Research Activities

Research Areas

• Life sciences, Urology

Published Papers

• Nivolumab in patients with unresectable locally advanced or metastatic urothelial carcinoma: CheckMate 275 2-year global and Japanese patient population analyses., Chikara Ohyama, Takahiro Kojima, Tsunenori Kondo, Yoshio Naya, Takamitsu Inoue, Yoshihiko Tomita, Masatoshi Eto, Shinichi Hisasue, Hirotsugu Uemura, Wataru Obara, Eiji Kikuchi, Padmanee Sharma, Matthew D Galsky, Arlene Siefker-Radtke, Gary Grossfeld, Sandra Collette, Kyna Gooden, Go Kimura, International journal of clinical oncology, International journal of clinical oncology, 24(9), 1089 - 1098, Sep. 2019 , Refereed
  Summary:BACKGROUND: Nivolumab has demonstrated antitumor activity and manageable safety in the single-arm, phase II CheckMate 275 study in patients with unresectable locally advanced or metastatic platinum-resistant urothelial carcinoma. We report updated results of the global population and a subanalysis of Japanese patients from this study. METHODS: Patients received nivolumab 3 mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR) confirmed by blinded independent review committee (BIRC) per Response Evaluation Criteria in Solid Tumors v1.1. Secondary endpoints included progression-free survival (PFS) by BIRC and overall survival (OS). Safety was also reported. The minimum follow-up was 21 months. RESULTS: Overall, 270 patients were treated with nivolumab globally; 23 patients were Japanese. In the global and Japanese populations, respectively, ORR per BIRC was 20.4% and 21.7%; median PFS was 1.9 (95% confidence interval [CI] 1.9-2.3) and 3.8 months (95% CI 1.9-7.2); and median OS was 8.6 (95% CI 6.1-11.3) and 21.0 months (95% CI 7.2-not reached). The most common any grade treatment-related adverse events were fatigue (18.1%) and diarrhea (12.2%) in the global population; the most common in the Japanese population were diarrhea (26.1%) and pyrexia (13.0%). Grade 3 or 4 treatment-related adverse events occurred in 61 (22.6%) and seven (30.4%) of the global and Japanese patients, respectively. CONCLUSIONS: Nivolumab continues to show antitumor activity and survival in the global population of CheckMate 275. Meaningful clinical benefit was also observed in Japanese patients. No new safety signals were identified.
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• Phase I trial of TAK-385 in hormone treatment-naïve Japanese patients with nonmetastatic prostate cancer., Suzuki H, Uemura H, Mizokami A, Hayashi N, Miyoshi Y, Nagamori S, Enomoto Y, Akaza H, Asato T, Kitagawa T, Suzuki K, Cancer medicine, Cancer medicine, Aug. 2019 , Refereed
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• Efficacy of acotiamide hydrochloride hydrate added to α-blocker plus cholinergic drug combination therapy., Koichi Sugimoto, Takahiro Akiyama, Naoki Matsumura, Takafumi Minami, Shigeya Uejima, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 26(8), 848 - 849, Aug. 2019 , Refereed
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• Apalutamide for Metastatic, Castration-Sensitive Prostate Cancer., Kim N Chi, Neeraj Agarwal, Anders Bjartell, Byung Ha Chung, Andrea J Pereira de Santana Gomes, Robert Given, Álvaro Juárez Soto, Axel S Merseburger, Mustafa Özgüroğlu, Hirotsugu Uemura, Dingwei Ye, Kris Deprince, Vahid Naini, Jinhui Li, Shinta Cheng, Margaret K Yu, Ke Zhang, Julie S Larsen, Sharon McCarthy, Simon Chowdhury, The New England journal of medicine, The New England journal of medicine, 381(1), 13 - 24, Jul. 04 2019 , Refereed
  Summary:BACKGROUND: Apalutamide is an inhibitor of the ligand-binding domain of the androgen receptor. Whether the addition of apalutamide to androgen-deprivation therapy (ADT) would prolong radiographic progression-free survival and overall survival as compared with placebo plus ADT among patients with metastatic, castration-sensitive prostate cancer has not been determined. METHODS: In this double-blind, phase 3 trial, we randomly assigned patients with metastatic, castration-sensitive prostate cancer to receive apalutamide (240 mg per day) or placebo, added to ADT. Previous treatment for localized disease and previous docetaxel therapy were allowed. The primary end points were radiographic progression-free survival and overall survival. RESULTS: A total of 525 patients were assigned to receive apalutamide plus ADT and 527 to receive placebo plus ADT. The median age was 68 years. A total of 16.4% of the patients had undergone prostatectomy or received radiotherapy for localized disease, and 10.7% had received previous docetaxel therapy; 62.7% had high-volume disease, and 37.3% had low-volume disease. At the first interim analysis, with a median of 22.7 months of follow-up, the percentage of patients with radiographic progression-free survival at 24 months was 68.2% in the apalutamide group and 47.5% in the placebo group (hazard ratio for radiographic progression or death, 0.48; 95% confidence interval [CI], 0.39 to 0.60; P<0.001). Overall survival at 24 months was also greater with apalutamide than with placebo (82.4% in the apalutamide group vs. 73.5% in the placebo group; hazard ratio for death, 0.67; 95% CI, 0.51 to 0.89; P = 0.005). The frequency of grade 3 or 4 adverse events was 42.2% in the apalutamide group and 40.8% in the placebo group; rash was more common in the apalutamide group. CONCLUSIONS: In this trial involving patients with metastatic, castration-sensitive prostate cancer, overall survival and radiographic progression-free survival were significantly longer with the addition of apalutamide to ADT than with placebo plus ADT, and the side-effect profile did not differ substantially between the two groups. (Funded by Janssen Research and Development; TITAN ClinicalTrials.gov number, NCT02489318.).
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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, Japanese journal of clinical oncology, 49(6), 506 - 514, Jun. 01 2019 , Refereed
  Summary: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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• Three-year follow-up of a phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer and bone metastases., Hirotsugu Uemura, Hiroji Uemura, Satsohi Nagamori, Yoshiaki Wakumoto, Go Kimura, Hiroaki Kikukawa, Akira Yokomizo, Atsushi Mizokami, Takeo Kosaka, Naoya Masumori, Yoshihide Kawasaki, Junji Yonese, Yasutomo Nasu, Satoshi Fukasawa, Takayuki Sugiyama, Seigo Kinuya, Makoto Hosono, Iku Yamaguchi, Takashi Akagawa, Nobuaki Matsubara, International journal of clinical oncology, International journal of clinical oncology, 24(5), 557 - 566, May 2019 , Refereed
  Summary:BACKGROUND: Radium-223 is a first-in-class targeted alpha therapy to prolong overall survival (OS) in castration-resistant prostate cancer with bone metastases (mCRPC). The aim of the present analysis was to assess the long-term safety with radium-223 in Japanese patients with mCRPC. METHODS: Patients with symptomatic mCRPC, ≥ 2 bone metastases and no known visceral metastases received up to 6 injections of radium-223 (55 kBq/kg), one every 4 weeks. Adverse events (AEs) considered to be related to radium-223 were reported until 3 years after the first injection. Pre-specified conditions, such as acute myelogenous leukemia, myelodysplastic syndrome, aplastic anemia, primary bone cancer, or other primary malignancies, were reported regardless of causality. RESULTS: Of the 49 patients enrolled in the study, 44 (89.8%) entered the survival follow-up period and 33 (67.3%) died. Throughout the entire study, there were no reports of second primary malignancy or other pre-specified conditions. Eight patients (16.3%) experienced post-treatment drug-related AEs, which were all hematological (anemia and decreased lymphocyte, platelet, and white blood cell counts). No serious post-treatment drug-related AEs were reported. Updated median OS was 19.3 months (95% CI: 14.2, 28.5). CONCLUSIONS: In Japanese patients with symptomatic mCRPC and bone metastases, radium-223 had a favorable long-term safety profile with no second primary malignancies reported. Taken together with median OS, which was comparable to that in the pivotal phase III ALSYMPCA study, these results support continued benefit from radium-223 in Japanese patients with mCRPC.
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• HOXA10 expression profiling in prostate cancer., Yuji Hatanaka, Marco A de Velasco, Takashi Oki, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, The Prostate, The Prostate, 79(5), 554 - 563, Apr. 2019 , Refereed
  Summary:BACKGROUND: HOX genes encode transcription factors that play key roles in modulating normal tissue morphogenesis, differentiation and homeostasis. Disruption of normal HOX gene expression occurs frequently in human cancers and is associated with both tumor promoting and suppressing activities. Among these is, HOXA10, a pleiotropic gene that is critical for normal prostate development. In this study we characterized HOXA10 expression in human and mouse PCa to gain insights into its clinical significance. METHODS: A meta-analysis of HOXA10 mRNA expression was carried out across several publicly available data sets. Expression of HOXA10 protein expression was assessed by immunohistochemistry (IHC) using human radical prostatectomy (RP) cases. We correlated HOXA10 expression to clinicopathological features and investigated its relationship to biochemical recurrence (BCR) after RP by the Kaplan-Meier method. HOXA10 mRNA and IHC protein expression was also examined in a mouse model of Pten-null PCa. RESULTS: A meta-analysis of HOXA10 gene expression indicated dysregulated expression of HOXA10 in human PCa. IHC profiling of HOXA10 revealed inverse correlations between HOXA10 expression and Gleason pattern, Gleason score, and pathological stage (P < 0.01). Patients with low expression profiles of HOXA10 were associated with a higher risk of BCR, (OR, 3.54; 95%CI, 1.21-16.14; P = 0.049) whereas patients with high HOXA10 expression experienced longer times to BCR (P = 0.045). However, HOXA10 was not an independent predictor of BCR (OR, 1.52; 95%CI, 0.42-5.54; P = 0.52). Evaluation of expression patterns of HOXA10 in mouse prostate tumors mimicked that of humans. CONCLUSIONS: Our findings show that HOXA10 expression is inversely associated with tumor differentiation and high HOXA10 expression is associated with improved BCR-free survival. This study provides human and mouse evidence to suggest tumor suppressive roles for HOXA10 in the context of prostate cancer.
