF INTRAVESICAL RECURRENCE AFTER RADICAL NEPHROURETERECTOMY: AN INDIVIDUALIZED RISK BASED APPROACH APPLYING THE WEIBULL MODEL

Shigeta Keisuke, Eiji Kikuchi, Masayuki Hagiwara, Takayuki Abe, Koichiro Ogihara, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E717 - E717 2019.04

Joint Work, ISSN 0022-5347

RISK FACTORS FOR HEMODYNAMIC INSTABILITY DURING LAPAROSCOPIC ADRENALECTOMY FOR PHEOCHROMOCYTOMA.

Toshikazu Takeda, Kimiharu Takamatsu, Yu Teranishi, Kyohei Hakozaki, Nobuyuki Tanaka, Kazuhiro Matsumoto, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Toshiaki Shinojima, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E985 - E986 2019.04

Joint Work, ISSN 0022-5347

PRETREATMENT NEUTROPHIL-TO-LYMPHOCYTE RATIO IS A NOVEL BIOMARKER FOR PREDICTING WORSE CLINICAL OUTCOME IN CHEMO-RESISTANT UROTHELIAL CARCINOMA PATIENTS TREATED WITH PEMBROLIZUMAB

Koichiro Ogihara, Eiji Kikuchi, Takashi Okabe, Seiya Hattori, Ryo Yamashita, Syunsuke Yoshimine, Suguru Shirotake, Kazuhiro Matsumoto, Ryuichi Mizuno, Satoshi Hara, Masafumi Oyama, Takeshi Masuda, Masashi Niwakawa, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E352 - E352 2019.04

Joint Work, ISSN 0022-5347

OVERCOMING CABAZITAXEL RESISTANCE BY G2/M REGULATING GENES IN CASTRATION-RESISTANT PROSTATE CANCER

Hiroshi Hongo, Takeo Kosaka, Yoshinori Yanai, Yota Yasumizu, Yasumasa Miyazaki, Nobuyuki Tanaka, Kazuhiro Matsumoto, Ryuichi Mizuno, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E1172 - E1173 2019.04

Joint Work, ISSN 0022-5347

OPTIMAL SUBCLASSIFICATION SYSTEM FOR INTERMEDIATE-RISK NON-MUSCLE INVASIVE BLADDER CANCER

Kazuhiro Matsumoto, Eiji Kikuchi, Yoshinori Yanai, Nozomi Hayakawa, Naoya Niwa, Maeda Takahiro, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E315 - E315 2019.04

Joint Work, ISSN 0022-5347

HIGH GAMMA-GLOBULIN LEVEL IS ASSOCIATED WITH ONCOLOGICAL OUTCOMES IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

Naoya Niwa, Kazuhiro Matsumoto, Hiroki Ide, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E622 - E623 2019.04

Joint Work, ISSN 0022-5347

COULD LAPAROSCOPIC SURGERY HAVE SAME LONG-TERM ONCOLOGICAL OUTCOMES AS OPEN RADICAL NEPHROURETERECTOMY IN T3N0M0 UPPER TRACT UROTHELIAL CARCINOMA? A MULTICENTER COHORT STUDY ADJUSTED BY PROPENSITY SCORE MATCHING

Keisuke Shigeta, Eiji Kikuchi, Takayuki Abe, Masayuki Hagiwara, Koichiro Ogihara, Toshikazu Takeda, Kazuhiro Matsumoto, Ryuichi Mizuno, Masahiro Jinzaki, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E716 - E716 2019.04

Joint Work, ISSN 0022-5347

COULD A HISTORY OF NON-MUSCLE INVASIVE BLADDER CANCER HAVE A PROGNOSTIC ROLE IN CT2-4AN0M0 BLADDER CANCER PATIENTS TREATED WITH RADICAL CYSTECTOMY AND NEOADJUVANT CHEMOTHERAPY?

Emina Kayama, Eiji Kikuchi, Kyohei Hakozaki, Nobuyuki Tanaka, Gou Kaneko, Suguru Shirotake, Yasumasa Miyazaki, Shunsuke Yokomine, Maeda Takahiro, Kunimitsu Kanai, Masafumi Oyama, Yosuke Nakajima, Satoshi Hara, Tetsuo Monma, Mototsugu Oya

JOURNAL OF UROLOGY (LIPPINCOTT WILLIAMS & WILKINS) 201 ( 4 ) E360 - E360 2019.04

Joint Work, ISSN 0022-5347

Is the occurrence of higher adverse effects associated with better oncological outcome in metastatic urothelial carcinoma patients treated with pembrolizumab?

Nozomi Hayakawa, Eiji Kikuchi, Koichirou Ogihara, Seiya Hattori, Shunsuke Yoshimine, Suguru Shirotake, Takashi Okabe, Ryo Yamashita, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 37 ( 7 ) 2019.03

Joint Work, ISSN 0732-183X

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The timing from perioperative chemotherapy and disease recurrence could have clinical impact on survival in bladder cancer patients treated with salvage chemotherapy.

Eiji Kikuchi, Nozomi Hayakawa, Koichirou Ogihara, Minami Omura, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 37 ( 7 ) 2019.03

Joint Work, ISSN 0732-183X

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Real-world use of sorafenib for advanced renal cell carcinoma patients with cardiovascular disease: Nationwide survey in Japan.

Inamoto Teruo, Azuma Haruhito, Oya Mototsugu, Hamada Yoko, Akaza Hideyuki

JOURNAL OF CLINICAL ONCOLOGY 37 ( 7 ) 2019.03

ISSN 0732-183X

PROPEL: A randomized, phase Ill trial evaluating the efficacy and safety of olaparib combined with abiraterone as first-line therapy in patients with metastatic castration-resistant prostate cancer (mCRPC).

Noel W. Clarke, Andrew J. Armstrong, Antoine Thiery-Vuillemin, Mototsugu Oya, Dingwei Ye, Joaquin Mateo, Carsten Dietrich Goessl, Jinyu Kang, Sherry Liu, Fred Saad

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 37 ( 7 ) 2019.03

Joint Work, ISSN 0732-183X

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Editor's Note

Oya Mototsugu

WORLD JOURNAL OF UROLOGY (SPRINGER) 37 ( 3 ) 576 - 576 2019.03

Single Work, ISSN 0724-4983

「2017年度前立腺がん啓発週間」の活動実績報告

五十嵐敦, 深貝隆志, 山中英壽, 木村剛, 柏原剛, 大家基嗣, 門間哲雄, 中島洋介, 森山正敏, 井上啓史, 斉藤史郎, 並木幹生, 小路直

日本腎泌尿器疾患予防医学研究会誌 (日本腎泌尿器疾患予防医学研究会) 27 ( 1 ) 28 - 30 2019.03

ISSN 1347-5010

Prediction of extraprostatic extension by MRI tumor contact length: difference between anterior and posterior prostate cancer.

Matsumoto K, Akita H, Narita K, Hashiguchi A, Takamatsu K, Takeda T, Kosaka T, Mizuno R, Kikuchi E, Oya M, Jinzaki M

Prostate cancer and prostatic diseases (NATURE PUBLISHING GROUP) 22 ( 4 ) 539 - 545 2019.02

Research paper (scientific journal), Joint Work, ISSN 1365-7852

BACKGROUND: Tumor contact length (TCL) is defined as the extent of contact between prostate cancer and the prostatic capsule, and its predictive value for microscopic extraprostatic extension (EPE) has been reported. However, the impact of the zonal origin (anterior or posterior tumor) of the tumor on the diagnosis of EPE is controversial. METHODS: We retrospectively analyzed the records of 233 consecutive patients who underwent preoperative MRI and radical prostatectomy. We designated their tumors as anterior or posterior, and evaluated the correlation between the TCL measured by MRI and microscopic EPE in the radical prostatectomy specimen. Then, we created the predicted probability curves for EPE versus TCL for anterior and posterior prostate cancer. RESULTS: There were 109 patients (47%) with an anterior tumor and 124 patients (53%) with a posterior tumor. Postoperative pathological analysis confirmed pT3 in 18 patients (17%) with an anterior tumor and in 53 patients (43%) with a posterior tumor. Multivariate analysis demonstrated that the zonal origin of the tumor was an independent predictive factor for EPE. We developed separate probability curves of EPE versus TCL for anterior and posterior prostate cancer, which revealed that anterior tumors were less likely to invade the extraprostatic tissues. Among patients whose TCL was 10-20 mm, 9/32 patients (28%) with an anterior tumor had EPE compared with 24/45 patients (53%) with a posterior tumor (p = 0.036). The decision curve of this EPE predictive model had high clinical efficacy. CONCLUSIONS: Our results indicate that anterior tumors have more favorable pathological characteristics than posterior tumors with the same TCL measured by MRI. We constructed two separate predicted probability curves for EPE after discriminating anterior and posterior tumors, which will be useful for decision making in clinical practice.

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Pre-donation BMI and preserved kidney volume can predict the cohort with unfavorable renal functional compensation at 1-year after kidney donation.

Kazunobu Shinoda, Shinya Morita, Hirotaka Akita, Satoshi Tamaki, Ryohei Takahashi, Hidaka Kono, Hiroshi Asanuma, Eiji Kikuchi, Masahiro Jinzaki, Ken Nakagawa, Mototsugu Oya

BMC nephrology (BMC) 20 ( 1 ) 46 - 46 2019.02

Research paper (scientific journal), Joint Work, ISSN 1471-2369

BACKGROUND: The magnitude of renal function recovery after kidney donation differs in donors with a heterogeneous background. Preoperative assessment of candidates with potentially unfavorable renal functional compensation is critical when baseline kidney function is marginal. We explored the significance of preserved kidney volume (PKV) and known preoperative risk factors for the prediction of unfavorable renal function compensation. METHODS: We enrolled 101 living donors for whom a 1-mm sliced enhanced computed tomography scan was performed preoperatively and clinical data could be collected up to 1 year after donation. The donors whose estimated glomerular filtration rate (eGFR) at 1 year after donation was 70% or higher of baseline eGFR were assigned to the "favorable renal compensation" group and the others to the "unfavorable renal compensation" group. RESULTS: Age, sex, and preoperative serum uric acid level were not significant predictors for "unfavorable renal compensation." Multivariable logistic regression analysis revealed that body mass index (BMI) and body surface area (BSA)-adjusted PKV were independent preoperative risk factors for "unfavorable renal compensation" (adjusted odds ratio, 1.342 and 0.929, respectively). Hypertension and preoperative eGFR were not independent predictors when adjusted with BMI and BSA-adjusted PKV. Receiver operative characteristic analysis revealed that the predictive equation with the two independent predictors yielded a good accuracy to detect donor candidates with unfavorable renal functional compensation (area under the curve = 0.803), and the optimal cut-off values were identified as 23.4 kg/m2 for BMI and 107.3 cm3/m2 for BSA-adjusted PKV. CONCLUSIONS: BMI and BSA-adjusted PKV may be useful to select candidates with potentially unfavorable renal function compensation before kidney donation.

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BCG-induced cytokine release in bladder cancer cells is regulated by Ca²⁺ signaling.

Ibarra C, Karlsson M, Codeluppi S, Varas-Godoy M, Zhang S, Louhivuori L, Mangsbo S, Hosseini A, Soltani N, Kaba R, Kalle Lundgren T, Hosseini A, Tanaka N, Oya M, Wiklund P, Miyakawa A, Uhlén P

Molecular oncology (WILEY) 13 ( 2 ) 202 - 211 2019.02

Research paper (scientific journal), Joint Work, ISSN 1574-7891

Bacillus Calmette-Guérin (BCG) is widely used in the clinic to effectively treat superficial urinary bladder cancer. However, a significant proportion of patients who fail to respond to BCG risk cystectomy or death. Though more than 3 million cancer treatments with BCG occur annually, surprisingly little is known about the initial signaling cascades activated by BCG. Here, we report that BCG induces a rapid intracellular Ca2+ (calcium ion) signal in bladder cancer cells that is essential for activating the transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and for synthesizing and secreting proinflammatory cytokines, including interleukin 8 (IL-8). A similar Ca2+ response was observed when cells were exposed to the supernatant of BCG. Studying cellular molecular mechanisms involved in the BCG signaling event, we found pivotal roles for phospholipase C and the Toll-like receptor 4. Further assessment revealed that this signaling pathway induces synthesis of IL-8, whereas exocytosis appeared to be controlled by global Ca2+ signaling. These results shed new light on the molecular mechanisms underlying BCG treatment of bladder cancer, which can help in improving therapeutic efficacy and reducing adverse side effects.

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Mutation of GALNTL5 gene identified in patients diagnosed with asthenozoospermia.

Jun Hagiuda, Nobuyoshi Takasaki, Mototsugu Oya, Hiromichi Ishikawa, Hisashi Narimatsu

Human fertility (Cambridge, England) (TAYLOR & FRANCIS LTD) 23 ( 4 ) 1 - 8 2019.01

Research paper (scientific journal), Joint Work, ISSN 1464-7273

Asthenozoospermia is commonly observed in infertile men. However, very few causative gene mutations have been identified because an efficient detection method has not been established. We previously identified a patient with asthenozoospermia carrying a heterozygous point deletion in GALNTL5 by detecting an abnormal reduction in the abundance of GALNTL5 and other marker proteins. To identify other mutations in GALNTL5, we screened sperm samples from 208 infertile men mainly diagnosed with asthenozoospermia using the same method, and conducted next-generation sequencing. Consequently, another case of GALNTL5 mutation was detected only in sperm at a low frequency but not in the somatic blood cells of a patient diagnosed with asthenozoospermia. In this patient, sperm motility improved and the mutation disappeared at 2 years after the first observation. In this man, carrying a heterozygotic deficiency of GALNTL5, the swim-up method was useful to concentrate the spermatozoa without mutation. Intracytoplasmic sperm injection of the selected motile spermatozoa into oocytes of the patient's partner resulted in successful conception, and a female child was safely delivered. These results suggest the feasibility of our approach for the screening and treatment of asthenozoospermia associated with GALNTL5 mutation.

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Patients with metastatic renal cell carcinoma who benefit from axitinib dose titration: analysis from a randomised, double-blind phase II study.

Yoshihiko Tomita, Hirotsugu Uemura, Mototsugu Oya, Nobuo Shinohara, Tomonori Habuchi, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H Bair, Brian I Rini

BMC cancer (BMC) 19 ( 1 ) 17 - 17 2019.01

Research paper (scientific journal), Joint Work, ISSN 1471-2407

BACKGROUND: A prospective, randomised phase II study demonstrated clinical benefit of axitinib dose titration in a subset of treatment-naïve patients treated with axitinib for metastatic renal cell carcinoma. This analysis evaluated patient baseline characteristics that may impact overall survival (OS) with axitinib dose titration. METHODS: Following a 4-week lead-in period during which all patients received axitinib 5 mg twice-daily (bid); patients meeting the predefined randomisation criteria were randomly assigned to receive axitinib 5 mg bid plus either axitinib or placebo titration. In exploratory analyses, patients were grouped into those who achieved OS ≥24 versus < 24 months, and compared their baseline characteristics with Fisher's exact test or Cochran-Armitage trend exact test, with a 5% significance level. Potential predictive baseline characteristics associated with effect of axitinib dose titration on OS were investigated using a Cox proportional hazard model. RESULTS: Overall, 112 patients were randomised. Three of 56 patients receiving axitinib titration were censored; of the remaining 53, 33 (62%) achieved OS ≥24 months versus 20 (38%) with OS < 24 months. Patients with OS ≥24 vs. < 24 months, respectively, had significantly fewer metastatic sites (≤2 metastases: 52% vs. 10%; ≥3 metastases: 48% vs. 90%), fewer lymph node (45% vs. 75%) or liver (15% vs. 45%) metastases, higher haemoglobin level (i.e., ≥ lower limit of normal: 67% vs. 25%) at baseline, lower neutrophil (≤ upper limit of normal, 97% vs. 75%) and platelet (≤ upper limit of normal, 82% vs. 50%) levels at baseline and ≥ 1 year between histopathological diagnosis and treatment (64% vs. 15%). The primary reason for treatment discontinuation in both OS groups was disease progression. The frequency of toxicity-related discontinuation was comparable between the 2 groups, indicating that it was not a factor for a shorter OS. The multivariate analysis showed that ≥1 year from histopathological diagnosis to treatment and baseline haemoglobin level equal or greater than lower limit of normal were significant covariates associated with favourable OS in patients receiving axitinib titration. CONCLUSIONS: The current analyses identified potentially predictive factors that could help selecting patients who may benefit from axitinib dose titration. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT00835978. Registered prospectively, February 4, 2009.

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Impact of inflammatory marker levels one month after the first-line targeted therapy initiation on progression-free survival prediction in patients with metastatic clear cell renal cell carcinoma.

Keiichi Ito, Ayako Masunaga, Nobuyuki Tanaka, Ryuichi Mizuno, Suguru Shirotake, Yota Yasumizu, Yujiro Ito, Yasumasa Miyazaki, Masayuki Hagiwara, Kent Kanao, Shuji Mikami, Tetsuo Momma, Takeshi Masuda, Ken Nakagawa, Masafumi Oyama, Tomohiko Asano, Mototsugu Oya

Japanese journal of clinical oncology (OXFORD UNIV PRESS) 49 ( 1 ) 69 - 76 2019.01

Research paper (scientific journal), Joint Work, ISSN 0368-2811

Objectives: Progression-free survival of first-line targeted therapy greatly influences the survival of patients with metastatic renal cell carcinoma. We evaluated whether post-treatment inflammatory markers and lactate dehydrogenase levels had impacts on progression-free survival prediction in addition to those of conventional predictors. Methods: Two hundred and fifteen patients whose tumors were clear cell type and in whom first-line targeted therapies could be continued for >1 month were evaluated. Pretreatment clinical factors, pathological factors and laboratory data 1 month after targeted therapy initiation-including inflammatory markers (neutrophil count, neutrophil-to-lymphocyte ratio and C-reactive protein) and lactate dehydrogenase-were reviewed. To identify progression-free survival predictors, multivariate analyses were done. Results: The 1-year progression-free survival rate was 47%. Female gender, Karnofsky performance status <80%, time from diagnosis to systemic treatment <12 months, pretreatment C-reactive protein >3.0 mg/dl and post-treatment neutrophil-to-lymphocyte ratio >3.0 were independent predictors for progression-free survival. In contrast, neither C-reactive protein increase nor neutrophil-to-lymphocyte ratio increase after targeted therapy initiation were independent predictors. Pretreatment lactate dehydrogenase, post-treatment lactate dehydrogenase and lactate dehydrogenase decline were not independent predictors. When all patients were stratified by these independent factors into three groups (0 risk vs. 1 or 2 risks vs. 3 or more risks), there were significant differences in progression-free survival rates between the groups (P < 0.0001). Furthermore, there were also significant differences in overall survival rates between the groups (P < 0.0001). Conclusions: Integration of post-treatment neutrophil-to-lymphocyte ratio value with pretreatment factors may lead to the establishment of effective predictive model for disease progression in patients with metastatic clear cell renal cell carcinoma who received first-line targeted therapies.

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Prospective clinical trial of 12-fraction carbon-ion radiotherapy for primary renal cell carcinoma.

Kasuya G, Tsuji H, Nomiya T, Makishima H, Haruyama Y, Kobashi G, Hayashi K, Ebner DK, Omatsu T, Kishimoto R, Yasuda S, Igarashi T, Oya M, Akakura K, Suzuki H, Ichikawa T, Shimazaki J, Kamada T, Working Group, for Genitourinary Tumors

Oncotarget (Oncotarget) 10 ( 1 ) 76 - 81 2019.01

Research paper (scientific journal), Joint Work

The aims of this study were to clarify the safety and efficacy of 12-fraction carbon-ion radiotherapy (CIRT) for primary renal cell carcinoma (RCC) and to confirm the recommended dose in a prospective clinical trial. This clinical trial was planned as a non-randomized, open-label, single-center phase I/II study of CIRT monotherapy. The incidence of acute adverse events was the primary endpoint. Dose-limiting toxicities (DLTs) were defined as grade ≥3 skin, gastrointestinal tract, or urologic adverse events. Based on the eligibility criteria, 8 patients with primary RCC, including 3 medically inoperable patients and 5 patients with tumors >4 cm, were enrolled. Of the 8 patients, 5 were treated with 66 Gy (relative biological effectiveness [RBE]), and subsequently, the dose was escalated to 72 Gy (RBE) for the remaining 3 patients. The median follow-up time was 43.1 months. No DLTs were observed at any dose level though the end of follow-up. Although 1 patient died of pneumonia 3 months after CIRT, which was determined to be unrelated to CIRT, no grade 3 or higher adverse events were observed, and both local control and cancer-specific survival rates were 100%. In conclusion, the safety and efficacy of CIRT hypofractionation using 12-fractions for the treatment of eligible RCC patients, including those with inoperable or tumor size >4 cm, were confirmed in this prospective trial, and a recommended dose of 72 Gy (RBE) was established.

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[Ⅳ. Current Economic Issues in Treatment for Metastatic Renal Cell Carcinoma].

Mizuno R, Oya M

Gan to kagaku ryoho. Cancer & chemotherapy 46 ( 1 ) 50 - 53 2019.01

Research paper (scientific journal), Joint Work, ISSN 0385-0684

Current economic issues in treatment for metastatic renal cell carcinoma

Mizuno R., Oya M.

Japanese Journal of Cancer and Chemotherapy (Japanese Journal of Cancer and Chemotherapy) 46 ( 1 ) 50 - 53 2019.01

ISSN 03850684

VURおよびRN診断におけるカラードプラ法超音波検査を用いた尿管口jet角測定の有用性　尿路感染症患児への新たな診断アプローチ

松井善一, 浅沼宏, 佐藤裕之, 青木裕次郎, 水野隆一, 大家基嗣

日本逆流性腎症フォーラム記録集 (日本逆流性腎症フォーラム) 26回 12 - 14 2019.01

VURおよびRNの診断と治療方針決定には、排尿時膀胱造影(VCUG)と腎シンチグラフィが必要となるが、両検査とも極めて侵襲的であるため、非侵襲的な検査法の開発が待たれている。原発性VURの病因として、ureteric budの発生異常に伴い尿管口が外側偏位し、壁内尿管が短くなることでflap valve機構が機能しないために発生すると考えられている。この点に着目し、VURが高度なほど尿管口からの蠕動運動による尿噴出(尿管口jet)はより垂直方向になると想定し、尿管口jetの方向は超音波カラードプラ法で非侵襲的に検出可能と考え、尿管口から膀胱内への尿噴出角度(尿管口jet角)を測定する方法を考案した。その有用性について検討するため尿路感染症児125例に試行したところ、VCUG所見と強い相関が認められた。

Suitable patients for single-port laparoscopic adrenalectomy : optimal cut-off value for body mass index

Matsumoto Kazuhiro, Takahashi Ryohei, Fukumoto Keishiro, Takeda Toshikazu, Kikuchi Eiji, Asanuma Hiroshi, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Endourology (Japanese Society of Endourology) 32 ( 2 ) 221 - 224 2019

ISSN 2186-1889

Introduction and Objective In this study, we clarified patients suitable for single-port laparoscopic adrenalectomy by focusing on the optimal cut-off values of the body mass index (BMI).Methods A retrospective study was conducted on 126 consecutive patients who underwent single-port adrenalectomy. We re-evaluated all medical records and surgical videos. The pneumoperitoneum time (PT) was employed as an objective index for the assessment of surgical difficulty.Results The total mean PT was 84 minutes. In 27 patients with a BMI less than 20 kg/m2, the mean PT was 71 minutes, whereas the mean PT was 104 minutes in 9 patients with a BMI exceeding 28 kg/m2.Conclusions Our results suggested that patients with a BMI less than 20 kg/m2 are suitable for novice surgeons. Conversely, even experienced surgeons should carefully consider performing single-port surgery on patients whose BMI exceeds 28 kg/m2.

成育医療における先天性腎尿路異常（CAKUT）の管理

浅沼宏, 大家基嗣

泌尿器外科 32 582 - 583 2019

Immunoglobulin G4-Related Disease Arising from the Bladder Wall.

Kufukihara R, Niwa N, Mizuno R, Ohara K, Mikami S, Kikuchi E, Oya M

Urologia internationalis (KARGER) 103 ( 4 ) 1 - 3 2018.12

Research paper (scientific journal), Joint Work, ISSN 0042-1138

Immunoglobulin G4-related disease (IgG4-RD) is a recently described inflammatory disease with multiorgan involvement. Although there were reports of IgG4-related kidney disease or prostatitis, this disease rarely presents in the bladder. In this report, we describe a case of IgG4-RD arising from bladder wall. This patient had a past history of autoimmune pancreatitis and presented with incidental bladder tumor. Magnetic resonance imaging showed low signal intensity tumor on T2-weighted image, and no invasion to the muscular layer. We performed transurethral resection. Pathological findings showed that there were chronic inflammatory changes infiltrates under the epithelium, and IgG4-positive plasma cells were scattered throughout the lesion. They met the pathological diagnostic criteria for IgG4-RD. We think this is the first case of IgG4-RD arising from and confined to the inside of the bladder wall.

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Is transperitoneal laparoscopic radical nephrectomy suitable for patients with a history of abdominal surgery?

Yanai Y, Takeda T, Miyajima A, Matsumoto K, Hagiwara M, Mizuno R, Kikuchi E, Asanuma H, Oya M

Asian journal of endoscopic surgery (WILEY) 12 ( 4 ) 429 - 433 2018.12

Research paper (scientific journal), Joint Work, ISSN 1758-5902

INTRODUCTION: Laparoscopic radical nephrectomy is the gold standard for treatment of renal cell carcinoma. However, previous abdominal surgery is generally regarded as a contraindication to the laparoscopic approach because it causes intraperitoneal adhesions, which are thought to interfere with subsequent laparoscopic procedures inside the abdominal cavity. Few studies have examined the influence of prior surgery on laparoscopic nephrectomy. Therefore, the aim of this study was to evaluate the impact of previous laparotomy on laparoscopic nephrectomy. METHODS: The records of 251 consecutive patients who had undergone laparoscopic nephrectomy for renal cell carcinoma at our hospital between 2005 and 2015 were reviewed retrospectively. RESULTS: Of the 251 laparoscopic nephrectomy patients, 76 patients (30%) had undergone prior abdominal surgery (surgery group), whereas the remaining 175 patients (70%) had not previously had abdominal surgery (control group). There were no significant differences between the control group and the surgery group with regard to pneumoperitoneum time (143 vs 135 min, P = 0.241) or blood loss (39 vs 36 mL, P = 0.763). Next, we divided the patients into two cohorts based on surgeon experience: 98 patients had been treated by an expert (i.e. someone who performs more than 50 laparoscopic procedures per year) and 153 patients had been treated by a non-expert. There was no significant difference in pneumoperitoneum time between the control and surgery groups in each cohort (treated by experts, 108 vs 103 min; treated by non-experts: 162 vs 166 min). CONCLUSION: We conclude that laparoscopic nephrectomy may be feasible after previous abdominal surgery and could be one of the surgical options.

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No significant impact of patient age and prior treatment profile with docetaxel on the efficacy of cabazitaxel in patient with castration-resistant prostate cancer

Kosaka T., Hongo H., Watanabe K., Mizuno R., Kikuchi E., Oya M.

Cancer Chemotherapy and Pharmacology (Cancer Chemotherapy and Pharmacology) 82 ( 6 ) 1061 - 1066 2018.12

Research paper (scientific journal), Joint Work, ISSN 03445704

© 2018, The Author(s). Background: The correlation of the oncological outcomes of docetaxel and cabazitaxel in Japanese metastatic castration-resistant prostate cancer (mCRPC) patients has not been unclear. Materials and methods: This study included a total of 47 consecutive Japanese mCRPC patients treated with cabazitaxel and assessed the prognostic significance of cabazitaxel, focusing on patient age and the correlation of efficacy between docetaxel and cabazitaxel. Results: Prostate-specific antigen (PSA) decline was observed in 27 patients (57.4%), including 19 (40.0%) achieving the response defined by PSA decline ≥ 30%. The median overall survival (OS) periods after the introduction of cabazitaxel was 16.1 months. Twenty (42.6%) were judged to have responded to cabazitaxel with a PSA decrease ≥ 30% from the baseline. A 30% PSA response to cabazitaxel was achieved in 4 (50.0%) patients with ≧ 75 years (n = 8) and 16 (41.0%) patients with less than 75 years (n = 39). There was no significant correlation between the PSA response and patients’ age (p = 0.707). A 30% PSA response to cabazitaxel was achieved in 13 (46.4%) and 7 (36.8%) patients with and without that to d

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Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer: a prospective blinded comparative study in Japan

Kojima T., Nishiyama H., Ozono S., Hinotsu S., Keino N., Yamaguchi A., Sakai H., Enomoto Y., Horie S., Fujimoto K., Matsuyama H., Okamura T., Kanimoto Y., Oya M., Nonomura N., Naito S., Akaza H.

International Journal of Clinical Oncology (International Journal of Clinical Oncology) 23 ( 6 ) 1140 - 1147 2018.12

Joint Work, ISSN 13419625

© 2018, Japan Society of Clinical Oncology. Background: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). Methods: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. Results: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2–64.8%) sensitivity and 72.4% (68.3–76.8%). Urine cytology had 4.5% (0.0–10.7%) sensitivity and 99.8% (99.3–100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.15

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Single-cell RNA-seq analysis reveals the platinum resistance gene COX7B and the surrogate marker CD63

Tanaka N., Katayama S., Reddy A., Nishimura K., Niwa N., Hongo H., Ogihara K., Kosaka T., Mizuno R., Kikuchi E., Mikami S., Miyakawa A., Arenas E., Kere J., Oya M., Uhlén P.

Cancer Medicine (Cancer Medicine) 7 ( 12 ) 6193 - 6204 2018.12

Research paper (scientific journal), Joint Work, ISSN 2045-7634

© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Cancers acquire resistance to systemic treatment with platinum-based chemotherapy (eg, cisplatin [CDDP]) as a result of a dynamic intratumoral heterogeneity (ITH) and clonal repopulation. However, little is known about the influence of chemotherapy on ITH at the single-cell level. Here, mapping the transcriptome of cancers treated with CDDP by scRNA-seq, we uncovered a novel gene, COX7B, associated with platinum-resistance, and surrogate marker, CD63. Knockdown of COX7B in cancer cells decreased the sensitivity of CDDP whereas overexpression recovered the sensitivity of CDDP. Low COX7B levels correlated with higher mortality rates in patients with various types of cancer and were significantly associated with poor response to chemotherapy in urinary bladder cancer. Tumor samples from patients, who underwent CDDP therapy, showed decreased COX7B protein levels after the treatment. Analyzing scRNA-seq data from platinum-naïve cancer cells demonstrated a low-COX7B subclone that could be sorted out from bulk cancer cells by assaying CD63. This low-COX7B subclone behaved as cells with acquired platinum-resistance

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Clinical Outcomes in Patients With Metastatic Papillary Renal-Cell Carcinoma: A Multi-Institutional Study in Japan

Ito K., Mikami S., Tatsugami K., Masumori N., Shinohara N., Kondo T., Nakanishi S., Nagashima Y., Eto M., Kamba T., Kuroda N., Tomita Y., Matsuyama H., Onishi T., Tsushima T., Nakazawa H., Oya M., Ozono S., Naito S., Asano T.

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 6 ) e1201 - e1214 2018.12

Research paper (scientific journal), Joint Work, ISSN 15587673

© 2018 Elsevier Inc. Background: Standard treatments have not been established in metastatic papillary renal-cell carcinoma (PRCC). We aimed to investigate treatment outcomes in patients with mPRCC. Patients and Methods: This study included 51 patients who were diagnosed with PRCC at 14 institutions. Pathologic slides were reviewed by pathologists. The associations between clinical factors and overall survival (OS) were analyzed. Results: Final pathologic diagnoses could be determined in 50 patients. Thirty-five tumors were diagnosed as PRCC (type 2 PRCC, 91.4%), and 15 were diagnosed as other histologic types. Targeted therapies (TTs) were provided to 25 mPRCC patients. Patients treated with TT survived significantly longer than those treated before the era of TT (median OS, 22.5 vs. 6.3 months; P = .0035). Median OS of patients who experienced stable disease for ≥ 9 months using single TT was 43.1 months. Patients treated with a tyrosine kinase inhibitor (TKI) as first-line TT survived longer after TT initiation than those treated with an mTOR inhibitor (median, 22.4 vs. 11.7 months; P = .2684). Patients treated with TKIs in both first- and second-line settings had significant

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Aldosterone and 18-Oxocortisol Coaccumulation in Aldosterone-Producing Lesions.

Yuki Sugiura, Emi Takeo, Shuichi Shimma, Mai Yokota, Tatsuya Higashi, Tsugio Seki, Yosuke Mizuno, Mototsugu Oya, Takeo Kosaka, Masao Omura, Tetsuo Nishikawa, Makoto Suematsu, Koshiro Nishimoto

Hypertension (Dallas, Tex. : 1979) (LIPPINCOTT WILLIAMS & WILKINS) 72 ( 6 ) 1345 - 1354 2018.12

Research paper (scientific journal), Joint Work, ISSN 0194-911X

Primary aldosteronism is a secondary hypertensive disease caused by autonomous aldosterone production that often caused by an aldosterone-producing adenoma (APA). Immunohistochemistry of aldosterone synthase (CYP11B2) shows the presence of aldosterone-producing cell clusters (APCCs) even in non-primary aldosteronism adult adrenal cortex. An APCC-like structure also exists as possible APCC-to-APA transitional lesions (a speculative designation) in primary aldosteronism adrenals. However, whether APCCs produce aldosterone or 18-oxocortisol, a potential serum marker of APA, remains unknown because of lack of technology to visualize adrenocorticosteroids on tissue sections. To address this obstacle, in this study, we used highly sensitive Fourier transform ion cyclotron resonance mass spectrometry to image various adrenocorticosteroids, including 18-oxocortisol, in adrenal tissue sections from 8 primary aldosteronism patients with APCC (cases 1-4), possible APCC-to-APA transitional lesions (case 5), and APA (cases 6-8). Further analyses by tandem mass spectrometry imaging allowed us to differentially visualize aldosterone from cortisone, which share identical mass-to-charge ratio value ( m/z). In conclusion, these advanced imaging techniques revealed that aldosterone and 18-oxocortisol coaccumulated within CYP11B2-expressing lesions. These imaging outcomes along with a growing body of aldosterone research led us to build a progressive development hypothesis of an aldosterone-producing pathology in the adrenal glands.

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The therapeutic effect of sulfasalazine for metastatic urothelial carcinoma targeting to cancer stem cell

Ogihara Koichiro, Kikuchi Eiji, Takeda Toshikazu, Kosaka Takeo, Saya Hideyuki, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 979 - 979 2018.12

Joint Work, ISSN 1349-7006

Roles of etoposide and cisplatin for CRPC in the post-cabazitaxel setting

Hongo Hiroshi, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 601 - 601 2018.12

Joint Work, ISSN 1349-7006

Risk stratification of castration-resistant prostate cancer patients treated with cabazitaxel.

Kosaka T, Hongo H, Mizuno R, Oya M

Molecular and clinical oncology (SPANDIDOS PUBL LTD) 9 ( 6 ) 683 - 688 2018.12

Research paper (scientific journal), Joint Work, ISSN 2049-9450

Patient characteristics before administering the first cycle of cabazitaxel for metastatic castration-resistant prostate cancer (mCRPC) were collected to assess prognostic factors for overall survival (OS). Multivariate analysis revealed that prostate-specific antigen (PSA) ≥100 ng/ml prior to cabazitaxel treatment, visceral metastasis, and low absolute monocyte count were independent prognostic indicators for OS. The aim of the present study was to investigate prognostic biomarkers in patients treated with cabazitaxel among Japanese metastatic castration-resistant prostate cancer (mCRPC) patients. In this retrospective study, 45 patients with mCRPC treated with cabazitaxel were reviewed retrospectively. Clinicopathological factors and laboratory data before administering the first cycle of cabazitaxel were collected to assess the prognostic factors for overall survival (OS). Treatment was generally well tolerated, with a median of 5 cycles (range, 1-26). Median OS from the start of cabazitaxel treatment was 16.1 months (95% confidence interval 6.8-25.5). Univariate analysis revealed that poor performance status, visceral metastasis, hemoglobin <11 mg/dl, absolute monocyte count <400/µl, and prostate-specific antigen ≥100 ng/ml prior to cabazitaxel treatment (P=0.002) were significantly associated with shorter OS. Multivariate analysis revealed that PSA ≥100 ng/ml prior to cabazitaxel treatment, visceral metastasis, and absolute monocyte count <400/µl were independent prognostic indicators for OS. Based on the relative risk of death, patients with mCRPC before cabazitaxel therapy were divided into three risk groups: Low, intermediate, and high (P<0.001). In conclusion, the practical implications of our results may assist in tailoring the introduction of cabazitaxel.

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Rare association of the anterior and posterior urethral valves.

Murakami T, Asanuma H, Shigeta K, Ezaki T, Oya M

Pediatrics international : official journal of the Japan Pediatric Society (WILEY) 60 ( 12 ) 1090 - 1091 2018.12

Research paper (scientific journal), Joint Work, ISSN 1328-8067

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MUC1C Oncoprotein Contributes to Acquiring Cisplatin and Gemcitabine Resistance in Urothelial Carcinoma Cells

Shigeta Keisuke, Kikuchi Eiji, Hasegawa Masanori, Ogihara Koichiro, Kosaka Takeo, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 1192 - 1192 2018.12

Joint Work, ISSN 1349-7006

Evaluation of prostate-specific antigen density in the diagnosis of prostate cancer combined with magnetic resonance imaging before biopsy in men aged 70 years and older with elevated PSA.

Yanai Y, Kosaka T, Hongo H, Matsumoto K, Shinojima T, Kikuchi E, Miyajima A, Mizuno R, Mikami S, Jinzaki M, Oya M

Molecular and clinical oncology (SPANDIDOS PUBL LTD) 9 ( 6 ) 656 - 660 2018.12

Research paper (scientific journal), Joint Work, ISSN 2049-9450

There is an increasing proportion of individuals aged 70 years and older, as well as an increasing life expectancy worldwide. The present study may guide the management of older patients with elevated prostate specific antigen (PSA). The medical records of 241 older men aged >70 years who underwent multiparametric magnetic resonance imaging (mpMRI) before prostate biopsy (PBx) at our institution were reviewed retrospectively. Multiple variables were evaluated as predictors for the diagnosis of prostate cancer (PCa). The variables included serum PSA level, digital rectal examination, size of region of interest on mpMRI, prostate volume and PSA density. PCa was positive in 162 (67.2%). Prostate volume and PSA density were significant PCa predictors (P<0.001). In patients aged 70-75 and >75 years, PSA density was significantly higher in patients with PCa (0.21 ng/ml/cc, P=0.014 and 0.24 ng/ml/cc, P<0.001, respectively). Similarly, PSA density was significant higher in patients with significant PCa (0.24 ng/ml/cc, P=0.004 and 0.29 ng/ml/cc, P<0.001, respectively). The cut-off value of PSA density was calculated using receiver operating characteristic curves. Area under curve of PSA density was 0.698, and the best cut-off value was 0.20 ng/ml/cc. These results indicate that the combination of PSA density with mpMRI before PBx is a helpful method and can be a decision-making model for a selection of PBx.

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専門医のための泌尿器科基本手術腹腔鏡下膀胱憩室切除術

篠島利明, 松本一宏, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 72 ( 12 ) 1012 - 1017 2018.11

ISSN 0385-2393

Retrocaval Ureter Manifested after Ureteral Reimplantation for Ipsilateral Vesicoureteral Reflux: A Case Report.

Katsui M, Asanuma H, Fukumoto K, Mizuno R, Oya M

Urology journal (UROL & NEPHROL RES CTR-UNRC) 15 ( 6 ) 397 - 399 2018.11

Research paper (scientific journal), Joint Work, ISSN 1735-1308

We report a female patient diagnosed with retrocaval ureter (RCU) after ureteral reimplantation for vesicoureteral reflux (VUR). She was diagnosed as right grade IV VUR with breakthrough urinary tract infections, and underwent ureteral reimplantation with Cohen cross-trigonal technique. Thereafter, she developed severe right hydronephrosis associated with RCU, which was presumably due to caudal traction of right ureter at ureteral reimplantation. Sheunderwent uretero-ureterostomy anterior to the inferior vena cava, and recovered well. Detailed evaluation for upper urinary tract is mandatory for high grade VUR, and Cohen technique should be avoided for VUR associated with RCU.

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Performance of diffusion-weighted MRI post-CT urography for the diagnosis of upper tract urothelial carcinoma

Akita Hirotaka, Kikuchi Eiji, Hayakawa Nozomi, Mikami Shuji, Sugiura Hiroaki, Oya Mototsugu, Jinzaki Masahiro

Clinical Imaging 52 208 - 215 2018.11

Joint Work, ISSN 0899-7071

Objectives: To evaluate the usefulness of adding diffusion-weighted MRI (DW-MRI) to CT urography (CTU) for diagnosing upper tract urothelial carcinoma (UTUC). Materials and methods: We retrospectively evaluated 102 high-risk patients with UTUC who underwent both CTU and DW-MRI. The diagnostic performance of CTU and DW-MRI was evaluated in all the patients. Then, the diagnostic performance of DW-MRI in the patients with positive CTU findings was assessed based on the types of CTU findings (mass formation, wall thickening, and small filling defects). The diagnostic performance of DW-MRI and selective urine cytology sampling in these patients was also compared. Results: The sensitivity of DW-MRI (92%) was less than that of CTU (98%) (P = 0.25), since DW-MRI could not detect any small papillary tumors. The specificity of DW-MRI (91%) was greater than that of CTU (78%) (P = 0.065), since DW-MRI could discriminate some benign conditions from UTUC. Among the 59 positive CTU lesions, DW-MRI correctly diagnosed all 41 mass-forming lesions and improved the accuracy from 36% using CTU alone to 79% for 14 wall-thickening lesions but could not add any additional information for 4 small filling-defect lesions. Among the 44 patients with positive CTU findings who underwent selective urine cytology sampling, the sensitivity of DW-MRI (95%) was significantly greater than that of selective urine cytology sampling (56%) (P < 0.001). Conclusions: The addition of DW-MRI would be useful for both mass-forming and wall-thickening lesions. DW-MRI has the potential to reduce the frequency of selective urine cytology sampling for such lesions.

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Selection of patients who would not require long-term prostate-specific antigen monitoring after low-dose-rate brachytherapy

Niwa N., Matsumoto K., Nishiyama T., Yagi Y., Ozu C., Nakamura K., Saito S., Oya M.

Brachytherapy (Brachytherapy) 17 ( 6 ) 899 - 905 2018.11

Research paper (scientific journal), Joint Work, ISSN 15384721

© 2018 American Brachytherapy Society Purpose: To identify patients at extremely low risk of biochemical recurrence (BCR) of prostate cancer after low-dose-rate brachytherapy (LDR-BT) to determine when prostate-specific antigen (PSA) monitoring can be stopped. Methods and Materials: We retrospectively reviewed clinicopathologic data of patients with prostate cancer who underwent LDR-BT between 2003 and 2011. Of 1569 patients reviewed, 689 (43.9%) received combination external beam radiotherapy, and 970 (61.8%) had neoadjuvant hormonal therapy. We stratified patients according to risk factors identified by multivariate analysis and assessed the factors for an association with BCR (defined as ≥2 ng/mL higher than the nadir). Results: The median followup was 96 months. Of 1531 patients who were BCR-free at 3 years after treatment, 76 subsequently developed BCR; of 1500 who were BCR-free at 5 years, 45 eventually had BCR. On multivariate analysis, independent risk factors for BCR were the National Comprehensive Cancer Network risk group at diagnosis and PSA levels at 3 or 5 years after radiotherapy. In the low-risk group, no patient with a PSA level ≤0.2 ng/mL at 3 years after rad

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Performance of diffusion-weighted MRI post-CT urography for the diagnosis of upper tract urothelial carcinoma: Comparison with selective urine cytology sampling

Akita H., Kikuchi E., Hayakawa N., Mikami S., Sugiura H., Oya M., Jinzaki M.

Clinical Imaging (Clinical Imaging) 52 208 - 215 2018.11

Joint Work, ISSN 08997071

© 2018 Objectives: To evaluate the usefulness of adding diffusion-weighted MRI (DW-MRI) to CT urography (CTU) for diagnosing upper tract urothelial carcinoma (UTUC). Materials and methods: We retrospectively evaluated 102 high-risk patients with UTUC who underwent both CTU and DW-MRI. The diagnostic performance of CTU and DW-MRI was evaluated in all the patients. Then, the diagnostic performance of DW-MRI in the patients with positive CTU findings was assessed based on the types of CTU findings (mass formation, wall thickening, and small filling defects). The diagnostic performance of DW-MRI and selective urine cytology sampling in these patients was also compared. Results: The sensitivity of DW-MRI (92%) was less than that of CTU (98%) (P = 0.25), since DW-MRI could not detect any small papillary tumors. The specificity of DW-MRI (91%) was greater than that of CTU (78%) (P = 0.065), since DW-MRI could discriminate some benign conditions from UTUC. Among the 59 positive CTU lesions, DW-MRI correctly diagnosed all 41 mass-forming lesions and improved the accuracy from 36% using CTU alone to 79% for 14 wall-thickening lesions but could not add any additional information for 4 small

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Particle Transport within the Pulsar Wind Nebula HESS J1825-137

H. E. S. S. Collaboration, H. Abdalla, F. Aharonian, F. Ait Benkhali, E. O. Angüner, M. Arakawa, C. Arcaro, C. Armand, M. Arrieta, M. Backes, M. Barnard, Y. Becherini, J. Becker Tjus, D. Berge, K. Bernlöhr, R. Blackwell, M. Böttcher, C. Boisson, J. Bolmont, S. Bonnefoy, P. Bordas, J. Bregeon, F. Brun, P. Brun, M. Bryan, M. Büchele, T. Bulik, T. Bylund, M. Capasso, S. Caroff, A. Carosi, S. Casanova, M. Cerruti, N. Chakraborty, T. Chand, S. Chandra, R. C. G. Chaves, A. Chen, S. Colafrancesco, B. Condon, I. D. Davids, C. Deil, J. Devin, P. deWilt, L. Dirson, A. Djannati-Ataï, A. Dmytriiev, A. Donath, V. Doroshenko, L. O'C. Drury, J. Dyks, K. Egberts, G. Emery, J. -P. Ernenwein, S. Eschbach, S. Fegan, A. Fiasson, G. Fontaine, S. Funk, M. Füßling, S. Gabici, Y. A. Gallant, F. Gaté, G. Giavitto, D. Glawion, J. F. Glicenstein, D. Gottschall, M. -H. Grondin, J. Hahn, M. Haupt, G. Heinzelmann, G. Henri, G. Hermann, J. A. Hinton, W. Hofmann, C. Hoischen, T. L. Holch, M. Holler, D. Horns, D. Huber, H. Iwasaki, A. Jacholkowska, M. Jamrozy, D. Jankowsky, F. Jankowsky, L. Jouvin, I. Jung-Richardt, M. A. Kastendieck, K. Katarzyński, M. Katsuragawa, U. Katz, D. Kerszberg, D. Khangulyan, B. Khélifi, J. King, S. Klepser, W. Kluźniak, Nu. Komin, K. Kosack, M. Kraus, G. Lamanna, J. Lau, J. Lefaucheur, A. Lemière, M. Lemoine-Goumard, J. -P. Lenain, E. Leser, T. Lohse, R. López-Coto, I. Lypova, D. Malyshev, V. Marandon, A. Marcowith, C. Mariaud, G. Martí-Devesa, R. Marx, G. Maurin, P. J. Meintjes, A. M. W. Mitchell, R. Moderski, M. Mohamed, L. Mohrmann, C. Moore, E. Moulin, T. Murach, S. Nakashima, M. de Naurois, H. Ndiyavala, F. Niederwanger, J. Niemiec, L. Oakes, P. O'Brien, H. Odaka, S. Ohm, M. Ostrowski, I. Oya, M. Panter, R. D. Parsons, C. Perennes, P. -O. Petrucci, B. Peyaud, Q. Piel, S. Pita, V. Poireau, A. Priyana Noel, D. A. Prokhorov, H. Prokoph, G. Pühlhofer, M. Punch, A. Quirrenbach, S. Raab, R. Rauth, A. Reimer, O. Reimer, M. Renaud, F. Rieger, L. Rinchiuso, C. Romoli, G. Rowell, B. Rudak, E. Ruiz-Velasco, V. Sahakian, S. Saito, D. A. Sanchez, A. Santangelo, M. Sasaki, R. Schlickeiser, F. Schüssler, A. Schulz, H. Schutte, U. Schwanke, S. Schwemmer, M. Seglar-Arroyo, M. Senniappan, A. S. Seyffert, N. Shafi, I. Shilon, K. Shiningayamwe, R. Simoni, A. Sinha, H. Sol, A. Specovius, M. Spir-Jacob, Ł. Stawarz, R. Steenkamp, C. Stegmann, C. Steppa, T. Takahashi, J. -P. Tavernet, T. Tavernier, A. M. Taylor, R. Terrier, L. Tibaldo, D. Tiziani, M. Tluczykont, C. Trichard, M. Tsirou, N. Tsuji, R. Tuffs, Y. Uchiyama, D. J. van der Walt, C. van Eldik, C. van Rensburg, B. van Soelen, G. Vasileiadis, J. Veh, C. Venter, P. Vincent, J. Vink, F. Voisin, H. J. Völk, T. Vuillaume, Z. Wadiasingh, S. J. Wagner, R. M. Wagner, R. White, A. Wierzcholska, R. Yang, H. Yoneda, D. Zaborov, M. Zacharias, R. Zanin, A. A. Zdziarski, A. Zech, F. Zefi, A. Ziegler, J. Zorn, N. Zywucka

A&A 621, A116 (2019) 2018.10

Aims: We present a detailed view of the pulsar wind nebula (PWN) HESS
J1825-137. We aim to constrain the mechanisms dominating the particle transport
within the nebula, accounting for its anomalously large size and spectral
characteristics. Methods: The nebula is studied using a deep exposure from over
12 years of H.E.S.S. I operation, together with data from H.E.S.S. II improving
the low energy sensitivity. Enhanced energy-dependent morphological and
spatially-resolved spectral analyses probe the Very High Energy (VHE, E > 0.1
TeV) gamma-ray properties of the nebula. Results: The nebula emission is
revealed to extend out to 1.5 degrees from the pulsar, ~1.5 times further than
previously seen, making HESS J1825--137, with an intrinsic diameter of ~100 pc,
potentially the largest gamma-ray PWN currently known. Characterisation of the
nebula's strongly energy-dependent morphology enables the particle transport
mechanisms to be constrained. A dependence of the nebula extent with energy of
R $\propto$ E^\alpha with \alpha = -0.29 +/- 0.04 (stat) +/- 0.05 (sys)
disfavours a pure diffusion scenario for particle transport within the nebula.
The total gamma-ray flux of the nebula above 1~TeV is found to be (1.12 +/-
0.03 (stat) +/- 0.25 (sys)) $\times 10^{-11}$ cm$^{-2}$ s$^{-1}$, corresponding
to ~64% of the flux of the Crab Nebula. Conclusions: HESS J1825-137 is a PWN
with clear energy-dependent morphology at VHE gamma-ray energies. This source
is used as a laboratory to investigate particle transport within middle-aged
PWNe. Deep observations of this highly spatially-extended PWN enable a spectral
map of the region to be produced, providing insights into the spectral
variation within the nebula.

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特集泌尿器科医のためのゲノム腫瘍学入門─時代に取り残されるな企画にあたって

大家基嗣

臨床泌尿器科 (株式会社医学書院) 72 ( 11 ) 865 - 865 2018.10

ISSN 0385-2393

Combined androgen blockade achieved better oncological outcome in androgen deprivation therapy for prostate cancer: Analysis of community-based multi-institutional database across Japan using propensity score matching

Onozawa M., Akaza H., Hinotsu S., Oya M., Ogawa O., Kitamura T., Suzuki K., Naito S., Namiki M., Nishimura K., Hirao Y., Tsukamoto T.

Cancer Medicine (Cancer Medicine) 7 ( 10 ) 4893 - 4902 2018.10

Joint Work, ISSN 2045-7634

© 2018 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. Background: This study investigated how differences in the method of the first-line androgen deprivation therapy (ADT) affected the time to castration-resistant prostate cancer. Methods: The Japan Study Group of Prostate Cancer compiled a nationwide community-based database on prostate cancer patients who underwent ADT. That database included 13 774 patients who were started on ADT by surgical or medical castration alone (monotherapy group, 5395 cases) or ADT in combination with a nonsteroidal anti-androgen (combined androgen blockade (CAB) group, 8379 cases). We used logistic regression analysis with background factors as independent factors to calculate propensity scores in regard to selection of CAB. Next, for 8826 cases of propensity score-matched patients, we compared the survival rates in the two groups. Results: The CAB group showed a significantly better progression-free survival (PFS) rate (65.6% vs 59.6% at 5 years; median time to progression, 11.6 vs 7.1 years; hazard ratio in the CAB group: 0.78, with a 95% confidence interval of 0.72 to 0.84; P < 0.001). In subgroup analysis based on the ba

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A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with castration resistant prostate cancer: DRREEM trial

Kosaka Takeo, Shinojima Toshiaki, Abe Takayuki, Ueda Koji, Kikuchi Kayoko, Saito Yasuko, Hagiwara Sachiko, Kikuchi Eiji, Kojima Shinichiro, Miyake Shinji, Saya Hideyuki, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 353 - 353 2018.10

Joint Work, ISSN 0919-8172

The establishment of new therapeutic strategy for metastatic urothelial carcinoma targeting against cancer stem cell

Ogihara Koichiro, Kikuchi Eiji, Hakozaki Kyohei, Okazaki Shogo, Hagiwara Masayuki, Takeda Toshikazu, Matsumoto Kazuhiro, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 332 - 332 2018.10

Joint Work, ISSN 0919-8172

The clinical impact of baseline serum C-reactive protein level in patients with metastatic renal cell carcinoma treated by targeted therapy

Takamatsu Kimiharu, Mizuno Ryuichi, Takeda Toshikazu, Morita Shinya, Matsumoto Kazuhiro, Kosaka Takeo, Shinojima Toshiaki, Kikuchi Eiji, Asanuma Hiroshi, Oyama Masafumi, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 257 - 257 2018.10

Joint Work, ISSN 0919-8172

Network Medicine to Overcome Drug Resistance in CRPC or NEPC: Drug Efficacy Reprogramming

Kosaka Takeo, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 153 - 153 2018.10

Joint Work, ISSN 0919-8172

Efficacy of TWIST score system for different diagnosis in acute scrotum

Teranishi Yu, Asanuma Hiroshi, Takamatsu Kimiharu, Takeda Toshikazu, Matsumoto Kazuhiro, Morita Shinya, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 374 - 374 2018.10

Joint Work, ISSN 0919-8172

Clinical Investigation of Homecare Urology in a Japanese Homecare Support Clinic

Yazawa Satoshi, Yamanaka Takashi, Kubota Kazumi, Kemei Jun, Nakahara Jin, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 201 - 201 2018.10

Joint Work, ISSN 0919-8172

Nivolumab (NIVO) v everolimus (EVE) in advanced renal cell carcinoma (aRCC): 3-year follow-up in Japanese patients (pts) from Check-Mate 025

Satoshi Fukasawa, Nobuo Shinohara, Hiroshi Kitamura, Mototsugu Oya, Masatoshi Eto, Kazunari Tanabe, Mitsuru Saito, Go Kimura, Junji Yonese, Masahiro Yao, Lingfeng Yang, Elmer Berghorn, Robert J. Motzer, Yoshihiko Tomita

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 257 - 257 2018.10

Joint Work, ISSN 0919-8172

Oncologic Surveillance After Radical Nephroureterectomy in Upper Tract Urothelial Carcinoma Patients: A Novel Risk-Based Approach

Shigeta Keisuke, Kikuchi Eiji, Hagiwara Masayuki, Abe Takayuki, Takeda Toshikazu, Matsumoto Kazuhiro, Shinojima Toshiaki, Nakagawa Ken, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY 25 438 - 438 2018.10

ISSN 0919-8172

Oncologic Surveillance After Radical Nephroureterectomy in Upper Tract Urothelial Carcinoma Patients: A Novel Risk-Based Approach

Keisuke Shigeta, Eiji Kikuchi, Masayuki Hagiwara, Takayuki Abe, Toshikazu Takeda, Kazuhiro Matsumoto, Toshiaki Shinojima, Ken Nakagawa, Mototsugu Oya

INTERNATIONAL JOURNAL OF UROLOGY (WILEY) 25 438 - 438 2018.10

Joint Work, ISSN 0919-8172

Updated long-term outcomes after carbon-ion radiotherapy for primary renal cell carcinoma

Kasuya Goro, Tsuji Hiroshi, Nomiya Takuma, Makishima Hirokazu, Haruyama Yasuo, Kobashi Gen, Ebner Daniel K., Hayashi Kazuhiko, Omatsu Tokuhiko, Kishimoto Riwa, Yasuda Shigeo, Igarashi Tatsuo, Oya Mototsugu, Akakura Koichiro, Suzuki Hiroyoshi, Ichikawa Tomohiko, Shimazaki Jun, Kamada Tadashi

Cancer Science (Cancer Science) 109 ( 9 ) 2873 - 2880 2018.09

Research paper (scientific journal), Joint Work, ISSN 1347-9032

Long-term oncological outcomes for primary renal cell carcinoma (RCC) treated with carbon-ion radiotherapy (CIRT) are poorly understood. Patients with primary RCC were treated with 12 or 16-fraction CIRT at The Hospital of the National Institute of Radiological Sciences outside of clinical trials. Outcome data were pooled and retrospectively analyzed for toxicity, local control, and disease-free, cancer-specific, and overall survival. From 1997 to 2014, 19 RCC patients (11 with T1aN0M0, 4 with T1bN0M0, and 4 with inoperable advanced stage [T4N0M0, T3aN1M0, and T1aN0M1]) were treated with CIRT and followed up for a median of 6.6 (range, 0.7-16.5) years; 9 of these patients were inoperable because of comorbidities or advanced-stage disease. Diagnoses were confirmed by imaging in 11 patients and by biopsy in the remaining 8. In 4 of 5 patients with definitive renal comorbidities, including diabetic nephropathy, sclerotic kidney or solitary kidney pre-CIRT progressed to grade 4 chronic kidney disease (CKD). In contrast, the remaining 14 patients without definitive renal comorbidities did not progress to grade 3 or higher CKD. Furthermore, although 1 case of grade 4 dermatitis was observed, there were no other grade 3 or higher non-renal adverse events. Local control rate, and disease-free, cancer-specific, and overall survival rates at 5 years of all 19 patients were 94.1%, 68.9%, 100%, and 89.2%, respectively. This updated retrospective analysis based on long-term follow-up data suggests that CIRT is a safe treatment for primary RCC patients without definitive renal comorbidities pre-CIRT, and yield favorable treatment outcomes, even in inoperable cases.

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Analysis of cabazitaxel-resistant mechanism in human castration-resistant prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Cancer Science (Cancer Science) 109 ( 9 ) 2937 - 2945 2018.09

Research paper (scientific journal), Joint Work, ISSN 1347-9032

Cabazitaxel (CBZ) is approved for docetaxel-resistant castration-resistant prostate cancer (CRPC). However, efficacy of CBZ for CRPC is limited and there are no effective treatments for CBZ-resistant CRPC. In order to investigate the CBZ-resistant mechanism, the establishment of a CBZ-resistant cell line is urgently needed. We established CBZ-resistant CRPC cell lines DU145CR and PC3CR by incubating DU145 and PC3 cells with gradually increasing concentrations of CBZ for approximately 2 years. We analyzed the gene expression profiles and cell cycle changes using microarray and flow cytometry. Pathway analysis revealed DU145CR cells had enhanced gene clusters of cell division and mitotic nuclear division. Enhancement of ERK signaling was detected in DU145CR cells. DU145CR cells had resistance to G₂/M arrest induced by CBZ through ERK signaling activation. The MEK inhibitor PD184352 significantly inhibited cell proliferation of DU145CR. In contrast to DU145CR, PC3CR cells had enhancement of PI3K/AKT signaling. The PI3K/mTOR inhibitor NVP-BEZ 235 had a significant antitumor effect in PC3CR cells. Cabazitaxel -resistant CRPC cells established in our laboratory had enhancement of cell cycle progression signals and resistance to G₂/M arrest induced by CBZ. Enhancement of ERK signaling or PI3K/AKT signaling were detected in the cell lines, so ERK or PI3K/AKT could be therapeutic targets for CBZ-resistant CRPC.

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Message from the Publications Chair

Mototsugu Oya

WORLD JOURNAL OF UROLOGY (SPRINGER) 36 ( 9 ) 1504 - 1504 2018.09

Single Work, ISSN 0724-4983

Incidence and timing of inadvertent nephrostomy catheter displacement in patients with ureteral obstruction

Niwa, Naoya, Matsumoto, Kazuhiro, Kikuchi, Eiji, Yazawa, Satoshi, Takeda, Toshikazu, Morita, Shinya, Kosaka, Takeo, Shinoda, Kazunobu, Mizuno, Ryuichi, Shinojima, Toshiaki, Asanuma, Hiroshi, Oya, Mototsugu

CLINICAL NEPHROLOGY (Clinical Nephrology) 90 ( 2 ) 112 - 116 2018.08

Research paper (scientific journal), Single Work, ISSN 0301-0430

© 2018 Dustri-Verlag Dr. K. Feistle. Introduction: To evaluate nephrostomy catheter displacement, we assessed the cumulative nephrostomy catheter displacement rate in patients with percutaneous nephrostomy and compared the nephrostomy displacement rates between pigtail and balloon catheters. Materials and methods: Between 2003 and 2011, 87 patients who underwent percutaneous nephrostomy catheter placement and more than one subsequent catheter replacement were retrospectively identified. We evaluated their inadvertent nephrostomy catheter displacement. Results: 20 patients (23.0%) experienced incidental nephrostomy catheter displacement during the follow-up period. Kaplan-Meier analysis revealed that the 1-year nephrostomy catheter displacement-free survival rate was 62 ± 9%. No significant independent risk factors for predicting nephrostomy catheter displacement were identified, including the type of catheter. The median time from initial placement to displacement of pigtail catheters was shorter than that of balloon catheters. Conclusion: There were no significant differences in the nephrostomy catheter displacement-free survival rates between the two types of catheters. Regardl

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Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older: A propensity score-matched analysis

Tatsugami K., Oya M., Kabu K., Akaza H.

British Journal of Cancer (British Journal of Cancer) 119 ( 2 ) 241 - 247 2018.07

Research paper (scientific journal), Joint Work, ISSN 00070920

© 2018 The Author(s). Background: The average age of patients diagnosed with renal cell carcinoma (RCC) is increasing, but a limited number of reports have described therapy of tyrosine kinase inhibitor for elderly RCC patients. Hence, we analysed the efficacy and safety of sorafenib in elderly patients aged ≥75 years with advanced RCC. Methods: Data were extracted from <75-year-old and ≥75-year-old patient groups, matching those demographics considered to affect prognosis. Differences in patients' characteristics, dose modification, adverse events, tumour response, progression-free survival, and renal function (glomerular filtration) were evaluated between the groups. Results: From 2536 and 703 patients aged <75 and ≥75 years, respectively, 397 pairs were matched. Median daily dose was higher and duration of treatment longer in patients <75 years; however, progression-free survival and tumour response were similar in both age groups. Incidence of all adverse events was not significantly different between groups. The proportion of patients discontinuing treatment was higher in patients ≥75 years, but there was no significant difference between groups in the number patients

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Clinical evaluation of two consecutive UroVysion fluorescence in situ hybridization tests to detect intravesical recurrence of bladder cancer

Kojima Takahiro, Nishiyama Hiroyuki, Ozono Seiichiro, Hinotsu Shiro, Keino Naoto, Yamaguchi Akito, Sakai Hideki, Enomoto Yutaka, Horie Shigeo, Fujimoto Kiyohide, Matsuyama Hideyasu, Okamura Takehiko, Kanimoto Yusuke, Oya Mototsugu, Nonomura Norio, Naito Seiji, Akaza Hideyuki

International Journal of Clinical Oncology 1 - 8 2018.07

Joint Work, ISSN 1341-9625

Background: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT). Methods: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests. Results: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2–64.8%) sensitivity and 72.4% (68.3–76.8%). Urine cytology had 4.5% (0.0–10.7%) sensitivity and 99.8% (99.3–100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up. Conclusions: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

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Androgen receptor signaling reduces radiosensitivity in bladder cancer

Ide Hiroki, Inoue Satoshi, Mizushima Taichi, Jiang Guiyang, Chuang Kuang Hsiang, Oya Mototsugu, Miyamoto Hiroshi

Molecular Cancer Therapeutics (Molecular Cancer Therapeutics) 17 ( 7 ) 1566 - 1574 2018.07

Research paper (scientific journal), Joint Work, ISSN 1535-7163

Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer.

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Recombinant Thrombomodulin Alpha Protects Kidney Graft from Damage after Long Cold Ischemia Time in a Rat Kidney Transplant Model

Shinoda Kazunobu, Tamaki Satoshi, Morita Shinya, Shimoda Masayuki, Oya Mototsugu

TRANSPLANTATION (LIPPINCOTT WILLIAMS & WILKINS) 102 S710 - S710 2018.07

Joint Work, ISSN 0041-1337

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RELATIONSHIP BETWEEN RADIATION DOSES AND DEVELOPMENT OF ERECTILE DYSFUNCTION IN PATIENTS TREATED WITH PERMANENT PROSTATE BRACHYTHERAPY FOR LOCALIZED PROSTATE CANCER

Hayakawa N, Kikuchi E, Shigeta K, Mizuno R, Oya M

JOURNAL OF SEXUAL MEDICINE 15 ( 7 ) S287 - S287 2018.07

Joint Work, ISSN 1743-6095

PKM2 under hypoxic environment causes resistance to mTOR inhibitor in human castration resistant prostate cancer

Yasumizu Yota, Hongo Hiroshi, Kosaka Takeo, Mikami Shuji, Nishimoto Koshiro, Kikuchi Eiji, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 45 ) 27698 - 27707 2018.06

Research paper (scientific journal), Joint Work, ISSN 1949-2553

The aim of this study was to explore the efficacy of mTOR inhibitor for castrationresistant prostate cancer (CRPC) under hypoxia. Although under normoxia C4-2AT6, it is a CRPC cell line, expressed elevated pAkt, pS6 and Pyruvate kinase M2 (PKM2) accompanied by elevated HIF-1a expression, 5% hypoxic condition further induced expression of these proteins. These results indicate hypoxic environment elevated PI3K/ Akt/mTOR pathway in aggressive prostate cancer. However, C4-2AT6 cells treated with mTOR inhibitor under hypoxia less decreased compared to cells treated with the same dose drugs under normoxia. Western blot analysis showed mTOR inhibitor: RAD001 not only inhibited pS6, but also increased the expression of PKM2 in a dose and time dependent manner. Pyruvate kinase acts on glycolysis. PKM2, which is frequently express in tumor cells, is one isoform of pyruvate kinase. PKM2 is reported to act as a transcription factor. In the present study overexpression of PKM2 in C4-2AT6 induced resistance to RAD001 under normoxia. To evaluate the therapeutic effect of targeting PKM2, we inhibited PKM2 in C4-2AT6 under hypoxia using si-PKM2. The number of C4-2AT6 under chronic hypoxia exposed to siPKM2 significantly decreased compared to intact C4-2AT6 under chronic hypoxia. Furthermore, si-PKM2 improved resistance to mTOR inhibitor in C4-2AT6. When examined using clinical samples, high PKM2 expression was correlated with a high Gleason score and poor PSA free survival. These results suggested that up-regulation of PKM2 is one possibility of resistance to mTOR inhibitor in CRPC. And it is possible that PKM2 is a useful therapeutic target of CRPC.

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Evaluation of efficacy and safety of sorafenib in kidney cancer patients aged 75 years and older

Tatsugami Katsunori, Oya Mototsugu, Kabu Koki, Akaza Hideyuki

British Journal of Cancer 1 - 7 2018.06

Joint Work, ISSN 0007-0920

Background: The average age of patients diagnosed with renal cell carcinoma (RCC) is increasing, but a limited number of reports have described therapy of tyrosine kinase inhibitor for elderly RCC patients. Hence, we analysed the efficacy and safety of sorafenib in elderly patients aged ≥75 years with advanced RCC. Methods: Data were extracted from <75-year-old and ≥75-year-old patient groups, matching those demographics considered to affect prognosis. Differences in patients’ characteristics, dose modification, adverse events, tumour response, progression-free survival, and renal function (glomerular filtration) were evaluated between the groups. Results: From 2536 and 703 patients aged <75 and ≥75 years, respectively, 397 pairs were matched. Median daily dose was higher and duration of treatment longer in patients <75 years; however, progression-free survival and tumour response were similar in both age groups. Incidence of all adverse events was not significantly different between groups. The proportion of patients discontinuing treatment was higher in patients ≥75 years, but there was no significant difference between groups in the number patients discontinuing due to adverse events. Conclusions: For patients aged ≥75 years, sorafenib treatment had minimal additional negative impact compared to younger patients and showed similar efficacy and safety without reducing renal function.

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The starburst galaxy NGC 253 revisited by H.E.S.S. and Fermi-LAT

H. E. S. S. Collaboration, H. Abdalla, F. Aharonian, F. Ait Benkhali, E. O. Angüner, M. Arakawa, C. Arcaro, C. Armand, M. Arrieta, M. Backes, M. Barnard, Y. Becherini, J. Becker Tjus, D. Berge, S. Bernhard, K. Bernlöhr, R. Blackwell, M. Böttcher, C. Boisson, J. Bolmont, S. Bonnefoy, P. Bordas, J. Bregeon, F. Brun, P. Brun, M. Bryan, M. Büchele, T. Bulik, T. Bylund, M. Capasso, S. Caroff, A. Carosi, S. Casanova, M. Cerruti, N. Chakraborty, S. Chandra, R. C. G. Chaves, A. Chen, S. Colafrancesco, B. Condon, I. D. Davids, C. Deil, J. Devin, P. de Wilt, L. Dirson, A. Djannati-Ataï, A. Dmytriiev, A. Donath, L. O'C. Drury, J. Dyks, K. Egberts, G. Emery, J. -P. Ernenwein, S. Eschbach, S. Fegan, A. Fiasson, G. Fontaine, S. Funk, M. Füßling, S. Gabici, Y. A. Gallant, T. Garrigoux, F. Gaté, G. Giavitto, D. Glawion, J. F. Glicenstein, D. Gottschall, M. -H. Grondin, J. Hahn, M. Haupt, G. Heinzelmann, G. Henri, G. Hermann, J. A. Hinton, W. Hofmann, C. Hoischen, T. L. Holch, M. Holler, D. Horns, D. Huber, H. Iwasaki, A. Jacholkowska, M. Jamrozy, D. Jankowsky, F. Jankowsky, L. Jouvin, I. Jung-Richardt, M. A. Kastendieck, K. Katarzyński, M. Katsuragawa, U. Katz, D. Kerszberg, D. Khangulyan, B. Khélifi, J. King, S. Klepser, W. Kluźniak, N. Komin, K. Kosack, S. Krakau, M. Kraus, P. P. Krüger, G. Lamanna, J. Lau, J. Lefaucheur, A. Lemière, M. Lemoine-Goumard, J. -P. Lenain, E. Leser, T. Lohse, M. Lorentz, R. López-Coto, I. Lypova, D. Malyshev, V. Marandon, A. Marcowith, C. Mariaud, G. Martí-Devesa, R. Marx, G. Maurin, P. J. Meintjes, A. M. W. Mitchell, R. Moderski, M. Mohamed, L. Mohrmann, E. Moulin, T. Murach, S. Nakashima, M. de Naurois, H. Ndiyavala, F. Niederwanger, J. Niemiec, L. Oakes, P. O'Brien, H. Odaka, S. Ohm, M. Ostrowski, I. Oya, M. Padovani, M. Panter, R. D. Parsons, C. Perennes, P. -O. Petrucci, B. Peyaud, Q. Piel, S. Pita, V. Poireau, A. Priyana Noel, D. A. Prokhorov, H. Prokoph, G. Pühlhofer, M. Punch, A. Quirrenbach, S. Raab, R. Rauth, A. Reimer, O. Reimer, M. Renaud, F. Rieger, L. Rinchiuso, C. Romoli, G. Rowell, B. Rudak, E. Ruiz-Velasco, V. Sahakian, S. Saito, D. A. Sanchez, A. Santangelo, M. Sasaki, R. Schlickeiser, F. Schüssler, A. Schulz, U. Schwanke, S. Schwemmer, M. Seglar-Arroyo, M. Senniappan, A. S. Seyffert, N. Shafi, I. Shilon, K. Shiningayamwe, R. Simoni, A. Sinha, H. Sol, F. Spanier, A. Specovius, M. Spir-Jacob, Ł. Stawarz, R. Steenkamp, C. Stegmann, C. Steppa, I. Sushch, T. Takahashi, J. -P. Tavernet, T. Tavernier, A. M. Taylor, R. Terrier, L. Tibaldo, D. Tiziani, M. Tluczykont, C. Trichard, M. Tsirou, N. Tsuji, R. Tuffs, Y. Uchiyama, D. J. van der Walt, C. van Eldik, C. van Rensburg, B. van Soelen, G. Vasileiadis, J. Veh, C. Venter, A. Viana, P. Vincent, J. Vink, F. Voisin, H. J. Völk, T. Vuillaume, Z. Wadiasingh, S. J. Wagner, P. Wagner, R. M. Wagner, R. White, A. Wierzcholska, A. Wörnlein, R. Yang, D. Zaborov, M. Zacharias, R. Zanin, A. A. Zdziarski, A. Zech, F. Zefi, A. Ziegler, J. Zorn, N. Żywucka

A&A 617, A73 (2018) 2018.06

(Abridged) Context. NGC 253 is one of only two starburst galaxies found to
emit $\gamma$-rays from hundreds of MeV to multi-TeV energies. Accurate
measurements of the very-high-energy (VHE) (E $>$ 100 GeV) and high-energy (HE)
(E $>$ 60 MeV) spectra are crucial to study the underlying particle
accelerators and cosmic-ray interaction and transport.
Aims. The measurement of the VHE $\gamma$-ray emission of NGC 253 published
in 2012 by H.E.S.S. was limited by large systematic uncertainties. Here, a
measurement of the $\gamma$-ray spectrum of NGC 253 is investigated in both HE
and VHE $\gamma$-rays.
Methods. The data of H.E.S.S. observations are reanalysed using an updated
calibration and analysis chain. The $Fermi$-LAT analysis employs more than 8
years of data processed using pass 8. The cosmic-ray particle population is
evaluated from the combined HE--VHE $\gamma$-ray spectrum using NAIMA.
Results. The VHE $\gamma$-ray energy spectrum is best fit by a power-law with
a flux normalisation of
$(1.34\,\pm\,0.14^{\mathrm{stat}}\,\pm\,0.27^{\mathrm{sys}}) \times 10^{-13}
\mathrm{cm^{-2} s^{-1} TeV^{-1}}$ at 1 TeV -- about 40 \% above, but compatible
with the value obtained in Abramowski et al. (2012). The spectral index $\Gamma
= 2.39 \pm 0.14^{\mathrm{stat}} \pm 0.25^{\mathrm{sys}}$ is slightly softer
than but consistent with the previous measurement. At energies above $\sim$3
GeV the HE spectrum is consistent with a power-law ranging into the VHE part of
the spectrum measured by H.E.S.S.
Conclusions. Two scenarios for the starburst nucleus are tested, in which the
gas in the starburst nucleus acts as a target for hadronic cosmic rays. In
these two models, the level to which NGC\,253 acts as a calorimeter is
estimated to a range of $f_{\rm cal} = 0.1$ to $1$ while accounting for the
measurement uncertainties.

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Prognostic Value of Pretreatment Albumin-to-Globulin Ratio in Patients With Non–Muscle-Invasive Bladder Cancer

Niwa Naoya, Matsumoto Kazuhiro, Ide Hiroki, Nagata Hirohiko, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 3 ) e655 - e661 2018.06

Research paper (scientific journal), Joint Work, ISSN 1558-7673

In an investigation of the relationship between albumin-to-globulin ratio (AGR) and oncologic outcomes in 364 non–muscle-invasive bladder cancer (NMIBC) patients, those with AGR < 1.6 had significantly poorer recurrence-free and progression-free survival than those with AGR ≥ 1.6. Multivariate analysis revealed that AGR < 1.6 is significantly associated with tumor recurrence. Low AGR is an independent risk factor for recurrence in NMIBC patients. Purpose: To investigate the relationship between albumin-to-globulin ratio (AGR) and oncologic outcomes in patients with non–muscle-invasive bladder cancer (NMIBC). Patients and Methods: We identified 364 patients with primary NMIBC who underwent transurethral surgery between 2000 and 2015. The association between pretreatment AGR and clinicopathologic variables, including oncologic outcomes, was statistically evaluated. Results: One hundred twenty patients (33.0%) experienced at least one tumor recurrence, and 23 (6.3%) developed muscle-invasive disease. The median (interquartile range) pretreatment AGR was 1.73 (1.53-1.89). The Kaplan-Meier curve revealed that tumor recurrence was strongly predicted in patients with pretreatment AGR < 1.6, and similar results were observed for disease progression (P <.01 and P <.01, respectively). On multivariate analysis, we found that pretreatment AGR < 1.6 is an independent risk factor for tumor recurrence (hazard ratio, 0.53; P <.01). On univariate analysis, pretreatment AGR < 1.6 was also associated with disease progression (hazard ratio, 0.24; P <.01). Conclusion: Low pretreatment AGR is an independent risk factor for tumor recurrence and is one risk factor for disease progression in NMIBC patients. This inexpensive and easily accessible biomarker may become useful in selecting patients with NMIBC with higher risk of recurrence and progression.

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Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non–muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

Niwa N., Kikuchi E., Matsumoto K., Kosaka T., Mizuno R., Oya M.

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 6 ) 306.e1 - 306.e8 2018.06

ISSN 10781439

© 2018 Elsevier Inc. Purpose: It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). Materials and methods: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). Result: The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. Conclusions: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.

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Recombinant Thrombomodulin alpha Attenuates Kidney Graft Damage after Long Cold Ischemia Time in a Rat Kidney Transplant Model.

Tamaki S, Shinoda K, Shimoda M, Morita S, Asanuma H, Oya M

AMERICAN JOURNAL OF TRANSPLANTATION 18 362 - 362 2018.06

Joint Work, ISSN 1600-6135

腎盂尿管癌に対するBCGの上部尿路注入療法に関する実態調査

大園誠一郎, 大家基嗣, 西山博之, 窪田吉信, 塚本泰司, 内藤誠二, 赤座英之

泌尿器外科 (医学図書出版(株)) 31 ( 6 ) 985 - 988 2018.06

Joint Work, ISSN 0914-6180

Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma

Guo Jun, Jin Jie, Oya Mototsugu, Uemura Hirotsugu, Takahashi Shunji, Tatsugami Katsunori, Rha Sun Young, Lee Jae Lyun, Chung Jinsoo, Lim Ho Yeong, Wu Hsi Chin, Chang Yen Hwa, Azad Arun, Davis Ian D., Carrasco-Alfonso Marlene J., Nanua Bhupinder, Han Jackie, Ahmad Qasim, Motzer Robert

Journal of Hematology and Oncology 11 ( 1 ) 2018.05

Joint Work, ISSN 1756-8722

Background: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Methods: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Results: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most common grade 3/4 AEs with pazopanib were hypertension (grade 3, 22%) and alanine aminotransferase increased (grade 3, 12%; grade 4, 1%); the most common grade 3/4 AEs with sunitinib were thrombocytopenia/platelet count decreased (grade 3, 36%; grade 4, 10%), neutropenia/neutrophil count decreased (grade 3, 24%; grade 4, 3%) hypertension (grade 3, 20%), and PPE (grade 3, 15%). Conclusions: A distinct pattern and severity of adverse events was observed in Asians when compared with non-Asians with both pazopanib and sunitinib. However, the two drugs were well tolerated in both subpopulations. Trial registration: ClinicalTrials.gov, NCT00720941, Registered July 22, 2008 ClinicalTrials.gov, NCT01147822, Registered June 22, 2010

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Association between expression of programmed cell death-1 and smoking status in patients with upper tract urothelial carcinoma treated by radical nephroureterectomy.

Nozomi Hayakawa, Eiji Kikuchi, Kimiharu Takamatsu, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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The clinical impact of serum C-reactive protein levels in metastatic renal-cell carcinoma patients treated by second-line molecular targeted therapies

Kimiharu Takamatsu, Ryuichi Mizuno, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Shuji Mikami, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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Does neoadjuvant chemotherapy affect postoperative complication rates in elderly patients treated with radical cystectomy for bladder cancer?

Nozomi Hayakawa, Eiji Kikuchi, Ryuichi Mizuno, Mototsugu Oya, Kimiharu Takamatsu

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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Constitutive activation of mTOR pathways in renal cell carcinoma arising in dialyzed patients

Ryuichi Mizuno, Shuji Mikami, Kimiharu Takamatsu, Nozomi Hayakawa, Takeo Kosaka, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 15 ) 2018.05

Joint Work, ISSN 0732-183X

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New targeted approach to CRPC

Kosaka T., Oya M.

Hormone Therapy and Castration Resistance of Prostate Cancer (Hormone Therapy and Castration Resistance of Prostate Cancer) 375 - 385 2018.05

Joint Work

© Springer Nature Singapore Pte Ltd. 2018. All rights reserved. Our understanding of the heterogeneity and genetic characteristics of CRPC demonstrates underlying their complexity, which has been thought to be associated with their intractability. Recent advance of integrative next generation sequencing unveiled the extensive mutational landscape of metastatic CRPC, many of which can be a targetable mutation and been linked to ongoing clinical trials. Molecular stratification of patient groups will clearly be critical to successful drug development and clinical trials from the view point of precision medicine. In this review, we discuss the potential of new targeted approach to impact the clinical management of CRPC.

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Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle-invasive Bladder Cancer Recurring After Initial Bacillus Calmette–Guérin Therapy

Fukumoto Keishiro, Kikuchi Eiji, Mikami Shuji, Hayakawa Nozomi, Matsumoto Kazuhiro, Niwa Naoya, Oya Mototsugu

Annals of Surgical Oncology (Annals of Surgical Oncology) 25 ( 8 ) 1 - 8 2018.05

Research paper (scientific journal), Joint Work, ISSN 1068-9265

Background: The programmed cell death-1 (PD-1) pathway has been suggested to play an important role in tumor immune escape. We evaluated changes in PD-1 expression before and after Bacillus Calmette–Guérin (BCG) therapy and its prognostic significance in non-muscle-invasive bladder cancer (NMIBC) patients.Methods: We examined 78 paired tissue samples of NMIBC in tumors just before BCG therapy and BCG-relapsing tumors, defined as recurrence after achieving disease-free status by initial BCG instillations for 6 months. We counted PD-1-positive cells, and PD-1 expression was defined as high when the number of PD-1-positive cells was more than 18 under ×200 magnification. Results: The median number of PD-1-positive cells in tumors just before BCG therapy was 3.5, significantly lower than that in BCG-relapsing tumors (17.0, p < 0.001). High PD-1 expression was observed in 20 tumors just before BCG therapy (25.6%) and 36 BCG-relapsing tumors (46.2%). Fifty-two cases (66.6%) showed an increase in the number of PD-1-positive cells in BCG-relapsing tumors. High PD-1 expression in BCG-relapsing tumors was independently associated with subsequent tumor recurrence (p = 0.011) and stage progression (p = 0.033). The 5-year recurrence-free and progression-free survival rates were 40.7 and 74.1% in patients with high PD-1 expression in BCG-relapsing tumors, significantly lower than those in their counterparts (72.9 and 94.1%, respectively). Conclusions: PD-1 was induced by BCG therapy, and its expression in BCG-relapsing tumors may be an important indicator for predicting worse clinical outcomes in NMIBC patients treated with BCG therapy.

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Change of the 5 alpha/5 beta ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride

Maeda, Takahiro, Kikuchi, Eiji, Hasegawa, Masanori, Homma, Keiko, Yasumizu, Yota, Hattori, Seiya, Kosaka, Takeo, Shinoda, Kazunobu, Miyajima, Akira, Oya, Mototsugu

CLINICAL BIOCHEMISTRY 55 36 - 41 2018.05

Research paper (scientific journal), ISSN 0009-9120

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Safety of pazopanib and sunitinib in treatment-naive patients with metastatic renal cell carcinoma: Asian versus non-Asian subgroup analysis of the COMPARZ trial

Guo, Jun, Jin, Jie, Oya, Mototsugu, Uemura, Hirotsugu, Takahashi, Shunji, Tatsugami, Katsunori, Rha, Sun Young, Lee, Jae-Lyun, Chung, Jinsoo, Lim, Ho Yeong, Wu, Hsi Chin, Chang, Yen Hwa, Azad, Arun, Davis, Ian D., Carrasco-Alfonso, Marlene J., Nanua, Bhupinder, Han, Jackie, Ahmad, Qasim, Motzer, Robert

JOURNAL OF HEMATOLOGY & ONCOLOGY (Journal of Hematology and Oncology) 11 ( 1 ) E655 - E661 2018.05

Research paper (scientific journal), Single Work, ISSN 1756-8722

© 2018 The Author(s). Background: The international, phase 3 COMPARZ study demonstrated that pazopanib and sunitinib have comparable efficacy as first-line therapy in patients with advanced renal cell carcinoma, but that safety and quality-of-life profiles favor pazopanib. Our report analyzed pazopanib and sunitinib safety in Asian and non-Asian subpopulations. Methods: Patients were randomized 1:1 to receive pazopanib 800 mg once daily (continuous dosing) or sunitinib 50 mg once daily in 6-week cycles (4 weeks on, 2 weeks off). Results: Safety population was composed of 363 Asian patients and 703 non-Asian patients. Asian patients had similar duration of exposure to either drug compared with non-Asian patients, although Asian patients had a higher frequency of dose modifications. Overall, hematologic toxicities, cytopenias, increased AST/ALT, and palmar-plantar erythrodysesthesia (PPE) were more prevalent in Asian patients, whereas gastrointestinal toxicities were more prevalent in non-Asian patients. Among Asian patients, hematologic adverse events and most non-hematologic AEs were more common in sunitinib-treated versus pazopanib-treated patients. Among Asian patients, the most

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Efficacy and safety of sorafenib for advanced renal cell carcinoma

Tatsugami Katsunori, Oya Mototsugu, Kabu Koki, Akaza Hideyuki

Oncotarget 9 ( 27 ) 19406 - 19414 2018.04

Joint Work, ISSN 1949-2553

Background: We retrospectively analysed the efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with renal impairment. Methods: Patients were divided into two groups by an estimated glomerular filtration rate (eGFR) cut-off of 45 mL/min/1.73 m². Background factors considered to affect prognosis were well balanced by propensity score matching between the groups. Demographics, dose modification, adverse events, tumour response, progression-free survival, and renal function (eGFR) were evaluated. Results: Among 935 and 2008 patients with an eGFR of < 45 and ≥45, respectively, 613 pairs were matched. The mean starting dose was significantly lower in patients with an eGFR of < 45; however, the mean daily dose, median treatment duration, progression-free survival, and tumour response were similar between the groups. In terms of safety, no significant differences were found in serious adverse events, although cytopaenia (16.6% vs 10.6%) and renal dysfunction (4.4% vs 0.7%) were higher in patients with an eGFR of < 45 than ≥45 in all adverse events. There were also no differences in dose modification, including dose reduction, dose interruption, and treatment discontinuation. Conclusion: Throughout the 12-month observation period, sorafenib in patients with an eGFR of < 45 and ≥45 showed similar safety and efficacy, and treatment was continued without affecting renal function.

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Efficacy and safety of sorafenib for advanced renal cell carcinoma: Real-world data of patients with renal impairment

Tatsugami K., Oya M., Kabu K., Akaza H.

Oncotarget (Oncotarget) 9 ( 27 ) 19406 - 19414 2018.04

Research paper (scientific journal), Joint Work, ISSN 1949-2553

© Tatsugami et al. Background: We retrospectively analysed the efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with renal impairment. Methods: Patients were divided into two groups by an estimated glomerular filtration rate (eGFR) cut-off of 45 mL/min/1.73 m2. Background factors considered to affect prognosis were well balanced by propensity score matching between the groups. Demographics, dose modification, adverse events, tumour response, progression-free survival, and renal function (eGFR) were evaluated. Results: Among 935 and 2008 patients with an eGFR of < 45 and ≥45, respectively, 613 pairs were matched. The mean starting dose was significantly lower in patients with an eGFR of < 45; however, the mean daily dose, median treatment duration, progression-free survival, and tumour response were similar between the groups. In terms of safety, no significant differences were found in serious adverse events, although cytopaenia (16.6% vs 10.6%) and renal dysfunction (4.4% vs 0.7%) were higher in patients with an eGFR of < 45 than ≥45 in all adverse events. There were also no differences in dose modification, including dose reduction, dose interr

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Continuation of axitinib for advanced renal cell carcinoma by the application of homecare urology-a case report and literature review

Yazawa Satoshi, Kato Yuji, Nakahara Jin, Miyata Toshio, Oya Mototsugu

Japanese Journal of Cancer and Chemotherapy (Japanese Journal of Cancer and Chemotherapy) 45 ( 4 ) 639 - 642 2018.04

Joint Work, ISSN 0385-0684

A 56-year-old man with advanced RCC and a past medical history of type 2 diabetes underwent a radical left nephrectomy following a histological diagnosis of papillary RCC, G2, INF β, pT3, V1 in 1999. In 2008, sorafenib was started to treat multiple pulmonary metastases of RCC. In 2011, sorafenib was switched to sunitinib when radiologic progression was observed. In 2014, sunitinib was switched to axitinib when further radiologic progression was observed. In 2015, the patient was referred to Yazawa clinic for homecare urology when hospital visits became difficult due to cancer pain and bilateral lower-extremity muscle weakness. Cancer pain was controlled using acetaminophen and a fentanyl patch. During the administration of axitinib, a CTCAE grade 1 vocal disorder was detected. We reduced the axitinib dose from 10 mg to 6 mg, and valsartan and an antiflatulent were administered due to CTCAE grade 2 hypertension and diarrhea, respectively. Axitinib administration continued until the patient died. He had survived more than 11 years following the detection of lung metastasis. In this patient, a good balance between cancer treatment and palliative care was achieved through the application of homecare urology. In a super-aged society such as Japan, urologists with an awareness of Zaitaku Medicine, a Japanese style of homecare that provides continuing appropriate medical treatment and welfare support to patients with access barriers to hospital treatment to enable them to live out the remainder of their lives with dignity, may play a key role in the development of Zaitaku Medicine.

Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100): an open-label, dose-finding and dose-expansion, phase 1b trial

Choueiri, Toni K., Larkin, James, Oya, Mototsugu, Thistlethwaite, Fiona, Martignoni, Marcella, Nathan, Paul, Powles, Thomas, McDermott, David, Robbins, Paul B., Chism, David D., Cho, Daniel, Atkins, Michael B., Gordon, Michael S., Gupta, Sumati, Uemura, Hirotsugu, Tomita, Yoshihiko, Compagnoni, Anna, Fowst, Camilla, di Pietro, Alessandra, Rini, Brian I.

LANCET ONCOLOGY (The Lancet Oncology) 19 ( 4 ) 451 - 460 2018.04

Research paper (scientific journal), Single Work, ISSN 1470-2045

© 2018 Elsevier Ltd Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg

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[Continuation of Axitinib for Advanced Renal Cell Carcinoma by The Application of Homecare Urology - A Case Report and Literature Review].

