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論文 - 大家　基嗣

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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年04月

研究論文（学術雑誌）, 共著, 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年04月

研究論文（学術雑誌）, 共著, 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年03月

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年03月

研究論文（学術雑誌）, 共著, 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年02月

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年02月

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年02月

研究論文（学術雑誌）, 共著, ISSN 0143-3334

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Renal cell carcinoma

Oya Mototsugu

Gan to kagaku ryoho. Cancer & chemotherapy 37 （ 1 ） 29 - 31 2010年01月

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年01月

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年

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年

研究論文（学術雑誌）, 共著

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年

研究論文（学術雑誌）, 共著, 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年12月

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年12月

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年12月

研究論文（学術雑誌）, 単著, 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年12月

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.

Yazawa S, Oya M, Nakajima Y

The Journal of urology （Journal of Urology） 182 （ 6 ） 2577 - 1000 2009年12月

研究論文（学術雑誌）, 共著, 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年12月

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年12月

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年11月

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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