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• Treatment patterns and outcomes in patients with unresectable or metastatic renal cell carcinoma in Japan., Kenichi Harada, Masahiro Nozawa, Motohide Uemura, Katsunori Tatsugami, Takahiro Osawa, Kazutoshi Yamana, Go Kimura, Masato Fujisawa, Norio Nonomura, Masatoshi Eto, Nobuo Shinohara, Yoshihiko Tomita, Yukihiro Kondo, Kenya Ochi, Yoshio Anazawa, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 26(2), 202 - 210, Feb. 2019 , Refereed
  Summary:OBJECTIVES: To clarify treatment patterns and outcomes for patients with unresectable or metastatic renal cell carcinoma in the molecular target therapy era in Japan. METHODS: A multicenter, retrospective medical chart review study was carried out. Patients diagnosed with unresectable or metastatic renal cell carcinoma between January 2012 and August 2015 were enrolled. Data extracted from medical records included treatment duration, grade ≥3 adverse events, reason for discontinuation for each targeted therapy and survival data until August 2016. RESULTS: Of 277 eligible patients, 266, 170 and 77 received first-, second- and third-line systemic treatment, respectively. Tyrosine kinase inhibitors were the most common first-line therapy (72.2%), followed by mammalian target of rapamycin inhibitors (14.3%) and cytokines (13.5%). Among 170 patients who received second-line treatment, tyrosine kinase inhibitor-tyrosine kinase inhibitor was the most common sequence (58.8%), followed by tyrosine kinase inhibitor-mammalian target of rapamycin inhibitor (14.1%) and cytokine-tyrosine kinase inhibitor (14.1%). With a median follow-up period of 19.8 months, median overall survival was not reached at 48 months. Patients who discontinued first-line tyrosine kinase inhibitors in <6 months showed poorer overall survival compared with patients who received first-line tyrosine kinase inhibitors for ≥6 months. CONCLUSIONS: The present analysis illustrates the contemporary treatment patterns and prognosis for patients with unresectable or metastatic renal cancer in a real-world setting in Japan. Tyrosine kinase inhibitor-tyrosine kinase inhibitor represents the most commonly used sequence. Shorter treatment duration of first-line tyrosine kinase inhibitors is associated with poorer prognosis, suggesting the need for better treatment options.
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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 cancer, 19(1), 17 - 17, Jan. 07 2019 , Refereed
  Summary: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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• Therapeutic effects of p38 MAP kinase inhibitor in storage and voiding dysfunction in mice with spinal cord injury (SCI)., Shimizu N, Suzuki T, Takaoka E, Shimizu T, Hirayama A, Uemura H, Kanai AJ, de Groat WC, Yoshimura N, Eur. Urol. Suppl., Eur. Urol. Suppl., 18, e5 - e6, 2019 , Refereed
• Generation of PTEN‑knockout (‑/‑) murine prostate cancer cells using the CRISPR/Cas9 system and comprehensive gene expression profiling., Akiko Takao, Kazuhiro Yoshikawa, Sivasundaram Karnan, Akinobu Ota, Hirotsugu Uemura, Marco A De Velasco, Yurie Kura, Susumu Suzuki, Ryuzo Ueda, Tokiko Nishino, Yoshitaka Hosokawa, Oncology reports, Oncology reports, 40(5), 2455 - 2466, Nov. 2018 , Refereed
  Summary:Phosphatase and tensin homolog (PTEN) deficiency is associated with development, progression, and metastasis of various cancers. However, changes in gene expression associated with PTEN deficiency have not been fully characterized. To explore genes with altered expression in PTEN‑deficient cells, the present study generated a PTEN‑knockout cell line (ΔPTEN) from a mouse prostate cancer‑derived cell line using the clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR‑associated protein 9 (CRISPR/Cas9) gene editing system. Following transfection of the CRISPR/Cas9 construct, DNA sequencing was performed to identify deletion of the Pten locus and PTEN inactivation was verified by western blotting. The ΔPTEN cell line exhibited enhanced RAC‑alpha serine/threonine‑protein kinase phosphorylation and cyclin D1 expression. In addition, an increase in cell proliferation and colony formation was observed in the ΔPTEN cell line. Gene expression profiling experiments were analyzed with microarray and microRNA (miRNA) arrays. In the microarray analysis, 111 genes exhibited ≥10‑fold increased expression compared with the parent strain and mock cell line and 23 genes were downregulated. The only miRNA with increased expression of 10‑fold or more was mmu‑miR‑210‑3p. Genes with enhanced expression included genes involved in the development, progression, and metastasis of cancer such as Tet methylcytosine dioxygenase 1, twist family BHLH transcription factor 2, C‑fos‑induced growth factor and Wingless‑Type MMTV Integration Site Family, Member 3, and genes involved in immunosuppression such as Arginase 1. The results of the present study suggest that PTEN deficiency mobilizes a variety of genes critical for cancer cell survival and host immune evasion.
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• Effects of nerve growth factor neutralization on TRP channel expression in laser-captured bladder afferent neurons in mice with spinal cord injury., Nobutaka Shimizu, Naoki Wada, Takahiro Shimizu, Takahisa Suzuki, Ei-Ichiro Takaoka, Anthony J Kanai, William C de Groat, Akihide Hirayama, Mamoru Hashimoto, Hirotsugu Uemura, Naoki Yoshimura, Neuroscience letters, Neuroscience letters, 683(14), 100 - 103, Sep. 14 2018 , Refereed
  Summary:Nerve growth factor (NGF) is reportedly involved in the changes in C-fiber bladder afferent pathways that induce detrusor overactivity (DO) following spinal cord injury (SCI). This study examined the roles of NGF in TRP channel expression in bladder afferent neurons in mice with SCI using laser-capture microdissection (LCM) methods. Spinal intact (SI) and SCI mice were divided into 3 groups: (1) SI with vehicle treatment; (2) SCI with vehicle treatment; and (3) SCI with anti-NGF antibody. Two weeks after SCI, an osmotic pump was placed subcutaneously into the back of the mice and vehicle or anti-NGF antibody was administered at a rate of 10 μg/kg per hour for two weeks. Four weeks after SCI, the L6 dorsal root ganglia (DRG) were removed. Expression of the TRPV1, TRPC1, TRPC3, and TRPC6 genes was analyzed using real-time polymerase chain reaction (PCR) following LCM of the bladder afferent neurons, which were labeled by Fast Blue injected into the bladder wall 1 week prior to tissue removal. The mRNA expression of TRPV1 was found to be higher in vehicle-treated SCI mice than in SI mice. The expression level of TRPC3 and TRPC6 in vehicle-treated SCI mice was lower than in SI mice. However, in SCI mice treated with anti-NGF antibody, the mRNA expression of TRPV1 was lower, and the mRNA levels of TRPC3 and TRPC6 were higher than in vehicle-SCI mice. These results suggest that the NGF-dependent changes in specific TRP channel genes, such as TRPV1, TRPC3, and TRPC6, could be involved in SCI-induced afferent hyperexcitability and DO.
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• Increased Urine Production Due to Leg Fluid Displacement Reduces Hours of Undisturbed Sleep., Keisuke Kiba, Akihide Hirayama, Motokiyo Yoshikawa, Yutaka Yamamoto, Kazumasa Torimoto, Nobutaka Shimizu, Nobumichi Tanaka, Kiyohide Fujimoto, Hirotsugu Uemura, Lower urinary tract symptoms, Lower urinary tract symptoms, 10(3), 253 - 258, Sep. 2018 , Refereed
  Summary:OBJECTIVE: To investigate whether or not the leg fluid displacement observed when moving from the standing to recumbent position at bedtime reduces the hours of undisturbed sleep (HUS). METHODS: Men aged 50 years or older who were hospitalized for urological diseases were investigated. Body water evaluation was performed three times with a bioelectric impedance method: (i) 17:00, (ii) 30 min after (short-term), and (iii) waking up (long-term). A frequency volume chart was used to evaluate the status of nocturnal urine production, and the factors affecting HUS were investigated. RESULTS: A total of 50 patients (mean age: 68 years) were enrolled. Short-term changes in extracellular fluid (ECF in the legs showed a significant positive correlation with urine production per unit of time at the first nocturnal voiding (UFN/HUS) (r = 0.45, P = 0.01). In the comparison between patients who had <3 HUS vs. those who had ≥3 HUS, the <3 HUS group showed significantly greater short-term changes in leg fluid volume, night-time water intake (17:00-06:00), and UFN/HUS. Multivariate analysis to assess the risk factors for <3 HUS indicated UFN/HUS as a risk factor in the overall model, and short-term changes in leg ECF and night-time water intake as risk factors in the model that only considered factors before sleep. CONCLUSIONS: Nocturnal leg fluid displacement may increase urine production leading up to first voiding after going to bed, and consequently, induce early awakening after falling asleep.