Yazawa S, Kato Y, Nakahara J, Miyata T, Oya M

Gan to kagaku ryoho. Cancer & chemotherapy 45 ( 4 ) 639 - 642 2018.04

Research paper (scientific journal), Joint Work, ISSN 0385-0684

A 56-year-old man with advanced RCC and a past medical history of type 2 diabetes underwent a radical left nephrectomy following a histological diagnosis of papillary RCC, G2, INF b, pT3, V1 in 1999. In 2008, sorafenib was started to treat multiple pulmonary metastases of RCC. In 2011, sorafenib was switched to sunitinib when radiologic progression was observed. In 2014, sunitinib was switched to axitinib when further radiologic progression was observed. In 2015, the patient was referred to Yazawa clinic for homecare urology when hospital visits became difficult due to cancer pain and bilateral lower-extremity muscle weakness. Cancer pain was controlled using acetaminophen and a fentanyl patch. During the administration of axitinib, a CTCAE grade 1 vocal disorder was detected. We reduced the axitinib dose from 10 mg to 6 mg, and valsartan and an antiflatulent were administered due to CTCAE grade 2 hypertension and diarrhea, respectively. Axitinib administration continued until the patient died. He had survived more than 11 years following the detection of lung metastasis. In this patient, a good balance between cancer treatment and palliative care was achieved through the application of homecare urology. In a super-aged society such as Japan, urologists with an awareness of Zaitaku Medicine, a Japanese style of homecare that provides continuing appropriate medical treatment and welfare support to patients with access barriers to hospital treatment to enable them to live out the remainder of their lives with dignity, may play a key role in the development of Zaitaku Medicine.

泌尿器科在宅医療を導入しアキシチニブを継続し得た進行性腎がんの1例

矢澤聰, 加藤裕二, 中原仁, 宮田俊男, 大家基嗣

癌と化学療法 ((株)癌と化学療法社) 45 ( 4 ) 639 - 642 2018.04

Joint Work, ISSN 0385-0684

症例は56歳、男性。1999年、左腎がんに対して根治的左腎摘除術を施行し、papillary RCC、G2、INFβ、pT3、V1でであった。2008年より多発肺転移に対してソラフェニブを開始した。2011年にprogressive disease(PD)となりスニチニブに変更、2014年にPDとなりアキシチニブ10mg/日に変更した。2015年よりがん疼痛と下肢筋力低下に伴い通院が困難となり、在宅医療を導入した。がん疼痛に対してはアセトアミノフェン4,000mg/日とフェンタニルテープ1mgでコントロール良好であった。アキシチニブ投与中の有害事象としては、CTCAE grade 2の高血圧を認め、バルサルタン80mgを開始した。またgrade 2の下痢を認め、アキシチニブ6mg/日への減量と整腸剤を投与し改善傾向を認め、アキシチニブを最期まで継続し得た。本症例において泌尿器科在宅医療の導入により、血管新生阻害薬の継続と緩和ケアとの両立が可能であった。超高齢社会における在宅医療に親和性の高い泌尿器科医が在宅医療の現場にでていくことで、新た

ニボルマブ関連間質性肺炎寛解後も肺転移巣縮小を維持したmRCCの1例

岩佐俊, 寺西悠, 水野隆一, 秋田大宇, 額賀重成, 大家基嗣

泌尿器外科 (医学図書出版(株)) 31 ( 4 ) 439 - 443 2018.04

Joint Work, ISSN 0914-6180

症例は71歳男性。腹腔鏡下根治的左腎摘除術を施行した。術後に多発肺転移、右脛骨転移が出現し、1st lineとしてスニチニブを開始したがPDとなった。2nd lineとしてニボルマブ3mg/kgを開始して肺転移は縮小したが両側肺底部に器質化肺炎が出現し、ニボルマブ関連間質性肺炎の診断でニボルマブを中止、プレドニゾロン(PSL)を開始した。PSL投与により間質性肺炎のコントロールは良好で、ニボルマブ中止後も肺転移巣は9ヵ月間縮小を維持できている。(著者抄録)

IMAGING MASS SPECTROMETRY REVEALS CO-ACCUMULATION OF ALDOSTERONE AND 18-OXOCORTISOL WITH CYP11B2 IN PRE-ADENOMATOUS STATES OF PRIMARY ALDOSTERONISM

Sugiura, Yuki, Takeo, Emi, Shimma, Shuichi, Yokota, Mai, Higashi, Tatsuya, Seki, Tsugio, Oya, Mototsugu, Kosaka, Takeo, Nishikawa, Tetsuo, Nishimoto, Koshiro, Suematsu, Makoto

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E23 - E23 2018.04

Joint Work, Accepted, ISSN 0022-5347

CAN UROLOGISTS INTRODUCE THE CONCEPT OF "OLIGOMETASTASIS" FOR METASTATIC BLADDER CANCER AFTER RADICAL CYSTECTOMY?

Koichiro Ogihara, Eiji Kikuchi, Keitaro Watanabe, Ryohei Kufukihara, Yoshinori Yanai, Kimiharu Takamatsu, Kazuhiro Matsumoto, Satoshi Hara, Masafumi Oyama, Tetsuo Monma, Takeshi Masuda, Shintaro Hasegawa, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E1043 - E1043 2018.04

Joint Work, ISSN 0022-5347

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BIOINFORMATIC ANALYSIS IDENTIFIED CANDIDATE DRUGS FOR ANDROGEN SIGNALING THROUGH MODULATING ANDROGEN RECEPTOR AND ITS SPLICE VARIANTS

Hiroshi Hongo, Takeo Kosaka, Yota Yasumizu, Yasumasa Miyazaki, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E852 - E852 2018.04

Joint Work, ISSN 0022-5347

COULD ADJUVANT CHEMOTHERAPY HAVE ADDITIONAL THERAPEUTIC BENEFIT IN BLADDER CANCER PATIENTS TREATED WITH RADICAL CYSTECTOMY AND NEOADJUVANT CHEMOTHERAPY?

Minami Omura, Eiji Kikuchi, Koichiro Ogihara, Kyohei Hakozaki, Keishiro Fukumoto, Gou Kaneko, Yasumasa Miyazaki, Nobuyuki Tanaka, Suguru Shirotake, Kunimitsu Kanai, Kazuhiro Matsumoto, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E530 - E530 2018.04

Joint Work, ISSN 0022-5347

THERAPEUTIC TARGETING OF TRANSCRIPTIONAL REPRESSOR BCL-6 FOR CASTRATION-RESISTANT PROSTATE CANCER THROUGH REPRESSING ANDROGEN RECEPTOR VARIANTS.

Hiroshi Hongo, Takeo Kosaka, Yota Yasumizu, Yasumasa Miyazaki, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E850 - E850 2018.04

Joint Work, ISSN 0022-5347

THE CLINICAL IMPACT OF INDURATION RESULTING FROM PURIFIED PROTEIN DEPRIVATION SKIN TEST IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER TREATED WITH BACILLUS-CALMETTE GUERIN

Naoya Niwa, Eiji Kikuchi, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E1230 - E1230 2018.04

Joint Work, ISSN 0022-5347

THE ANALYSIS OF EXPRESSION AND MOLECULAR MECHANISM FOR VASOHIBIN-2 IN PROSTATE CANCER

Yasumasa Miyazaki, Takeo Kosaka, Shuji Mikami, Hiroshi Hongo, Yota Yasumizu, Nobuyuki Tanaka, Eiji Kikuchi, Yasufumi Sato, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E857 - E857 2018.04

Joint Work, ISSN 0022-5347

SWITCHING OF BACILLUS CALMETTE-GUERIN (BCG) STRAIN AT SECOND BCG THERAPY MAY REDUCE BCG-RELATED SIDE EFFECTS IN PATIENTS WITH BCG-RELAPSING TUMOR

Naoya Niwa, Eiji Kikuchi, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E100 - E100 2018.04

Joint Work, ISSN 0022-5347

SUITABLE PATIENTS FOR SINGLE-PORT LAPAROSCOPIC ADRENALECTOMY: OPTIMAL CUT-OFF VALUE OF BODY MASS INDEX

Kazuhiro Matsumoto, Keishiro Fukumoto, Akira Miyajima, Masanori Hasegawa, Toshikazu Takeda, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E26 - E27 2018.04

Joint Work, ISSN 0022-5347

ROLES OF TOPOISOMERASE INHIBITORS AND CISPLATIN FOR CRPC IN THE POST-CABAZITAXEL SETTING

Takeo Kosaka, Hiroshi Hongo, Yota Yasumizu, Yasumasa Miyazaki, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E938 - E939 2018.04

Joint Work, ISSN 0022-5347

PURIFIED PROTEIN DERIVATIVE SKIN TEST PRIOR TO BACILLUS CALMETTE-GUERIN THERAPY ENHANCES THE CLINICAL EFFICACY OF BCG THERAPY IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER

Naoya Niwa, Eiji Kikuchi, Kazuhiro Matsumoto, Takeo Kosaka, Ryuichi Mizuno, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E97 - E97 2018.04

Joint Work, ISSN 0022-5347

ONCOLOGIC SURVEILLANCE AFTER RADICAL NEPHROURETERECTOMY IN UPPER TRACT UROTHELIAL CARCINOMA PATIENTS: A NOVEL RISK-BASED APPROACH

Keisuke Shigeta, Eiji Kikuchi, Masayuki Hagiwara, Toshikazu Takeda, Kazuhiro Matsumoto, Takayuki Abe, Toshiaki Shinojima, Ryuichi Mizuno, Ken Nakagawa, Akira Miyajima, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E217 - E218 2018.04

Joint Work, ISSN 0022-5347

MRI TUMOR CONTACT LENGTH AS A PREDICTOR OF EXTRACAPSULAR EXTENSION: OPTIMAL THRESHOLD FOR ANTERIOR AND POSTERIOR PROSTATE CANCER

Kazuhiro Matsumoto, Kimiharu Takamatsu, Seiya Hattori, Toshikazu Takeda, Takeo Kosaka, Ryuichi Mizuno, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E901 - E901 2018.04

Joint Work, ISSN 0022-5347

IN SILICO SCREENING USING RNA-SEQ DATA SETS OF NEUROENDOCRINE PROSTATE CANCER HAS IDENTIFIED CANDIDATE DRUGS FOR REPROGRAMMING NEPC-SPECIFIC SIGNATURES.

Takeo Kosaka, Hiroshi Hongo, Shuji Mikami, Kazuhiro Matsumoto, Eiji Kikuchi, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E853 - E853 2018.04

Joint Work, ISSN 0022-5347

IMPACT OF TUMOR LOCATION ON BIOCHEMICAL RECURRENCE AFTER LAPAROSCOPIC RADICAL PROSTATECTOMY

Kimiharu Takamatsu, Kazuhiro Matsumoto, Toshikazu Takeda, Shinya Morita, Takeo Kosaka, Ryuichi Mizuno, Toshiaki Shinojima, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E51 - E51 2018.04

Joint Work, ISSN 0022-5347

DOES NEOADJUVANT CHEMOTHERAPY WITH GEMCITABINE AND CISPLATIN IN BLADDER CANCER INCREASE THE COMPLICATIONS AT RADICAL CYSTECTOMY IN HIGH AGE PATIENTS?

Keishiro Fukumoto, Eiji Kikuchi, Suguru Shirotake, Kyohei Hakozaki, Yasumasa Miyazaki, Takahiro Maeda, Gou Kaneko, Shunsuke Yoshimine, Nobuhiro Tanaka, Kunimitsu Kanai, Masafumi Oyama, Yosuke Nakajima, Tetsuo Momma, Mototsugu Oya

JOURNAL OF UROLOGY (ELSEVIER SCIENCE INC) 199 ( 4 ) E1041 - E1042 2018.04

Joint Work, ISSN 0022-5347

Preoperative sarcopenia status is associated with lymphovascular invasion in upper tract urothelial carcinoma patients treated with radical nephroureterectomy

Anno Tadatsugu, Kikuchi Eiji, Fukumoto Keishiro, Ogihara Koichiro, Oya Mototsugu

Journal of the Canadian Urological Association (Journal of the Canadian Urological Association) 12 ( 3 ) E132 - E136 2018.03

Joint Work, ISSN 1911-6470

Introduction: Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). Methods: We identified 123 UTUC patients who underwent RNU between 2003 and 2014. We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes, such as cancer death and poor pathological findings at RNU. Results: A total of 50 (40.7%) patients had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer-specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI status (odds ratio 2.36; p=0.025). LVI was positive in 27 of 50 (54%) and 25 of 73 (34%) patients with and without sarcopenia, respectively (p=0.029). Conclusions: Preoperative sarcopenia predicted the LVI status, which was a strong prognostic factor for UTUC patients after RNU.

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IJU this issue

Oya Mototsugu

International Journal of Urology 25 ( 3 ) 173 - 174 2018.03

ISSN 0919-8172

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The preoperative sarcopenia status is associated with lymphovascular invasion in upper tract urothelial carcinoma patients treated with radical nephroureterectomy

Anno T., Kikuchi E., Fukumoto K., Ogihara K., Oya M.

Canadian Urological Association Journal (Canadian Urological Association Journal) 12 ( 3 ) 2018.03

Research paper (scientific journal), Joint Work, ISSN 19201214

Introduction: Sarcopenia is a novel concept representing skeletal muscle wasting and has been identified as a prognostic factor for several cancers. The aims of this study were to evaluate the prognostic significance of sarcopenia and the relationship between sarcopenia and poor pathological findings in upper tract urothelial carcinoma (UTUC) patients who underwent radical nephroureterectomy (RNU). Methods: We identified 123 UTUC patients who underwent RNU between 2003 and 2014.We assessed sarcopenia by measuring the area of skeletal muscle at the third lumber vertebra on preoperative computed tomography scans. Sarcopenia was classified based on a sex-specific consensus definition. We investigated whether sarcopenia predicts clinical outcomes such as cancer death and poor pathological findings at RNU. Results: A total of 40.7% of patients (n=50) had sarcopenia. In a multivariate Cox regression analysis, sarcopenia was not associated with cancer-specific survival (CSS), and lymphovascular invasion (LVI) (hazard ratio 5.88; p=0.002) was the only independent risk factor for CSS. A multivariate logistic regression analysis showed that sarcopenia independently correlated with the LVI st

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「2016年度前立腺がん啓発週間」の活動実績報告

五十嵐敦, 深貝隆志, 山中英壽, 木村剛, 柏原剛, 大家基嗣, 門間哲雄, 中島洋介, 森山正敏, 井上啓史, 斉藤史郎

日本腎泌尿器疾患予防医学研究会誌 (日本腎泌尿器疾患予防医学研究会) 26 ( 1 ) 72 - 74 2018.03

Joint Work, ISSN 1347-5010

「2016年度前立腺がん啓発週間」の活動実績を報告した。NPO法人前立腺がん啓発推進実行委員のメンバーが中心となり、日本全国19ヶ所の医療機関において、2016年9月〜10月にかけて前立腺癌に関する公開講座、情報提供、無料PSA検診、個別相談などの啓発活動を各施設に任意で行った。その結果、すべての参加施設で一般市民に前立腺癌に関する情報提供が行われ、16施設では前立腺癌に関する公開講座、11施設では無料PSA検診が行われた。全国合計でPSA検診参加者は670名であり、うち107名(16.0%)が4.0ng/mlを超える異常値を示し、精査の必要性が受診者に連絡された。尚、前年度に比べると、PSA検診の参加者の減少がみられた。

尿路上皮癌の再発・進展および治療における予測因子としてのpd-1発現の有用性の検討

早川望, 菊地栄次, 大家基嗣, 三上修治

大和証券ヘルス財団研究業績集 ((公財)大和証券ヘルス財団) 41 ( 41 ) 29 - 33 2018.03

Joint Work

上部尿路上皮癌におけるPD-1発現の役割について検討した。過去20年間に当院で上部尿路上皮癌に対して腎尿管全摘除術を施行した181例を対象に、切除検体のPD-1発現を免疫染色法にて評価した。PD-1発現は、腫瘍辺縁および腫瘍内部とそれぞれ400倍視野下で陽性細胞をカウントし、高発現群と低発現群に分類した。平均陽性個数は腫瘍内部で2個、腫瘍辺縁では11個であった。カットオフ値の設定にはX-tile softwareを使用し、腫瘍内部では10個以上を高発現、腫瘍辺縁では8個以上を高発現と定義した。PD-1発現は腫瘍辺縁において高発現群が103例(56.9%)、低発現群が78例(43.1%)、腫瘍内部において高発現群が44例(24.3%)、低発現群が137例(75.7%)であった。腫瘍内部におけるPD-1の高発現はhigh gradeおよびpT2≦と関連があり、一方腫瘍辺縁においては、high grade、pT2≦および壁内脈管侵襲陽性と関連があることが分かった。腫瘍内部のPD-1高発現は、切除可能な上部尿路上皮癌において有用な予後予測因子であるこ

A phase 1/2a trial of docetaxel plus ribavirin for reprogramming efficacy in patients with progressive metastatic castration resistant prostate cancer who have previously received docetaxel alone: DRREEM trial.

Kosaka Takeo, Shinojima Toshiaki, Kikuchi Kayoko, Hagiwara Sachiko, Kojima Shin-ichiro, Hongo Hiroshi, Ueda Koji, Miyake Shinji, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 6 ) 2018.02

Joint Work, ISSN 0732-183X

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Efficacy and safety of abiraterone acetate (AA) and low-dose prednisone (P) in Japanese patients with newly diagnosed, metastatic, hormone-naive prostate cancer (mHNPC): Subgroup analysis of LATITUDE trial.

Fukasawa Satoshi, Suzuki Hiroyoshi, Sato Fuminori, Hashine Katsuyoshi, Hasumi Hisashi, Matsumoto Hiroaki, Tsuchiya Tomohiro, Uemura Hirotsugu, Oya Mototsugu, Kanayama Hiroomi, Kawaguchi Kazushiro, Noguchi Hidehisa, Enjo Kentaro, Tran Namphuong, Todd Mary Beth, Fizazi Karim, Matsubara Nobuaki

JOURNAL OF CLINICAL ONCOLOGY (AMER SOC CLINICAL ONCOLOGY) 36 ( 6 ) 2018.02

Joint Work, ISSN 0732-183X

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Variant isoforms of CD44 involves acquisition of chemoresistance to cisplatin and has potential as a novel indicator for identifying a cisplatin-resistant population in urothelial cancer

Hagiwara Masayuki, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

BMC Cancer (BMC Cancer) 18 ( 1 ) 113 - 113 2018.01

Research paper (scientific journal), Joint Work, ISSN 1471-2407

Background: Cisplatin is the most commonly used chemotherapeutic agent in the treatment of patients with metastatic and/or recurrent urothelial cancer. However, the effectiveness of these treatments is severely limited due to the development of cisplatin resistance. Cancer stem cells have been documented as one of the key hypotheses involved in chemoresistance. CD44v8-10 has been identified as one of the new cancer stem cells markers and was recently shown to enhance the antioxidant system by interaction with xCT, a subunit of the cystine transporter modulating intracellular glutathione synthesis. The aim of the present study was to investigate the clinical role of CD44v8-10 and the molecular mechanism underlying the acquisition of cisplatin resistance through CD44v8-10 in urothelial cancer. Methods: We analyzed the clinical significance of the immunohistochemical CD44v9 expression, which detects the immunogen of human CD44v8-10, in 77 urothelial cancer patients treated with cisplatin-based systemic chemotherapy for recurrence and/or metastasis. We then evaluated the biological role of CD44v8-10 in the acquisition of cisplatin resistance using the urothelial cancer cell lines, T24 and T24PR, which were generated to acquire resistance to cisplatin. Results: The 5-year cancer-specific survival rate was significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.008). Multivariate analyses revealed that CD44v9 positivity was an independent risk factor of cancer-specific survival (P = 0.024, hazard ratio = 5.16) in urothelial cancer patients who had recurrence and/or metastasis and received cisplatin-based chemotherapy. The expression of CD44v8-10 and xCT was stronger in T24PR cells than in T24 cells. The amount of intracellular glutathione was significantly higher in T24PR cells than in T24 cells (p < 0.001), and intracellular reactive oxygen species production by cisplatin was lower in T24PR cells than in T24 cells. Furthermore, the knockdown of CD44v8-10 by siRNA led to the recovery of cisplatin sensitivity in T24PR cells. Conclusions: CD44v9 in tumor specimens has potential as a novel indicator for identifying a cisplatin-chemoresistant population among urothelial cancer patients. CD44v8-10 contributes to reactive oxygen species defenses, which are involved in chemoresistance, by promoting the function of xCT, which adjusts the synthesis of glutathione.

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Recent progress in prognostic and predictive biomarkers for target therapies in metastatic renal cell carcinoma

水野隆一, 浅沼宏, 大家基嗣

臨床泌尿器科 (株式会社医学書院) 72 ( 1 ) 64 - 69 2018.01

ISSN 0385-2393

Publisher Correction

Tanaka Nobuyuki, Kanatani Shigeaki, Tomer Raju, Sahlgren Cecilia, Kronqvist Pauliina, Kaczynska Dagmara, Louhivuori Lauri, Kis Lorand, Lindh Claes, Mitura Przemysław, Stepulak Andrzej, Corvigno Sara, Hartman Johan, Micke Patrick, Mezheyeuski Artur, Strell Carina, Carlson Joseph W., Fernández Moro Carlos, Dahlstrand Hanna, Östman Arne, Matsumoto Kazuhiro, Wiklund Peter, Oya Mototsugu, Miyakawa Ayako, Deisseroth Karl, Uhlén Per

Nature Biomedical Engineering 2018.01

Joint Work

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Vasohibin-1 as a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer

Kobayashi Hiroaki, Kosaka Takeo, Mikami Shuji, Miyazaki Yasumasa, Matsumoto Kazuhiro, Kikuchi Eiji, Miyajima Akira, Kameyama Kaori, Sato Yasufumi, Oya Mototsugu

Oncotarget (Oncotarget) 9 ( 12 ) 10203 - 10210 2018.01

Research paper (scientific journal), Joint Work, ISSN 1949-2553

Background: We previously reported high expression of vasohibin-1 (VASH1), which is specifically expressed in activated vascular endothelial cells, was a prognostic indicator of disease progression in prostate cancer. The aim of this study was to assess whether VASH1 expression at the area of normal prostatic tissue as well as that of intratumoral tissue could reflect the grade of malignancy of prostate cancer. Results: Pathological upgrade of Gleason Score ≥7 by radical prostatectomy was observed in 48 patients (upgraded group). The median VASH1 densities of the intratumoral and normal areas were 9.7 ± 9.5 and 13.3 ± 11.8, respectively, and the median MVDs were 58.6 ± 20.3 and 64.1 ± 23.5, respectively. We detected a strong positive correlation with each other for both VASH1 density (ρ = 0.589, p < 0.001) and MVD (ρ = 0.342, p < 0.001). VASH1 density was significantly higher in the upgreaded group than in the non-upgraded group regardless of prostatic location (intratumoral area: p < 0.001, normal area: p < 0.001). Conclusions: Even if the tumor volume was low in biopsy samples, VASH1 density reflected the grade of malignancy throughout the prostate. These results suggested that VASH1 expression could be a novel microenvironmental biomarker for patient risk reclassification in low-risk prostate cancer. Materials and Methods: Among the 1177 patients who underwent radical prostatectomy, 104 patients diagnosed with Gleason Score ≤6 and positive cores ≤3 were included. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD), and those with activated endothelial cells as VASH1 density using prostatic biopsy samples, and evaluated the association between their expressions and clinicopathological findings.

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Change of the 5α/5β ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Homma Keiko, Yasumizu Yota, Hattori Seiya, Kosaka Takeo, Shinoda Kazunobu, Miyajima Akira, Oya Mototsugu

Clinical Biochemistry 2018.01

Joint Work, ISSN 0009-9120

Background: The effects of the administration of dutasteride (DUT) on steroid metabolite pathways in BPH patients have not been examined. Methods: Urine and blood samples as well as clinical parameters were prospectively collected after the administration of DUT to 60 BPH patients, and after its withdrawal in another set of 25 BPH patients. Urine samples were assessed using gas chromatography/mass spectrometry for the urinary steroid profile (USP), which simultaneously measures 63 steroid metabolites. We examined pharmacological changes in the 5α/5β ratio of urinary metabolites and their relationships with clinical parameters in patients treated with DUT. Results: The mean urinary androsterone/etiocholanolone (An/Et) ratio in sex-steroid pathways significantly decreased from 1.39 to 0.02 (p < 0.01). Urinary metabolites in other steroid pathways such as 5αTHF/5βTHF in the glucocorticoid pathway and 5αTHB/5βTHB in the mineralocorticoid pathway also significant decreased after the DUT treatment. As compared to baseline level, the mean An/Et ratios in patients with the withdrawal of DUT were 0.7%, 1.4%, 12.6%, and 82.4% at just before, one month, 3 months, and 6 months after the withdrawal of DUT, respectively. All other steroid pathways changed in a similar manner without the aggravation of urinary symptoms. The recovery ratio of An/Et in USP before and 3 months after the withdrawal of DUT correlated with the recovery ratio of serum PSA levels (ρ = 0.61, p < 0.01). Conclusion: Urinary 5α/5β metabolites in all pathways were strongly suppressed after the administration of DUT for one month and the pharmacological effect of DUT prolonged even after withdrawal of DUT.

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Combined androgen blockade achieved better oncological outcome in androgen deprivation therapy for prostate cancer

Onozawa Mizuki, Akaza Hideyuki, Hinotsu Shiro, Oya Mototsugu, Ogawa Osamu, Kitamura Tadaichi, Suzuki Kazuhiro, Naito Seiji, Namiki Mikio, Nishimura Kazuo, Hirao Yoshihiko, Tsukamoto Taiji

Cancer Medicine 2018.01

Joint Work

Background: This study investigated how differences in the method of the first-line androgen deprivation therapy (ADT) affected the time to castration-resistant prostate cancer. Methods: The Japan Study Group of Prostate Cancer compiled a nationwide community-based database on prostate cancer patients who underwent ADT. That database included 13 774 patients who were started on ADT by surgical or medical castration alone (monotherapy group, 5395 cases) or ADT in combination with a nonsteroidal anti-androgen (combined androgen blockade (CAB) group, 8379 cases). We used logistic regression analysis with background factors as independent factors to calculate propensity scores in regard to selection of CAB. Next, for 8826 cases of propensity score-matched patients, we compared the survival rates in the two groups. Results: The CAB group showed a significantly better progression-free survival (PFS) rate (65.6% vs 59.6% at 5 years; median time to progression, 11.6 vs 7.1 years; hazard ratio in the CAB group: 0.78, with a 95% confidence interval of 0.72 to 0.84; P < 0.001). In subgroup analysis based on the background factors, the PFS rate was generally better in the CAB group in all risk subgroups except for those having significant risk factors. Conclusion: Propensity score matching analysis revealed the prolongation of PFS by CAB in prostate cancer patients without significant risk factors. It would possible to decide the type of the first-line ADT according to the prostate cancer risk.

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Does switching the bacillus Calmette-Guérin strain affect clinical outcome in patients with recurrent non-muscle-invasive bladder cancer after initial bacillus Calmette-Guérin therapy?

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2018.01

Joint Work, ISSN 1078-1439

Purpose: It is still unknown whether switching the bacillus Calmette-Guérin (BCG) strain at the second induction course of BCG therapy has a therapeutic benefit in patients with tumor recurrence after the initial BCG therapy (BCG-relapsing tumor). Materials and methods: We retrospectively reviewed the clinicopathological features of 97 patients treated with a second induction course of BCG therapy between 1986 and 2014. Among the patients initially treated with BCG Tokyo-172, the second course was either BCG Tokyo-172 in 56 (57.8%) or BCG Connaught in 15 (15.5%). Among those who were initially treated with BCG Connaught, the corresponding numbers were 13 (13.4%) or 13 (13.4%), respectively. Twenty-eight (28.9%) patients were given a different BCG strain at the 2 BCG therapies (switching group), and 69 (71.1%) patients were given the same BCG strain (non-switching group). Result: The 5-year recurrence-free survival rate of the switching group was 64.7 ± 9.6%, which was not significantly different from that of the non-switching group (54.8 ± 6.9%, P = 0.427). Switching or not switching the BCG strain was not significantly associated with tumor recurrence after the second BCG therapy. The 5-year progression-free survival rate of the switching group was 95.4 ± 2.6%, which was also not significantly different from that of the non-switching group (96.0 ± 3.9%, P = 0.674). Patients treated with BCG Tokyo-172 to Tokyo-172 had significantly higher incidences of side effects during the second BCG therapy. Conclusions: The results of this study indicate that in patients with a BCG-relapsing tumor after the initial BCG therapy, the same BCG strain as that administered at the initial BCG therapy could be utilized effectively for the second BCG therapy. Patients treated with BCG Tokyo-172 for an initial tumor had a higher incidence of side effects during the second BCG therapy using the same strain.

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Establishment of the optimal follow-up schedule after radical prostatectomy

Matsumoto Kazuhiro, Niwa Naoya, Hattori Seiya, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Asanuma Hiroshi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 7 ) 341.e9 - 341.e14 2018.01

Research paper (scientific journal), Joint Work, ISSN 1078-1439

Purpose: Monitoring the serum level of prostate specific antigen (PSA) is indispensable for surveillance after radical therapy, and the aim of this study was to establish the optimal follow-up schedule. Materials and methods: We retrospectively reviewed the clinicopathological data of 1,010 consecutive patients who underwent radical prostatectomy. After excluding patients who received neoadjuvant or adjuvant therapy and those without a nadir PSA level<0.2 ng/ml, the remaining 779 patients were enrolled. Biochemical recurrence (BCR) was defined as elevation of PSA to >0.2 ng/ml. We investigated the PSA doubling time (PSA-DT) following BCR at various times after surgery. Results: During a mean follow-up of 8.8 years, BCR occurred in 180/779 patients. The annual BCR rate was 6% in the first year after surgery, 6% between 1 and 2 years, 3% between 2 and 3 years, 3% between 3 and 5 years, and 2% at >5 years postoperatively. During these periods, the minimum PSA-DT after BCR was 1.6, 2.4, 3.1, 6.1, and 6.4 months, respectively. These minimum PSA-DTs were used to determine the optimal follow-up interval during each period after surgery. If the baseline level is 0.1 ng/ml, PSA should be measured at approximately 3-month intervals for the first year, at 4-month intervals between 1 and 2 years, at 6-month intervals between 2 and 3 years, and annually thereafter to definitely detect BCR before the serum PSA level exceeds 0.4 ng/ml. Conclusion: The PSA-DT following BCR varies according to the time after surgery. Our data on minimum PSA-DT values after BCR are useful for setting the optimal follow-up schedule.

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History of Non–Muscle-Invasive Bladder Cancer May Have a Worse Prognostic Impact in cT2-4aN0M0 Bladder Cancer Patients Treated With Radical Cystectomy

Kayama Emina, Kikuchi Eiji, Fukumoto Keishiro, Shirotake Suguru, Miyazaki Yasumasa, Hakozaki Kyohei, Kaneko Gou, Yoshimine Shunsuke, Tanaka Nobuyuki, Takahiro Maeda, Kanai Kunimitsu, Oyama Masafumi, Nakajima Yosuke, Hara Satoshi, Monma Tetsuo, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 5 ) e969 - e976 2018.01

Research paper (scientific journal), Joint Work, ISSN 1558-7673

We performed a retrospective study comparing clinical outcomes between patients with initially diagnosed muscle-invasive bladder cancer (MIBC) without a history of non-MIBC (NMIBC) and those with MIBC that progressed from NMIBC. A history of NMIBC was independently associated with cancer death in cT2-T4a MIBC patients treated with radical cystectomy and without lymph node involvement. MIBC that progresses from NMIBC may not respond to neoadjuvant chemotherapy. Purpose: To investigate whether a history of non–muscle-invasive bladder cancer (NMIBC) plays a prognostic role in patients with muscle-invasive bladder cancer (MIBC) treated with radical cystectomy in the era when neoadjuvant chemotherapy was established as standard therapy for MIBC. Patients and Methods: A total of 282 patients who were diagnosed with cT2-T4aN0M0 bladder cancer treated with open radical cystectomy at our institutions were included. Initially diagnosed MIBC without a history of NMIBC was defined as primary MIBC group (n = 231), and MIBC that progressed from NMIBC was defined as progressive MIBC (n = 51). Results: The rate of cT3/4a tumors was significantly higher in the primary MIBC group than in the progressive MIBC group (P = .004). Five-year recurrence-free survival and cancer-specific survival (CSS) rates for the primary MIBC group versus progressive MIBC group were 68.2% versus 55.9% (P = .039) and 76.1% versus 61.6% (P = .005), respectively. Progressive MIBC (hazard ratio, 2.170; P = .008) was independently associated with cancer death. In the primary MIBC group, the 5-year CSS rate in patients treated with neoadjuvant chemotherapy was 85.4%, which was significantly higher than that in patients without (71.5%, P = .023). In the progressive MIBC group, no significant differences were observed in CSS between patients treated with and without neoadjuvant chemotherapy. Conclusion: MIBC that progressed from NMIBC had a significantly worse clinical outcome than MIBC without a history of NMIBC and may not respond as well to neoadjuvant chemotherapy. These results are informative, even for NMIBC patients treated with conservative intravesical therapy.

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Influence of dutasteride treatment on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Homma Keiko, Ando Toshiyuki, Suzuki Kenjiro, Kaneko Gou, Mizuno Ryuichi, Miyajima Akira, Oya Mototsugu

International Journal of Urology (International Journal of Urology) 25 ( 1 ) 70 - 74 2018.01

Research paper (scientific journal), Joint Work, ISSN 0919-8172

Objectives: To clarify the effects of dutasteride on serum hormone levels and aging male symptoms in patients with benign prostatic enlargement. Methods: The present prospective study was carried out in 110 symptomatic benign prostatic enlargement patients treated with daily administration of 0.5 mg dutasteride. We analyzed serum hormonal levels and aging related symptoms using a validated Aging Male Symptom questionnaire at baseline and after 3 months of dutasteride treatment. Results: The mean total testosterone, free testosterone and luteinizing hormone levels after dutasteride treatment were approximately 20% higher than those at baseline. The percentage increases in total and free testosterone levels were negatively correlated with these baseline levels. Baseline age, levels of total testosterone and free testosterone, and the changes in the rate of luteinizing hormone after dutasteride treatment tended to be correlated with an increase in the rate of total testosterone and free testosterone after dutasteride treatment. In a subgroup of 26 patients with moderate-to-severe aging male symptoms, poor morning erection and free testosterone levels <8.5 pg/mL, total aging male symptoms, and somatic symptoms scores significantly decreased after dutasteride treatment with an increase of total and free testosterone. Conclusions: The increase of endogenous free testosterone and total testosterone by dutasteride might bring additional benefits of improvement of aging male-related symptoms, especially in patients with lower free testosterone baseline levels and moderate-to-poor aging-related symptoms.

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Preliminary results for avelumab plus axitinib as first-line therapy in patients with advanced clear-cell renal-cell carcinoma (JAVELIN Renal 100)

Choueiri Toni K., Larkin James, Oya Mototsugu, Thistlethwaite Fiona, Martignoni Marcella, Nathan Paul, Powles Thomas, McDermott David, Robbins Paul B., Chism David D., Cho Daniel, Atkins Michael B., Gordon Michael S., Gupta Sumati, Uemura Hirotsugu, Tomita Yoshihiko, Compagnoni Anna, Fowst Camilla, di Pietro Alessandra, Rini Brian I.

The Lancet Oncology 2018.01

Joint Work, ISSN 1470-2045

Background: The combination of an immune checkpoint inhibitor and a VEGF pathway inhibitor to treat patients with advanced renal-cell carcinoma might increase the clinical benefit of these drugs compared with their use alone. Here, we report preliminary results for the combination of avelumab, an IgG1 monoclonal antibody against the programmed cell death protein ligand PD-L1, and axitinib, a VEGF receptor inhibitor approved for second-line treatment of advanced renal-cell carcinoma, in treatment-naive patients with advanced renal-cell carcinoma. Methods: The JAVELIN Renal 100 study is an ongoing open-label, multicentre, dose-finding, and dose-expansion, phase 1b study, done in 14 centres in the USA, UK, and Japan. Eligible patients were aged 18 years or older (≥20 years in Japan) and had histologically or cytologically confirmed advanced renal-cell carcinoma with clear-cell component, life expectancy of at least 3 months, an Eastern Cooperative Oncology Group performance status of 1 or less, received no previous systemic treatment for advanced renal cell carcinoma, and had a resected primary tumour. Patients enrolled into the dose-finding phase received 5 mg axitinib orally twice daily for 7 days, followed by combination therapy with 10 mg/kg avelumab intravenously every 2 weeks and 5 mg axitinib orally twice daily. Based on the pharmacokinetic data from the dose-finding phase, ten additional patients were enrolled into the dose-expansion phase and assigned to this regimen. The other patients in the dose-expansion phase started taking combination therapy directly. The primary endpoint was dose-limiting toxicities in the first 4 weeks (two cycles) of treatment with avelumab plus axitinib. Safety and antitumour activity analyses were done in all patients who received at least one dose of avelumab or axitinib. This trial is registered with ClinicalTrials.gov, number NCT02493751. Findings: Between Oct 30, 2015, and Sept 30, 2016, we enrolled six patients into the dose-finding phase and 49 into the dose-expansion phase of the study. One dose-limiting toxicity of grade 3 proteinuria due to axitinib was reported among the six patients treated during the dose-finding phase. At the cutoff date (April 13, 2017), six (100%, 95% CI 54–100) of six patients in the dose-finding phase and 26 (53%, 38–68) of 49 patients in the dose-expansion phase had confirmed objective responses (32 [58%, 44–71] of all 55 patients). 32 (58%) of 55 patients had grade 3 or worse treatment-related adverse events, the most frequent being hypertension in 16 (29%) patients and increased concentrations of alanine aminotransferase, amylase, and lipase, and palmar-plantar erythrodysaesthesia syndrome in four (7%) patients each. Six (11%) of 55 patients died before data cutoff, five (9%) due to disease progression and one (2%) due to treatment-related autoimmune myocarditis. At the end of the dose-finding phase, the maximum tolerated dose established for the combination was avelumab 10 mg/kg every 2 weeks and axitinib 5 mg twice daily. Interpretation: The safety profile of the combination avelumab plus axitinib in treatment-naive patients with advanced renal-cell carcinoma seemed to be manageable and consistent with that of each drug alone, and the preliminary data on antitumour activity are encouraging. A phase 3 trial is assessing avelumab and axitinib compared with sunitinib monotherapy. Funding: Pfizer and Merck.

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Prognostic significance of grade 3/4 neutropenia in Japanese prostate cancer patients treated with cabazitaxel

Kosaka Takeo, Shinojima Toshiaki, Morita Shinya, Oya Mototsugu

Cancer Science (Cancer Science) 109 ( 5 ) 1570 - 1575 2018.01

Research paper (scientific journal), Joint Work, ISSN 1347-9032

The present study aimed to evaluate the efficacy of cabazitaxel in Japanese patients affected by metastatic castration-resistant prostate cancer (mCRPC) previously treated with a docetaxel-containing regimen. In this retrospective study, 41 patients with mCRPC treated with cabazitaxel at Keio University Hospital were retrospectively reviewed. Cabazitaxel at a dose of 20-25 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). An upfront dose-reduction was required in 52.5% of patients due to their reduced general condition or advanced age. Prophylactic G-CSF was prescribed to all the patients. Grade ≥3 neutropenia and febrile neutropenia occurred in 21 patients (53.6%) and 3 patients (6.8%), respectively. Treatment was generally well tolerated, with a median of 5 cycles (range 1-17). Median PFS and OS from the start of cabazitaxel treatment were 4.4 and 15.0 months (95% CI 8.9-21.2), respectively. Waterfall plot analysis revealed that a prostate-specific antigen (PSA) decline >50% was noticed in n = 11 patients receiving cabazitaxel (26.8%). Univariate analysis revealed that poor performance status, PSA ≥100 ng/mL prior to cabazitaxel treatment, visceral metastasis, absence of grade 3/4 neutropenia during cabazitaxel therapy and neutrophil-lymphocyte ratio were significantly associated with shorter overall survival. Multivariate analysis revealed that poor performance status, visceral metastasis, and the absence of grade 3/4 neutropenia during cabazitaxel therapy were the independent prognostic indicators for OS. The practical implication of our results might be to tailor cabazitaxel dosing on the basis of its hematological effects.

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Prognostic Value of Baseline Serum C-Reactive Protein Level in Intermediate-Risk Group Patients With Metastatic Renal-Cell Carcinoma Treated by First-Line Vascular Endothelial Growth Factor–Targeted Therapy

Takamatsu Kimiharu, Mizuno Ryuichi, Omura Minami, Morita Shinya, Matsumoto Kazuhiro, Shinoda Kazunobu, Kosaka Takeo, Takeda Toshikazu, Shinojima Toshiaki, Kikuchi Eiji, Asanuma Hiroshi, Oyama Masafumi, Mikami Shuji, Oya Mototsugu

Clinical Genitourinary Cancer (Clinical Genitourinary Cancer) 16 ( 4 ) e927 - e933 2018.01

Research paper (scientific journal), Joint Work, ISSN 1558-7673

Because accumulating evidence underlines the association of systemic inflammation with metastatic renal-cell carcinoma (mRCC) progression, we evaluated baseline C-reactive protein (CRP) levels as a prognostic marker in 107 intermediate-risk mRCC patients treated with first-line targeted therapy. Baseline CRP could be a biomarker correlated with overall survival in the intermediate-risk group. Its cost efficacy and availability make CRP a helpful tool for reclassifying the intermediate-risk group. Background: Almost half of patients with metastatic renal-cell carcinoma (mRCC) are classified as intermediate risk by the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model. The aim of this study was to evaluate whether baseline C-reactive protein (CRP) levels predict overall survival (OS) in intermediate-risk group mRCC patients. Patients and Methods: Data from 107 intermediate-risk group mRCC patients receiving first-line targeted therapy were retrospectively reviewed. We evaluated the correlation between baseline CRP levels as well as other indices and OS. Results: Of the 107 patients with intermediate-risk disease, 46 patients (43%) were classified as having elevated CRP levels. The elevation of pretreatment serum CRP levels was the independent prognostic factor of OS in patients with intermediate risk (hazard ratio, 4.609; P =.001). The 1- and 3-year survival rates of patients with intermediate–nonelevated CRP were 90.0% and 64.7% compared to the favorable-risk group, at 92.1% and 68.5%, respectively. In contrast, the 1- and 3-year survival rates of patients with intermediate–elevated CRP were 80.5% and 37.4% compared to the poor-risk group, at 65.2% and 24.2%, respectively. Conclusion: Baseline CRP levels could divide mRCC patients in the intermediate-risk group into 2 prognostic subgroups.

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Prostate-specific antigen nadir within 12 months as an early surrogate marker of biochemical failure and distant metastasis after low-dose-rate brachytherapy or external beam radiotherapy for localized prostate cancer

Nishimura Shuichi, Ohashi Toshio, Momma Tetsuo, Sakayori Masanori, Eriguchi Takahisa, Tanaka Tomoki, Yamashita Shoji, Kosaka Takeo, Oya Mototsugu, Shigematsu Naoyuki

Cancer Medicine (Cancer Medicine) 7 ( 5 ) 1794 - 1801 2018.01

Research paper (scientific journal), Joint Work, ISSN 2045-7634

Prostate-specific antigen nadir (nPSA) after radiotherapy for localized prostate cancer has been investigated as a predictor. However, nPSA usually requires several years, limiting its clinical utility. We investigated the significance of nPSA within 12 months (nPSA12) after low-dose-rate prostate brachytherapy (LDR-PB) or external beam radiotherapy (EBRT) on treatment outcomes. Between 2006 and 2014, 663 patients with prostate cancer were treated with LDR-PB or EBRT at two institutions. Four hundred and seventy-four men received LDR-PB and 189 men received EBRT, without androgen deprivation therapy. The Kaplan-Meier method was used for biochemical failure (BF)-free survival (BFFS) and distant metastasis (DM)-free survival (DMFS) analyses, and multivariable Cox regression analysis was performed. The median follow-up was 61.3 months. The median nPSA12 in the LDR-PB and EBRT cohorts was 0.7 and 1.0 ng/mL, respectively. The 7-year BFFS and DMFS rates in LDR-PB patients with nPSA12 ≤ 0.7 ng/mL were 99.1% and 99.5%, respectively; when nPSA12 was >0.7 ng/mL, they were 90.2% and 94.8%, respectively. In EBRT patients with nPSA12 ≤ 1.0 ng/mL, BFFS and DMFS rates were 85.4% and 98.5%, respectively; when nPSA12 was >1.0 ng/mL, they were 67.1% and 87.2%, respectively. nPSA12 was an independent predictor of BF and DM in both cohorts (LDR-PB, P = 0.004 and 0.020, respectively; EBRT, P = 0.005 and 0.041, respectively). The nPSA12 after LDR-PB or EBRT is significantly associated with treatment outcomes of prostate cancer. Higher nPSA12 may identify patients at high risk of relapse who might benefit from salvage treatment.

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Purified Protein Derivative Skin test prior to bacillus Calmette-Guérin Therapy May have Therapeutic Impact in Patients with Nonmuscle Invasive Bladder Cancer

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Journal of Urology (Journal of Urology) 199 ( 6 ) 1446 - 1451 2018.01

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Purpose: We investigated the clinical impact of the purified protein derivative skin test prior to bacillus Calmette-Guérin therapy in patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin therapy. Materials and Methods: A total of 498 patients with nonmuscle invasive bladder cancer treated with adjuvant bacillus Calmette-Guérin were included in study, of whom 320 underwent the purified protein derivative skin test 1 to 2 weeks prior to therapy. Oncologic outcomes and the rate of bacillus Calmette-Guérin related side effects were statistically evaluated. Results: The mean ± SD 5-year recurrence-free survival rate in patients who did vs did not undergo the purified protein derivative skin test was 66.6% ± 2.8% and 59.1% ± 4.1%, respectively, which was significantly different (p = 0.048). No significant difference was observed in the progression-free survival rate between patients who did vs did not undergo the test. Multivariate Cox regression analysis revealed that a history of recurrence (HR 1.59, p = 0.02), multiple tumors (HR 1.95, p <0.01), the bacillus Calmette-Guérin Connaught strain (HR 0.71, p = 0.04), 7 or more bacillus Calmette-Guérin instillations (HR 0.70, p = 0.04) and undergoing the purified protein derivative skin test (HR 0.72, p = 0.04) were independently associated with tumor recurrence. Major bacillus Calmette-Guérin related side effects were noted in 77 of the 320 patients (24.1%) who did vs 27 of the 178 (15.2%) who did not undergo the test, which was significantly different (p = 0.02). Conclusions: The purified protein derivative skin test prior to bacillus Calmette-Guérin treatment enhances the therapeutic effects of this treatment and potentially results in a higher incidence of major bacillus Calmette-Guérin related side effects. Combination therapy with bacillus Calmette-Guérin using the purified protein derivative skin test may improve the oncologic outcomes of that therapy.

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Recent progress in prognostic and predictive biomarkers for target therapies in metastatic tenat cell carcinoma

Mizuno Ryuichi, Asanuma Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Urology (Japanese Journal of Clinical Urology) 72 ( 1 ) 64 - 69 2018.01

Research paper (scientific journal), Joint Work, ISSN 0385-2393

The Role of PD-1 Positivity in the Tumour Nest on Clinical Outcome in Upper Tract Urothelial Carcinoma Patients Treated with Radical Nephroureterectomy

Hayakawa N., Kikuchi E., Mikami S., Fukumoto K., Oya M.

Clinical Oncology (Clinical Oncology) 30 ( 1 ) e1 - e8 2018.01

Research paper (scientific journal), Joint Work, ISSN 0936-6555

Aims The role of PD-1 (programmed cell death 1) expression on the clinical outcome of upper tract urothelial carcinoma has not yet been elucidated in detail. Materials and methods PD-1 expression was immunohistochemically examined in 181 upper tract urothelial carcinoma patients who underwent radical nephroureterectomy. A part of PD-1 protein expression in the tumour periphery and tumour nest was evaluated separately. The PD-1-positive cells were counted in the area showing the highest density of PD-1 expression at a magnification of 400×. Results PD-1 staining in the tumour nest was low in 137 (75.7%) and high in 44 (24.3%) patients. PD-1 staining in the tumour periphery was low in 78 (43.1%) and high in 103 (56.9%) patients. The 5 year progression-free survival rates in patients with the high PD-1 expression in the tumour nest and in the tumour periphery were 54.6% and 67.7%, respectively, which were significantly lower than those in their counterparts (79.4%, P < 0.001; 80.0%, P = 0.04). The 5 year cancer-specific survival rates in patients with the high PD-1 expression in the tumour nest and the tumour periphery were 69.1% and 75.7%, respectively, which were significantly lower than those in their counterparts (84.7%, P = 0.007; 87.8%, P = 0.01). A multivariate Cox regression analysis identified the high PD-1 expression in the tumour nest (hazard ratio 3.07, P < 0.001; hazard ratio 2.44, P = 0.011) and positive lymphovascular invasion (hazard ratio 4.86, P < 0.001; hazard ratio 4.03, P < 0.001) as independent predictors of disease progression and of cancer death, respectively. Conclusions PD-1 positivity in the tumour nest could be a strong predictor for a worse clinical outcome and may be a useful indicator for selecting appropriate candidates for adjuvant therapy such as chemotherapy in upper tract urothelial carcinoma patients treated with radical nephroureterectomy.

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Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity (vol 1, pg 796, 2017)

Tanaka, Nobuyuki, Kanatani, Shigeaki, Tomer, Raju, Sahlgren, Cecilia, Kronqvist, Pauliina, Kaczynska, Dagmara, Louhivuori, Lauri, Kis, Lorand, Lindh, Claes, Mitura, Przemyslaw, Stepulak, Andrzej, Corvigno, Sara, Hartman, Johan, Micke, Patrick, Mezheyeuski, Artur, Strell, Carina, Carlson, Joseph W., Moro, Carlos Fernandez, Dahlstrand, Hanna, Ostman, Arne, Matsumoto, Kazuhiro, Wiklund, Peter, Oya, Mototsugu, Miyakawa, Ayako, Deisseroth, Karl, Uhlen, Per

NATURE BIOMEDICAL ENGINEERING 2 ( 1 ) 48 - 48 2018.01

Research paper (scientific journal), Single Work, ISSN 2157-846X

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Overcoming enzalutamide-resistant castration-resistant prostate cancer by targeting transcriptional 71 repressor BCL-6.

Hongo Hiroshi, Kosaka Takeo, Miyazaki Yasumasa, Kikuchi Eiji, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 975 - 975 2018.01

Joint Work, ISSN 1349-7006

The prognostic significance of vasohibin-2 expression in patients with prostate cancer

Miyazaki Yasumasa, Kosaka Takeo, Mikami Shuji, Yasumizu Yota, Tanaka Nobuyuki, Kikuchi Eiji, Sato Yasufumi, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 1070 - 1070 2018.01

Joint Work, ISSN 1349-7006

The effect of sulfasalazine on bladder cancer stem like cells targeting to cystine transporter

Ogihara Koichiro, Kikuchi Eiji, Hagiwara Masayuki, Kosaka Takeo, Saya Hideyuki, Oya Mototsugu

CANCER SCIENCE (WILEY) 109 1049 - 1049 2018.01

Joint Work, ISSN 1349-7006

Laparoscopic vesical diverticulectomy

Shinojima T., Matsumoto K., Oya M.

Japanese Journal of Clinical Urology (Japanese Journal of Clinical Urology) 72 ( 12 ) 1012 - 1017 2018

ISSN 03852393

Investigation of particle balance in fusion experimental devices with QUEST wall model

Hanada K., Miyamoto M., Idei H., Nagashima Y., Onchi T., Hasegawa M., Nakamura K., Zushi H., Kuroda K., Kawasaki S., Higashijima A., Yoshida N., Nagata T., Shimabukuro S., Watanabe O., Takase Y., Murakami S., Takagi I., Hatayama A., Oya Y., Shikama T., Wang Z., Long H., Oya M.

Meeting Abstracts of the Physical Society of Japan (The Physical Society of Japan) 73 ( 0 ) 771 - 771 2018

A novel form of juvenile primary aldosteronism, which defined by immunohistochemistry for aldosterone synthase, super-selective adrenal venous sampling, and next generation sequencer.

Nishimoto Koshiro, Hayashi Yasuki, Nakagawa Ken, Oya Mototsugu

Official Journal of the Japan Association of Endocrine Surgeons and the Japanese Society of Thyroid Surgery (Japan Association of Endocrine Surgeons・Japanese Society of Thyroid Surgery) 35 ( 1 ) 13 - 17 2018

ISSN 2186-9545

症例は16歳，女性。８歳時に重度PAを発症し，ミネラルコルチコイド受容体阻害薬を含む薬剤治療を施行したが無効であった。超選択的副腎静脈サンプリングにより，右副腎下部を除く両側副腎から著明な自律的アルドステロン産生が確認された。右副腎下部温存両側副腎摘除術を施行した。術後PAは改善し降圧剤は不要となった。両側副腎皮質は，正常副腎皮質と多発する皮質過形成が混在する所見を認め，過形成はアルドステロン合成酵素強陽性であった。正常・過形成部位からの微量DNAの次世代シーケンサー解析により，すべての過形成部位ではKCNJ5体細胞変異（p.G151R）を認めたが，正常部位では認めなかった。発生学的に中胚葉細胞は左右の副腎原基に分化する。本症例は胎生期早期の中胚葉細胞にKCNJ5変異が発生し，変異のない細胞とモザイクとなって副腎皮質を形成して，左右副腎の多発過形成を発生させたと推定された。

腎癌薬物療法におけるバイオマーカー開発の進歩

Oya Mototsugu

臨床泌尿器科 72巻1号 64 - 69 2018

Accepted

腎細胞がん分子標的治療の国際比較

Oya Mototsugu

腎臓内科・泌尿器科 7巻1号 44 - 49 2018

Accepted

Significance of a frozen section analysis of the ureteral margin in bladder cancer patients treated with radical cystectomy and neoadjuvant chemotherapy

Hakozaki Kyohei, Kikuchi Eiji, Fukumoto Keishiro, Shirotake Suguru, Miyazaki Yasumasa, Maeda Takahiro, Kaneko Gou, Yoshimine Shunsuke, Tanaka Nobuyuki, Kanai Kunimitsu, Oyama Masafumi, Nakajima Yosuke, Momma Tetsuo, Oya Mototsugu

Medical Oncology (HUMANA PRESS INC) 34 ( 12 ) 187 - 187 2017.12

ISSN 1357-0560

Although the clinical utility of a frozen section analysis (FSA) at the time of radical cystectomy (RC) has already been established, its significance and utility in bladder cancer patients receiving neoadjuvant chemotherapy (NAC) have not yet been fully evaluated. We identified 458 patients (937 ureters) who underwent open RC for bladder cancer at our 7 Japanese institutions between 2004 and 2015. Among these patients, 139 (284 ureters) received NAC before RC (NAC group), while 319 (653 ureters) underwent RC alone (non-NAC group). FSA was performed on 356 out of 937 (38.0%) ureters and 179 out of 458 (39.1%) patients. FSA was positive in 30 out of 356 (8.4%) ureters and its sensitivity, specificity, and accuracy were 89.3, 98.5, and 97.8%, respectively. In the NAC group, FSA was performed on 138 out of 284 (48.6%) ureters and 68 out of 139 (48.9%) patients. FSA was positive in 8 out of 138 ureters (5.8%), and its sensitivity, specificity, and accuracy were 77.8, 99.2, and 97.8%, respectively. In the non-NAC group, FSA was performed on 218 out of 653 (33.4%) ureters and 111 out of 319 (34.8%) patients. FSA was positive in 22 out of 218 (10.1%) ureters, and its sensitivity, specificity, and accuracy were 94.7, 98.0, and 97.7%, respectively. No correlation was observed between preoperative clinical factors and FSA positivity in the NAC group; however, in the non-NAC group, the incidence of FSA positivity in the ureters of patients with concomitant CIS in TUR-BT specimens was 8/41 (19.5%), which was significantly higher than that in their counterpart (14/177, 7.9%, p = 0.033). Even in the era of NAC in the management of bladder cancer patients, the performance of FSA does not change and FSA at the time of RC may provide useful diagnostic information.

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Baseline risk stratification or duration of prior therapy predicts prognosis in patients with metastatic renal cell carcinoma treated with axitinib

Mizuno Ryuichi, Mikami Shuji, Takamatsu Kimiharu, Shinojima Toshiaki, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Oncology (OXFORD UNIV PRESS) 47 ( 12 ) 1170 - 1174 2017.12

ISSN 0368-2811

Background: To elucidate the clinical prognostic factors in patients with metastatic renal cell carcinoma (mRCC) treated with axitinib. Methods: A total of 58 patients were retrospectively analyzed. All patients received axitinib treatment for mRCC at Keio University hospital in Japan. Baseline clinical factors and on treatment adverse events were assessed to predict survival. Results: The median progression free survival (PFS) for axitinib treatment was 10.9 months (95% CI 5.8-13.5), and the median overall survival (OS) from the start of axitinib treatment was 39.8 months (95% CI 25.9-NR), respectively. The PFS (P < 0.0001) and OS (P = 0.0022) were significantly correlated with the International mRCC Database Consortium (IMDC) classification, respectively. The PFS and OS were significantly longer in patients who received longer prior treatment (P = 0.0424 and 0.0067, respectively). On-treatment hypertension, hand foot syndrome and hypothyroidism were associated with longer PFS (P = 0.0002, 0.0055 and 0.0290, respectively). Ontreatment hypertension, diarrhea, and hand foot syndrome were associated with longer OS (P = 0.0004, 0.0036 and 0.0115, respectively). Conclusions: Baseline and on treatment factors are identified as prognostic markers in mRCC patients treated with axitinib. Our findings might be helpful for clinicians to select the best treatment to individual patients.

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Can urologists introduce the concept of "oligometastasis" for metastatic bladder cancer after total cystectomy?

Ogihara, Koichiro, Kikuchi, Eiji, Watanabe, Keitaro, Kufukihara, Ryohei, Yanai, Yoshinori, Takamatsu, Kimiharu, Matsumoto, Kazuhiro, Hara, Satoshi, Oyama, Masafumi, Monma, Tetsuo, Masuda, Takeshi, Hasegawa, Shintaro, Oya, Mototsugu

ONCOTARGET (IMPACT JOURNALS LLC) 8 ( 67 ) 111819 - 111835 2017.12

Research paper (scientific journal), ISSN 1949-2553

We investigated whether the concept of oligometastasis may be introduced to the clinical management of metastatic bladder cancer patients. Our study population comprised 128 patients diagnosed with metastatic bladder cancer after total cystectomy at our 6 institutions between 2004 and 2014. We extracted independent predictors for identifying a favorable. Occurrence that fulfilled all 4 criteria which were independently associated with cancer-specific death was defined as oligometastasis: a solitary metastatic organ; number of metastatic lesions of 3 or less; the largest diameter of metastatic foci of 5cm or less; and no liver metastasis. We evaluated differences in clinical outcomes between patients with oligometastasis (oligometastasis group) and those without oligometastasis (non-oligometastasis group). Overall, there were 43 patients in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 53.3%, which was significantly higher than that in the non-oligometastasis group (16.1%, p<0.001). A multivariate analysis revealed that non-oligometastasis (p<0.001), not performing salvage chemotherapy (p<0.001), and not performing metastatectomy (p=0.028) were independent risk factors for cancer-specific death. In the subgroup of 83 patients who received salvage chemotherapy, 30 were in the oligometastasis group. The 2-year cancer-specific survival rate in the oligometastasis group was 55.0%, which was significantly higher than that in the non-oligometastasis group (22.0%, p=0.005). Non-oligometastasis (p=0.009) was the only independent risk factor for cancer-specific death. We presented that urothelial carcinoma with oligometastasis had a favorable prognosis and responded to systemic chemotherapy. Oligometastasis may be treated as a separate entity in the field of metastatic urothelial carcinoma.

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Pre-operative and post-operative estimated glomerular filtration rate in Japanese patients with urological malignancies

Niwa Naoya, Yoshida Tadashi, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Hayashi Matsuhiko, Oya Mototsugu

Clinical and Experimental Nephrology (SPRINGER) 22 ( 5 ) 1 - 8 2017.11

Research paper (scientific journal), Joint Work, ISSN 1342-1751

Background: The suitable methods evaluating glomerular filtration rate (GFR) have not been established in patients undergoing radical nephrectomy (RN) or radical nephroureterectomy (RNU) due to urological malignancies in Japan as well as worldwide. Methods: We examined the relationship between creatinine clearance-based measured GFR (mGFR) versus estimated GFR (eGFR) calculated by 3 popular equations, 4-variable Modification of Diet in Renal Disease equation adjusted by Japanese correction coefficient (cmMDRD), 3-variable MDRD equation for Japanese population (eGFRcreat), and Chronic Kidney Disease-Epidemiology Collaboration equation adjusted by Japanese correction coefficient (cmCKD-EPI) in Japanese patients who had undergone RN or RNU due to renal cell carcinoma or upper tract urothelial carcinoma before and after surgery. Results: Among the 3 equations examined, eGFRcreat was the closest to mGFR, although each eGFR was significantly higher than mGFR in the pre-operative period. In the post-operative period, cmMDRD and eGFRcreat, but not cmCKD-EPI, were comparable to mGFR. Each of eGFR was significantly correlated with mGFR in both the pre-operative and post-operative periods. Similar results were obtained by the subanalysis of the patients with pre-operative mGFR of < 60 mL/min/1.73 m². Results of κ statistics also showed that eGFRcreat was most appropriate to estimate GFR both before and after heminephrectomy, when cut-off value of GFR of < 60 mL/min/1.73 m² was used. Conclusion: Results of the present study suggest that eGFRcreat is likely to be the most appropriate equation for patients undergoing RN or RNU due to urological malignancies. However, more precise equations will be required for accurately estimating GFR.

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Whole-tissue biopsy phenotyping of three-dimensional tumours reveals patterns of cancer heterogeneity

Nature Biomedical Engineering 1 ( 10 ) 796 - 806 2017.10

Intratumoral heterogeneity is a critical factor when diagnosing and treating patients with cancer. Marked differences in the genetic and epigenetic backgrounds of cancer cells have been revealed by advances in genome sequencing, yet little is known about the phenotypic landscape and the spatial distribution of intratumoral heterogeneity within solid tumours. Here, we show that three-dimensional light-sheet microscopy of cleared solid tumours can identify unique patterns of phenotypic heterogeneity, in the epithelial-to-mesenchymal transition and in angiogenesis, at single-cell resolution in whole formalin-fixed paraffin-embedded (FFPE) biopsy samples. We also show that cleared FFPE samples can be re-embedded in paraffin after examination for future use, and that our tumour-phenotyping pipeline can determine tumour stage and stratify patient prognosis from clinical samples with higher accuracy than current diagnostic methods, thus facilitating the design of more efficient cancer therapies.

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Factors influencing the operating time for single-port laparoscopic radical nephrectomy

Matsumoto Kazuhiro, Miyajima Akira, Fukumoto Keishiro, Komatsuda Akari, Niwa Naoya, Hattori Seiya, Takeda Toshikazu, Kikuchi Eiji, Asanuma Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Oncology 47 ( 10 ) 976 - 980 2017.10

ISSN 0368-2811

Objective: It is considered that laparoscopic single-site surgery should be performed by specially trained surgeons because of the technical difficulty in using special instruments through limited access. We investigated suitable patients for single-port laparoscopic radical nephrectomy, focusing on the anatomy and distribution of the renal artery and vein. Methods: This retrospective study was conducted in 52 consecutive patients who underwent single-port radical nephrectomy by the transperitoneal approach. In patients undergoing right nephrectomy, a 2-mm port was added for liver retraction. We retrospectively re-evaluated all of the recorded surgical videos and preoperative computed tomography images. The pneumoperitoneum time (PT) was used as an objective index of surgical difficulty. Results: The PT was significantly shorter for right nephrectomy than left nephrectomy (94 vs. 123 min, P = 0.004). With left nephrectomy, dissection of the spleno-renal ligament to mobilize the spleen medially required additional time. Also, the left renal vein could only be divided after securing the adrenal, gonadal and lumbar veins. In patients whose renal artery was located cranial to the renal vein, PT tended to be longer than in the other patients (131 vs. 108 min, P = 0.070). In patients with a superior renal artery, the inferior renal vein invariably covered the artery and made it difficult to ligate the renal artery via the umbilical approach at the first procedure. Conclusions: These findings indicate that patients undergoing right nephrectomy in whom the renal artery is not located cranial to the renal vein are suitable for single-port laparoscopic radical nephrectomy.

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Factors influencing the operating time for single-port laparoscopic radical nephrectomy: Focus on the anatomy and distribution of the renal artery and vein

Kazuhiro Matsumoto, Akira Miyajima, Keishiro Fukumoto, Akari Komatsuda, Naoya Niwa, Seiya Hattori, Toshikazu Takeda, Eiji Kikuchi, Hiroshi Asanuma, Mototsugu Oya

Japanese Journal of Clinical Oncology (OXFORD UNIV PRESS) 47 ( 10 ) 976 - 980 2017.10

ISSN 0368-2811

© The Author 2017. Published by Oxford University Press. All rights reserved. Objective: It is considered that laparoscopic single-site surgery should be performed by specially trained surgeons because of the technical difficulty in using special instruments through limited access. We investigated suitable patients for single-port laparoscopic radical nephrectomy, focusing on the anatomy and distribution of the renal artery and vein. Methods: This retrospective study was conducted in 52 consecutive patients who underwent single-port radical nephrectomy by the transperitoneal approach. In patients undergoing right nephrectomy, a 2-mm port was added for liver retraction. We retrospectively re-evaluated all of the recorded surgical videos and preoperative computed tomography images. The pneumoperitoneum time (PT) was used as an objective index of surgical difficulty. Results: The PT was significantly shorter for right nephrectomy than left nephrectomy (94 vs. 123 min, P = 0.004). With left nephrectomy, dissection of the spleno-renal ligament to mobilize the spleen medially required additional time. Also, the left renal vein could only be divided after securing the adrenal, gonadal and lumbar veins. In patients whose renal artery was located cranial to the renal vein, PT tended to be longer than in the other patients (131 vs. 108 min, P = 0.070). In patients with a superior renal artery, the inferior renal vein invariably covered the artery and made it difficult to ligate the renal artery via the umbilical approach at the first procedure. Conclusions: These findings indicate that patients undergoing right nephrectomy in whom the renal artery is not located cranial to the renal vein are suitable for single-port laparoscopic radical nephrectomy.

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Ra-223 SPECT for semi-quantitative analysis in comparison with Tc-99m HMDP SPECT: phantom study and initial clinical experience

Owaki, Yoshiki, Nakahara, Tadaki, Kosaka, Takeo, Fukada, Junichi, Kumabe, Atsuhiro, Ichimura, Akira, Murakami, Mikoto, Nakajima, Kiyotaka, Fukushi, Masahiro, Inoue, Kazumasa, Oya, Mototsugu, Jinzaki, Masahiro

EJNMMI RESEARCH (SPRINGER HEIDELBERG) 7 ( 1 ) 976 - 980 2017.10

Research paper (scientific journal), ISSN 2191-219X

BACKGROUND: Image-based measurement of absorbed dose of Ra-223 dichloride may be useful in predicting therapeutic outcome in patients with castration-resistant prostate cancer (CRPC). In general, SPECT has been found to be more accurate than planar imaging in terms of lesion-based analysis. The aims of this study were to assess the feasibility and clinical usefulness of Ra-223 SPECT. The energy spectrum of Ra-223 and SPECT images of a cylindrical phantom with a hot rod were obtained to determine the collimator candidates and energy window settings suitable for clinical Ra-223 SPECT (basic study A). Another phantom with a tube-shaped chamber and two spheres simulating bowel activity and metastatic lesions in the lumbar spine was scanned with medium-energy general-purpose (MEGP) and high-energy general-purpose (HEGP) collimators (basic study B). Ten patients with CRPC underwent SPECT imaging 2 h after Ra-223 injection successively with MEGP and HEGP collimators in random order for 30 min each. Lesion detectability and semi-quantitative analyses of bone metastasis (i.e. lesion-to-background ratio (LBR)) were performed compared to Tc-99m HMDP SPECT. RESULTS: Basic study A revealed that an 84-keV photopeak ± 20% using the HEGP collimator offers better SPECT image quality than the other imaging conditions. Basic study B showed that uptake in one of the spheres was overestimated by overlapped activity of the tube-shaped chamber in planar imaging whereas the spheres had similar counts and significantly higher sphere-to-background ratio in SPECT. On both planar and SPECT images, HEGP gave higher image contrast than MEGP (p < 0.01). In the clinical study, Ra-223 SPECT at 84 keV ± 20% depicted more lesions with the HEGP than with the MEGP collimator (51 vs 36, p = 0.013). There was a positive correlation between LBR in Tc-99m SPECT and in Ra-223 SPECT (r = 0.67 with the MEGP and 0.69 with the HEGP collimator, p < 0.01). LBRs were significantly higher with the HEGP than with the MEGP collimator (p < 0.01). CONCLUSIONS: We recommended the use of the HEGP collimator at 84 keV ± 20% for Ra-223 SPECT imaging. Lesion-based semi-quantitative analysis in the human study revealed a good correlation between Ra-223 and Tc-99m HMDP SPECT in the early phase (2-3 h post injection).

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Angiogenic, inflammatory and immunologic markers in predicting response to sunitinib in metastatic renal cell carcinoma

OYA MOTOTSUGU

CANCER SCIENCE 108 ( 9 ) 1858 - 1863 2017.09

Research paper (scientific journal), ISSN 1349-7006

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Prognostic significance of erythrocyteproteinband 4.1-like5 expression in upper urinary tract urothelial carcinoma

Daimon, Tatsuaki, Kosaka, Takeo, Kikuchi, Eiji, Mikami, Shuji, Miyazaki, Yasumasa, Hashimoto, Ari, Hashimoto, Shigeru, Mizuno, Ryuichi, Miyajima, Akira, Okada, Yasunori, Sabe, Hisataka, Oya, Mototsugu

UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS 35 ( 9 ) 2017.09

Research paper (scientific journal), ISSN 1078-1439

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Simple and practical nomograms for predicting the stone-free rate after shock wave lithotripsy in patients with a solitary upper ureteral stone

Niwa, Naoya, Matsumoto, Kazuhiro, Miyahara, Makoto, Omura, Minami, Kobayashi, Hiroaki, Kikuchi, Eiji, Miyajima, Akira, Miyata, Kazutoyo, Oya, Mototsugu

WORLD JOURNAL OF UROLOGY 35 ( 9 ) 1455 - 1461 2017.09

Research paper (scientific journal), ISSN 0724-4983

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Guidelines for treatment of renal injury during cancer chemotherapy 2016

Horie Shigeo, Oya Mototsugu, Nangaku Masaomi, Yasuda Yoshinari, Komatsu Yasuhiro, Yanagita Motoko, Kitagawa Yuko, Kuwano Hiroyuki, Nishiyama Hiroyuki, Ishioka Chikashi, Takaishi Hiromasa, Shimodaira Hideki, Mogi Akira, Ando Yuichi, Matsumoto Koji, Kadowaki Daisuke, Muto Satoru

Clinical and Experimental Nephrology (Clinical and Experimental Nephrology) 22 ( 1 ) 1 - 35 2017.08

Research paper (scientific journal), Joint Work, ISSN 1342-1751

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Cost analysis of leuprorelin acetate in Japanese prostate cancer patients

Goto Rei, Uda Akihito, Hiroi Shinzo, Iwasaki Kosuke, Takashima Kenta, Oya Mototsugu

Journal of Medical Economics 1 - 8 2017.08

ISSN 1369-6998

Aims: This study aimed to evaluate the economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot from a societal perspective in Japanese prostate cancer patients. Methods: The cost analysis estimated the reduction in direct and indirect costs as well as intangible costs saved by having one less injection. Claims data were used for the analyses of direct and indirect costs reduction. A discrete choice experiment based on a web-based survey estimated the monetary value of the intangible costs for one injection. Another web-based survey of prostate cancer patients, who had received treatment with leuprorelin acetate injections, was carried out to calibrate the results of the discrete choice experiment. Results: Reductions in medical costs and loss of productivity for having one less injection in prostate cancer patients receiving leuprorelin acetate were JPY 5,670 and JPY 1,723, respectively. Intangible costs saved by using a 6-month depot formulation instead of a 3-month depot formulation for the injection of leuprorelin acetate were estimated to be JPY 19,872, including the values for a reduction in pain (JPY 3,131), injection site reactions (JPY 11,545), waiting time (JPY 9,479), and subtracting the value of medical consultation (JPY 4,283). The total cost reduction for having one less injection was JPY 27,265. Limitations: The respondents from the internet panel provided by a survey company are not necessarily a representative population of Japanese society. Conclusions: Leuprorelin acetate 6-month depot has an advantage in monetary value in the reduction in medical costs, loss of productivity, and intangible costs for having one less injection in prostate cancer patients compared with leuprorelin acetate 3-month depot. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.

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Obstructive azoospermia caused by low ligation of varicocele

Hagiuda Jun, Ishikawa Hiromichi, Hagiwara Masayuki, Kono Hidaka, Nakagawa Ken, Oya Mototsugu

Systems Biology in Reproductive Medicine 1 - 2 2017.08

ISSN 1939-6368

Varicocele is commonly observed in male partners of infertile couples. The surgical ligation of varicoceles under microscopy can be safely performed by a skilled andrologist with most patients subsequently experiencing an improvement in semen quality. This is the first case in which obstructive azoospermia occurred after high inguinal varicocelectomy. The vas deferens was disrupted near the internal inguinal ring by fibrous tissue. A vasovasostomy was performed and semen parameters subsequently recovered.

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IJU this issue

Oya Mototsugu

International Journal of Urology 24 ( 8 ) 2017.08

ISSN 0919-8172

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Increased vasohibin-1 expression is associated with metastasis and poor prognosis of renal cell carcinoma patients

Mikami Shuji, Oya Mototsugu, Kosaka Takeo, Mizuno Ryuichi, Miyazaki Yasumasa, Sato Yasufumi, Okada Yasunori

Laboratory Investigation 97 ( 7 ) 854 - 862 2017.07

ISSN 0023-6837

The microvascular density detected by markers of endothelial cells (ECs), such as CD31 and CD34, is considered to be a biomarker for angiogenesis, and it is generally associated with the malignant potential of solid tumors. However, there is a conflicting relationship between the microvascular density and prognosis in clear-cell renal cell carcinoma (ccRCC) patients. It may be explained by the suggestion that the microvascular density cannot fully reflect the angiogenic activity in ccRCC, as the markers of ECs are expressed by both quiescent and activated ECs. To investigate the real angiogenic activity, we examined vasohibin-1 (VASH1), a recently identified regulator of angiogenesis, which was demonstrated to be specifically expressed by ECs of newly formed blood vessels. Expression of VASH1 and CD34 were immunohistochemically examined in 116 primary untreated ccRCCs, 10 metastatic untreated ccRCCs, and 9 metastatic ccRCCs treated with sunitinib. ECs in the tumor microvessels were sporadically immunostained for VASH1, although no VASH1 staining was observed in the non-neoplastic renal tissues. CD34 was ubiquitously expressed by all ECs in both ccRCC and non-neoplastic renal tissues. Multivariate Cox analysis indicated that an elevated VASH1 density, but not microvascular density, was a significant and independent predictor of overall survival (odds ratio, 7.71; P=0.003). The microvascular density was significantly decreased in the sunitinib-treated metastases compared with untreated tumors (P=0.001). On the other hand, the VASH1 density was significantly higher in the metastatic ccRCCs treated with sunitinib compared with non-treated ones (P=0.010), indicating that VASH1 may be associated with the resistance of ECs to sunitinib treatment. Thus, VASH1 expression may reflect the actual activity of angiogenesis, and VASH1 can serve as a new prognostic and predictive biomarker in patients with ccRCC.

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Nivolumab versus everolimus in advanced renal cell carcinoma

Tomita Yoshihiko, Fukasawa Satoshi, Shinohara Nobuo, Kitamura Hiroshi, Oya Mototsugu, Eto Masatoshi, Tanabe Kazunari, Kimura Go, Yonese Junji, Yao Masahiro, Motzer Robert J., Uemura Hirotsugu, Brent McHenry M., Berghorn Elmer, Ozono Seiichiro

Japanese Journal of Clinical Oncology 47 ( 7 ) 639 - 646 2017.07

ISSN 0368-2811

Background: Nivolumab improved overall survival (OS) and objective response rate (ORR) versus everolimus in previously treated patients with advanced renal cell carcinoma in the phase III CheckMate 025 study (minimum follow-up: 14 months). We report efficacy and safety in the global and Japanese populations (minimum follow-up: 26 months).Methods: Patients were randomized 1:1 to receive nivolumab 3 mg/kg intravenously every 2 weeks or everolimus 10-mg tablet orally once daily. Primary endpoint: OS, key secondary endpoints: ORR, progression-free survival and safety. Results: Of 410 (nivolumab) and 411 (everolimus) patients, 37 (9%) and 26 (6%), respectively, were Japanese. Median OS for the global population was 26.0 months (nivolumab) and 19.7 months (everolimus; hazard ratio 0.73 [95% confidence interval [CI]: 0.61-0.88]; P = 0.0006), with medians not reached for Japanese patients. ORR for the global population was 26% (nivolumab) versus 5% (everolimus; odds ratio 6.13; 95% CI: 3.77-9.95); ORR for Japanese patients: 43% versus 8% (odds ratio 9.14; 95% CI: 1.76-88.33). In Japanese patients, any-grade treatment-related adverse events (AEs) occurred in 78% (Grade 3-4, 19%; most common, anemia [5%]) treated with nivolumab and 100% (Grade 3-4, 58%; most common, hypertriglyceridemia [12%]) treated with everolimus; the most common with nivolumab was diarrhea (19%) and with everolimus was stomatitis (77%). Quality of life was stable in the nivolumab arm. Conclusions: With >2 years of follow-up, Japanese patients had a higher response rate with nivolumab versus everolimus that was more pronounced yet consistent with the global population, with median OS not reached, and a favorable safety profile.

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Impact of baseline visceral fat accumulation on prognosis in patients with metastatic renal cell carcinoma treated with systemic therapy

Mizuno, Ryuichi, Miyajima, Akira, Hibi, Taizo, Masuda, Aya, Shinojima, Toshiaki, Kikuchi, Eiji, Jinzaki, Masahiro, Oya, Mototsugu

MEDICAL ONCOLOGY 34 ( 4 ) 37 - 46 2017.04

Research paper (scientific journal), ISSN 1357-0560

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Determining When to Stop Prostate Specific Antigen Monitoring after Radical Prostatectomy

Matsumoto Kazuhiro, Komatsuda Akari, Yanai Yoshinori, Niwa Naoya, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Journal of Urology 197 ( 3 ) 655 - 661 2017.03

ISSN 0022-5347

Purpose We analyzed long-term followup data after radical prostatectomy to determine how long we should follow patients in whom the serum prostate specific antigen level measured by an ultrasensitive assay was consistently low. Materials and Methods We retrospectively reviewed clinicopathological data for 582 consecutive patients who underwent open or laparoscopic radical prostatectomy between 1995 and 2004, excluding 4 patients who received adjuvant therapy. We stratified the patients according to prostate specific antigen at 3 and 5 years after surgery, and examined subsequent biochemical recurrence (elevation of prostate specific antigen to greater than 0.2 ng/ml) during followup. Mean followup was 9.7 years. Results At 3 years after surgery prostate specific antigen levels were measured by an ultrasensitive assay in 323 patients who had not experienced biochemical recurrence. In 187 patients with undetectable prostate specific antigen levels (less than 0.01 ng/ml) the 10 and 15-year biochemical recurrence-free survival rates were 99% and 96%, respectively. At 5 years after surgery prostate specific antigen was measured in 315 patients by the ultrasensitive assay. In 162 patients with undetectable prostate specific antigen levels the 10 and 15-year biochemical recurrence-free survival rates were both 100%. In this group the prostate specific antigen level at last followup was less than 0.01 ng/ml in 132 patients, 0.01 to 0.03 ng/ml in 27 patients, and 0.06 ng/ml, 0.07 ng/ml and 0.11 ng/ml in 1 patient each. Conclusions This long-term review indicates that if patients have continuously undetectable prostate specific antigen levels by an ultrasensitive assay for 5 years, prostate specific antigen monitoring can be stopped with an extremely low risk of subsequent biochemical recurrence.

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Prolonged pneumoperitoneum time is an independent risk factor for intravesical recurrence after laparoscopic radical nephroureterectomy in upper tract urothelial carcinoma

Shigeta, Keisuke, Kikuchi, Eiji, Hagiwara, Masayuki, Ando, Toshiyuki, Mizuno, Ryuichi, Miyajima, Akira, Nakagawa, Ken, Oya, Mototsugu

SURGICAL ONCOLOGY-OXFORD 26 ( 1 ) 73 - 79 2017.03

Research paper (scientific journal), ISSN 0960-7404

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Simple and practical nomograms for predicting the stone-free rate after shock wave lithotripsy in patients with a solitary upper ureteral stone

Niwa Naoya, Matsumoto Kazuhiro, Miyahara Makoto, Omura Minami, Kobayashi Hiroaki, Kikuchi Eiji, Miyajima Akira, Miyata Kazutoyo, Oya Mototsugu

World Journal of Urology 1 - 7 2017.02

ISSN 0724-4983

Purpose: To develop practical nomograms for predicting the stone-free rate after shock wave lithotripsy (SWL) in patients with a solitary stone in the proximal ureter. Methods: Between July 2006 and June 2015, 319 patients with a proximal ureteral stone who underwent preoperative non-contrast enhanced computed tomography (NCCT) and subsequently received SWL were identified. Patients’ age, gender, laterality, stone size, mean and maximum Hounsfield Unit (HU) of the stone, and skin-to-stone distance (SSD) were assessed. The stone-free status was defined as no radiopacity detected on the 3-month follow-up plain radiography or NCCT. Results: Mean stone size was 10 mm (range 3–20 mm). Mean and maximum HU of the stone ranged from 115 to 1447 (mean 701) and from 265 to 1881 (mean 1062), respectively. The overall stone-free rate was 70%. Multivariate analyses identified stone size (p < 0.001), maximum HU (p < 0.001), and SSD at 90° (p = 0.038) as independent predictive factors for the stone-free status after SWL. Nomograms could be constructed for predicting the probability of stone-free status after SWL corresponding to SSD of 8, 10, and 12 cm using maximum HU and stone size. Conclusions: This study demonstrated that stone size, maximum HU of the stone, and SSD at 90° are significant predictors of successful SWL outcome in patients with a proximal ureteral stone. We have developed simple and practical nomograms corresponding to three different SSDs for predicting the stone-free rate after SWL.

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Natural course of asymptomatic abnormal prostate findings incidentally detected by CT after intravesical BCG therapy

Matsushima Masashi, Kikuchi Eiji, Akita Hirotaka, Miyajima Akira, Oya Mototsugu, Jinzaki Masahiro

International Journal of Clinical Oncology 1 - 9 2017.02

ISSN 1341-9625

Background: Detailed information is not currently available on the incidence, natural course, and management of asymptomatic abnormal prostate findings incidentally detected by radiologic evaluations after BCG therapy for non-muscle-invasive bladder cancer patients. Methods: We identified 38 patients who were evaluated by contrast-enhanced CT scans before TUR-BT and after BCG therapy between 2006 and 2012. We evaluated the clinical courses of patients with abnormal radiologic findings of the prostate gland after BCG therapy. Results: Abnormal findings on CT scans were found in the prostate glands of 11 of the 38 patients examined (28.9%), none of whom exhibited any sign or symptom associated with prostatitis. Abnormal findings included a low attenuation area (n = 6, 15.8%), contrast enhancement (n = 3, 7.9%), and a low attenuation area and contrast enhancement in the prostate gland (n = 2, 5.3%). During the follow-up, abnormal prostate findings disappeared spontaneously in most cases without any anti-bacterial or anti-tuberculous drug treatments. No significant differences were observed in patient clinical backgrounds, with the exception of post-BCG prostate volumes, between patients with and without abnormal CT findings. Furthermore, no significant differences were noted in the incidence of the adverse effects of BCG therapy, tumor recurrence rates, or progression rates between patients with and without abnormal CT findings of the prostate gland after BCG therapy. Conclusions: Asymptomatic abnormal prostate findings incidentally detected by CT after BCG therapy are not rare, and these disappear over time during the follow-up period without any treatment.

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Somatic KCNJ5 mutation occurring early in adrenal development may cause a novel form of juvenile primary aldosteronism

Tamura Ai, Nishimoto Koshiro, Seki Tsugio, Matsuzawa Yoko, Saito Jun, Omura Masao, Gomez-Sanchez Celso E., Makita Kohzoh, Matsui Seishi, Moriya Nobukazu, Inoue Atsushi, Nagata Maki, Sasano Hironobu, Nakamura Yasuhiro, Yamazaki Yuto, Kabe Yasuaki, Mukai Kuniaki, Kosaka Takeo, Oya Mototsugu, Suematsu Sachiko, Nishikawa Tetsuo

Molecular and Cellular Endocrinology 441 134 - 139 2017.02

ISSN 0303-7207

We report a case of non-familial juvenile primary aldosteronism (PA). Super-selective adrenal venous sampling identified less aldosterone production in the right inferior adrenal segment than others. Bilateral adrenalectomy sparing the segment normalized blood pressure and improved PA. Both adrenals had similar histologies, consisting of a normal adrenal cortex and aldosterone synthase-positive hyperplasia/adenoma. An aldosterone-driving KCNJ5 mutation was detected in the lesions, but not in the histologically normal cortex. After taking into account that the two adrenal glands displayed a similar histological profile, as well as the fact that hyperplastic lesions in both glands exhibited a common KCNJ5 mutation, we conclude that the specific mutation may have occurred at an adrenal precursor mesodermal cell, at an early stage of development; its daughter cells were mixed with non-mutant cells and dispersed into both adrenal glands, resulting into a form of the condition known as genetic mosaicism.

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Diagnosis of Renal Angiomyolipomas

Jinzaki Masahiro, Silverman Stuart G., Akita Hirotaka, Mikami Shuji, Oya Mototsugu

Seminars in Ultrasound, CT and MRI 38 ( 1 ) 37 - 46 2017.02

ISSN 0887-2171

With the increasing discovery of small renal masses with cross-sectional imaging, there has been the concomitant rise in their treatment. With the intent of early curative surgery for a presumed renal cell carcinoma, many renal masses are being resected at surgery without a confirmed diagnosis. Many of them are benign, and some are angiomyolipomas. The diagnosis of renal angiomyolipoma using imaging is, therefore, is as important as ever. Although most, if not all angiomyolipomas with abundant fat are diagnosed readily, some have too little fat to be detected with imaging. This article reviews the current classification, imaging pitfalls, and diagnosis of angiomyolipoma with an emphasis on the fat-poor types. Proper imaging technique, a thorough search for fat, and the appropriate use of percutanoeus biopsy are all needed to eliminate the unnecessary treatment of these benign neoplasms.

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Prognostic value of neutrophil-to-lymphocyte ratio in patients with metastatic renal cell carcinoma treated with first-line and subsequent second-line targeted therapy

Tanaka Nobuyuki, Mizuno Ryuichi, Yasumizu Yota, Ito Keiichi, Shirotake Suguru, Masunaga Ayako, Ito Yujiro, Miyazaki Yasumasa, Hagiwara Masayuki, Kanao Kent, Mikami Shuji, Nakagawa Ken, Momma Tetsuo, Masuda Takeshi, Asano Tomohiko, Oyama Masafumi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 35 ( 2 ) 39.e19 - 39.e28 2017.02

ISSN 1078-1439

Purpose The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk model has been designed for prognostification in patients with metastatic renal cell carcinoma (mRCC) treated with targeted therapy. One factor is neutrophil count; however, increasing evidence has suggested the superiority of neutrophil-to-lymphocyte ratio (NLR) for predicting outcome. In this study, we evaluate the prognostic effect of NLR levels on patients with mRCC treated with targeted therapy, and then we compare the predictive accuracy of the IMDC risk model and its modified one by using NLR, instead of neutrophil count. Patients and method A total of 277 patients are included for the analysis. All patients underwent targeted therapies and associated outcome are assessed using multivariate analysis. Results Pretreatment NLR levels are elevated in 30.3% and 23.1% of patients in the first-line and subsequent second-line setting, respectively. Kaplan-Meier curves reveal that elevated pretreatment NLR is significantly associated with poor overall survival (OS) since first-line (P<0.001) and second-line targeted therapy administration (P<0.001). Also, multivariate analyses show that elevated pretreatment NLR is an independent predictor for poor OS since first-line and second-line targeted therapy administration. The addition of NLR to the IMDC risk model, instead of neutrophil count, significantly improves the predictive accuracy for OS, and estimated gain is 1.7% and 6.2% in first-line and second-line targeted therapy, respectively. Conclusion Changes in NLR levels could be predictive for prognosis in patients with mRCC treated with first-line and second-line targeted therapy. The addition of NLR significantly improves the predictive accuracy of the IMDC risk model in the first-line and subsequent second-line setting.

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IJU this issue

Oya Mototsugu

International Journal of Urology 24 ( 2 ) 93 2017.02

ISSN 0919-8172

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Immunohistochemistry of aldosterone synthase leads the way to the pathogenesis of primary aldosteronism

Nishimoto, Koshiro, Koga, Minae, Seki, Tsugio, Oki, Kenji, Gomez-Sanchez, Elise P., Gomez-Sanchez, Celso E., Naruse, Mitsuhide, Sakaguchi, Tomokazu, Morita, Shinya, Kosaka, Takeo, Oya, Mototsugu, Ogishima, Tadashi, Yasuda, Masanori, Suematsu, Makoto, Kabe, Yasuaki, Omura, Masao, Nishikawa, Tetsuo, Mukai, Kuniaki

MOLECULAR AND CELLULAR ENDOCRINOLOGY 441 ( C ) 124 - 133 2017.02

Research paper (scientific journal), ISSN 0303-7207

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Diagnosis of Renal Angiomyolipomas: Classic, Fat-Poor, and Epithelioid Types

Jinzaki, Masahiro, Silverman, Stuart G., Akita, Hirotaka, Mikami, Shuji, Oya, Mototsugu

SEMINARS IN ULTRASOUND CT AND MRI 38 ( 1 ) 37 - 46 2017.02

Research paper (scientific journal), ISSN 0887-2171

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Role of metastasectomy in patients with metastatic renal cell carcinoma

Takamatsu Kimiharu, Oya Mototsugu

Japanese Journal of Clinical Urology 71 ( 13 ) 1096 - 1100 2017.01

ISSN 0385-2393

Novel algorithm for management of acute epididymitis

Hongo Hiroshi, Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Kanao Kent, Kosaka Takeo, Mizuno Ryuichi, Miyajima Akira, Saito Shiro, Oya Mototsugu

International Journal of Urology 24 ( 1 ) 82 - 87 2017.01

ISSN 0919-8172

Objectives: To identify predictive factors for the severity of epididymitis and to develop an algorithm guiding decisions on how to manage patients with this disease. Methods: A retrospective study was carried out on 160 epididymitis patients at Keio University Hospital. We classified cases into severe and non-severe groups, and compared clinical findings at the first visit. Based on statistical analyses, we developed an algorithm for predicting severe cases. We validated the algorithm by applying it to an external cohort of 96 patients at Tokyo Medical Center. The efficacy of the algorithm was investigated by a decision curve analysis. Results: A total of 19 patients (11.9%) had severe epididymitis. Patient characteristics including older age, previous history of diabetes mellitus and fever, as well as laboratory data including a higher white blood cell count, C-reactive protein level and blood urea nitrogen level were independently associated with severity. A predictive algorithm was created with the ability to classify epididymitis cases into three risk groups. In the Keio University Hospital cohort, 100%, 23.5%, and 3.4% of cases in the high-, intermediate-, and low-risk groups, respectively, became severe. The specificity of the algorithm for predicting severe epididymitis proved to be 100% in the Keio University Hospital cohort and 98.8% in the Tokyo Medical Center cohort. The decision curve analysis also showed the high efficacy of the algorithm. Conclusions: This algorithm might aid in decision-making for the clinical management of acute epididymitis.

