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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年01月

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年

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

大家基嗣

INTERNATIONAL JOURNAL OF ENDOCRINOLOGY 1031 - 1041 2016年

研究論文（学術雑誌）, 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年

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年

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年

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年

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年

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年

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年12月

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年12月

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年12月

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年12月

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年11月

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年11月

ISSN 0923-7534

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IJU this issue

Oya Mototsugu

International Journal of Urology 22 （ 11 ） 981 2015年11月

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

大家基嗣

TRANSPLANT INTERNATIONAL 28 685 - 685 2015年11月

研究論文（学術雑誌）, 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

大家基嗣

RADIOTHERAPY AND ONCOLOGY 117 （ 2 ） 270 - 276 2015年11月

研究論文（学術雑誌）, 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年10月

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年10月

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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