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• THERAPEUTIC EFFECTS OF PDE9 INHIBITOR IN STORAGE AND VOIDING DYSFUNCTION IN MICE WITH SPINAL CORD INJURY (SCI), Shimizu Nobutaka, Takaoka Ei-ichiro, Suzuki Takahisa, Kwon Joonbeom, Hashimoto Mamoru, Uemura Hirotsugu, Hirayama Akihide, Kanai Anthony J, de Groat William C, Yoshimura Naoki, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 199(4), E396 - E397, Apr. 2018 , Refereed
• NOCTURNAL ANTIDIURESIS AFTER ADMINISTRATION OF IMIDAFENACIN IS INDUCED BY CONCENTRATION OF URINE OSMOLALITY, Hashimoto, Mamoru, Shimizu, Nobutaka, Takahashi, Tomoki, Sugimoto, Koichi, Minami, Takafumi, Uemura, Hirotsugu, Hirayama, Akihide, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 199(4), E1085 - E1086, Apr. 2018 , Refereed
• 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., Toni K Choueiri, James Larkin, Mototsugu Oya, Fiona Thistlethwaite, Marcella Martignoni, Paul Nathan, Thomas Powles, David McDermott, Paul B Robbins, David D Chism, Daniel Cho, Michael B Atkins, Michael S Gordon, Sumati Gupta, Hirotsugu Uemura, Yoshihiko Tomita, Anna Compagnoni, Camilla Fowst, Alessandra di Pietro, Brian I Rini, The Lancet. Oncology, The Lancet. Oncology, 19(4), 451 - 460, Apr. 2018 , Refereed
  Summary: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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• 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, JOURNAL OF CLINICAL ONCOLOGY, 36(6), Feb. 20 2018
• A low psoas muscle volume predicts longer hospitalization and cancer recurrence in upper urinary tract urothelial carcinoma., Tsutsumi S, Kawahara T, Teranishi JI, Yao M, Uemura H, Molecular and clinical oncology, Molecular and clinical oncology, 8(2), 320 - 322, Feb. 2018 , Refereed
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• Phase II study of radium-223 dichloride in Japanese patients with symptomatic castration-resistant prostate cancer., Nobuaki Matsubara, Satsohi Nagamori, Yoshiaki Wakumoto, Hirotsugu Uemura, Go Kimura, Akira Yokomizo, Hiroaki Kikukawa, Atsushi Mizokami, Takeo Kosaka, Naoya Masumori, Yoshihide Kawasaki, Junji Yonese, Yasutomo Nasu, Satoshi Fukasawa, Takayuki Sugiyama, Seigo Kinuya, Makoto Hosono, Iku Yamaguchi, Hirokazu Tsutsui, Hiroji Uemura, International journal of clinical oncology, International journal of clinical oncology, 23(1), 173 - 180, Feb. 2018 , Refereed
  Summary:BACKGROUND: Radium-223 dichloride (radium-223) is the first targeted alpha therapy approved for the treatment of castration-resistant prostate cancer (CRPC) with bone metastases. This study investigated the efficacy and safety of radium-223 in Japanese patients with symptomatic CRPC and bone metastases. METHODS: In this open-label, multicenter, phase II study, patients with progressive, symptomatic CRPC and bone metastases were treated with radium-223 (55 kBq/kg, intravenously) in a 4-week cycle for six cycles. The primary endpoint was the percent change in total alkaline phosphatase (ALP) from baseline at 12 weeks. Secondary endpoints included the percent ALP change from baseline to end of treatment (EOT), ALP response rates, percent change in prostate-specific antigen (PSA) from baseline to 12 weeks and EOT, PSA response rates, overall survival (OS), and time to symptomatic skeletal events (SSEs). Adverse events were monitored throughout the study period. RESULTS: Of the 49 Japanese patients (median age 74 years), 28 completed all infusions. Mean percent change in total ALP and PSA from baseline to 12 weeks was -19.3 and +97.4%, respectively. One-year OS and SSE-free rate at the end of active follow-up were 78 and 89%, respectively. The ALP response rate was 31%, while the PSA response rate was 6%. Grade 3/4 treatment-emergent adverse events observed in ≥10% of patients included decreased lymphocyte count (14%), anemia (14%), anorexia (10%), and bone pain (10%). CONCLUSIONS: Radium-223 is effective and well tolerated in Japanese patients with CRPC and bone metastases. Results were comparable with the Alpharadin in Symptomatic Prostate Cancer Patients (ALSYMPCA) trial. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01929655.
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• HIF-1 alpha-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+patients with RCC, Minami, Takafumi, Sugimoto, Koichi, Shimizu, Nobutaka, De Velasco, Marco, Nozawa, Masahiro, Yoshimura, Kazuhiro, Harashima, Nanae, Harada, Mamoru, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 331 - 331, Jan. 2018 , Refereed
• Inhibition of phosphodiesterase type 9 (PDE9) improves storage and voiding dysfunction in mice with spinal cord injury, Shimizu N, Hashimoto M, Suzuki T, Takaoka E, Kwon J, Shimizu T, Wada N, Hirayama A, Uemura H, Kanai AJ, de Groat WC, Yoshimura N, Neurourol. Urodyn., Neurourol. Urodyn., 37, S96 - S97, 2018 , Refereed
• Prostate cancer immunotherapy: where are we and where are we going?, Marco A De Velasco, Hirotsugu Uemura, Current opinion in urology, Current opinion in urology, 28(1), 15 - 24, Jan. 2018 , Refereed
  Summary:PURPOSE OF REVIEW: In this review, we present the progress and current landscape for prostate cancer immunotherapy and overview recent scientific findings that shed novel insights into immunoresistance and discuss potential therapeutic strategies. RECENT FINDINGS: Prostate cancer immunogenicity is hampered by a highly immunosuppressive microenvironment and low mutation burden. Complex interactions between resident immunosuppressive cells such regulatory T cells, macrophages, myeloid-derived suppressor cells, and cancer cells cooperate to suppress antitumor immune responses and promote disease progression. A biphasic approach that boosts tumor immunogenicity and blockade of immunosuppressive pathways will most likely be required in order to produce meaningful therapeutic responses. SUMMARY: Significant advances have shed new light on prostate cancer immunology. These findings should enhance the development of immunotherapeutic strategies, especially when used in combination with other cancer treatments.
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• The Change in Neutrophil Lymphocyte Ratio from the First to the Last Repeat Prostate Biopsy Proposed as a Marker of Carcinogenesis., Mamoru Hashimoto, Naoki Matsumura, Takayuki Ohzeki, Sachiko Hongo, Koichi Sugimoto, Nobutaka Shimizu, Yasunori Mori, Takafumi Minami, Masahiro Nozawa, Kazuhiro Nose, Hideo Tahara, Kazuhiro Yoshimura, Hirotsugu Uemura, Urologia internationalis, Urologia internationalis, 101(1), 74 - 79, 2018 , Refereed
  Summary:INTRODUCTION: We investigated whether the change in the neutrophil lymphocyte ratio (NLR) from the first to the last repeat prostate biopsy (ΔNLR) could be the diagnostic tool or not for prostate cancer (PCa) detection. MATERIALS AND METHODS: We retrospectively evaluated medical records of men who had undergone repeat prostate biopsy. The investigated parameters were white blood cell, neutrophil, lymphocyte counts, NLR at the last prostate biopsy, ΔNLR, prostate-specific antigen (PSA), PSA density (PSAD), and PSA velocity. Exclusion criteria were the presence of cancers other than prostate origin, medication, and diseases which induce the change of NLR. RESULTS: A total of 301 men who had undergone repeat prostate biopsy were selected for this study. After applying exclusion criteria, 223 patients were included. Of these patients, 94 were diagnosed with PCa (Group I) and 129 with no malignancy (Group II). Only a single patient had metastasis. On evaluating the area under the receiver operating characteristic curve of all study parameters, ΔNLR was the most accurate marker, followed by PSAD and then NLR measured at the last biopsy. CONCLUSIONS: ΔNLR was the most accurate marker to improve the total predictive value in repeat prostate biopsy for diagnosing PCa.
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• Morphological changes in different populations of bladder afferent neurons detected by herpes simplex virus (HSV) vectors with cell-type-specific promoters in mice with spinal cord injury., Nobutaka Shimizu, Mark F Doyal, William F Goins, Katsumi Kadekawa, Naoki Wada, Anthony J Kanai, William C de Groat, Akihide Hirayama, Hirotsugu Uemura, Joseph C Glorioso, Naoki Yoshimura, Neuroscience, Neuroscience, 364, 190 - 201, Nov. 19 2017 , Refereed
  Summary:Functional and morphological changes in C-fiber bladder afferent pathways are reportedly involved in neurogenic detrusor overactivity (NDO) after spinal cord injury (SCI). This study examined the morphological changes in different populations of bladder afferent neurons after SCI using replication-defective herpes simplex virus (HSV) vectors encoding the mCherry reporter driven by neuronal cell-type-specific promoters. Spinal intact (SI) and SCI mice were injected into the bladder wall with HSV mCherry vectors driven by the cytomegalovirus (CMV) promoter, CGRP promoter, TRPV1 promoter or neurofilament 200 (NF200) promoter. Two weeks after vector inoculation into the bladder wall, L1 and L6 dorsal root ganglia (DRG) were removed bilaterally for immunofluorescent staining using anti-mCherry antibody. The number of CMV promoter vector-labeled neurons was not altered after SCI. The number of CGRP and TRPV1 promoter vector-labeled neurons was significantly increased whereas the number of NF200 vector-labeled neurons was decreased in L6 DRG after SCI. The median size of CGRP promoter-labeled C-fiber neurons was increased from 247.0 in SI mice to 271.3μm2 in SCI mice whereas the median cell size of TRPV1 promoter vector-labeled neurons was decreased from 245.2 in SI mice to 216.5μm2 in SCI mice. CGRP and TRPV1 mRNA levels of laser-captured bladder afferent neurons labeled with Fast Blue were significantly increased in SCI mice compared to SI mice. Thus, using a novel HSV vector-mediated neuronal labeling technique, we found that SCI induces expansion of the CGRP- and TRPV1-expressing C-fiber cell population, which could contribute to C-fiber afferent hyperexcitability and NDO after SCI.
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• Safety and efficacy of radium-223 dichloride in Japanese patients with castration-resistant prostate cancer and bone metastases., Hiroji Uemura, Hirotsugu Uemura, Nobuaki Matsubara, Seigo Kinuya, Makoto Hosono, Yoko Yajima, Toshihiko Doi, International journal of clinical oncology, International journal of clinical oncology, 22(5), 954 - 963, Oct. 2017 , Refereed
  Summary:BACKGROUND: Radiation therapy with radium-223 dichloride improves overall survival, reduces symptomatic skeletal events in Caucasian patients with castration-resistant prostate cancer (CRPC) and bone metastases, and is well tolerated. We report here the results of the first efficacy and safety study of radium-223 dichloride in a Japanese population. METHODS: In this open-label, uncontrolled, non-randomized, phase I trial, radium-223 dichloride was given to Japanese patients with CRPC and ≥2 bone metastases in 4-week cycles. The patients were divided into three cohorts, with cohort 1 and the expansion cohort receiving injections of radium-223 dichloride [55 kBq/kg body weight (BW)] every 4 weeks (Q4W) for up to six injections, and cohort 2 receiving an initial single radium-223 dichloride injection of 110 kBq/kg BW followed by up to five injections of 55 kBq/kg BW Q4W. Safety was determined via adverse event (AE) reporting, and biochemical bone markers were assessed for treatment efficacy. RESULTS: In total 19 patients received at least one dose of radium-223 dichloride and 18 patients experienced at least one treatment-emergent AE (TEAE) of which the most common were anemia, thrombocytopenia, and lymphocytopenia. Serious AEs were reported in three patients but none were drug-related. In the patients of cohort 1 + expansion cohort (55 kBq/kg BW Q4W treatment; n = 16), prostate-specific antigen levels remained stable or slightly increased while the bone alkaline phosphatase (ALP) level significantly decreased. The response rates of bone ALP (≥30 and ≥50% reductions) were 81.8 and 36.4% at week 12, and 81.3 and 50.0% at the end of treatment. CONCLUSIONS: Radium-223 dichloride was well tolerated in these Japanese patients and, at a dose of 55 kBq/kg BW, efficacy on biomarkers was as expected. The outcomes in Japanese patients were consistent with those reported in other non-Japanese populations. TRIAL REGISTRATION: ClinicalTrials.gov record NCT01565746.