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Imaging features of renal cell carcinoma differential diagnosis, staging, and posttreatment evaluation

Jinzaki Masahiro, Akita Hirotaka, Oya Mototsugu

139 - 176 2017.01

With the widespread use of ultrasonography (US), computed tomography (CT), and magnetic resonance imaging (MRI), there has been an increase in the detection of various subtypes of renal cell carcinomas (RCCs) and benign renal tumors. The differentiation of RCCs from benign tumors such as fat-poor angiomyolipoma and oncocytoma is very important to prevent unnecessary surgery. In addition, the recent progress of therapies to treat RCCs, including nephronsparing surgery, percutaneous ablative procedures, and targeted antiangiogenic therapies, has increased the need for the accurate determination of subtypes and staging. With the development of imaging modalities, there have been significant improvements in correlating preoperative imaging with pathologic characteristics. Many studies performed within the last two decades have helped to clarify diagnostic imaging clues for both cystic and solid renal tumors. In this chapter, we discuss the current status of US, CT, and MRI for the detection and differential diagnosis of renal tumors as well as staging, postprocedural imaging, and imaging for the targeted antiangiogenic treatment of RCC.

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Refractory mechanisms

Oya Mototsugu, Shinojima Toshiaki, Mizuno Ryuichi

351 - 367 2017.01

Vascular endothelial growth factor (VEGF)-targeted agents have brought significant progress in pharmacotherapy of advanced renal cell carcinoma (RCC). Some RCCs, however, appear to have innate resistance to treatment. Moreover, majority of patients who primarily respond to VEGF-targeted therapy eventually develop disease progression after prolonged treatment. The mechanism of resistance is supposed to be so multifactorial that it cannot be explained by single molecular events. Despite various factors including cytokines, bone marrowderived cells, microenvironment, and genetic or epigenetic abnormality could be involved, tumor hypoxia seems to play one of crucial roles in most of the processes. The multiple mechanism in developing drug resistance might just represent the diversity of cellular response to hypoxia and nutrient deprivation, induced by the disruption of the blood vessels. In this chapter we comprehensively review current efforts aiming to clarify these process and to develop pharmacological strategies leading to overcome the drug resistance in RCC.

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Headache caused by brain metastases of castration-resistant prostate cancer during cabazitaxel therapy

Watanabe Keitaro, Kosaka Takeo, Hongo Hiroshi, Tamaki Satoshi, Oya Mototsugu

Keio Journal of Medicine 66 ( 4 ) 65 - 71 2017.01

ISSN 0022-9717

We describe the case of a 55-year-old man who underwent four cycles of cabazitaxel therapy for castration- resistant prostate cancer (CRPC). After the fourth cycle of cabazitaxel, the patient experienced severe headaches. Brain gadolinium (Gd) contrast-enhanced magnetic resonance imaging (MRI) revealed multiple brain metastases. A few days later, the patient suffered impaired consciousness that progressed rapidly. The patient was treated for the symptoms of increased intracranial pressure and underwent whole-brain radiation. One month later, the patient’s consciousness level and headache had improved. Although brain metastases of prostate cancer are rare, the possibility of brain metastases should be considered for prostate cancer patients, especially when a CRPC patient complains of headache. Additionally, even if major conditions such as cerebral hemorrhage are excluded by the use of non-contrast enhanced computed tomography, brain Gd contrast-enhanced MRI should be performed in consideration of the possibility of brain metastases of prostate cancer.

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Preface

Oya Mototsugu

v - vii 2017.01

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Purified protein derivative skin test reactions are associated with clinical outcomes of patients with nonmuscle invasive bladder cancer treated with induction bacillus Calmette-Guérin therapy

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations (Urologic Oncology: Seminars and Original Investigations) 36 ( 2 ) 77.e15 - 77.e21 2017.01

Research paper (scientific journal), Joint Work, ISSN 1078-1439

Objectives: To investigate the relationship between purified protein derivative (PPD) skin test reactions before bacillus Calmette-Guérin (BCG) therapy and the clinical outcomes of BCG-naïve nonmuscle invasive bladder cancer patients treated with adjuvant BCG therapy. Materials and methods: A total of 288 nonmuscle invasive bladder cancer patients subjected to the PPD skin test before BCG therapy were included. PPD skin test reactions were categorized into 3 groups: positive, slightly positive, and negative. The presence of an induration was positive. If an induration was absent, erythema of 10. mm or more and less than 10. mm corresponded to slightly positive and negative, respectively. Results: A total of 66 (22.9%), 149 (51.7%), and 73 (25.3%) patients exhibited a positive, slightly positive, and negative to PPD skin test, respectively. The 5-year recurrence-free survival rate of patients with positive PPD skin test reactions was 89.4 ± 4.1%, which was significantly higher than those of patients with slightly positive (65.5 ± 4.2%, P = 0.001) and negative reactions (56.4 ± 6.6%, P<0.001). A multivariate Cox regression analysis revealed that a positive PPD skin test reaction was independently associated with tumor recurrence (hazard ratio of 0.233, P<0.001), but not with stage progression. The incidence of fever persisting for more than 2 days or fever of ≥38°C was significantly higher in patients with a positive PPD skin test reaction (18.2%) than in patients with slightly positive (8.7%) and negative PPD skin test reactions (4.1%). Conclusions: The PPD skin test reactions before BCG therapy may predict clinical outcomes following BCG therapy and help clinicians counsel patients exhibiting strong therapeutic effects with BCG therapy and potentially major BCG-related side effects.

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The Conditional Survival with Time of Intravesical Recurrence of Upper Tract Urothelial Carcinoma

Shigeta Keisuke, Kikuchi Eiji, Hagiwara Masayuki, Ando Toshiyuki, Mizuno Ryuichi, Abe Takayuki, Mikami Shuji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Journal of Urology (ELSEVIER SCIENCE INC) 198 ( 6 ) 1278 - 1285 2017

ISSN 0022-5347

Purpose: Since conditional survival analysis provides better estimates of survival time at each followup, we assessed changes in conditional intravesical recurrence-free survival rates after radical nephroureterectomy. We also sought to determine how the impact of well-known risk factors evolves with time, particularly in patients with localized upper tract urothelial carcinoma. Materials and Methods: We identified 364 patients with Ta-3N0M0 localized upper tract urothelial carcinoma who underwent open or laparoscopic radical nephroureterectomy at 1 of our 3 institutions. Conditional intravesical recurrence-free and cancer specific survival rates were calculated using the Kaplan-Meier method. The changing impact of parameters on intravesical recurrence with time was assessed by multivariate Cox regression analysis. Results: Intravesical recurrence after radical nephroureterectomy was detected in 176 patients (48.4%) and 93 (25.5%) died of localized upper tract urothelial carcinoma. Five-year intravesical recurrence-free and cancer specific survival rates after surgery were 41.5% and 72.9%, respectively. Based on 1, 2, 3 and 4-year survivorship the 5-year conditional intravesical recurrence-free survival rate increased from 41.5% to 60.5%, 73.4%, 79.5% and 96.7%, respectively. The 5-year conditional cancer specific survival rate also improved from 72.9% to 78.4%, 85.4%, 90.9% and 95.5% at 1, 2, 3 and 4 years, respectively. The effects of well-known predictive factors on estimated conditional survival decreased with time for intravesical recurrence. In contrast, the impact of T2 or lower pathological stage and laparoscopic radical nephroureterectomy sustained statistical power with time. Conclusions: Conditional survival analysis revealed that the probability of intravesical recurrence-free survival increased with time in patients with localized Ta-3N0M0 upper tract urothelial carcinoma after radical nephroureterectomy. Patients with T2 or lower T stage who undergo laparoscopic radical nephroureterectomy may be recommended for longer followup to detect subsequent intravesical recurrence.

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Obstructive azoospermia caused by low ligation of varicocele: A case report

Hagiuda, Jun, Ishikawa, Hiromichi, Hagiwara, Masayuki, Kono, Hidaka, Nakagawa, Ken, Oya, Mototsugu

SYSTEMS BIOLOGY IN REPRODUCTIVE MEDICINE (TAYLOR & FRANCIS INC) 63 ( 5 ) 338 - 339 2017

Research paper (scientific journal), ISSN 1939-6368

© 2017 Taylor & Francis. Varicocele is commonly observed in male partners of infertile couples. The surgical ligation of varicoceles under microscopy can be safely performed by a skilled andrologist with most patients subsequently experiencing an improvement in semen quality. This is the first case in which obstructive azoospermia occurred after high inguinal varicocelectomy. The vas deferens was disrupted near the internal inguinal ring by fibrous tissue. A vasovasostomy was performed and semen parameters subsequently recovered.

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Overall survival of first-line axitinib in metastatic renal cell carcinoma

Oya Mototsugu, Tomita Yoshihiko, Fukasawa Satoshi, Shinohara Nobuo, Habuchi Tomonori, Rini Brian I., Fujii Yosuke, Kamei Yoichi, Umeyama Yoshiko, Bair Angel H., Uemura Hirotsugu

Cancer Science 2017

ISSN 1347-9032

Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6 months in treatment-naïve Japanese patients with metastatic renal cell carcinoma (RCC). This analysis evaluated overall survival (OS) and safety in 44 Japanese patients and compared the results with 169 non-Japanese patients. In addition, baseline characteristics for predictive factors that may influence OS in first-line metastatic RCC were explored in all patients using a Cox proportional hazard model. With median follow-up of 33 months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8 months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9 months (95% CI, 28.9-42.7). Estimated 1-year, 2-year and 3-year survival probability (95% CI) was 86.4% (76.2-96.5), 75.0% (62.2-87.8) and 68.2% (54.4-81.9), respectively, in Japanese patients, and was higher than that in non-Japanese patients (75.1% [68.4-81.8], 62.1% [54.5-69.7] and 47.2% [39.3-55.1], respectively). The updated safety analysis did not reveal any new adverse events of concern among Japanese or non-Japanese patients. The multivariate analysis identified that lower baseline Eastern Cooperative Oncology Group performance status, lower baseline tumor burden, and longer time from histopathological diagnosis to treatment were significant positive predictors of OS. The current analysis confirmed the clinical activity of axitinib in treatment-naïve Japanese patients with metastatic RCC, with an acceptable toxicity profile.

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Cost analysis of leuprorelin acetate in Japanese prostate cancer patients: comparison between 6-month and 3-month depot formulations

Goto, Rei, Uda, Akihito, Hiroi, Shinzo, Iwasaki, Kosuke, Takashima, Kenta, Oya, Mototsugu

JOURNAL OF MEDICAL ECONOMICS (TAYLOR & FRANCIS LTD) 20 ( 11 ) 1155 - 1162 2017

Research paper (scientific journal), ISSN 1369-6998

© 2017 Informa UK Limited, trading as Taylor & Francis Group. Aims: This study aimed to evaluate the economic value for leuprorelin acetate 6-month depot compared with leuprorelin acetate 3-month depot from a societal perspective in Japanese prostate cancer patients. Methods: The cost analysis estimated the reduction in direct and indirect costs as well as intangible costs saved by having one less injection. Claims data were used for the analyses of direct and indirect costs reduction. A discrete choice experiment based on a web-based survey estimated the monetary value of the intangible costs for one injection. Another web-based survey of prostate cancer patients, who had received treatment with leuprorelin acetate injections, was carried out to calibrate the results of the discrete choice experiment. Results: Reductions in medical costs and loss of productivity for having one less injection in prostate cancer patients receiving leuprorelin acetate were JPY 5,670 and JPY 1,723, respectively. Intangible costs saved by using a 6-month depot formulation instead of a 3-month depot formulation for the injection of leuprorelin acetate were estimated to be JPY 19,872, including the values for a reduction in pain (JPY 3,131), injection site reactions (JPY 11,545), waiting time (JPY 9,479), and subtracting the value of medical consultation (JPY 4,283). The total cost reduction for having one less injection was JPY 27,265. Limitations: The respondents from the internet panel provided by a survey company are not necessarily a representative population of Japanese society. Conclusions: Leuprorelin acetate 6-month depot has an advantage in monetary value in the reduction in medical costs, loss of productivity, and intangible costs for having one less injection in prostate cancer patients compared with leuprorelin acetate 3-month depot. In the costs for treating with leuprorelin acetate, the percentage of intangible costs might not be negligible. The intangible costs will probably be actively evaluated to proceed to patient-centered healthcare in society.

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Ra-223 SPECT for semi-quantitative analysis in comparison with Tc-99m HMDP SPECT

Owaki Yoshiki, Nakahara Tadaki, Kosaka Takeo, Fukada Junichi, Kumabe Atsuhiro, Ichimura Akira, Murakami Mikoto, Nakajima Kiyotaka, Fukushi Masahiro, Inoue Kazumasa, Oya Mototsugu, Jinzaki Masahiro

EJNMMI Research 7 2017

ISSN 2191-219X

Background: Image-based measurement of absorbed dose of Ra-223 dichloride may be useful in predicting therapeutic outcome in patients with castration-resistant prostate cancer (CRPC). In general, SPECT has been found to be more accurate than planar imaging in terms of lesion-based analysis. The aims of this study were to assess the feasibility and clinical usefulness of Ra-223 SPECT. The energy spectrum of Ra-223 and SPECT images of a cylindrical phantom with a hot rod were obtained to determine the collimator candidates and energy window settings suitable for clinical Ra-223 SPECT (basic study A). Another phantom with a tube-shaped chamber and two spheres simulating bowel activity and metastatic lesions in the lumbar spine was scanned with medium-energy general-purpose (MEGP) and high-energy general-purpose (HEGP) collimators (basic study B). Ten patients with CRPC underwent SPECT imaging 2 h after Ra-223 injection successively with MEGP and HEGP collimators in random order for 30 min each. Lesion detectability and semi-quantitative analyses of bone metastasis (i.e. lesion-to-background ratio (LBR)) were performed compared to Tc-99m HMDP SPECT. Results: Basic study A revealed that an 84-keV photopeak ± 20% using the HEGP collimator offers better SPECT image quality than the other imaging conditions. Basic study B showed that uptake in one of the spheres was overestimated by overlapped activity of the tube-shaped chamber in planar imaging whereas the spheres had similar counts and significantly higher sphere-to-background ratio in SPECT. On both planar and SPECT images, HEGP gave higher image contrast than MEGP (p < 0.01). In the clinical study, Ra-223 SPECT at 84 keV ± 20% depicted more lesions with the HEGP than with the MEGP collimator (51 vs 36, p = 0.013). There was a positive correlation between LBR in Tc-99m SPECT and in Ra-223 SPECT (r = 0.67 with the MEGP and 0.69 with the HEGP collimator, p < 0.01). LBRs were significantly higher with the HEGP than with the MEGP collimator (p < 0.01). Conclusions: We recommended the use of the HEGP collimator at 84 keV ± 20% for Ra-223 SPECT imaging. Lesion-based semi-quantitative analysis in the human study revealed a good correlation between Ra-223 and Tc-99m HMDP SPECT in the early phase (2–3 h post injection).

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Reactive oxygen species induction by cabazitaxel through inhibiting Sestrin-3 in castration resistant prostate cancer

Kosaka Takeo, Hongo Hiroshi, Miyazaki Yasumasa, Nishimoto Koshiro, Miyajima Akira, Oya Mototsugu

Oncotarget (IMPACT JOURNALS LLC) 8 ( 50 ) 87675 - 87683 2017

ISSN 1949-2553

Reactive oxygen species (ROS) production induced by taxanes in cancer cells may influence the taxane-induced cell death or the drug resistance. We investigated the correlation between the cytotoxic effect of taxanes and ROS production in human castration-resistant prostate cancer (CRPC) cell lines. Three human prostate cancer cell lines were treated with increasing concentrations of docetaxel or cabazitaxel in vitro. Cabazitaxel showed significantly higher cytotoxic efficacy than docetaxel in human CRPC cells, accompanied by elevated ROS production detected by FACS analysis. To investigate whether cabazitaxel-mediated cell death was caused by the ROS generation induced by cabazitaxel, we treated CRPC cells in the presence of antioxidant NAC. NAC reduced the cytotoxic effect induced by cabazitaxel. We found that ROS elimination by Sestrin-3 (SESN3) was significantly inhibited by cabazitaxel, but not by docetaxel. These results indicate higher sensitivity of human CRPC to cabazitaxel compared to docetaxel involves ROS production through inhibiting the expression of antioxidant enzyme SESN3.

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Renal dysfunction caused by urological cancer

Matsumoto Kazuhiro, Oya Mototsugu

Japanese Journal of Nephrology 59 ( 5 ) 606 - 609 2017

ISSN 0385-2385

Prognostic significance of erythrocyte protein band 4.1-like5 expression in upper urinary tract urothelial carcinoma

Daimon Tatsuaki, Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyazaki Yasumasa, Hashimoto Ari, Hashimoto Shigeru, Mizuno Ryuichi, Miyajima Akira, Okada Yasunori, Sabe Hisataka, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2016.12

ISSN 1078-1439

Objectives: The erythrocyte protein band 4.1-like5 (EPB4.1L5) regulates E-cadherin in cancer invasion and metastasis inducing epithelial-to-mesenchymal transition. This study aimed to investigate the biological significance of EPB4.1L5 in upper urinary tract urothelial carcinoma (UTUC). Methods: Retrospective analysis of the clinical records of 165 patients with UTUC (Ta-4N0M0) subjected to radical nephroureterectomy and immunohistochemical examination of EPB4.1L5 expression in those tissues. Results: The median follow-up period was 62.2 months (interquartile range = 77.0). The score of EPB4.1L5 significantly correlated with tumor grade, pathological T stage, and lymphovascular invasion (all P<0.001). The 5-year Kaplan-Meier recurrence-free survival and cancer-specific survival rates were 54.1% and 59.5% in patients with high EPB4.1L5 expression, compared with 81.6% and 87.2%, (all P<0.001) in their counterparts. Multivariate analyses revealed that high expression of EPB4.1L5 was one of the independent prognostic factors for tumor recurrence (P = 0.022, HR = 2.40) and cancer-specific survival (P = 0.015, HR = 2.94). Conclusion: High EPB4.1L5 expression was related to worse clinical outcome in patients with UTUC. These results indicated that EPB4.1L5 could provide prognostic information in patients with UTUC regarding epithelial-to-mesenchymal transition.

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Influence of physician years on urological journal publication productivity among Japanese urologists

Niwa Naoya, Kikuchi Eiji, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

SpringerPlus 5 ( 1 ) 2016.12

ISSN 2193-1801

Purpose: To evaluate the urological journal publication productivity of Japanese urologists based on their physician years. Methods: All original articles written by Japanese urologists and published from Japanese institutions in 6 primary urological journals between 2010 and 2014 were reviewed (N = 529 articles). Results: The median post-graduate years of the first and corresponding authors of all articles were 16 and 21 years, respectively. The publication productivities of the first and corresponding authors peaked from 11 to 15 and both 16–20 and 21–25 post-graduate years, respectively. In 187 publications in which the first and corresponding authors were different, first and corresponding author publication productivities peaked from 11 to 15 and 21–25 post-graduate years, respectively. In 342 publications in which the first author served as the corresponding author, first author publication productivity peaked from 16 to 20 post-graduate years. Of all articles examined, 130 (24.6%) were written by young urologists who had obtained their national medical license not less than 11 years ago. Only 0.9% (5/529) of all articles were written by female Japanese urologists, who account for 5.0% (332/6,649) of all Japanese Board Certified Urologists. Conclusions: The present study revealed that from 11 to 15 post-graduate years was the most productive time for Japanese urologists as the first author of urological publications and also that the role in manuscript preparation changed with increases in physician years. These results provide an insight into reconstructing future post-graduate training and educational urological programs in Japan.

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Overall Survival Analysis From a Randomized Phase II Study of Axitinib With or Without Dose Titration in First-Line Metastatic Renal Cell Carcinoma

Rini, Brian I., Tomita, Yoshihiko, Melichar, Bohuslav, Ueda, Takeshi, Gruenwald, Viktor, Fishman, Mayer N., Uemura, Hirotsugu, Oya, Mototsugu, Bair, Angel H., Andrews, Glen I., Rosbrook, Brad, Jonaschl, Eric

CLINICAL GENITOURINARY CANCER 14 ( 6 ) 499 - 503 2016.12

Research paper (scientific journal), ISSN 1558-7673

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Influence of physician years on urological journal publication productivity among Japanese urologists

Niwa, Naoya, Kikuchi, Eiji, Matsumoto, Kazuhiro, Miyajima, Akira, Oya, Mototsugu

SPRINGERPLUS 5 134 - 139 2016.11

Research paper (scientific journal), ISSN 2193-1801

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Plasma fibrinogen level

Obata Jun, Tanaka Nobuyuki, Mizuno Ryuichi, Kanao Kent, Mikami Shuji, Matsumoto Kazuhiro, Kosaka Takeo, Kikuchi Eiji, Jinzaki Masahiro, Oya Mototsugu

BJU International 118 ( 4 ) 598 - 603 2016.10

ISSN 1464-4096

Objectives: To investigate the impact of perioperative plasma fibrinogen level as a biomarker of oncological outcome in localised renal cell carcinoma (RCC). Patients and methods: We consecutively identified 601 patients with localised RCC who underwent curative surgery at a single institution. Subsequent disease recurrence and cancer-specific survival (CSS) were assessed using the Kaplan–Meier method. To evaluate the independent prognostic impact of plasma fibrinogen level, multivariate analysis was performed for these outcomes. Results: Using the defined threshold level of preoperative plasma fibrinogen of ≥420 mg/dL as elevated, we found 56 patients (9.3%) with an elevated plasma fibrinogen level preoperatively. In Kaplan–Meier analysis, there was a significant difference in disease-free survival and CSS rates between patients with and without preoperative plasma fibrinogen levels of ≥420 mg/dL. Multivariate analysis showed that elevated preoperative plasma fibrinogen level was an independent predictor of subsequent disease recurrence and cancer-specific mortality. In a subgroup analysis of the elevated preoperative plasma fibrinogen level group, postoperative normalisation of plasma fibrinogen level was significantly associated with CSS, showing that patients with non-normalised plasma fibrinogen levels tended to have a higher incidence of cancer-specific mortality after surgery. Conclusion: Patients with elevated preoperative plasma fibrinogen levels could be significantly predicted to have subsequent tumour metastasis and cancer-specific mortality, while there was a significant difference in CSS between patients in the normalised and non-normalised postoperative plasma fibrinogen groups. While these are hypothesis generating results, plasma fibrinogen levels may be a useful biomarker due to its low cost and ease of assessment.

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The Preoperative Neutrophil-to-lymphocyte Ratio is a Novel Biomarker for Predicting Worse Clinical Outcomes in Non-muscle Invasive Bladder Cancer Patients with a Previous History of Smoking

Ogihara Koichiro, Kikuchi Eiji, Yuge Kazuyuki, Yanai Yoshinori, Matsumoto Kazuhiro, Miyajima Akira, Asakura Hirotaka, Oya Mototsugu

Annals of Surgical Oncology 1 - 9 2016.09

ISSN 1068-9265

Purpose: We speculated that a heterogeneous population of non-muscle invasive bladder cancer (NMIBC) patients with a previous history of smoking may be more precisely stratified by a biomarker associated with tumor aggressiveness and then focused on the preoperative neutrophil-to-lymphocyte ratio (pre-NLR), which is a simple index of systemic inflammation. Methods: Our study population comprised 605 patients initially diagnosed with NMIBC at our 3 institutions between 1995 and 2013. We analyzed the relationships between pre-NLR levels and clinical outcomes in NMIBC. A pre-NLR level of ≥2.2 was defined as elevated according to a calculation by a receiver-operating curve analysis. Results: In overall, a total of 296 patients (48.9 %) had pre-NLR ≥ 2.2, and the pre-NLR level was one of independent risk factors for tumor recurrence and stage progression. Among 344 patients with a previous history of smoking, 184 (53.5 %) had pre-NLR ≥ 2.2 and the pre-NLR level was one of independent risk factors for tumor recurrence and stage progression. The 5-year recurrence-free survival and progression-free survival rates in patients with pre-NLR < 2.2 were 66.3 and 97.5 %, respectively, which were significantly higher than those in their counterparts (31.7 and 90.4 %, p < 0.001). In either subgroup of patients who were current smokers (N = 175) or former smokers (N = 169), the pre-NLR level was the only independent risk factor for tumor recurrence. The pre-NLR level was not associated with tumor recurrence or stage progression in 261 nonsmoking patients. Conclusions: Pre-NLR levels may be a useful marker for identifying worse clinical outcomes in NMIBC patients, particularly those with a previous history of smoking.

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Urinary pH Levels are Strongly Associated with Bladder Recurrence After Nephroureterectomy in Upper Tract Urothelial Carcinoma Patients with a Smoking History

Ide Hiroki, Kikuchi Eiji, Hagiwara Masayuki, Hayakawa Nozomi, Hongo Hiroshi, Miyajima Akira, Oya Mototsugu

Annals of Surgical Oncology 1 - 10 2016.09

ISSN 1068-9265

Purpose: Aromatic amines, well-known bladder carcinogens, derived from cigarette smoke are activated by acidic urine. We herein determined whether urinary pH levels are associated with bladder recurrence in upper tract urothelial carcinoma patients with a positive smoking history. Methods: A total of 256 upper tract urothelial carcinoma patients who were surgically treated at our institution between 1990 and 2013 were included. Urinary pH levels were defined as the median of at least two consecutive measurements within 1 month of surgery. Results: Ninety-six patients (37.5 %) had pH <5.5 and 160 (62.5 %) had pH ≥5.5, and urinary pH levels were identified as one of the significant predictors for bladder recurrence in univariate but not multivariate Cox regression analysis in overall. In patients with a positive smoking history among those without a history of bladder tumor (N = 110), the 5-year bladder recurrence-free survival rate was 52.5 % in patients with pH ≥5.5, which was significantly higher than that in those with pH <5.5 (25.9 %, p = 0.032). In the multivariate analysis, urinary pH <5.5 (p = 0.022, HR; 1.86) was independently associated with bladder recurrence. No significant difference for bladder recurrence was observed between these two groups in patients with no smoking history among them. Conclusions: Urinary pH <5.5 is associated with an increased risk of bladder recurrence in upper tract urothelial carcinoma patients with a positive smoking history among those without a history of bladder tumor. Modifications to pH for urine alkalization may prevent bladder recurrence.

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Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant

Morita Shinya, Shinoda Kazunobu, Tamaki Satoshi, Kono Hidaka, Asanuma Hiroshi, Nakagawa Ken, Oya Mototsugu

Journal of Clinical Virology 82 133 - 138 2016.09

ISSN 1386-6532

Ganciclovir-resistant cytomegalovirus infection is sometimes life-threatening for organ transplant recipients. Foscarnet is an alternative, although it may potentially worsen the preexistent impaired renal function. Here we report the case of a successful low-dose leflunomide treatment in a kidney transplant recipient with very high viral replication, who underwent kidney transplantation 10 years before. Administering 10 mg leflunomide daily for 5 months without a loading dose completely cleared the ganciclovir-resistant cytomegalovirus strains.

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Successful low-dose leflunomide treatment for ganciclovir-resistant cytomegalovirus infection with high-level antigenemia in a kidney transplant: A case report and literature review

Morita, Shinya, Shinoda, Kazunobu, Tamaki, Satoshi, Kono, Hidaka, Asanuma, Hiroshi, Nakagawa, Ken, Oya, Mototsugu

JOURNAL OF CLINICAL VIROLOGY 82 133 - 138 2016.09

Research paper (scientific journal), ISSN 1386-6532

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Tumor budding, a novel prognostic indicator for predicting stage progression in T1 bladder cancers

Fukumoto, Keishiro, Kikuchi, Eiji, Mikami, Shuji, Ogihara, Koichiro, Matsumoto, Kazuhiro, Miyajima, Akira, Oya, Mototsugu

CANCER SCIENCE 107 ( 9 ) 1338 - 1344 2016.09

Research paper (scientific journal), ISSN 1347-9032

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External Validation of the MSKCC and IMDC Risk Models in Patients Treated with Targeted Therapy as a First-line and Subsequent Second-line Treatment

Tanaka Nobuyuki, Mizuno Ryuichi, Ito Keiichi, Shirotake Suguru, Yasumizu Yota, Masunaga Ayako, Ito Yujiro, Miyazaki Yasumasa, Hagiwara Masayuki, Kanao Kent, Mikami Shuji, Nakagawa Ken, Momma Tetsuo, Masuda Takeshi, Asano Tomohiko, Oyama Masafumi, Oya Mototsugu

European Urology Focus 2 ( 3 ) 303 - 309 2016.08

ISSN 2405-4569

Background Two risk models, the Memorial Sloan Kettering Cancer Center (MSKCC) model and the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model, have been studied in metastatic renal cell carcinoma (mRCC) treated with targeted therapy. Objective To validate externally the predictive accuracies of the MSKCC and IMDC models for prognosis in mRCC patients treated with first-line and subsequent second-line targeted therapy. Design, setting, and participants A total of 311 patients were assessed retrospectively. Intervention All patients underwent targeted therapy. Outcome measurements and statistical analysis Survival outcomes were assessed using Kaplan-Meier analysis. The predictive ability was evaluated using the c-index. Results and limitations Regarding to the first-line targeted therapy, the 3-yr overall survival (OS) rates of the MSKCC (p < 0.001) and IMDC models (p < 0.001) were 76.2% and 77.3%, respectively, in the favorable-risk group; 46.7% and 47.9%, respectively, in the intermediate-risk group; and 13.4% and 15.6%, respectively, in the poor-risk group. The c-indexes were 0.68 for the MSKCC model and 0.69 for the IMDC model in a first-line setting. Regarding the second-line targeted therapy, the 1-yr OS rates of the MSKCC (p < 0.001) and IMDC models (p < 0.001) were 80.9% and 90.5%, respectively, in the favorable-risk group; 71.4% and 70.6%, respectively, in the intermediate-risk group; and 31.7% and 24.6%, respectively, in the poor-risk group. The c-indexes were 0.66 for the MSKCC model and 0.65 for the IMDC model in the second-line setting. The study is limited by its retrospective nature. Conclusions The results may assist physicians in providing more appropriate patient counseling and imply the need for a future prognostic tool in mRCC treated with targeted therapy. Patient summary Both risk models were useful for the risk stratification in metastatic renal cell carcinoma (mRCC) patients treated with first-line and second-line targeted therapy; however, it might be necessary to further update or optimize the models for our Japanese cohort of mRCC patients.

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Clinical practice patterns for upper tract urothelial carcinoma

Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Oncology 46 ( 8 ) 768 - 774 2016.08

ISSN 0368-2811

Objective: A comprehensive survey has not yet been conducted to investigate care patterns by urologists for the management of upper tract urothelial carcinoma.Methods: We conducted a nationwide survey for urologists treating upper tract urothelial carcinoma patients. The questionnaire was approved by the Japanese Urological Association and sent by mail in February 2014 to 1119 institutes in Japan. We identified 627 responders for this study.Results: Our survey demonstrated that (i) the mean number of radical nephroureterectomy cases per institution in 2013 was 7.6, (ii) the main detecting tool for upper tract urothelial carcinoma is contrast-enhanced computed tomography, (iii) the need for ureteroscopic evaluations is highly dependent on voiding urine cytology results, (iv) 67% of urologists always or often perform radical nephroureterectomy by laparoscopic surgery, (v) more than half of the urologists do not aggressively perform lymph node dissection, (vi) 75% of the urologists perform bladder cuff incision through an extravesical approach, (vii) urologists perform kidney-sparing surgery following various indications, (viii) 59% of the urologists always perform adjuvant systemic chemotherapy for high-risk upper tract urothelial carcinoma patients, (ix) the combination of gemcitabine and cisplatin is the most frequent chemo-regimen for metastatic upper tract urothelial carcinoma, and gemcitabine and cisplatin with dose reductions is also the first choice even in patients with impaired renal function and (x) 10.5% of urologists always or sometimes perform single intravesical chemotherapy immediately after radical nephroureterectomy.Conclusions: The management strategy for upper tract urothelial carcinoma has changed with the introduction of new devices and development of instruments. The lack of clear evidence for relatively uncommon upper tract urothelial carcinoma affects the consistency of its treatment strategies.

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High Absolute Monocyte Count Predicts Poor Clinical Outcome in Patients with Castration-Resistant Prostate Cancer Treated with Docetaxel Chemotherapy

Shigeta Keisuke, Kosaka Takeo, Kitano Shigehisa, Yasumizu Yota, Miyazaki Yasumasa, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Tanoguchi Hitoshi, Hasegawa Shintaro, Oya Mototsugu

Annals of Surgical Oncology 1 - 8 2016.06

ISSN 1068-9265

Background: The association of peripheral monocyte count and prostate cancer progression is not well characterized. Objective: Our aim was to investigate the prognostic value of absolute monocyte count (AMC), which is thought to modulate immune response in the tumor microenvironment, in castration-resistant prostate cancer (CRPC) patients treated with docetaxel chemotherapy. Methods: We retrospectively reviewed the medical records of 214 CRPC patients who received docetaxel therapy and were used as the training and validation set. Docetaxel at a dose of 75 mg/m² was administered every 3 or 4 weeks. Clinicopathological factors and laboratory data were collected to assess the prognostic factors for overall survival (OS) and progression-free survival (PFS). Results: In the training set, the median age was 73.0 years, and the median prostate-specific antigen (PSA) value was 31.7 ng/ml at initial treatment. The median OS and PFS were 23.0 months (range 1.20–84.0) and 11.2 months (range 3.6–78.0), respectively. According to multivariable Cox regression analysis, AMC ≥400/uL, PSA level ≥20 ng/ml, and Hb

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Testicular torsion

Asanuma Hiroshi, Oya Mototsugu

355 - 358 2016.06

Testicular torsion occurs most often in the neonatal period and around puberty. Perinatal testicular torsion mostly occurs extravaginally in the prenatal period. On the other hand, pubertal torsion usually occurs intravaginally and requires prompt surgical treatment. The degree of cord twisting and the time between onset of symptoms and detorsion are most important factors to decide early salvage rate of the testis. In order to revive blood supply until operation, consider manual detorsion by rotation from within outward in pubertal boys with intravaginal torsion. If the color of the testis recovers after untwisting it, orchiopexy is performed in the dartos pouch with at least three places of fixation using nonabsorbable sutures. In all cases, contralateral orchiopexy should be done to prevent future torsion. Patients would need a long-term follow-up mainly for fertility and hormonal issues.

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Pyeloplasty

Asanuma Hiroshi, Oya Mototsugu

301 - 304 2016.06

The widespread use of ultrasonography during pregnancy has resulted in a higher detection rate for antenatal hydronephrosis. Ureteropelvic junction obstruction is the most common pathological cause of neonatal hydronephrosis. Surgical indications for this hydronephrosis comprise a decrease of split renal function (>5 %) on renography or increased dilatation on ultrasonography in subsequent studies, or existence symptoms such as breakthrough urinary tract infection or the abdominal pain during follow-up. The Anderson-Hynes dismembered method has been adopted most widely now. It is available in any cases with ureteropelvic junction obstruction due to intrinsic or extrinsic stenosis or high insertion. It is key point for the success of pyeloplasty to anastomose the apex of caudal angle of the renal pelvis and the crotch of the spatulated ureter with five sutures as knock stitch and come the funnel shape with the double pigtail stent finally. Remove the stent 2-3 months postoperatively under cystoscopy. Evaluate renal pelvic dilatation and split renal function 6 months postoperatively. Success pyeloplasty should be defined as no symptom, reduced pelvic dilatation, and stable or improved split renal function compared to preoperative condition.

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Suprapubic cystostomy and vesicocutaneostomy

Asanuma Hiroshi, Oya Mototsugu

315 - 319 2016.06

Suprapubic cystostomy and vesicocutaneostomy continue to be used frequently as temporary vesical diversion in pediatric patients who develop urethral obstruction (posterior urethral valves, cloacal anomalies, urethral trauma), recurrent urinary tract infection with severe vesicoureteral reflux, or neurogenic bladder associated with spina bifida not responsive to clean intermittent catheterization. Vesicocutaneostomy is more appropriate for long-term usage because of no catheter. Suprapubic cystostomy is usually inserted into the bladder using Seldinger method in young children. Blocksom's method is easier and has been widely used in vesicocuta- neostomy. It is important to evaluate bladder capacity and superior border of full bladder for adequate stoma marking and not to place the stoma in a position which is too large and too low to prevent bladder prolapse. The decision to close a vesicocutaneostomy should be made only once the bladder function has been assessed and permanent therapy has been planned.

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Patient age was an independent predictor of cancer-specific survival in male patients with upper tract urothelial carcinoma treated by radical nephroureterectomy

Kobayashi Hiroaki, Kikuchi Eiji, Tanaka Nobuyuki, Shirotake Suguru, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Matsumoto Kazuhiro, Kaneko Gou, Hagiwara Masayuki, Kosaka Takeo, Oyama Masafumi, Nakajima Yosuke, Oya Mototsugu

Japanese Journal of Clinical Oncology 46 ( 6 ) 554 - 559 2016.06

ISSN 0368-2811

Objective: We hypothesized that there may be a prognostic difference in age between the genders and evaluated the influence of gender-adjusted age on prognosis in upper tract urothelial carcinoma patients. Methods: A total of 839 patients with upper tract urothelial carcinoma from a retrospective multi-institutional cohort were included. The patients were divided into four groups consisting of males (N = 610) and females (N = 229) according to age ((i) <60 years, (ii) 60-69.9 years, (iii) 70-79.9 years and (iv) ≥ 80 years), and we evaluated the associations of patient age and gender with clinicopathological features and oncological outcomes following radical nephroureterectomy. The median follow-up duration was 34 months. Results: Disease recurrence occurred in 249 patients and 192 patients died of upper tract urothelial carcinoma. The 3-year cancer-specific survival rates were (i) 84.3%, (ii) 80.2%, (iii) 77.1% and (iv) 71.5% in the entire patient population (P = 0.001); (i) 84.5%, (ii) 81.1%, (iii) 76.8% and (iv) 69.7% in males (P = 0.010); and (i) 83.3%, (ii) 76.9%, (iii) 77.7% and (iv) 72.9% in females (P = 0.287), respectively. No significant differences between disease recurrence and age were found in the male or female population. In multivariate analysis, older age was an independent predictor of cancer-specific survival, in addition to advanced pT stage, the presence of lymphovascular invasion and lymph node involvement in males. In contrast, age was not associated with cancer-specific survival in females, while high grade, advanced pT stage, the presence of lymph node involvement and multifocal tumor were independent predictors. Conclusion: The results indicate that gender-adjusted age might be a new prognostic factor in upper tract urothelial carcinoma patients.

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IJU this issue

Oya Mototsugu

International Journal of Urology 23 ( 6 ) 453 2016.06

ISSN 0919-8172

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Technical improvement using a three-dimensional video system for laparoscopic partial nephrectomy

Komatsuda Akari, Matsumoto Kazuhiro, Miyajima Akira, Kaneko Gou, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

Asian Pacific Journal of Cancer Prevention 17 ( 5 ) 2475 - 2478 2016.06

ISSN 1513-7368

Background: Laparoscopic partial nephrectomy is one of the major surgical techniques for small renal masses. However, it is difficult to manage cutting and suturing procedures within acceptable time periods. To overcome this difficulty, we applied a three-dimensional (3D) video system with laparoscopic partial nephrectomy, and evaluated its utility. Materials and Methods: We retrospectively enrolled 31 patients who underwent laparoscopic partial nephrectomy between November 2009 and June 2014. A conventional two-dimensional (2D) video system was used in 20 patients, and a 3D video system in 11. Patient characteristics and video system type (2D or 3D) were recorded, and correlations with perioperative outcomes were analyzed. Results: Mean age of the patients was 55.8±12.4, mean body mass index was 25.7±3.9 kg/m², mean tumor size was 2.0±0.8 cm, mean R.E.N.A.L nephrometry score was 6.9±1.9, and clinical stage was T1a in all patients. There were no significant differences in operative time (p=0.348), pneumoperitoneum time (p=0.322), cutting time (p=0.493), estimated blood loss (p=0.335), and Clavien grade of > II complication rate (p=0.719) between the two groups. However, warm ischemic time was significantly shorter in the 3D group than the 2D group (16.1 min vs. 21.2min, p=0.021), which resulted from short suturing time (9.1 min vs. 15.2 min, p=0.008). No open conversion occurred in either group. Conclusions: A 3D video system allows the shortening of warm ischemic time in laparoscopic partial nephrectomy and thus may be useful in improving the procedure.

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A prospective longitudinal survey of erectile function status in symptomatic benign prostatic hyperplasia patients treated with dutasteride

Maeda, Takahiro, Kikuchi, Eiji, Hasegawa, Masanori, Ando, Toshiyuki, Matsushima, Masashi, Yuge, Kazuyuki, Ito, Yujiro, Miyajima, Akira, Oya, Mototsugu

AGING MALE 19 ( 2 ) 111 - 116 2016.06

Research paper (scientific journal), ISSN 1368-5538

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Stem cell biology in prostate cancer

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 74 65 - 70 2016.05

ISSN 0047-1852

Risk factors in localized prostate cancer

Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 74 161 - 165 2016.05

ISSN 0047-1852

The learning curve of laparoendoscopic single-site adrenalectomy

Fukumoto Keishiro, Miyajima Akira, Hattori Seiya, Matsumoto Kazuhiro, Abe Takayuki, Kurihara Isao, Jinzaki Masahiro, Kikuchi Eiji, Oya Mototsugu

Surgical Endoscopy and Other Interventional Techniques 1 - 8 2016.05

ISSN 0930-2794

Background: Recently, laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an alternative treatment for adrenal tumors. Although LESS-A is more technically complex than conventional laparoscopic adrenalectomy, its learning curve and the factors associated with poor surgical outcomes are poorly understood. We analyzed the learning curve of LESS-A and attempted to identify risk factors associated with worse surgical outcomes. Methods: We identified 103 patients who underwent LESS-A [performed by the same surgeon (A.M.)] from 2009 to 2015. The learning curve was analyzed using the moving average method (the 10-case moving average), and we assessed potential risk factors for a prolonged pneumoperitoneum time. Results: The learning curve stabilized at 30 cases. The cases were divided into two groups, the learning stage (LS) (cases 1–29) and master stage (MS) (cases 30–103) groups. The percentage of females and the frequency of previous abdominal surgery were higher in the LS group (p = 0.022 and 0.001, respectively). In the LS group, the mean pneumoperitoneum time was 92 ± 35 min, which was significantly longer than the equivalent value for the MS group (55 ± 18 min, p <0.001). In the LS group, univariate analysis revealed that tumor size (≥50 mm) and the visceral fat area (VFA)/total fat area (TFA) ratio (≥0.49) were significantly associated with a prolonged pneumoperitoneum time (p = 0.046 and 0.046, respectively). In the multivariate analysis, tumor size and the VFA/TFA ratio were confirmed to be associated with a prolonged pneumoperitoneum time (p = 0.029 and 0.029, odds ratio 20.83 and 20.83, respectively). On the other hand, none of the examined factors were found to be associated with a prolonged pneumoperitoneum time in the MS group. Conclusions: LESS-A was performed safely in most cases. However, surgeons who are learning the LESS-A procedure need to pay attention to tumor size and visceral obesity.

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Little impact on renal function in advanced renal cell carcinoma patients treated with sorafenib-analyses of postmarketing surveillance in Japan in over 3, 200 consecutive cases

Oya Mototsugu, Tatsugami Katsunori, Kabu Koki, Adachi Masatoshi, Ito Yuichiro, Akaza Hideyuki

Japanese Journal of Cancer and Chemotherapy 43 ( 5 ) 559 - 569 2016.05

ISSN 0385-0684

Background: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance. Methods: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR):G1 (eGFR≥90), G2 (eGFR≥60- <90), G3a (eGFR≥45-<60), G3b (eGFR≥30-<45), G4 (eGFR≥15-<30), and G5 (eGFR<15). A total of 3, 255 and 3, 171 patients were included in this analysis for safety and efficacy, respectively. Results: The mean eGFRs (mL/min/1.73 m²) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726mg (G1), 522mg (G2), 524mg (G3a), 517mg (G3b), 483mg (G4), and 400mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4and G5 groups (9% and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. Oneyear survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%). Conclusions: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

Little Impact on Renal Function in Advanced Renal Cell Carcinoma Patients Treated with Sorafenib--Analyses of Postmarketing Surveillance in Japan in over 3,200 Consecutive Cases

Oya Mototsugu, Tatsugami Katsunori, Kabu Koki, Adachi Masatoshi, Ito Yuichiro, Akaza Hideyuki

Gan to kagaku ryoho. Cancer & chemotherapy 43 ( 5 ) 559 - 569 2016.05

ISSN 0385-0684

BACKGROUND: To assess the effect of sorafenib on renal function in patients with advanced renal cell carcinoma (RCC) included in a postmarketing surveillance.METHODS: All patients in Japan with advanced RCC treated with sorafenib between February 2008 and September 2009 were followed for 12 months. Baseline characteristics, renal function, survival, safety, and dosage were stratified according to baseline estimated glomerular filtration rate (eGFR): G1 (eGFR≥90), G2 (eGFR≥60-RESULTS: The mean eGFRs (mL/min/1.73 m2) were not substantially changed for each group at baseline and 12 months, respectively. Median daily doses of sorafenib were 726 mg (G1), 522 mg (G2), 524 mg (G3a), 517 mg (G3b), 483 mg (G4), and 400 mg (G5). Renal failure, reported as an adverse event, occurred more frequently in the G4 and G5 groups (9%and 3%, respectively) than in other groups. Objective response rates for each subgroup were as follows: G1, 23%; G2, 28%; G3a, 29%; G3b, 26%; G4, 24%; and G5, 18%. One-year survival was higher in the G3a and G3b groups (82% and 78%, respectively) and lower in the G1 group (50%).CONCLUSIONS: This study demonstrated little impact of sorafenib on renal function in advanced RCC patients during the observational period. Patients showed sufficient clinical response and safety irrespective of baseline eGFR value.

The prognostic significance of OCT4 expression in patients with prostate cancer

Kosaka, Takeo, Mikami, Shuji, Yoshimine, Shunsuke, Miyazaki, Yasumasa, Daimon, Tatsuaki, Kikuchi, Eiji, Miyajima, Akira, Oya, Mototsugu

HUMAN PATHOLOGY 51 1 - 8 2016.05

Research paper (scientific journal), ISSN 0046-8177

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Role of computed tomography urography in the clinical evaluation of upper tract urothelial carcinoma

Jinzaki Masahiro, Kikuchi Eiji, Akita Hirotaka, Sugiura Hiroaki, Shinmoto Hiroshi, Oya Mototsugu

International Journal of Urology 23 ( 4 ) 284 - 298 2016.04

ISSN 0919-8172

Intravenous urography has been widely used for the evaluation of upper tract urothelial carcinoma. However, computed tomography urography presently has a higher diagnostic accuracy for upper tract urothelial carcinoma (94.2-99.6%) than intravenous urography (80.8-84.9%), and has replaced intravenous urography as the first-line imaging test for investigating patients with a high risk of upper tract urothelial carcinoma. Although the detection rate for bladder tumors using standard computed tomography urography is not yet high enough to replace cystoscopy, the addition of a 60- to 80-s delayed scan after the administration of contrast material for the whole pelvis improves the detection rate. A drawback to computed tomography urography is the higher radiation dose of 15-35 mSv, compared with a mean effective dose of 5-10 mSv for intravenous urography. Among several approaches to reducing the radiation dose, the use of an iterative reconstruction algorithm is most likely to become an effective solution because of its simplicity. One advantage of computed tomography urography over intravenous urography is its ability to reliably differentiate between upper tract urothelial carcinoma and calculi or blood clots. Computed tomography urography also shows characteristic findings of other benign conditions. These findings, in combination with negative cytology, are very important diagnostic clues for avoiding an unnecessary nephroureterectomy. For the clinical staging, a recent study has reported the high diagnostic accuracy of computed tomography urography with respect to ≥pT3 tumors. The present review shows the current status of computed tomography urography for the evaluation of upper tract urothelial carcinoma.

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Spontaneous Regression of Epstein-Barr Virus-Positive Primary Diffuse Large Cell B-Cell Lymphoma of the Urinary Bladder after the Cessation of Enzalutamide

Ogihara Koichiro, Kosaka Takeo, Kikuchi Eiji, Hongo Hiroshi, Mikami Shuji, Oya Mototsugu

Clinical Genitourinary Cancer 14 ( 2 ) e215 - e218 2016.04

ISSN 1558-7673

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Placebo-Induced Severe Diarrhea in a Patient with Metastatic Castration-Resistant Prostate Cancer Participating in a Double-Blind, Randomized, Phase III International Trial

Niwa Naoya, Kosaka Takeo, Oya Mototsugu

Clinical Genitourinary Cancer 14 ( 2 ) e219 - e220 2016.04

ISSN 1558-7673

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A prospective longitudinal survey of erectile function status in symptomatic benign prostatic hyperplasia patients treated with dutasteride

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Ando Toshiyuki, Matsushima Masashi, Yuge Kazuyuki, Ito Yujiro, Miyajima Akira, Oya Mototsugu

Aging Male 1 - 6 2016.03

ISSN 1368-5538

We prospectively evaluated erectile function (EF) using the Sexual Health Inventory for Men (SHIM) and the erectile hardness score (EHS) as well as urinary statuses using the International Prostate Symptom Score (IPSS) and Overactive Bladder Symptom Score (OABSS) before and 3, 6, and 12 months after a daily treatment with 0.5 mg dutasteride (DUT). Significant improvements were observed in IPSS and OABSS in 98 patients with the DUT treatment, and the effects were similar between 28 patients with potency with baseline SHIM of 8 or greater and 70 severe erectile dysfunction (ED) patients at baseline. In the 28 patients with potency, significant decreases were observed in SHIM and EHS after 3, 6, and 12 months of the DUT treatment, with the severity of ED according to SHIM deteriorating in half of these patients after 12 months of the DUT treatment. Eighteen out of 28 patients (64.3%) with potency at baseline had awareness of the occurrence of ED before the DUT treatment, were younger, and had higher SHIM and EHS just before the DUT treatment than their counterparts. Regular assessments of EF may be needed, especially in younger patients and those with higher levels of EF before the administration of DUT.

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Erectile function status is highly associated with prostate-specific antigen bounce in localized prostate cancer patients treated with permanent prostate brachytherapy

Matsushima Masashi, Kikuchi Eiji, Matsumoto Kazuhiro, Kosaka Takeo, Mizuno Ryuichi, Ohashi Toshio, Mikami Shuji, Miyajima Akira, Shigematsu Naoyuki, Oya Mototsugu

International Journal of Urology 23 ( 3 ) 247 - 252 2016.03

ISSN 0919-8172

Objectives: To examine the relationship between erectile function status and prostate-specific antigen bounce after prostate brachytherapy for localized prostate cancer. Methods: We identified 154 patients who were followed up for at least 24 months after brachytherapy. Erectile function status was assessed prospectively before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15 questionnaire. Prostate-specific antigen bounce was defined as an increase of at least 0.4 ng/mL from a previous prostate-specific antigen level with a subsequent decline equal to, or less than, the initial nadir without treatment. A logistic regression analysis was used to identify a significant set of independent predictors of prostate-specific antigen bounce after brachytherapy. Results: Prostate-specific antigen bounce was observed in 38 (24.7%) men. The prostate-specific antigen bounce group had a higher erectile function domain score, higher orgasmic function domain score, and higher total International Index of Erectile Function-15 score before (at baseline) and after brachytherapy (3, 6, 12, 18, 24 and 36 months after brachytherapy) than their counterparts (P <0.05). Of the 77 patients who completed the International Index of Erectile Function-15 questionnaire 18 months after brachytherapy (the median time of prostate-specific antigen bounce), sexual desire and intercourse satisfaction domain scores, and total International Index of Erectile Function scores 18 months after brachytherapy correlated with the occurrence of prostate-specific antigen bounce. A multivariate analysis identified the intercourse satisfaction domain score 18 months after brachytherapy as an independent indicator for the occurrence of prostate-specific antigen bounce (P = 0.008). Conclusions: International Index of Erectile Function-15 score seems to be correlated with the prostate-specific antigen bounce in prostate cancer patients undergoing brachytherapy, and an occurrence of prostate-specific antigen bounce seems to be more likely in those who are more sexually active.

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Syndrome of inappropriate antidiuretic hormone secretion in a patient with castration-resistant prostate cancer treated with enzalutamide

Yanai, Yoshinori, Matsumoto, Kazuhiro, Niwa, Naoya, Kosaka, Takeo, Kikuchi, Eiji, Miyajima, Akira, Ito, Hiroshi, Oya, Mototsugu

ACTA ONCOLOGICA 55 ( 3 ) 399 - 400 2016.03

Research paper (scientific journal), ISSN 0284-186X

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Impact of novel techniques on minimally invasive adrenal surgery

Pavan Nicola, Autorino Riccardo, Lee Hak, Porpiglia Francesco, Sun Yinghao, Greco Francesco, Jeff Chueh S., Han Deok Hyun, Cindolo Luca, Ferro Matteo, Chen Xiang, Branco Anibal, Fornara Paolo, Liao Chun Hou, Miyajima Akira, Kyriazis Iason, Puglisi Marco, Fiori Cristian, Yang Bo, Fei Guo, Altieri Vincenzo, Jeong Byong Chang, Berardinelli Francesco, Schips Luigi, de Cobelli Ottavio, Chen Zhi, Haber Georges Pascal, He Yao, Oya Mototsugu, Liatsikos Evangelos, Brandao Luis, Challacombe Benjamin, Kaouk Jihad, Darweesh Ithaar

World Journal of Urology 1 - 7 2016.02

ISSN 0724-4983

Objective: To evaluate contemporary international trends in the implementation of minimally invasive adrenalectomy and to assess contemporary outcomes of different minimally invasive techniques performed at urologic centers worldwide. Methods: A retrospective multinational multicenter study of patients who underwent minimally invasive adrenalectomy from 2008 to 2013 at 14 urology institutions worldwide was included in the analysis. Cases were categorized based on the minimally invasive adrenalectomy technique: conventional laparoscopy (CL), robot-assisted laparoscopy (RAL), laparoendoscopic single-site surgery (LESS), and mini-laparoscopy (ML). The rates of the four treatment modalities were determined according to the year of surgery, and a regression analysis was performed for trends in all surgical modalities. Results: Overall, a total of 737 adrenalectomies were performed across participating institutions and included in this analysis: 337 CL (46 % of cases), 57 ML (8 %), 263 LESS (36 %), and 80 RA (11 %). Overall, 204 (28 %) operations were performed with a retroperitoneal approach. The overall number of adrenalectomies increased from 2008 to 2013 (p = 0.05). A transperitoneal approach was preferred in all but the ML group (p <0.001). European centers mostly adopted CL and ML techniques, whereas those from Asia and South America reported the highest rate in LESS procedures, and RAL was adopted to larger extent in the USA. LESS had the fastest increase in utilization at 6 %/year. The rate of RAL procedures increased at slower rates (2.2 %/year), similar to ML (1.7 %/year). Limitations of this study are the retrospective design and the lack of a cost analysis. Conclusions: Several minimally invasive surgical techniques for the management of adrenal masses are successfully implemented in urology institutions worldwide. CL and LESS seem to represent the most commonly adopted techniques, whereas ML and RAL are growing at a slower rate. All the MIS techniques can be safely and effectively performed for a variety of adrenal disease.

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Asia prostate cancer study (A-CaP Study) launch symposium

Akaza Hideyuki, Hirao Yoshihiko, Kim Choung Soo, Oya Mototsugu, Ozono Seiichiro, Ye Dingwei, Cooperberg Matthew, Hinotsu Shiro, Lee Ji Youl, Zhu Gang, Namiki Mikio, Horie Shigeo, Chung Byung Ha, Chen Chung Hsin, Fai Ng Chi, Hakim Lukman, Chiong Edmund, Letran Jason, Umbas Rainy, Suzuki Kazuhiro, Nishimura Kazuo, Ong Teng Aik, Lojanapiwat Bannakij, Wu Tong lin, Kim Wun Jae, Murphy Declan, Ogawa Osamu, Carroll Peter, Naito Seiji, Tsukamoto Taiji

Prostate International 2016.02

ISSN 2287-8882

The Asian Prostate Cancer (A-CaP) Study is an Asia-wide initiative that has been developed over the course of 2 years. The A-CaP Study is scheduled to begin in 2016, when each participating country or region will begin registration of newly diagnosed prostate cancer patients and conduct prognosis investigations. From the data gathered, common research themes will be identified, such as comparisons among Asian countries of background factors in newly diagnosed prostate cancer patients. This is the first Asia-wide study of prostate cancer and has developed from single country research efforts in this field, including in Japan and Korea. The inaugural Board Meeting of A-CaP was held on December 11, 2015 at the Research Center for Advanced Science and Technology, The University of Tokyo, attended by representatives of all participating countries and regions, who signed a memorandum of understanding concerning registration for A-CaP. Following the Board Meeting an A-CaP Launch Symposium was held. The symposium was attended by representatives of countries and regions participating in A-CaP, who gave presentations. Presentations and a keynote address were also delivered by representatives of the University of California San Francisco, USA, and the Peter MacCallum Cancer Centre, Australia, who provided insight and experience on similar databases compiled in their respective countries.

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Relationship Between Increased Expression of the Axl/Gas6 Signal Cascade and Prognosis of Patients with Upper Tract Urothelial Carcinoma

Hattori Seiya, Kikuchi Eiji, Kosaka Takeo, Miyazaki Yasumasa, Tanaka Nobuyuki, Miyajima Akira, Mikami Shuji, Oya Mototsugu

Annals of Surgical Oncology 23 ( 2 ) 663 - 670 2016.02

ISSN 1068-9265

Purpose: Axl, which is in the TAM family of receptor tyrosine kinases, and its ligand, growth arrest-specific gene 6 (Gas6), have been associated with worse prognoses after the surgical treatment of some types of cancers. We herein investigated the biological significance of the protein expression of Axl and Gas6 on the outcomes of patients with upper tract urothelial carcinoma (UTUC). Methods: The protein expression of Axl and Gas6 was evaluated by immunohistochemistry, and their relationships with clinicopathological features were investigated in surgical specimens obtained from 161 patients who had been surgically treated for UTUC. Results: Axl labeling was strong in 67 of 161 (42 %) cases, while Gas6 labeling was strong in 72 of 161 (45 %) cases. The strong expression of Axl correlated with that of Gas6. A high pathological stage (p = 0.009), strong expression of Gas6 (p = 0.038), and strong expression of Axl (p = 0.016) were independent factors for predicting worse cancer-specific survival (CSS). In a subgroup analysis of patients with pT

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Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer

Hashimoto, Shigeru, Mikami, Shuji, Sugino, Hirokazu, Yoshikawa, Ayumu, Hashimoto, Ari, Onodera, Yasuhito, Furukawa, Shotaro, Handa, Haruka, Oikawa, Tsukasa, Okada, Yasunori, Oya, Mototsugu, Sabe, Hisataka

NATURE COMMUNICATIONS 7 399 - 400 2016.02

Research paper (scientific journal), ISSN 2041-1723

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Impact of Second-Line Targeted Therapy Dose Intensity on Patients With Metastatic Renal Cell Carcinoma

Shirotake Suguru, Yasumizu Yota, Ito Keiichi, Masunaga Ayako, Ito Yujiro, Miyazaki Yasumasa, Hagiwara Masayuki, Kanao Kent, Mikami Shuji, Nakagawa Ken, Momma Tetsuo, Masuda Takeshi, Asano Tomohiko, Oyama Masafumi, Tanaka Nobuyuki, Mizuno Ryuichi, Oya Mototsugu

Clinical Genitourinary Cancer 2016.01

ISSN 1558-7673

Background: Relative dose intensity (RDI) is a simple index for evaluation of the amount of drug administered per unit time. We retrospectively investigated the prognostic impact of RDI for patients with metastatic renal cell carcinoma (mRCC) treated with second-line targeted therapy. Methods: We enrolled 168 patients with mRCC. We assessed RDI at 4 weeks after second-line targeted therapy induction. Results: The median follow-up after second-line targeted therapy was 18.1 months. The median time-to-treatment-failure (TTF) and overall survival (OS) were 4.9 and 25.4 months, respectively. In the Kaplan-Meier analysis, the median OS of patients with second-line RDI <0.7 was significantly shorter than those with RDI ≥ 0.7 (12.1 vs. 31.3 months; P = .030). In the subgroup analysis, second-line RDI was definitely prognostic in the poor-risk group of the International Metastatic Renal Cell Carcinoma Database Consortium criteria, showing second-line RDI was an independent predictor for both TTF (hazard ratio [HR], 3.6; 95% confidence interval [CI], 1.6-8.0; P = .002) and OS (HR, 3.1; 95% CI, 1.1-8.4; P = .026). Also, assessing the type of second-line regimen, the multivariate analysis showed that second-line RDI was an independent prognostic indicator of TTF (HR, 1.7; 95% CI, 1.0-2.9; P = .040) and OS (HR, 2.7; 95% CI, 1.3-5.7; P = .009) in patients treated with everolimus. In this group, the median TTF and OS of patients with RDI <0.7 were 2.4 and 11.1 months, and those with RDI ≥ 0.7 were 5.3 and 25.9 months, respectively. Conclusion: The results suggest that second-line RDI may be a prognostic predictor for patients with mRCC treated with second-line targeted therapy, particularly in both the International Metastatic Renal Cell Carcinoma Database Consortium poor-risk group and everolimus-treated group.

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Should We Try Antiandrogen Withdrawal in Castration-Resistant Prostate Cancer Patients? Insights From a Retrospective Study

Hongo Hiroshi, Kosaka Takeo, Mizuno Ryuichi, Ezaki Taisuke, Matsumoto Kazuhiro, Morita Shinya, Shinoda Kazunobu, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

Clinical Genitourinary Cancer 2016.01

ISSN 1558-7673

Background: It remains uncertain whether those with response to antiandrogen withdrawal (AAW) have a better prognosis. We investigated the predictors of a better response to AAW and overall survival after acquiring resistance to first-line androgen deprivation therapy inpatients with castration-resistant prostate cancer (CRPC). Patients and Methods: We retrospectively reviewed the medical records of 87 CRPC patients treated at Keio University Hospital. Sixty-seven of 87 CRPC patients underwent AAW. We analyzed clinicopathologic parameters to identify predictors of survival in CRPC patients and investigated predictors of good response to AAW. Results: Younger age, longer duration of androgen deprivation therapy before CRPC development, and better response to AAW were independent favorable prognostic factors for overall survival. Although better response to AAW was a favorable prognostic factor in this study, trying AAW was not significantly related to overall survival. Duration of hormone therapy was significantly longer in those whose disease responded to AAW (69.9 ± 11.0 months) than those with no response (45.3 ± 5.2 months). Conclusion: The prognostic benefit of AAW was not clearly determined in this study. However, AAW might be beneficial in patients who have favorable prognostic factors for a response to AAW-that is, those who have received hormone therapy for a long period. However, AAW should not be done in patients who do not have favorable factors and who had a high prostate-specific antigen level at the time of their prostate cancer diagnosis.

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A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer

Akaza Hideyuki, Uemura Hirotsugu, Tsukamoto Taiji, Ozono Seiichiro, Ogawa Osamu, Sakai Hideki, Oya Mototsugu, Namiki Mikio, Fukasawa Satoshi, Yamaguchi Akito, Uemura Hiroji, Ohashi Yasuo, Maeda Hideki, Saito Atsushi, Takeda Kentaro, Naito Seiji

International Journal of Clinical Oncology 1 - 10 2016.01

ISSN 1341-9625

Background: The safety, tolerability, pharmacokinetics (PK) and anti-tumor activity of enzalutamide were investigated in patients with castration-resistant prostate cancer (CRPC) in Japan through a multicenter phase I/II study. Methods: In phase I, patients with progressive metastatic CRPC received single, then multiple, ascending doses of enzalutamide 80, 160 or 240 mg/day. After assessment of tolerability at multiple doses of 160 mg/day for 4 weeks, post-docetaxel patients with CRPC and measurable disease were enrolled into phase II; receiving long-term administration of enzalutamide 160 mg/day. Results: Nine and 38 patients were enrolled in phase I and II, respectively. During phase I, enzalutamide was well tolerated in each cohort; PK parameters were similar to those of non-Japanese populations in other studies. By week 12, overall response rate was 5.3 % and clinical benefit rate was 47.4 %. Prostate-specific antigen response rate (≥50 % reduction from baseline) was 28.9 %. Treatment-emergent adverse events reported in >20 % of patients in phase II were decreased weight, decreased appetite and constipation. No seizures were observed. Conclusion: Enzalutamide at 160 mg/day was well tolerated, with PK and safety profiles similar to the non-Japanese population. Anti-tumor activity was observed in post-docetaxel Japanese patients with metastatic CRPC. Apparent differences in anti-tumor activity compared with the AFFIRM study (a phase III trial in a diverse population of patients with CRPC post-docetaxel) may be attributed to differences in treatment history prior to starting enzalutamide. Particularly in Japan, the influence of sequence in hormone treatments, including combined androgen blockade therapy, should be considered. Trial registration: ClinicalTrials.gov NCT01284920.

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Lymphovascular invasion status at transurethral resection of bladder tumors may predict subsequent poor response of T1 tumors to bacillus Calmette-Guérin

Fukumoto Keishiro, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Oya Mototsugu

BMC Urology 16 ( 1 ) 2016.01

ISSN 1471-2490

Background: Lymphovascular invasion (LVI) is an important step in the process of tumor dissemination and metastasis outside the primary organ, but the relationship between LVI and the prognosis of T1 non-muscle invasive bladder cancer (NMIBC) has not been fully evaluated. Accordingly, the present study was performed to evaluate whether LVI had an impact on the clinical outcome in patients with T1 NMIBC. Methods: A total of 116 consecutive patients were diagnosed with T1 NMIBC from 1994 to 2013 at Keio University Hospital. All cases were reviewed by a single uro-pathologist. The prognostic significance of LVI was assessed in relation to recurrence and stage progression. Results: The median follow-up period was 53 months. LVI was histologically confirmed in 30 patients (25.9%). There were no significant differences of clinical features between the patients with and without LVI. In T1 patients, univariate analysis demonstrated that LVI positivity was associated with stage progression (p = 0.003), but not with tumor recurrence (p = 0.192). Multivariate analysis confirmed that LVI was independently associated with stage progression (p = 0.006, hazard ratio = 4.00). In 85 patients who received BCG instillation, LVI was independently associated with both tumor recurrence and stage progression (p = 0.036 and 0.024, hazard ratio = 2.19 and 3.76). Conclusions: LVI is a strong indicator of an increased risk of recurrence and progression in BCG-treated patients with T1 NMIBC. This information might assist clinicians to develop appropriate management and counseling strategies for these patients.

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Variant isoforms of CD44 expression in upper tract urothelial cancer as a predictive marker for recurrence and mortality

Hagiwara Masayuki, Kikuchi Eiji, Kosaka Takeo, Mikami Shuji, Saya Hideyuki, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2016.01

ISSN 1078-1439

Purpose: The variant isoforms of CD44 (CD44v), which has been associated with treatment resistance and tumor recurrence, are contributed to the feature of some of the new cell surface markers for cancer stem cells. The aim of this study is to address the prognostic significant of CD44v expression in upper tract urothelial cancer (UTUC). Materials and methods: We retrospectively analyzed the medical records of 110 patients treated surgically for≥pT2 UTUC. To determine the biological significance of CD44v in UTUC, we examined the immunohistochemical expression of CD44v9 and its association with clinical features and oncological outcomes. Results: During the mean follow-up of 4.8 years, tumor recurrence, including local and distant metastasis, was observed in 57 patients (51.8%), and 42 patients (38.2%) died of the disease. The incidence of ureter cancers was significantly higher in patients expressing CD44v9. In this series, 37 patients in the CD44v9-positive group (45.1%) and 5 (17.9%) in the CD44v9-negative group died of the disease. Kaplan-Meier curves revealed that cancer-specific survival and recurrence-free survival rates were significantly lower in the CD44v9-positive group than in the CD44v9-negative group (P = 0.032 and P = 0.038, respectively). A multivariate analysis identified the expression of CD44v9 as one of the independent risk factors for cancer-specific survival (P = 0.040, hazard ratio = 2.67) in addition to tumor grade G3, and also for recurrence-free survival (P = 0.028, hazard ratio = 2.33), in addition to tumor grade G3 and lymphovascular invasion. Conclusions: The expression of CD44v9 may be a new biomarker of malignant potential in muscle invasive UTUC and provide additional prognostic information in patients with UTUC.

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Prostate cancer stem cell and drug resistance

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 74 ( 1 ) 45 - 49 2016.01

ISSN 0047-1852

Cancer tissues are comprised of cell population including a variety of cells, such as stem cell-like cancer cells, upon which a hierarchical society is constructed. This hypothesis has been applied not only to leukemia, in which the hypothesis was first experimentally confirmed, but also to solid cancers. Recent topics shed light on the modified heterogeneity by various treatments which evolve disease progression. In prostate cancer, the identification of cancer stem cells using surface markers and the relationship with prostate origin are of current interest. This article reviews studies related to the development of prostate cancer and introduce recent progress of our project, focusing on cancer stemness and drug resistance.

Case report

Nishimoto Koshiro, Seki Tsugio, Kurihara Isao, Yokota Kenichi, Omura Masao, Nishikawa Tetsuo, Shibata Hirotaka, Kosaka Takeo, Oya Mototsugu, Suematsu Makoto, Mukai Kuniaki

Journal of Clinical Endocrinology and Metabolism 101 ( 1 ) 6 - 9 2016.01

ISSN 0021-972X

Context: We previously reported that the human adrenal cortex remodels to form subcapsular aldosterone-producing cell clusters (APCCs).SomeAPCCs were recently found to carry aldosteroneproducing adenoma (APA)-associated somatic mutations in ion channel/pump genes, which implied that APCCs produce aldosterone autonomously and are an origin of APA. However, there has been no report describing an APCC-to-APA transitional lesion. Case Description: A histological examination revealed unilateral multiple adrenocortical micronodules in the adrenals of two patients with primary aldosteronism (PA). Based on immunohistochemistry for aldosterone synthase, some of the micronodules were identified as possible APCC-to-APA transitional lesions (pAATLs; a tentative term used in this manuscript), which consisted of a subcapsular APCC-like portion and an inner micro-APA-like (mAPA-like) portion without an apparent histological border. GenomicDNAsamples prepared from pAATL histological sections were analyzed by next-generation sequencing for the known APA-associated mutations. The mAPA-like portions from two of the three large pAATLs examined harbored mutations (KCNJ5 [p.G151R] in pAATL 3 and ATP1A1 [p.L337M] in pAATL 7), whereas their corresponding APCC-like portions did not, suggesting their role in the formation of mAPA. Another lesion carried novel mutations in ATP1A1 (p.Ile322-Ile325del and p.Ile327Ser) in both the mAPA-like and APCC-like portions, thereby supporting these portions having a clonal origin. Conclusion: A novel aldosterone-producing pathology, pAATL that causes unilateral PA, was detected in the adrenals of two patients. Next-generation sequencing analyses of the large pAATLs suggested that the introduction of APA-associated mutations in the ion channel/pump genes may be involved in the development of mAPA from existing APCCs.

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Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

Nishimoto Koshiro, Seki Tsugio, Hayashi Yuichiro, Mikami Shuji, Al-Eyd Ghaith, Nakagawa Ken, Morita Shinya, Kosaka Takeo, Oya Mototsugu, Mitani Fumiko, Suematsu Makoto, Kabe Yasuaki, Mukai Kuniaki

International Journal of Endocrinology 2016 2016

ISSN 1687-8337

Background. The immunohistochemical detection of aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) has enabled the identification of aldosterone-producing cell clusters (APCCs) in the subcapsular portion of the human adult adrenal cortex. We hypothesized that adrenals have layered zonation in early postnatal stages and are remodeled to possess APCCs over time. Purposes. To investigate changes in human adrenocortical zonation with age. Methods. We retrospectively analyzed adrenal tissues prepared from 33 autopsied patients aged between 0 and 50 years. They were immunostained for CYP11B2 and CYP11B1. The percentage of APCC areas over the whole adrenal area (AA/WAA, %) and the number of APCCs (NOA, APCCs/mm²) were calculated by four examiners. Average values were used in statistical analyses. Results. Adrenals under 11 years old had layered zona glomerulosa (ZG) and zona fasciculata (ZF) without apparent APCCs. Some adrenals had an unstained (CYP11B2/CYP11B1-negative) layer between ZG and ZF, resembling the rat undifferentiated cell zone. Average AA/WAA and NOA correlated with age, suggesting that APCC development is associated with aging. Possible APCC-to-APA transitional lesions were incidentally identified in two adult adrenals. Conclusions. The adrenal cortex with layered zonation remodels to possess APCCs over time. APCC generation may be associated with hypertension in adults.

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Human Adrenocortical Remodeling Leading to Aldosterone-Producing Cell Cluster Generation

Nishimoto, Koshiro, Seki, Tsugio, Hayashi, Yuichiro, Mikami, Shuji, Al-Eyd, Ghaith, Nakagawa, Ken, Morita, Shinya, Kosaka, Takeo, Oya, Mototsugu, Mitani, Fumiko, Suematsu, Makoto, Kabe, Yasuaki, Mukai, Kuniaki

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY 1031 - 1041 2016

Research paper (scientific journal), ISSN 1687-8337

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High-risk Tumor

Kikuchi Eiji, Matsumoto Kazuhiro, Oya Mototsugu

Japanese Journal of Clinical Urology 70 ( 2 ) 166 - 171 2016

ISSN 0385-2393

Color Doppler Ultrasound Evaluation of Ureteral Jet Angle to Detect Vesicoureteral Reflux in Children

Asanuma Hiroshi, Matsui Zenichi, Satoh Hiroyuki, Asai Nobuyoshi, Nukui Chizuko, Aoki Yujiro, Mizuno Ryuichi, Oya Mototsugu

Journal of Urology 2016

ISSN 0022-5347

Purpose: Vesicoureteral reflux is the most common urinary tract abnormality in children. Although voiding cystourethrography is the gold standard for diagnosing reflux, this approach is invasive. We evaluated color Doppler ultrasound measurement of ureteral jet angle as a noninvasive screening tool for detecting reflux. Materials and Methods: We retrospectively evaluated 125 children (250 renal units) who presented with urinary tract infections or hydronephrosis. All patients underwent color Doppler ultrasonography and voiding cystourethrography. Ureteral jet angle was measured as angle between the direction of the ureteral jet and interureteral ridge. Results: Reflux was diagnosed in 80 patients (117 renal units). Mean ± SD ureteral jet angle was significantly greater in refluxing units (67.9 ± 18.7 degrees) than in nonrefluxing units (47.8 ± 17.3 degrees, p

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Obstructive sleep apnea syndrome should be considered as a cause of nocturia in younger patients without other voiding symptoms

Maeda Takahiro, Fukunaga Koichi, Nagata Hirohiko, Haraguchi Mizuha, Kikuchi Eiji, Miyajima Akira, Yamasawa Wakako, Shirahama Ryutaro, Narita Midori, Betsuyaku Tomoko, Asano Koichiro, Oya Mototsugu

Journal of the Canadian Urological Association 10 ( 7-8 ) E241 - E245 2016

ISSN 1911-6470

Introduction: This study aimed to evaluate urination frequency among patients with obstructive sleep apnea syndrome (OSAS) and the effect of continuous positive airway pressure (CPAP) treatment. Methods: We evaluated 138 men with moderate-to-severe OSAS by using polysomnography. Urination status was assessed at baseline and three months using the International Prostate Symptom Score and Overactive Bladder Symptom Score. Nocturia was defined as ≥2 nighttime urinations and patients were classified into Group A (

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Recent advances in renal cell carcinoma from a pathological point of view

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Kosaka Takeo, Ishida Masaru, Kuroda Naoto, Nagashima Yoji, Katsube Ken ichi, Okada Yasunori

Pathology International 2016

ISSN 1320-5463

The purpose of this article is to review the recent advances in renal cell carcinoma (RCC) from a pathological point of view. Because the genetic features and morphological characteristics have become major criteria for the classification of RCC, special techniques, such as immunohistochemistry, are essential to the differential diagnosis of renal tumors. Metastasis is frequently observed among the RCC patients with curative nephrectomy, and extracellular matrix-degrading enzymes, such as matrix metalloproteinases (MMP) and heparanase, play a key role in invasion and metastasis of RCC. Snail and Slug, transcription factors of epithelial-mesenchymal transition (EMT), accelerate cancer cell invasion through downregulation of E-cadherin and up-regulation of MMP. Therapies targeted at the vascular endothelial growth factor pathway have become the standard treatment of metastatic RCC. Although they lead to tumor shrinkage mainly by inhibiting angiogenesis, they have typically been associated with drug resistance. The mechanism of the resistance remains largely unknown, but complex events including re-activation of angiogenesis, EMT and cancer stem cells, and immune escape are implicated in the refractory response to the therapy. Recent advances of the research on RCC have caused the changes of classification and therapy, and pathologists should take overall view of these as integrated pathology.

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Pyeloplasty

Asanuma Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Urology 70 ( 13 ) 1034 - 1039 2016

ISSN 0385-2393

Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma

Tomita Yoshihiko, Fukasawa Satoshi, Oya Mototsugu, Uemura Hirotsugu, Shinohara Nobuo, Habuchi Tomonori, Rini Brian I., Chen Ying, Bair Angel H., Ozono Seiichiro, Naito Seiji, Akaza Hideyuki

Japanese Journal of Clinical Oncology 46 ( 11 ) 1031 - 1041 2016

ISSN 0368-2811

Objectives: To conduct Japanese subgroup analyses of a randomized, global Phase II study of axitinib with and without dose titration in first-line metastatic renal cell carcinoma and to explore predictive factors for axitinib efficacy in first-line metastatic renal cell carcinoma. Methods: The data included 44 Japanese and 169 non-Japanese treatment-naïve patients with metastatic renal cell carcinoma. Patients received twice-daily axitinib 5mg during a 4-week lead-in period. Patients who met the pre-defined randomization criteria were stratified by Eastern Cooperative Oncology Group performance status and randomly assigned (1:1) to axitinib or placebo titration. The primary endpoint was objective response rate; secondary endpoints included progression-free survival and safety. Predictive factors were analyzed using data from all patients. Results: The objective response rate (95% confidence interval) was 66% (50-80%) vs. 44% (36- 52%) in Japanese and non-Japanese patients, respectively. At the primary analysis, median progression-free survival could not be estimated for Japanese patients, and was 27.6 months (95% confidence interval: 16.6-33.2) in an updated analysis. Hypertension, diarrhea, hand-foot syndrome, dysphonia, hypothyroidism and proteinuria were common adverse events in Japanese patients. Due to a small number of randomized patients, effects of axitinib dose titration could not sufficiently be confirmed among Japanese patients. The multivariate analysis identified time from histopathological diagnosis to treatment and sum of the longest diameter for target lesion at baseline as independent predictive factors for progression-free survival. Conclusions: Axitinib is effective and well tolerated as first-line metastatic renal cell carcinoma therapy in Japanese patients. Predictive factors for axitinib efficacy endpoints identified in this setting warrant further investigation.

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Are the Formulas Used to Estimate Renal Function Adequate for Patients Treated With Cisplatin-Based Chemotherapy After Nephroureterectomy for Upper Tract Urothelial Carcinoma?

Niwa Naoya, Kikuchi Eiji, Masashi Matsushima, Tanaka Nobuyuki, Nishiyama Toru, Miyajima Akira, Saito Shiro, Oya Mototsugu

Clinical Genitourinary Cancer 2015.12

ISSN 1558-7673

Objective: The relationship between endogenous creatinine clearance (eCrCl) and renal function values obtained using mathematical formulas has not yet been fully elucidated, especially in patients with upper tract urothelial carcinoma that are treated with radical nephroureterectomy followed by cisplatin-based chemotherapy. Methods: Sixty patients who received cisplatin-based chemotherapy for locally advanced or metastatic upper tract urothelial carcinoma after radical nephroureterectomy between 2000 and 2012 were retrospectively identified. eCrCl was measured based on 24-hour urine specimens obtained immediately prior to each cycle of chemotherapy. Renal function was estimated with 4 different formulas: the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas. We evaluated the relationship between eCrCl and the renal function values obtained with each formula using the Pearson correlation coefficient and κ statistics. Results: The median eCrCl was 53.9 mL/min. The Pearson correlation coefficients and κ statistics for the relationships between eCrCl and the renal function values obtained with each of the mathematical formulas ranged from 0.600 to 0.763 and from 0.29 to 0.67, respectively. Among the patients with eCrCl of ≥ 60 mL/min, 70%, 60%, 50%, and 20% were estimated to have the renal function values of <60 mL/min by the Cockcroft-Gault, Modification of Diet in Renal Disease, Chronic Kidney Disease Epidemiology Collaboration, and Wright formulas, respectively. Conclusions: All 4 of the tested formulas underestimated eCrCl. The values obtained with the Wright formula were most closely associated with eCrCl.

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A Case of Gemcitabine and Cisplatin Chemotherapy in a Patient With Metastatic Urothelial Carcinoma Receiving Hemodialysis

Ezaki Taisuke, Matsumoto Kazuhiro, Morita Shinya, Shinoda Kazunobu, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

Clinical Genitourinary Cancer 2015.12

ISSN 1558-7673

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Visceral to total obesity ratio and severe hydronephrosis are independently associated with prolonged pneumoperitoneum operative time in patients undergoing laparoscopic radical nephroureterectomy for upper tract urothelial carcinoma

Shigeta Keisuke, Kikuchi Eiji, Hagiwara Masayuki, Hattori Seiya, Kaneko Gou, Hasegawa Masanori, Takeda Toshikazu, Jinzaki Masahiro, Akita Hirotaka, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

SpringerPlus 4 ( 1 ) 2015.12

Background: Our aim was to evaluate the effect of visceral obesity and impact of severe hydronephrosis on surgical complexity in patients undergoing laparoscopic radical nephroureterectomy (LRNU). Methods: From January 2000 to December 2013, 169 patients underwent radical nephroureterectomy at our institution. We retrospectively reviewed the medical records of 70 patients who underwent LRNU. We measured total fat area (TFA) and visceral fat area (VFA) at the level of the umbilicus using computed tomography. We defined accumulated visceral fat distribution as a VFA/TFA ratio ≥0.45. Ipsilateral hydronephrosis was graded from 0 to 4 by two uro-radiologists blinded to the clinical outcomes. Results: Among the 70 patients, VFA/TFA ratio was ≥0.45 in 40 patients (57.1%) and 28 (40.0%) had severe hydronephrosis (grade 3 or greater). Patients with a VFA/TFA ratio ≥0.45 had significantly longer pneumoperitoneum and total operation times compared to their counterparts (p = 0.047 and p = 0.002, respectively). Patients with severe hydronephrosis had significantly longer pneumoperitoneum and total operative times compared to their counterparts (p = 0.006 and p = 0.002, respectively). Multivariate logistic regression analysis showed that a high VFA/TFA and severe hydronephrosis were independent predictive factors for prolonged pneumoperitoneum (p = 0.048, HR = 2.90; p = 0.015, HR = 3.82, respectively) and total operative times (p < 0.001, HR = 18.7; p = 0.003, HR = 10.7; respectively). Other pre-clinical factors such as age, gender, BMI, clinical stage, tumor size, location, laterality, degree of perinephric stranding, and surgical procedure did not affect the operation times. Conclusion: The present data indicated that the visceral type of adipose accumulation and presence of severe hydronephrosis could provide preoperative information on the degree of technical difficulty associated with LRNU.

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Refraining from Smoking for 15 Years or More Reduced the Risk of Tumor Recurrence in Non-muscle Invasive Bladder Cancer Patients

Ogihara Koichiro, Kikuchi Eiji, Yuge Kazuyuki, Ito Yujiro, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyajima Akira, Asakura Hirotaka, Oya Mototsugu

Annals of Surgical Oncology 1 - 8 2015.12

ISSN 1068-9265

Purpose: We investigated whether smoking cessation could have preventative effects against tumor recurrence in patients with non-muscle invasive bladder cancer (NMIBC). Methods: Our study population comprised 634 patients with initially diagnosed NMIBC at Keio University Hospital, Saiseikai Central Hospital, and Saitama Medical University Hospital between 1995 and 2012. We analyzed the relationships between tumor recurrence in NMIBC and patient clinicopathological parameters, including smoking status. Results: Overall, 181 patients (28.5 %) were classified as current smokers, 154 (24.3 %) as former smokers, and 299 (47.2 %) as non-smokers. Kaplan–Meier curve analysis revealed that the tumor recurrence rate was significantly lower in the non-smoker group than in the current- and former-smoker groups (p <0.001 and p <0.001, respectively). In the 154 former smokers, Kaplan–Meier curve analysis revealed that smoking intensity and duration was not associated with tumor recurrence rate; however, patients with a smoking cessation period of 15 years or more had a significantly lower tumor recurrence rate than their counterparts (p <0.001). A multivariate analysis identified a smoking cessation period of

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Continuous use of enzalutamide in a patient who developed enzalutamide-induced thrombocytopenia

Sato Atsuko, Kosaka Takeo, Oya Mototsugu

BMJ Case Reports 2015 2015.11

Drug-induced thrombocytopenia (DIT) is known to be caused by many drugs. In daily clinical practice, it is not uncommon to observe cases of thrombocytopenia related to enzalutamide. We report the case of a 69-year-old patient with metastatic castration-resistant prostate cancer (CRPC) who was started on enzalutamide at a dose of 160 mg/day. Two weeks after starting enzalutamide, asymptomatic thrombocytopenia (platelet count 14 000/μL) occurred. Enzalutamide was withdrawn and the patient received platelet transfusions. The platelet count recovered immediately. Because the prostate-specific antigen (PSA) level had started to fall during treatment with enzalutamide, the patient was restarted on enzalutamide, but at a dose of 80 mg/day. He has continued to use enzalutamide without developing thrombocytopenia and the PSA level has kept falling. This case suggests that it is possible to again use enzalutamide in patients who have developed enzalutamide-induced thrombocytopenia.

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Hemorrhagic cystitis in a patient without a past history of radiation therapy who was treated with cabazitaxel for CRPC

Kosaka T., Oya M.

Annals of Oncology 26 ( 11 ) 2355 - 2356 2015.11

ISSN 0923-7534

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IJU this issue

Oya Mototsugu

International Journal of Urology 22 ( 11 ) 981 2015.11

ISSN 0919-8172

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THE SENSE OF A NEW STEROID WITHDRAWAL PROTOCOL WITH EVEROLIMUS, MYCOPHENELATE MOFETIL AND MINIMAL CALCINEURIN INHIBITOR IN KIDNEY TRANSPLANTATION

Nakagawa, Ken, Kono, Hidaka, Morita, Shinya, Shinoda, Kazunobu, Oya, Mototsugu

TRANSPLANT INTERNATIONAL 28 685 - 685 2015.11

Research paper (scientific journal), ISSN 0934-0874

Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer: Conventional radiotherapy, intensity-modulated radiotherapy, and permanent iodine-125 implantation with or without external beam radiotherapy

Sutani, Shinya, Ohashi, Toshio, Sakayori, Masanori, Kaneda, Tomoya, Yamashita, Shoji, Momma, Tetsuo, Hanada, Takashi, Shiraishi, Yutaka, Fukada, Junichi, Oya, Mototsugu, Shigematsu, Naoyuki

RADIOTHERAPY AND ONCOLOGY 117 ( 2 ) 270 - 276 2015.11

Research paper (scientific journal), ISSN 0167-8140

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Effect of reclassification of the IMDC model in patients with metastatic renal cell carcinoma treated with targeted therapy in the first-line and second-line settings

Tanaka Nobuyuki, Mizuno Ryuichi, Shirotake Suguru, Ito Keiichi, Yasumizu Yota, Masunaga Ayako, Ito Yujiro, Miyazaki Yasumasa, Hagiwara Masayuki, Kanao Kent, Mikami Shuji, Nakagawa Ken, Momma Tetsuo, Masuda Takeshi, Asano Tomohiko, Oyama Masafumi, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2015.10

ISSN 1078-1439

Purpose: To investigate the prognostic effect of the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model reclassification after targeted therapy administration in metastatic renal cell carcinoma (mRCC). Patients and method: A total of 245 mRCC patients treated with targeted therapy are included. The IMDC model reclassification is performed at 1 month after treatment induction of both first-line and second-line targeted therapy. Results: Of the 245 patients, 74 (30.2%) are divided into different risk groups by the IMDC model reclassification after first-line targeted therapy, and patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.018). Of the 119 patients treated with subsequent second-line targeted therapy, 25 (21.0%) are divided into different risk groups by the IMDC model reclassification after second-line targeted therapy, and patients newly classified with poor risk tend to have increased all-cause mortality compared with those remaining in the primary intermediate-risk group (P = 0.007), whereas patients newly classified with intermediate risk tend to have better overall survival than those remaining in the primary poor-risk group (P = 0.034). Conclusion: Approximately a quarter of the mRCC patients are classified into different risk groups of the IMDC model following targeted therapy administration in the first-line and second-line settings. There is a significant difference in overall survival of subgroups after the IMDC model reclassifications.

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Three-dimensional conformal arc radiotherapy using a C-arm linear accelerator with a computed tomography on-rail system for prostate cancer

Kumabe Atsuhiro, Fukuhara Noboru, Utsunomiya Takuji, Kawase Takatsugu, Iwata Kunihiro, Okada Yukinori, Sutani Shinya, Ohashi Toshio, Oya Mototsugu, Shigematsu Naoyuki

Radiation Oncology 10 ( 1 ) 2015.10

Background: We report the feasibility and treatment outcomes of image-guided three-dimensional conformal arc radiotherapy (3D-CART) using a C-arm linear accelerator with a computed tomography (CT) on-rail system for localized prostate cancer. Methods and materials: Between 2006 and 2011, 282 consecutive patients with localized prostate cancer were treated with in-room CT-guided 3D-CART. Biochemical failure was defined as a rise of at least 2.0 ng/ml beyond the nadir prostate-specific antigen level. Toxicity was scored according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. Results: A total of 261 patients were analyzed retrospectively (median follow-up: 61.6 months). The median prescribed 3D-CART dose was 82 Gy (2 Gy/fraction, dose range: 78-86 Gy), and 193 of the patients additionally received hormonal therapy. The 5-year overall survival rate was 93.9 %. Among low-, intermediate-, and high-risk patients, 5-year rates of freedom from biochemical failure were 100, 91.5 and 90.3 %, respectively. Rates of grade 2-3 late gastrointestinal and genitourinary toxicities were 2.3 and 11.4 %, respectively. No patient experienced late grade 4 or higher toxicity. Conclusions: In-room CT-guided 3D-CART was feasible and effective for localized prostate cancer. Treatment outcomes were comparable to those previously reported for intensity-modulated radiotherapy.

