Details of a Researcher - Oya, Mototsugu

Papers - Oya, Mototsugu

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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

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