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• Personalized peptide vaccines and their relation to other therapies in urological cancer., Takahiro Kimura, Shin Egawa, Hirotsugu Uemura, Nature reviews. Urology, Nature reviews. Urology, 14(8), 501 - 510, Aug. 2017 , Refereed
  Summary:Immunotherapy is an important therapeutic modality for urological cancers and several immunological agents for their treatment, such as sipuleucel-T and immune checkpoint inhibitors, have been approved by the FDA. Personalized peptide vaccines (PPVs) are an immunotherapy that uses multiple cancer peptides that are selected to complement pre-existing host immunity. Vaccination with an appropriate, individualized selection of peptides, chosen from a list of candidates, induces stronger and more rapid antitumour immunity in comparison with inoculation of conventional peptide vaccines. Phase I and phase II trials have shown that PPVs are safe and effective in urological cancers. Randomized trials in patients with castration-resistant prostate cancer showed that PPVs can significantly improve progression-free survival and overall survival. However, further studies are needed to evaluate the utility of PPVs in other urological cancers, to identify those patients who will derive the greatest benefit from this approach and to optimize the protocols for combination therapies involving PPVs.
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• Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study., Yoshihiko Tomita, Satoshi Fukasawa, Nobuo Shinohara, Hiroshi Kitamura, Mototsugu Oya, Masatoshi Eto, Kazunari Tanabe, Go Kimura, Junji Yonese, Masahiro Yao, Robert J Motzer, Hirotsugu Uemura, M Brent McHenry, Elmer Berghorn, Seiichiro Ozono, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 47(7), 639 - 646, Jul. 01 2017 , Refereed
  Summary: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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• Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study., Mototsugu Oya, Yoshihiko Tomita, Satoshi Fukasawa, Nobuo Shinohara, Tomonori Habuchi, Brian I Rini, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H Bair, Hirotsugu Uemura, Cancer science, Cancer science, 108(6), 1231 - 1239, Jun. 2017 , Refereed
  Summary: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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• Hypoxia-inducing factor (HIF)-1α-derived peptide capable of inducing cancer-reactive cytotoxic T lymphocytes from HLA-A24+ patients with renal cell carcinoma., Takafumi Minami, Naoki Matsumura, Koichi Sugimoto, Nobutaka Shimizu, Marco De Velasco, Masahiro Nozawa, Kazuhiro Yoshimura, Nanae Harashima, Mamoru Harada, Hirotsugu Uemura, International immunopharmacology, International immunopharmacology, 44, 197 - 202, Mar. 2017 , Refereed
  Summary:Hypoxic tumor microenvironment makes cancer cells to be therapy-resistant and hypoxia-inducing factors (HIFs) play a central role in hypoxic adaptation. Especially, renal cell carcinoma (RCC) is often associated with von Hippel-Lindau (VHL) gene mutations, leading to up-regulation of HIFs. However, from a different point of view, this suggests the possibility that HIFs could be promising targets in anti-cancer therapy. In this study, we searched for HIF-1α-derived peptides that are able to induce RCC-reactive cytotoxic T lymphocytes (CTLs) from HLA-A24+ RCC patients. Among five peptides derived from HIF-1α, which were prepared based on the binding motif to the HLA-A24 allele, a HIF-1α278-287 peptide induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24+ RCC patients most effectively. In immunoblot assays, the expression of HIF-1α was lowly detected in whole and nuclear lysates of RCC cell lines even under normoxia (20% O2), and their expression in whole lysates was increased under hypoxia (1% O2). Additionally, HIF-1α278-287 peptide-stimulated T cells showed a higher cytotoxicity against HLA-A24+ HIF-1α-expressing RCC cells than against HLA-A24- HIF-1α-expressing RCC cells. The cytotoxicity was inhibited by the addition of HIF-1α278-287 peptide-pulsed cold target cells. Altogether, these results indicate that the HIF-1α278-287 peptide could be a candidate for peptide-based anti-cancer vaccines for HLA-A24+ RCC patients.
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• Acotiamide hydrochloride hydrate added to combination treatment with an α-blocker and a cholinergic drug improved the QOL of women with acute urinary retention: case series., Koichi Sugimoto, Takahiro Akiyama, Nobutaka Shimizu, Naoki Matsumura, Mamoru Hashimoto, Takafumi Minami, Kazuhiro Nose, Masahiro Nozawa, Kazuhiro Yoshimura, Hirotsugu Uemura, Research and reports in urology, Research and reports in urology, 9, 141 - 143, 2017 , Refereed
  Summary:Acute urinary retention is the most common urological emergency. To resolve this emergency, urethral catheterization is performed. If the procedure fails and permanent transurethral catheterization is required, the patient's quality of life is significantly affected. Therefore, catheter-free treatment is the ideal goal of therapy for patients with acute urinary retention. Especially, for women, placement of a catheter poses a cosmetic problem. Therefore, the aim of this study was to treat female patients who had already received urapidil/distigmine bromide with acotiamide. Acotiamide was administered at a dose of 100 mg three times daily for 2 weeks, and the outcome of trial without catheter was evaluated. Only female patients were enrolled for this study. Treatment proved successful and all patients become catheter free.
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• Key predictive factors for efficacy of axitinib in first-line metastatic renal cell carcinoma: subgroup analysis in Japanese patients from a randomized, double-blind phase II study., Yoshihiko Tomita, Satoshi Fukasawa, Mototsugu Oya, Hirotsugu Uemura, Nobuo Shinohara, Tomonori Habuchi, Brian I Rini, Ying Chen, Angel H Bair, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 46(11), 1031 - 1041, Nov. 01 2016 , Refereed
  Summary: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 5 mg 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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• Axitinib-induced proteinuria and efficacy in patients with metastatic renal cell carcinoma., Masahiro Nozawa, Koichi Sugimoto, Takayuki Ohzeki, Takafumi Minami, Nobutaka Shimizu, Shogo Adomi, Yoshitaka Saito, Kazuhiro Nose, Kazuhiro Yoshimura, Hirotsugu Uemura, International journal of clinical oncology, International journal of clinical oncology, 21(4), 748 - 755, Aug. 2016 , Refereed
  Summary:BACKGROUND: No report has evaluated axitinib-induced proteinuria as a biomarker for predicting treatment efficacy and survival of patients with metastatic renal cell carcinoma (mRCC). METHODS: The subjects were patients with mRCC treated with axitinib at Kinki University Hospital from February 2008 to November 2014. Clinical records were retrospectively reviewed including baseline patient characteristics, time-dependent changes of urinary protein status, computed tomography scans of metastatic lesions, treatment duration with axitinib, and survival time. RESULTS: A total of 45 patients were evaluable. Median tumor shrinkage rates were 32.3 and 35.0 % in patients with urinary protein increases ≥+2 and <+2, respectively (p = 0.496). Objective response rates were also similar between the two groups. Median progression-free survival (PFS) times with axitinib were 13.5 months [95 % confidence interval (CI) 0.0-27.5] and 11.0 months (95 % CI 0.0-26.7) in patients with urinary protein increases ≥+2 and <+2, respectively (p = 0.975). The maximum tumor shrinkage rate with axitinib was significantly associated with PFS with axitinib as a result of multivariate analysis (p = 0.002). Median overall survival (OS) times were 39.8 months (95 % CI 12.7-67.0) and 25.4 months (95 % CI 11.2-39.6) in patients with axitinib-induced urinary protein increases ≥+2 and <+2, respectively (p = 0.250). The number of metastatic sites (p = 0.006), the MSKCC risk (p = 0.009), and the maximum tumor shrinkage rate with axitinib (p = 0.019) were significantly associated with OS as a result of multivariate analysis. CONCLUSIONS: The degree of urinary protein increase during axitinib treatment was not associated with objective response, PFS, and OS in mRCC patients treated with axitinib.
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• A Phase 2 Randomized Controlled Trial of Personalized Peptide Vaccine Immunotherapy with Low-dose Dexamethasone Versus Dexamethasone Alone in Chemotherapy-naive Castration-resistant Prostate Cancer., Kazuhiro Yoshimura, Takafumi Minami, Masahiro Nozawa, Takahiro Kimura, Shin Egawa, Hiroyuki Fujimoto, Akira Yamada, Kyogo Itoh, Hirotsugu Uemura, European urology, European urology, 70(1), 35 - 41, Jul. 2016 , Refereed
  Summary:BACKGROUND: It is well known that the prognosis of castration-resistant prostate cancer (CRPC) is poor, and several immunotherapeutic strategies have been applied to the clinical trials. Research on immunotherapy has been of special interest for the treatment of CRPC for years. OBJECTIVE: To evaluate the safety of personalized peptide vaccine (PPV) immunotherapy and its clinical outcomes. DESIGN, SETTING, AND PARTICIPANTS: A phase 2 randomized controlled trial of PPV immunotherapy with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive CRPC began in 2008. Eligible patients (prostate-specific antigen [PSA] <10 ng/ml) were human leukocyte antigen (HLA) A02, A24, or A03 superfamily positive and had asymptomatic or minimally symptomatic CRPC. Patients were allocated (1:1) to PPV plus dexamethasone (1mg/d) or to dexamethasone (1mg/d) alone. A maximum of four HLA-matched peptides (each 3mg) was selected based on the preexisting immunoglobulin G responses against the 24 warehouse peptides and administered every 2 wk. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA, progression-free survival (PFS), time to initiation of chemotherapy, and overall survival (OS) were analyzed using the Kaplan-Meier method, a log-rank test, and proportional hazard analysis. RESULTS AND LIMITATIONS: Overall, 37 patients received peptide vaccinations and 35 received dexamethasone alone. The primary end point was PSA PFS, which was significantly longer in the vaccination group than in the dexamethasone group (22.0 vs 7.0 mo; p=0.0076). Median OS was also significantly longer in the vaccination group (73.9 vs 34.9 mo; p=0.00084). The relatively small number of patients enrolled is the major limitation of the study. CONCLUSIONS: PPV immunotherapy was well tolerated and associated with longer PSA PFS and OS in men with chemotherapy-naive CRPC. A larger phase 3 study is needed to confirm our findings. PATIENT SUMMARY: We compared clinical outcomes of the treatment with personalized peptide vaccine plus dexamethasone versus dexamethasone alone. Our data provide promising evidence of clinical benefit for peptide vaccines. TRIAL REGISTRATION: UMIN-CTR: 000000959.