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Clinical background analysis about transurethral electrocoagulation

Katsui Masahiro, Kikuchi Eiji, Yazawa Satoshi, Hagiwara Masayuki, Morita Shinya, Shinoda Kazunobu, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Asanuma Hiroshi, Miyajima Akira, Oya Mototsugu

Japanese Journal of Urology 106 ( 4 ) 255 - 263 2015.10

ISSN 0021-5287

(Purpose) Transurethral electrocoagulation (TUC) is a rare event but occurs in a constant manner with various causes or disorders and reduces patient quality of life. So far there have been no reports focusing on the details of TUC. We focused on the clinical background and related causes in cases of TUC in our institution. (Patients and methods) We identified 76 cases (65 patients) who underwent TUC at Keio University Hospital between April 2001 and March 2011. We focused on patient background, especially with respect to the primary disease, treatment modality, use of antiplatelet or anticoagulant agent, timing of TUC, type of electrosurgical device, and the incidence of transfusion. (Results) The primary disease for TUC included bladder tumor (BT) in 31 cases, benign prostate hyperplasia (BPH) in 13, prostate cancer (PCa) in 13, idiopathic bladder bleeding in 4, periarteritis nodosa in 3, uterine cervical cancer in 3, and others in 9. TUC after transurethral resection (TUR) was found in 38 cases, including transurethral resection of bladder tumor (TURBT) in 26 of 31 BT cases and transurethral resection of prostate (TURP) in 12 of 13 BPH cases. After TURBT, TUC was performed before removal of a urethral catheter in 7 cases, and after removal of a urethral catheter in 19 cases. With regard to TUC associated with TURP, the average estimated prostate volume in TUC cases before removal of the urethral catheter was 66.2 ml, which was significantly larger than that in TUC cases after removal of the urethral catheter (46.1 ml, p = 0.045). TUC after the radiation therapy was observed in 21 cases, and the average time from the radiation therapy to TUC was 3.4 years (7 months-10 years). (Conclusion) TUC was caused by multiple causes or disorders, and 75% of our TUC was associated with BT, BPH or PCa. TUC associated with TURBT frequently occurred within 1 week after TURBT but was still observed after 1 month following the operation. All TUC associated with TURP occurred within 3 weeks after operation. The average period from radiation therapy to TUC was 3.4 years (7 months-10 years) and TUC associated with radiation cystitis could occur beyond 5 years after radiation.

A large-scale prospective registration study of the safety and efficacy of sorafenib tosylate in unresectable or metastatic renal cell carcinoma in Japan

Akaza Hideyuki, Oya Mototsugu, Iijima Masafumi, Hyodo Ichinosuke, Gemma Akihiko, Itoh Hiroshi, Adachi Masatoshi, Okayama Yutaka, Sunaya Toshiyuki, Inuyama Lyo

Japanese Journal of Clinical Oncology 45 ( 10 ) 953 - 962 2015.10

ISSN 0368-2811

Objective: Real-life safety and efficacy of sorafenib in advanced renal cell carcinoma in a nationwide patient population were evaluated by post-marketing all-patient surveillance. Methods: All patients with unresectable or metastatic renal cell carcinoma in Japan who started sorafenib therapy from February 2008 to September 2009 were registered and followed for up to 12 months. Baseline characteristics, treatment status, tumor response, survival and safety data were recorded by the prescribing physicians. Results: Safety and efficacy were evaluated in 3255 and 3171 patients, respectively. The initial daily dose was 800 mg in 78.2% of patients. Median duration of treatment was 6.7 months and the mean relative dose intensity was 68.4%. Overall, 2227 patients (68.4%) discontinued the treatment by 12 months, half of which (52.0% of discontinued patients) were due to adverse events. The most common adverse drug reactions were hand-foot skin reaction (59%), hypertension (36%), rash (25%) and increase in lipase/amylase (23%). The median progression-free survival was 7.3 months (95% confidence intervals: 6.7-8.1), and the overall survival rate at 1 year was 75.4% (73.5-77.1). Prognostic factors for overall survival were mostly consistent with those in previous clinical trials in the univariate analysis and largely similar to those for progression-free survival and duration of treatment in the multivariate analysis.

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Clinical background of patients with sperm in their urinary sediment

Tomita Masuomi, Kikuchi Eiji, Maeda Takahiro, Kabeya Yusuke, Katsuki Takeshi, Oikawa Yoichi, Kato Kiyoe, Ohashi Masakazu, Nakamura So, Oya Mototsugu, Shimada Akira

PLoS One 10 ( 9 ) 2015.09

Introduction The detection rate and associated factors of at least one sperm in urinary sediment is not well-known in real clinical practice. Aims The aim of the present study was to evaluate the clinical features associated with the presence of sperm in urinary sediment in a large number of samples. Methods We conducted a cross-sectional study at Tokyo Saiseikai Central Hospital. We identified 5,005 males who were aged ≥20 years in whom urinary sedimentation had been performed at least twice between May 2011 and June 2012. The sperm group included patients in whom at least one urinary sediment test performed under a microscope had detected at least one sperm. We evaluated the associations between the presence of at least one sperm in urinary sediment and clinical parameters such as various diseases and the use of particular oral medicines. Main Outcomes In total, 1.6% (339/20,937) of urinary sediment samples contained at least one sperm. The sperm group consisted of 282 subjects (5.6%), and the no-sperm group included 4,723 subjects (94.3%). Results Multivariate analysis demonstrated that younger age (

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Nicotine induces tumor growth and chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer

Yuge Kazuyuki, Kikuchi Eiji, Hagiwara Masayuki, Yasumizu Yota, Tanaka Nobuyuki, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

Molecular Cancer Therapeutics 14 ( 9 ) 2112 - 2120 2015.09

ISSN 1535-7163

Continued smoking is highly associated with not only a higher incidence but also greater risk of tumor recurrence, progression, and acquired chemoresistance of urothelial carcinoma. We investigated whether nicotine affects urothelial carcinoma, and the detailed mechanism by which nicotine could induce tumor growth and any associated chemoresistance. Cell viability was evaluated in the human bladder cancer cell line T24 exposed to nicotine with or without cisplatin (CDDP) and NVP-BEZ235 as a PI3K/mTOR dual inhibitor by the WST-1 assay. Protein expression of the PI3K/Akt/mTOR pathway was investigated by Western blotting or immunohistochemical analysis. The influence of nicotine on tumor growth was also evaluated with or without CDDP and/or NVP-BEZ235 in a subcutaneous bladder tumor model. The result demonstrated that cell proliferation was increased in T24 cells after exposure to nicotine. Phospho-specific Akt (pAkt) and phospho-specific p70 S6 kinase (pS6) were significantly upregulated by nicotine exposure. Tumor growth in vivo was significantly induced by nicotine exposure in accordance with increased pS6 expression. Nicotine attenuated inhibition of T24 cell growth by CDDP and further upregulated pS6 expression in vitro and in vivo. NVP-BZE235 inhibited T24 cell proliferation and pAkt and pS6 expression induced after exposure to nicotine and/or CDDP. In conclusion, nicotine increases tumor growth and induces acquired chemoresistance through activation of the PI3K/Akt/mTOR pathway in bladder cancer.

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Clinical Background of Patients with Sperm in Their Urinary Sediment

Tomita, Masuomi, Kikuchi, Eiji, Maeda, Takahiro, Kabeya, Yusuke, Katsuki, Takeshi, Oikawa, Yoichi, Kato, Kiyoe, Ohashi, Masakazu, Nakamura, So, Oya, Mototsugu, Shimada, Akira

PLOS ONE 10 ( 9 ) 953 - 962 2015.09

Research paper (scientific journal), ISSN 1932-6203

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Characterizing intermediate-risk non-muscle-invasive bladder cancer

Matsumoto Kazuhiro, Kikuchi Eiji, Yanai Yoshinori, Hayakawa Nozomi, Ito Yujiro, Maeda Takahiro, Nagata Hirohiko, Miyajima Akira, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 2015.08

ISSN 1078-1439

Purpose: Patients with intermediate-risk non-muscle-invasive bladder cancer have traditionally been defined as those not included in the low- or high-risk groups. Therefore, the intermediate-risk group consists of heterogeneous patients. Materials and methods: We reviewed 326 patients diagnosed with intermediate-risk tumors. We subclassified these patients into 3 groups according to their clinical courses. Group A included patients with initial and multiple low-grade tumors (N = 170). Group B consisted of patients with a low-grade tumor that recurred after a low-risk tumor (N = 97), and Group C consisted of patients with a low-grade tumor that recurred after a high-risk tumor (N = 59). Results: The 2-year recurrence-free survival rate was significantly lower in Group C (42%) than in Groups A (69%, P<0.01) and B (70%, P<0.01). Regarding progression-free survival, no significant differences were observed among the groups. In total, 167 patients received adjuvant bacillus Calmette-Guérin (BCG), and 39 received adjuvant chemotherapy instillations. In Groups A and B, there were no significant differences in efficiency against tumor recurrence between BCG and chemotherapy. In Group C, the 5-year recurrence-free survival rate was 65% in patients receiving BCG, which was significantly higher when compared with patients receiving chemotherapy (P = 0.01). Furthermore, Group C included 11 BCG refractory cases, 5 of whom later experienced stage progression during follow-up. Conclusion: Our subclassification analysis suggested that intermediate-risk tumors that recurred after a high-risk tumor (Group C) should be treated with adjuvant BCG therapy, owing to the high probability of subsequent recurrence. Furthermore, the definition of intermediate risk may include some BCG refractory cases.

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Impact of Combined Use of Blood-based Inflammatory Markers on Patients with Upper Tract Urothelial Carcinoma Following Radical Nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Miyazaki Yasumasa, Kobayashi Hiroaki, Kaneko Gou, Hagiwara Masayuki, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Kosaka Takeo, Hara Satoshi, Nakagawa Ken, Jinzaki Masahiro, Oya Mototsugu

European Urology Focus 1 ( 1 ) 54 - 63 2015.08

Background: Previous studies showed the prognostic impact of preoperative levels of neutrophil-to-lymphocyte ratio (NLR), plasma fibrinogen, and serum C-reactive protein (CRP) in surgically treated upper tract urothelial carcinoma; however, few papers have discussed the proper use of these indices. Objective: To investigate whether combinations of these three markers, as a cumulative marker score (CMS), improve the accuracy of prognostic models following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 394 patients from multiple institutions were included. Median follow-up was 30 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy. Outcome measurements and statistical analysis: Associated outcomes were assessed using multivariate analysis. The CMS was defined as the number of elevated levels of preoperative NLR, plasma fibrinogen, and serum CRP. Results and limitations: Multivariate analyses revealed that an increasing CMS was independently associated with high rates of disease recurrence, cancer-specific mortality, and all-cause mortality following RNU. Addition of the CMS to a model that included standard clinicopathologic predictors significantly improved predictive accuracy by 2.7% for disease recurrence, 3.9% for cancer-specific mortality, and 4.0% for all-cause mortality, which were the highest among other prognostic models using each marker alone or combinations of two. The study is limited by its retrospective nature. Conclusions: Although the use of each inflammatory marker alone may be as predictive as clinicopathologic indices for prognosis, combinations like CMS can provide more accurate prognostic models following RNU. Patient summary: Elevation of blood-based inflammatory markers may be useful for predicting prognosis because of their low cost and accessibility. Among blood-based indices, we examined the efficacy of preoperative neutrophil-to-lymphocyte ratio, plasma fibrinogen, and serum C-reactive protein levels. Although use of each marker alone provides additional prognostic information, the combination of all three markers would be more predictive than any single marker or combinations of two.

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Renin-angiotensin system blockade

Miyajima Akira, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

International Journal of Urology 22 ( 8 ) 721 - 730 2015.08

ISSN 0919-8172

Angiotensin II is a key biological peptide in the renin-angiotensin system that regulates blood pressure and renal hemodynamics, and extensive experimental studies have shown that angiotensin II promotes diverse fibrotic changes and induces neovascularization in several inflammatory diseases. It is known that angiotensin II can be controlled using renin-angiotensin system blockade when angiotensin II is the main factor inducing a particular disease, and renin-angiotensin system blockade has assumed a central role in the treatment of inflammatory nephritis, cardiovascular disorders and retinopathy. In contrast, renin-angiotensin system blockade was found to have not only these effects but also other functions, such as inhibition of cancer growth, angiogenesis and metastasis. Numerous studies have sought to elucidate the mechanisms and support these antitumor effects. However, a recent meta-analysis showed that renin-angiotensin system blockade use might in fact increase the incidence of cancer, so renin-angiotensin system blockade use has become somewhat controversial. Although the renin-angiotensin system has most certainly made great contributions to experimental models and clinical practice, some issues still need to be resolved. The present review discusses the contribution and controversy surrounding the renin-angiotensin system up to the present time.

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Efficacy of treatment with a GnRH antagonist in prostate cancer patients previously treated with a GnRH agonist

Ezaki Taisuke, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

CANCER CHEMOTHERAPY AND PHARMACOLOGY 76 ( 2 ) 301 - 306 2015.08

Research paper (scientific journal), Joint Work, ISSN 0344-5704

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Comparison of continence outcomes of early catheter removal on postoperative day 2 and 4 after laparoscopic radical prostatectomy

Matsushima Masashi, Miyajima Akira, Hattori Seiya, Takeda Toshikazu, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

BMC Urology 15 ( 1 ) 2015.07

ISSN 1471-2490

Background: The optimal timing of catheter removal following laparoscopic radical prostatectomy (LRP) has not yet been determined. This prospective study was designed to compare the efficacy and safety of catheter removal on postoperative day (POD) 2 versus POD 4 after LRP and its impact on urinary continence outcomes. Methods: One hundred and thirteen patients underwent LRP and were prospectively randomized into two groups: group 1 (n = 57) had the urinary catheter removed on POD 2 while group 2 (n = 56) had the catheter removed on POD 4. The urine loss ratio (ULR) was defined as the weight of urine loss in the pad divided by the daily micturition volume. Continence was defined as a pad-free status. Results: No significant differences were observed in clinical features between groups 1 and 2. Acute urinary retention (AUR) after catheter removal occurred in 21 patients (18.6 %) (13 (22.8 %) in group 1 and 8 (14.3 %) in group 2 (p = 0.244). The first-day mean ULR values were 1.16 ± 4.95 in group 1 and 1.02 ± 3.27 in group 2 (p = 0.870). The last-day mean ULR values were 0.57 ± 1.60 in group 1 and 2.78 ± 15.49 in group 2 (p = 0.353). Continence rates at 3, 6, 9, and 12 months were 21.8, 41.1, 58.0, and 71.4 % in group 1 and 34.5, 66.0, 79.2, and 83.7 % in group 2 (p = 0.138, 0.009, 0.024, and 0.146, respectively). In AUR cases, continence rates at 3, 6, 9, and 12 months were 0, 23.1, 38.5, and 54.5 % in group 1 and 37.5, 75.0, 87.5, and 87.5 % in group 2 (p = 0.017, 0.020, 0.027, and 0.127, respectively). A multivariate analysis identified AUR after catheter removal on POD 2 as the only predictive factor for incontinence 6 and 9 months after LRP (p = 0.030 and 0.018, respectively). Conclusions: Our results demonstrated that early catheter removal on POD 2 after LRP may increase the risk of incontinence. Trial registration: The study was registered as Clinical trial: (UMIN000014944); registration date: 12 March 2012.

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Axitinib dose titration

Rini Brian I., Melichar B., Fishman M. N., Oya M., Pithavala Y. K., Chen Y., Bair A. H., Grünwald V.

Annals of Oncology 26 ( 7 ) 1372 - 1377 2015.07

ISSN 0923-7534

Background: In a randomized, double-blind phase II trial in patients with metastatic renal cell carcinoma (mRCC), axitinib versus placebo titration yielded a significantly higher objective response rate. We evaluated pharmacokinetic and blood pressure (BP) data from this study to elucidate relationships among axitinib exposure, BP change, and efficacy. Patients and methods: Patients received axitinib 5 mg twice daily during a lead-in period. Patients who met dose-titration criteria were randomized 1:1 to stepwise dose increases with axitinib or placebo. Patients ineligible for randomization continued without dose increases. Serial 6-h and sparse pharmacokinetic sampling were carried out; BP was measured at clinic visits and at home in all patients, and by 24-h ambulatory BP monitoring (ABPM) in a subset of patients. Results: Area under the plasma concentration-time curve from 0 to 24 h throughout the course of treatment (AUCstudy) was higher in patients with complete or partial responses than those with stable or progressive disease in the axitinib-titration arm, but comparable between these groups in the placebo-titration and nonrandomized arms. In the overall population, AUCstudy and efficacy outcomes were not strongly correlated. Mean BP across the population was similar when measured in clinic, at home, or by 24-h ABPM. Weak correlations were observed between axitinib steady-state exposure and diastolic BP. When grouped by change in diastolic BP from baseline, patients in the ≥10 and ≥15 mmHg groups had longer progression-free survival. Conclusions: Optimal axitinib exposure may differ among patients with mRCC. Pharmacokinetic or BP measurements cannot be used exclusively to guide axitinib dosing. Individualization of treatment with vascular endothelial growth factor receptor tyrosine kinase inhibitors, including axitinib, is thus more complex than anticipated and cannot be limited to a single clinical factor.

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Coincident detection of lung metastasis of prostate cancer and primary lung cancer

Muro Yusuke, Kosaka Takeo, Hato Tai, Mikami Shuji, Oya Mototsugu

Canadian Urological Association Journal 9 ( 7-8 ) E524 - E526 2015.07

ISSN 1920-1214

We report an extremely rare case of 79-year-old man, who was discovered with coincidental lung metastasis of prostate cancer and primary lung cancer. The patient presented with low prostatespecific antigen and two lung lesions: one in the right lower lobe, and one in the right upper lobe, 3 years after he was treated with external beam radiotherapy for Gleason score 4+3=7, cT3aN0M0 prostate cancer. A computed tomography-guided needle biopsy of a nodule in the right lower lobe revealed suspicious metastasis of prostate cancer. Thoracoscopic excisions of both lesions were performed, and each lung lesion was diagnosed as being metastatic prostate cancer and primary lung cancer.

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Intravesical dual PI3K/mTOR complex 1/2 inhibitor NVP-BEZ235 therapy in an orthotopic bladder cancer model

Matsushima Masashi, Kikuchi Eiji, Matsumoto Kazuhiro, Hattori Seiya, Takeda Toshikazu, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

INTERNATIONAL JOURNAL OF ONCOLOGY 47 ( 1 ) 377 - 383 2015.07

Research paper (scientific journal), Joint Work, ISSN 1019-6439

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Activation of aryl hydrocarbon receptor promotes invasion of clear cell renal cell carcinoma and is associated with poor prognosis and cigarette smoke

Ishida Masaru, Mikami Shuji, Shinojima Toshiaki, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Okada Yasunori, Oya Mototsugu

INTERNATIONAL JOURNAL OF CANCER 137 ( 2 ) 299 - 310 2015.07

Research paper (scientific journal), Joint Work, ISSN 0020-7136

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Predictive factors for severe and febrile neutropenia during docetaxel chemotherapy for castration-resistant prostate cancer

Shigeta Keisuke, Kosaka Takeo, Yazawa Satoshi, Yasumizu Yota, Mizuno Ryuichi, Nagata Hirohiko, Shinoda Kazunobu, Morita Shinya, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Hasegawa Shintaro, Oya Mototsugu

International Journal of Clinical Oncology 20 ( 3 ) 605 - 612 2015.06

ISSN 1341-9625

Background: The aim of this study is to identify factors that increase the occurrence of severe neutropenia (SN) and febrile neutropenia (FN) during docetaxel treatment for castration-resistant prostate cancer (CRPC). Methods: We retrospectively reviewed 258 courses during the first three cycles among 95 patients. Docetaxel at a dose of 75 mg/m2 was administered every 3 or 4 weeks. Patient background, laboratory data, and bone scan results were collected to assess predictive factors for SN and FN. We defined SN as an absolute neutrophil count (ANC) of <500/mm3 and defined FN as an ANC of <1000/mm3 with a body temperature of >38.3 °C. Results: The mean age of the patients was 72.6 ± 6.4 years and the mean prostate-specific antigen was 135.4 ± 290.9 ng/ml. During the first three courses of treatment, SN occurred in 72.6 % of patients and FN occurred in 9.5 % of patients. Univariate analysis demonstrated that age ≥75 years (p = 0.002), number of comorbidities ≥1.2 (p = 0.008 and p = 0.006) and previous external beam radiation therapy (EBRT) (p = 0.001) were predictive factors for the development of SN or FN. In multivariate analysis, significant predictors of SN or FN were age ≥75 years (hazard ratio [HR] 5.77; p = 0.004) and previous EBRT (HR 14.5; p = 0.012). According to the subgroup analysis dividing SN and FN separately, multivariate analysis also revealed that age ≥75 years and previous EBRT were also significant predictors for developing SN (HR 5.09; p = 0.023, HR 12.7; p = 0.020, respectively) and for developing FN (HR 5.45; p = 0.042, HR 7.72; p = 0.015, respectively). Conclusions: Patients aged ≥75 years and with a history of localized radiation therapy are at higher risk for significant neutropenic events and require closer surveillance.

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Follicle-stimulating hormone enhances recovery from low-dose doxorubicin-induced spermatogenic disorders in mice

Hagiuda, Jun, Ishikawa, Hiromichi, Kaneko, Satoru, Okazaki, Masako, Oya, Mototsugu, Nakagawa, Ken

JOURNAL OF ASSISTED REPRODUCTION AND GENETICS 32 ( 6 ) 917 - 923 2015.06

Research paper (scientific journal), ISSN 1058-0468

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Comparison of genitourinary and gastrointestinal toxicity among four radiotherapy modalities for prostate cancer

Sutani Shinya, Ohashi Toshio, Sakayori Masanori, Kaneda Tomoya, Yamashita Shoji, Momma Tetsuo, Hanada Takashi, Shiraishi Yutaka, Fukada Junichi, Oya Mototsugu, Shigematsu Naoyuki

Radiotherapy and Oncology 2015.05

ISSN 0167-8140

Purpose: To compare late genitourinary (GU) and gastrointestinal (GI) toxicity following different prostate cancer treatment modalities. Materials and methods: This study included 1084 consecutive prostate cancer patients treated with conventional radiotherapy, intensity-modulated radiotherapy (IMRT), permanent iodine-125 implantation (PI) alone, and PI combined with external beam radiotherapy (PI + EBRT). The effects of treatment- and patient-related factors on late grade. ≥. 2 (G2+) GU/GI toxicity risk were assessed. Results: The median follow-up was 43. months (range, 12-97. months). Compared to the PI + EBRT, there was significantly less G2+ GU toxicity in the conventional radiotherapy (hazard ratio [HR] = 0.39; 95% CI, 0.20-0.77) and the IMRT (HR = 0.45, 95% CI, 0.27-0.73). Compared to the PI + EBRT, there was significantly more G2+ GI toxicity in the IMRT (HR = 2.38; 95% CI, 1.16-4.87). In PI-related groups, prostate equivalent dose in 2. Gy fractions was a significant predictor of G2+ GU toxicity (p = 0.001), and the rectal volume receiving more than 100% of the prescribed dose was a significant predictor of G2+ GI toxicity (p = 0.001). Conclusion: The differences in the late G2+ GU/GI risk cannot be explained by the differences in treatment modalities themselves, but by the total radiation dose to the GU/GI tract, which had a causal role in the development of late G2+ GU/GI toxicity across all treatment modality groups.

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Solifenacin or Mirabegron Could Improve Persistent Overactive Bladder Symptoms After Dutasteride Treatment in Patients With Benign Prostatic Hyperplasia

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Ishioka Katsura, Hagiwara Masayuki, Miyazaki Yasumasa, Shinojima Toshiaki, Miyajima Akira, Oya Mototsugu

Urology 85 ( 5 ) 1151 - 1155 2015.05

ISSN 0090-4295

Objective To evaluate the clinical response and adverse events (AEs) of solifenacin (SOL) or mirabegron (MIR) in benign prostatic hyperplasia patients with persistent overactive bladder (OAB) symptoms after dutasteride (DUT) treatment. Methods Fifty cases with residual OAB symptom score (OABSS) ≥5 and OABSS Q3 ≥2 after at least 6 months treatment of DUT were included in this study. Patients were administered 5 mg/d of SOL (N = 25) or 50 mg/d of MIR (N = 25), and International Prostate Symptom Score (IPSS) and OABSS were prospectively collected at 4 and 12 weeks. The safety was evaluated by changes in postvoided residual urine volume and the incidence of AEs. Results After DUT administration, the mean prostate volume, IPSS, and OABSS were 39.0 mL, 17.6, and 8.1, respectively. SOL 5 mg significantly reduced the IPSS, OABSS, and OABSS Q3 at 4 and at 12 weeks (-3.1, -2.7, -1.3; P <.05); however, 4 patients could not continue the SOL treatment owing to AEs. All patients could continue the 12 weeks of MIR treatment, and MIR 50 mg reduced IPSS and OABSS at 4 weeks and reduced IPSS, OABSS, and the OABSS Q3 (-3.0, -2.5, -0.9; P <.05) at 12 weeks. Postvoided residual urine volume increased by ≥100 mL after treatment in 2 cases in the SOL group but not in any patient in the MIR group. Conclusion Additional SOL or MIR might result in amelioration of the persistent OAB symptom after DUT treatment in patients with an enlarged prostate.

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Evaluation of histopathological findings at the injection site following degarelix administration

Maeda Takahiro, Kosaka Takeo, Honda Aki, Okata Utako, Hayakawa Nozomi, Ito Yujiro, Nagata Hirohiko, Chen Ko Ron, Nakamura So, Oya Mototsugu

Supportive Care in Cancer 23 ( 5 ) 1377 - 1381 2015.05

ISSN 0941-4355

Purpose: The aims of the present study were to investigate the incidence of injection site reactions (ISRs) following administration of 240 mg degarelix and identify the risk factors for ISRs. Methods: This study was conducted in 50 consecutive men treated with degarelix for the first time. ISRs after an initial degarelix dose of 240 mg (administered subcutaneously as two 3 ml subcutaneous injection) were evaluated using the five categories of the Common Terminology Criteria for Adverse Events Version 4 of the National Cancer Institute. We also assessed the differences in patient background between patients with and without an ISR. Results: The mean age of patients and prostate-specific antigen (PSA) level just before degarelix administration were 75.6 and 198.4 ng/ml, respectively. Hormonal therapy with degarelix was administered for the first time to 33 patients; 11 of the 50 patients were receiving an oral steroid, 6 for prostate cancer, 1 for hematological disease, and 4 for allergic conditions. ISRs were observed in 25 patients, and all of the ISRs were categorized as grade 1 or 2; however, 2 patients discontinued this procedure due to the ISR. Significant differences in the first experience with subcutaneous therapy (p = 0.007) and rate of combination with a steroid (p = 0.017) were observed between patients with and without ISRs. Conclusion: The incidences of ISRs in patients receiving subcutaneous therapy for the first time and in patients also receiving an oral steroid were 64 and 18 %, respectively. Patients should be provided with information concerning the possible occurrence of ISR due to degarelix prior to the administration, particularly patients who are not receiving steroids and patients who have no experience with subcutaneous injections.

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Decision tree for the diagnosis of upper tract urothelial carcinoma: Can selective upper-tract urine cytology be omitted in diagnosis?

Hayakawa Nozomi, Kikuchi Eiji, Matshumoto Kazuhiro, Morita Shinya, Shinoda Kazunobu, Kosaka Takeo, Mizuno Ryuichi, Shinojima Toshiaki, Asanuma Hiroshi, Miyajima Akira, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 33 ( 15 ) E304 - E305 2015.05

Research paper (scientific journal), Joint Work, ISSN 0732-183X

Predictors of renal dysfunction during everolimus treatment in patients with metastatic renal cell carcinoma

Mizuno Ryuichi, Takahashi Ryohei, Shinojima Toshiaki, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 33 ( 15 ) 88 - 88 2015.05

Research paper (scientific journal), Joint Work, ISSN 0732-183X

Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Suzuki Eriko, Mizuno Ryuichi, Shinojima Toshiaki, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

BMC Cancer 15 ( 1 ) 2015.04

Background: No previous study has addressed the efficacy of NF-κ B blockade when bladder tumors develop acquired resistance toward CDDP-treatments. We investigated the changes in NF-κ B activation and therapeutic impact of NF-κ B blockade by the novel NF-κ B inhibitor dehydroxymethyl derivative of epoxyquinomicin (DHMEQ) in CDDP-resistant bladder cancer cells. Methods: Two human invasive bladder cancer cell lines, T24 and T24PR, were used. The T24PR cell line was newly established as an acquired platinum-resistant subline by culturing in CDDP-containing medium for 6 months. Expression of intranuclear p65 protein in the fractionated two cell lines was determined by Western blotting analysis. DNA-binding activity of NF-κ B was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis were analyzed in vivo and in vitro. Results: Intranuclear expression and DNA-binding activity of p65 were strongly enhanced in T24PR cells compared with those of T24 cells, and both were significantly suppressed by DHMEQ. Lowered cell viability and strong induction of apoptosis were observed by treatment with DHMEQ alone in these chemo-resistant cells compared with parent cells. As T24PR cells did not show dramatic cross-resistance to paclitaxel in the in vitro study, we next examined whether the combination of DHMEQ with paclitaxel could enhance the therapeutic effect of the paclitaxel treatment in T24PR tumors. Using mouse xenograft models, the mean volume of tumors treated with the combination of DHMEQ (2 mg/kg) and paclitaxel (10 mg/kg) was significantly smaller than those treated with paclitaxel alone (p < 0.05), and the reduction of tumor volume in mice treated with DHMEQ in combination with paclitaxel and paclitaxel alone as compared to vehicle control was 66.9% and 17.0%, respectively. Conclusion: There was a distinct change in the activation level of NF-κ B between T24 and T24PR cells, suggesting strong nuclear localization of NF-κ B could be a promising target after developing acquired platinum-resistance in bladder cancer.

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Therapeutic effect of intravesical administration of paclitaxel solubilized with poly(2-methacryloyloxyethyl phosphorylcholine-co-n-butyl methacrylate) in an orthotopic bladder cancer model

Tamura Koetsu, Kikuchi Eiji, Konno Tomohiro, Ishihara Kazuhiko, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

BMC Cancer 15 ( 1 ) 2015.04

Background: To evaluate the effects of intravesical administration of paclitaxel (PTX-30W), which was prepared by solubilization with a water-soluble amphiphilic polymer composed of PMB30W, a copolymer of 2-methacryloyloxyethyl phosphorylcholine and n-butyl methacrylate, in an orthotopic bladder cancer model. Methods: The cytotoxicities of PMB30W were examined in MBT-2 cell cultures and the results were compared with those of the conventional paclitaxel solubilizer Cremophor. In an orthotopic MBT-2 bladder cancer model, the effect of intravesical administration of PTX-30W was compared with that of paclitaxel solubilized with Cremophor (PTX-CrEL). The paclitaxel concentration in bladder tumors after the intravesical treatment was also evaluated using liquid chromatography tandem mass spectrometry (LC-MS/MS) system. Results: In vitro, Cremophor exhibited dose-dependent cytotoxicity towards MBT-2 cells, whereas no cytotoxicity was observed with PMB30W. In the orthotopic bladder cancer model, intravesical administration of PTX-30W resulted in a significant reduction of bladder wet weight compared with that of PTX-CrEL. The paclitaxel concentration in bladder tumors after the intravesical treatment was significantly higher in PTX-30W treated mice than in PTX-CrEL treated mice. Conclusions: Intravesically administered PTX-30W can elicit stronger antitumor effects on bladder tumors than conventional paclitaxel formulated in Cremophor, presumably because of its better penetration into tumor cells. PTX-30W might be a promising antitumor agent for intravesical treatment of non-muscle invasive bladder cancer.

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The efficacy of enzalutamide in castration resistant prostate cancer

Kosaka Takeo, Oya Mototsugu

Japanese Journal of Clinical Urology 69 ( 5 ) 386 - 392 2015.04

ISSN 0385-2393

Impact of an adjuvant chemotherapeutic regimen on the clinical outcome in high risk patients with upper tract urothelial carcinoma

Shirotake Suguru, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyazaki Yasumasa, Kobayashi Hiroaki, Ide Hiroki, Obata Jun, Hoshino Katsura, Kaneko Gou, Hagiwara Masayuki, Kosaka Takeo, Kanao Kent, Kodaira Kiichiro, Hara Satoshi, Oyama Masafumi, Momma Tetsuo, Miyajima Akira, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

Journal of Urology 193 ( 4 ) 1122 - 1128 2015.04

ISSN 0022-5347

Purpose Current guidelines do not yet provide any recommendations for adjuvant chemotherapy in patients with upper tract urothelial carcinoma managed with radical nephroureterectomy. We evaluated whether an adjuvant chemotherapeutic regimen would affect the clinical outcome in patients with high risk upper tract urothelial carcinoma. Materials and Methods We identified 873 patients who had undergone radical nephrouretectomy for localized upper tract urothelial carcinoma at 14 Japanese institutions between 1993 and 2011. We assessed whether the type of regimen, such as methotrexate, vinblastine, doxorubicin and cisplatin, and gemcitabine and cisplatin, in an adjuvant setting, could affect the subsequent clinical outcome of patients with upper tract urothelial carcinoma. Results On multivariate analysis pathological T stage, tumor grade, lymphovascular invasion and lymph node involvement were prognostic factors for recurrence-free survival and cancer specific survival. We defined 229 patients with 3 or more of these factors as the high risk group. In an analysis according to adjuvant regimen, Kaplan-Meier curves showed that the 1 and 2-year recurrence-free survival rates in the methotrexate, vinblastine, doxorubicin and cisplatin treated group were 71.4% and 47.9%, which were significantly higher than in the gemcitabine and cisplatin treated group (48.2% and not reached, p=0.022) or those not treated with adjuvant chemotherapy (53.4% and 39.6%, p=0.039). Similar results were observed in terms of cancer specific survival. Conclusions Our study showed that pT3-4, tumor grade 3, positive lymphovascular invasion and lymph node involvement were independent risk factors for disease mortality in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy. In the high risk group methotrexate, vinblastine, doxorubicin and cisplatin adjuvant chemotherapy contributed to improve subsequent mortality compared to gemcitabine and cisplatin or no adjuvant chemotherapy.

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Expression of TNF-α and CD44 is implicated in poor prognosis, cancer cell invasion, metastasis and resistance to the sunitinib treatment in clear cell renal cell carcinomas

Mikami Shuji, Mizuno Ryuichi, Kosaka Takeo, Saya Hideyuki, Oya Mototsugu, Okada Yasunori

International Journal of Cancer 136 ( 7 ) 1504 - 1514 2015.04

ISSN 0020-7136

Tumor necrosis factor-α (TNF-α) is involved in epithelial-mesenchymal transition (EMT) and expression of CD44, a cancer stem cell marker, in several cancers. This study was performed to clarify the significance of TNF-α and CD44 in clear cell renal cell carcinomas (ccRCCs). Expression of TNF-α and CD44 was examined by immunohistochemistry in 120 ccRCCs. Involvement of TNF-α in EMT and induction of CD44 was analyzed by monitoring expression of EMT-related genes and CD44, and invasion in cultured ccRCC cell lines. TNF-α and CD44 were immunolocalized mainly to carcinoma cells of high-grade ccRCCs with positive correlations with primary tumor stage. A positive correlation was also obtained between TNF-α and CD44 expression, and co-upregulation of TNF-α and CD44 was associated with primary tumor stage, distant metastasis, and poor prognosis. TNF-αenhanced migration and invasion of ccRCC cells together with down-regulation of E-cadherin expression and up-regulation of matrix metalloproteinase 9 and CD44 expression. TNF-α also up-regulated the expression of TNF-α itself in ccRCC cells. Among the 25 ccRCC patients treated with sunitinib for metastatic disease, high CD44 expression was associated with poor treatment outcome. Importantly, residual carcinoma cells in the sunitinib-treated metastatic ccRCCs were strongly positive for CD44, and the CD44 expression was significantly higher in the tumors from the sunitinib-treated patients than in those from untreated ones. Our data show that TNF-α plays an important role in progression of ccRCCs by inducing EMT and CD44 expression, and suggest that CD44 induced by TNF-α may be involved in the resistance to the sunitinib treatment.

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How does visceral obesity affect surgical performance in laparoscopic radical nephrectomy?

Yuge Kazuyuki, Miyajima Akira, Jinzaki Masahiro, Kaneko Gou, Hagiwara Masayuki, Hasegawa Masanori, Takeda Toshikazu, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 4 ) 373 - 377 2015.04

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Down-regulation of NF kappa B activation is an effective therapeutic modality in acquired platinum-resistant bladder cancer

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Kosaka Takeo, Suzuki Eriko, Mizuno Ryuichi, Shinojima Toshiaki, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

BMC CANCER 15 2015.04

Research paper (scientific journal), Joint Work, ISSN 1471-2407

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Clinical efficacy and prognostic factors of tumor progression in Japanese patients with advanced renal cell carcinoma treated with sorafenib

Kondo Tsunenori, Nakazawa Hayakazu, Oya Mototsugu, Kimura Go, Fujii Yasuhisa, Hatano Takashi, Kawata Nozomu, Kume Haruki, Morita Masashi, Nakajima Koichi, Ohno Yoshio, Okegawa Takatsugu, Takahashi Shunji, Wakumoto Yoshiaki, Horie Shigeo

Japanese Journal of Clinical Oncology 45 ( 3 ) 274 - 280 2015.03

ISSN 0368-2811

Objective: Result of clinical trial for registration purpose is often difficult to generalize because of its limited population in number and inclusion criteria. Methods: To understand the efficacy of sorafenib under daily medical practice, we retrospectively investigated therapeutic outcomes of 175 Japanese patients with advanced renal cell carcinoma treated with sorafenib at 15 centers. Results: The objective response rate and disease control rate were 15.4 and 77.1%, respectively, being similar to those in the Phase II study in Japanese patients (19.4 and 73.6 months). Any tumor shrinkage was observed with 53% of patients, while tumor control without growth was in 61%. Lung lesions were more sensitive to sorafenib than other lesions, in terms of any tumor shrinkage (54%) and the extent of maximal shrinkage, while tumor control was better in lymph node metastases (77%) than in lung (69%). Liver was worse in any tumor shrinkage (35%), tumor control (55%) and the extent of tumor growth. Slightly, shorter median overall survival of 21.1 months compared with Phase II clinical trial (25.3 months) is likely to be attributable to different patient population, because median overall survival was improved to 26.4 months when the population was matched to that in Phase II trial. Univariate and multivariate analyses identified prognostic factors for worse overall survival, including intermediate and poor Memorial Sloan-Kettering Cancer Center risk, Eastern Cooperative Oncology Group performance status ≥1, the presence of non-clear cell component and the presence of liver metastasis.Conclusions: In conclusion, the present study confirmed the efficacy of sorafenib in the real-world setting on advanced renal cell carcinoma.

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Prognostic Impact of Renin–Angiotensin System Blockade on Renal Cell Carcinoma After Surgery

Miyajima Akira, Yazawa Satoshi, Kosaka Takeo, Tanaka Nobuyuki, Shirotake Suguru, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

Annals of Surgical Oncology 22 ( 11 ) 3751 - 3759 2015.02

ISSN 1068-9265

Background: Angiotensin 2 is a key biologic peptide in the renin–angiotensin system (RAS) that regulates blood pressure and renal hemodynamics. The potential role of the RAS in the promotion of tumor growth, angiogenesis, and metastasis also has been shown in the past few decades. This study investigated the prognostic impact of RAS blockade on patients with renal cell carcinoma (RCC) after surgery. Methods: The study identified 557 patients with pathologically diagnosed RCC (pT1-4 N0M0) and evaluated the prognostic factors after surgery for patients administered or not administered angiotensin-converting enzyme inhibitors (ACEs) or angiotensin 2 receptor blockers (ARBs). Results: The median follow-up period was 5.1 years. Radical nephrectomy was performed for 349 patients (62.7 %), whereas the remaining 208 patients (37.3 %) underwent partial nephrectomy. A total of 104 patients (18.7 %) were administered RAS inhibitors: ACEs (n = 22) or ARBs (n = 82). Multivariate analysis showed that administration of RAS inhibitors (P = 0.044; HR 2.69), longer tumor length (P < 0.001; HR 1.02), high-grade tumor (P < 0.001; HR 3.55), and positive microvascular invasion (P < 0.003; HR 3.13) were not independent risk factors for a decrease in subsequent disease-specific survival after surgery for RCC. The 5-year disease-specific survival rate was 96.8 % among the patients administered RAS inhibitors and 89.8 % among their counterparts (P = 0.019). Conclusions: The authors propose renin–angiotensin blockade as a possible potent choice for effective treatment after surgical treatment of RCC.

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Effect and adverse event of enzalutamide and abiraterone in prostate cancer

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 73 308 - 312 2015.02

ISSN 0047-1852

Visceral obesity is associated with better recurrence-free survival after curative surgery for Japanese patients with localized clear cell renal cell carcinoma

Kaneko Gou, Miyajima Akira, Yuge Kazuyuki, Yazawa Satoshi, Mizuno Ryuichi, Kikuchi Eiji, Jinzaki Masahiro, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 45 ( 2 ) 210 - 216 2015.02

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Bladder metastasis from renal cell carcinoma: retrospective analysis of 65 reported cases

Matsumoto Kazuhiro, Hayakawa Nozomi, Nakamura So, Oya Mototsugu

CLINICAL & EXPERIMENTAL METASTASIS 32 ( 2 ) 135 - 141 2015.02

Research paper (scientific journal), Joint Work, ISSN 0262-0898

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New year's greetings

Oya Mototsugu

International Journal of Urology 22 ( 1 ) 1 2015.01

ISSN 0919-8172

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Evidenced-based clinical practice guideline for upper tract urothelial carcinoma (summary - Japanese Urological Association, 2014 edition)

Oya Mototsugu, Kikuchi Eiji

International Journal of Urology 22 ( 1 ) 3 - 13 2015.01

ISSN 0919-8172

Upper tract urothelial carcinoma is more rare than bladder cancer, although they are both categorized as urothelial carcinoma. Because of the low incidence, little clinical evidence is available regarding the treatment of the former. However, recently such evidence has slowly begun to accumulate. The guideline presented herein was compiled for the purpose of ensuring proper diagnosis and treatment by physicians involved in the treatment of upper tract urothelial carcinoma. We carefully selected 16 clinical questions essential for daily clinical practice and grouped them into four major categories: epidemiology, diagnosis, surgery and systemic chemotherapy/other matters. Related literature was searched using PubMed and Japan Medical Abstracts Society databases for articles published between 1987 and 2013. If the judgment was made on the basis of insufficient or inadequate evidence, the grade of recommendation was determined on the basis of committee discussions and resultant consensus statements. Here, we present a short English version of the original guideline, and overview its key clinical issues.

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Bladder metastasis from renal cell carcinoma

Matsumoto Kazuhiro, Hayakawa Nozomi, Nakamura So, Oya Mototsugu

Clinical and Experimental Metastasis 32 ( 2 ) 135 - 141 2015

ISSN 0262-0898

This study was carried out to clarify the presentation, treatment options, and prognosis of renal cell carcinoma (RCC) metastasis to the bladder in which we do not yet have a comprehensive understanding. A systematic Medline, Web of Science, Embase, Google, and Ichushi Web search was performed to identify articles describing RCC metastasis to the bladder. The final cohort included 65 patients. The majority (75 %) experienced gross hematuria at the point of diagnosis of RCC. RCC metastasis to the bladder occurred both synchronously (23 %) and metachronously (77 %), and the median time for metachronous bladder metastasis following the diagnosis of RCC was 33 months. Of the 58 patients whose metastatic data were available, 36 (62 %) had metastasis to the bladder only, while 22 (38 %) had additional sites of metastasis. On pathology, clear cell carcinoma was the most common histology (92 %) and all bladder tumors were consistent with RCC metastasis; the median tumor size was 2.1 cm, and two-thirds of cases were superficial (non-muscle invasive) disease. The 2-year cancer-specific survival rate in patients with solitary bladder metastasis was 71.1 %, which was significantly higher than in patients with additional distant metastasis (25.8 %, p = 0.007). Regarding the interval after the diagnosis of primary RCC, the 2-year cancer-specific survival rate in patients who experienced bladder metastasis after more than a 1 year follow-up was 58.4 %, compared to 34.6 % in their counterparts (p = 0.063). A curative resection may provide a good possibility of long-term survival, particularly in those with a solitary bladder metastasis and/or a long interval after nephrectomy.

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Limited in vitro efficacy of CYP17A1 inhibition on human castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Yasumizu Yota, Miyazaki Yasumasa, Kikuchi Eiji, Oya Mototsugu

Steroids 92 39 - 44 2014.12

ISSN 0039-128X

Although accumulating evidence indicates high expression of CYP17A1(P45017A1) allows castration resistant prostate cancer (CRPC) to maintain high intratumoral androgen levels, the potential P45017A1 activity has not been characterized yet. The aim of this study was to examine the potential CYP17A1 activity including 17α-hydroxylase and 17,20-lyase activities in human CRPC and the effect of a CYP17A inhibitor. We used three human CRPC cell lines: C4-2 and C4-2AT6 which was established from C4-2 under androgen ablation conditions for 6 months, and PC3. To ascertain the potential CYP17A1 activity, we cultured with the steroid precursors: ¹³C-[2,3,4]-progesterone (13C-Prog), and analyzed the sequential biosynthesis ¹³C-[2,3,4]-17-hydroxyprogesterone (13C-17OHP) and ¹³C-[2,3,4]-androstenedione(13C-Adione) by liquid chromatography/mass spectrometry (LC/MS/MS).The C4-2AT6 cells showed significantly higher CYP17A1 expression than C4-2 cells (p < 0.001). LC/MS/MS analysis enabled us to detect the 13C-17-OHP and 13C-A-dione in these cell lines. The concentration ratio of 13C-Adione/13C-17OHP (Adione-17OHP ratio), which is thought to reflect the differences between 17-hydroxylase and 17,20-lyase activities, was then determined. The Adione-17OHP ratio in C4-2AT6 cells was significantly higher than that of C4-2 cells (p < 0.001). Abiraterone were able to inhibit the CYP17A activities, although abiraterone did not have anti-proliferative effects on C4-2 and C4-2AT6 cells at clinically achievable concentrations of <1000 nM in vitro. The present study clearly demonstrates CRPC have the dual activities of CYP17A1 mediated by 17-hydroxylase activity and 17,20-lyase activity. Abiraterone doesn't have an in vitro anti-proliferative efficacy in CRPC cells, suggesting limited efficacy in vitro.

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Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Journal of the Canadian Urological Association 8 ( 11-12 DECEMBER ) e921 - e923 2014.12

ISSN 1911-6470

An 80-year-old man with an elevated prostate-specific antigen (PSA) level of 120 ng/mL) presented to the hospital in February 2011. A prostate needle biopsy was performed, and pathological examination revealed prostatic adenocarcinoma. The Gleason score was 4+5=9. Computed tomography revealed metastases of the pelvic lymph nodes. Combined androgen blockade was started. The PSA concentration decreased to 1.68 ng/mL, but started increasing again in August 2012 to 6.08 ng/mL. Although bicalutamide was discontinued due to antiandrogen withdrawal syndrome, the PSA concentration increased even more. The PSA concentration reached 21.62 ng/mL in September 2012, at which time ethnylestradiol was started. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2 years. To our knowledge, this is first case report describing a complete response to ethnylestradiol that lasted for almost 2 years in a patient with castration-resistant prostate cancer.

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[Molecular targeting drug of kinase inhibitors for castration resistant prostate cancer]

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 72 ( 12 ) 2186 - 2192 2014.12

ISSN 0047-1852

Prostate cancer (PCa) is the most common cancer type in men. One of the most troublesome aspects of PCa is that androgen-dependent PCa inevitably progresses to highly aggressive and life-threatening castration resistant prostate cancer (CRPC). Kinases are key regulators of critical cancer processes such as cancer cell proliferation, invasion, differentiation or angiogenesis. Recent advances have shed light on molecular targeting inhibitors of kinases in CRPC. Aberrant expression of certain kinases has been implicated in the development and progression of PCa. Among them, some kinase inhibitors have emerged as promising drug targets for CRPC. In this review, we provide an overview of new therapeutic agents which arrived in an advanced stage of clinical testing, especially focusing on the targets of HGF/c-Met and PI3K/AKT/mTOR signaling pathways.

Complete response to ethnylestradiol prolonged for almost two years in patients with castration-resistant prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

CUAJ-CANADIAN UROLOGICAL ASSOCIATION JOURNAL 8 ( 11-12 ) E921 - E923 2014.12

Research paper (scientific journal), Joint Work, ISSN 1911-6470

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A Multi-Institutional Validation of the Prognostic Value of the Neutrophil-to-Lymphocyte Ratio for Upper Tract Urothelial Carcinoma Treated with Radical Nephroureterectomy

Annals of Surgical Oncology 21 ( 12 ) 4041 - 4048 2014.10

ISSN 1068-9265

Background: To externally validate the prognostic impact of preoperative neutrophil–lymphocyte ratio (pre-NLR) in patients with upper tract urothelial carcinoma (UTUC) following radical nephroureterectomy (RNU).Methods: A total of 665 patients from 12 institutions were included. The median follow-up was 28 months. Associations between pre-NLR level and outcome were assessed using multivariate analysis. A pre-NLR level of >3.0 was defined as elevated.Results: Pre-NLR levels were elevated in 184 patients (27.7 %), and pre-NLR elevation was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive lymphovascular invasion (LVI), and lymph node involvement in RNU specimens. The 5-year recurrence-free and cancer-specific survival rates were 57.0 % (p < 0.001) and 60.2 % (p < 0.001), respectively, in patients with elevated pre-NLR, and 69.2 and 77.3 %, respectively, in their counterparts. Multivariate analysis showed that elevated pre-NLR was an independent risk factor for predicting subsequent disease recurrence (p = 0.037; hazard ratio (HR) 1.38) and cancer-specific mortality (p = 0.036;, HR 1.47), although the addition of pre-NLR slightly improved the accuracies of the base model for predicting both disease recurrence and cancer-specific mortality to 79.8 % (p = 0.041) and 83.0 % (p = 0.039), respectively (gain in predictive accuracy: 0.2 and 0.1 %, respectively).Conclusion: This multi-institutional study revealed that elevated pre-NLR was significantly associated with worse pathological features such as tumor grade 3, advanced pT stage, positive LVI, and lymph node involvement in RNU specimens, and elevated pre-NLR was an independent risk factor of disease recurrence and cancer-specific mortality in UTUC patients treated with RNU.

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Recent trends in the initial therapy for newly diagnosed prostate cancer in Japan

Onozawa Mizuki, Hinotsu Shiro, Tsukamoto Taiji, Oya Mototsugu, Ogawa Osamu, Kitamura Tadaichi, Suzuki Kazuhiro, Naito Seiji, Namiki Mikio, Nishimura Kazuo, Hirao Yoshihiko, Akaza Hideyuki

Japanese Journal of Clinical Oncology 44 ( 10 ) 969 - 981 2014.10

ISSN 0368-2811

OBJECTIVE: The objective of the present study was to investigate the trends over time in the initial treatment of prostate cancer in Japan.METHODS: A total of 8291 patients with newly diagnosed prostate cancer whose treatment started in 2010 were registered in a multi-institutional observational study undertaken nationwide across Japan by the Japan Prostate Cancer Study Group. Each patient's background characteristics and initial treatment were recorded.RESULTS: The median age at diagnosis was 71 years. The proportion of T1c disease was 40.5% and that of M1 disease was 10.4%. The prostate-specific antigen level was <10 ng/ml in 52.0% of the patients. High-, intermediate- and low-risk patients as determined by D'Amico's classification system made up 19.3, 29.8 and 25.9% of the cases, respectively. The initial treatment was androgen depletion therapy in 40.2%, radical prostatectomy in 32.0% (17.3% of these involved laparoscopic prostatectomy), radiation in 21.0% (46.4% of these involved brachytherapy). In cases of organ-confined disease, radical prostatectomy was selected in 39.5%, androgen depletion therapy in 28.0% and radiation in 23.9%. In D'Amico's low-risk group, the proportion treated with radiation was nearly equal to that treated with radical prostatectomy (30.2 and 32.7%, respectively); 73.2% of the radiation treatments involved brachytherapy.CONCLUSION: Compared with previous Japanese studies, radiation use was increased by ∼10%. This increased proportion of radiation use was a typical trend in initial therapy for newly diagnosed prostate cancer cases in Japan. Although androgen depletion therapy use was decreased, it was selected in a high proportion of the patients irrespective of the disease stage.

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Clinical pearls in treatment for the patients of adrenal tumor

Hattori Seiya, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Urology 68 ( 11 ) 822 - 825 2014.10

ISSN 0385-2393

Erratum

Togo Yoshikazu, Kubo Tatsuhiko, Taoka Rikiya, Hiyama Yoshiki, Uehara Teruhisa, Hashimoto Jiroh, Kurimura Yuichiro, Takahashi Satoshi, Tsukamoto Taiji, Miyazaki Jun, Nishiyama Hiroyuki, Kira Shinichiro, Kiyota Hiroshi, Yazawa Satoshi, Niwa Naoya, Hongo Hiroshi, Oya Mototsugu, Kato Taku, Yasuda Mitsuru, Deguchi Takashi, Ishikawa Kiyohito, Hoshinaga Kiyotaka, Matsumoto Minori, Shigemura Katsumi, Tanaka Kazushi, Arakawa Soichi, Fujisawa Masato, Wada Koichiro, Uehara Shinya, Watanabe Toyohiko, Kumon Hiromi, Kobayashi Kanao, Matsubara Akio, Matsumoto Masahiro, Sho Takehiko, Hamasuna Ryoichi, Matsumoto Tetsuro, Hayami Hiroshi, Nakagawa Masayuki, Yamamoto Shingo

Journal of Infection and Chemotherapy 20 ( 10 ) 660 2014.10

ISSN 1341-321X

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Expression level of dihydropyrimidine dehydrogenase is associated with clinical outcome in patients with T1G3 bladder cancer treated with Bacillus Calmette-Guerin

Ide Hiroki, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Oya Mototsugu

BMC Research Notes 7 ( 1 ) 2014.09

Background: Recently, it has been shown that 5-fluorouracil (5-FU) with a strong dihydropyrimidine dehydrogenase (DPD) inhibitor elicits a significant response in bladder cancer with a high level of DPD. However, only a few studies investigated the association between the level of the enzyme that regulates the metabolism of 5-FU and prognosis in bladder cancer. Furthermore, to our knowledge, there has also been no such report in T1G3 bladder tumors treated with BCG. Therefore, we evaluated enzymes that regulate the metabolism of 5-FU in T1G3 tumors treated with BCG immunotherapy using the Danenberg tumor profile (DTP) method, a highly accurate measurement of RNA from paraffin-embedded specimens. Methods. This study included 28 patients with T1G3 bladder cancer, each of whom underwent complete transurethral tumor resection and BCG intravesical instillation at our institution. The median follow-up period was 39 months (range, 3 to 159 months). The DTP method was used to analyze the mRNA expression of 3 enzymes related to 5-FU: DPD, orotate phosphoribosyltransferase (OPRT), and thymidylate synthase (TS). Results: Among the 28 patients, 13 developed recurrences (46.4%) and 5 experienced disease progression (17.9%). An elevated DPD mRNA level was significantly associated with recurrence (p = 0.048) and progression (p = 0.045). However, TS and OPRT mRNA levels were not significantly associated with any other clinical features or outcomes. Furthermore, the high DPD group had a significantly lower recurrence-free survival rate than the low DPD group (p = 0.047). Among patients with low DPD, the 2- and 5-year recurrence-free survival rates were 88.9% and 74.1%, respectively; while among patients with high DPD, the corresponding rates were 61.3% and 36.8%, respectively. TS and OPRT were not significantly associated with recurrence-free survival rates. Conclusion: DPD is significantly associated with recurrence and progression among T1G3 bladder cancer patients treated with BCG.

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Unidirectional barbed suture for vesicourethral anastomosis during laparoscopic radical prostatectomy

Takeda Toshikazu, Miyajima Akira, Kaneko Gou, Hasegawa Masanori, Kikuchi Eiji, Oya Mototsugu

Asian journal of endoscopic surgery 7 ( 3 ) 241 - 245 2014.08

INTRODUCTION: We investigated the impact of unidirectional barbed suture (UBS) for vesicourethral anastomosis (VUA) during laparoscopic radical prostatectomy.METHODS: The polyglyconate UBS V-Loc 180 was used for VUA during laparoscopic radical prostatectomy in 30 consecutive patients who were diagnosed with organ-confined prostate cancer between January and October 2012. The operative and postoperative parameters were then compared with those of 30 consecutive patients who had previously undergone the same procedure but with the monofilament poliglecaprone suture Monocryl. All procedures were performed by the same experienced surgeon.RESULTS: VUA time was significantly shorter in the V-Loc group (13.2 ± 2.3 min) than in the Monocryl group (19.1 ± 3.3 min) (P < 0.001). The V-Loc group required significantly more stitches than the Monocryl group (11.4 ± 1.3 vs 10.6 ± 1.6 stitches; P = 0.031). The percentage of patients who required no more than one pad per day at 3 months postoperatively was significantly higher in the V-Loc group (63.3%) than in the Monocryl group (23.3%) (P = 0.020). No significant differences in other perioperative parameters were observed between the two groups.CONCLUSION: Using UBS prevents suture slippage and enables tieless anastomosis. VUA using a UBS may relieve surgeon stress because a rapid and secure anastomosis is achievable.

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Activity of axitinib in patients with metastatic renal cell carcinoma previously treated with both vascular endothelial growth factor receptor tyrosine-kinase inhibitor and mammalian target of rapamycin inhibitor

Mizuno Ryuichi, Miyajima Akira, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY 21 ( 7 ) 740 - 740 2014.07

Research paper (scientific journal), Joint Work, ISSN 0919-8172

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Surgical outcome of laparoscopic surgery, including laparoendoscopic single-site surgery, for retroperitoneal paraganglioma compared with adrenal pheochromocytoma

Hattori Seiya, Miyajima Akira, Hirasawa Yousuke, Kikuchi Eiji, Kurihara Isao, Miyashita Kazutoshi, Shibata Hirotaka, Nakagawa Ken, Oya Mototsugu

Journal of Endourology 28 ( 6 ) 686 - 692 2014.06

ISSN 0892-7790

Objective: Paraganglioma (PGL) is a rare type of tumor that arises from the extra-adrenal paraganglia. A PGL tumor hypersecretes catecholamines and causes symptoms identical to those in patients with hyper-functioning adrenal pheochromocytoma (PCC). In this study, we compared the surgical outcome of laparoscopic surgery, including laparoendoscopic single-site (LESS) surgery, in patients with PCC and patients with retroperitoneal solitary PGL. Methods: The records of 49 patients with PCC and 9 patients with unilateral retroperitoneal PGL at our institution from January 2001 to March 2013 were retrospectively reviewed. Multiple tumors, tumors suspected of being malignant preoperatively, and tumors operated on using a retroperitoneal approach were excluded from the study. Results: Each group was equivalent with respect to patient background, hemodynamic variables, and preoperative biochemical assessments, including plasma catecholamine levels and catecholamine levels in 24-hour urine samples. The mean operative time was significantly longer in the PGL group (149.4±56.5 minutes v 189.8±44.9 minutes, P=0.019). In univariate and multivariate analyses, tumor size ≥50 mm and PGL were statistically significant factors that predicted prolonged operative time. Intraoperative hypotension occurred in 15 patients in the PCC group and in 8 patients in the PGL group, and the difference was statistically significant (P=0.002). One postoperative complication in the PCC group and two postoperative complications (Clavien-Dindo grade II or higher) in the PGL group were observed, and the difference was statistically significant (P=0.012). Twenty-two patients in this series underwent LESS surgery (PCC: n=19; PGL: n=3), and there was no statistically significant difference in the perioperative outcomes between the two groups. Conclusions: The present results demonstrate that the operation for solitary extraperitoneal PGL required a longer operative time and had more hypotensive episodes and higher postoperative morbidity than the PCC group. Though the perioperative outcome of LESS surgery for PGL is comparable to that of PCC, we should treat the patients with PGL accordingly.

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Surgical Outcome of Laparoscopic Surgery, Including Laparoendoscopic Single-Site Surgery, for Retroperitoneal Paraganglioma Compared with Adrenal Pheochromocytoma

Hattori Seiya, Miyajima Akira, Hirasawa Yousuke, Kikuchi Eiji, Kurihara Isao, Miyashita Kazutoshi, Shibata Hirotaka, Nakagawa Ken, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 28 ( 6 ) 686 - 692 2014.06

Research paper (scientific journal), Joint Work, ISSN 0892-7790

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Renal angiomyolipoma: a radiological classification and update on recent developments in diagnosis and management

Jinzaki Masahiro, Silverman Stuart G., Akita Hirotaka, Nagashima Yoji, Mikami Shuji, Oya Mototsugu

ABDOMINAL IMAGING 39 ( 3 ) 588 - 604 2014.06

Research paper (scientific journal), Joint Work, ISSN 0942-8925

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Androgen deprivation therapy improves pneumoperitoneum time during laparoscopic radical prostatectomy in Japanese patients with enlarged prostates

Takeda Toshikazu, Miyajima Akira, Kaneko Gou, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Asian journal of endoscopic surgery 7 ( 2 ) 145 - 151 2014.05

INTRODUCTION: The aim of this study was to investigate if neoadjuvant hormone therapy (NHT) is associated with surgical outcomes of laparoscopic radical prostatectomy.METHODS: A total of 286 patients with organ-confined prostate cancer and a preoperative prostate volume that could be estimated by transrectal ultrasound underwent laparoscopic radical prostatectomy between 2006 and 2011 at our institution. We examined whether NHT was associated with pneumoperitoneum time (PT) or estimated blood loss during laparoscopic radical prostatectomy.RESULTS: NHT was performed in 80 patients; the mean duration of NHT was 5.2 ± 0.2 months. Multivariate analysis demonstrated that history of NHT and no NHT were not independent predictors of prolonged PT or higher estimated blood loss. Next, we evaluated 57 patients whose estimated preoperative baseline prostate volume was over 50 mL. Multivariate analysis demonstrated that no history of NHT (P = 0.011) was an independent predictor of prolonged PT. PT was significantly shorter in the NHT group (164.5 ± 39.0 min, n = 26) than in the non-NHT group (184.0 ± 36.7 min, n = 31) (P = 0.048). In the NHT group, mean prostate volume was reduced from 63.7 ± 16.0 mL to 42.1 ± 18.6 mL (33.9% reduction) by NHT.CONCLUSION: NHT shortened the PT of the patients whose preoperative baseline prostate volume was over 50 mL. This suggests NHT downsized prostate volume, resulting in greater working space and shorter PT.

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Erythrocyte protein bond 4.1-like5 expression in patients with upper urinary tract urothelial carcinoma correlates with tumor recurrence

Daimon Tatsuaki, Kosaka Takeo, Mikami Shuji, Miyazaki Yasumasa, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Sabe Hisataka, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 32 ( 15 ) E264 - E264 2014.05

Research paper (scientific journal), Joint Work, ISSN 0732-183X

METABOLIC SHIFT UNDER HYPOXIC ENVIRONMENT CAUSES RESISTANCE TO MTOR INHIBITOR IN HUMAN CASTRATION RESISTANT PROSTATE CANCER.

Yasumizu Yota, Kosaka Takeo, Miyazaki Yasumasa, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E264 - E264 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

THERAPEUTIC EFFECT BY TARGETING BCL-XL PROTEIN IN UROTHELIAL CARCINOMA CELLS

Yoshimine Shunsuke, Kikuchi Eiji, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E230 - E230 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

METFORMIN IS A NEW THERAPEUTIC STRATEGY FOR TARGETING CD44 VARIANT IN BLADDER CANCER

Hagiwara Masayuki, Kikuchi Eiji, Kosaka Takeo, Yuge Kazuhiro, Yasumizu Yota, Saya Hideyuki, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E431 - E431 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

ERECTILE FUNCTION IS HIGHLY ASSOCIATED WITH PROSTATE-SPECIFIC ANTIGEN BOUNCE IN LOCALIZED PROSTATE CANCER PATIENTS TREATED WITH PERMANENT PROSTATE BRACHYTHERAPY

Matsushima Masashi, Kikuchi Eiji, Maeda Takahiro, Ando Toshiyuki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E334 - E334 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

DEVELOPMENT OF AN ALGORITHM FOR PREDICTING SEVERE ACUTE EPIDIDYMITIS

Hongo Hiroshi, Shinojima Toshiaki, Yazawa Satoshi, Kanao Kent, Morita Shinya, Kosaka Takeo, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Nagata Hirohiko, Asanuma Hiroshi, Miyajima Akira, Nakagawa Ken, Saito Shiro, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E160 - E160 2014.04

Research paper (scientific journal), ISSN 0022-5347

INCREASED EXPRESSION OF ARYL HYDROCARBON RECEPTOR IN CLEAR CELL RENAL CELL CARCINOMA AND INFILTRATING LYMPHOCYTES: IMPLICATIONS FOR CANCER INVASION, PROGNOSIS AND TUMOR IMMUNITY

Ishida Masaru, Mikami Shuji, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Okada Yasunori, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E304 - E305 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

AXL IS A NOVEL PROGNOSTIC MARKER IN UPPER URINARY TRACT UROTHELIAL CARCINOM

Hattori Seiya, Kikuchi Eiji, Kosaka Takeo, Miyajima Akira, Mikami Shuji, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E297 - E297 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

PROSPECTIVE EVALUATION OF EFFICACY AND SAFETY OF SOLIFENACIN AND MIRABEGRON TREATMENT IN BPH PATIENTS TREATED WITH DUTASTERIDE BUT HAVING OAB SYMPTOMS

Ishioka Katsura, Kikuchi Eiji, Maeda Takahiro, Hasegawa Masanori, Kosaka Takeo, Shinojima Toshiaki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E670 - E671 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

METABOLIC SHIFT UNDER HYPOXIC ENVIRONMENT CAUSES RESISTANCE TO MTOR INHIBITOR IN HUMAN CASTRATION RESISTANT PROSTATE CANCER.

Yasumizu Yota, Kosaka Takeo, Miyazaki Yasumasa, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

JOURNAL OF UROLOGY 191 ( 4 ) E264 - E264 2014.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Metastatic behavior of upper tract urothelial carcinoma after radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Ide Hiroki, Miyazaki Yasumasa, Obata Jun, Hoshino Katsura, Shirotake Suguru, Akita Hirotaka, Kosaka Takeo, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Jinzaki Masahiro, Oya Mototsugu

Annals of Surgical Oncology 21 ( 3 ) 1038 - 1045 2014.03

ISSN 1068-9265

Purpose: To investigate the site-specific pattern of disease recurrence and/or metastasis and the associated patient outcomes after radical nephroureterectomy (RNU) in upper tract urothelial carcinoma (UTUC). Methods: A total of 733 patients with UTUC from a retrospective multi-institutional cohort were included, with a median follow-up of 34 months. Associated patient outcomes were analyzed by multivariate analysis. To evaluate the influence of primary tumor location, we divided it into four areas: renal pelvis, and upper, middle, and lower ureter. Results: A total of 218 patients experienced disease recurrence, with the majority of relapses occurring within the first 3 years. Cumulative incidence rates of first disease recurrence at 1 and 3 years were 18.9 and 29.8 %, respectively. Of these patients, 38.5 % developed distant recurrence; 17.4 % experienced both local and distant recurrences; and 44.0 % developed isolated local recurrence. The predominant sites of distant metastasis were lung, liver, and bone. Multivariate analysis revealed that the prevalence of local recurrence and lung metastasis was significantly associated, with primary tumor location being independent of other clinicopathological variables. Lower/middle ureter tumors had a higher rate of local recurrence in the pelvic cavity, and renal pelvic tumors had a higher prevalence of distant relapse in the lungs. Similar results were obtained when rerunning the data set by excluding patients who received adjuvant chemotherapy (n = 131). Conclusions: This multi-institutional study provided a detailed picture of metastatic behavior after RNU, and primary tumor locations were associated with unique patterns of metastatic spread in UTUC patients.

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Metastatic Behavior of Upper Tract Urothelial Carcinoma After Radical Nephroureterectomy: Association with Primary Tumor Location

ANNALS OF SURGICAL ONCOLOGY 21 ( 3 ) 1038 - 1045 2014.03

Research paper (scientific journal), Joint Work, ISSN 1068-9265

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Sunitinib versus sorafenib as first-line therapy for patients with metastatic renal cell carcinoma with favorable or intermediate MSKCC risk factors: A multicenter randomized trial, CROSS-J-RCC.

Tomita Yoshihiko, Naito Sei, Sassa Naoto, Takahashi Atsushi, Kondo Tsunenori, Koie Takuya, Obara Wataru, Kobayashi Yasuyuki, Teishima Jun, Takahashi Masayuki, Matsuyama Hideyasu, Ueda Takeshi, Yamaguchi Kenya, Kishida Ken, Shiroki Ryoichi, Saika Takashi, Nobuo Shinohara, Oya Mototsugu, Kanayama Hiro-Omi

JOURNAL OF CLINICAL ONCOLOGY 32 ( 4 ) 619 - 624 2014.02

Research paper (scientific journal), Joint Work, ISSN 0732-183X

Multicenter phase II clinical trial of everolimus in Japanese patients with unresectable or metastatic renal cell carcinoma (mRCC) after failure of treatment with first-line tyrosine kinase inhibitor (TKI) therapy

Ozono Seiichiro, Oyama Masafumi, Nozawa Masahiro, Fujimoto Kiyohide, Kishida Ken, Tokuda Noriaki, Kimura Go, Nishimura Kazuo, Matsubara Akio, Matsuyama Hideyasu, Sugiyama Takayuki, Kamba Tomomi, Kume Haruki, Masumori Naoya, Oya Mototsugu, Kanayama, Hiro-Omi, Naito, Seiji, Hinotsu, Shiro, Shimozuma, Kojiro, Akaza, Hideyuki

JOURNAL OF CLINICAL ONCOLOGY 32 ( 4 ) 853 - 863 2014.02

Research paper (scientific journal), Joint Work, ISSN 0732-183X

Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors

Kobayashi Hiroaki, Kikuchi Eiji, Mikami Shuji, Maeda Takahiro, Tanaka Nobuyuki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

BMC Urology 14 ( 1 ) 2014.01

Background: We evaluated the clinical outcome of low grade Ta bladder cancer followed-up for a long period using the 2004 WHO grading system. Methods. We retrospectively reviewed 190 patients with primary, low grade Ta bladder cancer. We defined worsening progression (WP) as confirmed high grade Ta, all T1 or Tis/concomitant CIS of bladder recurrence, upper urinary tract recurrence (UTR), or progression to equal to or more than T2. The associations between clinicopathological factors and tumor recurrence as well as WP pattern were analyzed. We also evaluated the late recurrence of 76 patients who were tumor-free for more than 5 years. Results: Tumor recurrence and WP occurred in 82 (43.2%) and 21 (11.1%) patients during follow-up (median follow-up: 101.5 months), respectively. WP to high grade Ta, all T1 or Tis/concomitant CIS was seen in 17 patients, and UTR and progression to equal to or more than T2 were seen in 2 and 2 patients, respectively. Multivariate analyses demonstrated that multiple tumor (p < 0.001, HR: 2.97) and absence of intravesical instillation (IVI) (p < 0.001, HR: 2.88) were significant risk factors for tumor recurrence while multiple tumor was the only risk factor for WP (p = 0.001, HR: 5.26). After a 5-year tumor-free period, 9 patients experienced late recurrence in years 5 and 10 and were diagnosed at a follow-up cystoscopy, however, only 2 patients recurred beyond 10 years and were found by gross hematuria. There were no significant risk factors of late recurrence. Conclusions: Multiple tumor was a risk factor for both tumor recurrence and WP while IVI did not affect the occurrence of WP. Our results suggest that routine follow-up of patients with low grade Ta bladder cancer is needed up to 10 years from the initial diagnosis.

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The predictive value of positive urine cytology for outcomes following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Kosaka Takeo, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Jinzaki Masahiro, Nakajima Yosuke, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 32 ( 1 ) 2014.01

ISSN 1078-1439

Background and objective: Few studies have addressed the predictive value of positive urine cytology for prognosis in patients with upper tract urothelial carcinoma (UTUC). We investigated whether the status of preoperative urine cytology could provide additional prognostic information following radical nephroureterectomy (RNU). Materials and methods: The study included 474 patients with primary nonmetastatic UTUC (pTa-4N0M0) from a retrospective multi-institutional cohort. The median follow-up period was 35 months. Associations between the status of urine cytologic evaluation and outcomes were analyzed using multivariate Cox regression models. Urine cytology was evaluated preoperatively using voided samples. Disease recurrence was defined as any relapse in nonbladder lesions and was coded separately from intravesical recurrence. Results: Positive urine cytology was detected in 184 patients (38.8%) preoperatively. Disease recurrence occurred in 127 patients, while intravesical recurrence occurred in 219 patients; 83 patients died of UTUC during follow-up. Kaplan-Meier analysis revealed that only the incidence of intravesical recurrence was significantly associated with the status of urine cytologic evaluation (P = 0.024); the intravesical recurrence-free survival rates at 1 and 3 years following RNU were 61.4% and 46.2% in patients with positive urine cytology and 71.1% and 51.6% in their counterparts, respectively. Multivariate analysis showed that gender (hazard ratio [HR] = 1.74, 95% confidence interval [CI]; 1.28-2.43), tumor multifocality in RNU specimens (HR = 1.64, 95% CI; 1.09-2.47), and positive urine cytology (HR = 1.41, 95% CI; 1.08-1.85) were independent risk factors for subsequent intravesical recurrence. Conclusions: The results showed the prognostic value of positive urine cytology in patients with primary UTUC, and preoperative positive urine cytology may be associated with a significant increase in the prevalence of intravesical recurrence following RNU.

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Occurrence of infection following prostate biopsy procedures in Japan Japanese Research Group for Urinary Tract Infection (JRGU) - A multi-center retrospective study

Togo Yoshikazu, Kubo Tatsuhiko, Taoka Rikiya, Hiyama Yoshiki, Uehara Teruhisa, Hashimoto Jiroh, Kurimura Yuichiro, Takahashi Satoshi, Tsukamoto Taiji, Miyazaki Jun, Nishiyama Hiroyuki, Kira Shinichiro, Kiyota Hiroshi, Yazawa Satoshi, Niwa Naoya, Hongo Hiroshi, Oya Mototsugu, Kato Taku, Yasuda Mitsuru, Deguchi Takashi, Ishikawa Kiyohito, Hoshinaga Kiyotaka, Matsumoto Minort, Shigemura Katsumi, Tanaka Kazushi, Arakawa Soichi, Fujisawa Masato, Wada Koichiro, Uehara Shinya, Watanabe Toyohiko, Kumon Hiromi, Kobayashi Kanao, Matsubara Akio, Matsumoto Masahiro, Sho Takehiko, Hamasuna Ryoichi, Matsumoto Tetsuro, Hayami Hiroshi, Nakagawa Masayuki, Yamamoto Shingo

JOURNAL OF INFECTION AND CHEMOTHERAPY 20 ( 3-4 ) 232 - 237 2014.01

Research paper (scientific journal), Joint Work, ISSN 1341-321X

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Long term follow-up in patients with initially diagnosed low grade Ta non-muscle invasive bladder tumors: tumor recurrence and worsening progression

Kobayashi Hiroaki, Kikuchi Eiji, Mikami Shuji, Maeda Takahiro, Tanaka Nobuyuki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

BMC UROLOGY 14 619 - 624 2014.01

Research paper (scientific journal), Joint Work, ISSN 1471-2490

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The predictive value of C-reactive protein for prognosis in patients with upper tract urothelial carcinoma treated with radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Shirotake Suguru, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Ito Yujiro, Kosaka Takeo, Kodaira Kiichiro, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Ueno Munehisa, Oya Mototsugu

European Urology 65 ( 1 ) 227 - 234 2014.01

ISSN 0302-2838

Background: Few studies have discussed the prognostic impact of serum C-reactive protein (CRP) level in upper tract urothelial carcinoma (UTUC). Objective: To investigate whether the perioperative level of CRP provides additional prognostic information following radical nephroureterectomy (RNU). Design, setting, and participants: A total of 564 patients with UTUC from a retrospective multi-institutional cohort were included. The median follow-up was 32 mo. Intervention: All patients underwent RNU without neoadjuvant chemotherapy, while 106 patients (18.8%) received adjuvant chemotherapy. Outcome measurements and statistical analysis: Associations between perioperative CRP level and outcome were assessed using multivariate analysis. A serum CRP level >0.50 mg/dl was defined as elevated. Results and limitations: Preoperative CRP (pre-CRP) level was elevated in 136 patients (24.1%). Multivariate analysis showed that pre-CRP elevation was an independent predictor of subsequent disease recurrence (hazard ratio [HR]: 1.47 for CRP 0.51-2.00; HR: 1.89 for CRP >2.00). Five-year recurrence-free survival rates were 69.2% in patients with pre-CRP levels ≤0.50 mg/dl, 54.3% in patients with pre-CRP levels between 0.51 and 2.00 mg/dl, and 35.4% in patients with pre-CRP levels >2.00 mg/dl (p < 0.001). Similar results were found in cancer-specific mortality, showing that pre-CRP elevation was an independent predictor of worse outcome (HR: 1.74 for CRP 0.51-2.00; HR: 2.31 for CRP >2.00). In a subgroup analysis of the elevated pre-CRP group, postoperative normalisation of CRP level was an independent predictor of better outcome. This study is limited by its retrospective nature as well as its heterogeneous group of patients and variable follow-up protocols resulting from the multi-institution design. Conclusions: Serum CRP may become a possible biomarker in UTUC, suggesting that patients with an elevated pre-CRP level could be predicted to have subsequent disease recurrence and cancer-specific mortality, while postoperative normalisation of CRP level was an independent predictor for prognosis.

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Dual PI3K/mTOR inhibitor NVP-BEZ235 sensitizes docetaxel in castration resistant prostate cancer

Yasumizu Yota, Miyajima Akira, Kosaka Takeo, Miyazaki Yasumasa, Kikuchi Eiji, Oya Mototsugu

Journal of Urology 191 ( 1 ) 227 - 234 2014.01

ISSN 0022-5347

Purpose: Effective therapeutic strategies that can achieve long-term improvement in patients with castration resistant prostate cancer are urgently needed. We recently reported that the activated PI3K/Akt/mTOR signaling pathway induced by docetaxel explains resistance to docetaxel in castration resistant prostate cancer. In this study we explored the efficacy of NVP-BEZ235, a dual PI3K and mTORC1/2 inhibitor, for docetaxel resistant castration resistant prostate cancer. Materials and Methods: We used the 2 human castration resistant prostate cancer cell lines C4-2 and C4-2AT6. At our laboratory C4-2AT6 cells were established from C4-2 under androgen ablated treatment for 6 months. We investigated the efficacy of NVP-BEZ235 monotherapy and NVP-BEZ235 combined with docetaxel in vitro and in vivo. Results: Increased phosphorylated Akt in C4-2AT6 cells was significantly inhibited by NVP-BEZ235 in a dose and time dependent manner. WST cell proliferation assay results in C4-2AT6 cells revealed that combined administration of NVP-BEZ235 and docetaxel had significant, synergistically greater cytotoxicity than NVP-BEZ235 or docetaxel monotherapy. Combined NVP-BEZ235 (40 mg/kg) and docetaxel (4 mg/kg) in vivo in a castrated mouse xenograft model inhibited C4-2AT6 tumor growth to a greater degree than in the monotherapy groups. Also, NVP-BEZ235 showed significant efficacy with docetaxel at a low concentration in vivo, suggesting that NVP-BEZ235 effectively decreased resistance to docetaxel. Conclusions: Results suggest that inhibition of the PI3K/Akt/mTOR signaling pathway by NVP-BEZ235 can overcome docetaxel resistance in human castration resistant prostate cancer. Our findings provide a molecular basis for the clinical use of combined administration of NVP-BEZ235 and docetaxel in patients with castration resistant prostate cancer.

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New year's greetings

Oya Mototsugu

International Journal of Urology 21 ( 1 ) 1 2014.01

ISSN 0919-8172

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Renal angiomyolipoma

Jinzaki Masahiro, Silverman Stuart G., Akita Hirotaka, Nagashima Yoji, Mikami Shuji, Oya Mototsugu

Abdominal Imaging 39 ( 3 ) 588 - 604 2014

ISSN 0942-8925

Angiomyolipoma is the most common benign solid renal neoplasm observed in clinical practice. Once thought to be a hamartoma and almost always diagnosed by the imaged-based detection of fat, angiomyolipomas are now known to consist of a heterogeneous group of neoplasms. Although all are considered perivascular epithelioid cell tumors, many display different pathology, imaging features, and clinical behavior. The importance of understanding this group of neoplasms is emphasized by the fact that many types of angiomyolipoma contain little to no fat, and despite being benign, sometimes escape a pre-operative diagnosis. These types of angiomyolipomas can all be considered when encountering a renal mass that is both hyperattenuating relative to renal parenchyma on unenhanced CT and T2-hypointense, features that reflect their predominant smooth muscle component. We review recent developments and provide a radiological classification of angiomyolipomas that helps physicians understand the various types and learn how to both diagnose and manage them.

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Invasion and metastasis of renal cell carcinoma

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Kosaka Takeo, Katsube Ken Ichi, Okada Yasunori

Medical Molecular Morphology 47 ( 2 ) 63 - 67 2014

ISSN 1860-1480

Renal cell carcinoma (RCC) represents over 80 % of kidney cancer, and about 30 % of the patients with RCC develop metastasis after the surgery. Invasion of basement membrane (BM) and extracellular matrix (ECM) is an essential event in tumor invasion and metastasis. Matrix metalloproteinases (MMPs), which digest the main components of BM and ECM, are expressed in RCC. Heparanase, which degrades heparan sulfate proteoglycans, is predominantly expressed in high-grade RCCs with a positive correlation with pathological tumor stage and poor prognosis. Bone metastasis is common among the patients with RCC, and increased osteoclastic activity was observed at metastatic sites. Receptor activator of nuclear factor κB ligand (RANKL), which plays an important role in osteoclastogenesis, is predominantly expressed in high-grade RCC and its expression level is associated with bone metastasis and prognosis. Epithelial-mesenchymal transition (EMT), a switch of epithelial cells to sarcomatoid phenotype, is considered to be critical step during metastasis, and Snail, a major regulator of EMT, is predominantly expressed in high-grade RCC, and high Snail expression is a worse prognostic factor. Accordingly, heparanase, RANKL and Snail may be targets for the development of anti-tumor therapies for RCCs.

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Renal arteriolar injury by salt intake contributes to salt memory for the development of hypertension

Oguchi Hideyo, Sasamura Hiroyuki, Shinoda Kazunobu, Morita Shinya, Kono Hidaka, Nakagawa Ken, Ishiguro Kimiko, Hayashi Kaori, Nakamura Mari, Azegami Tatsuhiko, Oya Mototsugu, Itoh Hiroshi

Hypertension 64 ( 4 ) 784 - 791 2014

ISSN 0194-911X

The role of salt intake in the development of hypertension is prominent, but its mechanism has not been fully elucidated. Our aim was to examine the effect of transient salt intake during the prehypertensive period in hypertensive model animals. Dahl salt-sensitive rats and spontaneously hypertensive rats were fed from 6 to 14 weeks with lowsalt (0.12% NaCl), normal-salt (0.8% NaCl), high-salt (7% NaCl), or high-sodium/normal-chloride diet and returned to normal-salt diet for 3 months. Rats in the high-salt group saw elevations in blood pressure (BP) not only during the treatment period but also for the 3 months after returning to normal-salt diet. We named this phenomenon salt memory. Renal arteriolar injury was found in the high-salt group at the end of experiment. Dahl salt-sensitive rats were fed from 6 to 14 weeks with high-salt diet with angiotensin receptor blocker, vasodilator, calcium channel blocker, and calcium channel blocker+angiotensin receptor blocker and returned to normal-salt diet. Although BP was suppressed to control levels by vasodilator or calcium channel blocker, elevated renal angiotensin II and renal arteriolar injury were observed, and salt memory did not disappear because of sustained renal arteriolar injury. Calcium channel blocker+angiotensin receptor blocker suppressed renal arteriolar injury, resulting in the disappearance of salt memory. Cross-transplantation of kidneys from Dahl salt-sensitive rats on high salt to control rats caused increase of BP, whereas control kidneys caused reduction in BP of hypertensive rats, inducing the central role of the kidney. These results suggest that renal arteriolar injury through BP and renal angiotensin II elevation plays important roles in the development of salt memory for hypertension.

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Individualized prostate-specific antigen threshold values to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy in elderly men

Kanao Kent, Komori Osamu, Nakashima Jun, Ohigashi Takashi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Eguchi Shinto, Oya Mototsugu

Japanese Journal of Clinical Oncology 44 ( 9 ) 852 - 859 2014

ISSN 0368-2811

Objective: To individualize prostate-specific antigen threshold values to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy in elderly men. Methods: A total of 406 men aged over 70 years old with prostate-specific antigen levels between 4.0 and 20.0 ng/ml, normal digital rectal examination results and diagnosed by transrectal needle biopsy were retrospectively analyzed. The patients were divided into a no/favorable-risk cancer group or an unfavorable-risk cancer group based on their Gleason score and the number of positive cores. Prostate-specific antigen levels, percent free prostate specific antigen level, prostate transition zone volume and the number of previous biopsies were used to discriminate between the two groups.The optimal individualized prostate-specific antigen threshold values based on the other variables that gave a sensitivity of 95% for the detection of unfavorable-risk cancer were calculated using a boosting method for maximizing the area under the receiver operating characteristic curve. Results: A total of 66 men had favorable-risk cancer, and 139 had unfavorable-risk cancer. The area under the receiver operating characteristic curve of the combination model determined by the boosting method for maximizing the area under the receiver operating characteristic curve was 0.852. The sensitivity and specificity of the threshold values for the detection of unfavorable-risk cancer were 95 and 36%, respectively. By using the threshold values, 100 (25%) of the subjects with no/favorable-risk cancer could have avoided undergoing biopsies, with a <5% risk of missing the detection of unfavorable-risk cancer. Conclusions: These individualized prostate-specific antigen threshold values may be useful for determining an indication of prostate biopsy for elderly men to avoid overdiagnosis of prostate cancer and reduce unnecessary biopsy.

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Optimal timing of hormonal therapy for prostate-specific antigen recurrence after radical prostatectomy

Matsumoto Kazuhiro, Mizuno Ryuichi, Tanaka Nobuyuki, Ide Hiroki, Hasegawa Masanori, Ishida Masaru, Hayakawa Nozomi, Yasumizu Yota, Hagiwara Masayuki, Hara Satoshi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Nakajima Yosuke, Nakamura So, Nakashima Jun, Oya Mototsugu

Medical Oncology 31 ( 7 ) 2014

ISSN 1357-0560

The present study was undertaken to examine biochemical progression in patients who received salvage hormonal therapy (HT) for biochemical disease recurrence (BCR) after radical prostatectomy (RP), and to determine the optimal timing for the administration of HT. The study population consisted of 156 patients who underwent RP and received salvage HT for BCR. The starting point of this study was the timing of RP, and the endpoint was biochemical prostate-specific antigen (PSA) progression (castration-resistance) after HT. The mean follow-up period after surgery was 8.1 years. First, we excluded 18 patients with persistent PSA (≥0.2 ng/mL) after RP from an analysis below because their prognoses were significantly poorer compared with 138 patients whose PSA nadirs had reached <0.2 ng/mL. Multivariate analysis demonstrated that Gleason score ≥8 (p = 0.010, hazard ratio (HR) 3.02), and PSA doubling time (PSA-DT) <6 months (p = 0.001, HR 7.39) was independently associated with subsequent biochemical progression after HT. Using these two variables (Gleason score and PSA-DT), we could stratify patients into three risk groups for BCR after salvage HT. Regarding the optimal timing for HT administration for these high-risk patients with both risk factors (relative risk = 22.3), the PSA cutpoint of 1.0 ng/mL at the initiation of HT showed a significant difference in progression-free survival rates (p = 0.023). The findings indicated that for high-risk patients, salvage HT for BCR after PSA nadir (<0.2 ng/mL) should be started before the PSA level exceeds 1.0 ng/mL; otherwise, there is a significant risk of subsequent biochemical progression after HT.

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Clinical characteristics and outcomes of congenital midureteral stricture detected by fetal ultrasonography

Ogihara Koichiro, Yazawa Satoshi, Asanuma Hiroshi, Takamatsu Kimiharu, Masuda Aya, Yasumizu Yota, Sato Hiroyuki, Matsui Zenichi, Muramatsu Masaki, Kono Hidaka, Mizuno Ryuichi, Oya Mototsugu

Japanese Journal of Urology 105 ( 3 ) 122 - 128 2014

ISSN 0021-5287

(Objectives) Congenital midureteral stricture (CMS), which develops from obstructive lesion between pyeloureteral junction and ureterovesical junction, is relatively rare and its clinical condition and therapeutic strategy have not yet been established. We analyzed the clinical characteristics and surgical outcomes of CMS. (Patients and methods) From November 2006 to December 2012, out of 137 patients presented with congenital hy-drohephrosis, we identified 4 pediatric patients diagnosed with CMS at our institutions. We retrospectively investigated clinical characteristics and surgical outcomes in these 4 patients. (Results) Three boys and one girl were identified in this study. All patients were detected hydronephrosis by fetal ultrasonography. The median age at the diagnosis of CMS was 1 year and 11 months. Three patients had obstructive lesion in left side and 1 patient in right CMSs were located at the level of L4 in 2 patients, and at the level of L5 and SI in each 1. Split renal function was decreased less than 45% in 3 of 4 patients. Ipsilateral pyeloureteral junction obstruction and ipsilateral hypoplastic kidney were identified in 2 and 1 patient respectively. One patient developed urosepsis and underwent nephrostomy. Partial ureterectomy and ureteroureterostomy, pyeloplasty were performed in 3 and 1 patient respectively. Extrinsic obstruction was detected in just 1 patient intraoperatively. In all patients, there were no protruded lesion and atrophied, fibrotic and ischemic muscles were not detected in pathological finding. Neither urinary tract infection nor recurrence of obstructive lesion was detected in all patients at the mean follow-up period of 3 years and 1 month. (Conclusion) We analyzed the clinical characteristics of 4 pediatric patients with CMS. In order to prevent critical infection and maintain renal function, it could be considered that surgical intervention is undertaken just after making the diagnosis of CMS.

Investigation of the management and risk of febrile neutropenia associated with chemotherapy in the urological field

Wada Koichiro, Tanimoto Ryuta, Nose Hiroyuki, Uehara Shinya, Watanabe Toyohiko, Hayami Hiroshi, Nagai Shingo, Yasuda Mitsuru, Deguchi Takashi, Shigeta Keisuke, Yazawa Satoshi, Kikuchi Eiji, Oya Mototsugu, Hashimoto Jiro, Uehara Teruhisa, Kurimura Yuichiro, Hiyama Yoshiki, Takahashi Satoshi, Tsukamoto Taiji, Sho Takehiko, Hamasuna Ryoichi, Miyazaki Jun, Togo Yoshikazu, Taoka Rikiya, Nakao Atsushi, Yamamoto Shingo, Kobayashi Kanao, Matsubara Akio, Ishikawa Kiyohito, Kumon Hiromi, Matsumoto Tetsuro

Japanese Journal of Chemotherapy 62 ( 3 ) 374 - 381 2014

ISSN 1340-7007

In Japan, chemotherapy for urogenital malignant diseases is commonly performed by urologists and febrile neutropenia (FN) is one of the major adverse events associated with chemotherapy, however, few reports exist from the urological field about FN. In this present study, a total of 883 courses of chemotherapy (326 patients) performed from 2010 to 2011 at 10 University Hospitals were retrospectively reviewed. The regimens were GC (gemcitabine and cisplatin), GCP (gemcitabine, cisplatin and paclitaxel) and M-VAC (methotrexate, vinblastine, doxorubicin, cisplatin) for urothelial carcinoma, and EP (etoposide and cisplatin) and BEP (bleomycin, etoposide and cisplatin) for testicular cancer. In 81 courses (9.2%, 66 patients; 20.2%) including FN, antimicrobials and granulocyte-colony stimulating factor (G-CSF) were administered in 69 courses (85.2%) and in 77 courses (95.1%), respectively. The MASCC risk-index score was evaluated in no more than 51 courses (63.0%) and 1 patient with 18 points on the MASCC score died due to myelotoxicity and infections. According to statistical investigations, FN is significantly more frequent in GCP and M-VAC than in GC (p = 0.0073, <0.0001) and in a similar manner in BEP than in EP (p = 0.0405). In patients with afebrile neutropenia (AN), observed in 232 courses (26.3%), antimicrobials and G-CSF were administered in 5 courses (2.2%) and in 144 courses (62.1%), respectively. Further evidence from the urological field is required to investigate the treatment and risk of FN for management of patients with urogenital malignancies.

Prognostic value of preoperative multiparametric magnetic resonance imaging (MRI) for predicting biochemical recurrence after radical prostatectomy

Hattori Seiya, Kosaka Takeo, Mizuno Ryuichi, Kanao Kent, Miyajima Akira, Yasumizu Yota, Yazawa Satoshi, Nagata Hirohiko, Kikuchi Eiji, Mikami Shuji, Jinzaki Masahiro, Nakagawa Ken, Tanimoto Akihiro, Oya Mototsugu

BJU International 113 ( 5 ) 741 - 747 2014

ISSN 1464-4096

Objective To evaluate the suitability of preoperative multiparametric magnetic resonance imaging (MRI) positivity as a predictor of biochemical recurrence after radical prostatectomy (RP). Patients and Methods We reviewed the clinical records of patients who underwent either standard RP or laparoscopic RP between January 2005 and December 2009 at our institution. Patients who received radiotherapy or androgen deprivation therapy before surgery were excluded. A total of 314 patients met the study inclusion criteria. Cox proportional hazard regression models were used for analyses. In accordance with the criteria in the established guidelines, a radiologist scored the probability of the presence of prostate cancer using a five-point scale of diagnostic confidence level. The highest confidence level of any pulse sequence was considered as the evaluation result. Results MRI positivity was significantly associated with a high clinical stage (cT ≥ 2; P = 0.039), a high positive biopsy core rate (≥0.2; P < 0.001), a high biopsy Gleason score ([GS] ≥8; P < 0.001) and a high pathological GS (≥8; P = 0.005). Univariate analysis and multivariate analysis showed that MRI positivity was a prognostic indicator in the analysis that included only preoperative variables and also in the analysis including preoperative and pathological variables. Conclusion Multiparametric MRI positivity can independently predict biochemical recurrence after RP.

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Cushing's syndrome

Miyajima Akira, Hattori Seiya, Oya Mototsugu

Japanese Journal of Clinical Urology 68 ( 8 ) 600 - 606 2014

ISSN 0385-2393

Renal cell carcinoma in patients with acquired cystic disease of the kidney

Akita Hirotaka, Jinzaki Masahiro, Akita Ayano, Mikami Shuji, Oya Mototsugu, Kuribayashi Sachio

Journal of Magnetic Resonance Imaging 39 ( 4 ) 924 - 930 2014

ISSN 1053-1807

Purpose To evaluate the MRI findings of renal cell carcinoma (RCC), including findings on diffusion-weighted images (DWIs) and chemical shift images (CSIs), in patients with acquired cystic disease of the kidney (ACDK) in relation to the histopathologic findings. Materials and Methods Two radiologists retrospectively reviewed the MRI findings of 10 RCCs in seven consecutive patients with ACDK. They evaluated the signal intensities (SIs) and signal homogeneity of the lesions on T2-weighted images, DWIs, and T1-weighted images. Thereafter, they evaluated the cytoplasmic fat in the lesions by CSIs. After image analyses, the MRI findings were correlated with the histopathologic findings. Results The RCCs tended to show heterogeneous high SIs on T2-weighted images and DWIs. The high SIs on DWIs were mainly attributable to the viable parts, and the heterogeneity was due to the various SIs arising from the intratumoral degenerative components. Unlike the reported findings for hemorrhagic cysts, the RCCs did not show homogeneous high SIs or fluid-iron levels on T1-weighted images. The four lesions, in which the presence of cytoplasmic fat was suggested on CSIs, were clear cell RCCs. Conclusion The MRI findings, including findings on DWIs and CSIs, well reflected the histopathologic findings of RCC in patients with ACDK.

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Development of a novel interferon-α2b gene construct with a repetitive hypoxia-inducible factor binding site and its suppressive effects on human renal cell carcinoma cell lines in vitro

Fukui Naotaka, Kageyama Yukio, Higashi Yotsuo, Kihara Kazunori, Kizaka-Kondoh Shinae, Hiraoka Masahiro, Shinojima Toshiaki, Suzuki Kenjiro, Oya Mototsugu

International Journal of Clinical Oncology 19 ( 3 ) 497 - 504 2014

ISSN 1341-9625

Background: Despite the advent of targeted therapies, interferon-alpha (IFN-α) remains a therapeutic option for advanced renal cell carcinoma (RCC), especially in Japan, with a treatment response rate of 15-20 %. To improve the efficacy of IFN-α-based therapies, we evaluated a novel treatment strategy for RCC using an IFN-α2b gene construct with a repetitive hypoxia-inducible factor binding site. Methods: We constructed an expression plasmid designated 5HREp-IFN-α2b containing the coding region of the IFN-α2b gene. Five copies of the hypoxia-response element (HRE) sequences were inserted upstream of the IFN-α2b gene, and the construct was transfected into human RCC cell lines ACHN, 786-O and KU19-20. The concentrations of IFN-α2b in the conditioned media were measured by enzyme-linked immunosorbent assay. Cell viabilities were determined by MTS assays. Results: Construct-induced IFN-α secretion was confirmed in all three cell lines. IFN-α production was significantly enhanced by the hypoxia-mimicking agent deferoxamine mesylate in cell lines expressing the wild-type von Hippel-Lindau (VHL) gene (KU19-20 and ACHN) compared with cells expressing the mutant VHL gene (786-O). The construct exerted significant suppressive effects on the viabilities of all RCC cell lines. Conclusion: This is the first study to report on the construction of a cytokine gene with a repetitive hypoxia-inducible factor binding site and its application in the suppression of human cancer cells. Gene therapy using this IFN-α2b gene construct with HREs may represent a novel treatment modality for advanced RCC.

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Complete response to bicalutamide withdrawal prolonged for almost 2 years in patients with metastatic prostate cancer

Hongo Hiroshi, Kosaka Takeo, Oya Mototsugu

Urology Case Reports 2 ( 5 ) 150 - 151 2014

ISSN 2214-4420

This is the first case report describing a complete response to bicalutamide withdrawal that lasted for almost 2years in a patient with metastatic prostate cancer. An 80-year-old man who had prostate-specific antigen (PSA) level elevation (168.1ng/mL) visited our hospital in February 2010. Bone scintigraphy showed pelvic metastases. We started hormonal therapy with leuprorelin and bicalutamide. The PSA concentration decreased to <0.1ng/mL but started increasing again and reached 1.64ng/mL in October 2012, at which time bicalutamide administration was discontinued. The PSA concentration decreased again and has remained below the limit of sensitivity for almost 2years.

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Independent predictors for bladder outcomes after treatment of intravesical recurrence following radical nephroureterectomy in patients with primary upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Shirotake Suguru, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Hayakawa Nozomi, Hagiwara Masayuki, Kosaka Takeo, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Jinzaki Masahiro, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

Annals of Surgical Oncology 21 ( 9 ) 3151 - 3158 2014

ISSN 1068-9265

Background. Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU. Methods. A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis. Results. Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors. Conclusions. This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

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Age at diagnosis on prostate cancer survival undergoing androgen deprivation therapy as primary treatment in daily practice

Inamoto Teruo, Azuma Haruhito, Hinotsu Shiro, Tsukamoto Taiji, Oya Mototsugu, Ogawa Osamu, Kitamura Tadaichi, Kazuhiro Suzuki, Naito Seiji, Namiki Mikio, Nishimura Kazuo, Hirao Yoshihiko, Usami Michiyuki, Murai Masaru, Akaza Hideyuki

Journal of Cancer Research and Clinical Oncology 140 ( 7 ) 1197 - 1204 2014

ISSN 0171-5216

Objectives: Primary androgen deprivation therapy (PADT) had been used extensively in Japan than in the USA and European countries regardless of the disease risk or patient's age. To illustrate the consequence of PADT from daily clinical practice, we evaluated the relationship among age, disease risk, and survival of patients with prostate cancer treated by PADT in largest Asian cohort. Patients and methods: The 19,246 men subjected to PADT enrolled in the Japan Study Group of Prostate Cancer were enrolled for the present analysis. Patients were divided into four groups based on age at diagnosis: age <66, 66-70, 71-75, and >75. Risk was stratified according to the Japan Cancer of the Prostate Risk Assessment (J-CAPRA). Multivariate competing risks regression analysis was performed for OS and PFS. Results: There was downward stage migration over age. Among men aged >75 years, 34.1 % had nodal or distant metastatic disease. In contrast, 56.0 % of patients aged <66 years presented with advanced disease. The modality of hormonal therapy varied with age across risk groups; the younger age group showed a higher proportion of maximal androgen blockade, while the proportion of monotherapy use was higher in older men. The likelihood of low-risk disease by J-CAPRA classification increased significantly with increasing age (p < 0.0001 by Pearson's chi-square test). The same as OS, the PFS rate increased with age until after the age of 75. Men aged 71-75 had better survival rates even after adjustments for treatment modality alone, or for treatment modality plus disease risk. Conclusions: Age cohorts do affect orientation toward favorable disease course after PADT with men aged 71-75 being benefiting more from PADT than other age groups.

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Ureteral metastasis from prostate cancer

Hongo Hiroshi, Kosaka Takeo, Yoshimine Shunsuke, Oya Mototsugu

BMJ Case Reports 2014 2014

A 59-year-old man had an elevated prostate-specific antigen (PSA) concentration (439 ng/mL) in December 2008. We diagnosed prostatic adenocarcinoma by prostate needle biopsy. CT and MRI showed a prostatic tumour with bone and lymph node metastases. Combined androgen blockade therapy reduced the PSA level temporarily. After the PSA level gradually started to increase again and reached 27.27 ng/mL in October 2010, the patient was diagnosed with castration-resistant prostate cancer and treated with docetaxel chemotherapy. Radiological examination detected left hydronephrosis and a tumour in the left lower ureter in March 2011. Retrograde pyelography and urine cytology of class 3 from the left ureter indicated that the ureteral mass was a urothelial carcinoma. A left nephroureterectomy was performed. After the operation, the pathological examination showed a metastatic prostate carcinoma, accompanied by a decrease in the serum PSA level from 59.56 to 45.33 ng/mL.

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Laparoendoscopic single-site adrenalectomy versus conventional laparoscopic adrenalectomy

Hirasawa Yosuke, Miyajima Akira, Hattori Seiya, Miyashita Kazutoshi, Kurihara Isao, Shibata Hirotaka, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Surgical Endoscopy and Other Interventional Techniques 28 ( 10 ) 2911 - 2919 2014

ISSN 0930-2794

Background: Conventional laparoscopic adrenalectomy (LA) is the gold standard procedure for benign adrenal tumors. Laparoendoscopic single-site adrenalectomy (LESS-A) has been developed as an extension of standard laparoscopic minimally invasive procedures.Methods: This retrospective study compared the first experience of one surgeon with 70 LESS-A to 140 LA cases with respect to evaluating the influence of the inexperience on surgical outcomes and to assess this surgeon’s learning curve for LESS-A.Results: Age, gender, BMI, percentage of patients with prior abdominal surgery, tumor laterality, and tumor size were all comparable between the two groups. There were no statistically significant differences in any surgical outcomes, including mean operative time, pneumoperitoneum time, estimated blood loss, transfusion requirements, hemoglobin decrease at postoperative day 1, analgesic requirements, postoperative day of oral intake, conversion rate, or morbidity between the two groups. The one exception was hospital stay. There were no mortalities or reoperations in either group. The morbidity rates in the LESS-A group and LA group were 4.2 and 6.4 %, respectively (p = 0.528). LESS-A appears to have a steep learning curve and the operative time of the initial 70 cases decreased markedly and remained stable when the experience level exceeded 12 cases. There was no morbidity or conversion in these first 12 LESS-A cases. Multiple regression analysis revealed that surgeon experience (p = 0.008) and tumor size (p = 0.001) were independent predictors of prolonged operative time.Conclusions: Surgical outcomes of LESS-A were equivalent to those of LA without compromising safety. The introduction of LESS-A at our hospital was smooth and safe. While the indication for LESS-A has been controversial, LESS-A was a useful procedure, especially for cases in which cosmesis is of paramount importance.

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Is DHT production by 5a-reductase friend or foe in prostate cancer?

Kosaka Takeo, Miyajima Akira, Oya Mototsugu

Frontiers in Oncology 4 ( SEP ) 2014

ISSN 2234-943X

The first advance in the history of studies on prostate cancer (PCa) and androgens was the development of treatment with castration and administration of estrogen by Charles B. Huggins, who won the Nobel Prize in Physiology and Medicine. Since then, and for 70 years, androgen deprivation therapy has been the standard therapy for advanced PCa and the center of studies on PCa. However, recent advances have shed light on the relationship between androgens and the development or the progression of PCa. The use of 5AR inhibitors to prevent progression of PCa continues to be widely discussed. Discussion has been fueled by the findings of two large randomized, placebo-controlled trials: the Prostate Cancer Prevention Trial with finasteride and the Reduction by Dutasteride of Prostate Cancer Events trial. Does the development of PCa or progression to castration-resistant PCa depend on dihydrotestosterone (DHT)? Here, we summarize and discuss recent topics of local androgen production of DHT in PCa.

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Occurrence of infection following prostate biopsy procedures in Japan Japanese Research Group for Urinary Tract Infection (JRGU)-A multi-center retrospective study

Journal of Infection and Chemotherapy 20 ( 4 ) 232 - 237 2014

ISSN 1341-321X

We retrospectively investigated the incidence of genitourinary tract infection in 5895 patients who underwent transrectal and/or transperineal prostate biopsy procedure between January and December 2011 at 46 institutions belonging to Japanese Research Group for Urinary Tract Infection (JRGU). The total rate of genitourinary tract infection after prostate biopsy was 0.76%, while that following transrectal procedure was 0.83% and following transperineal procedure was 0.57%, which were not significantly different. In contrast, febrile infection associated with a fever (≥38 °C) occurred significantly more frequently after transrectal (0.71%) than transperineal (0.16%) approach (P = 0.04). Notably, in infectious cases, Escherichia coli was most frequently isolated. Of the 9 E. coli strains isolated by urine culture, 6 (66.7%) produced extended spectrum β-lactamase (ESBL) and 7 (77.8%) showed levofloxacin resistance. Similarly, of 6 E. coli strains isolated by blood culture, 4 (66.7%) produced ESBL and 6 (100%) showed levofloxacin resistance. When the efficacy of antimicrobial prophylaxis (AMP) with levofloxacin for the patients undergoing transrectal or transperineal biopsy was compared between a single dose (500 mg) and that given for 2 or more days, no significant difference was observed for the rate of infection (transrectal: 0.82% vs. 1.04%, p = 0.94; transperineal: 0.30% vs. 0.46%, p = 0.68).

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Visceral fat is correlated with prolonged operative time in laparoendoscopic single-site adrenalectomy and laparoscopic adrenalectomy

Hasegawa Masanori, Miyajima Akira, Jinzaki Masahiro, Maeda Takahiro, Takeda Toshikazu, Kikuchi Eiji, Shibata Hirotaka, Oya Mototsugu

Urology 82 ( 6 ) 1312 - 1318 2013.12

ISSN 0090-4295

Objective To investigate the effect of visceral fat on operative time and discuss whether the measurement of adipose accumulation could be used as a sensitive predictor of technical difficulty in performing laparoendoscopic single-site adrenalectomy (LESS-A) and laparoscopic adrenalectomy (LA). Methods We reviewed the medical records of 106 patients undergoing LA or LESS-A at our institution. Total fat area (TFA) and visceral fat area (VFA) were measured at the level of the L4 vertebra by computed tomography. To categorize the type of obesity, the VFA/TFA ratio was calculated. Multiple logistic regression analyses were performed to identify independent predictors of prolonged operative time. Results The VFA/TFA ratio does not always coincide with body mass index (BMI, r = 0.415), and a higher correlation coefficient was observed between operative time and the VFA/TFA ratio (r = 0.359) than with that of BMI (r = 0.189). Multivariate analysis revealed that pheochromocytoma, tumor size ≥5 cm, and the VFA/TFA ratio ≥0.35, defined as the visceral type of adipose accumulation, were independent predictive factors for prolonged operative time in LA and LESS-A. We were able to stratify patients into short, intermediate, and long operative times using these preoperative variables. Conclusion This study revealed that the visceral type of adipose accumulation increases operative complexity in LA and LESS-A as measured by operative time. The VFA/TFA ratio might be a more sensitive indicator of technical difficulty than that of BMI.

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Periprostatic fat area is an independent factor that prolonged operative time in laparoscopic radical prostatectomy

Kaneko Gou, Miyajima Akira, Yuge Kazuyuki, Hasegawa Masanori, Takeda Toshikazu, Jinzaki Masahiro, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Urology 82 ( 6 ) 1304 - 1309 2013.12

ISSN 0090-4295

Objective To evaluate the effect of visceral obesity on surgical outcomes in laparoscopic radical prostatectomy (LRP). Methods Visceral fat area (VFA) and periprostatic fat area (PPFA) were used as index of visceral obesity. In addition to VFA and PPFA, age, body mass index (BMI), prostate weight, cross-section area of Retzius space, history of previous abdominal surgery, repeated transrectal needle biopsy, and neoadjuvant hormone therapy were recorded. LRP was separated into 7 steps (1: port insertion and lymph node dissection, 2: endopelvic fascia incision, 3: dorsal vein complex ligation, 4: prostate dissection from bladder neck, 5: dissection of seminal vesicle and vas deferens, 6: prostate dissection from rectum, and 7: vesicourethral anastomosis). Potential factors that prolonged total operative time (OT), pneumoperitoneum time, and duration of each step were assessed by multivariate logistic regression analysis. The association between visceral obesity and other surgical outcomes was also evaluated. Results One hundred sixteen LRPs were performed by a single experienced surgeon. High PPFA and prostate weight were independent factors that prolonged total OT and pneumoperitoneum time. High BMI was not a factor. PPFA affected steps 1, 4, 5, and 6, and prostate weight affected prolonged steps 5 and 6. Estimated blood loss, duration of urethral catheterization, postoperative hospital stay, perioperative complications, and margin status were not affected by visceral obesity. Conclusion PPFA was more useful to accurately predict prolonged OT than VFA or BMI. Safety and margin status were not compromised even in high PPFA group when operations were performed by an experienced surgeon.

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Radiolucent circular line in pelvis on plain X-rays

Niwa Naoya, Yazawa Satoshi, Oya Mototsugu

Journal of Emergency Medicine 45 ( 6 ) 2013.12

ISSN 0736-4679

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Epithelioid angiomyolipoma of the kidney

Tsukada Jitsuro, Jinzaki Masahiro, Yao Masahiro, Nagashima Yoji, Mikami Shuji, Yashiro Hideki, Nozaki Miwako, Mizuno Ryuichi, Oya Mototsugu, Kuribayashi Sachio

International Journal of Urology 20 ( 11 ) 1105 - 1111 2013.11

ISSN 0919-8172

Objectives: To review the imaging findings of renal epithelioid angiomyolipomas. Methods: Eight patients treated at two institutions were pathologically diagnosed as having epithelioid angiomyolipoma. All of them underwent computed tomography, and four underwent magnetic resonance imaging. The tumor size, existence of fat, heterogeneity, computed tomography attenuation, degree of enhancement, enhancement pattern and magnetic resonance imaging signal intensity were evaluated. Results: Intratumoral fat was not detected in any of the cases. On unenhanced computed tomography, the intratumoral attenuation was hyperattenuating in six of the seven patients who were examined using this modality. On T2-weighted images, the signal intensity of the solid component, cyst wall or septum was low in three of the four cases. Four of the eight cases were heterogeneous solid-type accompanied by hemorrhage, necrosis or hyalinization. One homogeneous solid-type lesion was large in size and was pathologically accompanied by neither hemorrhage nor necrosis. All three multilocular cystic types were pathologically accompanied by massive hemorrhage in the cystic component. One was accompanied by spontaneous perirenal hematoma. Conclusions: The radiological appearance of most epithelioid angiomyolipomas has a tendency to be hyperattenuating on unenhanced computed tomography images, with low intensities on T2-weighted images. They can be heterogeneously solid, homogeneously solid or a multilocular cystic lesion with massive hemorrhage.

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Effect of a Novel Nuclear Factor-kappa B Activation Inhibitor on Renal Ischemia-Reperfusion Injury

Kono Hidaka, Nakagawa Ken, Morita Shinya, Shinoda Kazunobu, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

TRANSPLANTATION 96 ( 10 ) 863 - 870 2013.11

Research paper (scientific journal), Joint Work, ISSN 0041-1337

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C-reactive protein

Obata Jun, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Hayakawa Nozomi, Ide Hiroki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Urologic Oncology: Seminars and Original Investigations 31 ( 8 ) 1725 - 1730 2013.11

ISSN 1078-1439

Background and objective: Serum C-reactive protein (CRP) is one particular marker of systemic inflammation, and an elevated CRP level is associated with poor outcome in various malignancies. While the clinical value of CRP levels in upper tract urothelial carcinoma (UTUC) has not yet been fully evaluated, we investigated the impact of CRP elevation as a biomarker of patient prognosis in UTUC. Materials and methods: A total of 183 patients who underwent radical nephroureterectomy (RNU) for localized UTUC (pTa-4N0M0) were identified between 1993 and 2009. The associations between the levels of serum CRP and patient outcome were analyzed. Results: Thirty-three patients experienced disease recurrence, and 28 died of the disease during the median follow-up period of 39 months. Using the defined cutoff level of CRP >0.5 mg/dl as elevated, preoperative CRP (pre-CRP) levels were elevated in 42 patients (23.0%). Kaplan-Meier curves revealed that subsequent tumor recurrences and worse cancer-specific survival could be significantly predicted in the elevated pre-CRP group. The 5-year recurrence-free survival rate was 63.6% in the elevated pre-CRP group and 83.4% in their counterparts (P < 0.001), and the 5-year cancer-specific survival rate was 64.7% in the elevated pre-CRP group and 84.3% in their counterparts (P = 0.001). Multivariate analysis revealed that elevated pre-CRP, in addition to pathologic T stage, was an independent risk factor for subsequent disease recurrence (P = 0.003, hazard ration (HR) = 2.83), and the decrease in cancer-specific survival (P = 0.012, HR = 2.65). In subgroup analysis using patients with pT3 tumors or greater, multivariate analysis also showed that elevated pre-CRP was an independent risk factor for a decrease in both recurrence-free and cancer-specific survival. Conclusions: Pre-CRP level was an independent predictor of patient survival in localized advanced UTUC. Patients with pre-CRP >0.5 mg/dl were strongly predicted to have worse prognostic outcomes following RNU. Due to its low cost and easy accessibility, CRP may be a useful biomarker for localized UTUC.

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Differential diagnosis of upper urinary tract disorders

Yazawa Satoshi, Kikuchi Eiji, Oya Mototsugu, Jinzaki Masahiro

Japanese Journal of Clinical Urology 67 ( 11 ) 863 - 870 2013.10

ISSN 0385-2393

Identification of drug candidate against prostate cancer from the aspect of somatic cell reprogramming

Kosaka Takeo, Nagamatsu Go, Saito Shigeru, Oya Mototsugu, Suda Toshio, Horimoto Katsuhisa

Cancer Science 104 ( 8 ) 1017 - 1026 2013.08

ISSN 1347-9032

Considering the similarities between the transcriptional programming involved in cancer progression and somatic cell reprogramming, we tried to identify drugs that would be effective against malignant cancers. We used the early transposon Oct4 and Sox2 enhancer (EOS) system to select human prostate cancer (PCA) cells expressing high levels of OCT4. Patients with metastatic castration-resistant PCA that does not respond to treatment with docetaxel have few therapeutic options. The OCT4-expressing PCA cells selected using the EOS system showed increased tumorigenicity and high resistance to docetaxel, both in vitro and in vivo. By using their gene expression data, expression signature-based prediction for compound candidates identified an antiviral drug, ribavirin, as a conversion modulator from drug resistance to sensitivity. Treatment of PCA cells with ribavirin decreased their resistance against treatment with docetaxel. This indicated that ribavirin reversed the gene expression, including that of humoral factors, in the OCT4-expressing PCA cells selected using the EOS system. Thereby, ribavirin increased the efficacy of docetaxel for cancer cells. We propose a novel cell reprogramming approach, named drug efficacy reprogramming, as a new model for identifying candidate antitumor drugs.

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Therapeutic enhancement of S-1 with CPT-11 through down-regulation of thymidylate synthase in bladder cancer

Ide Hiroki, Kikuchi Eiji, Hasegawa Masanori, Hattori Seiya, Yasumizu Yota, Miyajima Akira, Oya Mototsugu

CANCER MEDICINE 2 ( 4 ) 488 - 495 2013.08

Research paper (scientific journal), Joint Work, ISSN 2045-7634

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Patient characteristics and outcomes in metastatic upper tract urothelial carcinoma after radical nephroureterectomy

Tanaka Nobuyuki, Kikuchi Eiji, Kanao Kent, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Shirotake Suguru, Hayakawa Nozomi, Kosaka Takeo, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Hasegawa Shintaro, Nakajima Yosuke, Oya Mototsugu

BJU International 112 ( 2 ) 2013.07

ISSN 1464-4096

Objectives To investigate oncological outcomes and prognostic factors in patients with upper tract urothelial carcinoma (UTUC) who experienced disease recurrence after radical nephroureterectomy (RNU). Few studies have focused on the clinical courses of patients who experienced disease recurrence after RNU. Patients and Methods A total of 204 UTUC patients who experienced disease recurrence from a retrospective multi-institutional cohort were included in the present study. Associated patient outcomes were analyzed using multivariate analysis. Results The mean time from RNU to first disease recurrence was 15.0 months and ≈90% of patients experienced disease recurrence within the first 3 years after RNU. During a median follow-up of 8.1 month after disease recurrence, 165 patients died from UTUC and five patients died from other causes. In the 204 cohorts, 1- and 3-year cancer-specific survival rates were 40.2% and 9.7%, respectively, and 1- and 3-year overall survival rates were 39.5% and 9.4%, respectively. After disease recurrence, 132 patients underwent systemic chemotherapy, and a subgroup analysis of patients who underwent systemic chemotherapy multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently prognostic of cancer-specific and overall survival after relapsing. According to three significant variables, 1- and 3-year cancer-specific survival rates were 72.7% and 20.8% in patients with no risk factors, 46.5% and 7.5% in patients with one risk factor, and 26.4% and 4.4% in patients with two or three risk factors, respectively (P < 0.001). Conclusions Most patients died from UTUC within 3 years, even though systemic chemotherapies were administered after relapsing. Multivariate analysis showed that performance status, the presence of liver metastasis and the number of recurrence sites were independently related to poor survival after systemic chemotherapy.

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Greeting from the new Editor-in-Chief

Oya Mototsugu

International Journal of Urology 20 ( 7 ) 648 2013.07

ISSN 0919-8172

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A questionnaire survey of antimicrobial prophylaxis to prevent perioperative infection in urological field in Japan

Togo Yoshikazu, Taoka Rikiya, Yamamoto Shingo, Hiyama Yoshiki, Uehara Teruhisa, Hashimoto Jiroh, Kurimura Yuichiro, Takahashi Satoshi, Tsukamoto Taiji, Miyazaki Jun, Nishiyama Hiroyuki, Kiyota Hiroshi, Yazawa Satoshi, Oya Mototsugu, Yasuda Mitsuru, Deguchi Takashi, Ishikawa Kiyohito, Hoshinaga Kiyotaka, Matsumoto Minori, Shigemura Katsumi, Tanaka Kazushi, Arakawa Soichi, Fujisawa Masato, Wada Koichiro, Uehara Shinya, Watanabe Toyohiko, Kumon Hiromi, Kobayashi Kanao, Matsubara Akio, Matsumoto Masahiro, Sho Takehiko, Hamasuna Ryoichi, Matsumoto Tetsuro, Hayami Hiroshi, Yamane Takashi, Nakagawa Masayuki

Japanese Journal of Urology 104 ( 4 ) 579 - 588 2013.07

ISSN 0021-5287

(Purpose): To survey the present condition of administration method of the antimicrobial prophylactic (AMP) agents for the perioperative infection in Japan on revising "The Japanese guidelines for prevention of perioperative infections in urologic field (2006)". (Patients and methods): With the approval of the Japanese Urological Association (JUA) in 2011, all of the principal urological training institutions certified by JUA (n = 836) were encouraged to participate to survey their adherence to the JUA guidelines (published in 2006) for AMP to prevent perioperative infection in urological field, and 446 (53.3%) institutions responded to the questionnaire. (Results): The rates of following the JUA guidelines of, "completely", "mainly", "not too much", and "not at all" were 6.5%, 69.7%, 22.0% and 1.6%, respectively. The guidelines were followed for open clean operations in 48.5%, open clean-contaminated operations in 66.4%, open contaminated operations in 61.8%, laparoscopic clean operations in 54.1%, laparoscopic clean-contaminated operations in 61.2%, transurethral resection of bladder tumor in 71.5%, transurethral resection of prostate in 68.9%, ureteroscopy and transurethral ureterolithotomy in 68.2%, prostate biopsy in 43.2%, and cystoscopy were in 42.2%, respectively. However, in terms of duration of AMP administration, the longer duration than those recommended by the guidelines were observed for clean surgery, transurethral resection of bladder tumor, ureteroscopy and transurethral ureterolithotomy, prostate biopsy, and cystoscopy. (Conclusions): In terms of kinds of AMP, the guidelines were almostly followed in all operative procedures. However, the duration of AMP administration were longer than those recommended by the guidelines. On revision of "Japanese guidelines for prevention of perioperative infections in urologie field (2006)", these data would be taken into consideration to avoid dissociation between the guidelines and the practical side in the urologists.

Three cases of IgG4-related disease associated with urinary tract obstruction

Yazawa Satoshi, Ohara Rei, Maeda Takahiro, Kanao Kent, Hattori Seiya, Nakajima Yosuke, Oya Mototsugu

Japanese Journal of Urology 104 ( 4 ) 620 - 625 2013.07

ISSN 0021-5287

IgG4-related disease (IgG4RD) is a novel clinical entity characterized by tissue infiltration of IgG4-positive plasma cells. We report here 3 cases of IgG4RD associated with urinary tract obstruction. Patient 1 was a 59-year-old male who complained of difficulty on urination. A CT scan showed bilateral ureteral wall thickness, hydronephrosis, and an enlarged prostate. His serum IgG4 was 817 mg/dl. We made a diagnosis of IgG4RD and performed bilateral ureteral stenting and steroid therapy. A significant reduction in the size of the lesion was detected, and IgG4 was decreased to 272 mg/dl. He was doing well after removal of the ureteral stent. Patient 2 was a 51-year-old female who complained of bilateral swelling of the submaxillary gland. A CT scan showed left ureteral wall thickness and hydronephrosis. Her serum IgG4 was 1, 020 mg/dl. We made a diagnosis of IgG4RD and performed left ureteral stenting and steroid therapy. A significant reduction in the size of the lesion was detected, and IgG4 was decreased to 337 mg/dl. She was doing well after removal of the ureteral stent. Patient 3 was a 64-year-old male who underwent evaluation for autoimmune pancreatitis. He complained of back pain and bilateral hydronephrosis was detected. His serum IgG4 level was 649 mg/dl. Bilateral ureteral stenting was performed based on a diagnosis of IgG4RD. He did not receive steroid therapy because of poorly-controlled diabetes mellitus. After insertion of the ureteral stent, hydronephrosis and back pain were relieved. We could only find a few case reports in the literature on IgG4RD associated with urinary tract obstruction. It is important for clinicians to bear in mind that IgG4RD sometimes causes urinary tract obstruction.

Prognostic significance of Bcl-xL expression and efficacy of Bcl-xL targeting therapy in urothelial carcinoma

Yoshimine S., Kikuchi E., Kosaka T., Mikami S., Miyajima A., Okada Y., Oya M.

British Journal of Cancer 108 ( 11 ) 2312 - 2320 2013.06

ISSN 0007-0920

Background: Bcl-xL has an important role in the control of cell death through its inhibition of apoptosis. The aim of this study was to investigate the clinicopathological significance of Bcl-xL in upper urinary tract urothelial carcinoma (UTUC) and the therapeutic effect of targeting Bcl-xL protein in urothelial carcinoma (UC) cells. Methods: We evaluated the immunohistochemical expression of Bcl-xL in 175 UTUC patients to determine the clinical role of BclxL expression in clinical outcome. We used bafilomycin A1 (BMA) as a specific inhibitor of Bcl-xL to examine the biological effects in UC cells in vitro and in vivo. Results: Immunohistochemical analysis of Bcl-xL expression revealed that patients with a high Bcl-xL score had a significantly lower 5-year cancer-specific survival (CSS) rate (53.2%) than those with a low Bcl-xL score (77.2%) (P = 0.0011). Multivariate analysis indicated that a high Bcl-xL score was an independent prognostic factor of CSS (P = 0.023). BMA inhibited UMUC-3 cell proliferation in vitro by induction of apoptosis. Treatment with BMA significantly inhibited tumour growth in UMUC-3 tumours in this mouse xenograft model accompanied by an elevated apoptosis induction. Conclusion: Bcl-xL appears to be a significant molecular marker for the prognosis of UTUCs. Targeting Bcl-xL may be a promising therapeutic strategy for patients with UC.

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Impact of smoking status on bladder tumor recurrence after radical nephroureterectomy for upper tract urothelial carcinoma

Hagiwara Masayuki, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Ide Hiroki, Miyajima Akira, Masuda Takeshi, Nakamura So, Oya Mototsugu

Journal of Urology 189 ( 6 ) 2062 - 2068 2013.06

ISSN 0022-5347

Purpose: Although smoking status has a significant association with clinical features in patients with bladder cancer, there are few reports of the impact of smoking on the clinical outcome of upper tract urothelial cancer. We investigated the possible influence of smoking status on bladder tumor recurrence after radical nephroureterectomy. Materials and Methods: We identified a study population of 245 consecutive patients treated surgically for upper tract urothelial cancer at our 3 institutions between 1994 and 2010. We analyzed associations between subsequent bladder tumor recurrence and patient clinicopathological parameters, including smoking status. Results: The 3-year bladder tumor recurrence-free survival rate was 32.6% in current smokers, 37.6% in former smokers and 61.7% in nonsmokers. Multivariate analysis revealed that male gender (HR 1.90, 95% CI 1.15-3.16, p = 0.013) and smoking status (former vs none HR 1.77, 95% CI 1.07-2.93, p = 0.027 and current vs none HR 1.58, 95% CI 1.03-2.42, p = 0.035) were independent risk factors for subsequent bladder tumor recurrence. Also, of patients with a positive smoking history those with 50 pack-years or greater showed a significantly higher incidence of bladder tumor recurrence after radical nephroureterectomy (HR 2.00, p = 0.003). Conclusions: Positive smoking history and male gender were independent risk factors for bladder tumor recurrence after radical nephroureterectomy. A larger number of cigarettes smoked may increase the incidence of bladder tumor recurrence in patients with upper tract urothelial cancer.

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CLINICAL FEATURES OF LONG-TERM USE OF PDE-5 INHIBITORS IN PATIENTS WITH ED

Daimon Tatsuaki, Kikuchi Eiji, Matsushima Masashi, Ando Toshiyuki, Miyajima Akira, Marumo Ken, Oya Mototsugu

JOURNAL OF SEXUAL MEDICINE 10 216 - 216 2013.06

Research paper (scientific journal), Joint Work, ISSN 1743-6095

A PROSPECTIVE LONGITUDINAL SURVEY OF ERECTILE FUNCTION FOLLOWING TREATMENT FOR LOCALIZED PROSTATE CANCER WITH PROSTATE BRACHYTHERAPY

Matsushima Masashi, Kikuchi Eiji, Maeda Takahiro, Sugawara Akitomo, Ando Toshiyuki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF SEXUAL MEDICINE 10 243 - 244 2013.06

Research paper (scientific journal), Joint Work, ISSN 1743-6095

The prognostic significance of vasohibin-1 expression in patients with prostate cancer

Kosaka T., Miyazaki Y., Miyajima A., Mikami S., Hayashi Y., Tanaka N., Nagata H., Kikuchi E., Nakagawa K., Okada Y., Sato Y., Oya M.

British Journal of Cancer 108 ( 10 ) 2123 - 2129 2013.05

ISSN 0007-0920

Background:We recently isolated vasohibin-1 (VASH1), a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells (ECs), and the status of VASH1 expression has been documented in various cancer angiogenesis. The aim of this study was to assess the prognostic value of VASH1 expression in prostate cancer (PCa).Methods:In this study, we retrospectively analysed the clinical records and evaluated the VASH1 expression of tumour microvessels in 167 patients with PCa who underwent radical prostatectomy. We immunohistochemically examined the microvessels positive for anti-CD34 as microvessel density (MVD) and the microvessels with activated ECs positive for VASH1 density.Results:We found that the VASH1 expression was restricted to ECs in the tumour stroma. VASH1 density was significantly associated with pathological T stage, Gleason score and MVD. The 5-year PSA recurrence-free survival rate was 58.8% in patients with higher VASH1 density (≧12 per mm 2) and 89.1% in patients with lower VASH1 density (<12 per mm 2), respectively (P<0.001). Microvessel density was not an independent predictor of PSA recurrence. Multivariate analysis revealed that high VASH1 density was an independent prognostic indicator of PSA recurrence (P=0.007, HR=2.950).Conclusion:VASH1 density represents a clinically relevant predictor of patient prognosis and can be a new biomarker that would provide additional prognostic information in PCa.

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Prognostic value of plasma fibrinogen levels in patients with localized upper tract urothelial carcinoma

Tanaka Nobuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Hayakawa Nozomi, Ide Hiroki, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU INTERNATIONAL 111 ( 6 ) 857 - 864 2013.05

Research paper (scientific journal), Joint Work, ISSN 1464-4096

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Efficacy and safety of docetaxel-based chemotherapy in Japanese men over 80 years old with castration-resistant prostate cancer.

Kosaka Takeo, Yasumizu Yota, Mizuno Ryuichi, Miyajima, Akira, Kikuchi Eiji, Shinya Morita, Kono Hidaka, Nakagawa Ken, Oya Mototsugu

JOURNAL OF CLINICAL ONCOLOGY 31 ( 15 ) 619 - 624 2013.05

Research paper (scientific journal), Joint Work, ISSN 0732-183X

How can lymphocele development be prevented after laparoscopic radical prostatectomy?

Yasumizu Yota, Miyajima Akira, Maeda Takahiro, Takeda Toshikazu, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Journal of Endourology 27 ( 4 ) 447 - 451 2013.04

ISSN 0892-7790

Objectives: Lymphocele development is the most frequently reported postoperative complication of pelvic lymph node dissection (PLND) performed with laparoscopic radical prostatectomy (LRP). This study evaluated the efficacy of a vessel-sealing device (VSD) for the prevention of lymphocele development. Methods: A total of 120 patients who underwent LRP with PLND were prospectively enrolled. The patients were randomly assigned to one of the two groups: PLND using a conventional technique (group 1), and PLND performed with VSD (group 2). All patients underwent computed tomography (CT) scanning 1 month postoperatively to evaluate the maximum sectional area of the lymphoceles. Results: Lymphoceles developed in 63 cases (52.5%). One case (0.8%) was symptomatic with infection, and drainage tube placement was required. In the other 62 patients, the lymphoceles developed asymptomatically and were detected by CT scanning. There was no significant difference in the lymphocele development ratio between the two groups. However, when we defined a lymphocele over 1500 mm² as being a significant size, lymphoceles were present in 16 of 60 patients in group 1 and 4 of 60 patients in group 2. The incidence of significant lymphoceles over 1500 mm² in the group using VSD was much lower than that of the group without VSD (p<0.01). Multivariate analysis demonstrated that VSD was the only independent factor that had an effect on preventing the development of lymphoceles over 1500 mm² (p<0.01, odds ratio=4.96). Conclusion: The results indicate that the development of large lymphoceles can be prevented by using VSD in LRP with PLND.

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PREDICTIVE VALUE OF POSITIVE URINE CYTOLOGY FOR PROGNOSIS IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA FOLLOWING RADICAL NEPHROURETERECTOMY

Tanaka Nobuyuki, Kikuchi Eiji, Miyazaki Yasumasa, Shirotake Suguru, Kobayashi Hiroaki, Matsumoto Kazuhiro, Ide Hiroki, Obata Jun, Hoshino Katsura, Kosaka Takeo, Kanao Kent, Oyama Masafumi, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Nakajima Yosuke, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E162 - E162 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

HYPOXIC MICROENVIRONMENT PROMOTES PI3K/AKT/MTOR SIGNALING PATHWAYS IN HUMAN CASTRATION RESISTANT PROSTATE CANCER

Yasumizu Yota, Kosaka Takeo, Miyazaki Yasumasa, Kikuchi Eiji, Miyajima Akira, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E539 - E539 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

THE PROGNOSTIC SIGNIFICANCE OF VASOHIBIN-1 EXPRESSION IN PATIENTS WITH UPPER URINARY TRACT UROTHELIAL CARCINOMA

Miyazaki Yasumasa, Kosaka Takeo, Mikami Shuji, Kikuchi Eiji, Tanaka Nobuyuki, Maeda Takahiro, Ishida Masaru, Miyajima Akira, Nakagawa Ken, Okada Yasunori, Sato Yasufumi, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E288 - E288 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

UNDETECTABLE TUMOR THROUGH PREOPERATIVE MRI PREDICTS ORGAN CONFINED DISEASE AND LOWER TUMOR VOLUME IN PATIENTS WITH CLINICALLY LOCALIZED PROSTATE CANCER

Muro Yusuke, Mizuno Ryuichi, Yazawa Satoshi, Kosaka Takeo, Morita Shinya, Kono Hidaka, Kikuchi Eiji, Asanuma Hiroshi, Miyajima Akira, Nakagawa Ken, Jinzaki Masahiro, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E275 - E275 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

CHARACTERISTICS AND OUTCOME IN METASTATIC UPPER TRACT UROTHELIAL CARCINOMA FOLLOWING RADICAL NEPHROURETERECTOMY: THE MULTI-INSTITUTIONAL EXPERIENCE

Tanaka Nobuyuki, Kikuchi Eiji, Shirotake Suguru, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Obata Jun, Hoshino Katsura, Kosaka Takeo, Kanao Kent, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Nakajima Yosuke, Hasegawa Shintaro, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E161 - E161 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

MTOR PATHWAY REGULATES THE EXPRESSION OF ANGIOTENSIN 2 TYPE 1 RECEPTOR IN RENAL CELL CARCINOMA

Kaneko Gou, Miyajima Akira, Kosaka Takeo, Mizuno Ryuichi, Kikuchi Eiji, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E126 - E126 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

C-REACTIVE PROTEIN INDEPENDENTLY PREDICTS THE PROGNOSIS OF PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA TREATED WITH RADICAL NEPHROURETERECTOMY: A MULTI-INSTITUTIONAL STUDY

Obata Jun, Kikuchi Eiji, Tanaka Nobuyuki, Ishioka Katsura, Shirotake Suguru, Matsumoto Kazuhiro, Kobayashi Hiroaki, Miyazaki Yasumasa, Ide Hiroki, Hayakawa Nozomi, Ito Yujiro, Kanao Kent, Miyajima Akira, Momma Tetsuo, Nakagawa Ken, Ueno Munehisa, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E286 - E287 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

SHOULD A FIRST RECURRENT LOW GRADE TA BLADDER CANCER BE MANAGED AS AN INTERMEDIATE-RISK GROUP TUMOR?

Kobayashi Hiroaki, Kikuchi Eiji, Maeda Takahiro, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Nakamura So, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E732 - E733 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

IS IT NECESSARY TO ROUTINELY PERFORM MULTIPLE BIOPSIES FROM NORMAL-APPEARING UROTHELIUM WHEN URINE CYTOLOGY IS POSITIVE IN PATIENTS WITH NON-MUSCLE INVASIVE BLADDER CANCER?

Matsushima Masashi, Kikuchi Eiji, Hasegawa Masanori, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E732 - E732 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

PREDICTING PROSTATE SPECIFIC ANTIGEN RECURRENCE AFTER RADICAL PROSTATECTOMY BY CLINICOPATHOLOGICAL FACTORS: SUITABILITY OF MAGNETIC RESONANCE IMAGING

Hattori Seiya, Kosaka Takeo, Mizuno Ryuichi, Yasumizu Yota, Miyajima Akira, Nagata Hirohiko, Yazawa Satoshi, Kikuchi Eiji, Nakagawa Ken, Mikami Shuji, Tanimoto Akihiro, Jinzaki Masahiro, Oya Mototsugu

JOURNAL OF UROLOGY 189 ( 4 ) E99 - E99 2013.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

A prospective longitudinal survey of erectile dysfunction in patients with localized prostate cancer treated with permanent prostate brachytherapy

Matsushima Masashi, Kikuchi Eiji, Maeda Takahiro, Nakashima Jun, Sugawara Akitomo, Ando Toshiyuki, Mizuno Ryuichi, Nagata Hirohiko, Miyajima Akira, Shigematsu Naoyuki, Oya Mototsugu

Journal of Urology 189 ( 3 ) 1014 - 1018 2013.03

ISSN 0022-5347

Purpose: Few studies have evaluated changes in erectile function with time before and after prostate brachytherapy using the International Index of Erectile Function-15, a sensitive, validated tool for assessing male sexual dysfunction. In this prospective study we evaluated the natural history of erectile function after prostate brachytherapy without supplemental therapy (external beam radiotherapy, phosphodiesterase-5 inhibitors or androgen deprivation therapy) using the International Index of Erectile Function-15. Materials and Methods: We identified 119 patients who were followed at least 12 months after prostate brachytherapy between 2004 and 2010. Sexual and erectile function status were assessed before brachytherapy (baseline), and 3, 6, 12, 18, 24 and 36 months postoperatively using the International Index of Erectile Function-15. Results: Mean total International Index of Erectile Function-15 score, and scores on the erectile function, orgasmic function, sexual desire and intercourse satisfaction domains 3 months after brachytherapy were significantly lower than at baseline (p <0.05). They remained lower until 36 months after prostate brachytherapy. Erectile function was maintained 12 months after brachytherapy in 16 of the 48 men (33.3%) with a baseline erectile function domain score of 11 or greater. There was no significant difference in clinical features except the age of patients who maintained the erectile function domain score and their counterparts 12 months after brachytherapy. Multivariate analysis revealed that age 70 years or greater was the only predictive factor for deteriorating erectile function after brachytherapy (p = 0.035). Conclusions: Findings indicate a global decrease in all domains of the International Index of Erectile Function-15 score 12 months after prostate brachytherapy. Also, patient age may influence the preservation of brachytherapy related potency.

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Lymphoceles post radical prostatectomy

Yasumizu Yota, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Urology 67 ( 3 ) 241 - 245 2013.03

ISSN 0385-2393

What is the predictor of prolonged operative time during laparoscopic radical prostatectomy?

Kaneko Gou, Miyajima Akira, Yazawa Satoshi, Yuge Kazuyuki, Kikuchi Eiji, Asanuma Hiroshi, Nakagawa Ken, Oya Mototsugu

International Journal of Urology 20 ( 3 ) 330 - 336 2013.03

ISSN 0919-8172

Objectives: To study the impact of high body mass index and large prostate weight on operative time of laparoscopic radical prostatectomy. Methods: A retrospective analysis of medical records from patients who had undergone extraperitoneal laparoscopic radical prostatectomy by a single surgeon at our institution between September 2008 and April 2011 was carried out. For each case, the following parameters were recorded: age, body mass index, prostate weight, cross-section area of the Retzius space, and history of previous lower abdominal surgery, repeated prostate biopsy and neoadjuvant hormone therapy. The laparoscopic radical prostatectomy procedure was divided into seven surgical steps: (i) port insertion and lymph node dissection; (ii) endopelvic fascia incision; (iii) dorsal vein complex ligation; (iv) prostate dissection from bladder neck; (v) dissection of seminal vesicles and vas deferens; (vi) prostate dissection from rectum; and (vii) vesicourethral anastomosis. The overall operative time and the duration of each surgical step were retrieved. Potential predictors of prolonged total operative time and prolonged duration of a step were assessed by multivariate logistic regression analysis. Results: A total of 152 patients were analyzed. High body mass index (≥25.0kg/m²) and prostate weight were independent predictors of prolonged total operative time. High body mass index was an independent predictor of prolonged step1, 3, 4, 5 and 6. Prostate weight was an independent predictor of prolonged step2, 5 and 6. A history of previous lower abdominal surgery was a predictor of prolonged step1. Conclusions: High body mass index and high prostate weight are independent predictors of prolonged total operative time in extraperitoneal laparoscopic radical prostatectomy. Although high body mass index seems to affect most of the surgical steps of the procedure, prostate weight mainly impacts the dissection close to the prostate, as enlarged prostate results in a narrower working space.

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Induction of pluripotent stem cells from primordial germ cells by single reprogramming factors

Nagamatsu Go, Kosaka Takeo, Saito Shigeru, Honda Hiroaki, Takubo Keiyo, Kinoshita Taisuke, Akiyama Hideo, Sudo Tetsuo, Horimoto Katsuhisa, Oya Mototsugu, Suda Toshio

Stem Cells 31 ( 3 ) 479 - 487 2013.03

ISSN 1066-5099

Germ cells are similar to pluripotent stem cells in terms of gene expression patterns and the capacity to convert to pluripotent stem cells in culture. The factors involved in germ cell development are also able to reprogram somatic cells. This suggests that germ cells are useful tools for investigating the mechanisms responsible for somatic cell reprograming. In this study, the expression of reprograming factors in primordial germ cells (PGCs) was analyzed. PGCs expressed Oct3/4, Sox2, and c-Myc but not Klf4. However, Klf2, Klf5, Essrb, or Essrg, which were expressed in PGCs, could compensate for Klf4 during somatic cell reprograming. Furthermore, PGCs could be converted to a pluripotent state by infection with any of the known reprogramming factors (Oct3/4, Sox2, Klf4, and c-Myc). These cells were designated as multipotent PGCs (mPGCs). Contrary to differences in the origins of somatic cells in somatic cell reprogramming, we hypothesized that the gene expression levels of the reprogramming factors would vary in mPGCs. Candidate genes involved in the regulation of tumorigenicity and/or reprogramming efficiency were identified by comparing the gene expression profiles of mPGCs generated by the exogenous expression of c-Myc or L-Myc.

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Is inflammation related to any diseases?

Oya Mototsugu

International journal of urology : official journal of the Japanese Urological Association 20 ( 2 ) 135 2013.02

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Does laparoendoscopic single-site adrenalectomy increase surgical risk in patients with pheochromocytoma?

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES 27 ( 2 ) 593 - 598 2013.02

Research paper (scientific journal), Joint Work, ISSN 0930-2794

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Human castration resistant prostate cancer rather prefer to decreased 5 alpha-reductase activity

Kosaka Takeo, Miyajima Akira, Nagata Hirohiko, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

SCIENTIFIC REPORTS 3 E304 - E305 2013.02

Research paper (scientific journal), Joint Work, ISSN 2045-2322

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Editorial Comment to How to prepare and present scientific manuscripts in English

Oya Mototsugu

International Journal of Urology 20 ( 2 ) 139 2013.02

ISSN 0919-8172

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New targeted agents for advanced renal cell carcinoma

Mizuno Ryuichi, Oya Mototsugu

Japanese Journal of Clinical Urology 67 ( 1 ) 67 - 72 2013.01

ISSN 0385-2393

Human castration resistant prostate cancer rather prefer to decreased 5α-reductase activity

Kosaka Takeo, Miyajima Akira, Nagata Hirohiko, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Scientific Reports 3 2013

Physiologically relevant steroid 5α-reductase (SRD5A) activity that is essential for dihydrotestosterone (DHT) biosynthesis in human castration-resistant prostate cancer (CRPC) has not been fully characterized yet. In this study to ascertain the potential SRD5A activity, we cultured two human CRPC cell lines, C4-2 and C4-2AT6, with the steroid precursor: ¹³C-[2,3,4]-androstenedione (¹³C-Adione), and analyzed the sequential biosynthesis of ¹³C-[2,3,4]-testosterone ( ¹³C-T) and ¹³C-[2,3,4]-DHT (¹³C-DHT) by liquid chromatography/mass spectrometry (LC/MS/MS). The ¹³C-DHT/ ¹³C-T concentration ratio detected by LC/MS/MS in C4-2AT6 cells appeared to reflect the SRD5A activity. The ratio in C4-2AT6 was significantly lower than that in C4-2. An increased concentration of DHT did not have a positive effect on cell proliferation, rather it exhibited inhibitory effects. 5α-reductase inhibitors did not have any inhibitory effect at clinically achievable concentrations. These results indicate that CRPC cells may have an unknown regulation system to protect themselves from an androgenic suppressive effect mediated by SRD5A activity.

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Chromophobe renal cell carcinoma, oncocytic variant

Kuroda Naoto, Tanaka Azusa, Yamaguchi Tadanori, Kasahara Kotaro, Naruse Keishi, Yamada Yosuke, Hatanaka Kanako, Shinohara Nobuo, Nagashima Yoji, Mikami Shuji, Oya Mototsugu, Hamashima Takeru, Michal Michal, Hes Ondrej

Medical Molecular Morphology 46 ( 1 ) 49 - 55 2013

ISSN 1860-1480

In chromophobe renal cell carcinoma (RCC), two forms of typical and eosinophilic variants have been reported to date. We have previously reported a new variant of chromophobe RCC, namely an oncocytic variant. However, little is known on the histological features of this variant. In this article, we report such five cases. Macroscopically, the tumor was well demarcated, but unencapsulated. The cut surface of the tumor showed brown in color, but neither hemorrhage nor necrosis was seen. Microscopically, the tumor consisted of predominant tubular configuration with or without various proportion of solid-sheet pattern. In one tumor, tumor cells microscopically invaded branches of renal vein. In addition, the constituting cells were characterized by the oncocytic cytoplasm, trivial to minimal variation in tumor size, indistinct to slightly distinct cell border, centrally located round nuclei and the absence of perinuclear halo. These characteristics entirely resembled renal oncocytoma. However, neoplastic cells immunohistochemically showed the diffuse and strong labeling for cytokeratin 7 and mitochondrial antigen in all cases. In addition, in fluorescence in situ hybridization (FISH) study the loss of more than four chromosomes among chromosomes 7, 10, 13, 17 and 21 was confirmed in all tumors and the diagnosis of chromophobe RCC was rendered. In conclusion, we propose a new variant, namely an oncocytic variant, of chromophobe RCC morphologically resembling renal oncocytoma and biologically showing characteristics of chromophobe RCC, and this recognition is practically crucial in the differential diagnosis from renal oncocytoma.

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Technical difficulties of transumbilical laparoendoscopic single-site adrenalectomy

Ishida Masaru, Miyajima Akira, Takeda Toshikazu, Hasegawa Masanori, Kikuchi Eiji, Oya Mototsugu

World Journal of Urology 31 ( 1 ) 199 - 203 2013

ISSN 0724-4983

Purpose: Interest in laparoendoscopic single-site (LESS) surgery has increased in recent years. The aim of this study was to evaluate the feasibility and safety of transumbilical LESS adrenalectomy and to elucidate the technical differences between LESS and conventional laparoscopic surgery. Methods: This study was comparing 10 consecutive transumbilical LESS adrenalectomies and 10 conventional laparoscopic adrenalectomies performed between March 2006 and April 2010 for benign adrenal tumors. Perioperative parameters were compared, and we reviewed our surgical videos and analyzed technical characteristics of the surgeries. Results: There was no open conversion in laparoscopic group, no additional port placement in LESS group, and no perioperative complications in either group. No significant differences in operative time, estimated blood loss, or resumption of oral intake were observed between two groups. Pneumoperitoneum time did not differ between LESS and laparoscopic groups (91. 2 vs. 74. 3 min, P = 0. 257). In LESS group only, time was needed for adjustment of roticulator (14. 5 ± 8. 1 min). After subtracting the time needed for adjustment, operative time between two groups was more comparable (76. 7 vs. 74. 3 min, P = 0. 880). One-handed manipulation time in LESS group decreased in a time-dependent manner (r = -0. 806, P < 0. 0049). Tissue re-grasping during operation was more frequently observed in LESS group (16. 2 vs. 2. 2 times, P < 0. 001). Conclusions: Transumbilical LESS adrenalectomy is feasible and comparable to conventional laparoscopic adrenalectomy. There are still obvious technical difficulties associated with LESS surgery, and it is essential that these be overcome in order to improve this surgical technique.

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What is the most effective tool for detecting prostate cancer using a standard MR scanner?

Osugi Kei, Tanimoto Akihiro, Nakashima Jun, Shinoda Kazunobu, Hashiguchi Akinori, Oya Mototsugu, Jinzaki Masahiro, Kuribayashi Sachio

Magnetic Resonance in Medical Sciences 12 ( 4 ) 271 - 280 2013

ISSN 1347-3182

Purpose: We aimed to determine which of the following magnetic resonance (MR) imaging sequences is most effective for detecting prostate cancer: T₂-weighted (T₂W), dynamic contrast-enhanced (DCE) T₁-weighted (T₁W), or diffusion-weighted (DWI) imaging or apparent diffusion coefficient (ADC) mapping. Materials and Methods: We included 37 male patients with prostate cancer who underwent MR imaging before radical prostatectomy in this retrospective study. Sixty-four foci (>5 mm in size; 35 in the peripheral zone [PZ], 29 in the transitional zone [TZ]) were histopathologically determined to be prostate cancer. We determined the capacity of T₂W, DCE-T₁W, DWI, ADC mapping alone, and the combination of ADC mapping with DWI, and conventional MR sequences to detect prostate cancer, including their sensitivity and positive predictive value (PPV), with reference to the results obtained in histopathological examinations of whole-mount sections. Results: In the PZ, sensitivities were 31.4% (T₂W), 37.1% (DCE-T₁W), 51.4% (DWI), and 71.4% (ADC mapping); PPVs were 78.6% (T₂W), 92.9% (DCE-T₁W), 94.7% (DWI), and 96.0% (ADC mapping). Sensitivity was significantly higher of ADC mapping than other sequences. In the TZ, sensitivities were 55.1% (T₂W), 44.8% (DCE-T₁W), 82.8% (DWI), and 89.7% (ADC mapping); PPVs were 64.0% (T₂W), 46.4% (DCE-T₁W), 70.6% (DWI), and 72.2% (ADC mapping). Sensitivity was significantly higher of ADC mapping and DWI than conventional MR imaging, but there was no significant correlation between DWI/ADC mapping and T₂W/DCE-T₁W with respect to PPVs. Combining sequences did not improve sensitivity; only the PPV in the TZ improved when ADC mapping was combined with DCE-T₁W. Conclusion: ADC mapping is the most effective standard MR imaging tool for detecting prostate cancer. The addition of DCE-T₁W may improve the PPV of ADC mapping for diagnosing cancer in the TZ.

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Burden of overactive bladder symptom on quality of life in stroke patients

Itoh Yoshiaki, Yamada Satoshi, Konoeda Fumie, Koizumi Kenzo, Nagata Hirohiko, Oya Mototsugu, Suzuki Norihiro

Neurourology and Urodynamics 32 ( 5 ) 428 - 434 2013

ISSN 0733-2467

Aims Overactive bladder (OAB) affects the daily life of many stroke victims. In contrast to urinary incontinence, little is known about the prevalence and risk factors for OAB among stroke patients. Therefore, we conducted a questionnaire survey and analyzed the results together with the clinical data and MRI findings. Methods A total of 500 volunteer patients with chronic-phase stroke were enrolled. The overactive bladder symptom score (OABSS), Short Form 8 (SF-8) health survey questionnaire, and some key international questionnaires about urinary dysfunction were assessed. Results We diagnosed 141 patients (28%) with OAB, among whom 103 (73%) had never been treated for their symptoms. Patients with OAB showed lower scores in both the physical and mental components of the SF-8, which suggested the burden of OAB on the quality of life of stroke patients. Advanced age and male gender were closely related to high OABSS. The modified Rankin Scale (mRS) was positively correlated with OABSS. Patients with cerebral infarction and those with intracerebral hemorrhage showed a similarly high OABSS. The severity of deep white-matter hyperintensity on MRI, classified by the 4-grade Fazekas scoring system, was significantly associated with high OABSS irrespective of presence of accompanying infarcts. Patients with cerebral infarcts in the region of anterior circulation showed a higher OABSS than those with cerebral infarcts in the posterior circulation. Conclusions Based on the present risk analysis, patient care should be preferentially focused on the detection and treatment of OAB to improve the quality of life of stroke patients.

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Effect of a novel nuclear factor-jb activation inhibitor on renal ischemia-reperfusion injury

Kono Hidaka, Nakagawa Ken, Morita Shinya, Shinoda Kazunobu, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

Transplantation 96 ( 10 ) 863 - 870 2013

ISSN 0041-1337

Background. In kidney transplantation, the relationship between prolonged warm or cold ischemic storage of kidneys and a higher incidence of delayed graft function is previously known, and delayed graft function has been known to aggravate poor long-term graft survival. We investigated the effect of a novel nuclear factor-JB activation inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), on renal ischemia-reperfusion (I/R) injury. Methods. DHMEQ was administered to Lewis rats once just before renal artery clamping (DHMEQ pretreatment group), and the effect on I/R injury was investigated. Results. In the DHMEQ pretreatment group, the 24-hr urine volume on days 1 to 3 after I/R was significantly larger, and the protein concentration of the urine on days 2 to 7 was significantly smaller than in the untreated group. The serum creatinine level was significantly improved, and significantly lower levels of the inflammatory cells and inflammatory cytokines were present in the kidneys on day 1. The relative ratio of nuclear to cytoplasmic nuclear factor-JB and oxidative stress of kidney tissue on day 1 were significantly decreased. Conclusions. Treatment with DHMEQ before renal artery clamping may therefore be useful for renal I/R injury and application to renal transplantation is expected.

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Risk of subsequent tumour recurrence and stage progression in bacille Calmette-Guérin relapsing non-muscle-invasive bladder cancer

Matsumoto Kazuhiro, Kikuchi Eiji, Shirakawa Hiroshi, Hayakawa Nozomi, Tanaka Nobuyuki, Ninomiya Akiharu, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU International 110 ( 11 B ) 2012.12

ISSN 1464-4096

OBJECTIVE • To investigate the risk of subsequent tumour recurrence and stage progression in bacillus Calmette-Guérin (BCG)-relapsing non-muscle-invasive bladder cancer, defined as recurrence after achieving a disease-free status for 6 months. PATIENTS AND METHODS • A total of 183 patients with BCGrelapsing tumours were treated with conservative therapy between 1985 and 2008 at our three institutions. • We analysed the association between their clinicopathological parameters and subsequent tumour recurrence or stage progression. RESULTS • Additional induction courses of BCG or anticancer drug (mitomycin C or epirubicin) instillations were performed in 119 patients and 24 patients, respectively. The remaining 40 patients did not undergo any adjuvant therapy. • Multivariate analysis showed that a relapsing tumour with a pathologically high risk (defined as tumours with G3 and/or pT1 and/or concomitant carcinoma in situ ) was a significant risk factor for subsequent tumour recurrence ( P = 0.002; hazard ratio [ HR ] 2.15). Additional BCG instillation significantly decreased the subsequent tumour recurrence rate ( P < 0.001; HR 0.41). • Multivariate analysis also showed that a relapsing tumour with a pathologically high risk was also significantly associated with stage progression ( P < 0.001; HR 8.05). CONCLUSIONS • An additional course of BCG instillation might be effective in patients with BCG-relapsing tumours with pathologically intermediate risk. • Nevertheless, some patients with high-risk pathological features developed subsequent stage progression. Such patients should be followed up closely and counselled on the need for aggressive therapeutic options, such as radical cystectomy.

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Visceral obesity is a strong predictor of perioperative outcome in patients undergoing laparoscopic radical nephrectomy

Hagiwara Masayuki, Miyajima Akira, Hasegawa Masanori, Jinzaki Masahiro, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

BJU International 110 ( 11 C ) 2012.12

ISSN 1464-4096

OBJECTIVE • To examine the impact of visceral fat on surgical complexity in patients undergoing laparoscopic nephrectomy. PATIENTS AND METHODS • We reviewed the medical records of 121 patients who underwent laparoscopic nephrectomy from 2006 to 2010 at our institution. • The total fat area, visceral fat area (VFA) and subcutaneous fat area were measured at the level of the umbilicus using computed tomography (CT). • To identify the type of obesity, we divided VFA into ≥ 100 cm 2 and < 100 cm 2 . A VFA ≥ 100 cm 2 was used as the definition of visceral obesity. • We evaluated the impact of the VFA on technical difficulties encountered during laparoscopic nephrectomy by measuring operating time. RESULTS • A significant correlation was observed between body mass index (BMI) and operating time ( P < 0.001, r =0.316) in the patients undergoing laparoscopic nephrectomy. • VFA was also significantly correlated with operating time ( P < 0.001, r =0.348), and the correlation coefficient of VFA was higher than that of BMI. • Multivariate analysis showed that a high VFA was an independent risk factor for prolonged operating time ( P =0.009, odds ratio; 3.70), whereas BMI was not found to be a risk factor. CONCLUSIONS • The present data indicate that measurement of VFA by CT is of benefit for predicting the technical difficulty associated with laparoscopic radical nephrectomy. • Visceral obesity, which is one factor involved in metabolic syndrome, has a greater impact than BMI on the complexity of laparoscopic radical nephrectomy.

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Risk factors for perioperative complications of laparoscopic adrenalectomy including single-site surgery

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Shibata Hirotaka, Oya Mototsugu

Journal of Endourology 26 ( 11 ) 1463 - 1467 2012.11

ISSN 0892-7790

Purpose: To determine predictive factors for perioperative complications of laparoscopic adrenalectomy (LA) including single-site surgery performed or supervised by experienced laparoscopic surgeons. Patients and Methods: We retrospectively reviewed 265 consecutive unilateral LAs performed at a single institution from 2001 to 2011. All surgical procedures were performed or supervised by one of two experienced laparoscopic surgeons. The transabdominal approach was used in 248 patients, while a retroperitoneal approach was used in 17 patients. Laparoendoscopic single-site adrenalectomy was performed in 58 patients. Predictive factors for postoperative complications were analyzed. Results: There were no postoperative deaths. At least one postoperative complication occurred in 12 (4.6%) patients. No patient underwent reoperation for a complication. Only one (0.4%) patient's procedure was converted to open surgery, and only this patient needed a blood transfusion during the operation. One patient who underwent laparoendoscopic single-site adrenalectomy had the procedure converted to conventional laparoscopic adrenalectomy. Multivariable logistic regression analysis showed that an American Society of Anesthesiologists-physical status grade 3 or above was the only predictive factor for perioperative complications. Conclusion: American Society of Anesthesiologists-physical status grade 3 or above was a statistically significant factor for perioperative complications associated with laparoscopic adrenalectomy that involved laparoendoscopic single-site adrenalectomy, which was performed or supervised by an experienced laparoscopic surgeon. According to the findings of this retrospective study, single-site operation, obesity, adrenal tumor size, and tumor type may not be considered as risk factors for perioperative complications after LA performed or supervised by an experienced laparoscopic surgeon.

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[The molecular mechanisms of resistance to androgen deprivation therapy in prostate cancer].

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 70 Suppl 8 353 - 359 2012.11

ISSN 0047-1852

Risk Factors for Perioperative Complications of Laparoscopic Adrenalectomy Including Single-Site Surgery

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Shibata Hirotaka, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 26 ( 11 ) 1463 - 1467 2012.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

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Prognostic value of renin-angiotensin system blockade in non-muscle-invasive bladder cancer

Yuge Kazuyuki, Miyajima Akira, Tanaka Nobuyuki, Shirotake Suguru, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Annals of Surgical Oncology 19 ( 12 ) 3987 - 3993 2012.11

ISSN 1068-9265

Background. To determine whether the administration of renin-angiotensin system (RAS) inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), affect disease outcome in non-muscle-invasive bladder cancer (NMIBC). Methods. A total of 330 patients with initially diagnosed NMIBC were identified. We retrospectively investigated the clinical outcomes after transurethral resection of bladder tumor (TUR-BT) in patients who did or did not receive RAS inhibitors. The median follow-up period was 4.1 years. Results. A total of 128 patients (38.8 %) experienced subsequent tumor recurrence, and stage progression was observed in 17 patients (5.2 %) during follow-up. Fifty-one patients (15.5 %) had received ACEI or ARB administration at transurethral resection. Multivariate analysis demonstrated that tumor multiplicity, absence of bacillus Calmette-Guérin instillation, and no administration of ACEI or ARB (P = 0.010, hazard ratio 2.26) were independent risk factors for subsequent tumor recurrence. The 5-year recurrence-free survival rate was 78.4 % in patients administered ACEIs or ARBs, and 53.3 % in their counterparts (P = 0.011). Conclusions. The absence of RAS inhibitor administration was an independent risk factor for subsequent tumor recurrence in patients with initially diagnosed NMIBC. Our data support further investigation of the role of RAS inhibitors as a potential therapy to decrease tumor recurrence in NMIBC.

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Prostate brachytherapy seed migration to a left varicocele

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Brachytherapy 11 ( 6 ) 502 - 506 2012.11

ISSN 1538-4721

Purpose: To report a rare case of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose iodine-125 (¹²⁵I) seeds. Methods and Materials: A 73-year-old man presented with a serum prostate-specific antigen level of 5.21ng/mL, Gleason score of 7 (3+4), and clinical T1c adenocarcinoma of the prostate. The patient underwent transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds followed by external beam radiation therapy. Two weeks after seed implantation, a followup pelvic radiograph was obtained. One month after seed implantation, a pelvic computed tomography scan for postimplant dosimetric analysis was carried out. Subsequent ultrasound examination of the scrotum was undertaken. Results: Two weeks after seed implantation, an anteroposterior pelvic radiograph showed that a migrated seed was overlapped by the scrotum. Postimplant pelvic computed tomography revealed that a seed had migrated to the left side of the scrotum. Subsequent ultrasound examination of the scrotum revealed that the patient had a left varicocele to which the seed had migrated. The patient had no symptoms related to the migrated seed. Conclusions: This is the first report of seed migration to a left varicocele after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds. For the present case, we suggest that the seed moved from the prostate to the left varicocele through the pelvic veins, bypassing the systemic circulation.

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Optimal ratio of transcription factors for somatic cell reprogramming

Nagamatsu Go, Saito Shigeru, Kosaka Takeo, Takubo Keiyo, Kinoshita Taisuke, Oya Mototsugu, Horimoto Katsuhisa, Suda Toshio

Journal of Biological Chemistry 287 ( 43 ) 36273 - 36282 2012.10

ISSN 0021-9258

Somatic cell reprogramming is achieved by four reprogramming transcription factors (RTFs), Oct3/4, Sox2, Klf4, and c-Myc. However, in addition to the induction of pluripotent cells, these RTFs also generate pseudo-pluripotent cells, which do not show Nanog promoter activity. Therefore, it should be possible to fine-tune the RTFs to produce only fully pluripotent cells. For this study, a tagging system was developed to sort induced pluripotent stem (iPS) cells according to the expression levels of each of the four RTFs. Using this system, the most effective ratio (Oct3/4-high, Sox2-low, Klf4-high, c-Myc-high) of the RTFs was 88 times more efficient at producing iPS cells than the worst effective ratio (Oct3/4-low, Sox2-high, Klf4-low, c-Myclow). Among the various RTF combinations, Oct3/4-high and Sox2-low produced the most efficient results. To investigate the molecular basis, microarray analysis was performed on iPS cells generated under high (Oct3/4-high and Sox2-low) and low (Oct3/4-low and Sox2-high) efficiency reprogramming conditions. Pathway analysis revealed that the G protein-coupled receptor (GPCR) pathway was up-regulated significantly under the high efficiency condition and treatment with the chemokine, C-C motif ligand 2, a member of the GPCR family, enhanced somatic cell reprogramming 12.3 times. Furthermore, data from the analysis of the signature gene expression profiles of mouse embryonic fibroblasts at 2 days after RTF infection revealed that the genetic modifier, Whsc1l1 (variant 1), also improved the efficiency of somatic cell reprogramming. Finally, comparison of the overall gene expression profiles between the high and low efficiency conditions will provide novel insights into mechanisms underlying somatic cell reprogramming.

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Metastatic urothelial carcinoma to pericardia manifested by dyspnea from cardiac tamponade during systemic chemotherapy

Hattori Seiya, Miyajima Akira, Maeda Takahiro, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Kikuchi Eiji, Oya Mototsugu

Journal of the Canadian Urological Association 6 ( 5 ) 2012.10

ISSN 1911-6470

A 53-year-old man presented for further evaluation due to microscopic hematuria and left lumbar pain. Computed tomography revealed a large tumour in the left renal pelvis with multiple metastases. Despite effective systemic chemotherapy, he developed dyspnea, and was diagnosed with cardiac tamponade. Pericardial involvement in an advanced malignancy is common, but symptomatic cardiac metastasis from urothelial carcinoma is rare. Of the reports of symptomatic cardiac metastasis from urothelial carcinoma, only 3 cases presented as cardiac tamponade. We report here a rare case of cardiac tamponade caused by a renal pelvic carcinoma with positive cytodiagnosis of pericardial effusion. We also summarize and discuss the symptoms, treatment, and prognosis of the pathological condition, and present a brief review of previously published reports.

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Optimal Ratio of Transcription Factors for Somatic Cell Reprogramming

Nagamatsu Go, Saito Shigeru, Kosaka Takeo, Takubo Keiyo, Kinoshita Taisuke, Oya Mototsugu, Horimoto Katsuhisa, Suda Toshio

JOURNAL OF BIOLOGICAL CHEMISTRY 287 ( 43 ) 36273 - 36282 2012.10

Research paper (scientific journal), Joint Work, ISSN 0021-9258

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Diagnosis of acute bacterial prostatitis

Yazawa Satoshi, Kanao Kento, Hongo Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 11 ) 817 - 822 2012.10

ISSN 0385-2393

Does pelvic lymph node dissection improve the biochemical relapse-free survival in low-risk prostate cancer patients treated by laparoscopic radical prostatectomy?

Daimon Tatsuaki, Miyajima Akira, Maeda Takahiro, Hattori Seiya, Yasumizu Yota, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Journal of Endourology 26 ( 9 ) 1199 - 1202 2012.09

ISSN 0892-7790

Background and Purpose: The roles and criteria for pelvic lymph node dissection (PLND) are not fully evaluated in patients with low-risk prostate cancer who are treated by laparoscopic radical prostatectomy (LRP). In this study, the outcome of PLND was assessed in terms of the biochemical relapse-free survival rates of low-risk prostate cancer patients who had undergone LRP. Patients and Methods: Included were 286 consecutive patients who were treated with LRP without previous endocrine therapy between 2002 and 2006 at our institution. Failure rates for LRP were compared in 139 patients with low-risk prostate cancer between those who underwent PLND (n=85) and those who did not (n=54). Biochemical relapse-free survival for each group was estimated by Kaplan-Meier analysis. Results: The mean number of retrieved lymph nodes was 5.4±0.4 (range 2-22). The 5- and 7-year biochemical relapse-free survival rates were 90.1% and 88.3% in patients with PLND, and 82.4% and 82.4% in those without PLND (P=0.278), respectively (median follow-up 69.4 mos). None of the 85 patients undergoing PLND had positive lymph nodes. Only one patient had symptomatic lymphocele, and he was treated as an inpatient. The average time needed for PLND was 16 minutes, which corresponded to 7% of the entire operative time. Conclusion: These results indicate that the dissection of pelvic lymph nodes is not related to biochemical relapse-free survival. The omission of PLND in patients with low-risk prostate cancer not only does not adversely affect biochemical relapse-free survival, but might decrease the incidence of complication and operative time of LRP.

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Prognostic significance of high nuclear grade in patients with pathologic t1a renal cell carcinoma

Suzuki Kenjiro, Mizuno Ryuichi, Mikami Shuji, Tanaka Nobuyuki, Kanao Kent, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 42 ( 9 ) 831 - 835 2012.09

ISSN 0368-2811

Objective: A reliable prognostic indicator in patients with pathologic T1a renal cell carcinoma has not yet been fully elucidated. The aim of this study was to investigate the prognosis of pathologic T1a renal cell carcinoma cases with a special focus on pathological factors. Methods: The study population consisted of 338 patients diagnosed with solitary renal cell carcinoma at our hospital between 1996 and 2009. The relationship between disease progression and clinicopathologic features was analyzed retrospectively to determine if it affected recurrence and distant metastasis. Results: The Fuhrman nuclear grade distribution between the tumors was 1, 2, 3 and 4 in 68 (20.1%), 242 (71.6%), 21 (6.2%) and 7 cases (2.1%), respectively. A total of 11 subjects were identified as having recurrent tumors (3.3%), 9 of whom had metastatic lesions. Multivariate analysis showed that the appearance of tumor Grade 3 and 4 (hazard ratio: 13.0, 95% confidence interval: 3.90-43.0, P < 0.001) was an independent risk factor for tumor recurrence, while no significant correlation was found between tumor recurrence and age, gender, tumor side, tumor size, surgical methods, histology, microvascular invasion or surgical margin status. The 5-year recurrence-free survival rate was 67.8% in patients with a high nuclear grade tumor, and 96.8% in their counterparts. Conclusions: High nuclear grade is possibly one of the most important prognostic factors for predicting tumor recurrence and metastasis after surgery in pathologic T1a renal cell carcinoma. Thus, careful follow-up may be required in patients with pathologic T1a renal cell carcinoma of a high nuclear grade.

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Prognostic significance of Bacillus Calmette-Guerin failure classification in non-muscle-invasive bladder cancer

Shirakawa Hiroshi, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU INTERNATIONAL 110 ( 6B ) E216 - E221 2012.09

Research paper (scientific journal), Joint Work, ISSN 1464-4096

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Prognostic significance of 5-fluorouracil metabolism-relating enzymes and enhanced chemosensitivity to 5-fluorouracil by 5-chloro 2,4-dihydroxy-pyridine in urothelial carcinoma

Ide Hiroki, Kikuchi Eiji, Hasegawa Masanori, Kozakai Norihide, Kosaka Takeo, Miyajima Akira, Oya Mototsugu

BMC CANCER 12 E732 - E732 2012.09

Research paper (scientific journal), Joint Work, ISSN 1471-2407

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Prognostic Significance of High Nuclear Grade in Patients with Pathologic T1a Renal Cell Carcinoma

Suzuki Kenjiro, Mizuno Ryuichi, Mikami Shuji, Tanaka Nobuyuki, Kanao Kent, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 9 ) 831 - 835 2012.09

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Prognostic significance of Bacillus Calmette-Guérin failure classification in non-muscle-invasive bladder cancer

Shirakawa Hiroshi, Kikuchi Eiji, Tanaka Nobuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakamura So, Oya Mototsugu

BJU International 110 ( 6B ) 2012.09

ISSN 1464-4096

Objective To investigate the differences in the clinical features and subsequent stage progression and disease-specific survival among patients with Bacillus Calmette-Guérin (BCG) failure, after dividing these patients into BCG-refractory, -resistant, -relapsing, and -intolerant groups. Patients and Methods We identified 173 patients with initial BCG failure from 521 patients who had undergone induction BCG therapy for non-muscle-invasive bladder cancer, excluding CIS, between 1987 and 2009. Patients were stratified into four BCG-failure groups, and each prognostic outcome was evaluated. Results Median follow-up period from initial BCG failure was 4.7 years. A total of 42 patients (24.3%) were stratified into the BCG-refractory, three (1.7%) into the BCG-resistant, 106 (61.3%) into the BCG-relapsing, and 22 (12.7%) into the BCG-intolerant group. Twenty-four patients (13.9%) experienced stage progression during follow-up. Multivariate analysis showed that pathological G3 at BCG failure (P= 0.014; risk ratio 2.84) and BCG-refractory (P < 0.001; risk ratio 4.68) were independent predictors for stage progression. The 10-year progression-free survival rates were 53.2%, 91.1% and 93.8% in the BCG-refractory, BCG-relapsing and BCG-intolerant groups, respectively. The stage progression rate was higher in the BCG-refractory than in the BCG-relapsing (P < 0.001) and BCG-intolerant (P= 0.007) groups. Similarly, the 10-year disease-specific survival rate in the BCG-refractory group was significantly worse than those in the other BCG failure groups (P < 0.001). Conclusions Stratification of BCG failure into the above-mentioned four groups can identify patients with BCG-failure in terms of their prognosis. The potential risk for critical adverse events was higher in the BCG-refractory group than in the other BCG-failure groups, despite the fact that patients in each group all underwent induction BCG therapy, therefore, treatment decisions, protocols and recommendations should be established based on each individual BCG-failure pattern.

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Predicting pubic arch interference in prostate brachytherapy on transrectal ultrasonography-computed tomography fusion images.

Fukada Junichi, Shigematsu Naoyuki, Nakashima Jun, Ohashi Toshio, Kawaguchi Osamu, Oya Mototsugu

Journal of Radiation Research 53 ( 5 ) 753 - 759 2012.09

ISSN 0449-3060

We investigated the usefulness of the fusion image created by transrectal ultrasonography (TRUS) and large-bore computed tomography (CT) for predicting pubic arch interference (PAI) during prostate seed brachytherapy. The TRUS volume study was performed in 21 patients, followed by large-bore computed tomography of patients in the lithotomy position. Then, we created TRUS-CT fusion images using a radiation planning treatment system. TRUS images in which the prostate outline was the largest were overlaid on CT images with the narrowest pubic arch. PAI was estimated in the right and left arch separately and classified to three grades: no PAI, PAI positive within 5 mm and PAI of >5 mm. If the estimated PAI was more than 5 mm on at least one side of the arch, we judged there to be a significant PAI. Brachytherapy was performed in 18 patients who were evaluated as not having significant PAI on TRUS. Intra-operative PAI was observed in one case, which was also detected with a fusion image. On the other hand, intra-operative PAI was not observed in one case that had been evaluated as having significant PAI with a fusion image. In the remaining three patients, TRUS suggested the presence of significant PAI, which was also confirmed by a fusion image. Intra-operative PAI could be predicted by TRUS-CT fusion imaging, even when it was undetectable by TRUS. Although improvement of the reproducibility of the patients' position to avoid false-positive cases is warranted, TRUS-CT fusion imaging has the possibility that the uncertainty of TRUS can be supplemented.

Preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Takeda Atsuya, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Keio Journal of Medicine 61 ( 3 ) 89 - 94 2012.09

ISSN 0022-9717

The dose received by 90% of the prostate volume (D90) is the key parameter of dosimetric analysis in prostate brachytherapy. The aim of this analysis was to identify preimplant factors affecting prostate D90 after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds. We reviewed the records of 210 patients who underwent transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds for clinical T1/T2 prostate cancer at our institution. Patients who received supplemental external-beam radiation therapy were excluded. One hundred and nine patients (51.9%) received neoadjuvant hormonal therapy (NHT). One month after seed implantation, postimplant computed tomography and dosimetric analysis were performed. Univariate and multivariate analyses were carried out to identify preimplant factors affecting postimplant prostate D90. The postimplant prostate D90 values ranged from 123.3 to 234.1 Gy (mean ± standard error, 177.1 ± 1.4 Gy). Postimplant prostate D90 differed significantly between patients who had and had not undergone NHT (P = 0.001). In addition, simple regression analyses showed positive correlations with the estimated preimplant prostate D90, preimplant prostate volume by transrectal ultrasound (TRUS), total radioactivity, number of needles, and number of seeds. On stepwise multiple regression analysis, postimplant prostate D90 showed significant negative correlations with NHT and preimplant prostate volume by TRUS, and a significant positive correlation with total radioactivity. In conclusion, NHT, preimplant prostate volume by TRUS, and total radioactivity are significant preimplant factors affecting postimplant prostate D90 in prostate cancer patients treated with transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds.

Enhancement of radiosensitivity by a unique novel NF-B inhibitor, DHMEQ, in prostate cancer

Kozakai N., Kikuchi E., Hasegawa M., Suzuki E., Ide H., Miyajima A., Horiguchi Y., Nakashima J., Umezawa K., Shigematsu N., Oya M.

British Journal of Cancer 107 ( 4 ) 652 - 657 2012.08

ISSN 0007-0920

Background: Inducible activation of nuclear factor (NF)-B is one of the principal mechanisms through which resistant prostate cancer cells are protected from radiotherapy. We hypothesised that inactivation of inducible NF-B with a novel NF-B inhibitor, DHMEQ, would increase the therapeutic effects of radiotherapy.Methods:PC-3 and LNCaP cells were exposed to irradiation and/or DHMEQ. Cell viability, cell cycle analysis, western blotting assay, and NF-B activity were measured. The antitumour effect of irradiation combined with DHMEQ in vivo was also assessed.Results:The combination of DHMEQ with irradiation resulted in cell growth inhibition and G2/M arrest relative to treatment with irradiation alone. Inducible NF-B activity by irradiation was inhibited by DHMEQ treatment. The expression of p53 and p21 in LNCaP, and of 14-3-3 in PC-3 cells, was increased in the combination treatment. In the in vivo study, 64 days after the start of treatment, tumour size was 85.1%, 77.1%, and 64.7% smaller in the combination treatment group than that of the untreated control, DHMEQ-treated alone, and irradiation alone groups, respectively.Conclusion:Blockade of NF-B activity induced by radiation with DHMEQ could overcome radio-resistant responses and may become a new therapeutic modality for treating prostate cancer.

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The prognostic significance of vasohibin-1 expression in patients with upper urinary tract urothelial carcinoma

Miyazaki Yasumasa, Kosaka Takeo, Mikami Shuji, Kikuchi Eiji, Tanaka Nobuyuki, Maeda Takahiro, Ishida Masaru, Miyajima Akira, Nakagawa Ken, Okada Yasunori, Sato Yasufumi, Oya Mototsugu

Clinical Cancer Research 18 ( 15 ) 4145 - 4153 2012.08

ISSN 1078-0432

Purpose: Vasohibin-1 (VASH1) is a novel angiogenic molecule that is specifically expressed in activated vascular endothelial cells, and the status of VASH1 expression has been documented in cancer angiogenesis. The aim of this study was to address the prognostic value of VASH1 expression in upper urinary tract urothelial carcinomas (UTUC). Experimental Design: We retrospectively analyzed the clinical records of 171 patients with locally advanced UTUC (Ta-3N0M0). The median follow-up period was 3.8 years. We immunohistochemically examined the accomplished microvessels with anti-CD34 as microvessel density (MVD) and the microvessels with activated endothelial cells as VASH1 density. Then, we analyzed the association between immunohistochemical expression and clinical outcomes. Results: Forty-two patients experienced tumor recurrence and of these 34 died of the disease during follow-up. VASH1 density was significantly associated with tumor grade, pathologic T stage, and MVD. The 5-year recurrence-free and cancer-specific survival rates were 66.1% and 72.8% in patients with VASH1 density (≥ 40/mm²) and 81.0% and 86.5% in their counterparts, respectively (P < 0.05). MVD was not an independent predictor of tumor recurrence or cancer-specific survival. Multivariate analyses revealed that high VASH1 density was an independent prognostic indicator of both tumor recurrence (P = 0.024, HR = 2.10) and cancer-specific survival (P = 0.031, HR = 2.23) as well as other standard prognostic factors including high tumor grade and lymphovascular invasion. Conclusions: VASH1 density represents a clinically relevant predictor of patient prognosis in UTUC. The results suggest that VASH1 density could become a new biomarker and provide additional prognostic information in patients with UTUC.

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Renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient

Miyazaki Yasumasa, Miyajima Akira, Maeda Takahiro, Ito Yujiro, Tanaka Nobuyuki, Kosaka Takeo, Masuda Aya, Mizuno Ryuichi, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Clinical and Experimental Nephrology 16 ( 4 ) 647 - 651 2012.08

ISSN 1342-1751

A 60-year-old man undergoing hemodialysis for 13 years was referred to our department for evaluation of gross hematuria and a right renal mass. Voided urine cytology was negative. Computed tomography and magnetic resonance imaging demonstrated a right renal mass (32 × 22 × 20 mm in diameter). We clinically diagnosed the tumor as renal cell carcinoma staged T1aN0M0 arising from a horseshoe kidney, and performed right heminephrectomy. Pathological examination of the surgical specimen showed a grade 2, pT1a, clear cell carcinoma and negative surgical margin. To our knowledge, this is a rare case of a renal cell carcinoma arising from a horseshoe kidney in a chronic hemodialysis patient.

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Two cases of bowel perforation associated with sunitinib treatment for renal cell carcinoma

Hoshino Yoshinori, Hasegawa Hirotoshi, Ishii Yoshiyuki, Endo Takashi, Ochiai Hiroki, Okabayashi Koji, Kaneko Gou, Mikami Shuji, Mukai Makio, Oya Mototsugu, Kitagawa Yuko

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 17 ( 4 ) 412 - 416 2012.08

Research paper (scientific journal), Joint Work, ISSN 1341-9625

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Transumbilical laparoendoscopic single-site varicocelectomy

Takeda Toshikazu, Miyajima Akira, Tanaka Nobuyuki, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 9 ) 675 - 678 2012.08

ISSN 0385-2393

We performed transumbilical laparoendoscopioc singlesite varicocelectomy (LESS-V) for three patients with left painful varicocele. Their average age was 34.7 years old (23-46 years old) and their varicocele grades were grade III in all cases. The operation was performed by the same laparoscopic surgeon. The average operative time was 65 minutes (49-96 minutes) and the estimated blood loss was little. Postoperative pain was tolerant and analgesics was not used in all cases. There were no remarkable complications and the patients were discharged 2 or 3 days after surgery. All cases had complete resolution of pain within 5 months (2-5 months) and hydrocele, testicular atrophy, or recurrence was not seen. LESS-V is safe and feasible for laparoscopic surgeons.

The benefit of laparoscopic partial nephrectomy in high body mass index patients

Kaneko Gou, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 42 ( 7 ) 619 - 624 2012.07

ISSN 0368-2811

Objective: The aims of the present study were to evaluate the effect of body mass index on the surgical outcomes of open partial nephrectomy and laparoscopic partial nephrectomy, and to analyze whether higher body mass index patients may derive greater benefit from laparoscopic partial nephrectomy. Methods: We reviewed 110 patients who underwent open partial nephrectomy and 47 patients who underwent laparoscopic partial nephrectomy at our institution. We analyzed the data to determine what kind of factor would be associated with prolonged operative time, increased estimated blood loss and prolonged ischemic time, and compared the result of open partial nephrectomy with that of laparoscopic partial nephrectomy. Results: A statistically significant correlation was observed between body mass index and operative time or estimated blood loss in open partial nephrectomy. Multivariate analysis also demonstrated that body mass index was an independent predictor for prolonged operative time and higher estimated blood loss in open partial nephrectomy, but not in laparoscopic partial nephrectomy. In the normal body mass index group (body mass index < 25.0 kg/m. ²), although mean operative time in the laparoscopic partial nephrectomy group was significantly longer than that in the open partial nephrectomy group, the difference was relatively small. In the high body mass index group (body mass index ≥ 25.0 kg/m. ²), the mean operative time of the two groups was not statistically different. The estimated blood loss of open partial nephrectomy was significantly higher than that of laparoscopic partial nephrectomy in both groups. In both operative procedures, tumor size was an independent predictor for prolonged ischemic time in multivariate analysis. Conclusions: Body mass index was an independent predictor for prolonged operative time and higher estimated blood loss in open partial nephrectomy but not in laparoscopic partial nephrectomy. Laparoscopic partial nephrectomy was less influenced by body mass index and had a greater benefit, especially in high body mass index patients.