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• Efficacy of targeted AKT inhibition in genetically engineered mouse models of PTEN-deficient prostate cancer., Marco A De Velasco, Yurie Kura, Kazuhiro Yoshikawa, Kazuto Nishio, Barry R Davies, Hirotsugu Uemura, Oncotarget, Oncotarget, 7(13), 15959 - 76, Mar. 29 2016 , Refereed
  Summary:The PI3K/AKT pathway is frequently altered in advanced human prostate cancer mainly through the loss of functional PTEN, and presents as potential target for personalized therapy. Our aim was to determine the therapeutic potential of the pan-AKT inhibitor, AZD5363, in PTEN-deficient prostate cancer. Here we used a genetically engineered mouse (GEM) model of PTEN-deficient prostate cancer to evaluate the in vivo pharmacodynamic and antitumor activity of AZD5363 in castration-naïve and castration-resistant prostate cancer. An additional GEM model, based on the concomitant inactivation of PTEN and Trp53 (P53), was established as an aggressive model of advanced prostate cancer and was used to further evaluate clinically relevant endpoints after treatment with AZD5363. In vivo pharmacodynamic studies demonstrated that AZD5363 effectively inhibited downstream targets of AKT. AZD5363 monotherapy significantly reduced growth of tumors in castration-naïve and castration-resistant models of PTEN-deficient prostate cancer. More importantly, AZD5363 significantly delayed tumor growth and improved overall survival and progression-free survival in PTEN/P53 double knockout mice. Our findings demonstrate that AZD5363 is effective against GEM models of PTEN-deficient prostate cancer and provide lines of evidence to support further investigation into the development of treatment strategies targeting AKT for the treatment of PTEN-deficient prostate cancer.
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• Low serum dehydroepiandrosterone examined by liquid chromatography-tandem mass spectrometry correlates with poor prognosis in hormone-naïve prostate cancer., Yasuhide Miyoshi, Hiroji Uemura, Susumu Umemoto, Kentaro Sakamaki, Masataka Taguri, Kazuhiro Suzuki, Yasuhiro Shibata, Naoya Masumori, Tomohiko Ichikawa, Atsushi Mizokami, Yoshiki Sugimura, Norio Nonomura, Hideki Sakai, Seijiro Honma, Masaoki Harada, Yoshinobu Kubota, The Prostate, The Prostate, 76(4), 376 - 82, Mar. 2016 , Refereed
  Summary:BACKGROUND: There is no consensus on blood adrenal androgen concentrations in men with different stages and pathological grades of prostate cancer. In this study, dehydroepiandrosterone (DHEA) concentrations in blood were examined by ultrasensitive liquid chromatography-tandem mass spectrometry (LC-MS/MS). We analyzed the correlation between DHEA concentrations in blood and clinicopathological findings of prostate cancer. METHODS: We analyzed 196 men (mean age 70 years) with prostate cancer. The patients underwent systematic needle biopsy, and peripheral blood sampling was conducted for measurement of DHEA. DHEA concentrations in blood were determined using LC-MS/MS method. Patient age, serum prostate-specific antigen, prostate volume measured by ultrasound, and DHEA levels in blood were compared with Gleason score and clinical stage by multivariate analyses. RESULTS: Median value of PSA and prostate volume were 11.5 ng/ml and 27.7 ml, respectively. Median concentration of DHEA in blood was 1,506.4 pg/ml. There was no correlation between serum DHEA and clinical variables such as age, serum PSA, and prostate volume. In multivariate analysis, low serum DHEA levels in prostate cancer patients were significantly related to high Gleason score and advanced clinical stage. Serum PSA levels in prostate cancer patients were also significantly associated with high Gleason score and advanced clinical stage. High serum PSA and low serum DHEA levels were significantly associated with poor prognosis factors in men with hormone-naïve prostate cancer. CONCLUSIONS: DHEA concentrations in blood were examined by newly developed ultrasensitive LC-MS/MS. We confirmed that low serum DHEA levels in prostate cancer patients were related to high Gleason score and advanced clinical stage. These results suggest that serum DHEA level may be a useful prognostic factor in prostate cancer patients.
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• Involvement of renin-angiotensin-aldosterone system in calcium oxalate crystal induced activation of NADPH oxidase and renal cell injury., Hidenori Tsuji, Wei Wang, Joshi Sunil, Nobutaka Shimizu, Kazuhiro Yoshimura, Hirotsugu Uemura, Ammon B Peck, Saeed R Khan, World journal of urology, World journal of urology, 34(1), 89 - 95, Jan. 2016 , Refereed
  Summary:INTRODUCTION AND OBJECTIVES: Reactive oxygen species (ROS) are produced during the interaction between oxalate/calcium oxalate monohydrate (COM) crystals and renal epithelial cells and are responsible for the various cellular responses through the activation of NADPH oxidase (Nox). Ox and COM also activate the renin-angiotensin-aldosterone system (RAAS). Aldosterone stimulates ROS production through activation of Nox with the involvement of mineralocorticoid receptor (MR), Rac1 and mitogen-activated protein kinases (MAPK). We investigated RAAS pathways in vivo in an animal model of hyperoxaluria and in vitro by exposing renal epithelial cells to COM crystals. METHODS: Hyperoxaluria was induced in male SD rats by administering ethylene glycol. One group of rats was additionally given spironolactone. Total RNA was extracted and subjected to genomic microarrays to obtain global transcriptome data. Normal rat kidney cell line (NRK-52E) was incubated with aldosterone(10(-7) M) and COM(67 μg/cm(2)) with or without spironolactone(10(-5) M), a selective inhibitor of SRC family of kinases; protein phosphatase 2(pp2) (10(-5) M) and Nox inhibitor; diphenylene iodonium (DPI) (10(-5) M). RESULTS: Relative expression of genes encoding for AGT, angiotensin receptors 1b and 2, Renin 1, Cyp11b, HSD11B2, Nr3c2, NOx4 and Rac1 was upregulated in the kidneys of rats with hyperoxaluria. Treatment with spironolactone reversed the effect of hyperoxaluria. Both aldosterone and COM crystals activated Nox and Rac1 expression in NRK52E, while spironolactone inhibited Nox and Rac1 expression. Increased Rac1 expression was significantly attenuated by treatment with PP2 and spironolactone. CONCLUSIONS: Results indicate that hyperoxaluria-induced production of ROS, injury and inflammation are in part associated with the activation of Nox through renin-angiotensin-aldosterone pathway.
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• An Open-Label, Randomized Phase II Trial of Personalized Peptide Vaccination in Patients with Bladder Cancer that Progressed after Platinum-Based Chemotherapy., Masanori Noguchi, Kazumasa Matsumoto, Hirotsugu Uemura, Gaku Arai, Masatoshi Eto, Seiji Naito, Chikara Ohyama, Yasutomo Nasu, Masatoshi Tanaka, Fukuko Moriya, Shigetaka Suekane, Satoko Matsueda, Nobukazu Komatsu, Tetsuro Sasada, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh, Clinical cancer research : an official journal of the American Association for Cancer Research, Clinical cancer research : an official journal of the American Association for Cancer Research, 22(1), 54 - 60, Jan. 01 2016 , Refereed
  Summary:PURPOSE: The prognosis of platinum-based chemotherapy-resistant metastatic urothelial cancer of the bladder remains poor. Personalized selection of the right peptides for each patient could be a novel approach for a cancer vaccine to boost anticancer immunity. EXPERIMENTAL DESIGN: In this randomized, open-label, phase II study, patients ages ≥18 years with progressive bladder cancer after first-line platinum-based chemotherapy were randomly assigned (1:1) to receive personalized peptide vaccination (PPV) plus best supportive care (BSC) or BSC. PPV treatment used a maximum of four peptides chosen from 31 candidate peptides according to human leukocyte antigen types and peptide-reactive IgG titers, for 12 s.c. injections (8 injections, weekly; 4 injections, bi-weekly). The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall survival (OS), immune response, and toxicity. RESULTS: Eighty patients were randomly assigned to receive either PPV plus BSC (n = 39) or BSC (n = 41). No significant improvement in PFS was noted [HR, 0.7; 95% confidence interval (CI), 0.4-1.2, P = 0.17]. For the secondary endpoints, PPV plus BSC significantly prolonged OS compared with BSC (HR, 0.58; 95% CI, 0.34-0.99, P = 0.049), with median OS of 7.9 months (95% CI, 3.5-12.0) in the PPV plus BSC and 4.1 months (95% CI, 2.8-6.9) in the BSC. PPV treatment was well tolerated, without serious adverse drug reactions. CONCLUSIONS: PPV could not prolong PFS, but OS appeared to be improved with low toxicity and immune responses. Further large-scale, randomized trials are needed to confirm these results.
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• Evaluation of biochemical recurrence in patients with high-risk prostate cancer treated with radical prostatectomy and radiotherapy plus androgen deprivation therapy., Yutaka Yamamoto, Keisuke Kiba, Motokiyo Yoshikawa, Akihide Hirayama, Seiji Kunikata, Hirotsugu Uemura, Research and reports in urology, Research and reports in urology, 8, 225 - 231, 2016 , Refereed
  Summary:OBJECTIVE: The aim of this study was to evaluate the biochemical recurrence (BCR) in patients with high-risk prostate cancer (PCa) treated with radical prostatectomy (RP) or radiotherapy (RT) plus androgen deprivation therapy (ADT). METHODS: Subjects were patients with National Comprehensive Cancer Network-defined high-risk PCa treated with either RP or RT plus ADT. We calculated BCR-free survival in patients with those treatments and evaluated risk factor against BCR. RESULTS: A total of 114 patients, 71 RP and 43 RT plus ADT, were evaluated. A total of 59 and 20.9% of patients experienced BCR in the RP and RT treatment groups, respectively. The 5-year BCR-free survival probabilities improved significantly for patients who received RT compared to those who received RP (81.3 vs 37.3%, P<0.001). According to the number of risk factors, 59.2% of patients in the RP and 51.2% of patients in the RT treatment groups were classified with one risk factor (P<0.014). The 5-year BCR-free survival probabilities for patients treated with RP were 46.6 and 21.7% for one and multiple risk factors, respectively (P=0.008). On univariate analysis, only the number of risk factors had a significant impact on the risk of BCR. Meanwhile, there were no significant differences in the 5-year BCR-free survival probabilities between one and multiple risk factors in patients treated with RT. CONCLUSION: Among patients treated with RP, a marked heterogeneity existed in the oncological outcomes. Based on these findings, the number of risk factors should be emphasized to decide the optimal treatments for patients with high-risk PCa.