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The Benefit of Laparoscopic Partial Nephrectomy in High Body Mass Index Patients

Kaneko Gou, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 7 ) 619 - 624 2012.07

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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IJU this issue

Oya Mototsugu

International Journal of Urology 19 ( 7 ) 593 2012.07

ISSN 0919-8172

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A case of spinal and bulbar muscular atrophy with high-stage and high-gleason score prostate cancer responded to maximal androgen blockade therapy

Kosaka Takeo, Miyajima Akira, Kikuchi Eiji, Takahashi Shinichi, Suzuki Norihiro, Oya Mototsugu

Journal of Andrology 33 ( 4 ) 563 - 565 2012.07

ISSN 0196-3635

Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of CAG triplets in the androgen receptor. Because the length of CAG repeat is inversely related with androgen receptor function, patients with a longer CAG repeat are expected to have a lower incidence of prostate cancer. Here, we report an extremely rare case of highstage prostate cancer in a patient with spinal and bulbar muscular atrophy, which responded to maximal androgen blockade therapy.

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Testosterone and 5 alpha-reductase

Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 7 ) 495 - 502 2012.06

ISSN 0385-2393

Tracing the conversion process from primordial germ cells to pluripotent stem cells in mice

Nagamatsu Go, Kosaka Takeo, Saito Shigeru, Takubo Keiyo, Akiyama Hideo, Sudo Tetsuo, Horimoto Katsuhisa, Oya Mototsugu, Suda Toshio

Biology of Reproduction 86 ( 6 ) 2012.06

ISSN 0006-3363

To understand mechanisms underlying acquisition of pluripotency, it is critical to identify cells that can be converted to pluripotent stem cells. For this purpose, we focused on unipotent primordial germ cells (PGCs), which can be reprogrammed into pluripotent embryonic germ (EG) cells under defined conditions. Treatment of PGCs with combinations of signaling inhibitors, including inhibitors of MAP2K (MEK), GSK3B (GSK-3beta), and TGFB (TGFbeta) type 1 receptors, induced cells to enter a pluripotent state at a high frequency (12.1%) by Day 10 of culture. When we employed fluorescence-activated cell sorting to monitor conversion of candidate cells to a pluripotent state, we observed a cell cycle shift to S phase, indicating enrichment of pluripotent cells, during the early phase of EG formation. Transcriptome analysis revealed that PGCs retained expression of some pluripotent stem cell-associated genes, such as Pou5f1 and Sox2, during EG cell formation. On the other hand, PGCs lost their germ lineage characteristics and acquired expression of pluripotent stem cell markers, such as Klf4 and Eras. The overall gene expression profiles revealed by this system provide novel insight into how pluripotency is acquired in germcommitted cells.

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Patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma

Mizuno Ryuichi, Asano Koichiro, Mikami Shuji, Nagata Hirohiko, Kaneko Gou, Oya Mototsugu

Japanese Journal of Clinical Oncology 42 ( 5 ) 442 - 446 2012.05

ISSN 0368-2811

Objective: To elucidate the patterns of interstitial lung disease during everolimus treatment in patients with metastatic renal cell carcinoma, we reviewed seven cases of everolimus-induced interstitial lung disease. Methods: Seven patients with metastatic renal cell carcinoma, which continued to progress despite treatment with sunitinib or sorafenib, developed interstitial lung disease after treatment with everolimus. Results: Chest X-ray demonstrated diffuse infiltrates in lung fields, and chest computed tomography showed bilateral reticular and ground-glass opacities. Serum levels of lactate dehydrogenase (7/7), C-reactive protein (6/7), pulmonary surfactant associated protein D (1/7) and Krebs von den Lungen 6 (5/7) were elevated. The bronchoalveolar lavage fluid obtained from four patients with Grade 3 interstitial lung disease showed lymphocytosis. The transbronchial lung biopsy specimens showed interstitial lymphocytic infiltration and septal thickening of alveolar walls. In two cases with mild interstitial lung disease, the everolimus therapy was successfully continued. In four cases with Grade 3 interstitial lung disease, the drug was discontinued and steroid therapy was initiated. Pulmonary symptoms and radiological abnormalities resolved within 2 months. Conclusions: Serum Krebs von den Lungen 6 was elevated compared with baseline in all cases with interstitial lung disease. Some patients who developed mild interstitial lung disease during everolimus treatment could continue to receive the treatment. Even when severe interstitial lung disease developed, withdrawal of the drug and short-term use of high-dose steroids resulted in rapid recovery. Prompt recognition of interstitial lung disease exacerbation as well as exclusion of progressive disease or infection is of primary importance.

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Patterns of Interstitial Lung Disease During Everolimus Treatment in Patients with Metastatic Renal Cell Carcinoma

Mizuno Ryuichi, Asano Koichiro, Mikami Shuji, Nagata Hirohiko, Kaneko Gou, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 42 ( 5 ) 442 - 446 2012.05

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Lymphorrhea and lymphocele

Shinoda Kazunobu, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 4 ) 151 - 155 2012.04

ISSN 0385-2393

Urethroplasty for hypospadias

Asanuma Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 4 ) 404 - 410 2012.04

ISSN 0385-2393

Extrapancreatic solid pseudopapillary tumor

Miyazaki Yasumasa, Miyajima Akira, Maeda Takahiro, Yuge Kazuyuki, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Kameyama Kaori, Jinzaki Masahiro, Nakagawa Ken, Oya Mototsugu

International Journal of Clinical Oncology 17 ( 2 ) 165 - 168 2012.04

ISSN 1341-9625

A 22-year-old woman complained of abdominal discomfort. Ultrasonography, computed tomography, and an endocrinologic work-up revealed a 7-cm nonfunctional tumor at the left adrenal lesion. A transumbilical laparo-endoscopic single-site adrenalectomy was successfully completed in 166 min. The postoperative period was uneventful. The pathologic examination confirmed the solid pseudopapillary tumor occurred in the retroperito-neum. There are only five previous reports of extrapan-creatic solid pseudopapillary tumors. In this case, the tumor was separated from the pancreas and no ectopic pancreas was histologically observed. To the best of our knowledge, this case is the first report of a solid pseudopapillary tumor of the retroperitoneum.

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Three cases of granulocyte colony-stimulating factor-producing urinary upper tract carcinomas

Shirakawa Hiroshi, Kikuchi Eiji, Mikami Shuji, Fukamachi Shigeru, Miyazaki Yasumasa, Tanaka Nobuyuki, Miyajima Akira, Oya Mototsugu

SCANDINAVIAN JOURNAL OF UROLOGY AND NEPHROLOGY 46 ( 2 ) 136 - 141 2012.04

Research paper (scientific journal), Joint Work, ISSN 0036-5599

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PREDICTION AND CLINICAL IMPLICATION OF SEED MIGRATION AFTER BRACHYTHERAPY WITH I-125 FREE SEEDS IN PATIENTS WITH LOCALIZED PROSTATE CANCER

Nakashima Jun, Sugawara Akitomo, Nagata Hirohiko, Mizuno Ryuichi, Shigematsu Naoyuki, Oya Mototsugu, Tachibana Masaaki

JOURNAL OF UROLOGY 187 ( 4 ) E455 - E456 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

REGULATION OF MCP-1 EXPRESSION THROUGH ANGIOTENSIN II TYPE 1 RECEPTOR IN CASTRATION-RESISTANT PROSTATE CANCER

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Kikuchi Eiji, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E394 - E394 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Extrapancreatic solid pseudopapillary tumor: case report and review of the literature

Miyazaki Yasumasa, Miyajima Akira, Maeda Takahiro, Yuge Kazuyuki, Hasegawa Masanori, Kosaka Takeo, Kikuchi Eiji, Kameyama Kaori, Jinzaki Masahiro, Nakagawa Ken, Oya Mototsugu

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 17 ( 2 ) 165 - 168 2012.04

Research paper (scientific journal), Joint Work, ISSN 1341-9625

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PI3K/AKT DUAL INHIBITOR RESTORES DOCETAXEL SENSITIVITY IN CASTRATION RESISTANT PROSTATE CANCER

Yasumizu Yota, Miyajima Akira, Kosaka Takeo, Shirotake Suguru, Kikuchi Eiji, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E394 - E395 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

PREOPERATIVE GRADING OF HYDRONEPHROSIS CAN IMPROVE THE ACCURACY OF WORSE PATHOLOGICAL PREDICTION IN PATIENTS WITH UPPER TRACT UROTHELIAL CARCINOMA TREATED SURGICALLY

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Akita Hirotaka, Jinzaki Masahiro, Mikami Shuji, Miyajima Akira, Nakagawa Ken, Kuribayashi Sachio, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E884 - E884 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Prognostic Role of KiSS-1 and Possibility of Therapeutic Modality of Metastin, the Final Peptide of the KiSS-1 Gene, in Urothelial Carcinoma

Takeda Toshikazu, Kikuchi Eiji, Mikami Shuji, Suzuki Eriko, Matsumoto Kazuhiro, Miyajima Akira, Okada Yasunori, Oya Mototsugu

MOLECULAR CANCER THERAPEUTICS 11 ( 4 ) 853 - 863 2012.04

Research paper (scientific journal), Joint Work, ISSN 1535-7163

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NOVEL NF-KAPPAB INHIBITOR DHMEQ: THE NEW STRATEGY FOR ACQUIRED CHEMO-RESISTANT BLADDER CANCER

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Shirakawa Hiroshi, Miyajima Akira, Horiguchi Yutaka, Nakashima Jun, Nakagawa Ken, Umezawa Kazuo, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E227 - E228 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

COLOR DOPPLER SONOGRAPHIC EVALUATION OF URETERIC JET ANGLE IN DETECTING HIGH GRADE VESICOURETERAL REFLUX IN CHILDREN

Asanuma Hiroshi, Satoh Hiroyuki, Matsui Zenichi, Mizuno Ryuichi, Masuda Aya, Kono Hidaka, Shinoda Kazunobu, Kikuchi Eiji, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E248 - E248 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

A PROSPECTIVE STUDY OF THE EFFECT OF 5-ALPHA-REDUCTASE INHIBITOR (DUTASTERIDE) TREATMENT ON SERUM FREE TESTOSTERONE LEVEL AND AGING MALE SYMPTOMS IN JAPANESE PATIENTS WITH BENIGN PROSTATIC HYPERPLASIA

Maeda Takahiro, Kikuchi Eiji, Hasegawa Masanori, Kaneko Gou, Shinoda Kazunobu, Kono Hidaka, Mizuno Ryuichi, Nagata Hirohiko, Asanuma Hiroshi, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E463 - E463 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

THERAPEUTIC EFFECT AFTER TRANSUMBILICAL LAPAROSCOPIC SINGLE-SITE ADRENALECTOMY IN PATIENTS WITH PRIMARY ALDOSTERONISM: A MATCHED CASE-CONTROL STUDY

Maeda Takahiro, Miyajima Akira, Hasegawa Masanori, Hattori Seiya, Takeda Toshikazu, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E414 - E415 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

A PROSPECTIVE LONGITUDINAL SURVEY OF ERECTILE DYSFUNCTION RATE IN PATIENTS WITH LOCALIZED PROSTATE CANCER TREATED WITH PERMANENT PROSTATE BRACHYTHERAPY

Matsushima Masashi, Kikuchi Eiji, Maeda Takahiro, Sugawara Akitomo, Ando Toshiyuki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Shigematsu Naoyuki, Oya Mototsugu

JOURNAL OF UROLOGY 187 ( 4 ) E466 - E466 2012.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Carbon-ion radiation therapy for prostate cancer

Ishikawa Hitoshi, Tsuji Hiroshi, Kamada Tadashi, Akakura Koichiro, Suzuki Hiroyoshi, Shimazaki Jun, Tsujii Hirohiko, Shimazaki Jun, Akakura Koichiro, Akimoto Tetsuo, Ichikawa Tomohiko, Igarashi Tatsuo, Kawamura Koji, Ueda Takeshi, Oya Mototsugu, Sakurai Hideyuki, Onozawa Mizuki, Kanehira Chihiro, Kamura Koichi, Suzuki Hiroyoshi, Nakamura Kazumasa, Harada Masaoki, Fujime Makoto, Marumo Ken, Tsujii Hirohiko, Kamada Tadashi, Tsuji Hiroshi

International Journal of Urology 19 ( 4 ) 296 - 305 2012.04

ISSN 0919-8172

In 1994, carbon-ion radiotherapy was started at the National Institute of Radiological Sciences using the Heavy-Ion Medical Accelerator in Chiba. Between June 1995 and March 2000, two phaseI/II dose escalation studies (protocols 9402 and 9703) of hypofractionated carbon-ion radiotherapy for both early- and advance-stage prostate cancer patients had been carried out to establish radiotherapy technique and to determine the optimal radiation dose. To validate the feasibility and efficacy of hypofractionated carbon-ion radiotherapy, a phaseII study (9904) was initiated in April 2000 using the shrinking field technique and the recommended dose fractionation (66 gray equivalents in 20 fractions over 5weeks) obtained from the phaseI/II studies, and was successfully completed in October 2003. The data from 175 patients in the phaseII study showed the importance of an appropriate use of androgen deprivation therapy according to tumor risk group. Since November 2003, carbon-ion radiotherapy for prostate cancer was approved as "Highly Advanced Medical Technology" from the Ministry of Health, Labor, and Welfare, and since then approximately 1100 patients have received carbon-ion radiotherapy as of July 2011. In this review, we introduce our steps thorough three clinical trials carried out at National Institute of Radiological Sciences, and show the updated data of carbon-ion radiotherapy obtained from approximately 1000 prostate cancer patients. In addition, our recent challenge and future direction will be also described.

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Transumbilical approach for laparo-endoscopic single-site adrenalectomy

Miyajima Akira, Hattori Seiya, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Kikuchi Eiji, Asanuma Hiroshi, Nakagawa Ken, Oya Mototsugu

International Journal of Urology 19 ( 4 ) 331 - 335 2012.04

ISSN 0919-8172

Objectives: To report our initial experience with transumbilical laparo-endoscopic single-site adrenalectomy for adrenal tumors by using a single port with a multichannel cannula and bent laparoscopic instrumentation. Methods: Between December 2009 and December 2010, 30 patients underwent transumbilical laparo-endoscopic single-site adrenalectomy at our hospital. The procedure was carried out for adrenal cortical adenoma in 17 patients, adrenal pheochromocytoma in seven patients and other types of tumors in six patients. A multichannel port, bent laparoscopic instruments and Opti4 laparoscopic electrodes were used in all patients. The intraperitoneal space was approached through the umbilicus. The multichannel port was placed through a 2-cm incision at the inner edge of the umbilicus. A 5-mm flexible laparoscope was introduced to maintain an adequate laparoscopic view, and surgical specimens were extracted using an Endocatch bag. Results: All procedures were successfully completed, with only one incision through the umbilicus, and without conversion to a standard laparoscopic approach. Mean operative time was 120.1±34.7min. Tumor laterality and patient body mass index did not affect surgical morbidity. The initial 15 patients had a significantly longer mean pneumoperitoneum time (95.8±37.5min) than the last 15 patients (70.5±18.7min). Only one postoperative complication was observed (postoperative hematoma). Conclusions: A transumbilical approach for laparo-endoscopic single-site adrenalectomy is safe and feasible, and it results in superior cosmesis. Improvements in surgical devices might facilitate further development of this approach.

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Regulation of monocyte chemoattractant protein-1 through angiotensin II type 1 receptor in prostate cancer

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Kikuchi Eiji, Mikami Shuji, Okada Yasunori, Oya Mototsugu

American Journal of Pathology 180 ( 3 ) 1008 - 1016 2012.03

ISSN 0002-9440

Monocyte chemoattractant protein-1 (MCP-1/CCL2) is reported to contribute to tumor progression and is regulated by the renin-angiotensin system in hypertensive disease. In this study, we investigated the clinical outcome of MCP-1 expression in patients with prostate cancer (CaP) and the regulation of MCP-1 through angiotensin II (AngII) type 1 receptor (AT1R) in CaP. Specimens were obtained from 138 CaP patients and analyzed by immunostaining for both MCP-1 and macrophages. We investigated the regulation of MCP-1 expression through AT1R both in vivo and in vitro using three human prostate cancer cell lines: LNCaP, C4-2, and C4-2AT6. Specimens with a high Gleason score (<7) and a high pathological classification (≤pT3), and those with castration-resistant prostate cancer showed significantly higher MCP-1 expression and higher macrophage infiltration than low malignant potential CaP. High MCP-1 expression in CaP correlated significantly with high prostate-specific antigen (PSA) recurrence rates. AngII induced significantly higher MCP-1 levels in C4-2AT6 than in LNCaP, whereas AT1R blockade (ARB) inhibited MCP-1 production via the inhibition of the PI3K/Akt pathway in C4-2AT6. ARB also significantly suppressed MCP-1 expression in C4-2AT6 tumors. Our study is the first to demonstrate that both high MCP-1 expression and high macrophage infiltration in CaP specimens correlate with a high PSA recurrence rate and that ARB inhibits MCP-1 expression through the PI3K/Akt pathway and blocks macrophage infiltration in castration-resistant prostate cancer.

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Preoperative hydronephrosis

Hoshino Katsura, Kikuchi Eiji, Tanaka Nobuyuki, Akita Hirotaka, Ito Yujiro, Miyajima Akira, Jinzaki Masahiro, Oya Mototsugu

Japanese Journal of Clinical Oncology 42 ( 3 ) 202 - 207 2012.03

ISSN 0368-2811

Objective: Partial or complete urinary obstruction caused by a tumor itself may affect renal function and the eligibility for perioperative cisplatin-based chemotherapy in patients with upper tract urothelial carcinoma. We investigated whether the status of preoperative hydronephrosis provides additional predictive information concerning changes in perioperative renal function. Methods: A total of 155 patients who underwent nephroureterectomy for upper tract urothelial carcinoma from 1997 to 2010 were identified. The association between preoperative parameters including the grade of hydronephrosis and perioperative renal function was analyzed. Results: Hydronephrosis was observed in 104 patients. The grade of hydronephrosis was 1, 2, 3 and 4 in 6 (3.9%), 25 (16.1%), 42 (27.1%) and 31 (20.0%) cases. Using a defined cut-off creatinine clearance value of ≥50 ml/min indicating eligibility for cisplatin-based chemotherapy, only 94 patients (60.6%) were eligible in the neoadjuvant setting. Of these 94 patients, 30 (31.9%) were judged to be ineligible in the adjuvant setting. Multivariate analysis demonstrated that patient age ≥70 years [P < 0.001, hazard ratio (HR) 27.9] and the absence of a higher grade hydronephrosis (P = 0.013, HR 7.40) were independent risk factors for predicting patients ineligible to receive adjuvant cisplatin-based chemotherapy. The proportion of patients ineligible to receive cisplatin-based chemotherapy changed from 40.9 to 88.6% following nephroureterectomy in patients aged ≥70 years and those with no or a lower grade hydronephrosis. Conclusions: The status of hydronephrosis is an independent predictor of eligibility to receive adjuvant cisplatin-based chemotherapy. The information on preoperative hydronephrosis and patient age may assist in part of the decision-making when considering neoadjuvant cisplatin-based chemotherapy.

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Surgical and chemotherapeutic options for urachal carcinoma

Yazawa Satoshi, Kikuchi Eiji, Takeda Toshikazu, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Urologia Internationalis 88 ( 2 ) 209 - 214 2012.03

ISSN 0042-1138

Objective: Several studies have associated urachal carcinoma with a poor prognosis, because the disease tends to be detected later as the patient is asymptomatic, there are few therapeutic options, and it has a high local recurrence rate. We review our experience with urachal carcinoma and discuss the role of surgical management and chemotherapeutic options. Patients and Methods: We reviewed the records of 10 cases with urachal carcinoma evaluated at Keio University Hospital from 1998 to 2009, and examine the surgical and chemotherapeutic options in the management of urachal carcinoma. Results: Median age was 55.0 years. Applying the TNM staging system, 1 case was in stage I, 4 cases in stage II, 4 cases in stage III, and 1 case was in stage IV. Nine cases were managed initially with surgery; 5 by partial cystectomy and 4 by total cystectomy. The median follow-up period was 3.5 years and the survival rate at 2 years was 87.5%. Six of the resected cases remain disease-free. Salvage chemotherapy was performed in 3 cases, and adjuvant chemotherapy was performed in 2 cases. Conclusions: We had 10 cases with urachal carcinoma. While there is still no standard chemotherapy combination, CPT-11 plus TS-1 produced stable disease in 1 case.

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What do we need for eradicating kidney cancer cells?

Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY 19 ( 2 ) 96 - 97 2012.02

Research paper (scientific journal), Joint Work, ISSN 0919-8172

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Biomarkers in renal cell carcinoma

Mizuno Ryuichi, Oya Mototsugu

Japanese Journal of Clinical Urology 66 ( 1 ) 51 - 55 2012.01

ISSN 0385-2393

Prognonstic impact of renin-angiotensin system blockade in localised upper-tract urothelial carcinoma

Tanaka N., Miyajima A., Kikuchi E., Matsumoto K., Hagiwara M., Ide H., Kosaka T., Masuda T., Nakamura S., Oya M.

British Journal of Cancer 106 ( 2 ) 290 - 296 2012.01

ISSN 0007-0920

Background: The potential role of the renin-angiotensin system (RAS) in the promotion of tumour growth has been investigated, and the administration of RAS inhibitors, such as angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), may improve disease control in malignancy. We investigated the prognostic impact of RAS inhibitors by analysing data from patients with upper-tract urothelial carcinoma (UTUC). Methods: A total of 279 patients who underwent nephroureterectomy for localised UTUC (pTa-3N0M0) were identified at our three institutions. We retrospectively investigated the prognostic outcomes following nephroureterectomy in patients administered or not administered ACEIs or ARBs. Results: The median follow-up period was 3.4 years. RAS inhibitors were administered to 48 patients (17.2%). Multivariate analysis showed that the appearance of pathological T3, positive lymphovascular invasion, and no RAS inhibitor administration (P=0.027 HR=3.14) were independent risk factors for a decrease in subsequent metastasis-free survival. The 5-year metastasis-free survival rate was 93.0% in patients who administered RAS inhibitors, and 72.8% in their counterparts who did not (P=0.008). Conclusion: The absence of RAS inhibitor administration was an independent risk factor for subsequent tumour metastasis in patients with localised UTUC. We propose RAS inhibitors may be a potent choice as an effective treatment following nephroureterectomy.

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Low-dose docetaxel enhances the sensitivity of S-1 in a xenograft model of human castration resistant prostate cancer

Hasegawa Masanori, Miyajima Akira, Kosaka Takeo, Yasumizu Yota, Tanaka Nobuyuki, Maeda Takahiro, Shirotake Suguru, Ide Hiroki, Kikuchi Eiji, Oya Mototsugu

International Journal of Cancer 130 ( 2 ) 431 - 442 2012.01

ISSN 0020-7136

S-1 is a recently developed dihydropyrimidine dehydrogenase inhibitor fluoropyrimidine and has demonstrated high maximum plasma 5-Fluorouracil (5-FU) levels with mild toxicity, and an oral formulation has resulted in an improvement in patient quality of life. The aims of the present study were to determine the efficacy of S-1 or S-1 combined with docetaxel (DOC) using castration resistant prostate cancer (CRPC) cells and to explore their clinical potential for treating CRPC patients. LNCaP cells, androgen dependent prostate cancer (ADPC) cells and C4-2 cells, which are a CRPC subline of LNCaP cells, were used. Specimens obtained from ADPC and CRPC patients were also evaluated. The CRPC specimens and C4-2 cells exhibited significantly lower thymidylate synthase (TS) expression, a target of 5-FU, than the ADPC specimens and LNCaP cells. In vitro, C4-2 cells exhibited higher sensitivity to 5-FU than LNCaP cells. In C4-2 xenograft model, S-1 monotherapy suppressed tumor growth and low-dose DOC enhanced the anti-tumor effect of S-1. In vitro, low-dose DOC, which did not induce G2/M arrest, increased p53 and p21 and resulted in down-regulation of TS in C4-2 cells, and down-regulation of TS is considered to be responsible for the synergistic effect of S-1 in vivo. The present findings indicate that CRPC patients with androgen ablation may be good candidates for 5-FU based chemotherapy, and these regimens have attractive therapeutic potential for clinical practice, and they may have a significant impact on therapeutic options.

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[Biomarker for molecular targeting therapy against renal cell carcinoma].

Mizuno Ryuichi, Oya Mototsugu

Gan to kagaku ryoho. Cancer & chemotherapy 39 ( 1 ) 39 - 42 2012.01

ISSN 0385-0684

Prognostic role of KiSS-1 and possibility of therapeutic modality of metastin, the final peptide of the KiSS-1 gene, in urothelial carcinoma

Takeda Toshikazu, Kikuchi Eiji, Mikami Shuji, Suzuki Eriko, Matsumoto Kazuhiro, Miyajima Akira, Okada Yasunori, Oya Mototsugu

Molecular Cancer Therapeutics 11 ( 4 ) 853 - 863 2012

ISSN 1535-7163

The KiSS-1 gene has been reported to be a metastasis suppressor gene in human melanoma. The gene product was isolated from human placenta as the ligand of GPR54, a G protein-coupled receptor, and the C-terminally amidated peptide of 54 amino acids is called metastin. The binding of metastin to GPR54 has been shown to inhibit tumor metastasis in some tumor cells; however, its function remains unclear in urothelial carcinoma. We first evaluated KiSS-1 expression and GPR54 expression in 151 patients with upper urinary tract urothelial carcinoma to determine their prognostic significance. Next, we examined the role of metastin in the invasiveness and lung metastasis of MBT-2 variant (MBT-2V), which is a highly metastatic murine bladder cancer cell. Multivariate analysis revealed that KiSS-1 expression was an independent predictor of metastasis and overall survival. However, GPR54 expression was not selected. Hematogeneous metastasis had a significantly lower level of KiSS-1 expression compared with lymph node metastasis. Metastin treatment significantly reduced the invasiveness of MBT-2V cells and inhibited the DNA-binding activity of NF-κB by blocking its nuclear translocation, leading to a reduction in the expression and activity of matrix metalloproteinase-9. Metastin treatment dramatically prevented the occurrence of lung metastatic nodules (6.3 ± 2.3, n = 15) compared with controls (30.4 ± 5.1, n = 15; P < 0.01), as well as had survival benefit. KiSS-1 plays an important role in the prognosis of upper tract urothelial carcinoma and metastin may be an effective inhibitor of metastasis in urothelial carcinoma through its blockade of NF-kB function.

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Role of mTOR inhibition in the treatment of metastatic renal cell carcinoma

Mizuno Ryuichi, Miyajima Akira, Oya Mototsugu

Japanese Journal of Nephrology 54 ( 5 ) 581 - 585 2012

ISSN 0385-2385

Radiological findings of primary localized amyloidosis of the ureter

Tsujioka Yuko, Jinzaki Masahiro, Tanimoto Akihiro, Nakagawa Ken, Akita Hirotaka, Kikuchi Eiji, Okuda Shigeo, Mikami Shuji, Oya Mototsugu, Kuribayashi Sachio

Journal of Magnetic Resonance Imaging 35 ( 2 ) 431 - 435 2012

ISSN 1053-1807

Localized amyloidosis is a rare condition, especially that involving the ureter. Because of its rarity and the difficulty in differentiating this condition from urothelial carcinoma by intravenous urography and computed tomography, nephroureterectomy has often been performed unnecessarily for this disease. The authors encountered two cases of this disease, both of which showed a negative urine cytology, no obvious mass effect, and a hypointensity on T2-weighted imaging. Because these findings are very rare in urothelial carcinoma, ureteroscopy-guided biopsy was performed, which yielded the diagnosis of amyloidosis. The patients were then treated and followed up at our institute. Primary localized amyloidosis of the ureter should be considered when evaluating ureteric lesions visualized as hypointensities on T2-weighted images that do not show an obvious mass effect, which could help in the avoidance of unnecessary surgery.

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IJU this issue.

Oya Mototsugu

International journal of urology : official journal of the Japanese Urological Association 18 ( 12 ) 805 2011.12

Long-term outcome of feminizing genitoplasty

Asanuma Hiroshi, Oya Mototsugu

Japanese Journal of Clinical Urology 65 ( 12 ) 931 - 938 2011.11

ISSN 0385-2393

Intravesical interleukin-15 gene therapy in an orthotopic bladder cancer model

Matsumoto Kazuhiro, Kikuchi Eiji, Horinaga Minoru, Takeda Toshikazu, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Human Gene Therapy 22 ( 11 ) 1423 - 1432 2011.11

ISSN 1043-0342

Interleukin-15 (IL-15) is known to stimulate the proliferation of CD8 ⁺ T-cells and natural killer cells, and also to help to maintain memory CD8 ⁺ T cells, suggesting that it may be of value in cytokine treatment of bladder cancer. In this experiment, we tested the efficiency of intravesical liposomal IL-15 gene delivery and its antitumor effect in a mouse orthotopic bladder cancer model. We established an orthotopic bladder cancer model by implanting 5×10 ⁵ MBT-2 cells into female C3H/HeN mice through the urethra. The mice received repeated intravesical gene delivery injected with liposome-mediated plasmids (5μg) transurethrally. On day 23, the bladder weights in the group receiving medium alone, the beta-galactosidase gene delivery control group, and the IL-15 gene therapy group were 196±36mg, 201±35mg, and 96±29mg, respectively (p<0.05), demonstrating the antitumor effect of intravesical IL-15 gene therapy in this model. In the bladders treated with IL-15 gene plasmid instillation, histological analysis revealed that many inflammatory cells were induced around the tumors. Immunohistochemical analysis confirmed that there was predominant infiltration of CD8 ⁺ T cells around the tumor nest. After the intravesical IL-15 gene therapy, the growth of rechallenged subcutaneous MBT-2 cells in surviving mice was inhibited again via tumor-specific cytotoxic T lymphocytes, although newly implanted FM3A cells in the same mice were not rejected. The present findings indicate that IL-15 gene therapy may be a promising new adjuvant therapy for bladder cancer.

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LAPAROENDOSCOPIC SINGLE-SITE RADICAL PROSTATECTOMY: THE ESTABLISHMENT OF FEASIBLE TECHNIQUES IN JAPANESE INITIAL EXPERIENCES

Nakagawa Ken, Hagiwara Masayuki, Matsushima Masashi, Kaneko Go, Miyazaki Yasumasa, Kikuchi Eiji, Miyajima Akira, Asanuma Hiroshi, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 25 A274 - A274 2011.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

VISCERAL ADIPOSITY IS STRONG PARAMETER OF PERIOPERATIVE OUTCOME FOR LAPAROSCOPIC NEPHRECTOMY.

Hagiwara Masayuki, Miyajima Akira, Jinzaki Masahiro, Hasegawa Masanori, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 25 A208 - A208 2011.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

WHAT PREVENTS LYMPHOCELE DEVELOPMENT AFTER LAPAROSCOPIC RADICAL PROSTATECTOMY?

Yasumizu Yota, Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Shinoda Kazunobu, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Nagata Hirohiko, Asanuma Hiroshi, Nakagawa Ken, Oya Mototsugu

JOURNAL OF ENDOUROLOGY 25 A227 - A227 2011.11

Research paper (scientific journal), Joint Work, ISSN 0892-7790

Acquired platinum resistance enhances tumour angiogenesis through angiotensin II type 1 receptor in bladder cancer

Tanaka N., Miyajima A., Kosaka T., Miyazaki Y., Shirotake S., Shirakawa H., Kikuchi E., Oya M.

British Journal of Cancer 105 ( 9 ) 1331 - 1337 2011.10

ISSN 0007-0920

Background: We investigated the changes in reactive oxygen species (ROS) and angiogenesis through angiotensin II (Ang II) type 1 receptor (AT1R) after the development of acquired platinum resistance in bladder cancer. Methods: Four invasive human bladder cancer cell lines, T24, 5637, T24PR, and 5637PR, were used in vitro, whereas in vivo, T24 and T24PR cells were used. T24PR and 5637PR cells were newly established at our institution as acquired platinum-resistant sublines by culturing in cisplatin (CDDP)-containing conditioned medium for 6 months. Results: Ang II induced significantly higher vascular endothelial growth factor (VEGF) production in T24PR and 5637PR cells than in their corresponding parent cells in vitro, whereas Ang II induced a further increase in VEGF production. These platinum-resistant cells also showed significantly higher AT1R expression than their corresponding parent cells. ROS was also significantly upregulated in T24PR and 5637PR cells, whereas increased AT1R expression was significantly downregulated by scavenging free radicals. We also demonstrated the efficacy of AT1R blockade at suppressing the growth of platinum-resistant xenograft model. Conclusion: Our findings indicate a new molecular mechanism for upregulated AT1R signalling through increased ROS when tumours progressed after the CDDP-based regimens, and shed light on the importance of AT1R blockade for platinum-resistant bladder cancers.

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Incidence of seed migration to the chest, abdomen, and pelvis after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Mizuno Ryuichi, Seki Satoshi, Shiraishi Yutaka, Kouta Ryuichi, Oya Mototsugu, Shigematsu Naoyuki

Radiation Oncology 6 ( 1 ) 2011.10

Background: The aim was to determine the incidence of seed migration not only to the chest, but also to the abdomen and pelvis after transperineal interstitial prostate brachytherapy with loose ¹²⁵I seeds.Methods: We reviewed the records of 267 patients who underwent prostate brachytherapy with loose ¹²⁵I seeds. After seed implantation, orthogonal chest radiographs, an abdominal radiograph, and a pelvic radiograph were undertaken routinely to document the occurrence and sites of seed migration. The incidence of seed migration to the chest, abdomen, and pelvis was calculated. All patients who had seed migration to the abdomen and pelvis subsequently underwent a computed tomography scan to identify the exact location of the migrated seeds. Postimplant dosimetric analysis was undertaken, and dosimetric results were compared between patients with and without seed migration.Results: A total of 19,236 seeds were implanted in 267 patients. Overall, 91 of 19,236 (0.47%) seeds migrated in 66 of 267 (24.7%) patients. Sixty-nine (0.36%) seeds migrated to the chest in 54 (20.2%) patients. Seven (0.036%) seeds migrated to the abdomen in six (2.2%) patients. Fifteen (0.078%) seeds migrated to the pelvis in 15 (5.6%) patients. Seed migration occurred predominantly within two weeks after seed implantation. None of the 66 patients had symptoms related to the migrated seeds. Postimplant prostate D90 was not significantly different between patients with and without seed migration.Conclusion: We showed the incidence of seed migration to the chest, abdomen and pelvis. Seed migration did not have a significant effect on postimplant prostate D90.

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Phosphorylated Akt up-regulates angiotensin II type-1 receptor expression in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Kikuchi Eiji, Oya Mototsugu

Prostate 71 ( 14 ) 1510 - 1517 2011.10

ISSN 0270-4137

BACKGROUND Accumulating evidences has suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that castration-resistant prostate cancer (CRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that AT1R blockade (ARB) exerted protective effects by inhibiting angiogenesis. However, the detailed molecular mechanisms for the increase of AT1R expression in CRPC has not been fully elucidated yet. METHODS In this study we used C4-2 and C4-2AT6 cells, which were PTEN-null, androgen receptor (AR) positive, PSA-producing CRPC cell lines. We investigated the association between phosphorylated Akt (pAkt) and AT1R expression, and used LY294002 as a PI3K/Akt inhibitor. RESULTS Western blot analysis revealed C4-2AT6 cells showed significantly higher pAkt expression than C4-2 cells, although there were no significant differences in total Akt (tAkt) expression. Immunohistochemical (IHC) analysis also revealed significant higher pAkt expression in C4-2AT6 tumors obtained from castrated male nude mice. These results indicated that C4-2AT6 cells acquired elevated pAkt status under androgen-ablated treatment in vitro. Treatment with LY294002 at the same dose reduced the viability of C4-2AT6 more effectively than that of C4-2, reflecting the dependency of cancer cells on PI3K/Akt pathway. The up-regulated AT1R expression in C4-2AT6 cells was reduced by LY294002 in a dose-dependent manner. On the other hand, in C4-2 cells, serum starvation induced pAkt up-regulation, which led to an increase of AT1R expression. CONCLUSIONS These findings indicated that up-regulation of pAkt contributed to elevated AT1R expression in CRPC.

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Expression of snail and slug in renal cell carcinoma

Mikami Shuji, Katsube Ken Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mukai Makio, Okada Yasunori

Laboratory Investigation 91 ( 10 ) 1443 - 1458 2011.10

ISSN 0023-6837

The Snail family transcription factors have been proposed as important mediators of epithelial-mesenchymal transition because of their role in down-regulation of E-cadherin and up-regulation of matrix metalloproteinases (MMPs). The present study was undertaken to investigate the expression of Snail, Slug and their associations with cancer invasion and prognosis in renal cell carcinomas (RCCs). Ninety-seven primary RCCs were analyzed for the protein expression of Snail, Slug, MMP2 and MMP9 by immunohistochemistry. Snail protein expression level was positively correlated with pathological tumor stage, histological grade and the presence of sarcomatoid carcinoma. On the contrary, Slug protein expression level was negatively correlated with pathological tumor stage, suggesting that Slug was down-regulated in advanced RCCs. Because Snail was positively associated with malignant potential of RCCs, involvement of Snail in the invasiveness of an RCC cell line 786-O was examined in the Matrigel invasion assay by down-regulating the gene expression with small interfering RNA (siRNA). Targeting the Snail, not Slug, expression in 786-O cells with siRNA caused down-regulation of the gene expression of Snail, vimentin, MMP2 and MMP9, but up-regulated the E-cadherin. Invasion of the cells through Matrigel in vitro was inhibited under this condition. Furthermore, expression levels of MMP2 and MMP9 were positively correlated with pathological tumor stage and the presence of sarcomatoid carcinoma. Statistical analysis indicated that elevated Snail, MMP2 and MMP9 protein expression are significantly worse predictors of disease-free and disease-specific survival of the patients with RCC. In conclusion, these data suggest that Snail has an important role in invasion and metastasis, and that silencing the gene may be a potential therapeutic target in RCCs.

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Expression of Snail and Slug in renal cell carcinoma: E-cadherin repressor Snail is associated with cancer invasion and prognosis

Mikami Shuji, Katsube Ken-Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mukai Makio, Okada Yasunori

LABORATORY INVESTIGATION 91 ( 10 ) 1443 - 1458 2011.10

Research paper (scientific journal), Joint Work, ISSN 0023-6837

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Biomarkers of response to molecular targeted therapy in renal cell carcinoma

Mizuno Ryuichi, Oya Mototsugu

Japanese Journal of Cancer and Chemotherapy 38 ( 7 ) 1088 - 1091 2011.07

ISSN 0385-0684

Therapeutic options for metastatic renal cell carcinoma (mRCC) have been evolving rapidly, with the approval of a variety of effective molecular targeted agents. With increasing choices of treatment modalities that may potentially improve survival, it is of great clinical benefit to be able to predict the clinical outcome of mRCC patients treated with molecular targeted agents. In addition, predictors of severe adverse events are warranted since those molecular targeted agents present a toxicity profile that is very different from that of conventional chemotherapeutic agents. Their use requires knowledge of a large number of possible adverse events. Although validation of previous criteria, such as the Motzer criteria, is important, a further implementation of RCC molecular biology knowledge would be ideal for finding a new predictive marker in this new age of molecular targeted therapies. The most prominent biomarker is vascular endothelial-derived growth factor (VEGF). Those patients who presented low serum VEGF showed prolonged progression-free survival when treated with sunitinib. Genetic markers such as single nucleotide polymorphisms (SNPs) are continuously being validated as markers, predicting molecular targeted therapy response as well as severe adverse events. The identification of biomarkers that predict response or severe adverse events from molecular targeted agents will aid in patient selection and guide therapy development.

Neoadjuvant gemcitabine plus cisplatin for muscle-invasive bladder cancer

Kaneko Gou, Kikuchi Eiji, Matsumoto Kazuhiro, Obata Jun, Nakamura So, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 7 ) 908 - 914 2011.07

ISSN 0368-2811

Objective: Downstaging by neoadjuvant chemotherapy improves the survival of patients with muscle-invasive bladder cancer. In salvage setting, gemcitabine plus cisplatin has demonstrated an efficacy similar to that of methotrexate, vinblastine, doxorubicin and cisplatin with less toxicity. Therefore, the application of neoadjuvant gemcitabine plus cisplatin is also being anticipated. Methods: Twenty-two patients who received neoadjuvant gemcitabine plus cisplatin were evaluated. The rate of downstaging, chemotherapy delivery profile and toxicity data were assessed. As comparator group, nine patients who were administered with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were evaluated. Results: A mean of 1.9 cycles of neoadjuvant gemcitabine plus cisplatin were performed. Achieved drug intensity for gemcitabine and cisplatin was 83.8 and 95.4%. Downstaging to pT0 and <pT2 was achieved in 50.0 and 63.6%. Grade 3 or 4 neutropenia, anemia, thrombocytopenia and febrile neutropenia appeared in 14.3, 2.4, 21.4 and 2.4%, respectively. Grade 3 or 4 non-hematologic toxicity was not observed. Thrombocytosis developed in 26.2%. A mean of 2.3 cycles of neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin were performed. The achieved drug intensities for methotrexate, vinblastine, doxorubicin and cisplatin were 59.6, 69.8, 100 and 88.6%. In patients treated with neoadjuvant methotrexate, vinblastine, doxorubicin and cisplatin, downstaging to pT0 and <pT2 was achieved in 22.2 and 44.4%. Grade 3 or 4 neutropenia, anemia and thrombocytopenia was present in 19.1, 9.5 and 4.8%. Grade 3 nausea developed in 28.6%. Conclusions: The rate of downstaging by neoadjuvant gemcitabine plus cisplatin was comparable with that by methotrexate, vinblastine, doxorubicin and cisplatin. Gemcitabine plus cisplatin was associated with less non-hematologic toxicity than methotrexate, vinblastine, doxorubicin and cisplatin.

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Coactivation of SF-1-mediated transcription of steroidogenic enzymes by Ubc9 and PIAS1

Suda Noriko, Shibata Hirotaka, Kurihara Isao, Ikeda Yayoi, Kobayashi Sakiko, Yokota Kenichi, Murai-Takeda Ayano, Nakagawa Ken, Oya Mototsugu, Murai Masaru, Rainey William E., Saruta Takao, Itoh Hiroshi

Endocrinology 152 ( 6 ) 2266 - 2277 2011.06

ISSN 0013-7227

Steroidogenic factor-1 (SF-1) is a nuclear orphan receptor, which is essential for adrenal development and regulation of steroidogenic enzyme expression. SF-1 is posttranslationally modified by small ubiquitin-related modifier-1 (SUMO-1), thus mostly resulting in attenuation of transcription. We investigated the role of sumoylation enzymes, Ubc9 and protein inhibitors of activated STAT1 (PIAS1), in SF-1-mediated transcription of steroidogenic enzyme genes in the adrenal cortex. Coimmunoprecipitation assays showed that both Ubc9 and PIAS1 interacted with SF-1. Transient transfection assays in adrenocortical H295R cells showed Ubc9 and PIAS1 potentiated SF-1-mediated transactivation of reporter constructs containing human CYP17, CYP11A1, and CYP11B1 but not CYP11B2 promoters. Reduction of endogenous Ubc9 and PIAS1 by introducing corresponding small interfering RNA significantly reduced endogenous CYP17, CYP11A1, and CYP11B1 mRNA levels, indicating that they normally function as coactivators of SF-1. Wild type and sumoylation-inactive mutants of Ubc9 and PIAS1 can similarly enhance the SF-1-mediated transactivation of the CYP17gene, indicating that the coactivation potency of Ubc9 and PIAS1 isindependentof sumoylation activity. Chromatin immunoprecipitation assays demonstrated that SF-1, Ubc9, and PIAS1 were recruited to an endogenous CYP17 gene promoter in the context of chromatin in vivo. Immunohistochemistry and Western blotting showed that SF-1, Ubc9, and PIAS1 were expressed in the nuclei of the human adrenal cortex. In cortisol-producing adenomas, the expression pattern of SF-1 and Ubc9 were markedly increased, whereas that of PIAS1 was decreased compared with adjacent normal adrenals. These results showed the physiological roles of Ubc9 and PIAS1 as SF-1 coactivators beyond sumoylation enzymes in adrenocortical steroidogenesis and suggested their possible pathophysiological roles in human cortisol-producing adenomas.

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Coactivation of SF-1-Mediated Transcription of Steroidogenic Enzymes by Ubc9 and PIAS1

ENDOCRINOLOGY 152 ( 6 ) 2266 - 2277 2011.06

Research paper (scientific journal), Joint Work, ISSN 0013-7227

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[History and current review of basic research for prostate cancer].

Kosaka Takeo, Oya Mototsugu

Nihon rinsho. Japanese journal of clinical medicine 69 Suppl 5 7 - 12 2011.06

ISSN 0047-1852

Long-term androgen ablation and docetaxel up-regulate phosphorylated Akt in castration resistant prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Suzuki Eriko, Kikuchi Eiji, Oya Mototsugu

Journal of Urology 185 ( 6 ) 2376 - 2381 2011.06

ISSN 0022-5347

Purpose: There are still few effective therapeutic options for advanced prostate cancer. One of the most troublesome aspects of prostate cancer is that androgen dependent prostate cancer inevitably progresses to highly aggressive, life threatening castration resistant prostate cancer after androgen ablation therapy. To our knowledge it remains unknown how sensitivity to docetaxel changes during progression to more aggressive castration resistant prostate cancer under androgen ablation. Materials and Methods: We investigated sensitivity to docetaxel and phosphorylated Akt status in C4-2 and C4-2AT6 cells established at our institution. Results: C4-2AT6 cells established under androgen ablation conditions for 6 months showed significantly higher resistance to docetaxel than C4-2 cells in vivo and in vitro. Resistance was accompanied by increased phosphorylated Akt. In C4-2AT6 cells phosphorylated Akt activity was significantly up-regulated by docetaxel in a dose dependent manner. After treatment with docetaxel and a phosphatidylinositol 3-kinase/Akt inhibitor the sensitivity of C4-2AT6 cells to docetaxel markedly increased through enhanced apoptotic death. Conclusions: Findings indicated that up-regulation of phosphorylated Akt during androgen ablation and its further activation by docetaxel explains at least in part the resistance to docetaxel and progression to castration resistant prostate cancer under androgen ablation conditions.

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Selection and efficacy of PDE5 inhibitors

Kikuchi Eiji, Ando Toshiyuki, Oya Mototsugu

Japanese Journal of Clinical Urology 65 ( 6 ) 377 - 383 2011.05

ISSN 0385-2393

Prospective survey of erectile dysfunction after external beam radiotherapy for prostate cancer

Kikuchi Eiji, Nakashima Jun, Ando Toshiyuki, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Marumo Ken, Oya Mototsugu

Japanese Journal of Urology 102 ( 3 ) 575 - 580 2011.05

ISSN 0021-5287

(Objective) We prospectively evaluated the effect of external beam radiotherapy on erectile function in patients with localized or locally advanced prostate cancer using the Japanese version of the International Index of Erectile Function (IIEF) survey. (Patients and methods) From 2000 to 2007, we identified 55 patients who underwent external beam radiotherapy at our institution for localized or locally advanced prostate cancer and could respond to the IIEF survey. The patients did not receive neo- and/or adjuvant hormone therapy and they were followed-up for at least 12 months after radiotherapy. Mean patient age was 69 years and the mean PSA level before radiotherapy was 24.9 ng/ml. (Results) First we evaluated the change of the erectile function domain score over time before and after radiotherapy. The population of severe erectile dysfunction (ED) increased while those with no or mild ED decreased after radiotherapy. The erectile function and intercourse satisfaction domain score of the IIEF declined significantly after radiotherapy, however, the orgasmic function, sexual desire, and overall satisfaction domain scores did not change after external beam radiation. Of the 34 patients who had erectile function at baseline, 10 patients could maintain erectile function 12 months after radiotherapy. Though there were no significant differences in clinical features between patients who could maintain erectile function and those who had worsening erectile function 12 months after radiotherapy, the sexual desire domain score before radiotherapy was significantly higher in patients who could maintain erectile function than their counterparts. (Conclusion) Using the IIEF survey, external beam radiation was found to affect erectile function in patients with localized or locally advanced prostate cancer.

Preoperative hydronephrosis grade independently predicts worse pathological outcomes in patients undergoing nephroureterectomy for upper tract urothelial carcinoma

Ito Yujiro, Kikuchi Eiji, Tanaka Nobuyuki, Miyajima Akira, Mikami Shuji, Jinzaki Masahiro, Oya Mototsugu

Journal of Urology 185 ( 5 ) 1621 - 1626 2011.05

ISSN 0022-5347

Purpose: We analyzed the prognostic impact of hydronephrosis grade on disease specific survival and evaluated whether hydronephrosis grade could preoperatively predict worse pathological outcomes in cases of upper tract urothelial carcinoma treated surgically. Materials and Methods: We identified and retrospectively reviewed the records of 91 patients who were evaluated by multidetector computerized tomography and/or magnetic resonance imaging preoperatively, and treated with nephroureterectomy at our institution from 2000 to 2009. Ipsilateral hydronephrosis was graded 0 to 4 by 2 urological radiologists blinded to clinical outcomes. We analyzed the associations between hydronephrosis grade, and pathological findings and patient outcomes. Results: Preoperatively 67 patients (73.6%) had ipsilateral hydronephrosis. Grade was 1 to 4 in 3 (3.3%), 17 (18.7%), 23 (25.3%) and 24 cases (26.4%), respectively. Higher hydronephrosis grade was significantly associated with a ureteral tumor (p = 0.0307), higher pT stage (p = 0.0002) and lymphovascular invasion (p = 0.0014). Higher hydronephrosis grade was not associated with disease specific or metastasis-free survival. On preoperative multivariate analysis high hydronephrosis grade predicted pathological T stage (T3 or greater) (HR 4.98, p = 0.0228), positive lymphovascular invasion (HR 6.37, p = 0.0022) and grade 3 (HR 2.98, p = 0.0311). Conclusions: On image analysis preoperative hydronephrosis grade was associated with features of aggressive disease and predicted an advanced pathological outcome in patients with upper tract urothelial carcinoma. This information could prove useful to select candidates for neoadjuvant chemotherapy and make decisions concerning surgical options.

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Could patient age influence tumor recurrence rate in non-muscle-invasive bladder cancer patients treated with BCG immunotherapy?

Yuge Kazuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Takeda Toshikazu, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 4 ) 565 - 570 2011.04

ISSN 0368-2811

Objective: The effect of local immunotherapy with bacille Calmette-Guérin in elderly patients with non-muscle-invasive bladder cancer has not yet been fully evaluated. The aim of the present study was to evaluate whether patients' age influences the response to bacille Calmette-Guérin treatment for the prevention of tumor recurrence and whether the side effects were tolerable. Methods: We reviewed 1252 cases with non-muscle-invasive bladder cancer treated with transurethral bladder tumor resection, and 447 cases who underwent bacille Calmette- Guérin immunotherapy were included. The associations between patient age or pathological findings and tumor recurrence were determined. Side effects were classified as minor or major and were analyzed on the basis of their incidences in each age group. Results: The patients were divided into four age categories: younger than 55 (n = 86), 55-64 (n = 143), 65-74 (n = 132) and equal or older than 75 years (n = 86). The Kaplan-Meier curves of recurrence-free survival rates demonstrated that patients aged 55-64 had been continuously tumor-free than the equal or older than 75 group. The presence of previous bladder cancer and Grade 3 were independent predictors for tumor recurrence; however, patients' age was not selected. The incidence of fever was slightly higher and that of cystitis was lower in the younger group. Conclusions: Age does not certainly affect recurrence in patients with bladder cancer treated with bacille Calmette-Guérin therapy. The related side effects in the elderly patients were almost equal to those in the younger. With careful monitoring, bacille Calmette-Guérin therapy is safe even in elderly patients.

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Could Patient Age Influence Tumor Recurrence Rate in Non-muscle-invasive Bladder Cancer Patients Treated with BCG Immunotherapy?

Yuge Kazuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Takeda Toshikazu, Miyajima Akira, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 4 ) 565 - 570 2011.04

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Angiotensin II type 1 receptor expression and microvessel density in human bladder cancer

Shirotake Suguru, Miyajima Akira, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kikuchi Eiji, Oya Mototsugu

Urology 77 ( 4 ) 2011.04

ISSN 0090-4295

Objectives: To determine whether angiotensin II type 1 receptor (AT1R) expression and tumor angiogenesis in human bladder cancer (BCa) specimens acquired by transurethral resection (TUR). It has recently been reported that AT1R is expressed in several tumors and is involved in tumor angiogenesis. However, no study has investigated AT1R expression in association with angiogenesis in clinical specimens of bladder cancer. Methods: Surgical specimens were obtained from 108 patients who had undergone TUR for bladder cancer. All specimens were pathologically diagnosed as urothelial carcinoma. AT1R expression and microvessel density (MVD) were determined by immunostaining. The clinical and pathologic characteristics were retrospectively reviewed. Results: The MVD was greater in muscle-invasive BCa (MIBC; 29 cases, 34.4 ± 4.1/0.25 mm²) than in non-MIBC (NMIBC; 79 cases, 17.4 ± 1.1/0.25 mm², P < .0001). AT1R expression was greater in the MIBC (P = .0004) and high-grade (P = .0063) specimens than in the NMIBC and low-grade specimens. In addition, the greater expression of AT1R was significantly associated with MVD (P < .05). In NMIBC, the factors significantly affecting recurrence-free survival on univariate analysis were AT1R (P = .02), MVD (P < .0001), tumor multiplicity (P = .0007), and bacille Calmette-Guérin intravesical instillation after TUR (P = .0026). Multivariate analysis revealed that tumor multiplicity and no BCG intravesical instillation after TUR were independent predictors of 5-year recurrence-free survival, and AT1R and MVD were independent predictors of 1-year recurrence-free survival (P < .01). Conclusions: AT1R expression and MVD were related to early intravesical recurrence in NMIBC. The results suggest that AT1R could become a new molecular target and a prognostic factor for NMIBC.

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A germ cell-specific gene, Prmt5, works in somatic cell reprogramming

Nagamatsu Go, Kosaka Takeo, Kawasumi Miyuri, Kinoshita Taisuke, Takubo Keiyo, Akiyama Hideo, Sudo Tetsuo, Kobayashi Takashi, Oya Mototsugu, Suda Toshio

Journal of Biological Chemistry 286 ( 12 ) 10641 - 10648 2011.03

ISSN 0021-9258

Germ cells possess the unique ability to acquire totipotency during development in vivo as well as give rise to pluripotent stem cells under the appropriate conditions in vitro. Recent studies in which somatic cells were experimentally converted into pluripotent stem cells revealed that genes expressed in primordial germ cells (PGCs), such as Oct3/4, Sox2, and Lin28, are involved in this reprogramming. These findings suggest that PGCs may be useful for identifying factors that successfully and efficiently reprogram somatic cells into toti- and/or pluripotent stem cells. Here, we show that Blimp-1, Prdm14, and Prmt5, each of which is crucial forPGCdevelopment, have the potential to reprogram somatic cells into pluripotent stem cells. Among them, Prmt5 exhibited remarkable reprogramming of mouse embryonic fibroblasts into which Prmt5, Klf4, and Oct3/4 were introduced. The resulting cells exhibited pluripotent gene expression, teratoma formation, and germline transmission in chimeric mice, all of which were indistinguishable from those induced with embryonic stem cells. These data indicate that some of the factors that play essential roles in germ cell development are also active in somatic cell reprogramming.

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The clinical impact of the classification of carcinoma in situ on tumor recurrence and their clinical course in patients with bladder tumor

Hayakawa Nozomi, Kikuchi Eiji, Mikami Shuji, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 3 ) 424 - 429 2011.03

ISSN 0368-2811

Objective: To evaluate recurrence and clinical course of bladder carcinoma in situ according to the current carcinoma in situ classification by analyzing the patients with diagnosed carcinoma in situ in our hospital. Methods: Between January 1993 and September 2008, 93 patients were initially diagnosed with bladder carcinoma in situ in our hospital. All specimens underwent an additional review by one uro-pathologist. Primary, secondary and concurrent carcinoma in situ were found in 26, 21 and 46 patients, respectively. Sixty-nine patients (74.2%) underwent bacillus Calmette-Guérin instillation therapy. Results: The multivariate analysis determined that the secondary carcinoma in situ and the absence of bacillus Calmette-Guérin therapy were the independent unfavorable risk factors for tumor recurrence. The 5-year recurrence-free survival rates on primary, concurrent and secondary carcinoma in situ were 60.9, 63.2 and 25.4%, respectively, and the differences between secondary and primary carcinoma in situ, and secondary and concurrent were significant (P= 0.023 and P= 0.006, respectively). During the median follow-up period of 47 months, 19 patients had tumor recurrence in the bladder after the first bacillus Calmette-Guérin therapy, and 13 of them were treated with a second bacillus Calmette-Guérin therapy. After the second bacillus Calmette-Guérin therapy six patients eventually had distant metastasis and three had upper tract recurrence, whereas totally four had a tumor-free status after the second bacillus Calmette-Guérin therapy. Conclusions: The first induction course of bacillus Calmette-Guérin therapy proved to be effective for the prevention of bladder cancer recurrence, however, the efficacy of a second bacillus Calmette-Guérin therapy on a recurrent tumor was somewhat limited.

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The Clinical Impact of the Classification of Carcinoma In Situ on Tumor Recurrence and their Clinical Course in Patients with Bladder Tumor

Hayakawa Nozomi, Kikuchi Eiji, Mikami Shuji, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 41 ( 3 ) 424 - 429 2011.03

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Urinary pH is highly associated with tumor recurrence during intravesical mitomycin c therapy for nonmuscle invasive bladder tumor

Maeda Takahiro, Kikuchi Eiji, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

Journal of Urology 185 ( 3 ) 802 - 806 2011.03

ISSN 0022-5347

Purpose In recent years some reports have suggested without any significant evidence that mitomycin C instillation would be more effective with urinary alkalinization. We investigated the association between urinary pH and the efficiency of mitomycin C instillation. Materials and Methods We identified 130 patients treated with transurethral resection of a bladder tumor and adjuvant intravesical mitomycin C instillation between 1985 and 2008 at Keio University Hospital. Urinary pH was determined in 124 of the 130 patients just before mitomycin C administration during the scheduled instillation period. These 124 patients were assigned to groups according to urinary pH in increments of 0.5 and the association between urinary pH and clinicopathological characteristics was evaluated. Results Mean ± SD urinary pH was 5.77 ± 0.05 (range 5.00 to 7.66) during the scheduled instillation period. Urinary pH was 5.00 to 5.49, 5.50 to 5.99, 6.00 to 6.49, 6.50 to 6.99 and 7.00 in 39, 46, 25, 7 and 7 patients, respectively. Patients were further divided into 2 groups by urinary pH using a cutoff of 5.5, including 39 with pH less than 5.5 and 85 with pH 5.5 or more. Age, gender, tumor grade, primary/recurrent disease, pathological stage and the presence or absence of concomitant carcinoma in situ were not significantly difference between the 2 groups. Multivariate analysis revealed that categorical urinary pH was an independent risk factor for tumor recurrence (HR 1.75, p = 0.032). Three and 5-year recurrence-free rates were 64.2% and 52.9% in patients with pH 5.5 or greater, and 41.9% and 38.4% in those with pH less than 5.5, respectively (p = 0.046). Multivariate analysis showed that the HR of urinary pH for tumor recurrence was 1.84 and 2.54 at the 5.4 and 5.2 cutoffs, respectively. Conclusions Results suggest that urinary pH more than 5.5 is associated with a decreased risk of tumor recurrence in patients treated with intravesical mitomycin C for nonmuscle invasive bladder cancer. Monitoring urinary pH during mitomycin C adjuvant treatment and modifying pH for urine alkalization may improve the therapeutic efficacy of mitomycin C instillation.

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Benefit of laparoscopic radical nephrectomy in patients with a high BMI

Hagiwara Masayuki, Miyajima Akira, Matsumoto Kazuhiro, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 41 ( 3 ) 400 - 404 2011.03

ISSN 0368-2811

Objective: The aim of the present study was to analyze all relevant data collected thus far at our hospital in order to compare the laparoscopic vs. open techniques in terms of the intraoperative results and to analyze whether patients with a higher BMI may derive greater benefit from laparoscopy. Methods: We reviewed the medical records of 93 patients treated with laparoscopic nephrectomy and 91 patients treated with the open method at our institution. We analyzed the data with the aim of determining what kind of factor would be associated with an increase in estimated blood loss and prolongation of operative time, and we compared the results for laparoscopic and open nephrectomy. Results: A statistically significant correlation was observed between body mass index and operating time (P = 0.018) or estimated blood loss (P = 0.017) in laparoscopic nephrectomy. Multivariate analysis demonstrated that body mass index was an independent risk factor for prolonged operating time (P = 0.030, odds ratio = 1.174). In the open nephrectomy patients, body mass index also had a significant correlation with operating time (P < 0.001) and estimated blood loss (P < 0.001). Multivariate analysis also revealed that operating time depended on body mass index (P < 0.001, odds ratio = 1.348) and tumor size (P = 0.030, odds ratio = 1.320), and the odds ratio of body mass index was higher than that in laparoscopic nephrectomy. Conclusions: As body mass index increases, both laparoscopic nephrectomy and open nephrectomy become technically more difficult. However, our data showed that for patients with a high body mass index, the laparoscopic approach is comparatively safer and of greater benefit.

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Frequency of tumor recurrence

Tanaka Nobuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Journal of Urology 185 ( 2 ) 450 - 455 2011.02

ISSN 0022-5347

Purpose Patients with nonmuscle invasive bladder cancer usually experience multiple instances of tumor recurrence until stage progression occurs. However, it has not yet been fully evaluated whether the timing and/or pattern of tumor recurrence could affect subsequent stage progression. We examined whether the frequency of tumor recurrence provides additional predictive information concerning stage progression. Materials and Methods A total of 484 patients with initially diagnosed nonmuscle invasive bladder cancer were identified between 1985 and 2006 at our institution. Median followup was 7.2 years. Frequency of tumor recurrence was analyzed to determine if it affected subsequent stage progression. Results Of these patients 40 (8.3%) experienced stage progression during followup. Using Kaplan-Meier analysis subsequent stage progression could be most strongly predicted in patients with a recurrence rate of 1 or more per year during the first 2 years, although similar results were observed for various cutoff periods and recurrence rates. The 10-year progression-free survival rate was 58.0% in patients with a recurrence rate of 1 or more per year and 93.3% in their counterparts (p <0.001). Multivariate analysis demonstrated that the appearance of tumor grade 3 (p = 0.027, risk ratio 2.36), carcinoma in situ (p = 0.045, risk ratio 2.44) and a recurrence rate of 1 or more per year during the first 2 years (p <0.001, risk ratio 7.40) were independent risk factors for subsequent stage progression. Conclusions Frequency of tumor recurrence is a strong predictor of subsequent stage progression in patients initially diagnosed with nonmuscle invasive bladder cancer. More appropriate followup and aggressive treatment due to a higher malignant potential for stage progression might be recommended in patients with a recurrence rate of 1 or more per year during the first 2 years.

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Frequency of Tumor Recurrence: A Strong Predictor of Stage Progression in Initially Diagnosed Nonmuscle Invasive Bladder Cancer

Tanaka Nobuyuki, Kikuchi Eiji, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 185 ( 2 ) 450 - 455 2011.02

Research paper (scientific journal), Joint Work, ISSN 0022-5347

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Torsion of the spermatic cord

Asanuma Hiroshi, Oya Mototsugu, Satoh Hiroyuki, Ezaki Taisuke

Japanese Journal of Clinical Urology 65 ( 1 ) 7 - 13 2011.01

ISSN 0385-2393

Enhanced antitumor effect of combination intravesical mitomycin c and bacillus calmette-guerin therapy in an orthotopic bladder cancer model

Matsushima Masashi, Horinaga Minoru, Fukuyama Ryuichi, Yanaihara Hitoshi, Kikuchi Eiji, Kawachi Makoto, Iida Masahiro, Nakahira Yoko, Oya Mototsugu, Asakura Hirotaka

Oncology Letters 2 ( 1 ) 13 - 19 2011.01

ISSN 1792-1074

Intravesical immunotherapy with bacillus Calmette-Guerin (BCG) is currently the most successful adjuvant agent for the treatment and/or prophylaxis of non-muscle-invasive bladder cancer (NMIBC). However, NMIBCs recur in 60-70% of cases and 30% of these recurrent tumors present with a higher grade and more invasive properties. Patients that do not respond to intravesical BCG therapy are considered to be a challenge for urologists. Thus, novel conservative possibilities should be explored. To test the efficacy of a novel therapeutic approach, we examined the antitumor effect of combination therapy by intravesical administration of mitomycin C (MMC) plus BCG, infusing the two drugs simultaneously, in an orthotopic bladder cancer model. Intravesical BCG and MMC administration showed a dose-dependent survival (n=8 per group). The combination of MMC and BCG provided a significant survival advantage compared to the BCG-alone (p=0.035) and MMC-alone groups (p=0.040) (n=8 per group). The group with combined MMC/BCG exhibited a survival period similar to that achieved with an amount eight times higher that of BCG (n=10 per group). Ki-67 labeling index of cancer cells, showing tumor proliferation, was significantly lower in the combined group compared to the BCG-alone (p<0.05), MMC-alone (p<0.01) and control groups (p<0.01). No difference was detected between the combined group and the BCG-alone group with regard to CD3, T-cell infiltration and CD68 macrophage activity. The combined MMC/BCG treatment decreased the tumor appearance rate, improved the survival period and reduced the cellular proliferation rate in tumors compared to the BCG-alone treatment. The results suggest that the combined intravesical MMC/BCG treatment induced an enhanced antitumor effect against bladder tumors. The combined MMC/BCG treatment also showed a survival period similar to that achieved using a dose eight times higher of BCG-alone.

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Recurrence of bladder cancer in remnant urethra and inguinal lymph node metastasis nine years after total cystectomy

Obata Jun, Kikuchi Eiji, Kaneko Gou, Miyajima Akira, Kameyama Kaori, Jinzaki Masahiro, Oya Mototsugu

Japanese Journal of Urology 102 ( 1 ) 34 - 38 2011.01

ISSN 0021-5287

A 68-year-old man underwent total cystectomy, urethrectomy preserving fossa naviculars, and an Indiana pouch urinary diversion in 1997. The histopathology was UC, G3, pT4 (prostate). Nine years after the operation, he had multiple metastases to the inguinal and paraaortic lymph nodes (LNs), and he complained of erosion around the glans. Histological diagnosis of the glans revealed recurrent UC to the urethra of the glans. We considered the possibility that the inguinal LN metastasis was due to lymphatic spread from a remnant urethral recurrence. Thus, a partial penectomy and inguinal LN dissection were undertaken. Systemic chemotherapy was administered. Remnant urethral recurrence after urethrectomy preserving the fossa navicularis and inguinal LN metastasis are rare.

Transumbilical laparo-endoscopic single site surgery for adrenal cortical adenoma inducing primary aldosteronism

Miyajima Akira, Maeda Takahiro, Hasegawa Masanori, Takeda Toshikazu, Ishida Masaru, Kosaka Takeo, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

BMC Research Notes 4 2011

Background: We have started using laparo-endoscopic single-site surgery (LESS) in urologic surgery, although its use has not gained momentum due to its level of difficulty. We here report our initial experience with transumbilical LESS for adrenal cortical adenoma by using a single port with a multichannel cannula (SILS port) and bent laparoscopic instrumentation. Findings. A multichannel port (SILS port), bent laparoscopic instrument (Roticulator Endo Mini-Shears) and Opti4 laparoscopic electrodes were used in all cases. The intraperitoneal space was approached through the umbilicus. The SILS port was placed through a 2 cm incision at the inner edge of the umbilicus. A 5 mm flexible laparoscope was introduced to keep the laparoscope outside, and surgical specimens were extracted using an Endocatch bag. In addition, as a case control study, we compared perioperative data of LESS adrenalectomy (LESS-A) with that of conventional laparoscopic adrenalectomy (LA). We performed transumbilical LESS-A for adrenal cortical adenoma in 12 cases, beginning in December, 2009. All procedures were successfully completed, with only one incision through the umbilicus, and without conversion to a standard laparoscopic approach. Mean operative time for LESS-A was 121.2± 7.8 min, which was slightly longer than LA (110.2± 7.3 min). For right adrenal tumors, we used a miniport (2 mm port) in addition to a SILS port, and were able to successfully perform adrenalectomy "with no visible scaring". Tumor laterality and patient BMI did not affect surgical morbidity in these procedures. Moreover, there was no significant difference between LESS-A and LA in blood loss, analgesic requirement, hospital stay, and scar satisfaction. Conclusions: The transumbilical approach in LESS for adrenalectomy is safe and feasible and also improves cosmetic outcome compared with standard laparoscopic procedures. Improvements in surgical devices may aid the further development of this approach.

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Renal cell carcinoma accompanied by left-sided IVC

Maeda Takahiro, Miyajima Akira, Kikuchi Eiji, Oya Mototsugu

Internal Medicine 50 ( 10 ) 1127 2011

ISSN 0918-2918

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Imaging findings of renal angiomyolipoma with epithelial cysts

Akita Hirotaka, Jinzaki M., Tanimoto A., Sugiura H., Osugi K., Kuribayashi S., Mikami S., Oya M.

Japanese Journal of Clinical Radiology 55 ( 13 ) 1695 - 1698 2010.12

ISSN 0009-9252

Expression of snail in upper urinary tract urothelial carcinoma

Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Shirotake Suguru, Ishida Masaru, Okada Yasunori, Oya Mototsugu

Clinical Cancer Research 16 ( 23 ) 5814 - 5823 2010.12

ISSN 1078-0432

Purpose: There are few molecular markers known to predict upper urinary tract urothelial carcinomas (UTUC) prognosis. Snail, which contributes to epithelial-mesenchymal transition (EMT), has been documented in cancer progression, but not clear yet in UTUC. We therefore addressed the expression and biological significance of Snail in UTUC. Experimental Design: To elucidate the biological significance of Snail in UTUC, we examined the immunohistochemical expression of snail in UTUC and analyzed its clinical significance in 150 patients with UTUC. Biological effects of Snail in EMT and invasion were evaluated by using small interfering RNA (siRNA) specific for Snail in urothelial carcinoma cell lines and the Matrigel invasion assay. Results: Nuclear Snail staining was very weak in superficial UTUC. In contrast, strong Snail staining was observed in many of the nucleus of invasive UTUC. Snail expression was significantly higher in the high tumor stage, high grade, and in tumors showing lymphovascular invasion (LVI). Multivariate Cox regression analysis revealed that elevated Snail expression was a significant and an independent prognostic predictor of recurrence-free survival and cancer-specific survival. Patients with positive LVI and high Snail expression showed the worse outcome. Targeting of Snail mRNA expression in UMUC-3 cells with Snail-specific siRNA downregulated the mRNA expression of Snail, Vimentin, MMP2, and MMP9. Furthermore, the cells with siRNA for Snail showed decreased invasion activity in comparison with the cells transfected with a nontargeting siRNA. Conclusion: Snail-induced EMT represents a clinically relevant mechanism of UTUC progression and an attractive target for the treatment of patients with UTUC.

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Non-muscle invasive bladder cancer with concomitant vaginal urothelial carcinoma

Kaneko Gou, Kikuchi Eiji, Hasegawa Masanori, Miyajima Akira, Nakagawa Ken, Kameyama Kaori, Oya Mototsugu

International Journal of Clinical Oncology 15 ( 6 ) 626 - 630 2010.12

ISSN 1341-9625

A 74-year-old female was referred to our hospital for non-muscle invasive bladder tumors initially treated at another hospital. Preoperatively, computed tomography and magnetic resonance imaging demonstrated non-muscle invasive bladder tumors and a vaginal tumor. A second transurethral resection of the bladder tumors, transvaginal tumor resection, and systemic chemotherapy were performed. The histopathological appearances of both tumors were very similar and the diagnoses were urothelial carcinoma (UC). The pathogenesis of the vaginal UC was considered to be the primary UC or metastasis from the bladder UC. Vaginal UC is extremely rare and this is only the 15th report in the literature.

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Non-muscle invasive bladder cancer with concomitant vaginal urothelial carcinoma: a case report and review of the literature

Kaneko Gou, Kikuchi Eiji, Hasegawa Masanori, Miyajima Akira, Nakagawa Ken, Kameyama Kaori, Oya Mototsugu

INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY 15 ( 6 ) 626 - 630 2010.12

Research paper (scientific journal), Joint Work, ISSN 1341-9625

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Cis-dichlorodiammineplatinum upregulates angiotensin II type 1 receptors through reactive oxygen species generation and enhances VEGF production in bladder cancer

Tanaka Nobuyuki, Miyajima Akira, Kosaka Takeo, Shirotake Suguru, Hasegawa Masanori, Kikuchi Eiji, Oya Mototsugu

Molecular Cancer Therapeutics 9 ( 11 ) 2982 - 2992 2010.11

ISSN 1535-7163

We previously reported that angiotensin II type 1 receptor (AT1R) antagonists enhanced the cytotoxity of cis-dichlorodiammineplatinum (CDDP) in a bladder cancer xenograft model. To elucidate the synergistic mechanism, we investigated whether reactive oxygen species (ROS) generation induced by CDDP may affect the regulation of AT1R expression. Five invasive human bladder cancer cell lines, T24, UMUC-3, 5637, KU-1, and KU-19-19, were used in the in vitro study. For the in vivo study, T24 cells were used. We also examined AT1R and vascular endothelial growth factor (VEGF) expression in human bladder cancer specimens that had been treated with CDDP-based chemotherapy. The in vitro study showed that AT1R expression was significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. On the other hand, AT1R expression was not changed in UMUC-3 and 5637 cells. ROS generation was also significantly upregulated by CDDP in T24, KU-1, and KU-19-19 cells. The upregulation of AT1R expression induced by CDDP was significantly suppressed by scavenging free radicals. Angiotensin II induced VEGF production in CDDP-treated cells; however, the AT1R antagonist significantly inhibited the increase in VEGF. The in vivo study results also showed that CDDP treatment upregulated AT1R expression, resulting in increased VEGF. Clinical specimens from patients who underwent cystectomy after neoadjuvant CDDP-based chemotherapy showed significantly higher AT1R and VEGF expression than corresponding transurethral resection specimens. Our findings indicate that CDDP upregulates AT1R expression though ROS generation and enhances VEGF production. Therefore, AT1R blockade may be an effective strategy for bladder cancer in combination with CDDP-based chemotherapy.

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Contrast-enhanced ultrasonography of the prostate with sonazoid

Matsumoto Kazuhiro, Nakagawa Ken, Hashiguchi Akinori, Kono Hidaka, Kikuchi Eiji, Nagata Hirohiko, Miyajima Akira, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 11 ) 1099 - 1104 2010.11

ISSN 0368-2811

Objective: The diagnosis of prostate cancer is based on the results of ultrasonography-guided needle biopsy of the prostate, but cancer foci are often not visible in conventional transrectal ultrasonography. Sonazoid is a new microbubble contrast agent. The purpose of our study was to compare areas of contrast material enhancement in the prostate at ultrasonography with whole-mount radical prostatectomy specimens to determine if the use of Sonazoid improves the detection rate of prostate cancer. Methods: Fifty patients with biopsy-proven cancer of the prostate who were scheduled to undergo radical prostatectomy were recruited for this study. The day before the operation, each patient was evaluated with ultrasonography at baseline and again during intravenous infusion of Sonazoid. A map of ultrasonography findings was created prospectively at the time of imaging. Following radical prostatectomy, independent mapping of the pathologic results was performed and the maps were compared. Results: Ultrasonography evaluation at baseline demonstrated that at least one focus of cancer was identified in 20 of the 50 subjects (40.0%). Meanwhile at least one cancer focus was enhanced in 31 of the 50 patients (62.0%) when Sonazoid was used. The combination of baseline grayscale imaging and contrast-enhanced imaging allowed identification of at least one focus of cancer in 40 patients (80.0%). Contrast-enhanced ultrasonography can improve sensitivity, especially for the detection of large cancer, peripheral zone cancer and highly malignant cancer. Conclusions: Our study has demonstrated significantly improved detection of prostate cancer with the combination of baseline grayscale imaging and contrast-enhanced imaging compared with conventional ultrasonography techniques only, and this technique may be applicable to targeted biopsy.

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Everolimus and tacrolimus

Kono Hidaka, Nakagawa Ken, Oya Mototsugu

Biotherapy 24 ( 6 ) 520 - 524 2010.11

ISSN 0914-2223

The mammalian target of rapamycin (mTOR) protein complex functions as a key protein for proliferation, cell survival, and angiogenesis in intracellular signaling pathways. Everolimus (RAD001), which is one of the mTOR inhibitors, is applied to treat patients with unresectable or metastatic renal cell cancers as second-line treatment for those refractory to sorafenib or sunitinib. Tacrolimus (FK506), which is one of the calcineurin inhibitors, is a strong immunosuppressive agent. Tacrolimus is known as an immunosuppressive agent greatly increasing the risk of malignancy by impairing cancer surveillance, and the drug enhances the production of transforming growth factor β1 (TGF-β1). In cytoplasm, everolimus and tacrolimus bind to the same target, which is called FK506 binding protein 12 (FKBP12), and the complexes play different roles in the cell. We here describe the mechanism of action, the side effects, biomarker, and the role of the two drugs in the future.

Gemcitabine and cisplatin chemotherapy induced reversible posterior leukoencephalopathy syndrome in a bladder cancer patient

Maeda Takahiro, Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Hagiuda Jun, Miyajima Akira, Nakagawa Ken, Fujiwara Hirokazu, Hoshino Haruhiko, Oya Mototsugu

International Journal of Clinical Oncology 15 ( 5 ) 508 - 511 2010.10

ISSN 1341-9625

Reversible posterior leukoencephalopathy syndrome (RPLS) is a rare clinical entity, the common clinical symptoms of which are headache, disturbance of consciousness, altered mental status, seizures, and visual disturbance. Recently, some cases have been reported in association with the increased use of cytotoxic and immunosuppressive agents in cancer patients, and relevant reports have increased with advances in radiological examinations. We describe here the case of a 50-year-old man with advanced bladder cancer who suddenly experienced diminished spontaneity and speech, and finally became semicomatose. Two months previously, he had received gemcitabine and cisplatin chemotherapy. Computed tomography and magnetic resonance imaging revealed symmetrical edema of the posterior occipital lobe and thalamus. Based on these findings, we made a diagnosis of RPLS and treated him with supportive measures. His mental status gradually improved in 2 weeks, although slight neurological symptoms persisted. When the level of consciousness of a cancer patient worsens rapidly, this syndrome should be included in the differential diagnosis and recognized at an early stage. Early supportive management and discontinuation of the causative medication may reverse the clinical and radiological manifestations of the syndrome.

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Preimplant factors affecting postimplant CT-determined prostate volume and the CT/TRUS volume ratio after transperineal interstitial prostate brachytherapy with ¹²⁵I free seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko, Asakura Hirotaka, Oya Mototsugu, Shigematsu Naoyuki

Radiation Oncology 5 ( 1 ) 2010.09

Background: The aim was to identify preimplant factors affecting postimplant prostate volume and the increase in prostate volume after transperineal interstitial prostate brachytherapy with ¹²⁵I free seeds.Methods: We reviewed the records of 180 patients who underwent prostate brachytherapy with ¹²⁵I free seeds for clinical T1/T2 prostate cancer. Eighty-one (45%) of the 180 patients underwent neoadjuvant hormonal therapy. No patient received supplemental external beam radiotherapy. Postimplant computed tomography was undertaken, and postimplant dosimetric analysis was performed. Univariate and multivariate analyses were performed to identify preimplant factors affecting postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.Results: Preimplant prostate volume by transrectal ultrasound, serum prostate-specific antigen, number of needles, and number of seeds implanted were significantly correlated with postimplant prostate volume by computed tomography. The increase in prostate volume after implantation was significantly higher in patients with neoadjuvant hormonal therapy than in those without. Preimplant prostate volume by transrectal ultrasound, number of needles, and number of seeds implanted were significantly correlated with the increase in prostate volume after implantation. Stepwise multiple linear regression analysis showed that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy were significant independent factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.Conclusions: The results of the present study show that preimplant prostate volume by transrectal ultrasound and neoadjuvant hormonal therapy are significant preimplant factors affecting both postimplant prostate volume by computed tomography and the increase in prostate volume after implantation.

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Kidney cancer working group report

Naito Seiji, Tomita Yoshihiko, Rha Sun Young, Uemura Hirotsugu, Oya Mototsugu, Song He Zhi, Zhong Li Han, Wahid Mohamed Ibrahim Bin A

Japanese Journal of Clinical Oncology 40 ( SUPPL. 1 ) 2010.09

ISSN 0368-2811

Kidney cancer accounts for approximately 2% of all cancers worldwide, with renal cell carcinoma being the most common form and this report is focused on renal cell carcinoma. Globally, the incidence and mortality rates are increasing by 2-3% per decade. Kidney cancer is less common in Asia compared with the West. Cigarette smoking, obesity, acquired cystic kidney disease and inherited susceptibility are known risk factors for kidney cancer. The National Comprehensive Cancer Network Guidelines recommend surgical excision as first line of treatment for Stage I, II or III kidney cancer patients and Stage IV patients with resectable tumours. Immunotherapy has a 20-year history in treatment of metastatic kidney cancer. Highdose interleukin-2 (IL-2) is administered in some countries, whereas low-dose IL-2 and interferon-alpha (IFN-α) are popular in Japan. Molecular-targeted drugs, including sunitinib, bevacizumab and sorafenib, are being used for previously untreated and refractory patients. Asian and non-Asian populations have shown large differences in the incidences of adverse events with sorafenib and sunitinib. Consensus Statement: Kidney cancer is relatively uncommon in Asia compared with the West, but its incidence is increasing in more developed Asian nations. Guidelines from the National Comprehensive Cancer Network, etc., for treating metastatic renal cell carcinoma are based on Phase III clinical trials conducted primarily in Western patients. Targeted therapies are now becoming primary recommendations, but efficacy/toxicity data from Asian patients are lacking. Some drugs cause adverse effects in Asians because their recommended dosages are optimal for Caucasians but may be too high for Asians. Further research is necessary to develop optimal treatment strategies for Asians.

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Kidney Cancer Working Group Report

Naito Seiji, Tomita Yoshihiko, Rha Sun Young, Uemura Hirotsugu, Oya Mototsugu, Song He Zhi, Zhong Li Han, Wahid Mohamed Ibrahim Bin A.

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 i51 - i56 2010.09

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Preimplant factors affecting postimplant CT-determined prostate volume and the CT/TRUS volume ratio after transperineal interstitial prostate brachytherapy with I-125 free seeds

Sugawara Akitomo, Nakashima Jun, Kunieda Etsuo, Nagata Hirohiko Asakura Hirotaka, Oya Mototsugu, Shigematsu Naoyuki

RADIATION ONCOLOGY 5 619 - 624 2010.09

Research paper (scientific journal), Joint Work, ISSN 1748-717X

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Regulation of human dendritic cells by a novel specific nuclear factor-κB inhibitor, dehydroxymethylepoxyquinomicin

Shinoda Kazunobu, Nakagawa Ken, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

Human Immunology 71 ( 8 ) 763 - 770 2010.08

ISSN 0198-8859

Regulation of antigen-presenting cells (APC) is crucial in controlling allograft rejection. Dendritic cells (DC) are the most potent APC and must mature to present antigens to T-cell receptors. During DC maturation, nuclear factor-κB (NF-κB) is a key transcriptional factor. We synthesized dehydroxymethylepoxyquinomicin (DHMEQ), which specifically inhibits the final step of nuclear translocation of activated NF-κB proteins and examined its immunoregulatory effects on human monocyte-derived DC (Mo-DC). Regulatory Mo-DC were generated by pretreatment with DHMEQ before LPS stimulation, which were termed dl-DC. DHMEQ pretreatment (5 μg/ml) completely inhibited nuclear translocation of activated NF-κB. DHMEQ significantly inhibited DC production of κproinflammatory cytokines (IL-6, TNF-α, and IL-12 p70) in a dose-dependent manner. IL-12 was most potently inhibited. However, IL-10 production by dl-DC was only moderately affected by DHMEQ. Although CD40 and the expression of HLA-DR (HLA-DR) expression on dl-DC was downregulated, CD80 and CD86 expression was moderately upregulated. Induction of T helper 1 cell responses was efficiently impaired by dl-DC. This confirmed that DHMEQ-treated Mo-DC exhibited immunoregulatory effects. These findings suggest that DHMEQ has potential as an immunosuppressive drug for human immune cells.

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Regulation of human dendritic cells by a novel specific nuclear factor-kappa B inhibitor, dehydroxymethylepoxyquinomicin

Shinoda Kazunobu, Nakagawa Ken, Kosaka Takeo, Tanaka Nobuyuki, Maeda Takahiro, Kono Hidaka, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Umezawa Kazuo, Oya Mototsugu

HUMAN IMMUNOLOGY 71 ( 8 ) 763 - 770 2010.08

Research paper (scientific journal), ISSN 0198-8859

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Long-term results of children with renal cell carcinoma

Asanuma Hiroshi, Mizuno Ryuichi, Kono Hidaka, Shinoda Nobuyuki, Kikuchi Eiji, Satoh Hiroyuki, Muramatsu Masaki, Matsui Zenichi, Nagara Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY 17 A141 - A141 2010.08

Research paper (scientific journal), Joint Work, ISSN 0919-8172

[Genitourinary cancers].

Mizuno Ryuichi, Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 68 Suppl 8 485 - 488 2010.08

ISSN 0047-1852

Risk classification for non-muscle invasive bladder cancer

Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Urology 64 ( 9 ) 633 - 638 2010.08

ISSN 0385-2393

Retroperitoneal mixed-type perinephric liposarcoma

Daimon Tatsuaki, Maeda Takahiro, Shirakawa Hiroshi, Mikami Shuji, Mukai Makio, Oya Mototsugu

Japanese Journal of Clinical Urology 64 ( 9 ) 665 - 668 2010.08

ISSN 0385-2393

A 66-year-old man, with abdominal distention, was referred to our department for the treatment of an abdominal tumor. Contrast computed tomogram and magnetic resonance imaging revealed a large retroperitoneal fatty tissue mass with calcification measured about 25 cm in diameter. The tumor, displacing the jejunum and the descending colon, was diagnosed as a liposarcoma. The previous contrast computed tomogram showed the abnormal signal in the left renal capsule, suggesting that the tumor was originated from the perinephric tissue. A complete excision of the tumor with concomitant resection of the left kidney was performed in September, 2009. The tumor did not involve other organs and weighed 5.88 kg. Histological examination disclosed retroperitoneal mixed-type liposarcoma composed of well-differentiated and dedifferentiated type. The patient did not consent to receive any adjuvant therapy. Neither local recurrence nor metastasis has been seen at 5 months after the operation.

How do young residents practice laparoscopic surgical skills?

Miyajima Akira, Hasegawa Masanori, Takeda Toshikazu, Tamura Kouetsu, Kikuchi Eiji, Nakagawa Ken, Oya Mototsugu

Urology 76 ( 2 ) 352 - 356 2010.08

ISSN 0090-4295

Objectives: To investigate whether a training system using a dry box is feasible for training young urologists. Despite laparoscopic surgery being widely indicated for several urological diseases, a laparoscopic training system for young urologists has not been fully established yet. However, the learning curve for laparoscopic surgery has not yet been ascertained. Methods: We continued to test 11 sixth-year residents (postgraduate year: PGY6) and third-year residents (PGY3) in our department in terms of surgical skills using a dry box. We gave them several tasks (cutting and suturing) and let them practice until task completion. We continued to test all participants by these tasks for 16 weeks. Results: At the beginning of the present study, the PGY6 residents achieved significantly better scores than the PGY3 residents. However, the difference between the 2 groups became insignificant over time. Furthermore, statistical analysis revealed that a practice time of 100 minutes per week was the only significant factor affecting the last test score. For the final test, the mean practice time for all participants was 79.1 minutes per week. Conclusions: These results suggest that laparoscopic surgical skills can definitely be polished by adequate voluntary practice.

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Characteristics and management of erectile dysfunction after various treatments for prostate cancer

Soh Jintetsu, Kaiho Yasuhiro, Kikuchi Eiji, Oya Mototsugu, Yoshioka Kunihiko, Nakagami Yoshihiro, Hatano Tadashi, Ozu Choichirou, Horiguchi Yutaka, Namiki Kazunori, Tachibana Masaaki, Hisasue Shin Ichi, Tanaka Nobumichi, Asakawa Isao

International Journal of Urology 17 ( 8 ) 689 - 697 2010.08

ISSN 0919-8172

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How do young residents practice laparoscopic surgical skills?

Miyajima A., Hasegawa M., Takeda T., Tamura K., Kikuchi E., Nakagawa K., Oya M.

International Braz J Urol 36 ( 4 ) 502 2010.07

ISSN 1677-5538

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mTOR inhibitors

Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 68 ( 6 ) 1067 - 1071 2010.06

ISSN 0047-1852

Mammalian target of rapamycin (mTOR) protein complex functions as an integration center for various intracellular signaling pathways involving proliferation, cell survival, and angiogenesis. These pathways are frequently abnormally regulated in cancer. Notably, Akt is an upstream molecule which is over-expressed and/or activated in several cancers. Therefore, mTOR inhibitors can be options for the treatment of cancers. At present, mTOR inhibitors are applied to treat patients with metastatic renal cell carcinoma (RCC). Temsirolimus is indicated as the first line therapy for RCC patients with poor prognosis, whereas everolimus as the second line for those refractory to sorafenib or sunitinib. Interstitial pneumonia is the most serious adverse event for both agents. Clinical trials are under way to explore indications for various cancers.

Late Recurrence and Progression in Non-muscle-invasive Bladder Cancers After 5-year Tumor-free Periods

Matsumoto Kazuhiro, Kikuchi Eiji, Horiguchi Yutaka, Tanaka Nobuyuki, Miyajima Akira, Nakagawa Ken, Nakashima Jun, Oya Mototsugu

UROLOGY 75 ( 6 ) 1385 - 1390 2010.06

Research paper (scientific journal), Joint Work, ISSN 0090-4295

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The clinical significance of urine cytology after a radical cystectomy for urothelial cancer

Yoshimine Shunsuke, Kikuchi Eiji, Matsumoto Kazuhiro, Ide Hiroki, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

INTERNATIONAL JOURNAL OF UROLOGY 17 ( 6 ) 527 - 532 2010.06

Research paper (scientific journal), ISSN 0919-8172

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Impact of Tumor Location on Prognosis for Patients with Upper Tract Urothelial Carcinoma Managed by Radical Nephroureterectomy

Raman Jay D., Ng Casey K., Scherr Douglas S., Margulis Vitaly, Lotan Yair, Bensalah Karim, Patard Jean Jacques, Kikuchi Eiji, Montorsi Francesco, Zigeuner Richard, Weizer Alon, Bolenz Christian, Koppie Theresa M., Isbarn Hendrik, Jeldres Claudio, Kabbani Wareef, Remzi Mesut, Waldert Mathias, Wood Christopher G., Roscigno Marco, Oya Mototsuga, Langner Cord, Wolf J. Stuart, Ströbel Philipp, Fernández Mario, Karakiewcz Pierre, Shariat Shahrokh F.

European Urology 57 ( 6 ) 1072 - 1079 2010.06

ISSN 0302-2838

Background: There is a lack of consensus regarding the prognostic significance of ureteral versus renal pelvic upper tract urothelial carcinoma (UTUC). Objective: To investigate the association of tumor location on outcomes for UTUC in an international cohort of patients managed by radical nephroureterectomy (RNU). Design, setting, and participants: A retrospective review of institutional databases from 10 institutions worldwide identified patients with UTUC. Intervention: The 1249 patients in the study underwent RNU with ipsilateral bladder cuff resection between 1987 and 2007. Measurements: Data accrued included age, gender, race, surgical approach (open vs laparoscopic), tumor pathology (stage, grade, lymph node status), tumor location, use of perioperative chemotherapy, prior endoscopic therapy, urothelial carcinoma recurrence, and mortality from urothelial carcinoma. Tumor location was divided into two groups (renal pelvis and ureter) based on the location of the dominant tumor. Results and limitations: The 5-yr recurrence-free and cancer-specific survival estimates for this cohort were 75% and 78%, respectively. On multivariate analysis, only pathologic tumor (pT) classification (p < 0.001), grade (p < 0.02), and lymph node status (p < 0.001) were associated with disease recurrence and cancer-specific survival. When adjusting for these variables, there was no difference in the probability of disease recurrence (hazard ratio [HR]: 1.22; p = 0.133) or cancer death (HR: 1.23; p = 0.25) between ureteral and renal pelvic tumors. Adding tumor location to a base prognostic model for disease recurrence and cancer death that included pT stage, tumor grade, and lymph node status only improved the predictive accuracy of this model by 0.1%. This study is limited by biases associated with its retrospective design. Conclusions: There is no difference in outcomes between patients with renal pelvic tumors and with ureteral tumors following nephroureterectomy. These data support the current TNM staging system, whereby renal pelvic and ureteral carcinomas are classified as one integral group of tumors.