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• Significance of baseline bone markers on disease progression and survival in hormone-sensitive prostate cancer with bone metastasis., Masahiro Nozawa, Isao Hara, Hideyasu Matsuyama, Masayuki Iki, Kazuhiro Nagao, Tsukasa Nishioka, Takahiro Komura, Atsunobu Esa, Shigeya Uejima, Masaaki Imanishi, Yasunari Uekado, Takatoshi Ogawa, Hiroshi Kajikawa, Hirotsugu Uemura, World journal of urology, World journal of urology, 33(9), 1263 - 8, Sep. 2015 , Refereed
  Summary:PURPOSE: This study evaluated the baseline patient characteristics associated with the time to biochemical progression and overall survival in patients who participated in a phase II trial on zoledronic acid combined with the initial androgen-deprivation therapy for treatment-naïve bone-metastatic prostate cancer. METHODS: Patients received zoledronic acid 4 mg intravenously every 4 weeks for up to 24 months, concomitantly started with bicalutamide 80 mg orally every day and goserelin acetate 10.8 mg subcutaneously every 12 weeks. RESULTS: A total of 53 Japanese patients were enrolled between July 2008 and April 2010, and 52 patients were evaluable. Median follow-up period was 41.6 months. Updated median time to biochemical progression was 25.9 months (95 % confidence interval 14.5-49.9). Higher serum bone-specific alkaline phosphatase was an independent risk factor for time to biochemical progression based on multivariate analysis (hazard ratio 6.51; 95 % confidence interval 2.71-15.62; P < 0.001). Median time to biochemical progression for patients with serum bone-specific alkaline phosphatase level higher than 26 μg/L was 12.7 months. Multivariate analysis indicated that higher serum C-terminal telopeptide of type I collagen independently increased the risk of death (hazard ratio 9.62; 95 % confidence interval 2.11-43.89; P = 0.003). Median overall survival for patients with serum C-terminal telopeptide of type I collagen level higher than 8.0 ng/ml was 31.1 months. CONCLUSIONS: Baseline bone markers can be useful as predictors for disease progression and survival time in patients with bone metastasis from treatment-naïve prostate cancer treated with upfront zoledronic acid concomitantly started with androgen-deprivation therapy.
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• Identification of Programmed Death Ligand 1-derived Peptides Capable of Inducing Cancer-reactive Cytotoxic T Lymphocytes From HLA-A24+ Patients With Renal Cell Carcinoma., Takafumi Minami, Tomoko Minami, Nobutaka Shimizu, Yutaka Yamamoto, Marco De Velasco, Masahiro Nozawa, Kazuhiro Yoshimura, Nanae Harashima, Mamoru Harada, Hirotsugu Uemura, Journal of immunotherapy (Hagerstown, Md. : 1997), Journal of immunotherapy (Hagerstown, Md. : 1997), 38(7), 285 - 91, Sep. 2015 , Refereed
  Summary:Molecular therapy targeting tumor angiogenesis has been the standard treatment for metastatic renal cell carcinoma (mRCC). However, despite their significant antitumor effects, most of patients with mRCC have not been cured. Under such circumstances, anticancer immunotherapy has been considered a promising treatment modality for mRCC, and cancer-reactive cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells. However, anticancer CTLs can be inhibited by several immune inhibitory mechanisms, including the interaction between programmed death 1 (PD-1) and its ligand PD-L1, on T cells and cancer cells, respectively. Alternatively, this also means that PD-L1 could be a promising target for anticancer immunotherapy. Therefore, we searched for PD-L1-derived peptides that are applicable for anticancer vaccine for HLA-A24(+) RCC patients. Among 5 peptides derived from PD-L1, which were prepared based on the binding motif to the HLA-A24(+) allele, both PD-L1(11-19) and PD-L1(41-50) peptides induced peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients. Such PD-L1 peptide-stimulated CD8 T cells showed cytotoxicity against HLA-A24(+) and PD-L1-expressing RCC cells. Although IFN-γ treatment increased PD-L1 expression on PD-L1(low) RCC cells, their sensitivity to cytotoxicity of PD-L1 peptide-stimulated CD8(+) T cells varied between patients. Altogether, these results indicate that both PD-L1(11-19) and PD-L1(41-50) peptides could be candidates for peptide-based anticancer vaccines for HLA-A24(+) mRCC patients.
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• Differences in adverse event profiles between everolimus and temsirolimus and the risk factors for non-infectious pneumonitis in advanced renal cell carcinoma., Masahiro Nozawa, Takayuki Ohzeki, Satoshi Tamada, Fumiya Hongo, Satoshi Anai, Kiyohide Fujimoto, Tsuneharu Miki, Tatsuya Nakatani, Satoshi Fukasawa, Hirotsugu Uemura, International journal of clinical oncology, International journal of clinical oncology, 20(4), 790 - 5, Aug. 2015 , Refereed
  Summary:BACKGROUND: There have been few reports of the differences in safety between the mammalian target of rapamycin inhibitors, everolimus and temsirolimus. The purpose of this study is to compare the adverse event profiles of both agents and to estimate the risk factors for non-infectious pneumonitis in patients with advanced renal cell carcinoma on the basis of our real-world clinical experience. METHODS: Data from 218 consecutive patients that received either everolimus or temsirolimus for advanced renal cell carcinoma at five Japanese centers were retrospectively analyzed. Chi-squared test and univariate and multivariate logistic regression analyses were performed to investigate the differences in adverse event profiles and the risk factors associated with non-infectious pneumonitis, respectively. RESULTS: A total of 196 patients were evaluable. In the everolimus group compared with temsirolimus, stomatitis (56 vs 30 %, p < 0.001) and non-infectious pneumonitis (38 vs 22 %, p = 0.018) were more frequently observed, and asthenia (11 vs 23 %, p = 0.027), rash (20 vs 36 %, p = 0.018), and fatigue (33 vs 48 %, p = 0.032) occurred less frequently in all grades. On multivariate analysis, male gender (odds ratio 3.65; 95 % confidence interval 1.44-9.26, p = 0.007) and everolimus treatment (odds ratio 2.00; 95 % confidence interval 1.01-3.96, p = 0.046) were significantly associated with development of non-infectious pneumonitis. CONCLUSION: Our findings suggest that adverse event profiles may differ between everolimus and temsirolimus and that non-infectious pneumonitis may occur more frequently in patients treated with everolimus than temsirolimus. Further investigations are needed to confirm these results.
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• Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer., Yutaka Yamamoto, Marco A De Velasco, Yurie Kura, Masahiro Nozawa, Yuji Hatanaka, Takashi Oki, Takayuki Ozeki, Nobutaka Shimizu, Takafumi Minami, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, Journal of translational medicine, Journal of translational medicine, 13, 150 - 150, May 08 2015 , Refereed
  Summary:BACKGROUND: Despite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus. METHODS: Conditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays. RESULTS: Pharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30-60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naïve and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3β and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers. CONCLUSIONS: In summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.
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• Add-on anticholinergic therapy for residual nocturia in patients with lower urinary tract symptoms receiving α1-blocker treatment: a multi-centre, prospective, randomised study., Osamu Yokoyama, Akira Tsujimura, Hironobu Akino, Naoki Segawa, Satoshi Tamada, Naoki Oguchi, Yasuhide Kitagawa, Hidenori Tsuji, Akihiko Watanabe, Teruo Inamoto, Nobutaka Shimizu, Yasuyoshi Fujiuchi, Yoji Katsuoka, Haruhito Azuma, Tadashi Matsuda, Mikio Namiki, Hirotsugu Uemura, Akihiko Okuyama, Norio Nonomura, Hideki Fuse, Tatsuya Nakatani, World journal of urology, World journal of urology, 33(5), 659 - 67, May 2015 , Refereed
  Summary:PURPOSE: To evaluate the efficacy and safety of imidafenacin (IM), a novel short half-life anticholinergic, as add-on therapy for male LUTS with nocturia and nocturnal polyuria. MATERIALS AND METHODS: This multicenter, prospective, randomized, open-labelled study was conducted and involved men who had frequency, urgency, and nocturia despite receiving a stable dose of α1-blocker for ≥1 month. Subjects were randomised to control (α1-blocker alone), IM twice/day (α1-blocker +0.1 mg imidafenacin twice daily), or IM nightly (α1-blocker plus 0.1 mg imidafenacin nightly) group; the treatment period was 8 weeks. Primary endpoints included improvements in night-time frequency and Nocturia Quality of Life Questionnaire (N-QOL) scores. Secondary endpoints included changes from the baseline in frequency volume chart variables, and post-void residual volume. RESULTS AND LIMITATIONS: Compared with the controls, IM twice/day and IM nightly patients had a significantly lower night-time frequency (changes from baseline: 0.1 ± 0.8 in control, -0.6 ± 0.9 in IM twice/day, and -0.4 ± 1.0 in IM nightly, p = 0.5227, 0.0006 and 0.0143, respectively). The hours of undisturbed sleep and N-QOL score were significantly improved in IM twice/day group, though not IM nightly group. Nocturnal urine volume was significantly reduced in IM nightly group, although total urine volume remained unchanged. CONCLUSIONS: A short half-life anticholinergic is suggested to be safe and effective as an add-on therapy for residual nocturia in patients with male LUTS receiving α1-blocker treatment. Anticholinergic administration nightly could reduce the nocturnal urine volume.