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Adrenocortical zonation in humans under normal and pathological conditions

Nishimoto Koshiro, Nakagawa Ken, Li Dan, Kosaka Takeo, Oya Mototsugu, Mikami Shuji, Shibata Hirotaka, Itoh Hiroshi, Mitani Fumiko, Yamazaki Takeshi, Ogishima Tadashi, Suematsu Makoto, Mukai Kuniaki

Journal of Clinical Endocrinology and Metabolism 95 ( 5 ) 2296 - 2305 2010.05

ISSN 0021-972X

Context: Aldosterone synthase (CYP11B2) and steroid 11β-hydroxylase (CYP11B1) catalyze the terminal steps for aldosterone and cortisol syntheses, respectively, thereby determining the functional differentiationofhumanadrenocortical cells. Little isknown, however, about how the cells expressing the enzymes are actually distributed in the adrenals under normal and pathological conditions. Objective: The objective of the study was to determine the localization of CYP11B2 and -B1 in human adrenal specimens by using developed antibodies capable of distinguishing the two enzymes from each other. Results: Under normal conditions, CYP11B2 was sporadically detected in the zona glomerulosa, whereas CYP11B1 was entirely detected in the zonae fasciculata-reticularis. Adrenocortical cells lacking both enzymes were observed in the outer cortical regions. In addition to conventional zonation, we found a variegated zonation consisting of a subcapsular cell cluster expressing CYP11B2, which we termed aldosterone-producing cell cluster,andaCYP11B1- expressing area. Aldosterone-producing adenomas differed in cell populations expressing CYP11B2 from one another, whereas CYP11B1-expressing and double-negative cells were also intermingled. Adenomas from patients with Cushing's syndrome expressed CYP11B1 entirely but not CYP11B2, resulting in atrophic nontumor glands. The nontumor portions of both types of adenomas bore frequently one or more aldosterone-producing cell clusters, which sustained CYP11B2 expression markedly under the conditions of the suppressed renin-angiotensin system. Conclusion: Immunohistochemistry of the human normal adrenal cortex for CYP11B2 and CYP11B1 revealed a variegated zonation with cell clusters constitutively expressing CYP11B2. This technique may provide a pathological confirmatory diagnosis of adrenocortical adenomas.

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Adrenocortical Zonation in Humans under Normal and Pathological Conditions

Nishimoto Koshiro, Nakagawa Ken, Li Dan, Kosaka Takeo, Oya Mototsugu, Mikami Shuji, Shibata Hirotaka, Itoh Hiroshi, Mitani Fumiko, Yamazaki Takeshi, Ogishima Tadashi, Suematsu Makoto, Mukai Kuniaki

JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM 95 ( 5 ) 2296 - 2305 2010.05

Research paper (scientific journal), Joint Work, ISSN 0021-972X

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Evidence-based Sex-related Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma: Results of a Large Multicenter Study (vol 73, pg 142, 2009)

Fernandez Mario I., Shariat Shahrokh F., Margulis Vitaly, Bolenz Christian, Montorsi Francesco, Suardi Nazareno, Remzi Mesut, Wood Christopher G., Roscigno Marco, Kikuchi Eiji, Oya Mototsugu, Zigeuner Richard, Langner Cord, Weizer Alon, Lotan Yair, Koppie Theresa M., Raman Jay D., Karakiewicz Pierre, Bensalah Karim, Schultz Marcela, Bernier Pablo

UROLOGY 75 ( 5 ) 1243 - 1243 2010.05

Research paper (scientific journal), Joint Work, ISSN 0090-4295

Potent Cytotoxic Effect of a Novel Nuclear Factor-κB Inhibitor Dehydroxymethylepoxyquinomicin on Human Bladder Cancer Cells Producing Various Cytokines

Kodaira Kiichiro, Kikuchi Eiji, Kosugi Michio, Horiguchi Yutaka, Matsumoto Kazuhiro, Kanai Kunimitsu, Suzuki Eriko, Miyajima Akira, Nakagawa Ken, Tachibana Masaaki, Umezawa Kazuo, Oya Mototsugu

Urology 75 ( 4 ) 805 - 812 2010.04

ISSN 0090-4295

Objectives: To explore the potential therapeutic effects of the nuclear factor-κB (NF-κB) inhibitor dehydroxymethylepoxyquinomicin (DHMEQ). KU-19-19 cells, originally derived from a patient with invasive bladder cancer who exhibited marked leukocytosis, produce multiple cytokines. This model of clinically advanced bladder cancer, in which NF-κB is constitutively activated, was used in this study. Methods: Expression of p65 protein in fractionated KU-19-19 cells was determined by Western blotting analysis. DNA-binding activity of NF-κB was detected by electrophoretic mobility shift assay. The cytotoxic effects and induction of apoptosis by DHMEQ were analyzed, and cytokines in the supernatant of KU-19-19 cells cultured with or without DHMEQ were measured by enzyme-linked immunosorbent assay (ELISA). Athymic nude mice bearing KU-19-19 subcutaneous tumors were subjected to intraperitoneal administration of 2 mg/kg/d DHMEQ for 3 weeks. Tumor growth was monitored and microvessel density, vascular endothelial growth factor expression, and the apoptotic index of tumors were evaluated by tissue immunohistochemistry. Results: NF-κB was constitutively activated in KU-19-19 cells. DHMEQ reversibly inhibited the DNA-binding activity of NF-κB by blocking its nuclear translocation. Both cell viability and production of cytokines were significantly and dose-dependently suppressed by DHMEQ, and significant apoptosis was also induced. In in vivo studies, the mean tumor volume in mice treated with DHMEQ was significantly smaller than in controls. Immunohistochemical analysis of tumors revealed marked reduction in microvessel density, vascular endothelial growth factor expression, and induction of apoptosis. Conclusions: Blockade of NF-κB function by DHMEQ may be a useful new molecular targeting treatment for highly aggressive bladder cancer.

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Tumour Necrosis Is an Indicator of Aggressive Biology in Patients with Urothelial Carcinoma of the Upper Urinary Tract

Zigeuner Richard, Shariat Shahrokh F., Margulis Vitaly, Karakiewicz Pierre I., Roscigno Marco, Weizer Alon, Kikuchi Eiji, Remzi Mesut, Raman Jay D., Bolenz Christian, Bensalah Karim, Capitanio Umberto, Koppie Theresa M., Kassouf Wassim, Sircar, Kanishka, Patard, Jean-Jacques, Fernandez, Mario I., Wood Christopher G., Montorsi Francesco, Stroebel Philipp, Wheat Jeffery C., Haitel Andrea, Oya Mototsugu, Guo Charles C., Ng Casey, Chade Daher C., Sagalowsky Arthur, Langner Cord

EUROPEAN UROLOGY 57 ( 4 ) 575 - 581 2010.04

Research paper (scientific journal), Joint Work, ISSN 0302-2838

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Potent Cytotoxic Effect of a Novel Nuclear Factor-kappa B Inhibitor Dehydroxymethylepoxyquinomicin on Human Bladder Cancer Cells Producing Various Cytokines

Kodaira Kiichiro, Kikuchi Eiji, Kosugi Michio, Horiguchi Yutaka, Matsumoto Kazuhiro, Kanai Kunimitsu, Suzuki Eriko, Miyajima Akira, Nakagawa Ken, Tachibana Masaaki, Umezawa Kazuo, Oya Mototsugu

UROLOGY 75 ( 4 ) 805 - 812 2010.04

Research paper (scientific journal), Joint Work, ISSN 0090-4295

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Predicting the probability of significant prostate cancer in Japanese men with serum prostate-specific antigen less than 10 ng/mL

Ohigashi Takashi, Kanao Kent, Mizuno Ryuichi, Kikuchi Eiji, Nakashima June, Oya Mototsugu

International Journal of Urology 17 ( 3 ) 274 - 280 2010.03

ISSN 0919-8172

Objectives: To develop and assess a new nomogram incorporating pre-biopsy clinical data to predict significant prostate cancer in Japanese men with a serum prostate-specific antigen (PSA) level of less than 10 ng/mL. Methods: We collected pre-biopsy data from 620 men with a serum total PSA of less than 10 ng/mL. They included 491 men with a negative biopsy and 129 men who were confirmed to have histological prostate cancer and subsequently underwent radical prostatectomy. Clinically significant tumors were defined as those with a tumor volume larger than 0.5 mL and/or a Gleason score of 7 or more. Results: One hundred and seven prostatectomy patients had clinically significant cancers. Stepwise multivariate logistic regression analysis showed that digital rectal examination findings, PSA adjusted for transition zone volume and free-to-total PSA ratio were the significant independent predictors of significant cancers (P < 0.0001). Using these pre-biopsy independent factors, a nomogram was developed to predict significant cancers. According to a receiver operating characteristics analysis, the nomogram showed an area under the curve of 0.831. Conclusion: This represents the first nomogram to predict the probability of clinically significant cancers before biopsy. This tool is most likely to be useful in the management of patients with moderate to elevated PSA.

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Role of Pelvic Lymph Node Dissection in Lymph Node-Negative Patients with Invasive Bladder Cancer

Shirotake Suguru Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Kosaka Takeo, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

JAPANESE JOURNAL OF CLINICAL ONCOLOGY 40 ( 3 ) 247 - 251 2010.03

Research paper (scientific journal), Joint Work, ISSN 0368-2811

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Ets-1 and hypoxia inducible factor-1α inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer

Kosaka Takeo, Miyajima Akira, Shirotake Suguru, Kikuchi Eiji, Hasegawa Masanori, Mikami Shuji, Oya Mototsugu

Prostate 70 ( 2 ) 162 - 169 2010.02

ISSN 0270-4137

BACKGROUND. Accumulating evidences have suggested that the renin-angiotensin system (RAS) participates in the regulation of tumor angiogenesis. We previously demonstrated that hormone-refractory prostate cancer (HRPC) showed significantly higher angiotensin II (Ang II) type-1 receptor (AT1R) expression, and that the AT1R blocker (ARB) exerted protective effects by inhibiting angiogenesis. However, the downstream transcriptional factors induced by Ang II in prostate cancer cells have not been fully elucidated yet. METHODS. Three human prostate cancer cell lines: LNCap, C4-2 and C4-2AT6 were used and analyzed. C4-2AT6 cells were established by culture in androgen-ablated conditioned medium for 6 months. RESULTS. C4-2AT6 cells showed significantly higher AT1R expression, accompanied by higher HIF-1α and Ets-1 expression in the nucleus. In C4-2AT6 cells, VEGF production was significantly higher than in C4-2 cells and LNCaP cells. These results suggested that HRPC exhibited aggressive angiogenic properties, accompanied by up-regulated HIF-1α and Ets-1. Ang II stimulated VEGF production in C4-2 cells and C4-2AT6 cells but not in LNCaP cells. ARB significantly inhibited VEGF production. Western blot analysis demonstrated that AngII induced nuclear expression of HIF-1α and Ets-1 in C4-2 and C4-2AT6 cells, but not in LNCaP cells. ARB significantly inhibited HIF-1α and Ets-1 induction in C4-2 and C4-2AT6 cells. CONCLUSIONS. This study suggests that AT1R blockade may have a significant impact on HRPCthrough the inhibition of HIF-1α and Ets-1 and the resulting suppression of angiogenesis. Our results provide the molecular basis of the clinical benefit of ARB as an angiogenic inhibitor in HRPC.

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Prognostic stratification in patients who received hormonal therapy for prostate-specific antigen recurrence after radical prostatectomy

Ide Hiroki, Nakashima Jun, Kono Hidaka, Kikuchi Eiji, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 2 ) 177 - 180 2010.02

ISSN 0368-2811

The present study was undertaken to investigate the predictors in patients who received hormonal therapy (HT) for prostate-specific antigen recurrence (PSAR) after surgery. Predictors for the progression-free survival were assessed in 55 patients who received HT for PSAR after surgery. In multivariate analysis, primary Gleason grade ≥4 and PSA doubling time (PSA-DT) <6 months were independent predictors. The patients were stratified into low-risk group (Gleason grade <4 and PSA-DT ≥6), high-risk group (Gleason grade ≥4 and PSA-DT <6) and intermediate-risk group (all others). In the intermediate-and high-risk groups, progression-free survival rate was significantly higher in patients with PSA level <2 than in those with PSA level ≥2 at the initiation of HT. Primary Gleason grade ≥4 and PSA-DT <6 months are independent predictors. Patients in the intermediate-and high-risk groups may benefit from early HT for PSAR after surgery.

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Activation of the aryl hydrocarbon receptor pathway enhances cancer cell invasion by upregulating the MMP expression and is associated with poor prognosis in upper urinary tract urothelial cancer

Ishida Masaru, Mikami Shuji, Kikuchi Eiji, Kosaka Takeo, Miyajima Akira, Nakagawa Ken, Mukai Makio, Okada Yasunori, Oya Mototsugu

CARCINOGENESIS 31 ( 2 ) 287 - 295 2010.02

Research paper (scientific journal), Joint Work, ISSN 0143-3334

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Renal cell carcinoma

Oya Mototsugu

Gan to kagaku ryoho. Cancer & chemotherapy 37 ( 1 ) 29 - 31 2010.01

ISSN 0385-0684

Vitamin E succinate induced apoptosis and enhanced chemosensitivity to paclitaxel in human bladder cancer cells in vitro and in vivo

Kanai Kunimitsu, Kikuchi Eiji, Mikami Shuji, Suzuki Eriko, Uchida Yasumitsu, Kodaira Kiichiro, Miyajima Akira, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Cancer Science 101 ( 1 ) 216 - 223 2010.01

ISSN 1347-9032

There have been several studies on the antitumor activities of vitamin E succinate (α-TOS) as complementary and alternative medicine. In the present study, we investigated the cytotoxic effect of α-TOS and the enhancement of chemosensitivity to paclitaxel by α-TOS in bladder cancer. KU-19-19 and 5637 bladder cancer cell lines were cultured in α-TOS and/or paclitaxel in vitro. Cell viability, flow cytometric analysis, and nuclear factor-kappa B (NF-γB) activity were analyzed. For in vivo therapeutic experiments, pre-established KU-19-19 tumors were treated with α-TOS and/or paclitaxel. In KU-19-19 and 5637 cells, the combination treatment resulted in a significantly higher level of growth inhibition, and apoptosis was significantly induced by the combination treatment. NF-γB was activated by paclitaxel; however, the activation of NF-γB was inhibited by α-TOS. Also, the combination treatment significantly inhibited tumor growth in mice. In the immunostaining of the tumors, apoptosis was induced and proliferation was inhibited by the combination treatment. Combination treatment of α-TOS and paclitaxel showed promising anticancer effects in terms of inhibiting bladder cancer cell growth and viability in vitro and in vivo. One of the potential mechanisms by which the combination therapy has synergistic cytotoxic effects against bladder cancer may be that α-TOS inhibits NF-γB induced by chemotherapeutic agents.

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Clinical impact of bladder biopsies with TUR-BT according to cytology results in patients with bladder cancer

Matsushima Masashi, Kikuchi Eiji, Hasegawa Masanori, Matsumoto Kazuhiro, Miyajima Akira, Oya Mototsugu

BMC Urology 10 2010

ISSN 1471-2490

Background. There seems to be no consensus concerning taking bladder biopsies during transurethral resection of bladder tumor (TUR-BT). We investigate the clinical significance of bladder biopsy with TUR-BT and the relationship between urinary cytology and the biopsy results. Methods. We reviewed a total of 424 patients with non-muscle invasive bladder cancer treated with TUR-BT between 1998 and 2005. Of the total, 293 patients also underwent a bladder biopsy. Biopsies from suspicious-appearing urothelium (N = 59) and those from normal-appearing urothelium (N = 234) were evaluated separately. Results. Bladder cancer was observed in 23 cases (39.0%) who underwent a biopsy of suspicious-appearing urothelium. Among these 23 cases, 9 cases with visible tumor resection had carcinoma in situ (CIS) only in the biopsies from suspicious-appearing urothelium. Urinary cytology was negative in 3 of the 9 cases. Bladder cancer was observed in 26 cases (11.1%) who underwent a biopsy of normal-appearing urothelium. Of them, 5 cases with visible tumors had CIS only in the multiple biopsies from normal-appearing urothelium. Urinary cytology was positive in all of the 5 cases. No upstaging or upgrading cases were found in these patients by the addition of these two types of biopsy. Furthermore, therapy was not altered in these patients. With or without bladder biopsy was not a significant factor for tumor recurrence in either the univariate or multivariate analysis. Conclusions. Based on the results, it is concluded the multiple biopsies from normal-appearing urothelium are not necessary in patients with negative cytology results because of the low detection rate and lack of influence on therapeutic decisions. Meanwhile, biopsy of suspicious-appearing urothelium is needed in patients with negative cytology results in order to detect CIS due to staging properties. This result supports a recent EAU guideline.

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Ets-1 and hypoxia inducible factor-1alpha inhibition by angiotensin II type-1 receptor blockade in hormone-refractory prostate cancer

Kosaka T, Miyajima A, Shirotake S, Kikuchi E, Hasegawa M, Mikami S, Oya M

Prostate 70(2) 162 - 169 2010

Research paper (scientific journal), Joint Work

Initial experience of transumbilical laparoendoscopic single-site surgery of partial adrenalectomy in patient with aldosterone-producing adenoma

Yuge Kazuyuki, Miyajima Akira, Hasegawa Masanori, Miyazaki Yasumasa, Maeda Takahiro, Takeda Toshikazu, Takeda Ayano, Miyashita Kazutoshi, Kurihara Isao, Shibata Hirotaka, Kikuchi Eiji, Oya Mototsugu

BMC UROLOGY 10 527 - 532 2010

Research paper (scientific journal), Joint Work, ISSN 1471-2490

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Extraperitoneal approach induces postoperative inguinal hernia compared with transperitoneal approach after laparoscopic radical prostatectomy

Yoshimine Shunsuke, Miyajima Akira, Nakagawa Ken, Ide Hiroki, Kikuchi Eiji, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 4 ) 349 - 352 2009.12

ISSN 0368-2811

Objective: The aim of this study was to determine the incidence and risk factors of postoperative inguinal hernia and to investigate whether the difference of approach could induce postoperative inguinal hernia after laparoscopic radical prostatectomy. Methods: We reviewed 493 consecutive patients who underwent laparoscopic radical prostatectomy from November 2000 to November 2007, and evaluated various preoperative parameters, specifically age, prostate-specific antigen (ng/ml), body mass index (kg/m²), prostate volume (ml), previous major abdominal surgery, previous appendectomy, previous inguinal hernia repair and laparoscopic approach as risk factors for postoperative inguinal hernia. Results: Inguinal hernia occurred in 4 (4.9%) of the 81 patients in the transperitoneal approach group, and in 37 (9.0%) of the 412 patients in the extraperitoneal approach group. The overall incidence of inguinal hernia was 8.3% (41 of 493 patients). The median inguinal hernia-free survival time was 35 months and 6 months in the transperitoneal approach and extraperitoneal approach groups, respectively. Inguinal hernia developed within 2 years after surgery in 2 (50%) of 4 patients in the transperitoneal approach group, in 34 (91.9%) of 37 patients in the extraperitoneal approach group, for a total of 36 (87.8%) of 41 patients overall. Multivariate analysis showed that the extraperitoneal approach was a significant risk factor (P = 0.043) for inguinal hernia. Conclusions: Inguinal hernia is a frequent complication after laparoscopic radical prostatectomy, and the incidence of inguinal hernia is greater with the extraperitoneal approach than with the transperitoneal approach.

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Glycogen synthase kinase-3

Bilim V., Ougolkov A., Yuuki K., Naito S., Kawazoe H., Muto A., Oya M., Billadeau D., Motoyama T., Tomita Y.

British Journal of Cancer 101 ( 12 ) 2005 - 2014 2009.12

ISSN 0007-0920

Background: Renal cell carcinoma (RCC) is highly resistant to chemotherapy because of a high apoptotic threshold. Recent evidences suggest that GSK-3Β positively regulates human pancreatic cancer and leukaemia cell survival in part through regulation of nuclear factor (NF-B)-mediated expression of anti-apoptotic molecules. Our objectives were to determine the expression pattern of GSK-3Β and to assess the anti-cancer effect of GSK-3Β inhibition in RCC. Methods: Immunohistochemistry and nuclear/cytosolic fractionation were performed to determine the expression pattern of GSK-3Β in human RCCs. We used small molecule inhibitor, RNA interference, western blotting, quantitative RT-PCR, BrDU incorporation and MTS assays to study the effect of GSK-3Β inactivation on renal cancer cell proliferation and survival. Results: We detected aberrant nuclear accumulation of GSK-3Β in RCC cell lines and in 68 out of 74 (91.89%) human RCCs. We found that pharmacological inhibition of GSK-3 led to a decrease in proliferation and survival of renal cancer cells. We observed that inhibition of GSK-3 results in decreased expression of NF-B target genes Bcl-2 and XIAP and a subsequent increase in renal cancer cell apoptosis. Moreover, we show that GSK-3 inhibitor and Docetaxel synergistically suppress proliferation and survival of renal cancer cells. Conclusions: Our results show nuclear accumulation of GSK-3Β as a new marker of human RCC, identify that GSK-3 positively regulates RCC cell survival and proliferation and suggest inhibition of GSK-3 as a new promising approach in the treatment of human renal cancer.

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Phosphatidylinositol-3-Kinase/Akt Signaling Pathway and Kidney Cancer, and the Therapeutic Potential of Phosphatidylinositol-3-Kinase/Akt Inhibitors EDITORIAL COMMENT

Oya Mototsugu

JOURNAL OF UROLOGY 182 ( 6 ) 2577 - 2577 2009.12

Research paper (scientific journal), Single Work, ISSN 0022-5347

Primary intratesticular leiomyosarcoma

Yoshimine Shunsuke, Kono Hidaka, Nakagawa Ken, Kikuchi Eiji, Miyajima Akira, Kameyama Kaori, Mukai Makio, Oya Mototsugu

Journal of the Canadian Urological Association 3 ( 6 ) 2009.12

ISSN 1911-6470

This report presents a case of primary intratesticular leiomyosarcoma. A 73-year-old male presented with a 6-year history of left scrotal swelling. A radiological examination revealed a left testicular tumour with multiple metastases in the lung, para-aortic lymph node and other organs. A radical orchiectomy was carried out and the pathology revealed an intratesticular leiomyosarcoma. The patient received additional chemotherapy. Cases of primary intratesticular leiomyosarcoma are rare. This is, to the best of our knowledge, only the tenth case of leiomyisaocoma in an adult reported in the literature, and the first case involving multiple metastases.

Editorial Comment

Oya Mototsugu

Journal of Urology (Journal of Urology) 182 ( 6 ) 2577 - 1000 2009.12

Research paper (scientific journal), Joint Work, ISSN 0022-5347

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Prediction of PSA bounce after permanent prostate brachytherapy for localized prostate cancer

Kanai Kunimitsu, Nakashima Jun, Sugawara Akitomo, Shigematsu Naoyuki, Nagata Hirohiko, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Kubo Atsushi, Oya Mototsugu

International Journal of Clinical Oncology 14 ( 6 ) 502 - 506 2009.12

ISSN 1341-9625

Background: We aimed to calculate the frequency and features of the development of a prostate-specific antigen (PSA) bounce after prostate brachytherapy alone, to correlate the bounce with clinical and dosimetric factors and to identify factors that predict PSA bounce. Methods: PSA bounce was evaluated in 86 patients with T1-T2 prostate cancer who underwent radioactive seed implantation using iodine-125 (I-125) without hormonal therapy or external-beam radiation therapy (EBRT) from September 2004 to December 2007. A PSA bounce was defined as a rise of at least 0.4 ng/ml greater than a previous PSA level with a subsequent decline equal to, or less than, the initial nadir. Results: Calculated by the Kaplan-Meier method, the incidence of PSA bounce at a 2-year follow-up was 26%. Median time to the PSA bounce was 15 months. Univariate analysis demonstrated that age, dose received by 90% of the prostate gland (D90), volume of gland receiving 100% of the prescribed dose (V100), and V150 were significantly associated with the PSA bounce, while pretreatment PSA level, Gleason score, pretreatment prostate volume, clinical T stage, and V200 were not. In multivariate analysis, age 67 years or less and D90 more than 180 Gy were identified as independent factors for predicting the PSA bounce (P < 0.05). Conclusion: PSA bounce is not a rare phenomenon after prostate brachytherapy. It is more common in younger patients and patients receiving higher doses of radiation.

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Are predictive models for cancer volume clinically useful in localized prostate cancer?

Ishida Masaru, Nakashima Jun, Hashiguchi Akinori, Mizuno Ryuichi, Shinoda Kazunobu, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Mukai Makio, Oya Mototsugu

International Journal of Urology 16 ( 12 ) 936 - 940 2009.12

ISSN 0919-8172

Objectives:To evaluate the correlation between preoperatively predicted and pathologically measured prostate cancer volumes and to investigate the clinical use of preoperatively predicted cancer volume in predicting pathological stage. Methods:Correlations between pathological findings and various preoperative parameters, including the cancer volumes as predicted by using two methods (Vca and estimated PCvol), were analyzed in 196 patients who underwent radical prostatectomy for clinically localized prostate cancer. Results:Pathologically measured prostate cancer volume was significantly correlated with the Vca and estimated PCvol, but the correlation coefficients were respectively only 0.46 and 0.35. Prostate-specific antigen (PSA), PSA density (PSAD), primary Gleason score, Vca, Vca fraction (Vcafx), and estimated PCvol were significantly higher in 82 patients with extraprostatic cancer than in 114 patients with organ-confined cancer. Magnetic resonance imaging (MRI) findings were significantly correlated with pathological stage. Multivariate logistic regression analysis indicated that the Vcafx and MRI findings were significant predictors of extraprostatic cancer, but receiver operating characteristic analysis revealed that the combination of Vcafx and MRI findings had no advantage over the combination of Gleason score, PSAD, and MRI findings. Conclusions:Vca and estimated PCvol are significantly correlated with the pathologically measured cancer volume but their ability to accurately predict cancer volume is limited. Vcafx and MRI findings were statistically significant predictors of extraprostatic cancer but their combination was not superior to the combination of Gleason score, PSAD, and MRI findings.

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Role of pelvic lymph node dissection in lymph node-negative patients with invasive bladder cancer

Shirotake Suguru, Kikuchi Eiji, Matsumoto Kazuhiro, Yazawa Satoshi, Kosaka Takeo, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 3 ) 247 - 251 2009.11

ISSN 0368-2811

Objectives: The role of pelvic lymphadenectomy in patients with lymph node-negative bladder cancer at radical cystectomy (RC) has not yet been examined in detail. We retrospectively reviewed patients who underwent RC with pelvic lymphadenectomy for bladder cancer from January 1987 to March 2008. Methods: We identified consecutive data on 169 patients who underwent RC for bladder cancer. The mean follow-up was 64 months (range: 1-253 months). Node-positive status (pN(+)) was seen in 16 patients and 91 were diagnosed as node-negative (pN(-)). The lymph node status of the remaining 62 patients was unclear (pN(x)). We analysed the association between lymph node status and cancer-specific survival (CSS), and examined the role of the number of retrieved lymph nodes, particularly in pN(-). Results: The median number of retrieved nodes was 12.9 and 10.2 for stage pN(+) and stage pN(-), respectively. In 91 patients with pN(-), multivariate analysis revealed that pathological T3-4 (P = 0.0276) and less than nine retrieved lymph nodes (P = 0.0108) were independent risk factors for CSS. In a subgroup of 83 patients with pT3-4, Kaplan-Meier curves showed that the 5-year CSS rate in pN(-) patients with less than nine retrieved lymph nodes was 38.8%, which was extremely similar to the 40.8% in pN(+) and 45.1% in pN(x). Conclusions: Our results demonstrate that at least nine lymph nodes should be removed to improve the survival of pN(-) patients at RC and lymphadenectomy, and would provide information not only on prognosis but also on the therapeutic impact on pT3-4 invasive bladder cancer.

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Tumour length of the largest focus predicts prostate-specific antigen-based recurrence after radical prostatectomy in clinically localized prostate cancer

Mizuno Ryuichi, Nakashima Jun, Mukai Makio, Okita Hajime, Kosugi Michio, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Oya Mototsugu

BJU INTERNATIONAL 104 ( 9 ) 1215 - 1218 2009.11

Research paper (scientific journal), Joint Work, ISSN 1464-4096

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Docetaxel in combination with prednisolone for hormone refractory prostate cancer

Ide Hiroki, Kikuchi Eiji, Kono Hidaka, Nagata Hirohiko, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Japanese Journal of Clinical Oncology 40 ( 1 ) 2009.10

ISSN 0368-2811

Objective: The objective of this study was to evaluate the efficacy and toxicity of docetaxel in combination with prednisolone in Japanese patients with hormone refractory prostate cancer. Methods: Twenty patients with hormone refractory prostate cancer (HRPC) were administered a treatment regimen consisting of docetaxel 75 mg/m² once every 3 or 4 weeks and prednisolone 5 mg twice daily at our institution between 2006 and 2008. Results: The patients received a median of 5.5 cycles of treatment (range, 2-12 cycles). Nine of the 20 patients (45%) had a ≥50% decrease in serum prostate-specific antigen (PSA). The median duration of response was 4 months (range, 1-11 months). The number of cycles performed, the presence of bone metastasis and the extent of disease had statistically significant associations with the response. Three patients had a transient PSA rise among the patients who ultimately had a response. Grade 3/4 leukopenia and neutropenia occurred in 80.0% and 85.0% of the patients, respectively. Interstitial pneumonia occurred in only one patient; however, the patient recovered. Finally, no treatment-related deaths were seen during the observation period. Conclusions: The combination of docetaxel 75 mg/m² every 3 weeks and prednisolone 10 mg daily was effective and well tolerated in Japanese patients with HRPC. The results of this study suggest that a decision concerning discontinuation of this treatment should be carefully considered because a transient PSA rise was observed. Although interstitial pneumonia was rare, the potential risk of its development should be taken into consideration.

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Renal Damage Inhibited in Mice Lacking Angiotensinogen Gene Subjected to Unilateral Ureteral Obstruction

Uchida Yasumitsu, Miyajima Akira, Kikuchi Eiji, Kozakai Norihide, Kosaka Takeo, Ieda Masaki, Fukuda Keiichi, Ohigashi Takashi, Oya Mototsugu

Urology 74 ( 4 ) 938 - 943 2009.10

ISSN 0090-4295

Objectives: To determine how angiotensin II (Ang II) contributes to renal interstitial fibrosis, the inflammatory response, and tubular cell apoptosis and proliferation in unilateral ureteral obstruction using mice genetically deficient in angiotensinogen (Agt^-/-). Methods: The left kidney of wild-type mice (WT; C57BL/6) and Agt^-/- mice was obstructed for 2 weeks, and then both kidneys were harvested. The serum Ang II levels were determined by radioimmunoassay. The expression of transforming growth factor-β in renal tissue was assessed using enzyme-linked immunosorbent assay. The renal tissue was stained with Masson's trichrome. Renal tubular proliferation and apoptosis was detected by immunostaining for proliferating cell nuclear antigen and single-stranded DNA, respectively. Interstitial leukocyte and macrophage infiltration was investigated by immunostaining for CD45 and F4/80, respectively. Results: The serum Ang II levels in the Agt^-/- mice were significantly lower than those in the WT mice (P < .01), and tissue transforming growth factor-β in the obstructed kidney of Agt^-/- mice was significantly lower than that in WT mice (P < .05). Interstitial collagen deposition was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01). Tubular proliferation was significantly greater and tubular apoptosis was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). Interstitial infiltration by leukocytes and macrophages was significantly lower in the Agt^-/- obstructed kidneys than in the WT obstructed kidneys (P < .01 and P < .01, respectively). Conclusions: The results of the present study support the targeting of Ang II as a reasonable approach by which to prevent renal tissue damage in unilateral ureteral obstruction.

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Adjuvant Chemotherapy for High Risk Upper Tract Urothelial Carcinoma

Hellenthal Nicholas J., Shariat Shahrokh F., Margulis Vitaly, Karakiewicz Pierre I., Roscigno Marco, Bolenz Christian, Remzi Mesut, Weizer Alon, Zigeuner Richard, Bensalah Karim, Ng Casey K., Raman Jay D., Kikuchi Eiji, Montorsi Francesco, Oya Mototsugu, Wood Christopher G., Fernandez Mario, Evans Christopher P., Koppie Theresa M.

Journal of Urology 182 ( 3 ) 900 - 906 2009.09

ISSN 0022-5347

Purpose: There is relatively little literature on adjuvant chemotherapy after radical nephroureterectomy in patients with upper tract urothelial carcinoma. We determined the incidence of adjuvant chemotherapy in high risk patients and the ensuing effect on overall and cancer specific survival. Materials and Methods: Using an international collaborative database we identified 1,390 patients who underwent nephroureterectomy for nonmetastatic upper tract urothelial carcinoma between 1992 and 2006. Of these cases 542 (39%) were classified as high risk (pT3N0, pT4N0 and/or lymph node positive). These patients were divided into 2 groups, including those who did and did not receive adjuvant chemotherapy, and stratified by gender, age group, performance status, and tumor grade and stage. Cox proportional hazard modeling and Kaplan-Meier analysis were used to determine overall and cancer specific survival in the cohorts. Results: Of high risk patients 121 (22%) received adjuvant chemotherapy. Adjuvant chemotherapy was more commonly administered in the context of increased tumor grade and stage (p <0.001). Median survival in the entire cohort was 24 months (range 0 to 231). There was no significant difference in overall or cancer specific survival between patients who did and did not receive adjuvant chemotherapy. However, age, performance status, and tumor grade and stage were significant predictors of overall and cancer specific survival. Conclusions: Adjuvant chemotherapy is infrequently used to treat high risk upper tract urothelial carcinoma after nephroureterectomy. Despite this finding it appears that adjuvant chemotherapy confers minimal impact on overall or cancer specific survival in this group.

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Increased RANKL expression is related to tumour migration and metastasis of renal cell carcinomas

Mikami Shuji, Katsube Ken Ichi, Oya Mototsugu, Ishida Masaru, Kosaka Takeo, Mizuno Ryuichi, Mochizuki Satsuki, Ikeda Tohru, Mukai Makio, Okada Yasunori

Journal of Pathology 218 ( 4 ) 530 - 539 2009.08

ISSN 0022-3417

Receptor activator of NF-κB ligand (RANKL) and its receptor, receptor activator of NF-κB (RANK), play a key role in osteoclastogenesis, and osteoprotegerin (OPG) acts as a decoy receptor for RANKL. We investigated the role of the RANKL-RANK-OPG system in renal cell carcinomas (RCCs), which frequently metastasize to bones. Real-time quantitative PCR revealed that RANKL mRNA expression was higher in clear cell RCCs than in papillary and chromophobe RCCs. Similarly, RANKL protein expression level in clear cell RCCs was higher than that in papillary and chromophobe RCCs, showing positive correlations with the primary tumour stage and distant metastasis. There was no significant association between the expression level of RANK, OPG and histological subtypes of RCC. RANKL and RANK expression was observed in metastatic RCCs in the bone and other organs, suggesting that they play a role in metastasis to the bone and other organs. Recombinant RANKL protein stimulated migration of a clear cell RCC cell line, Caki-1, in vitro, and this enhanced migration was inhibited by the administration of recombinant OPG protein. Furthermore, multivariate Cox analysis revealed that elevated RANKL and RANK expression with low-OPG expression was a significant and independent predictor of recurrence, bone metastasis and a poor prognosis. These data suggest that the RANKL-RANK-OPG system is involved not only in the bone metastasis of RCCs but also in metastasis to other organs through the stimulation of cancer cell migration.

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Comparison of Oncologic Outcomes for Open and Laparoscopic Nephroureterectomy

Capitanio Umberto, Shariat Shahrokh F., Isbarn Hendrik, Weizer Alon, Remzi Mesut, Roscigno Marco, Kikuchi Eiji, Raman Jay D., Bolenz Christian, Bensalah Karim, Koppie Theresa M., Kassouf Wassim, Fernández Mario I., Ströbel Philipp, Wheat Jeffrey, Zigeuner Richard, Langner Cord, Waldert Matthias, Oya Mototsugu, Guo Charles C., Ng Casey, Montorsi Francesco, Wood Christopher G., Margulis Vitaly, Karakiewicz Pierre I.

European Urology 56 ( 1 ) 1 - 9 2009.07

ISSN 0302-2838

Background: Data regarding the oncologic efficacy of laparoscopic nephroureterectomy (LNU) compared to open nephroureterectomy (ONU) are scarce. Objective: We compared recurrence and cause-specific mortality rates of ONU and LNU. Design, setting, and participants: Thirteen centers from three continents contributed data on 1249 patients with nonmetastatic upper tract urothelial carcinoma (UTUC). Measurements: Univariable and multivariable survival models tested the effect of procedure type (ONU [n = 979] vs LNU [n = 270]) on cancer recurrence and cancer-specific mortality. Covariables consisted of institution, age, Eastern Cooperative Oncology Group (ECOG) performance status score, pT stage, pN stage, tumor grade, lymphovascular invasion, tumor location, concomitant carcinoma in situ, ureteral cuff management, previous urothelial bladder cancer, and previous endoscopic treatment. Results and limitations: Median follow-up for censored cases was 49 mo (mean: 62). Relative to ONU, LNU patients had more favorable pathologic stages (pT0/Ta/Tis: 38.1% vs 20.8%, p < 0.001) and less lymphovascular invasion (14.8% vs 21.3%, p = 0.02) and less frequently had tumors located in the ureter (64.5 vs 71.1%, p = 0.04). In univariable recurrence and cancer-specific mortality models, ONU was associated with higher cancer recurrence and mortality rates compared to LNU (hazard ratio [HR]: 2.1 [p < 0.001] and 2.0 [p = 0.008], respectively). After adjustment for all covariates, ONU and LNU had no residual effect on cancer recurrence and mortality (p = 0.1 for both). Conclusions: Short-term oncologic data on LNU are comparable to ONU. Since LNU was selectively performed in favorable-risk patients, we cannot state with certainty that ONU and LNU have the same oncologic efficacy in poor-risk patients. Long-term follow-up data and morbidity data are necessary before LNU can be considered as the standard of care in patients with muscle-invasive or high-grade UTUC.

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Discontinuance of Bacille Calmette-Guérin Instillation Therapy for Nonmuscle-invasive Bladder Cancer Has Negative Effect on Tumor Recurrence

Takeda Toshikazu, Kikuchi Eiji, Yuge Kazuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

Urology 73 ( 6 ) 1318 - 1322 2009.06

ISSN 0090-4295

Objectives: To investigate whether the occurrence of side effects or discontinuance of bacille Calmette-Guérin (BCG) therapy because of side effects is associated with its therapeutic efficacy. Methods: We analyzed the data from 145 patients who had had nonmuscle-invasive bladder cancer (Stage pTa, pT1, or pTis) and had undergone an initial course of adjuvant BCG therapy after transurethral resection of bladder tumor from 1996 and 2006 at Keio University Hospital. Side effects were classified as minor and major, and the association between the occurrence of side effects or discontinuance of BCG therapy because of side effects and tumor recurrence or progression was analyzed. Results: Side effects occurred in 106 patients (73.1%) during BCG instillation. Of these 106 patients, 38 had major side effects and 95 had minor; 27 patients had both. BCG therapy was discontinued in 19 patients (13.1%) because of severe hematuria in 2, high fever in 8, and severe lower urinary tract symptoms in 9. Multivariate analyses demonstrated that discontinuance of BCG therapy (P = .018) was an independent predictor for tumor recurrence, in addition to multiplicity (P = .043). However, the occurrence of side effects was not an independent predictor for tumor recurrence (P = .935). Multivariate analyses also demonstrated that neither discontinuance of BCG therapy (P = .308) nor the occurrence of side effects (P = .333) was an independent predictor for tumor progression. Conclusions: Discontinuation of BCG therapy has a significantly deleterious effect on reducing the incidence of tumor recurrence. When major side effects occur, it might be preferable to attempt to mitigate the major side effects to maintain the BCG therapy on schedule.

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Discontinuance of Bacille Calmette-Guerin Instillation Therapy for Nonmuscle-invasive Bladder Cancer Has Negative Effect on Tumor Recurrence

Takeda Toshikazu, Kikuchi Eiji, Yuge Kazuyuki, Matsumoto Kazuhiro, Miyajima Akira, Nakagawa Ken, Oya Mototsugu

UROLOGY 73 ( 6 ) 1318 - 1322 2009.06

Research paper (scientific journal), Joint Work, ISSN 0090-4295

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Brain metastasis of a papillary renal cell carcinoma, identified as type 2

Hasegawa Masanori, Kikuchi Eiji, Yasumizu Yota, Hattori Seiya, Takeda Toshikazu, Morita Shinya, Kosaka Takeo, Miyajima Akira, Horiguchi Takashi, Mikami Shuji, Oya Mototsugu

International Journal of Clinical Oncology 14 ( 3 ) 270 - 272 2009.06

ISSN 1341-9625

Papillary renal cell carcinomas (PRCCs) tend to metastasize to lymph nodes, while metastasis to the brain is extremely rare. We report the case of a man who had a brain metastasis of PRCC type 2. He was brought to our hospital due to the sudden onset of convulsions. Diagnostic imaging studies showed a metastatic brain tumor in the left parietal lobe, and a primary renal tumor in the right kidney, with paraaortal lymph node metastases. An excision of brain tumor was performed. The brain tumor had a papillary structure with eosinophilic cytoplasm. Five weeks later nephrectomy was carried out. Histological analysis of the nephrectomy specimen revealed the same papillary structure, which was compatible with PRCC type 2.

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PROGNOSTIC SIGNIFICANCE OF SNAIL EXPRESSION IN PATIENTS WITH UPPER URINARY TRACT UROTHELIAL CARCINOMA (UUT-UC)

Kosaka Takeo, Kikuchi Eiji, Mikami Shuji, Miyajima Akira, Ishida Masaru, Nakagawa Ken, Oya Mototsugu

JOURNAL OF UROLOGY 181 ( 4 ) 69 - 69 2009.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Angiotensin II Type 1 Receptor Antagonist Enhances Cis-dichlorodiammineplatinum-Induced Cytotoxicity in Mouse Xenograft Model of Bladder Cancer

Kosugi Michio, Miyajima Akira, Kikuchi Eiji, Kosaka Takeo, Horiguchi Yutaka, Murai Masaru, Oya Mototsugu

Urology 73 ( 3 ) 655 - 660 2009.03

ISSN 0090-4295

Objectives: To examine whether candesartan enhances the cytotoxicity of cis-dichlorodiammineplatinum (CDDP) in mice with bladder cancer as a method to enhance the therapeutic effects of CDDP. CDDP is an antitumor agent conventionally used against bladder cancer; however, its therapeutic efficacy appears to not be fully satisfactory. Recent studies have shown the antitumor activity of the angiotensin II type 1 receptor antagonist candesartan. Methods: A xenograft model was prepared in nude mice using human bladder cancer cells (KU-19-19). Candesartan (1 mg/kg/d) was administered daily by oral gavage from the day of implantation plus 28 days, and CDDP (1 mg/kg/d) was administered intraperitoneally from days 5 to 9. The microvessel density, vascular endothelial growth factor expression, and apoptosis were investigated immunohistochemically. Results: Candesartan, CDDP, and candesartan-CDDP suppressed tumor growth to 41.9%, 33.8%, and 13.2%, respectively, of the tumor volume in the control group, showing that combined treatment significantly inhibited tumor growth compared with each single agent alone. The microvessel density was significantly decreased in the candesartan and candesartan-CDDP groups compared with the control group. Vascular endothelial growth factor expression was significantly decreased in the candesartan, CDDP, and candesartan-CDDP groups compared with the control group. The apoptotic index was significantly increased in the CDDP and candesartan-CDDP groups compared with the control and candesartan groups. Conclusions: It is quite likely that candesartan and CDDP suppressed tumor growth by inhibiting angiogenesis and inducing apoptosis, respectively. Furthermore, combined treatment with candesartan enhanced CDDP-induced cytotoxicity by further suppressing angiogenesis. These results suggest that candesartan could be a candidate for innovational therapy of bladder cancer.

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Renal cell carcinoma

Oya Mototsugu

Keio Journal of Medicine 58 ( 1 ) 1 - 11 2009.03

ISSN 0022-9717

Cancer cells are characterized by indefinite proliferation, invasiveness and metastases. These characteristics are usually related to one another. Namely, cancer cells that proliferate rapidly tend to invade and metastasize. Renal cell carcinoma (RCC) typically does not proliferate rapidly nor does it invade the surrounding tissues, but it does metastasize. RCC has several peculiar characteristics that are not observed in other cancers: a relatively late recurrence, a high frequency of paraneoplastic syndrome, hypervascularity and the spontaneous regression of metastatic lesions after the excision of the primary tumor. These clinical observations suggest that cytokines or growth factors are important contributors to microenvironments favoring the growth of cancer cells. Thus, the blockade of cell-to-cell communication might have some therapeutic potential. Accordingly, a popular strategy for molecular-targeted therapy for RCC targets the vasculization of RCC induced by vascular endothelial growth factor (VEGF). This review highlights the biological features of RCC that are relevant to molecular-targeted therapy.

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Clinical outcome of tumor recurrence for Ta, T1 non-muscle invasive bladder cancer from the data on registered bladder cancer patients in Japan

Kikuchi Eiji, Fujimoto Hiroyuki, Mizutani Yoichi, Okajima Eijiro, Koga Hiroshi, Hinotsu Shiro, Shinohara Nobuo, Oya Mototsugu, Miki Tsuneharu

International Journal of Urology 16 ( 3 ) 279 - 286 2009.03

ISSN 0919-8172

Objective: To characterize the clinical outcome in a large contemporary series of Japanese patients with newly diagnosed Ta, T1 non-muscle invasive bladder cancer who underwent transurethral bladder tumor resection with or without intravesical chemotherapy or Bacillus Calmette-Guérin (BCG) therapy. Methods: We developed a database incorporating newly diagnosed non-muscle invasive bladder cancer data and outcomes from a Japanese bladder cancer registry between 1999 and 2001 and identified a study population of 3237 consecutive patients who had complete data based on pathological features. Median patient age was 69.9 years. Results: The 1-year, 3-year, and 5-year overall recurrence-free survival rates were 77.0%, 61.3%, and 52.8%, respectively. In multivariate analyses, the multiplicity of bladder tumors, tumor size greater than 3 cm, pathological stage T1, tumor grade G3, and the absence of adjuvant intravesical instillation were independent risk factors for tumor recurrence. Overall, 1710 patients (52.8%) received intravesical instillation; chemotherapy in 1314 (76.8%) and BCG treatment in 396 (23.2%). In patients treated with intravesical chemotherapy in which an anthracycline chemo-agent was used in 90.5% of the cases, multivariate analyses demonstrated that male gender, multiple bladder tumors, a tumor size greater than 3 cm, and pathological stage T1 were associated with tumor recurrence. Conclusions: The accumulation and analysis of data from the Japanese National Bladder Cancer Registry made it possible to determine the clinical characteristics, management trends, and survival rates for the period studied. Further study with a dataset created from longer follow-up data would be warranted to analyze tumor progression and disease survival.

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Lymphovascular invasion predicts clinical outcomes in patients with node-negative upper tract urothelial carcinoma

Kikuchi Eiji, Margulis Vitaly, Karakiewicz Pierre I., Roscigno Marco, Mikami Shuji, Lotan Yair, Remzi Mesut, Bolenz Christian, Langner Cord, Weizer Alon, Montorsi Francesco, Bensalah Karim, Koppie Theresa M., Fernández Mario I., Raman Jay D., Kassouf Wassim, Wood Christopher G., Suardi Nazareno, Oya Mototsugu, Shariat Shahrokh F.

Journal of Clinical Oncology 27 ( 4 ) 612 - 618 2009.02

ISSN 0732-183X

Purpose: To assess the association of lymphovascular invasion (LVI) with cancer recurrence and survival in a large international series of patients treated with radical nephroureterectomy (RNU) for upper urinary tract urothelial carcinoma (UTUC). Patients and Methods: Data were collected on 1,453 patients treated with RNU at 13 academic centers and combined into a relational database. Pathologic slides were rereviewed by genitourinary pathologists according to strict criteria. LVI was defined as presence of tumor cells within an endothelium-lined space. Results: LVI was observed in 349 patients (24%). Proportion of LVI increased with advancing tumor stage, high tumor grade, presence of tumor necrosis, sessile tumor architecture, and presence of lymph node metastasis (all P < .001). LVI was an independent predictor of disease recurrence and survival (P < .001 for both). Addition of LVI to the base model (comprising pathologic stage, grade, and lymph node status) marginally improved its predictive accuracy for both disease recurrence and survival (1.1%, P = .03; and 1.7%, P < .001, respectively). In patients with negative lymph nodes and those in whom a lymphadenectomy was not performed (n = 1,313), addition of LVI to the base model improved the predictive accuracy of the base model for both disease recurrence and survival by 3% (P < .001 for both). In contrast, LVI was not associated with disease recurrence or survival in node-positive patients (n = 140). Conclusion: LVI was an independent predictor of clinical outcomes in nonmetastatic patients who underwent RNU for UTUC. Assessment of LVI may help identify patients who could benefit from multimodal therapy after RNU. After confirmation, LVI should be included in staging of UTUC.

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Preoperative Prognostic Nomogram (Probability Table) for Renal Cell Carcinoma Based on TNM Classification

Kanao Kent, Mizuno Ryuichi, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Journal of Urology 181 ( 2 ) 480 - 485 2009.02

ISSN 0022-5347

Purpose: Recently several prognostic nomograms have been developed to predict the prognosis of malignant diseases, including renal cell carcinoma. However, to our knowledge a preoperative prognostic nomogram that predicts survival in patients with renal cell carcinoma is not available. We developed a preoperative nomogram based on the TNM classification that predicts cause specific survival in patients with renal cell carcinoma. Materials and Methods: A total of 545 patients with renal cell carcinoma, including metastatic disease, who underwent radical nephrectomy or nephron sparing surgery at our institution were included in the study. Cases were staged according to the 2002 UICC TNM system, 6th edition. T, N and M factors were used as prognostic factors and a Cox proportional hazards regression model was developed to predict cause specific survival. A nomogram to predict cause specific survival was developed by repeating the analysis on 200 bootstrap samples. To validate the nomogram a concordance index was estimated and calibration was also examined by plotting the predictions made by the nomogram. Results: Overall 1, 3 and 5-year patient survival was 95.2%, 92.0% and 89.9%, respectively. T, N and M factors were significant prognostic factors in the Cox proportional hazards regression model. Using the combined TNM factors we developed a nomogram predicting 1, 3 and 5-year cause specific survival rates. The nomogram had excellent ability to discriminate, as evidenced by a concordance index of 0.81, and it was generally well calibrated. Conclusions: The preoperative information shown by this nomogram may be important for obtaining informed consent from patients with renal cell carcinoma who have indications for surgery.

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Evidence-based Sex-related Outcomes After Radical Nephroureterectomy for Upper Tract Urothelial Carcinoma

Fernández Mario I., Shariat Shahrokh F., Margulis Vitaly, Bolenz Christian, Montorsi Francesco, Suardi Nazareno, Remzi Mesut, Wood Christopher G., Roscigno Marco, Kikuchi Eiji, Oya Mototsugu, Zigeuner Richard, Langner Cord, Weizer Alon, Lotan Yair, Koppie Theresa M., Raman Jay D., Karakiewizc Pierre, Bensalah Karim, Schultz Marcela, Bernier Pablo

Urology 73 ( 1 ) 142 - 146 2009.01

ISSN 0090-4295

Objectives: To assess the sex differences in the clinical and pathologic characteristics of upper tract urothelial carcinoma (UTUC) and to determine the effect on prognosis after radical nephroureterectomy (RNU) in a large multicenter series. Methods: The records of 1363 patients who had undergone RNU were reviewed from the UTUC Collaboration database. The median follow-up was 47 months (range 0-250). The pathologic slides were re-evaluated by genitourinary pathologists unaware of the original findings from the slides and the clinical outcomes. The endpoints were freedom from tumor recurrence and disease-specific survival. Results: The male-to-female ratio was 2.1:1. The women were older than the men at diagnosis (70 ± 11 vs 68 ± 11 years; P < .001). No significant sex-related differences were found in the presence of symptoms at presentation (P = .70), pathologic stage (P = .98), tumor grade (P = .28), tumor architecture (P = .27), presence of lymphovascular invasion (P = .42), presence of concomitant carcinoma in situ (P = .08), or the presence of lymph node metastases (P = .24). Recurrence developed in 379 patients (28%), and 313 patients (23%) died of their disease. Sex was not associated with disease recurrence (P = .07) or disease-specific survival (P = .13). An adjustment for the effects of the pathologic features did not change the lack of association of sex with the clinical outcomes. Conclusions: To our knowledge, this is the largest series analyzing the effect of sex on the outcomes after RNU. No difference was found in the clinicopathologic features or prognosis between women and men treated with RNU for UTUC. The results of this large, international series show that RNU provides durable local control and disease-specific survival for both men and women with UTUC.

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Angiotensin II type 1 receptor antagonist as an angiogenic inhibitor in urogenital cancer

Miyajima Akira, Kikuchi Eiji, Kosaka Takeo, Oya Mototsugu

Reviews on Recent Clinical Trials 4 ( 2 ) 75 - 78 2009

ISSN 1574-8871

The potential for angiotensin II (AII) to promote tumor growth has been suspected based on its known hormonal actions and its vasoconstrictor effect. It has been suggested that angiotensin-converting enzyme (ACE) inhibitors may offer protection against cancer and may prevent carcinogenesis. Several studies report that AII can induce neovascularization in experimental systems by way of the AII type 1 receptor (AT1R). AT1R is also frequently expressed in such human tumors as skin cancer, renal cell carcinoma, and breast cancer. A growing number of recent studies focusing on treatment with an AT1R antagonist have demonstrated that angiotensin receptor blockade (ARB) appears to inhibit not only the growth of cancer cells but also tumor angiogenesis. We describe here the effects of AT1R blockade that implicate tumor angiogenesis in urogenital cancer since ARB may be an alternative modality for anti-cancer treatment.

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The checkpoints for the diagnosis of renal neoplasms

Jinzaki Masahiro, Oya Mototsugu

Japanese Journal of Clinical Urology 63 ( 9 ) 671 - 678 2009

ISSN 0385-2393

Gemcitabine and paclitaxel chemotherapy for advanced urothelial carcinoma in patients who have received prior cisplatin-based chemotherapy

Kanai Kunimitsu, Kikuchi Eiji, Ohigashi Takashi, Miyajima Akira, Nakagawa Ken, Nakashima Jun, Oya Mototsugu

International Journal of Clinical Oncology 13 ( 6 ) 510 - 514 2008.12

ISSN 1341-9625

Background. The objective of this study was to evaluate the efficacy and toxicity of combination chemotherapy with gemcitabine and paclitaxel as a second-line regimen in patients with advanced urothelial carcinoma. Methods. Twenty patients with advanced urothelial carcinoma who were resistant to an M-VAC (methotrexate, vinblastine, doxorubicin, and cisplatin) chemotherapy regimen were administered chemotherapy consisting of intravenous gemcitabine 2500 mg/m² and paclitaxel 150 mg/m² (GP) every 2 or 3 weeks. Results. The patients received a median of 7.7 cycles of treatment (range, 2-20 cycles). Six of the 20 patients (30%; 95% confidence interval [CI], 10%-50%) had a major response to treatment (a complete response [CR] in 5% and a partial response [PR] in 25%). Seven patients (35%) had stable disease (SD). The median duration of response was 4.5 months (range, 1-9 months) and the disease control rate (CR + PR + SD) was 65%. The median survival was 11.5 months (range, 2-22 months) and the 1-year survival rate was 35%. The patients tolerated this regimen well, with only grade 3-4 neutropenia being observed in 6 patients (30%), anemia in 3 (15%), and thrombocytopenia in 1 (5%). The response rate to M-VAC in the first-line chemotherapy was significantly associated with the response to GP as the second-line chemotherapy. Conclusion. The combination of gemcitabine and paclitaxel is active and well tolerated as a second-line treatment in patients with advanced urothelial carcinoma.

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Expression of heparanase in renal cell carcinomas

Mikami Shuji, Oya Mototsugu, Shimoda Masayuki, Mizuno Ryuichi, Ishida Masaru, Kosaka Takeo, Mukai Makio, Nakajima Motowo, Okada Yasunori

Clinical Cancer Research 14 ( 19 ) 6055 - 6061 2008.10

ISSN 1078-0432

Purpose: Heparanase activity has been detected in many malignant tumors, showing a correlation with the metastatic potential. The present study was undertaken to investigate the expression of heparanase and its prognostic significance in renal cell carcinomas (RCC). Experimental Design: Nineteen RCCs and 6 nonneoplastic renal tissues were analyzed for heparanase mRNA expression by real-time PCR. Heparanase protein expression was semiquantitatively investigated by immunohistochemistry in 70 RCCs. Involvement of heparanase in the invasiveness of RCC cell lines, 786-O and Caki-2 cells, was examined by down-regulating the gene expression with small interfering RNA (siRNA) using the Matrigel invasion assay. Results: The expression level of heparanase mRNA was significantly higher in clear cell RCCs than in papillary RCCs, chromophobe RCCs, and nonneoplastic renal tissues. Heparanase was predominantly immunolocalized to cell surface and cytoplasm of clear cell RCCs and mean expression levels of heparanase were significantly higher in clear cell RCCs than in papillary and chromophobe RCCs. The protein expression levels were positively correlated with primary tumor stage, distant metastasis, and histologic grade. Targeting of heparanase mRNA expression in 786-O and Caki-2 cells with siRNA down-regulated the mRNA expression and inhibited the Matrigel invasion by these cells, whereas nonsilencing siRNA showed no effect. Multivariate Cox analysis revealed that elevated heparanase expression was a significant and an independent predictor of disease-specific survival (odds ratio, 8.814; P = 0.019). Conclusions: These data suggest that heparanase plays an important role in invasion and metastasis and silencing of the gene might be a potential therapeutic target in clear cell RCCs.

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Angiomyolipoma with epithelial cysts of the kidney in a man

Mikami Shuji, Oya Mototsugu, Mukai Makio

PATHOLOGY INTERNATIONAL 58 ( 10 ) 664 - 667 2008.10

Research paper (scientific journal), Joint Work, ISSN 1320-5463

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The novel NF-κB activation inhibitor dehydroxymethyl-epoxyquinomicin suppresses anti-thy1.1-induced glomerulonephritis in rats

Kosaka Takeo, Miyajima Akira, Kikuchi Eiji, Horiguchi Yutaka, Umezawa Kazuo, Ohigashi Takashi, Nakashima Jun, Asano Tomohiko, Oya Mototsugu

Nephron - Experimental Nephrology 110 ( 1 ) 2008.09

ISSN 1660-2129

Background: NF-κB participates in the transcriptional regulation of numerous genes, and many studies have confirmed the activation of NF-κB in inflammatory renal diseases. Therefore, NF-κB is a promising target for the treatment of these diseases. We tested the effects of dehydroxymethyl- epoxyquinomicin (DHMEQ), a novel NF-κB activation inhibitor, on anti-thy1.1 antibody-induced glomerulonephritis (Thy1.1 GN). Methods: Thy1.1 GN was induced in Sprague-Dawley rats (6/group) by intravenous injection of anti-thy 1.1 antibody. The effects of DHMEQ (8 mg/kg/day) on the glomerular disease were evaluated using periodic acid-Schiff and Masson trichrome stains, immunohistochemistry for proliferating cell nuclear antigen, fibronectin and CD45 (leukocyte common antigen) and TUNEL staining. NF-κB activation was analyzed by a fluorescent electrophoretic mobility shift assay. Results: On day 7, DHMEQ treatment resulted in marked inhibition of NF-κB, decreased proteinuria (223.2 ± 42.3 vs. 434.8 ± 16.5 mg/kg/day, p < 0.05), preserved creatinine clearance (1.93 ± 0.38 vs. 1.07 ± 0.29 l/day, p < 0.01), decreased glomerular cell proliferation (15.8 ± 1.2 vs. 31.2 ± 0.8 nuclei/glomerular cross-section) and mesangial matrix deposition, and an increase in glomerular and tubular apoptosis without inducing any obvious adverse effects. Conclusion: DHMEQ inhibited NF-κB and thereby suppressed the inflammatory renal responses in rats with Thy1.1 GN.

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Decreased Acetylation of Histone H3 in Renal Cell Carcinoma

Kanao Kent, Mikami Shuji, Mizuno Ryuichi, Shinojima Toshiaki, Murai Masaru, Oya Mototsugu

Journal of Urology 180 ( 3 ) 1131 - 1136 2008.09

ISSN 0022-5347

Purpose: Recent studies suggest that alterations in chromatin structure by histone acetylation may have an important role in the neoplastic process. We evaluated histone H3 acetylation in renal cell carcinoma and the effects of a histone deacetylase inhibitor on renal cancer cell lines. Materials and Methods: The expression of acetylated histone H3 (Lys9) in renal cell carcinoma and corresponding nonneoplastic tissue specimens was evaluated. We next assessed immunohistologically the relationships between acetylated histone H3 expression and clinicopathological parameters in 44 cases of renal cell carcinoma. Furthermore, we evaluated the effects of the histone deacetylase inhibitor depsipeptide on the renal cancer cell lines Caki-1, ACHN, 769P and 786O (ATCC®). Results: Acetylated histone H3 expression was decreased in 85.0% of renal cell carcinomas compared to levels in nonneoplastic tissue. Decreased expression was related to high nuclear tumor grade and advanced pathological tumor stage (p = 0.048 and 0.032, respectively). Depsipeptide inhibited cell line proliferation in a time and dose dependent manner. Depsipeptide induced apoptosis in Caki-1, ACHN and 786O, and induced G2 cell cycle arrest in 769P. Concomitantly depsipeptide increased acetylated histone H3 and p21^WAF/CIP1 expression, and induced Bcl-2 phosphorylation. Conclusions: These results suggest that the decreased acetylation of histone H3 is a common alteration in a malignant phenotype of renal cell carcinoma. Increasing the amount of acetylated histone H3 might be a therapeutic option for renal cell carcinoma.

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Prediction of extraprostatic extension by prostate specific antigen velocity, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer

Nishimoto Koshiro, Nakashima Jun, Hashiguchi Akinori, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Oya Mototsugu, Murai Masaru

International Journal of Urology 15 ( 6 ) 520 - 523 2008.06

ISSN 0919-8172

Objectives: To investigate the clinical value of prostate specific antigen velocity (PSAV) in predicting the extraprostatic extension of clinically localized prostate cancer. Methods: One hundred and three patients who underwent radical prostatectomy for clinically localized prostate cancer were included in the analysis. The correlation between preoperative parameters, including PSA-based parameters, clinical stage, and histological biopsy findings, and the pathological findings were analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for the local extent of the disease. Results: Sixty-four (60.2%) patients had organ confined prostate cancer and 39 (39.8%) patients had extraprostatic cancer. The biopsy Gleason score, PSA, PSA density, PSA density of the transition zone, and PSAV were significantly higher in the patients with extraprostatic cancer than in those with organ confined cancer. Multivariate logistic regression analysis indicated that the biopsy Gleason score, endorectal magnetic resonance imaging findings, and PSAV were significant predictors of extraprostatic cancer (P < 0.01). Probability curves for extraprostatic cancer were generated using these three preoperative parameters. Conclusions: The combination of PSAV, endorectal magnetic resonance imaging findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.

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Papillary renal cell carcinoma

Kosaka Takeo, Mikami Shuji, Miyajima Akira, Kikuchi Eiji, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Clinical and Experimental Nephrology 12 ( 3 ) 195 - 199 2008.06

ISSN 1342-1751

Background: Two different subtypes of papillary renal cell carcinoma (PRCC) have so far been identified, type-1 with small cells and pale cytoplasm and type-2 with large cells and eosinophilic cytoplasm. It has generally been accepted that type-1 tumors have favorable features in comparison with type-2 tumors, suggesting that these subtypes could be different clinicopathological entities, and, as a result, that the subtypes need to be characterized. Forty cases of PRCCs were reviewed, with special attention to the distinct clinicopathological difference and the response to cytokine therapy. Methods: Thirty-five cases of PRCC diagnosed between January 1997 and August 2007 were reviewed. PRCCs were classified according to the criteria of Delahunt and Eble. Results: Of these 40 patients, 20 and 20 were diagnosed to be type-1 and type-2 PRCCs, respectively. No lymphatic or vascular invasion or distant metastasis were observed in patients with type-1 PRCC. The nuclear grade in all type-1 PRCCs was low grade. The nuclear grade (P ≤ 0.01) and the positive rate of vascular invasion (P ≤ 0.05) was significantly higher in type-2 than in type-1 PRCCs. Distant metastasis was detected preoperatively in three patients with type-2 PRCC. One patient with metastatic type-2 PRCCs demonstrated a response to IL-2 therapy. Conclusion: PRCCs include two distinct morphological types of tumor and type-2 PRCCs tends to have unfavorable features in comparison with type-1 PRCCs. These results support the clinical basis for the need to perform morphological subtyping of PRCCs when clinically evaluating such patients.

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Prediction of bone metastases by combination of tartrate-resistant acid phosphatase, alkaline phosphatase and prostate specific antigen in patients with prostate cancer

Ozu Choichiro, Nakashima Jun, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

International Journal of Urology 15 ( 5 ) 419 - 422 2008.05

ISSN 0919-8172

Objective: The clinical value of serum tartrate-resistant acid phosphatase (TRACP), prostate specific antigen (PSA), alkaline phosphatase (ALP), and prostatic acid phosphatase (PACP) for the prediction of bone metastases in prostate cancer were investigated. Methods: TRACP, PACP, ALP, and PSA serum levels were measured in 215 patients with prostate cancer, including 160 without and 55 with bone metastases. Correlation of serum marker levels with bone metastases was assessed using receiver operating characteristics (ROC) analysis. Sensitivity, specificity, accuracy, positive and negative predictive values were calculated for each serum marker. Multivariate stepwise logistic regression analysis was used to identify independent predictors for the presence of bone metastasis. Results: Mean serum TRACP, PACP, ALP, and PSA levels were significantly elevated in patients with bone metastases compared with those without (P < 0.05). PSA and PACP levels increased significantly with clinical stage of the disease, whereas TRACP and ALP levels only increased significantly in stage D2. Serum TRACP levels correlated significantly with extent of disease on bone scans. ROC analyses showed no significant differences in area under the curve for these markers. Logistic regression analysis demonstrated that PSA, ALP, and TRACP were significant predictors of bone metastasis. Predicted and observed risks of bone metastasis were well correlated when TRACP, ALP, and PSA were combined and bone scan could have been omitted in 70% of patients by assessing these three markers. Conclusions: Serum TRACP can be considered a useful predictor of bone metastases in prostate cancer. A combination of TRACP, ALP, and PSA can obviate the need for a bone scan in 70% of cases.

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The predictors of local recurrence after radical cystectomy in patients with invasive bladder cancer

Ide Hiroki, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Ohigashi Takashi, Nakashima Jun, Oya Mototsugu

Japanese Journal of Clinical Oncology 38 ( 5 ) 360 - 364 2008.05

ISSN 0368-2811

Objectives: To examine the association between local recurrence and distant metastasis or disease-specific survival and identify independent factor predictors for local recurrence. Methods: We identified a study population of 146 consecutive patients treated surgically for invasive bladder cancer at our institution between 1987 and 2003. We clarified the relationship among local recurrence, distant metastasis and disease-specific survival and identified significant predictors for local recurrence. Results: Local recurrence developed in 26 (17.8%) of the 146 patients at a median of 10 months (range, 1-73 months) after cystectomy. It was independently associated with distant metastasis in addition to the number of retrieved lymph nodes. The 2- and 5-year metastasis-free rates were 86.7 and 76.5% in patients without local recurrence and 26.5 and 0% in those with local recurrence (P < 0.001), respectively. The presence or absence of local recurrence and tumor grade were independent predictors of disease-specific survival. The 2- and 5-year disease-specific survival rates were 93.5 and 88.3% in patients without local recurrence and 55.1 and 35.4% in those with local recurrence (P < 0.001). The presence of concomitant adenocarcinoma component, pathological nodal involvement and the number of retrieved lymph nodes were independent predictors of local recurrence. Conclusions: Local recurrence was independently associated with distant metastasis and disease-specific survival. Patients who have the predictive factors described above may benefit from integrated surgical therapies with post-operative adjuvant chemotherapy.

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Metastatic type-2 papillary renal cell carcinoma responded to interleukin-2 therapy

Kosaka Takeo, Mikami Shuji, Miyajima Akira, Oya Mototsugu

Clinical and Experimental Nephrology 12 ( 2 ) 155 - 158 2008.04

ISSN 1342-1751

This report documents a case of metastatic papillary renal cell carcinoma (PRCC) which successfully responded to interleukin-2 (IL-2) therapy. A 59-year-old male presented with a left renal mass measuring 3.0 cm in diameter and a right adrenal mass measuring 5.0 cm in diameter. He underwent a left partial nephrectomy and a right adrenalectomy. The histological findings revealed pT1bN1M1 type-2 PRCC and metastatic renal cell carcinoma in the right adrenal gland. The patient was given interferon-α (IFN-α) after the operation for 3 months. A CT scan revealed a metastatic nodule measuring 6.0 cm in diameter near the surface of the liver at 4 months after the opereation. The patient was given interleukin-2 (IL-2), 7 × 10⁵ units/day intravenously, for 3 days per week. A CT scan revealed this hepatic nodule to have decreased in size from 6.0 to 4.0 cm after 4 months of IL-2 therapy. However, a new metastatic nodule measuring 6.0 cm in diameter was found which came in contact with the spleen. Next, the patient was given an increased dose of IL-2 from 7 × 10⁵ to 1.4 × 10⁶ units/day intravenously, for 3 days per week. At 9 months of follow-up after the dose escalation, a CT scan revealed a dramatic decrease in the size of these two metastatic nodules to 1.5 and 0.5 cm, respectively. This is a very rare case in that it represents a type-2 PRCC which dramatically responded to low-dose IL-2 therapy.

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RANKL expression in clear cell renal cell carcinomas and its association with bone metastasis and cancer cell migration

Mikami Shuji, Katsube Ken-Ichi, Oya Mototsugu, Mochizuki Satsuki, Shimoda Masayuki, Mizuno Ryuichi, Ishida Masaru, Ikeda Tohru, Mukai Makio, Okada Yasunori

JOURNAL OF UROLOGY 179 ( 4 ) 88 - 88 2008.04

Research paper (scientific journal), Joint Work, ISSN 0022-5347

Simple stratification of survival using bone scan and serum C-reactive protein in prostate cancer patients with metastases

Nakashima Jun, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Urologia Internationalis 80 ( 2 ) 129 - 133 2008.03

ISSN 0042-1138

Background: IL-6 has been reported to be a significant prognostic factor for prostate cancer and induces synthesis of C-reactive protein (CRP) by hepatocytes. The present study was undertaken to evaluate the clinical value of serum CRP in prostate cancer patients with metastases. Methods: The prognostic significance of serum CRP as well as tumor histology, extent of disease (EOD) on bone scan, serum levels of prostate-specific antigen (PSA) and alkaline phosphatase (ALP) and hemoglobin was assessed using Cox's proportional hazards model analyses in 126 prostate cancer patients with metastases treated with endocrine therapy. Results: Serum levels of CRP, PSA and ALP significantly increased and hemoglobin significantly decreased with advancing EOD grade. Univariate analysis demonstrated that EOD, CRP, PSA, ALP, hemoglobin and tumor histology are significantly associated with disease-specific survival. Multivariate analysis demonstrated that serum CRP and EOD were significant prognostic factors. The 5-year survival rates in low-risk patients (CRP ≤0.15 mg/dl and EOD ≤1) and high-risk patients (CRP >0.15 mg/dl and EOD ≥2) were 74 and 24%, respectively. Conclusion: These results indicate that a combination of serum CRP and EOD can identify patients with a poor prognosis who may be candidates for innovative treatments among prostate cancer patients with metastases.

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Right orbital metastasis from left renal cell carcinoma

Takeda Toshikazu, Yasumizu Yota, Hasegawa Masanori, Morita Shinya, Oya Mototsugu

Japanese Journal of Clinical Urology 62 ( 5 ) 319 - 321 2008

ISSN 0385-2393

A 76-year-old woman receieved right thyroidectomy for a right thyroid tumor and the histopathological diagnosis was clear cell carcinoma. Radiological examination revealed left renal cell carcinoma with metastasis to the pancreas and left radical nephrectomy was performed. After the operation, IFN therapy was performed. But the tumor recurred at the same region in 2 years and metastasized to the lung in 3 years, to the right orbit in 6 years. Tumorectomy of the orbital tumor was performed and the histopathological diagnosis was suggestive of metastatic tumor from renal cell carcinoma.

腹部腫瘤を主訴とする後腹膜原発粘液嚢胞腺癌

Ando Toshiyuki

臨床泌尿器科 62(1) 57 2008

Research paper (scientific journal), Joint Work

The novel NF-kappa B activation inhibitor dehydroxymethyl-epoxyquinomicin suppresses anti-thy1.1-induced glomerulonephritis in rats

Kosaka Takeo, Miyajima Akira, Kikuchi Eiji, Horiguchi Yutaka, Umezawa Kazuo, Ohigashi Takashi, Nakashima Jun, Asano Tomohiko, Oya Mototsugu

NEPHRON EXPERIMENTAL NEPHROLOGY 110 ( 1 ) E17 - E24 2008

Research paper (scientific journal), Joint Work, ISSN 1660-2129

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Development of testicular alpha-fetoprotein-secreting germ cell tumor 3 years after treatment of intracranial lesion identified as non-secreting germ cell tumor on the basis of clinical data - Case report

Takahashi Satoshi, Yoshida Kazunari, Mikami Shuji, Oya Mototsugu, Kawase Takeshi

Neurologia Medico-Chirurgica 48 ( 11 ) 522 - 525 2008

ISSN 0470-8105

A 22-year-old Asian male developed testicular alpha-fetoprotein (AFP)-secreting germ cell tumor 3 years after treatment of a disseminated intracranial lesion identified as non-secreting germ cell tumor on the basis of clinical data. Magnetic resonance imaging showed a massive lesion with necrosis appearing as hypointense on T₁- and hyperintense on T ₂-weighted imaging, with heterogeneous enhancement. The blood AFP level was as high as 129 ng/ml (previously, as low as 5 ng/ml) and abdominal computed tomography showed para-aortic lymph node swelling. Left orchidectomy was performed and histological examination indicated the presence of AFP-secreting germ cell tumor despite severe necrosis of the tissue. Improved chemoradiotherapy for intracranial germ cell tumor will lead to long-term survival of most patients with germ cell tumor. Patients may subsequently develop germ cell tumors at other sites in the body. Therefore, follow up should monitor for tumor recurrence not only in the brain but also in other locations.

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A case of primary retroperitoneal cystadenocarcinoma

Ito Yujiro, Oya Mototsugu, Ishida Masaru, Ando Toshiyuki, Hashiguchi Akinori, Murai Masaru

Japanese Journal of Clinical Urology 62 ( 1 ) 57 - 59 2008

ISSN 0385-2393

A 71-year-old woman was admitted to our hospital complaining of right lower abdominal mass. Computed tomography, and magnetic resonance imaging showed a cystic tumor, 14 cm in diameter, located at the right lower abdomen with cyst wall calcification. Immunohistochemical staining was positive for CA19-9, but not for CEA and CA125. A transabdominal tumorectomy was performed. The removed tumor was 17.7 x 14.4 x 11.2 cm in size, weighing 1,870 g, and hisotopathological retroperitoneal cystadenocarcinoma.

Clinical Implications of Tumor Size and Local Extent of Primary Prostatic Lesions in Prostate Cancer Patients with Metastases

Nakashima Jun, Tanimoto Akihiro, Kikuchi Eiji, Miyajima Akira, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Urology 70 ( 1 ) 86 - 90 2007.07

ISSN 0090-4295

Objectives: To investigate the clinical significance of local assessment by endorectal magnetic resonance imaging (MRI) in prostate cancer patients with metastases. Methods: The local extent and tumor size were determined by endorectal MRI in 95 prostate cancer patients with metastases, and their clinical implications were assessed. Results: The maximum diameter and tumor volume significantly correlated with the local extent of disease but not with extent of disease (EOD) on bone scan. In univariate analyses, EOD, serum prostate-specific antigen level, serum alkaline phosphatase level, and hemoglobin level were significantly associated with disease-specific survival, whereas tumor size and local extent of primary lesions were not. In a multivariate analysis EOD on bone scan was a significant prognostic factor. Conclusions: Tumor size and local extent of the primary lesion estimated by endorectal MRI were not associated with disease-specific survival. Assessment of the primary lesion by endorectal MRI is of limited value in predicting the prognosis of prostate cancer patients with metastases.

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Prevalence of renal cell carcinoma

Marumo Ken, Kanayama Hiroomi, Miyao Noriomi, Nakazawa Hayakazu, Ozono Seiichiro, Horie Shigeo, Nagamori Satoshi, Igarashi Tatsuo, Hasegawa Michihiko, Kimura Go, Nakao Masahiro, Nakamoto Takahisa, Naito Seiji, Tsushima Tomoyasu, Onishi Tetsuro, Fukuda Momokuni, Shinohara Nobuo, Eto Masatoshi, Kobayashi Mikio, Senga Yutaka, Tomita Yoshihiko, Terachi Toshiro, Tokuda Noriaki, Nonomura Norio, Hayakawa Masamichi, Matsuzaki Osamu, Nagashima Yoji, Fujii Yasuhisa, Wada Yoshihiro, Mizutani Yoichi, Oya Mototsugu

International Journal of Urology 14 ( 6 ) 479 - 482 2007.06

ISSN 0919-8172

Objective: To investigate the incidence of renal cell carcinoma, classified by sex, age group and region in Japan, following a 5-year interval after a previous survey performed in 1997. Methods: The survey was conducted between the beginning of January 2002 and the end of December 2002. A total of 1288 institutions in all 47 prefectures throughout Japan were requested to register cases. Results: There were 7405 persons with renal cell carcinoma, consisting of 5063 males and 2342 females. Crude incidence rates were 8.2 and 3.6 per 100 000 population for men and women, respectively. Incidence rates in the Hokkaido region were highest followed by the Shikoku region. Conclusions: Despite incidence of renal cell carcinoma increasing to 7405 from the 6358 persons in 1997, statistical data reported by the Ministry of Health, Labor and Welfare indicate that rising age-adjusted death rate for this tumor reached a ceiling in the past decade. Early detection may have contributed to this current trend; however, further epidemiological research is required to fully elucidate this.

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Renal cancer cells lacking hypoxia inducible factor (HIF)-1α expression maintain vascular endothelial growth factor expression through HIF-2α

Shinojima Toshiaki, Oya Mototsugu, Takayanagi Atsushi, Mizuno Ryuichi, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 28 ( 3 ) 529 - 536 2007.03

ISSN 0143-3334

Recent efforts have been aimed at targeting the hypoxia inducible factor (HIF)-mediated hypoxia-induced gene pathway for renal cell carcinomas (RCC) therapy. Among the various genes induced by HIF, vascular endothelial growth factor (VEGF) is one of the critical mediators in angiogenesis, tumor growth and metastasis. To date, however, limited information is available on the functional differences regarding VEGF transcription between the HIF subunits, namely HIF-1α and HIF-2α. To investigate the HIF-1α and HIF-2α-dependent effect on VEGF gene induction in RCC, a panel of human RCC cell lines was analyzed. We found that a loss of HIF-1α protein expression was a common event in RCC cell lines, which was associated not only with truncated HIF-1α mRNA transcripts but also with transcriptional silencing. Since the CpG rich promoter region of the HIF-1α gene contained a similar frequency of methylated CpG dinucleotides in RCC cell lines, a complex and non-uniform mechanism may be involved in this phenomenon. In these HIF-1α defective cell lines, the knockdown of the HIF-2α gene demonstrated that HIF-2α regulated the VEGF production, irrespective of the VHL gene mutation status. In contrast, HIF-1α played a predominant role in VEGF secretion in the cells expressing both wild-type HIF-1α and HIF-2α proteins. HIF-1α may therefore represent an important target molecule for RCC therapy; however, HIF-2α should be targeted in HIF-1α defective renal cancer cells.

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Interleukin 6 Is Associated with Cachexia in Patients with Prostate Cancer

Kuroda Kenji, Nakashima Jun, Kanao Kent, Kikuchi Eiji, Miyajima Akira, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Urology 69 ( 1 ) 113 - 117 2007.01

ISSN 0090-4295

Objectives: To evaluate the relationship between serum interleukin (IL)-6 and cachexia in patients with prostate cancer. Methods: Serum levels of IL-6, total protein, albumin, total cholesterol, and hemoglobin concentration were determined in 164 blood samples from patients with prostate cancer. The body mass index and performance status were also determined. Results: The serum total protein, albumin, and cholesterol levels, hemoglobin levels, and body mass index of the patients whose serum IL-6 level was 7 pg/mL or greater were significantly lower (P <0.05) than the corresponding values in patients with a serum IL-6 level of less than 7 pg/mL. The serum IL-6 level of patients with a serum albumin level of less than 3.5 g/dL, serum total protein level of less than 7.0 g/dL, serum total cholesterol level of less than 180 mg/dL, hemoglobin level of less than 11.0 g/dL, and body mass index of less than 21 kg/m² were significantly greater (P <0.05) than the values in their respective counterparts. A significant correlation was found between the elevation of serum IL-6 and performance status (P <0.05). The mortality rate of patients with greater serum IL-6 levels was significantly greater than that of those with lower serum IL-6 levels in patients with untreated disease, patients in remission, and patients with relapse (all P <0.05). Conclusions: These findings suggest that IL-6 may be one of the factors contributing to the complex syndrome of cachexia in patients with prostate cancer (all P <0.05).

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Preoperative Nomograms for Predicting Stone-Free Rate After Extracorporeal Shock Wave Lithotripsy

Kanao Kent, Nakashima Jun, Nakagawa Ken, Asakura Hirotaka, Miyajima Akira, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Journal of Urology 176 ( 4 ) 1453 - 1457 2006.10

ISSN 0022-5347

Purpose: Extracorporeal shock wave lithotripsy is currently accepted as a first line treatment modality for urolithiasis. In obtaining informed consent it is important to inform patients of the stone-free rate with extracorporeal shock wave lithotripsy before surgery. The present study was performed to develop preoperative nomograms for predicting stone-free rates after extracorporeal shock wave lithotripsy. Materials and Methods: A total of 435 patients with 507 urinary stones were treated with extracorporeal shock wave lithotripsy with a Dornier Lithotripter D. Patient age, sex, body mass index, number of stone(s) in each treatment, stone length, side and location were evaluated before extracorporeal shock wave lithotripsy, and treatment efficacies were evaluated at 3 months after each session. The treated stones were divided into 2 groups, those in cases that were stone-free with a single extracorporeal shock wave lithotripsy session and those in all other cases. Multivariate analysis was performed using a logistic regression model. The nomograms were developed by repeating the analysis on 200 bootstrap samples. Results: Stone length, location and number were identified as significant variables on multivariate analysis, and a logistic regression model was developed using these variables. The nomograms predicting stone-free rate at 3 months after single extracorporeal shock wave lithotripsy treatment were finally developed from 200 bootstrap samples. In these nomograms the stone-free probability was highest for solitary proximal ureteral stones less than 5 mm in size (93.8%) and lowest for multiple caliceal stones greater than 21 mm (10.5%). Conclusions: This study demonstrated that stone size, location and number are significant predictors of extracorporeal shock wave lithotripsy outcome. We have developed nomograms for predicting the stone-free rate of extracorporeal shock wave lithotripsy, which is useful for counseling patients with urolithiasis before surgery.

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Expression of Ets-1 in human clear cell renal cell carcinomas

Mikami Shuji, Oya Mototsugu, Mizuno Ryuichi, Murai Masaru, Mukai Makio, Okada Yasunori

Cancer Science 97 ( 9 ) 875 - 882 2006.09

ISSN 1347-9032

Expression of vascular endothelial growth factor (VEGF) has been reported in renal cell carcinoma (RCC), a highly angiogenic carcinoma. However, little or no information is available on the expression of Ets-1, which is one of the target molecules of VEGF. In the present study, we examined the expression of Ets-1 and VEGF in RCC by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR), and correlations between expression and the microvessel density (MVD) were evaluated. Ets-1 was immunolocalized to carcinoma cells and endothelial cells of the microvessels in clear cell RCC, but not in papillary RCC. Immunohistochemical Ets-1 expression and MVD were significantly higher in clear cell RCC than in papillary RCC. Predominant mRNA expression of Ets-1 in clear cell RCC was confirmed by RT-PCR. The expression of Ets-1 correlated directly with MVD in clear cell RCC. Hypoxic treatment upregulated the mRNA expression of Ets-1 and VEGF in cell lines derived from clear cell RCC, suggesting that hypoxia is a key regulator for these molecules. These results demonstrate the expression of Ets-1 in human clear cell RCC and suggest the possibility that Ets-1 is involved in angiogenesis in clear cell RCC.

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Assessment of long-term quality of life using the FACT-BL questionnaire in patients with an ileal conduit, continent reservoir, or orthotopic neobladder

Kikuchi Eiji, Horiguchi Yutaka, Nakashima Jun, Ohigashi Takashi, Oya Mototsugu, Nakagawa Ken, Miyajima Akira, Murai Masaru

Japanese Journal of Clinical Oncology 36 ( 11 ) 712 - 716 2006.09

ISSN 0368-2811

Objective: To assess and compare quality of life (QOL) of patients followed for a long time who underwent an ileal conduit (IC), continent reservoir (CR) or ileal neobladder (NB) using FACT-BL, a bladder-cancer-specific questionnaire. Methods: One hundred and forty-seven patients underwent radical cystectomy and urinary diversion for bladder cancer from 1987 to 2002 at our institution. Of them, 79 (54%) patients were asked to participate in this study. Forty-nine patients (20 IC, 14 CR and 15 NB) returned the answered questionnaire for a survey response rate of 62%. Mean follow-up was 83.0 months. Results: Four categories (physical, social/familial, emotional and functional well-being) in FACT-G were equally favorable in these groups. Patients with IC had less trouble controlling urine but had a worse image on altered body appearance compared with NB patients. Interest in sex was extremely low in all patients and capability of maintaining an erection was also low in 39 male patients. The mean total value of FACT-BL in IC, CR and NB patients was 106.3 ± 16.4, 104.0 ± 14.2, and 110.9 ± 18.0, respectively, showing no significant difference. Ten (77%) of 13 IC, seven (78%) of nine CR and six (86%) of seven NB patients answered that they would choose the same type of diversion if they had the choice again. Conclusions: The type of urinary diversion does not appear to be associated with a different QOL by general cancer-related assessment. Urinary function and body image are affected and related to the method used to reconstruct the urinary system.

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Usefulness of alpha₁-antichymotrypsin-PSA complex for predicting bone metastases of prostate cancer

Kikuchi Eiji, Nakashima Jun, Ishibashi Midori, Ohigashi Takashi, Oya Mototsugu, Nakagawa Ken, Miyajima Akira, Murai Masaru

Urology 68 ( 2 ) 371 - 375 2006.08

ISSN 0090-4295

Objectives: To determine the usefulness of alpha₁-antichymotrypsin-prostate-specific antigen (PSA) complex (PSA-ACT)-based parameters in predicting bone metastasis in patients with prostate cancer. Methods: PSA-ACT, total PSA, free PSA, their volume-adjusted values, and alkaline phosphatase were evaluated in 220 consecutive patients with newly diagnosed prostate cancer. Results: Bone metastases were detected by bone scan in 27 (12.3%) of the 220 patients. The serum levels of PSA-ACT, total PSA, free PSA, PSA density, PSA adjusted for transition zone volume, PSA-ACT density, PSA-ACT adjusted for transition zone volume, alkaline phosphatase, PSA-ACT/PSA ratio, and Gleason score in patients with bone metastases were each significantly greater than in those without bone metastases. On receiver operating characteristic analyses, PSA-ACT had the greatest area under the curve (0.88), but the receiver operating characteristic curve demonstrated that the sensitivity and specificity of PSA-ACT were marginally better than those of total PSA at only a few selected cutoff points. At a sensitivity of 93% (2 patients with bone metastasis missed), unnecessary bone scans would have been avoided in 107 and 102 patients using a PSA-ACT cutoff value of 10 ng/mL and total PSA cutoff value of 11.5 ng/mL, respectively. Multivariate logistic regression analysis demonstrated that PSA-ACT and Gleason score were significant independent predictors of bone metastasis. Conclusions: PSA-ACT is as useful as total PSA for identifying patients with a low probability of having bone metastasis. PSA-ACT could replace PSA for predicting negative bone scans in a clinical setting in which PSA-ACT is used for monitoring and screening patients for prostate cancer.

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Clinicopathological features predicting nodal metastasis of testicular seminoma

Sato Akinori, Ohigashi Takashi, Oya Mototsugu, Nakashima Jun, Marumo Ken, Murai Masaru

Urologia Internationalis 77 ( 1 ) 64 - 68 2006.07

ISSN 0042-1138

Background/Aims: To investigate the clinical and pathological features which predict nodal metastasis and/or the prognosis of testicular seminoma and to evaluate the current treatment strategy in a single institute. Methods: We retrospectively analyzed 100 patients who had been pathologically diagnosed as having testicular seminoma in our institute. Ninety-one patients (91%) had stage I disease, 9 patients (9%) were stage II and none stage III. The median follow-up was 63.2 months (range 0.5-249). Results: The duration between the tumor recognition and the first outpatient visit ranged from 0 to 144 weeks, with a median of 5 weeks, which did not influence the clinical stage. The tumor diameter and the preoperative serum lactate dehydrogenase (LDH) level were the significant predictors of stage II disease. Following orchiectomy, 68 patients (74.7%) with stage I disease received radiotherapy. Only 1 patient who had not received adjuvant radiotherapy died from the recurrent disease. The 5-year survival was 100% for the irradiation group but 95% for the surveillance group, although the difference was not statistically significant. All the stage II patients were successfully treated with chemotherapy following orchiectomy. Conclusion: The maximum tumor diameter and the preoperative serum LDH level were the significant predictors of nodal metastasis. Adjuvant radiotherapy in patients with stage I seminoma did not influence the survival. Systemic chemotherapy promised good survival for the seminoma, even with nodal metastasis, in this series. Our results support the good prognosis of testicular seminoma with the current treatment strategy.

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Treatment of renal cell carcinoma with interferons

Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 64 ( 7 ) 1281 - 1285 2006.07

ISSN 0047-1852

Renal cell carcinoma (RCC) is considered to be an immunogenic cancer. RCC is refractory to chemotherapy and radiation. Immunotherapy including interferon (IFN)-alpha, gamma and interleukin-2 are the treatment of choice for metastatic RCC. IFN-alpha is most widely used in Japan. The response rate of IFN-alpha is 10-20 %. Lung lesions and lymphnodes are the usual effective sites. The survival benefit of IFN-alpha in patients with metastatic RCC has been shown in prospective randomized studies. Nephrectomy is recommended before interferon therapy if the patients have good performance status. Adjuvant interferon therapy failed to show any survival benefit after curative excision of primary RCC. The place of IFN-alpha is going to be changed due to the recent use of molecular targeting drugs.