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• New polycomb group protein enhancer of zeste homolog (EZH) 2-derived peptide with the potential to induce cancer-reactive cytotoxic T lymphocytes in prostate cancer patients with HLA-A3 supertype alleles., Takafumi Minami, Tomoko Minami, Nobutaka Shimizu, Yutaka Yamamoto, Marco A De Velasco, Masahiro Nozawa, Kazuhiro Yoshimura, Nanae Harashima, Mamoru Harada, Hirotsugu Uemura, International immunopharmacology, International immunopharmacology, 26(1), 133 - 8, May 2015 , Refereed
  Summary:Analyses on reactivity of anti-cancer cytotoxic T lymphocytes (CTLs) and clinical application of peptide-based anti-cancer vaccine have been mainly focused on patients with HLA-A2 or -A24 alleles. In this study, we identified an enhancer of zeste homolog (EZH) 2-derived peptide applicable for anti-cancer vaccine for prostate cancer patients with HLA-A3 supertype alleles. Five EZH2-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were functionally screened for their potential to induce peptide-specific CTLs from peripheral blood mononuclear cells (PBMCs) of HLA-A3 supertype allele(+) prostate cancer patients. As a result, EZH2733-741 peptide was found to efficiently induce peptide-specific CTLs. The EZH2733-741 peptide-stimulated and purified CD8(+) T cells from PBMCs of HLA-A3 supertype allele(+) prostate cancer patients showed higher cytotoxicity against HLA-A3 supertype allele-expressing LNCaP prostate cancer cells than against parental LNCaP cells. This cytotoxicity against HLA-A3 supertype allele-expressing LNCaP cells was partially but significantly inhibited by the addition of EZH2733-741 peptide-pulsed competitive cells. These results indicate that the EZH2733-741 peptide could be a promising candidate for peptide-based immunotherapy for HLA-A3 supertype allele(+) prostate cancer patients.
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• Conditional PTEN-deficient mice as a prostate cancer chemoprevention model., Hiroyuki Koike, Masahiro Nozawa, Marco A De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, Asian Pacific journal of cancer prevention : APJCP, Asian Pacific journal of cancer prevention : APJCP, 16(5), 1827 - 31, 2015 , Refereed
  Summary:BACKGROUND: We generated a mouse model of prostate cancer based on the adult-prostate-specific inactivation of phosphatase and tensin homolog (PTEN) using the Cre-loxP system. The potential of our mice as a useful animal model was examined by evaluating the chemopreventive efficacy of the anti-androgen, chlormadinone acetate (CMA). MATERIALS AND METHODS: Six-week-old mice were treated subcutaneously with 50 μg/g of CMA three times a week for 9 or 14 weeks and sacrificed at weeks 15 and 20. Macroscopic change of the entire genitourinary tract (GUT) and histologically evident prostate gland tumor development were evaluated. Proliferation and apoptosis status in the prostate were examined by immunohistochemistry. RESULTS: CMA triggered significant shrinkage of not only the GUT but also prostate glands at 15 weeks compared to the control (p=0.017 and p=0.010, respectively), and the trend became more marked after a further five-weeks of treatment. The onset of prostate adenocarcinoma was not prevented but the proliferation of cancer cells was inhibited by CMA, which suggested the androgen axis is critical for cancer growth in these mice. CONCLUSIONS: Conditional PTEN-deficient mice are useful as a preclinical model for chemoprevention studies and serve as a valuable tool for the future screening of potential chemopreventive agents.
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• Efficacy of silodosin in patients undergoing brachytherapy: a randomized trial involving a pressure flow study., Nobutaka Shimizu, Takafumi Minami, Koichi Sugimoto, Yoshitaka Saito, Yutaka Yamamoto, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Kiyoshi Nakamatsu, World journal of urology, World journal of urology, 32(6), 1423 - 32, Dec. 2014 , Refereed
  Summary:PURPOSE: The purpose of the study is to investigate the efficacy of an alpha-1 adrenergic receptor antagonist (silodosin) for the treatment of lower urinary tract symptoms (LUTS) associated with interstitial (125)I implantation for prostate cancer. METHODS: This randomized single-center study involved 105 patients (53 with and 52 without silodosin). Silodosin was postoperatively administered, daily, for 6 months (8 mg/day). Urinary symptoms and pressure flow were evaluated preoperatively and postoperatively at 1, 3, 6, and 12 months. RESULTS: At 12 months, interstitial (125)I implantation had induced a significant decrease in prostate volume (28.3 ± 11.1-20.5 ± 8.1 g in the silodosin group and 26.1 ± 9.7-17.7 ± 4.9 g in the controls) and the prostate-specific antigen level (7.1 ± 3.6-1.4 ± 1.7 ng/mL in the silodosin group and 8.1 ± 4.3-1.3 ± 1.2 ng/mL in the controls). Significant improvements in the international prostate symptom voiding subscores at 6 months and quality of life at 3 months were observed in those receiving silodosin. The pressure flow studies demonstrated that silodosin had significantly enlarged the bladder capacity when the first non-voiding contraction was seen at 3 and 12 months (3M: 127.1 ± 74.8 vs. 118.2 ± 83.9 mL, p = 0.001; 12M: 123.7 ± 79.3 vs. 100.3 ± 73.4 mL, p = 0.01); however, there were no improvements in the bladder outlet obstruction index (BOOI) or urinary flow. CONCLUSIONS: Silodosin temporarily improved LUTS, but did not improve the BOOI after (125)I implantation in the prostate.
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• Overall survival and final efficacy and safety results from a Japanese phase II study of axitinib in cytokine-refractory metastatic renal cell carcinoma., Masatoshi Eto, Hirotsugu Uemura, Yoshihiko Tomita, Hiroomi Kanayama, Nobuo Shinohara, Yoichi Kamei, Yosuke Fujii, Yoshiko Umeyama, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza, Cancer science, Cancer science, 105(12), 1576 - 83, Dec. 2014 , Refereed
  Summary:In an open-label, multicenter phase II study of Japanese patients with cytokine-refractory metastatic renal cell carcinoma, axitinib showed substantial antitumor activity with an acceptable safety profile. Here, we report overall survival and updated efficacy and safety results. Sixty-four Japanese patients with metastatic renal cell carcinoma following prior therapy with cytokines were treated with axitinib at a starting dose of 5 mg b.i.d. Following median treatment duration of 14.2 months, median overall survival was 37.3 months (95% CI, 28.6-49.9). The objective response rate, the primary endpoint of the study, was 51.6% (95% CI, 38.7-64.2); the median duration of response, 11.1 months (95% CI, 8.2-13.7); and the median progression-free survival was 11.0 months (95% CI, 9.2-12.0), assessed by the independent review committee. Common treatment-related all-grade adverse events were hypertension (88%), hand-foot syndrome (75%), diarrhea (66%), proteinuria (63%), fatigue (55%) and dysphonia (53%). In an exploratory analysis, median overall survival was found to be significantly longer in patients who had greater decreases in plasma levels of soluble vascular endothelial growth factor receptor-2 during the first cycle of treatment. In conclusion, the present study showed axitinib to be effective, and toxicities with long-term treatment were generally controllable with axitinib dose modification and/or standard medications in these Japanese patients. Some frequently reported adverse events warrant close monitoring and management. Changes in the plasma levels of soluble vascular endothelial growth factor receptor-2 may be used as a prognostic factor for overall survival in metastatic renal cell carcinoma following axitinib treatment. This study is registered at ClinicalTrial.gov (identifier NCT00569946).
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• A phase 2 trial of abiraterone acetate in Japanese men with metastatic castration-resistant prostate cancer and without prior chemotherapy (JPN-201 study)., Nobuaki Matsubara, Hirotsugu Uemura, Takefumi Satoh, Hiroyoshi Suzuki, Tsutomu Nishiyama, Hiroji Uemura, Katsuyoshi Hashine, Keiichiro Imanaka, Seiichiro Ozono, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 44(12), 1216 - 26, Dec. 2014 , Refereed
  Summary:OBJECTIVE: Abiraterone acetate has been approved in >70 countries for chemotherapy-naïve metastatic castration-resistant prostate cancer patients. Efficacy and safety of abiraterone acetate (1000 mg/once daily) with prednisolone (5 mg/twice daily) in chemotherapy-naïve Japanese patients with metastatic castration-resistant prostate cancer was evaluated. METHODS: Men, ≥20 years, with prostate-specific antigen levels of ≥5 ng/ml and evidence of progression were enrolled in this Phase 2, multicenter, open-label study. Primary efficacy endpoint was proportion of patients achieving a prostate-specific antigen decline of ≥50% from baseline (prostate-specific antigen response) after 12 week of treatment. Secondary efficacy endpoints and safety were assessed. RESULTS: A confirmed prostate-specific antigen response was observed in 29/48 (60.4%) patients by week 12; lower limit of two-sided 90% confidence interval was >35% (threshold response rate), demonstrating efficacy of abiraterone acetate. Secondary efficacy endpoints: prostate-specific antigen response rate during treatment period: 62.5%; objective radiographic response, partial response: 4/18 (22.2%) patients; complete response: none; stable disease: 11/18 (61.1%) patients; median percent change in prostate-specific antigen level from baseline at Week 12: -66.62%. Median prostate-specific antigen response duration and progression-free survival were not reached, and median radiographic progression-free survival was 253 days. Of 31/48 (64.6%) patients experienced adverse events of special interest; most common was hepatic function abnormality (37.5%, Grade 3: 10.4%). One Grade 3 hypertension was the only mineralocorticoid adverse event >Grade 1/2. CONCLUSIONS: Efficacy of abiraterone acetate plus prednisolone was demonstrated by decline in prostate-specific antigen levels with evidence of antitumor activity by radiography in Japanese patients with chemotherapy-naïve metastatic castration-resistant prostate cancer. Abiraterone acetate plus prednisolone had an acceptable safety profile. CLINICAL TRIAL REGISTRATION NO: NCT01756638.