Maximum tumor diameter is a simple and valuable index associated with the local extent of disease in clinically localized prostate cancer

Mizuno Ryuichi, Nakashima Jun, Mukai Makio, Ookita Hajime, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

International Journal of Urology 13 ( 7 ) 951 - 955 2006.07

ISSN 0919-8172

Background: The present study was undertaken to investigate the association of pathological features, including the total tumor volume (TTV), maximum tumor area (MTA), and maximum tumor diameter (MTD), with the local extent of disease in clinically localized prostate cancer. Methods: Serial whole sections of the prostate from 164 patients who underwent radical prostatectomy for localized prostate cancer were investigated. The correlations between the indicators of tumor size, including the TTV, MTA, and MTD, and other pathological parameters were evaluated. Results: The MTD, MTA, and TTV were significantly correlated with each other. Multivariate stepwise logistic regression analysis indicated that the Gleason score, perineural invasion, microvascular invasion, and MTD were significant independent parameters associated with extraprostatic disease. Conclusion: The histological tumor grade, perineural invasion, microvascular invasion, and tumor size were correlated with the local extent of disease. The MTD, a simple, easy, and inexpensive parameter, is a more significant pathological feature associated with the local extent of disease than the MTA or TTV.

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Survivin associates with cell proliferation in renal cancer cells

Sato Akinori, Oya Mototsugu, Ito Keiichi, Mizuno Ryuichi, Horiguchi Yutaka, Umezawa Kazuo, Hayakawa Masamichi, Murai Masaru

International Journal of Oncology 28 ( 4 ) 841 - 846 2006.04

ISSN 1019-6439

Although survivin has been widely recognized as an attractive target for cancer therapy, the exact mechanism regarding the regulation of survivin and its effect on cell proliferation have yet to be clearly defined in renal cell carcinoma (RCC). We investigated herein the association between survivin expression and cell proliferation in a RCC cell line, KU19-20. In KU19-20 cells, cell proliferation and survivin expression were significantly induced by IGF-1, whereas they were inhibited by a novel NF-κB inhibitor dehydroxymethyl-epoxyquinomicin (DHMEQ) and IFN-γ. The combination of DHMEQ and IFN-γ inhibited cell proliferation synergistically with a pronounced attenuation of survivin expression. Furthermore, treatment with survivin-specific siRNA reduced expression of survivin and significantly inhibited cell proliferation. Survivin expression was thus associated with cell proliferation in KU19-20 cells. The regulation of survivin by IFN-γ and/or an NF-κB inhibitor may therefore be a potential treatment modality for RCC.

Survivin associates with cell proliferation in renal cancer cells: Regulation of survivin expression by insulin-like growth factor-1, interferon-α and a novel NF-κB inhibitor

Akinori Sato, Mototsugu Oya, Keiichi Ito, Ryuichi Mizuno, Yutaka Horiguchi, kazuo Umezawa, Masamichi Hayakawa and Masaru Murai

International Jounrnal of Oncology 28 841+846 2006.03

Research paper (scientific journal), Joint Work

腎細胞癌における分子異常

OYA MOTOTSUGU

日本臨床 64 ( 増刊号2 ) 593-596 2006.02

Research paper (scientific journal), Single Work

Genetic backgrounds of renal cell carcinoma

Oya Mototsugu

Nippon rinsho. Japanese journal of clinical medicine 64 Suppl 2 593 - 596 2006

ISSN 0047-1852

Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells

Mizuno Ryuichi, Oya Mototsugu, Hara Satoshi, Matsumoto Mayuko, Horiguchi Akio, Ohigashi Takashi, Marumo Ken, Murai Masaru

Oncology Reports 14 ( 3 ) 639 - 644 2005.09

ISSN 1021-335X

Protein phosphatases have been classified into two basic types, namely protein serine/threonine phosphatase (PP), and protein tyrosine phosphatase (PTP). Cpd 5 is a selective inhibitor of cdc25 phosphatases, which belong to members of PTPs and regulate cell proliferation by controlling cyclin-dependent kinases (cdks). The present study was undertaken to investigate the potential utility of Cpd 5 as an anti-neoplastic agent for renal cell carcinomas (RCCs). Three renal cancer cell lines, 769P, Sw839, and A498 were used. The effects of Cpd 5 on the viability of renal cancer cell lines was analyzed using an Alamar Blue assay. Apoptosis was determined by flow cytometric TUNEL analysis. Changes in the expression of cdc25 phosphatases, mitogen-activated protein kinases (MAPKs), and bcl-2 family proteins were detected using Western blot analysis. The apoptosis-inducing effect of Cpd 5 on human RCC tissue was analyzed through TUNEL staining of organ cultures from RCCs. Cpd 5 showed a strong cytotoxicity against all renal cancer cell lines with an apoptosis-inducing effect. All cell lines treated with Cpd 5 resulted in a down-regulation of cdc25A, cdc25B, and cdc25C, however, the MAPK pathways were not affected. In addition, the up-regulation of bax, and the downregulation of bcl-2 and bcl-xL, was observed. In organ cultures from RCCs, TUNEL-positive apoptotic nuclei were observed when treated with Cpd 5. Cpd 5 was thus found to effectively inhibit the proliferation of human renal cancer cells while also inducing apoptosis by inhibiting cdc25 phosphatases and modulating bcl-2 family proteins. The administration of Cpd 5 may thus be an effective therapeutic approach for RCCs.

c-Jun activation in acquired cystic kidney disease and renal cell carcinoma

Oya Mototsugu, Mikami Shuji, Mizuno Ryuichi, Marumo Ken, Mukai Makio, Murai Masaru

Journal of Urology 174 ( 2 ) 726 - 730 2005.08

ISSN 0022-5347

Purpose: Activator protein-1 has a central role in transducing cytokine signals. Activator protein-1 is composed of 2 proto-oncogene families, namely Jun and Fos. Of them c-Jun has been suggested to have a role in cell cycle progression and neoplastic transformation. We examined the impact of c-Jun protein activation on pathological parameters in renal cell carcinoma (RCC). Materials and Methods: The expression of total c-Jun protein and phosphorylated c-Jun protein was determined by immunohistochemistry in 72 patients with RCC, including 10 with tumor arising from acquired cystic kidney disease (ACKD) of end stage kidneys. Results: c-Jun expression was observed in the distal but not the proximal tubules. Atypical hyperplastic cells in ACKD were positive for phosphorylated c-Jun. RCC arising in end stage kidneys was pT1 and 5 of these cases showed increased c-Jun activation. Of 62 cases arising from normally functioning kidneys 21 showed an increased degree of c-Jun activation. In localized small cell cases (pT1a) 55.5% (10 of 18) showed enhanced activation, whereas such enhanced activation was only observed in 25% (11 of 44) of more advanced cases (pT1b or greater). Therefore, c-Jun activation was considered to be related to the early carcinogenesis of RCC. Conclusions: This study emphasizes the role that c-Jun activation has in early RCC carcinogenesis. Thus, chronic stimulation of cytokines inducing c-Jun activation may have a role in the aberrant proliferation of hyperplastic atypical cells in ACKD and RCC.

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Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alpha preparations

Oya Mototsugu, Asakura Hirotaka, Mizuno Ryuichi, Marumo Ken, Murai Masaru

Biomedical Research 26 ( 3 ) 135 - 137 2005.06

ISSN 0388-6107

A 49-year-old man with pulmonary metastasis from renal cell carcinoma (RCC) was treated with recombinant IFN-α2b (Intron A®). A complete response was achieved within 4 months and thereafter persisted for 5 years until he developed another lung lesion. Interleukin-2 (Imunace®) was administered without any response. Finally, lie was treated by natural IFN-α (OIF®). The pulmonary lesion achieved a partial response after 11 months of treatment. Because IFN-α preparations include different subtypes, changing the use of IFN-α preparations may thus be a potentially useful option for the successful immunotherapy of RCC.

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Akt activation in renal cell carcinoma

Hara S., Oya Moto, Mizuno R., Horiguchi A., Marumo K., Murai M.

Annals of Oncology 16 ( 6 ) 928 - 933 2005.06

ISSN 0923-7534

Background: Akt has been implicated in the oncogenesis of human malignant tumors, because Akt regulates many key effector molecules involved in cell survival. PTEN (phosphatase and tensin homolog deleted on chromosome 10) negatively regulates Akt activation. Materials and methods: The expression of phosphorylated Akt (p-Akt), total Akt and PTEN was analyzed by Western blotting in 45 renal cell carcinoma (RCC) patients. The Bad and phosphorylated Bad (p-Bad) statuses were analyzed in 20 RCC patients. A phosphatidylinositol ether analog was used as an Akt inhibitor to treat four RCC cell lines, namely Caki-1, KU19-20, SW839 and Caki-2. Results: The PTEN expression in RCC was observed to decrease and p-Akt expression to increase significantly in comparison with that in the corresponding normal kidney tissue. The PTEN expression inversely correlated with the p-Akt expression. These alterations were specific for clear cell type RCC, but not for papillary or chromophobe type RCC. Alterations in Bad phosphorylation were also specifically observed in clear cell type. The Akt inhibitor induced apoptosis in KU19-20 and Caki-2 cells with a high Akt activity. Conclusions: A decreased expression of PTEN may be an underlying mechanism for Akt activation. An Akt inhibitor may be a therapeutic option for a subset of RCC with an elevated Akt activity.

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New genetic causes of pheochromocytoma

Neumann Hartmut P H, Cybulla Markus, Shibata Hirotaka, Oya Mototsugu, Naruse Mitsuhide, Higashihara Eiji, Terachi Toshiro, Ling Hao, Takami Hiroshi, Shuin Taro, Murai Masaru

Keio Journal of Medicine 54 ( 1 ) 15 - 21 2005.03

ISSN 0022-9717

Pheochromocytoma and paraganglioma are tumors of the autonomous nervous system mainly occurring in the adrenal medulla, but also in the extraadrenal paraganglias of the abdomen, thorax, neck and skull basis. The etiology comprises germline mutations of now 6 genes. About 10 years known are the RET gene susceptible for multiple endocrine neoplasia type 2, the VHL gene for von Hippel-Lindau Disease, and the NF 1 gene for neurofibromatosis Recklinghausen (neurofibromatosis type 1). Since 2000 the genes for succinatedehydrogenase subunits SDHB, SDHC, and SDHD have been identified for paraganglioma syndromes type 4, type 3, and type 1 respectively. Investigations of series of pheochromocytoma patients identified germline mutations in one of the genes SDHB, SDHD, VHL and RET in 24% to 50% of the patients. Multifocal tumors, young age and positive family history, known features associated with inheritence, have not been present in all patients. Therefore, analyses of blood DNA for mutations in these genes are recommended. Positive tests provide the patients and their relatives with essential platforms for clinical care. Experiences in this field of medicine have shown that optimal management of patients with pheochromocytoma-associated syndromes is a high challenge. National registries may be instrumental in order to provide with adequate facilities.

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Akt activation in renal cell carcinoma: contribution of a decreased PTEN expression and the induction of apoptosis by an Akt inhibitor.

Hara, S., Oya, M., Mizuno, R., Horiguchi, A., Marumo, K and Murai, M.

Ann Oncol 16 928-933 2005

Research paper (scientific journal), Joint Work

Repeated regression of pulmonary metastases from renal cell carcinoma after treatment using different interferon-alfa preparations.

Oya, M., Asakura, H., Mizuno, R., Marumo, K and Murai, M.

Biomed Res 26 135-137 2005

Research paper (scientific journal), Joint Work

C-jun activation in acquired cystic kidney disease and renal cell carcinoma.

Oya, M., Mikami, S., Mizuno, R., Marumo, K., Mukai, M., and Murai,

J Urol 174 726-730 2005

Research paper (scientific journal), Joint Work

Modulation of bcl-2 family proteins in MAPK independent apoptosis induced by a cdc25 phosphatase inhibitor Cpd 5 in renal cancer cells.

Mizuno, R., Oya, M., Hara, S., Matsumoto, M., Horiguchi, A., Ohigashi, T., Marumo, K., and Murai, M.

Oncol Rep 14 639-644 2005

Research paper (scientific journal), Joint Work

血清PSAを用いた前立腺検診の検討

KODAIRA KIICHIROU

泌尿器外科 18 ( 8 ) 1017-1019 2005

Research paper (scientific journal), Joint Work

New genetic causes of pheochromocytoma: current concepts and the clinical relevance.

Neumann, H. P. H., Cybulla, M., Shibata, H., Oya, M., Naruse, M., Higashihara, E., Terachi, T., Ling, H., Takami, H., Shuin, T. and Murai, M.

Keio J Med, 54 15-21 2005

Research paper (scientific journal), Joint Work

Three-dimensional ultrasonography in evaluation of benign prostatic hyperplasia

Kanao Kent, Kikuchi Eiji, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

International Journal of Urology 11 ( 12 ) 1087 - 1091 2004.12

ISSN 0919-8172

Background: The clinical application of volume estimation by 3-D ultrasound has recently gained much attention. However, there have been no reports evaluating the prostate volume by 3-D transrectal ultrasound (TRUS) before transurethral resection of the prostate (TURP). The purpose of the present study was to evaluate the value of 3-D TRUS for prediction of prostate morphology and resected weight before TURP and to investigate whether 3-D TRUS is a more useful examination than 2D TRUS in patients with benign prostatic hyperplasia (BPH). Methods: Transurethral resection of the prostate was performed in 23 patients with BPH. We evaluated the prostate morphology and measured both the volumes of the whole prostate and the transition zone using 2-D and 3-D TRUS, respectively. The actual resected weight was recorded and compared with the volume of the whole prostate and that of the transition zone measured by 2D and 3-D TRUS. Results: The volume of the transition zone measured by 3-D TRUS correlated most strongly with the resected weight (r = 0.84). A large median lobe was seen in three patients in whom the transition zone volume measured by 2-D TRUS was considerably larger than the resected weight. However, overestimation in the three patients decreased by the use of 3-D TRUS. Conclusions: It was concluded that 3-D TRUS was equal or superior to 2-D TRUS in prediction of the resected weight and 3-D TRUS offers better information as a diagnostic tool before TURP.

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Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induces apoptosis in renal cancer cells.

Ishizawa J., Yoshida Shuichi, Oya Mototsugu, Mizuno Ryuichi, Shinojima Toshiaki, Marumo Ken, Murai Masaru

International Journal of Oncology 25 ( 3 ) 697 - 702 2004.09

ISSN 1019-6439

The ubiquitin-proteasome pathway plays a critical role in the degradation of cellular proteins related to signal transduction. Cytokine and growth factor-dependent aberrant proliferation has been implicated in renal cell carcinoma (RCC). We hypothesized that inhibiting the proteasome function might activate a proapoptotic signal transduction by modulating the cytokine and growth factor related signal transduction pathway. We therefore investigated the effectiveness of a proteasome inhibitor in the treatment of RCC regarding the involvement of Mitogen-activated protein kinases (MAP kinases), because MAP kinases are major signal transduction molecules that are known to play a pivotal role in cancer cell proliferation or apoptosis triggered by extra-cellular cytokines and growth factors. A proteasome inhibitor, MG132 inhibited the proliferation of RCC cell lines, 786-O and KU20-01 in a time and dose-dependent manner. 786-O cells have truncated von-Hippel Lindau (VHL) tumor suppressor gene protein due to a one base pair deletion at exon 1, whereas KU20-01 cells have a wild-type VHL protein. MG132 induced apoptosis in both cell lines. The inhibition of the ubiquitin-proteasome pathways was confirmed by the accumulation of ubiquitin-tagged proteins. MG132 induced the phosphorylation of ERK at 4 h and thereafter persisted for 8 to 16 h. In contrast, JNK and p38 activation persisted for longer periods and remained enhanced until 24 h. The concomitant activation of effector caspases, caspase-3 and caspase-7 was observed in 786-O cells. The inhibition of the proteasome function can induce apoptosis in RCC irrespective of the VHL protein status. The persistence of JNK and p38 activation may therefore be a unique mechanism underlying MG132 induced apoptosis.

Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells

Mizuno Ryuichi, Oya Mototsugu, Shiomi Takayuki, Marumo Ken, Okada Yasunori, Murai Masaru

Journal of Urology 172 ( 2 ) 723 - 727 2004.08

ISSN 0022-5347

Purpose: Mitogen-activated protein kinases (MAPKs) comprise 3 subgroups, that is extracellular signal-regulated protein kinase, c-Jun N-terminal kinase (JNK) and p38 MAPK (p38). In this study we analyzed the role of JNK as well as the expression of MAPK phosphatase-1 (MKP-1) in renal cancers. Materials and Methods: Four renal cell carcinoma (RCC) cell lines were used. The effects of anisomycin (JNK activator) and Ro-318220 (MKP-1 expression inhibitor) were analyzed by alamar blue assay. Apoptosis was determined by flow cytometric TUNEL analysis, nuclear morphological alternations and the detection of DNA fragmentation. Changes in MKP-1 expression as well as the activation of extracellular signal-regulated protein kinases and JNK were analyzed by Western blotting. Results: All cell lines treated with anisomycin resulted in a transient activation of JNK without inducing apoptosis. Since we hypothesized that elevated MKP-1 expression could possibly prevent persistent JNK activation, Ro-318220 was used. When cells were treated with Ro-318220, MKP-1 expression decreased in Caki-1 and KU 20-01 cells but not in ACHN or 769P cells. Combined treatment of Caki-1 and KU 20-01 cells with anisomycin and Ro-318220 resulted in a decrease in MKP-1 expression concomitant with persistent JNK activation. Apoptosis was induced in each cell line. Conclusions: These results suggest that prevalent MKP-1 expression in RCC contributes to cancer cell survival by attenuating an apoptosis inducing signal cascade via JNK. Since Ro-318220 potentiated JNK related apoptosis, JNK activation by blocking MKP-1 expression may be an effective therapeutic approach to RCC.

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Dexamethasone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome

Shinojima Toshiaki, Oya Mototsugu, Kohno Hidaka, Marumo Ken, Murai Masaru

International Journal of Urology 11 ( 7 ) 553 - 556 2004.07

ISSN 0919-8172

Interleukin-2 (IL-2) in combination with dexamethasone was administered to a 48-year-old man with renal cell carcinoma accompanied by paraneoplastic inflammatory syndrome, including progressive multiple lung metastases and inferior vena caval tumor thrombus. Although non-steroidal anti-inflammatory drugs had no apparent antipyretic effect on the systemic inflammatory syndrome, oral administration of dexamethasone achieved complete antipyresis and improved his quality of life. After a 4-week period of IL-2 treatment, regression of metastasized lesions was demonstrated despite concurrent oral administration of dexamethasone. Steroids might reduce the action of immunotherapeutic drugs, but in some cases, combination therapy can achieve both alleviation of the paraneoplastic syndrome and tumor shrinkage.

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Differential expression of activator protein-2 isoforms in renal cell carcinoma

Oya Mototsugu, Mikami Shuji, Mizuno Ryuichi, Miyajima Akira, Horiguchi Yutaka, Nakashima Jun, Marumo Ken, Mukai Makio, Murai Masaru

Urology 64 ( 1 ) 162 - 167 2004.07

ISSN 0090-4295

Objectives To investigate the expression of activator protein-2 (AP-2) in renal cell carcinoma (RCC) by immunohistochemistry. Three AP-2 isoforms alpha (α), beta (β), and gamma (γ) are known to exhibit a highly homologous structure; however, their functions are considered to be different. AP-2 has been implicated to play a role in carcinogenesis, as well as in the development of the kidney. Methods The expression of the three AP-2 isoforms, α, β, and γ, was determined in 58 patients with RCC by immunohistochemistry. Epidermal growth factor receptor and erbB2 expression in 42 patients with RCC was also evaluated to investigate the correlation with AP-2 isoforms. Results AP-2 isoforms are differentially expressed in normal renal tubules. Of 58 RCC tissue specimens, 15 (25.9%) demonstrated nuclear and cytoplasmic expression of AP-2α. Clear cell RCC had a significantly greater rate of AP-2α expression than the nonclear subtypes (14 of 41 clear versus 1 of 17 nonclear subtypes). Of the 58 specimens, 8 (13.8%) showed nuclear staining for AP-2β; notably, localized small cases had a significantly greater rate of nuclear staining for AP-2β (5 of 13 in pT1a versus 3 of 45 in pT1b or greater). In addition, only 2 cases (3.5%) demonstrated nuclear staining for AP-2γ. Epidermal growth factor receptor and erbB2 expression did not correlate with expression of the AP-2 isoforms. Conclusions AP-2 isoforms were differentially expressed in RCC, as well as in the adult normal kidney. AP-2α was dominantly expressed in clear cell RCC. AP-2β expression was observed in the low-stage subtypes of RCC, and this transcription factor may be related to early carcinogenesis.

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Renal cell carcinoma

Murai Masaru, Oya Mototsugu

Current Opinion in Urology 14 ( 4 ) 229 - 233 2004.07

ISSN 0963-0643

Purpose of review: The incidence of renal cell carcinoma has been increasing worldwide. Although the etiology of renal cell carcinoma is largely unknown, recent epidemiological investigations have shed some light on the issue. This article reviews the literature related to etiology, incidence and epidemiology of renal cell carcinoma published between May 1, 2003 and April 30, 2004. Recent findings: Accumulating evidence has confirmed the increasing incidence of renal cell carcinoma. A racial disparity has been reported for the first time. Being overweight and obesity were confirmed to be risk factors for renal cell carcinoma. Recreational exercise was shown to reduce the risk, whereas a Western-style diet and smoking increased the risk. Occupational exposure may relate to the development of renal cell carcinoma; however, no definite carcinogens have so far been identified. A susceptibility to develop renal cell carcinoma may also exist in relation to the gene polymorphisms of detoxifying enzymes including glutathione S-transferase and cytochrome P450. Summary: Although high-risk groups for renal cell carcinoma have been identified, a large portion of renal cell carcinoma still has an unknown etiology. Life-style modifications might reduce renal cell carcinoma risks. Further studies are thus needed to explore the etiology of renal cell carcinoma in terms of gene-environment interactions.

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Endorectal MRI for prediction of tumor site, tumor size, and local extension of prostate cancer

Nakashima Jun, Tanimoto Akihiro, Imai Yutaka, Mukai Makio, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Urology 64 ( 1 ) 101 - 105 2004.07

ISSN 0090-4295

Objectives To assess the value of endorectal magnetic resonance imaging (MRI) for detecting the tumor site, tumor size, and disease extent in patients with localized prostate cancer. Methods The MRI findings were compared with the histopathologic findings of radical prostatectomy specimens in 95 patients. Results The histologic examination revealed 186 cancer foci. Endorectal MRI detected 109 cancer foci. The accuracy, sensitivity, and positive predictive value of endorectal MRI for detecting tumor foci greater than 1.0 cm in diameter was 79.8%, 85.3%, and 92.6%, respectively; the corresponding value for detecting tumor foci smaller than 1.0 cm was 24.2%, 26.2%, and 75.9%, respectively. The maximal tumor diameter on endorectal MRI correlated with that shown by histologic examination for tumors larger than 1.0 cm in diameter. However, it did not correlate significantly with the histologic diameter of tumors smaller than 1.0 cm. The accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of endorectal MRI was 74.7%, 57.1%, 82.1%, 57.1%, and 82.1%, respectively, for the detection of extracapsular extension and was 75.8%, 62.1%, 81.8%, 60.0%, and 83.1%, respectively, for local staging. Conclusions The results of the present study suggest that endorectal MRI is useful for predicting local extension, as well as tumor site and tumor size, of cancer foci greater than 1.0 cm in diameter.

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The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors

Ito Keiichi, Nakashima Jun, Hanawa Yasumasa, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Journal of Urology 171 ( 1 ) 120 - 125 2004.01

ISSN 0022-5347

Purpose: Since middle-aged and elderly patients seem to have risk factors affecting renal function, it is important to predict postoperative renal function prior to unilateral nephrectomy (UNx). We evaluated preoperative factors for predicting postoperative renal function in middle-aged and elderly patients with renal cell carcinoma (RCC) treated with radical nephrectomy (RNx). Materials and Methods: In 201 patients who underwent RNx preoperative records and postoperative serum creatinine (SCR) 6 years after nephrectomy were available. Postoperative renal insufficiency was defined as serum creatinine 1. 4 mg/dl or greater. The relationship of each preoperative and postoperative factor was analyzed. Logistic regression analysis was performed to evaluate preoperative factors for predicting postoperative SCR 1.4 mg/dl or greater after 6 years. Results: There was a significant difference in postoperative SCR between female and male patients, and between those with and without hypertension, diabetes and proteinuria (p <0.05). Age, hemoglobin, preoperative SCR, blood urea nitrogen, uric acid and K significantly correlated with postoperative SCR (p <0.05). The increase in SCR during 6 years after UNx was significantly higher in patients with hypertension, diabetes and proteinuria than in their respective counterparts (p <0.05). Multivariate stepwise logistic regression analysis demonstrated that preoperative serum creatinine, hypertension and proteinuria were significant independent factors predicting postoperative renal function 6 years after UNx in patients with RCC (p <0.05). Conclusions: Preoperative SCR, hypertension and proteinuria are useful factors for predicting postoperative renal function after RNx in patients with RCC.

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The prediction of renal function 6 years after unilateral nephrectomy using preoperative risk factors

'Ito Keiichi, Nakashima Jun, Hanawa Yasumasa, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru'

Journal of Urology 171 120-125 2004.01

Research paper (scientific journal), Joint Work

Dexamethazone and interleukin-2 combination therapy for advanced renal cell carcinoma in a patient with paraneoplastic inflammatory syndrome.

Shinojima, T., Oya, M., Kohno, H., Marumo, K. and Murai, M.

Int J Urol., 11 553-556 2004

Research paper (scientific journal), Joint Work

内分泌治療を受けている前立腺癌患者の骨粗鬆症診断の意義

MARUMO KEN

腎泌尿器予防医学会雑誌 12 ( 1 ) 62-66 2004

Research paper (scientific journal), Joint Work

Endorectal MRI for prediction of tumor site, tumor size, and local extension of prostate cancer

Jun Nakashima, Akihiro Tanimoto, Yutaka Imai, Makio Mukai, Yutaka Horiguchi, Ken Nakagawa, Mototsugu Oya, Takashi Ohigashi, Ken Marumo, Masaru Murai

Urology 64 101-105 2004

Research paper (scientific journal), Joint Work

Three-dimensional ultrasonography in evaluation of benign prostatic hyperplasia.

Kanao K, Kikuchi E, Nakashima J, Horiguchi Y, Nakagawa K, Oya M, Ohigashi T, Marumo K, Murai M.

Int J Urol 11 1087-1091 2004

Research paper (scientific journal), Joint Work

内分泌療法が施行された進行性前立腺癌におけるＣ反応性蛋白の意義

NAKASHIMA JUN

泌尿器外科 17 951-954 2004

Research paper (scientific journal), Joint Work

Inhibition of MKP-1 expression potentiates JNK related apoptosis in renal cancer cells.

Mizuno, R., Oya, M., Shiomi, T., Marumo, K., Okada, Y., and Murai, M

J. Urol., 172 723-727 2004

Research paper (scientific journal), Joint Work

Differential expression of activator protein-2 isoforms in renal cell carcinoma.

Oya, M., Mikami, S., Mizuno, M., Miyajima, A., Horiguchi, Y., Nakashima, J., Marumo, K., Mukai, M., and Murai, M.

Urology, 64 162-167 2004

Research paper (scientific journal), Joint Work

Inhibition of the ubiquitin-proteasome pathway activates stress kinases and induce apoptosis in renal cancer cells.

Ishizawa, J., Yoshida, S., Oya, M., Mizuno, R., Shinojima, T., Marumo, K., and Murai, M.

Int J Oncol., 25 697-702 2004

Research paper (scientific journal), Joint Work

Renal cell carcinoma: etiology, incidence and epidemiology.

Murai, M. and Oya, M.

Curr Opin Urol, 14 229-233 2004

Research paper (scientific journal), Joint Work

Renal cell carcinoma

Oya Mototsugu, Murai Masaru

Current Opinion in Urology 13 ( 6 ) 445 - 449 2003.11

ISSN 0963-0643

Purpose of review: Although pathological findings including tumour grade and tumour-node-metastasis stage provide prognostic information, the outcome for patients with renal cell carcinoma is occasionally unpredictable. Many studies have been undertaken to improve prediction of the prognosis of renal cell carcinoma, along with efforts to clarify the pathogenesis of renal cell carcinoma at the molecular level. This article reviews the advances in renal cell carcinoma research relevant to pathology published between 1 May 2002 and 30 April 2003. Recent findings: The establishment of a strict tumour grading system or adding microscopic venous invasion or tumour necrosis is potentially useful for predicting patient outcomes. The contribution of the von Hippel-Lindau-related pathway in early carcinogenesis has been partly revealed with regard to angiogenesis and cell cycle control. Tumour development in renal cell carcinoma can be considered as accumulating heterogenous molecular events related to cytokine production, cell cycle control, anti-apoptotic signal machinery and angiogenesis. Summary: Finding the target genes related to the von Hippel-Lindau pathway may explain the resistance of chemotherapy, and also provide a clue to finding a novel therapeutic option. Molecular targeting therapy can be applicable after more general molecules leading to tumour development and the metastasis of renal cell carcinoma have been identified.

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Detection of Circulating Prostate Cells during Radical Prostatectomy by Standardized PSMA RT-PCR

Schmidt Bettina, Anastasiadis Aristotelis G., Seifert Hans Helge, Franke Knut H., Oya Mototsugu, Ackermann Rolf

Anticancer Research 23 ( 5 A ) 3991 - 3999 2003.09

ISSN 0250-7005

Background: The purpose of this study was to establish a quantitative standardized RT-PCR for the detection of Prostate Specific Membrane Antigen (PSMA)-expressing circulating cells and to evaluate clinical relevance in patients undergoing radical retropubic prostatectomy (RRP) for clinically localized prostate cancer (PCa). Materials and Methods: An external standard molecule (PSMA MIMIC) was constructed for standardization of PSMA RT-PCR reactions. It has the same sequence as endogenous PSMA, except for a central 85 bp deletion, allowing the amplification of both targets simultaneously with nearly the same amplification characteristics as in a nested PCR. PSMA RT-PCR was performed from peripheral blood samples of 73 patients with clinically localized PCa, 4 with metastatic PCa, 27 with benign prostatic hyperplasia (BPH) and 27 controls. Pre, intra- and postoperative blood samples were tested for circulating PSMA expressing cells in 54 out of 73 patients with clinically localized PCa. We also tested intraoperative blood samples of 19 BPH patients treated by transurethral or open surgery. Results: Endogenous PSMA signals from PCa patients varied between 850 and 9900 transcript molecules, corresponding to 2-20 PSMA-expressing cells/ml blood. Standardized RT-PCR using the PSMA MIMIC molecule revealed a significant decrease of "false-positives" in cancer-free controls (p=0.004). Controls could clearly be distinguished from prostate cancer patients based on PSMA PCR positivity (p=0.003). Thirty-two % of patients with localized prostate cancer, 11% of BPH patients and 7% of healthy controls were positive in standardized assays compared to 48%, 30% and 27% without PSMA MIMIC, respectively. Preoperatively, a correlation with tumor stage (p=0.030), grade (p=0.035) and Gleason Score (p=0.03) could be demonstrated in clinically localized PCa patients. Dissemination of prostate cells during surgery occurred in 32% of the RRPs and 21% of BPH patients. Positive PCR signals from intraoperative blood samples correlated with positive lymph node status (p=0.007) and tumor grade (p=0.005). Postoperative positive results correlated with grade (p=0.012) and Gleason Score (p=0.035). Conclusion: Counseling the patient with clinically localized prostate cancer can be challenging. Surgery may be, in retrospect, inappropriate in a number of patients due to preoperative understaging. This newly constructed external standard allows quantitative detection of circulating prostate cells, and therefore may open new perspectives for PSMA RT-PCR techniques as diagnostic assays and tools for post-therapeutic follow-up.

Prediction of extraprostatic cancer by prostate specific antigen density, endorectal MRI, and biopsy gleason score in clinically localized prostate cancer

Horiguchi Akio, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Prostate 56 ( 1 ) 23 - 29 2003.06

ISSN 0270-4137

BACKGROUNDS. The present study was designed to identify the preoperative parameters, including PSA-based parameters, and endorectal MRI, predictive of pathological stage in males who underwent radical prostatectomy. METHODS. We studied 114 patients who underwent radical retropubic prostatectomy and pelvic lymphadenectomy for clinically localized prostate cancer. Clinical stage was assessed by DRE, pelvic CT scan, endorectal MRI, and bone scan. The correlation between the preoperative parameters, including PSA-based parameters, clinical stage, and histological findings of biopsy specimens, and the pathological stage was analyzed. Logistic regression analysis was performed to identify a significant set of independent predictors for local extent of disease. RESULTS. Seventy-six (66.6%) patients had organ confined cancer and 38 (33.4%) patients had extraprostatic cancer. Of the 38 patients with extraprostatic cancer, four had seminal vesicle involvement, while, none had pelvic lymph node involvement. Biopsy Gleason score, PSA, PSA-α1-antichymotrypsin (PSA-ACT), PSA-density (PSAD), PSA-transition zone density, PSA-ACT density, and PSA-ACT transition zone (TZ) density were significantly higher and percent free PSA was lower in the patients with organ confined cancer than those with extraprostatic cancer (P < 0.01). PSAD showed the largest area under the ROC curve (AUC) among those parameters (AUC = 0.732). Sixty-eight (74.7%) of 91 patients with T2 on endorectal MRI had organ confined cancer, while 15 (65.2%) of 23 patients with T3 had extraprostatic cancer (P < 0.01). Multivariate logistic regression analysis indicated that Gleason score (≥7 vs. ≤6), endorectal MRI findings, and PSAD were significant predictors of extraprostatic cancer (P < 0.01). CONCLUSIONS. The present study demonstrated that preoperative PSAD was the most valuable predictor among PSA-based parameters for extraprostatic disease in patients with clinically localized prostate cancer. The combination of PSAD, endorectal MRI findings, and biopsy Gleason score can provide additional information for selecting appropriate candidates for radical prostatectomy.

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'Prediction of extraprostatic cancer by prostate specific antigen density, endorectal MRI, and biopsy Gleason score in clinically localized prostate cancer'

'Horiguchi Akio, Nakashima Jun, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Marumo Ken and Murai Masaru'

Prostate 56 ( 1 ) 23-29 2003.06

Research paper (scientific journal), Joint Work

Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma

Oya Mototsugu, Takayanagi Atsushi, Horiguchi Akio, Mizuno Ryuichi, Ohtsubo Masafumi, Marumo Ken, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 24 ( 3 ) 377 - 384 2003.03

ISSN 0143-3334

Although an aggressive phenotype of renal cell carcinoma (RCC) is known to frequently be associated with inflammatory paraneoplastic syndrome including serum C-reactive protein (CRP) elevation, the molecular mechanism underlying this clinical phenomenon as well as what yields the malignant phenotype leading to the progression of RCC has yet to be elucidated. Based on the increased level of inflammatory cytokines such as interleukin-6 in advanced cases of RCC, a cytokine-inducible transcription factor, namely, nuclear factor-κB (NF-κB), may thus play a role in the progression of RCC. An electrophoretic mobility shift assay (EMSA) was carried out to determine the activity of NF-κB. Out of 45 cases of RCC, 15 cases (33%) showed a >200% increase in the NF-κB activity in comparison with that seen in normal renal tissue. In locally advanced cases (≥pT3), 64% (9/14) showed an increased activity whereas it was only observed in 19% (6/31) of localized cases (≤pT2). All three cases with metastases showed an increased NF-κB activity. The NF-κB activity determined by EMSA was further confirmed by an immunohistochemical analysis using an antibody recognizing the nuclear localization signal (NLS) in p65 subunit of NF-κB. The serum CRP elevation correlated with the increased NF-κB activation, and therefore NF-κB may be a causative transcription factor of inflammatory paraneoplastic syndrome. A high NF-κB activity was associated with an increased expression of both the p65 and p50 subunits of NF-κB and a concomitant decreased expression of IκBα. No functional mutations of the IκBα gene were detected. The NF-κB activity may therefore be a late event in carcinogenesis related to tumor development, thereby representing a possible molecular target in the treatment of RCC.

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Increased activation of CCAAT/enhancer binding protein-β correlates with the invasiveness of renal cell carcinoma

Oya Mototsugu, Horiguchi Akio, Mizuno Ryuichi, Marumo Ken, Murai Masaru

Clinical Cancer Research 9 ( 3 ) 1021 - 1027 2003.03

ISSN 1078-0432

Positive inflammatory reactions in an aggressive phenotype are typical features of renal cell carcinoma (RCC). Although a high blood level of inflammatory cytokines, such as interleukin-6, interleukin-8, and tumor necrosis factor-α, has been observed in these patients, the mechanisms underlying this clinical phenomenon remain to be elucidated. CCAAT/enhancer binding protein (C/EBP) family are transcription factors which play a role in cell differentiation and inflammatory reactions. Among these, C/EBP-β induces a variety of cytokines and thus may play a role in the pathogenesis of RCC. We studied the activation of C/EBP-β determined by electrophoretic mobility shift assay in nine RCC cell lines and 44 tissue samples. Six cell lines showed an activation of C/EBP-β, whereas three cell lines did not, and two of these three had no expression at all of C/EBP-β protein. Of 44 tissue samples, 12 (27.3%) showed a >200% increase in the activity compared with the corresponding normal kidney tissues. Locally advanced cases had a significantly higher rate of increased C/EBP-β activity (5 of 8 = 62.5% in advanced cases versus 7 of 36 = 19.4% in localized cases). Especially, all four cases with renal vein invasion had an increased C/EBP-β activity. These data suggest that the increased activation of C/EBP-β may contribute to promote tumor invasiveness and render a malignant phenotype of RCC, although it needs to be validated in a larger series.

Increased nuclear factor-κB activation is related to the tumor development of renal cell carcinoma

Oya Mototsugu, Takayanagi Atsushi, Horiguchi Akio, Mizuno Ryuichi, Ohtsubo Masafumi, Marumo Ken, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 24 ( 3 ) 377-384 2003.03

Research paper (scientific journal), Joint Work

Elevated Akt activation and its impact on clinicopathological features of renal cell carcinoma

Horiguchi Akio, Oya Mototsugu, Uchida Atsushi, Marumo Ken, Murai Masaru

Journal of Urology 169 ( 2 ) 710 - 713 2003.02

ISSN 0022-5347

Purpose: Akt has been implicated in the pathogenesis and progression of numerous human malignant tumors because Akt regulates many key effector molecules involved in controlling the balance of survival and apoptosis. Elevated Akt activation has been demonstrated in various types of malignant tumors. In the current study we evaluated Akt activation in renal cell carcinoma and investigated its association with pathological features and clinical outcome. Materials and Methods: Akt activation was evaluated by immunohistochemistry using antiphospho-specific Akt antibody, which recognizes only activated Akt, in 48 patients with renal cell carcinoma. High immunostaining tumors were defined as tumors with increased staining intensity compared with adjacent nonneoplastic kidney tissue and low immunostaining tumors were defined as tumors with equivalent or decreased staining intensity. The association of Akt activation status with clinicopathological features was analyzed. Results: Of 48 patients examined 18 (37.5%) demonstrated high antiphospho-specific Akt immunostaining compared with adjacent nonneoplastic kidney tissue, while 30 (62.5%) demonstrated low immunostaining. Elevated immunostaining was significantly associated with tumor grade (p = 0.0354) and metastatic disease (p = 0.0044), while it was not associated with tumor stage or histological subtype. In addition, high antiphospho-specific Akt immunostaining was significantly associated with a poor cancer specific survival rate on univariate analysis (p = 0.0109) but not on multivariate analysis. Conclusions: Elevated Akt activation could be a common finding, especially in high grade tumor and metastatic disease. It could have an important role in the pathogenesis and progression of renal cell carcinoma.

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Enhancement of diethylstilbestrol induced cytotoxicity by Bcl-2 antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer

Kikuchi Eiji, Nakashima Jun, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Journal of Urology 169 ( 2 ) 730 - 734 2003.02

ISSN 0022-5347

Purpose: Bcl-2 has been shown to prolong cancer cell survival by blocking apoptosis and have the function of scavenging reactive oxygen species. We assessed the efficacy of a novel strategy that relies on antisense bcl-2 oligodeoxynucleotides as well as a glutathione depletor combined with diethylstilbestrol (DES) for hormone independent prostate cancer. Materials and Methods: The cytotoxic effects of antisense bcl-2 oligodeoxynucleotides and DES on PC-3 cells were determined using spectrophotometry measurement. The expression of Bcl-2 protein was detected by Western blot analysis. Intracellular reactive oxygen species generation was estimated from the amount of intracellular dichlorofluorescein. Apoptosis was determined by the terminal deoxynucleotidyl transferase mediated deoxyuridine triphosphate-biotin nick end labeling assay. Results: Antisense bcl-2 oligodeoxynucleotides decreased Bcl-2 protein levels and significantly inhibited PC-3 cell growth in a dose dependent manner. Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity. A significant increase in apoptotic cells was induced by the combination of antisense bcl-2 oligodeoxynucleotides and DES compared with the oligodeoxynucleotides alone. The glutathione depletor buthionine sulfoximine significantly decreased the intracellular concentration of glutathione and augmented DES induced cytotoxicity and reactive oxygen species generation in PC-3 cells. Neither the generation of reactive oxygen species nor the intracellular concentration of glutathione was influenced by antisense bcl-2 oligodeoxynucleotide treatment. Conclusions: Antisense bcl-2 oligodeoxynucleotides significantly enhanced DES induced cytotoxicity in hormone independent prostate cancer cells through the apoptotic pathway independent of augmented reactive oxygen species generation, whereas the glutathione depletor augmented cytotoxicity and reactive oxygen species generation.

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Incidence and growth pattern of simple cysts of the kidney in patients with asymptomatic microscopic hematuria

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Nakashima Jun, Murai Masaru

International Journal of Urology 10 ( 2 ) 63 - 67 2003.02

ISSN 0919-8172

Background: We examined the incidence and natural history of simple renal cysts found by ultrasonography (US) in patients referred for asymptomatic microscopic hematuria. Methods: Among the 906 patients aged 18-78 years, 743 patients who had undergone US were included in the present study. The natural history of simple renal cysts was investigated in 55 patients who underwent periodical US examinations for more than 3 years. Results: The incidence of simple renal cysts was 4.3% for ages 29 years or younger, 15.3% for ages 30-39, 21.8% for ages 40-49, 23.3% for ages 50-59 and 32.6% for ages 60 years or older; thus the incidence increased in older age groups (P = 0.0005 for men, P = 0.0020 for women). Men tended to have a higher incidence than women. The degree of hematuria did not influence the incidence of renal cysts (P = 0.9044). The annual growth rate of the mean maximum diameter was 4.2% during a 3-year follow-up period in 55 patients and 5.1% during a 6-year follow-up in 31 patients. Conclusion: Since the diameter of a renal cyst may increase by 5% annually, the diameter of the cyst may increase by 1.6 times in 10 years. The scheduling of follow-up examinations depends on the size at the time of disclosure, the effects on calyceal systems, or the suspicion of a concurrent malignant disease. However, the most simple renal cysts may be followed-up at an interval of more than 10 years, once a diagnosis has been established.

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Incidence and growth pattern of simple cysts of the kidney in patients with asymptomatic microscopic hematuria

'Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Nakashima Jun and Murai Masaru.'

International Journal of Urology 10 ( 2 ) 63-67 2003.02

Research paper (scientific journal), Joint Work

Suppression of hormone-refractory prostate cancer by a novel nuclear factor κB inhibitor in nude mice

Kikuchi Eiji, Horiguchi Yutaka, Nakashima Jun, Kuroda Kenji, Oya Mototsugu, Ohigashi Takashi, Takahashi Nozomu, Shima Yutaka, Umezawa Kazuo, Murai Masaru

Cancer Research 63 ( 1 ) 107 - 110 2003.01

ISSN 0008-5472

We have synthesized and explored the feasibility of using a novel nuclear factor (NF) κB inhibitor, a dehydroxymethylepoxyquinomicin designated as DHMEQ, against prostate cancer. The activity of NFκB, evaluated by transient transfection of a luciferase reporter DNA containing a specific binding sequence for NFκB, was inhibited by DHMEQ in three human hormone-refractory prostate cancer cell lines, DU145, JCA-1, and PC-3. Statistically significant growth inhibition was achieved by 20 μg/ml of DHMEQ, and marked levels of apoptosis were induced 48 h after DHMEQ administration in vitro. Electrophoretic mobility shift assay showed that DHMEQ completely inhibited NFκB DNA binding activity in JCA-1 cells. Furthermore, i.p. administrations of DHMEQ significantly inhibited pre-established JCA-1 s.c. tumor growth in nude mice without any side effects. Our result indicates the possibility of using a novel NFκB activation inhibitor, DHMEQ, as a new treatment strategy against hormone-refractory prostate cancer.

Suppresion of Hormone-refractory Prostate Cancer by a Novel Nuclear Factor kB Inhibitor in Nude Mice

Eiji Kikuchi, Yutaka Horiguchi, Jun Nakashima, Kenji Kuroda, Mototsugu Oya, Takashi Ohigashi, Nozomu Takahashi, Yutaka Shima, Kazuo Umezawa, Masaru Murai

Cancer Research 63 107-110 2003.01

Research paper (scientific journal), Joint Work

A case of renal cell carcinoma associated with renal tubulopapillary adenoma in hemodialysis patient

Ebine Takashi, Nakagawa Ken, Oya Mototsugu, Murai Masaru, Mukai Makio

Japanese Journal of Clinical Urology 57 ( 10 ) 839 - 841 2003

ISSN 0385-2393

A 67-year-old male with chronic renal failure had been on a hemodialysis treatment for 3 years and 4 months. He presented with a left renal mass incidentally detected on abdominal ultrasound examination. The T2-weighted MRI demonstrated a hyperintense mass at the lower pole and a hypointense mass at the upper pole respectively. They were diagnosed as renal cell carcinomas and left radical nephrectomy was performed. Histopathological diagnoses of the specimen were renal cell carcinoma and renal tubulopapillary adenoma respectively.

振動装置付き陰茎締め付けバンドの評価

丸茂健、　堀口裕、　中川健、　大家基嗣、　大東貴志、　中島　淳、　村井勝

日本性機能学会雑誌 18 ( 1 ) 39087 2003

Research paper (scientific journal), Joint Work

Renal cell carcinoma: relevance of pathology

'Mototsugu Oya, Murai Masaru'

Current Opinion in Uroloyg 13 445-449 2003

Research paper (scientific journal), Joint Work

Detection of Circulating Prostate Cells during Radical Prostatectomy by Standardized PSMA RT-PCR: Association with Positive Lymph Nodes and High Malignant Grade

'Bettina Schmidt, Aristotelis G. Anastasiadis, Hans-Helge Seifert, Knut H. Franke,Mototsugu Oya and Rolf Ackermann'

Anticancer Research 23 3991-4000 2003

Research paper (scientific journal), Joint Work

高プロラクチン血症を有する勃起障害患者の検討

MARUMO KEN

日本性機能学会雑誌 18 ( 3 ) 313-317 2003

Research paper (scientific journal), Joint Work

透析腎に発生した乳糖状腺腫を伴う腎細胞癌

'EBINE TAKASHI, Nakagawa Ken, Oya Mototsugu, Murai Masaru, Mukai Makio'

臨床泌尿器科 57 839-841 2003

Research paper (scientific journal), Joint Work

経皮的膀胱癌穿刺とcystostomy

OYA MOTOTSUGU, MURAI MASARU

消化器外科 ( 26 ) 921-927 2003

Research paper (scientific journal), Single Work

腎細胞癌におけるアポトーシスの誘導ーTRAILの抗腫瘍効果とNFκBを標的とした遺伝子治療を中心にー

OYA MOTOTSUGU

泌尿器科外科 ( 16 ) 1089-1091 2003

Research paper (scientific journal), Single Work

予防医学的側面からみた勃起障害の検討

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Ooya Mototsugu, Oohigashi Takashi, Nakashima Jun, Murai Masaru

腎泌尿器疾患予防医学会雑誌 11 ( 1 ) 59-60 2003

Research paper (scientific journal), Joint Work

Enhancement of diethylstilbestrol induced cytotoxicity by bcl-2 antisense oligodeoxynucleotides and a glutathione depletor for prostate cancer

Kikuchi Eiji, Nakashima Jun, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Murai Masaru

Journal of urology 169 730-734 2003

Research paper (scientific journal), Joint Work

Increased nuclear factor-kB activation is related to the tumor development of renal cell carcinoma

Oya Mototsugu, Takayanagi Atushi, Horiguchi Akio, Mizuno M, Ohtsubo Masafumi, Marumo Ken, Shimizu Nobuyoshi, Murai Masaru

Carcinogenesis 24 377-384 2003

Research paper (scientific journal), Joint Work

Increased activation of CCAAT/enhancer binding protein-b correlates with the invasiveness of renal cell carcinoma

Oya Mototsugu, Horiguchi Akio, Mizuno M, Marumo Ken, Murai Masaru

Clinical cancer research 9 1021-1027 2003

Research paper (scientific journal), Joint Work

Elevated AKT activation and its impact on clinicopathological features of renal cell carcinoma

Horiguchi Akio, Oya Mototsugu, Shimada T, Uchida Atsushi, Marumo Ken, Murai Masaru

Journal of urology 169 710-713 2003

Research paper (scientific journal), Joint Work

泌尿器科領域における薬の使い方

Ooya Mototsugu, Murai Masaru

腎腫瘍　クリニカ 30 36-39 2003

Research paper (scientific journal), Joint Work

What is the impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma?

Oya Mototsugu, Murai Masaru

Japanese Journal of Cancer and Chemotherapy 29 ( 10 ) 1732 - 1737 2002.10

ISSN 0385-0684

The impact of cytoreductive nephrectomy in patients with metastatic renal cell carcinoma (RCC) is discussed herein with consideration of prolonged survival and quality of life. A nephrectomy can be indicated in a patient with good performance status and pulmonary metastases when adjuvant immunotherapy is an option. In contrast, in a patient with poor performance status and/or metastases including multiple organs, a nephrectomy is not indicated. To relieve symptoms, options other than nephrectomy should be considered.

Clinical value of prostate specific antigen based parameters for the detection of prostate cancer on repeat biopsy

Horinaga Minoru, Nakashima Jun, Ishibashi Midori, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Journal of Urology 168 ( 3 ) 986 - 990 2002.09

ISSN 0022-5347

Purpose: To our knowledge the indications for repeat prostate needle biopsy in men whose previous transrectal ultrasound guided biopsy results revealed no evidence of cancer have not yet been defined. We identified the most effective method for detecting prostate cancer on repeat biopsy. Materials and Methods: One or more systematic repeat prostate biopsies were performed in 144 consecutive patients, including 86 with prostate specific antigen (PSA) levels between 4 and 10 ng./ml. at repeat biopsy. Men in whom cancer was detected on repeat biopsies were compared with their counterparts in terms of digital rectal examination findings, PSA based parameters and an atypical prostate on initial prostate biopsy. Results: Prostate cancer was detected on repeat biopsy in 39 of the 144 patients and in 19 on subset analysis of 86. Serum PSA levels at repeat biopsy did not differ significantly in patients with and without prostate cancer. According to receiver operating characteristics analysis the α1-antichymotrypsin-PSA complex adjusted for transition zone volume had the greatest area under the curve values, that is 0.756 for all 144 patients and 0.768 for the subset analysis of 86. Multiple logistic regression analysis of the subset of 86 patients showed that α1-antichymotrypsin-PSA complex adjusted for transition zone volume was the only significant independent predictor of cancer. Conclusions: α1-Antichymotrypsin-PSA complex adjusted for transition zone volume was the most powerful predictor of cancer in men who had undergone previous negative prostate biopsies. This parameter may be used to avoid more unnecessary repeat biopsies with an acceptable decrease in sensitivity.

STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P

Horiguchi Akio, Oya Mototsugu, Marumo Ken, Murai Masaru

Kidney International 61 ( 3 ) 926-938 2002.03

Research paper (scientific journal), Joint Work

顕微鏡的血尿患者における単純性腎嚢胞の頻度と経時的変化

Marumo Ken，Horiguchi Yutaka，Nakagawa Ken，Ooya Mototsugu，Asakura Hirotaka，Oohigashi Takashi，Nakashima Jun，Marumo Ken，Murai Masaru

日本腎泌尿器疾患予防医学研究会誌 10 ( 1 ) 26-27 2002.01

Research paper (scientific journal), Joint Work

Significance and diagnostic accuracy of renal calculi found by ultrasonography in patients with asymptomatic microscopic hematuria

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Nakashima Jun, Murai Masaru

International Journal of Urology 9 ( 7 ) 363 - 367 2002

ISSN 0919-8172

Background: The purpose of the present study was to evaluate the clinical significance and the accuracy of the diagnosis of renal calculi incidentally found by ultrasonography (US). Methods: A total of 906 subjects (639 men and 267 women) aged 18-78 years were referred for asymptomatic microscopic hematuria. Of these, 743 patients who underwent US were studied. Results: Hyperechogenic spots in the central echo complex suggesting renal calculi were noted in 195 patients (21.5%). The occurrence of hyperechogenic spots was higher in patients with 20 or more urinary red blood cells per high-power field (χ² = 4.896, P = 0.0269) and in men than in women (χ² = 7.101, P = 0.0077), but it was lowest in patients who were 29 years old or younger. Of these 195 patients, who were followed up for 1-161 months (average: 33.5 months), 24 patients (12.3%) needed urological management. Extracorporeal shockwave lithotripsy was carried out in eight patients, transureteral lithotripsy was carried out in three patients, spontaneous passage occurred in 11 patients and medication for hyperuricemia was initiated in two patients (1%). Among the patients in whom hyperechogenic spots were found in the kidney by US but calculi were not visible on abdominal plain radiographs, 39 patients underwent computed tomography. Of them, 31 patients were confirmed to have renal calculi. Conclusion: The obtained results suggest that US is an effective and reliable means of detecting renal calculi in patients with asymptomatic microscopic hematuria, and in facilitating prompt urological intervention or predicting the natural course of renal calculi.

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Significance and diagnostic accuracy of renal calculi found by ultrasonography in patients with asymptomatic microscopic hematuria

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotak, Nakashima Jun, Murai Masaru

International journal of urology 9 363-367 2002

Research paper (scientific journal), Joint Work

直腸癌S状結腸癌に対する根治的手術後の勃起障害の臨床的検討

Marumo Ken, Horiguchi Yutaka, Nakagawa Ken, Ooya Mototsugu, Oohigashi Takashi, Nakashima Jun, Murai Masaru

日本性機能学会雑誌 17 ( 3 ) 219-223 2002

Research paper (scientific journal), Joint Work

Activation of signal transducer and activator of transcription 3 in renal cell carcinoma: a study of incidence and its association with pathological features and clinical outcome

Horiguchi Akio, Oya Mototsugu, Shimada T, Uchida Atsushi, Marumo Ken, Murai Masaru

Journal of urology 168 762-765 2002

Research paper (scientific journal), Joint Work

腎摘除術・腎部分摘除術・腎尿管全摘術

Ooya Mototsugu

臨床泌尿器科 56 255-259 2002

Research paper (scientific journal), Single Work

腎実質の縫合

Ooya Mototsugu

臨床泌尿器科 56 855-860 2002

Research paper (scientific journal), Single Work

転移巣を有する腎細胞癌患者における腎摘出術の意義

Ooya Mototsugu, Murai Masaru

癌と化学療法 29 1732-1737 2002

Research paper (scientific journal), Joint Work

泌尿器科領域における最近の医療機器

Ooya Mototsugu, Mizuno Ryuuichi, Kanao Kento, Murai Masaru

学会新報 23 6-12 2002

Research paper (scientific journal), Joint Work

Clinical value of prostate specific antigen based parameters for the detection of prostate cancer on repeat biopsy: The usefulness of complexed prostate specific antigen adjusted for transition zone volume

Horinaga Minoru, Nakashima Jun, Ishibashi Midori, Oya Mototsugu, Ohigashi Takashi, Marumo Ken, Murai Masaru

Journal of urology 168 986-990 2002

Research paper (scientific journal), Joint Work

STAT3, but not ERKs, mediates the IL-6-induced proliferation of renal cancer cells, ACHN and 769P

Horiguchi Akio, Oya Mototsugu, Marumo Ken, Murai Masaru

Kidney International 61 ( 3 ) 926 - 938 2002

ISSN 0085-2538

Background. Although interleukin-6 (IL-6) has been suggested to function as an autocrine growth factor in renal cell carcinoma (RCC), the underlying mechanism responsible for the IL-6-induced proliferation of RCC has not been defined. The aim of this study was to characterize the signaling cascades mediating IL-6-induced proliferation and to investigate the use of effective novel interventions to block the IL-6-induced autocrine growth of renal cancer cells. Methods. IL-6-induced proliferation and intracellular signaling cascades were analyzed in four human renal cancer cell lines Caki-1, ACHN, 769P and A498. IL-6-induced activation of STAT3 (signal transducer and activator of transcription-1) and extracellular signal-regulated kinases (ERKs), and the effects of anti-IL-6 neutralizing antibody, Jak inhibitor AG 490, and MEK1 inhibitor PD 98059 were analyzed by Western blotting using phospho-specific antibodies. The DNA-binding activities of STATs were analyzed by EMSA. Apoptosis was determined by using nuclear staining and the TUNEL assay. Changes in the apoptosis-related proteins, bcl-2, bcl-xL, and bax were analyzed by Western blotting. Results. IL-6 induced tyrosine phosphorylation and increased the DNA binding activity of STAT3 and, to a lesser extent, STAT1 in all cell lines except for Caki-1, which did not express the IL-6 receptor subunit gp130. ERKs were constitutively activated in all cell lines and the activation level was not up-regulated further by exogenously added IL-6 nor down-regulated by anti-IL-6 neutralizing antibody. IL-6-induced STAT3 tyrosine phosphorylation and DNA binding activity was inhibited by treatment with Jak specific inhibitor AG 490; however, it was not affected by the MEK1 inhibitor PD 98059. Moreover, treatment with AG 490 inhibited IL-6-induced proliferation of ACHN and 769P cells and induced apoptosis with the down-regulation of bcl-2 and the up-regulation of bax. Conclusions. This study identified STAT3, but not ERKs, to be a major mediator of IL-6-induced proliferation of renal cancer cells. Although ERKs were constitutively activated, ERKs were not found to be essential for the IL-6-induced proliferation and modulation of the STAT3 activity. Because the Jak specific inhibitor AG 490 effectively inhibited the IL-6-induced STAT3 activity and induced apoptosis, the blockade of the STAT3 signaling pathways is considered to be potentially useful as a novel therapeutic approach for RCC.

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Activation of signal transducer and activator of transcription 3 in renal cell carcinoma

Horiguchi Akio, Oya Mototsugu, Shimada Tetsuya, Uchida Atsushi, Marumo Ken, Murai Masaru

Journal of Urology 168 ( 2 ) 762 - 765 2002

ISSN 0022-5347

Purpose: Signal transducer and activator of transcription 3 (STAT3) is known to have an important role in cytokine and growth factor signaling pathways. In various types of human malignant tumors STAT3 has been shown to be constitutively activated due to aberrant production of cytokines and growth factors. We examined the presence of STAT3 activation and its association with pathological features and clinical outcome in renal cell carcinoma cases. Materials and Methods: We examined 48 paraffin embedded renal cell carcinoma specimens and corresponding nonneoplastic kidney tissues for the activation status of STAT3 on immunohistochemistry using anti-phospho-specific (p)-STAT3 antibody, which recognizes only activated STAT3. Based on the percent of cells with positive nuclear staining the activation status of STAT3 was determined and categorized into 2 groups, including low-less than 10% and high90% or more tumor cells positive. The associations of the activation status of STAT3 with pathological features and clinical outcome were analyzed. Results: Of 48 tumors 24 (50%) demonstrated high levels of nuclear immunostaining for p-STAT3, while the other 24 (50%) showed low levels. Adjacent nonneoplastic kidney tissues showed only little immunostaining for p-STAT3. A significant association of high levels of p-STAT3 with metastasis was observed (p = 0.0094). No significant associations of p-STAT3 immunostaining with pathological stage or grade were observed. A high level of p-STAT3 was a significant indicator of a poor prognosis on univariate and multivariate analysis (p = 0.0117 and 0.0439, respectively) Conclusions: Our results indicate a high frequency of STAT3 activation in renal cell carcinoma, especially in metastatic disease. STAT3 activation was an independent prognostic variable in renal cell carcinoma cases. Our results strongly suggest that the activation of STAT3 contributes to the development and progression of renal cell carcinoma.

勃起障害患者治療における血清テストステロン値の意義

Marumo Ken，Horiguchi Yutaka，Ooya Mototsugu，Oohigashi Takashi，Nakashima Jun，Murai Masaru

日本性機能学会雑誌 3 ( 16 ) 273-277 2001.12

Research paper (scientific journal), Joint Work

マルチスライスCTによる三次元再構築画像を用いた腎病変の評価

Mizuno Ryuuichi，Nakagawa Ken，Ooya Mototsugu，Oohigashi Takashi，Nakashima Jun，Marumo Ken，Murai Masaru

腎移植・血管外科 13 ( 1 ) 48-54 2001.12

Research paper (scientific journal), Joint Work

高齢者における勃起障害の治療

Satou Akinori，Marumo Ken，Horiguchi Yutaka，Nakagawa Ken，Ooya Mototsugu，Oohigashi Takashi，Nakashima Jun，Murai Masaru

日本性機能学会雑誌 16 ( 3 ) 321-325 2001.10

Research paper (scientific journal), Joint Work

腎細胞癌治療における腎保存手術

Ooya Mototsugu

慶應医学 78 ( 5 ) 159-160 2001.09

Research paper (scientific journal), Single Work

Constitutive activation of nuclear factor-κB prevents TRAIL-induced apoptosis in renal cancer cells

Oya Mototsugu, Ohtsubo Masafumi, Takayanagi Atsushi, Tachibana Masaaki, Shimizu Nobuyoshi, Murai Masaru

Oncogene 20 ( 29 ) 3888 - 3896 2001.06

ISSN 0950-9232

TRAIL has gained much attention for its specific induction of apoptosis in cancer cells but not in normal cells. This phenomenon has been explained thus: that cancer cells dominantly express death receptors while normal cells express decoy receptors. However, recent reports have shown that some cancer cell lines are resistant to TRAIL-induced apoptosis despite the absence of decoy receptors and the presence of death receptors. This suggested the existance of an inhibitory factor. We herein showed that NF-κB is a key molecule underlying the TRAIL-resistant mechanism in renal cell carcinoma (RCC) cell lines. We observed that NF-κB is constitutively activated in resistant cell lines. Forced expression of antisense cDNA of IκBα, a specific inhibitor of NF-κB, in TRAIL-sensitive cell lines with a low NF-κB activity result in constitutive activation of NF-κB and resistance to TRAIL-induced apoptosis. Adenoviral expression of a stable form of IκBα in the TRAIL-resistant cell lines induced apoptosis. These data suggest that RCC can be classified into two subsets: TRAIL-sensitive RCC with a low NF-κB activity and TRAIL-resistant RCC with constitutively activated NF-κB. In the former group TRAIL can be a treatment option, while in the latter group a molecular approach targeting NF-κB appears to be a promising therapy.

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Constitutive activation of nuclear factor-kB prevents TRAIL-induced apoptosis in renal cancer cells

Oya Mototsugu, Ohtsubo Masafumi, Takayanagi Atsushi, Tachibana Masaaki, Shimizu Nobuyoshi, Murai Masaru

Oncogene 20 ( 29 ) 3888-3896 2001.06

Research paper (scientific journal), Joint Work

Constitutive activation of nuclear factor-κB prevents TRAIL-induced apoptosis in renal cancer cells

Oya Mototsugu, Ohtsubo Masafumi, Takayanagi Atsushi, Tachibana Masaaki, Shimizu Nobuyoshi, Murai Masaru

Oncogene 20 ( 29 ) 3888-3896 2001.06

Research paper (scientific journal), Joint Work

前立腺癌診断におけるPSA関連マーカーの有用性

Nakashima Jun，Kikuchi Eiji，Ishibashi Midori，Ooya Mototsugu，Oohigashi Takashi，Marumo Ken，Murai Masaru

泌尿器外科 14 445-446 2001

Research paper (scientific journal), Joint Work

勃起障害治療における陰茎締めつけバンドの有用性

Marumo Ken，Horiguchi Yutaka，Nakagawa Ken，Ooya Mototsugu，Oohigashi Takashi，Nakashima Jun，Murai Masaru

日本性機能学会雑誌 16 15-19 2001

Research paper (scientific journal), Joint Work

Serum interleukin 6 as a prognostic factor in patients with prostate cancer

Nakashima Jun, Tachibana Masaaki, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Murai Masaru

Clinical Cancer Research 6 ( 7 ) 2702 - 2706 2000.07

ISSN 1078-0432

The present study was undertaken to evaluate the prognostic significance of the serum levels of interleukin 6 (IL-6) in patients with prostate cancer. Serum IL-6 levels were measured in 74 patients with prostate cancer. The tumor was stage B in 23 patients, stage C in 14 patients, and stage D in 37 patients. Prognostic significance of tumor histology, performance status (PS), bone metastasis, serum prostate-specific antigen (PSA) level, serum alkaline phosphatase (ALP) level, serum lactate dehydrogenase level, serum IL-6 levels, and hemoglobin on disease-specific survival was assessed using univariate and multivariate Cox's proportional hazards model analyses. Serum IL-6 was significantly correlated with the clinical stage of prostate cancer. Univariate analysis of all patients demonstrated that an extent of disease (EOD) on bone scanning ≥1, IL-6 ≥7 pg/ml, PS ≥1, PSA >100 ng/ml, and ALP >620 IU/liter were associated with a significantly lower survival rate than their respective counterparts. In multivariate analysis, however, the only two significant prognostic factors were EOD and IL-6. In 51 patients with stage C and stage D prostate cancer, univariate analysis showed that EOD ≥1, IL-6 ≥7 pg/ml, PS ≥1, PSA >100 ng/ml, LDH >200 IU/liter, and ALP >620 IU/liter were significantly related to survival, whereas multivariate analysis again demonstrated that EOD ≥1 and IL-6 ≥7 pg/ml were significant prognostic factors. These results indicate that the serum IL-6 level is a significant prognostic factor for prostate cancer as well as EOD.

Serm interleukin 6 as a prognostic factor in patients with prostatic cancer

Nakashima Jun, Tachibana Masaaki, Horiguchi Yutaka, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Murai Masaru

Clinical Cancer Research 6 ( 7 ) 2702-2706 2000.07

Research paper (scientific journal), Joint Work

Appricationof condetionally replicating herpes vector for gene therapy treatment of urologic neoplasms

Oyama Masafumi, Yazaki Takahito, Ohigashi Takashi, Hoshi Michio, Horiguchi Yutaka, Oya Mototsugu, Asakura Hirotaka, Nakashima Jun, Tachibana Masaaki, Uyemura Keiichi, Murai Masaru

Molecular Urology 4 ( 2 ) 83-87 2000.07

Research paper (scientific journal), Joint Work

Complications of laparoscopic and retroperotoneoscopic adrenalectomies in 370 cases in Japan: a multi-institutional study

Terachi Toshiro, Yoshida Osamu, Matsuda Tadashi, Orikasa Seiichi, Chiba Yutaka, Takahashi Kota, Takeda Masayuki, Higashihara Eiji, Murai Masaru, Baba Shiro, Fujita Kimio, Suzuki Koji, Ohshima Shinichi, Ono Yoshinari, Kumazawa Joichi, Naito Seiji

Biomedicine & Pharmacotherapy 54 ( Suppl 1 ) 211-214 2000.06

Research paper (scientific journal), Joint Work

How to Make Proper Specimens for Surgically Resected Renal Cell Carcinoma

Oya Mototsugu

Japanese Journal of Clinical Urology 54 ( 6 ) 377 - 383 2000.05

ISSN 0385-2393

Prognositic value of alkaline phosphatase flase in patients with metastatic prostate cancer treated with endocrine therapy

Nakashima Jun, Ozu Choichiro, Nishiyama Toru, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Tachibana Masaaki, Murai Masaru

Urology 56 ( 5 ) 834-847 2000.05

Research paper (scientific journal), Joint Work

腎癌切除標本の取り扱い方

Ooya Mototsugu，Murai Masaru

臨床泌尿器科 54 ( 6 ) 377-383 2000.05

Research paper (scientific journal), Joint Work

Application of conditionally replicating herpes vector for gene therapy treatment of urologic neoplasms

Oyama M, Yazaki T, Ohigashi T, Hoshi M, Horiguchi Y, Oya M, Asakura H, Nakashima J, Tachibana M, Uyemura K, Murai M

Molecular Urology 4 ( 2 ) 83-87 2000.05

Research paper (scientific journal), Joint Work

Decreased expression of p57(KIP2) mRNA in human bladder cancer

Oya M., Schulz W. A.

British Journal of Cancer 83 ( 5 ) 626 - 631 2000

ISSN 0007-0920

To identify targets of genetic and epigenetic alterations on chromosome 11p15.5 in human bladder cancer, expression of the imprinted KIP2, IGF2 and H19 genes was studied by quantitative RT-PCR in 24 paired samples of urothelial carcinomas and morphologically normal mucosa obtained by cystectomy, and in bladder carcinoma cell lines. The most frequent alteration in tumour tissue was decreased expression of KIP2 identified in 9/24 (37%) specimens. Decreased IGF2 and H19 mRNA levels were found in five (21%) and three (13%) tumours, respectively. One tumour each overexpressed IGF2 and H19. Loss of H19 expression was only found associated with loss of KIP2 expression, whereas decreased expression of IGF2 mRNA occurred independently. Almost all bladder carcinoma cell lines showed significant changes in the expression of at least one gene with diminished expression of KIP2 mRNA as the most frequent alteration. IGF2 mRNA levels were diminished in several lines, but increased in others. The KIP2 gene could be an important target of genetic and epigenetic alterations in bladder cancer affecting the maternal chromosome 11p15.5. However, reminiscent of the situation in Wilms' tumours, expression of the IGF2 gene on the paternal chromosome can also be disturbed in bladder cancers. (C) 2000 Cancer Research Campaign.

Prognostic value of alkaline phosphatase flare in patients with metastatic prostate cancer treated with endocrine therapy

Nakashima Jun, Ozu Choichiro, Nishiyama Toru, Oya Mototsugu, Ohigashi Takashi, Asakura Hirotaka, Tachibana Masaaki, Murai Masaru

Urology 56 ( 5 ) 843 - 847 2000

ISSN 0090-4295

Objectives. To assess the prognostic significance of alkaline phosphatase (ALP) flare in 114 patients with metastatic prostate cancer treated with endocrine therapy.Methods. ALP flare was defined as a transient increase of the serum ALP level to 120% or more of the pretreatment value after the initiation of endocrine therapy, followed by a subsequent decrease.Results. Univariate analysis demonstrated that patients with poorly differentiated adenocarcinoma, an extent of disease of 2 or greater, a serum ALP level above twice the upper limit of normal, a serum prostate-specific antigen level greater than 100 ng/mL, an ALP flare, and a hemoglobin level of 12 g/dL or less had a significantly lower survival rate than their respective counterparts. Multivariate Cox's proportional hazards model analysis demonstrated that tumor histologic features and ALP flare were significant prognostic indicators for survival.Conclusions. The results of the present study suggest that the tumor histologic features and the ALP flare are significant prognostic indicators for survival in patients with metastatic prostate cancer treated with endocrine therapy. Copyright (C) 2000 Elsevier Science Inc.

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Application of conditionally replicating herpes vector for gene therapy treatment of urologic neoplasms

Oyama M., Uyemura K., Murai M., Yazaki T., Ohigashi T., Hoshi M., Horiguchi Y., Oya M., Asakura H., Nakashima J., Tachibana M.

Molecular Urology 4 ( 2 ) 83 - 87 2000

ISSN 1091-5362

Herpes vector has been widely used for experimental gene therapy. We herein review the strategies of such therapy for the treatment of urologic neoplasms. Most experimental studies of genetically altered viruses have employed replication-incompetent vectors. However, such viruses are unable to infect additional cells subsequent to the initial infection event. Therefore, this strategy has relied heavily on the bystander effect because a large number of noninfected tumor cells remain. Conditionally replicating herpes vector G207 has been developed in order to overcome potential problems of safety and tumor specificity for human use. It has been used to treat malignant brain tumors because of its neural tropism. In the last few years, applications of G207 for non-neural tumors have been reported. Because G207 may be useful for the treatment of urologic malignant tumors, we evaluated the antitumor effect against several types of tumor cells both in vitro and in vivo. Our data suggest that G207 may be applicable for the treatment of urologic malignant tumors.

High frequency of inactivation of the imprinted H19 gene in sporadic hepatoblastoma

Fukuzawa R, Umezawa A, Ouchi K, Ikeda H, Hata J

International Journal of Cancer 82 ( 4 ) 490-497 1999.08

Research paper (scientific journal), Joint Work

臨床病期C前立腺癌における放射線療法と内分泌療法

Oyama Masafumi, Nakashima Jun, Kikuchi Eiji, Saitou Shirou, Ooya Mototsugu, Oohigashi Takashi, Asakura Hirotaka, Tachibana Masaaki, Murai Masaru

泌尿器外科 12 ( 8 ) 962-965 1999.08

Research paper (scientific journal), Joint Work

A Case of Solitary Contralateral Adrenal Metastasis of Renal Cell Carcinoma

Mizuno Ryuichi, Kikuchi Eiji, Ohya Mototsugu, Murai Masaru

Japanese Journal of Clinical Urology 53 ( 7 ) 517 - 519 1999.06

ISSN 0385-2393

A 72-year-old male visited our out-patient clinic with right incidentally found renal tumor, which was discovered by computed tomography (CT) for the follow up study of chronic pancreatitis. CT also showed a left adrenal mass. Further evaluation suggested right renal cell carcinoma and left adrenal metastasis. Right nephrectomy and left adrenalectomy, saving the right adrenal gland, were performed on June 22, 1998. Histology confirmed renal cell carcinoma with contralateral adrenal metastasis.

Expression of G1→S transition regulatory molecules in human urothelial cancer

Oya Mototsugu, Schmidt Bettina, Schmitz-Dräger Bernd J., Schulz Wolfgang A.

Japanese Journal of Cancer Research 89 ( 7 ) 719 - 726 1998.07

ISSN 0910-5050

Growth of cancer cells is characterized by accelerated passage through the cell cycle, which is often caused by deregulation of the G1→S transition. In this study the expression of G1→S transition regulatory molecules was analyzed in 32 transitional cell carcinoma specimens and fifteen normal tissues obtained by cystectomy or nephroureterectomy of mainly locally advanced tumors, as well as six bladder cancer cell lines. Expression of mRNAs for cyclins D1 and D2 and cyclin-dependent kinases (CDK) 2 and 4 was investigated by quantitative reverse transcription-polymerase chain reaction. Overexpression of cyclin D1 compared to normal mucosa was observed in 3 tumors (9.4%), but in neither of the cell lines. All tumors with overexpression were moderately differentiated (G2) pT1 or pT2 tumors, and thus among the less advanced specimens. Cyclin D2 was not expressed in normal bladder mucosa or in tumors. The expression of CDK4 mRNA varied within the same range in mucosa, tumors, and cell lines, CDK2 mRNA expression varied more strongly and was diminished in individual tumors and in four cell lines. It is concluded that cyclin D1 overexpression can play an important role in the early stage of urothelial tumorigenesis, driving cell proliferation. Ectopic expression of cyclin D2 or amplification of CDK4 does not occur at a significant frequency in urothelial carcinomas. Different expression patterns of cyclin D1 and CDK2 indicate heterogeneity in the mechanisms of G1→S transition deregulation in individual bladder tumors which may elicit differences in their biological and clinical behavior.

Control of cell cycle regulatory proteins and modulation of STATI proteins by INF-r in human prostatic JCA 1 cells

Oya Mototsugu, Konno S, Chen Y, Tazaki Hiroshi, Mallouch C, Wu JM

Int J Oncol 10 835-839 1997.12

Research paper (scientific journal), Joint Work

Control of cell cycle regulatory proteins and modulation of STAT1 proteins by IFN-γ in human prostatic JCA-1 cells

Oya M., Konno S., Chen Y., Tazaki H., Mallouh C., Wu J. M.

International Journal of Oncology 10 ( 4 ) 835 - 839 1997

ISSN 1019-6439

The addition of human recombinant IFN-γ (10² and 10³ IU/ml) inhibited human prostatic JCA-1 cell growth by 27% and 64%, respectively. Since the high dose of IFN-γ elicited an increase in G₁ concomitant with a decrease in G₂/M phases of the cell cycle, changes in the expression of cell cycle regulatory protein molecules were analyzed by Western blots. Results of these experiments show that IFN-γ down regulated the G₁/S transition molecules, e.g., cyclin D1, the cyclin-dependent protein kinase Cdk4, and the retinoblastoma gene product (pRB), but increased the G₂/M transition molecules, e.g., cyclin B1 and p34(cdc2) (Cdk1). Possible modulation of Cdk-inhibitors (CDKIs), e.g., p53 and p21(WAF1), which have checkpoint functions in the cell cycle, by IFN-γ, was also studied. The p53 was induced by both 10² and 10³ IU/ml IFN-γ. At 10³ IU/ml, IFN-γ inhibited p21(WAF1) increased the expression of STAT1α, and sustained the elevated STAT1α for up to 96 h. Thus several mechanisms may be involved in the antiproliferative effects of IFN-γ.

Application of the interferon minipellet to human renal cell carcinoma in nude mice

Marumo Ken, Oya Mototsugu, Murai Masaru

International Journal of Urology 4 ( 1 ) 55 - 61 1997

ISSN 0919-8172

Background: The interferon (IFN) minipellet is a sustained-release formulation of human lymphoblastoid IFN, with atelocollagen used as the carrier material. We evaluated the antitumor effect of the IFN minipellet on an established human renal cell carcinoma cell line (KU-2) transplanted in nude mice. Methods: The treatment was started when tumor nodules had grown to 6 to 8 mm in diameter. The IFN minipellet, or an aqueous solution of IFN, was given by subcutaneous injection, or peritumor injection, on days 1 and 10. Antitumor effects were evaluated according to tumor weights calculated as (long diameter) x (short diameter)²/2 in 7 groups consisting of 6 mice each. Results: IFN levels remained detectable in both tumor tissue and serum up to in days after peritumor injection of the IFN minipellet. Administered by the peritumor route, the IFN minipellet inhibited growth of the tumor significantly as compared with tumor growth in the untreated mice. The IFN minipellet showed greater inhibition of tumor growth by peritumor injection compared to subcutaneous injection. The aqueous solution of IFN was not effective either by subcutaneous or by peritumoral injection. Conclusion: Results indicate that the IFN minipellet is useful in the treatment of renal cell carcinoma.

Biochemical modulation of 5-fluorouracil with murine interferon-α/β against murine renal cell carcinoma

Marumo Ken, Oya Mototsugu, Murai Masaru

International Journal of Urology 4 ( 2 ) 163 - 168 1997

ISSN 0919-8172

Background: Conventional therapy for renal cell carcinoma using interferon (IFN) has shown limited antitumor action. The purpose of our study was to investigate synergistic antitumor effects of IFN and 5-fluorouracil (5-FU), and to elucidate the mechanisms of interaction between the 2 agents in mice. Methods: Antitumor effects and biochemical modulation of murine IFN-α/β and 5-FU were determined against the murine renal cell carcinoma cell line, Renca, in vivo. The activity of thymidylate synthetase and thymidine kinase was measured using cytosolic extract of the tumors. Results: Combination treatment with IFN-α/β and 5-FU produced a significant enhancement of growth inhibition against Renca tumor. Treatment with 5-FU resulted in a 2.7-fold increase in the total amount of thymidylate synthetase and an 11.6-fold increase in the thymidylate synthetase inhibition rate, while the administration of IFN-α/β did not significantly reduce the 5-FU-induced increase in thymidylate synthetase. The administration of IFN-α/β decreased thymidine kinase activity to 65.5% maximally, compared with that in the control mice or the mice treated with 5-FU. Conclusions: The reduction of thymidine kinase caused by treating the mice with IFN-α/β changes the utilization of exogenous thymidine for DNA synthesis, and may represent the mechanism of the additive antitumor effect of the 2 agents, through the suppression of the salvage pathway for deoxythymidine monophosphate induction.

Application of cytokine drug delivery systems to the immunotherapy of renal cell carcinoma in mice

Marumo Ken, Oya Mototsugu, Murai Masaru

Int J Urol 3 ( Supple 1 ) 24-27 1996.11

Research paper (scientific journal), Joint Work

Pharmacokinetics and Antitumor Effects of an Interleukin-2 Immunocomplexing Agent in Murine Renal Cell Carcinoma

Oya Mototsugu, Marumo Ken, Murai Masaru, Tazaki Hiroshi

International Journal of Urology 3 ( 2 ) 141 - 144 1996

ISSN 0919-8172

Background: Conventional therapy for renal cell carcinoma (RCC) using systemic administration of interleukin-2 (IL-2) has shown limited anti-tumor action. The purpose of this study was to investigate the anti-tumor effects of a newly developed immune complex of IL-2 (IC) against RCC. Methods: IC was prepared by mixing IL-2 and an anti-IL-2 monoclonal antibody at a molar ratio of 2:1. The pharmacokinetics and anti-tumor effects of IC were then studied in a murine RCC line, Renca. Results: Serum IL-2 levels were sustained longer in mice given IC than in mice given IL-2 alone after either subcutaneous or intratumoral injections. After an intratumoral injection of IC, the IL-2 concentration in the tumor nodules remained higher compared with mice given IL-2 alone. The anti-tumor effect was most pronounced in mice treated with intratumoral injections of IC. Conclusions: Results obtained here indicate that an immune complex of IL-2 provides a useful tool for the treatment of RCC by altering the pharmacokinetics of IL-2 in vivo.

Application of cytokine drug delivery systems to the immunotherapy of renal cell carcinoma in mice

Marumo K., Oya M., Murai M., Tazaki H.

International Journal of Urology 3 ( SUPPL. ) 1996

ISSN 0919-8172

We have investigated the antitumor effects of human lymphoblastoid interferon (HLBI) mini-pellets, interleukin-2 (IL-2) entrapped in liposome (IL-2 liposome) and an immune complex of IL-2 and monoclonal antibody against IL-2 (IC-1). The HLBI mini-pellets were administered to nude mice bearing a human renal cancer cell line (KU-2). HLBI levels remained detectable both in the tumor tissue and the serum up to 10 days after peritumor injection. The HLBI mini-pellet significantly suppressed tumor growth by peritumor administration. The antitumor effect of IL-2 liposome on Renca, a murine renal cancer, resulted in the inhibition of tumor growth. An accumulation of Lyt-2^- and L3T4^- lymphocytes was seen in the tumor tissue which was treated with IL-2 liposomes. The IC-1 was prepared by mixing IL-2 and anti-IL-2 monoclonal antibody at a molar ratio of 2:1. Plasma IL-2 levels were sustained longer in mice given the IC-1 than in mice given IL-2 alone. The IC-1 complex exerted a more significant antitumor effect by local administration in Renca-bearing mice than the administration of IL-2 alone. We speculated that these effects were a result of sustained tumor IL-2 levels due to the increase in molecular weight. The results we obtained indicate that the cytokine drug delivery system has a long-acting cytotoxicity by administration to the tumor sites through efficient stimulation of the local immune response, and thus provides a useful tool for treatment of renal cell carcinoma.

Characteristics and prognostic factor in patients with advanced renal cell carcinoma (RCC) achieving complete response by treatment using biological response modifiers (BRM)

Marumo K., Huang Y., Oya M., Tachibana M., Murai M., Tazaki H.

Biotherapy 10 ( 3 ) 554 - 556 1996

ISSN 0914-2223

One of 24 patients treated with human lymphoblastoid interferon (IFN), 2 of 20 patients treated by sequential administration of IFN and OK-432, and 3 of 18 patients treated with interleukin 2 achieved a complete response. All 6 patients had been nephrectomized, and had a common type of renal cell carcinoma. Metastatic sites were lung and mediastinum in one patient and lung alone in the other 5 patients. Five of 6 patients developed a recurrence between 11 months and 6 years of disease-free periods and did not respond to primarily effective therapy. The results demonstrated that careful observation is needed even after disappearance of a tumor by treatment with BRMs and establishment of a new modality for recurrent RCD was encouraged.

Intrarenal satellites of renal cell carcinoma ・ Histopathologic manifestation and clinical implication

Oya M, Nakamura K, Baba S, Hata J, Tazaki H

Urology 46 ( 2 ) 161-164 1995.07

Research paper (scientific journal), Joint Work

Retroperitoneal Ewing's sarcoma

Oya M., Nakashima J., Ishii T., Nakamura K., Hata J. I., Tazaki H.

Urologia Internationalis 54 ( 2 ) 104 - 106 1995

ISSN 0042-1138

We report a case of extraskeletal Ewing's sarcoma arising in the retroperitoneal cavity. The tumor was excised en bloc with the left kidney and infiltrated portion of the left ureter. Histological diagnosis was confirmed by both electron micrograph and immunohistochemical staining using a newly developed mouse monoclonal antibody 5C11, which specifically reacts with Ewing's sarcoma. An adjuvant chemotherapy T-11 regimen has been successfully preventing the recurrence.

腎細胞癌のインターロイキン2治療に与える宿主免疫能の影響

Marumo Kne, Oya Mototsugu, Ueno Munehisa, Nakamura Kaoru, Murai Masaru, Tazaki Hiroshi

Biotherapy 9 ( 7 ) 905-910 1995

Research paper (scientific journal), Joint Work

Laparoscopy assisted orchiopexy-Technical feasibility and indications

Baba S, Asanuma H, Oya M

Jpn J Endourol ESWL 8 ( 2 ) 144-147 1995

Research paper (scientific journal), Joint Work

Antitumor effects of interleukin 2 against advanced renal cell carcinoma and prognosis of the patients by long term follow-up

Oya M., Marumo K., Tazaki H.

Biotherapy 9 ( 3 ) 348 - 349 1995

ISSN 0914-2223

Eighteen patients with advanced renal cell carcinoma (RCC) were treated by systemic administration of interleukin-2 (IL-2) from March 1986 to October 1988. All of the patients received 1 x 10⁶ units of IL-2 twice a day for at least 4 weeks. Three patients achieved complete response (CR), 10 no change (NC) and 5 progressive disease (PD). Therefore, the response rate was 16.7%. Survival rate was compared with historical control group of 27 patients with advanced RCC in our institution. One, three and five year survival rate of the patients treated with IL-2 was 78%, 44% and 33%, although the historical group was 57%, 19% and 19%. We conclude that IL-2 can improve prognosis of patients with advanced RCC.

Host immune reactivity as a prognostic factor in interleukin-2 therapy of renal cell carcinoma

Marumo K., Oya M., Ueno M., Nakamura K., Murai M., Tazaki H.

Biotherapy 9 ( 7 ) 905 - 910 1995

ISSN 0914-2223

Eighteen patients with advanced renal cell carcinoma (RCC) were treated with interleukin-2 (IL-2). Seven patients were compared in terms of immunological aspects. They had survived for 55 months or more, and included three patients whose metastatic lesions had disappeared (group A) and 11 patients (group B) who had survived for 1.5 to 39 months. ECOG performance status (PS) was 0 or 1 in six of seven patients in group A, whereas no patient had a PS of 0, three patients had a PS of 1, two patients a PS of 2, and six of the 11 patients in group B had a PS of 3 or 4. Mean natural killer (NK) activity (% ⁵¹Cr release) before initiation of the therapy was 50 in group A and 26 in group B patients. However, at 2 weeks and 4 weeks, respectively, after initiation of the therapy, there was no marked difference between the two groups. Lymphokine-activated killer (LAK) activity and the number of peripheral blood lymphocytes before and after initiation of the therapy tended to be higher in group A patients. These results indicated that those patients who had achieved an objective response to IL-2 therapy or survived relatively longer exhibited a better immune status before the initiation of therapy. However, this tendency was not in evidence in some individual patients. Moreover, tumor response to IL-2 therapy was suggested to depend on the sensitivity to killer cells and other biological characteristics of each tumor cell as well as on the immune status of the patients.

Intrarenal satellites of renal cell carcinoma

Oya Mototsugu, Nakamura Kaoru, Baba Shiro, Hata Jun Ichi, Tazaki Hiroshi

Urology 46 ( 2 ) 161 - 164 1995

ISSN 0090-4295

Objectives: This study was designed to gain more insight into the incidence of satellites of renal cell carcinoma related to the pathologic stage and grade of the primary tumor. Methods: One hundred eight nephrectomized kidneys with renal cell carcinoma were sectioned at 3-mm intervals and inspected microscopically for satellite carcinomas. The number, site, size, and distance of satellite carcinomas found were recorded in relation to the primary carcinoma. Results: The overall incidence of satellite carcinoma was 6.5% (7 of 108). The incidence of satellite carcinoma in relation to the pathologic staging of the primary tumor was 7.1 % (1 of 14) in pT1, 3.0% (2 of 66) in pT2, and 14.3% (4 of 28) in pT3. The incidence was higher in patients with N1 disease (25%) than in those with NO (5.0%), and higher in M1 disease (25%) than in those in MO (5.77%). There was no relationship between the grade and multicentricity. Conclusions: The incidence of satellite carcinoma was higher in cases with high-stage primary carcinoma. However, even in localized diseases (pT1, pT2), satellite carcinomas were found at a 3.75% incidence. When nephron-sparing surgery is indicated in low-stage cases, precise clinical staging using a combination of various imaging modalities is mandatory, with intraoperative ultrasonography being one possible modality for detecting a concomitant satellite carcinoma.

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Laparoscopic surgical correction ofcircuivicaval ureter

Baba Shiro, Oya Mototsugu, Miyahara Makoto, Deguchi Nobuhiro, Tazaki Hiroshi

Urology 44 ( 1 ) 122 - 126 1994

ISSN 0090-4295

Laparoscopic transposition and reanastomosis of a circumcaval ureter were performed in a 52-year-old man with right flank pain. A preoperative perfusion pressure study revealed abnormally high intrapelvic pressure. Under laparoscopy, the renal pelvis was divided above the ureteropelvic junction and the ureter was relocated from behind the vena cava. A 5 cm segment of redundant ureter containing the postcaval segment was resected and the ureteral end and renal pelvis were reapproximated with interrupted.

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Antitumor effect of interleukin-2 entrapped in liposomes on murine renal cell carcinoma

Oya M.

Keio Journal of Medicine 43 ( 1 ) 37 - 44 1994

ISSN 0022-9717

Antitumor effects of interleukin-2 entrapped in liposomes (IL-2 liposomes) on Renca, murine renal cell carcinoma of spontaneous origin, were evaluated by in vivo and in vitro experiments. As a local treatment model, IL-2 liposomes at a dose of 1.0 x 10⁴ units were for 7 days injected adjacent to the Renca tumors inoculated in the back of BALB/c mice. The treatment inhibited the tumor growth and prolonged the survival time of mice significantly compared to the control (p<0.01). Serum IL-2 levels after subcutaneous administration of IL-2 liposomes confirmed its slow releasing mechanism into blood circulation. The spleen cells from mice following the IL-2 liposome treatment showed higher cytotoxicity in vitro than that of IL-2 alone using Renca, YAC-1, and P-815 cells, which was determined by ⁵¹Cr-release assay. Indirect immunoperoxidase staining of tumor-infiltrating lymphocytes (TILs) showed that accumulation of Lyt-2⁺ and L3T4⁺ cells were seen in the tumor treated with IL-2 liposomes. These results indicate that IL-2 liposomes have a long-acting cytotoxicity against renal cell carcinoma caused by a slow release mechanism generated through the efficient local immune response mediated by TILs.

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