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• Pazopanib for recurrent extraosseous Ewing's sarcoma of the retroperitoneum., Yutaka Yamamoto, Masahiro Nozawa, Nobutaka Shimizu, Takafumi Minami, Kazuhiro Yoshimura, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 21(11), 1183 - 4, Nov. 2014 , Refereed
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• Combination of hemoglobin, alkaline phosphatase, and age predicts optimal docetaxel regimen for patients with castration-resistant prostate cancer., Hideyasu Matsuyama, Tomoyuki Shimabukuro, Isao Hara, Yasuo Kohjimoto, Kazuhiro Suzuki, Hidekazu Koike, Hirotsugu Uemura, Taiji Hayashi, Munehisa Ueno, Kiichiro Kodaira, Yoshihiko Tomita, Toshihiko Sakurai, Nobuaki Shimizu, International journal of clinical oncology, International journal of clinical oncology, 19(5), 946 - 54, Oct. 2014 , Refereed
  Summary:BACKGROUND: We aimed to find the prognostic factors predicting overall survival (OS) in patients with castration-resistant prostate cancer (CRPC) who had docetaxel (DTX) chemotherapy, and to construct a model predicting the optimum number of cycles of DTX. METHODS: A total of 279 CRPC patients who received DTX (≥50 mg/m(2)) every 3-4 weeks were studied retrospectively. Prognostic factors predicting treatment cycles as well as OS were analyzed, and a risk table for predicting treatment cycles was constructed. RESULTS: The longer treatment group (>10 cycles) had a significantly longer OS than the standard treatment group (p < 0.0001). Multivariate analysis demonstrated that a decrease of ≥50 % in prostate-specific antigen (PSA), serum markers at the start of DTX therapy [PSA, alkaline phosphatase (ALP), and C-reactive protein (CRP)], and the number of DTX courses were independent predictors of OS. The risk table employing the combination of three factors [ALP (cut-off 189 IU/L), hemoglobin (11.3 g/dL), and age (65 years) at the start of DTX therapy], and scoring based on the hazard ratio of each risk factor (ALP 4, hemoglobin 2, age 3) could effectively predict the probability of the length of DTX therapy, with lower score (0-6) predicting >10 cycles, and higher score (7-9) predicting ≤5 cycles (p < 0.0001). No significant difference was found regarding grade 3/4 adverse events between the two groups. CONCLUSION: A model using three factors prior to chemotherapy may be beneficial for deciding the duration of DTX therapy in patients with CRPC.
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• Efficacy of traditional and alternative sunitinib treatment schedules in Japanese patients with metastatic renal cell carcinoma., Takayuki Ohzeki, Satoshi Fukasawa, Atsushi Komaru, Takeshi Namekawa, Yosuke Sato, Kimiaki Takagi, Masayuki Kobayashi, Hirotsugu Uemura, Tomohiko Ichikawa, Takeshi Ueda, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 21(10), 1065 - 8, Oct. 2014 , Refereed
  Summary:We report the adverse events and efficacy of traditional (4 weeks on 2 weeks off) and alternative sunitinib treatment schedules for Japanese patients with metastatic renal cell carcinoma. We retrospectively investigated 54 patients who received sunitinib for metastatic renal cell carcinoma between May 2006 and June 2012: 32 received a traditional treatment schedule and 22 received an alternative schedule. According to the Memorial Sloan-Kettering Cancer Center risk classification, five patients had favorable prognoses, 42 had intermediate prognoses and seven had poor prognoses. The mean observation periods were 16.3 and 20 months for the traditional and alternative schedule groups, respectively. Adverse events were significantly less common in the alternative schedule group, including most high-grade events. In the traditional and alternative schedule groups, median times to failure were 4.1 and 11.6 months (P = 0.040), median progression-free survival times were 4.1 and 11.3  months (P = 0.031), and median overall survival times were 12.0 and 32.1 months (P = 0.018), respectively. Each of these measures was better in the group of patients who received an alternative treatment schedule, suggesting that individualized changes to the sunitinib administration schedule can be effective.
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• Transfection of poly(I:C) can induce reactive oxygen species-triggered apoptosis and interferon-β-mediated growth arrest in human renal cell carcinoma cells via innate adjuvant receptors and the 2-5A system., Nanae Harashima, Takafumi Minami, Hirotsugu Uemura, Mamoru Harada, Molecular cancer, Molecular cancer, 13, 217 - 217, Sep. 17 2014 , Refereed
  Summary:BACKGROUND: Synthetic double-stranded RNA poly(I:C) is a useful immune adjuvant and exhibits direct antitumor effects against several types of cancers. In this study, we elucidated the mechanisms underlying the effects induced in poly(I:C)-transfected human renal cell carcinoma (RCC) cells. RESULTS: In contrast to the lack of an effect of adding poly(I:C), poly(I:C) transfection drastically decreased RCC cell viability. Poly(I:C) transfection induced reactive oxygen species (ROS)-dependent apoptosis in RCC cells and decreased the mitochondrial membrane potential (ΔΨm). Treatment with N-acetyl-L-cysteine (NAC), a ROS scavenger, suppressed apoptosis and restored the ΔΨm. Although the levels of phosphorylated γH2A.X, an indicator of DNA damage, increased in poly(I:C)-transfected RCC cells, NAC treatment decreased their levels, suggesting ROS-mediated DNA damage. Furthermore, poly(I:C) transfection increased the levels of phosphorylated p53, NOXA, and tBid. Immunoblots and assays with a panel of caspase inhibitors revealed that poly(I:C) transfection-induced apoptosis was dependent on caspase-8 and -9, as well as caspase-2. Alternatively, poly(I:C) transfection increased mRNA expression of interferon (IFN)-β, and treatment with IFN-β suppressed growth of RCC cells without apoptosis. In addition, cyclinD1 and c-Myc expression decreased in poly(I:C)-transfected RCC cells. Moreover, RNA interference experiments revealed that poly(I:C) transfection exerted apoptotic effects on RCC cells through innate adjuvant receptors and the 2-5A system, the latter of which induces apoptosis in virus-infected cells. CONCLUSIONS: These results suggest that poly(I:C) transfection induced two types of effects against RCC cells such as apoptosis, as a result of ROS-mediated DNA damage, and IFN-β-mediated growth arrest, both of which were exerted via innate adjuvant receptors and the 2-5A system.
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• Androgen deprivation induces phenotypic plasticity and promotes resistance to molecular targeted therapy in a PTEN-deficient mouse model of prostate cancer., Marco A De Velasco, Motoyoshi Tanaka, Yutaka Yamamoto, Yuji Hatanaka, Hiroyuki Koike, Kazuto Nishio, Kazuhiro Yoshikawa, Hirotsugu Uemura, Carcinogenesis, Carcinogenesis, 35(9), 2142 - 53, Sep. 2014 , Refereed
  Summary:Castration-resistant prostate cancer is an incurable heterogeneous disease that is characterized by a complex multistep process involving different cellular and biochemical changes brought on by genetic and epigenetic alterations. These changes lead to the activation or overexpression of key survival pathways that also serve as potential therapeutic targets. Despite promising preclinical results, molecular targeted therapies aimed at such signaling pathways have so far been dismal. In the present study, we used a PTEN-deficient mouse model of prostate cancer to show that plasticity in castration-resistant tumors promotes therapeutic escape. Unlike castration-naïve tumors which depend on androgen receptor and PI3K/AKT signal activation for growth and survival, castration-resistant tumors undergo phenotypic plasticity leading to increased intratumoral heterogeneity. These tumors attain highly heterogeneous phenotypes that are characterized by cancer cells relying on alternate signal transduction pathways for growth and survival, such as mitogen-activated protein kinase and janus kinase/signal transducer and activator of transcription, and losing their dependence on PI3K signaling. These features thus enabled castration-resistant tumors to become insensitive to the therapeutic effects of PI3K/AKT targeted therapy. Overall, our findings provide evidence that androgen deprivation drives phenotypic plasticity in prostate cancer cells and implicate it as a crucial contributor to therapeutic resistance in castration-resistant prostate cancer. Therefore, incorporating intratumoral heterogeneity in a dynamic tumor model as a part of preclinical efficacy determination could improve prediction for response and provide better rationale for the development of more effective therapies.
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• Phase II trial of zoledronic acid combined with androgen-deprivation therapy for treatment-naïve prostate cancer with bone metastasis., Masahiro Nozawa, Takeshi Inagaki, Kazuhiro Nagao, Tsukasa Nishioka, Takahiro Komura, Atsunobu Esa, Michio Kitagawa, Masaaki Imanishi, Yasunari Uekado, Takatoshi Ogawa, Hiroshi Kajikawa, Shigeya Uejima, Hideyasu Matsuyama, Isao Hara, Hirotsugu Uemura, International journal of clinical oncology, International journal of clinical oncology, 19(4), 693 - 701, Aug. 2014 , Refereed
  Summary:BACKGROUND: The efficacy of zoledronic acid in patients with treatment-naïve prostate cancer is unclear. We conducted a phase II study to investigate the benefits of combined zoledronic acid and androgen deprivation therapy in treatment-naïve prostate cancer with bone metastasis. The primary endpoint was skeletal-related event-free survival at 24 months. METHODS: Subjects were treatment-naïve patients with histologically confirmed adenocarcinoma of the prostate and radiological evidence of bone metastasis. Treatment consisted of bicalutamide 80 mg daily, goserelin acetate 10.8 mg every 12 weeks, and zoledronic acid 4 mg every 4 weeks. Zoledronic acid was continued for 24 months. RESULTS: Of the patients enrolled between July 2008 and April 2010, 52 were included in the analyses. The median age of the patients was 72 years. The median baseline prostate-specific antigen level was 249.4 ng/mL. The median follow-up period was 33.3 months. The 24-month skeletal-related event-free survival rate was 84.4 % (95 % confidence interval 71.2-91.9). The median time to prostate-specific antigen progression was 25.9 months (95 % confidence interval 14.7-36.3). The median overall survival time was not reached. Improvement in pain or maintenance of no pain during the first 12 weeks was observed in 70 % of patients and the extent of bone disease was decreased in 10 % of patients at 12 months. Grade 3 osteonecrosis of the jaw was observed in three patients (5.8 %). CONCLUSION: Zoledronic acid concomitant with androgen deprivation therapy as initial treatment in patients with treatment-naïve prostate cancer with bone metastasis resulted in an encouraging skeletal-related event-free survival rate at 24 months.
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• Use of targeted therapies for advanced renal cell carcinoma in the Asia-Pacific region: opinion statement from China, Japan, Taiwan, Korea, and Australia., Dingwei Ye, Masatoshi Eto, Jin Soo Chung, Go Kimura, Wen-Cheng Chang, Yen-Hwa Chang, See-Tong Pang, Jae Lyun Lee, Yuanjie Niu, Howard Gurney, Hirotsugu Uemura, Clinical genitourinary cancer, Clinical genitourinary cancer, 12(4), 225 - 33, Aug. 2014 , Refereed
  Summary:Rates of renal cell carcinoma (RCC) morbidity and mortality vary widely by geography, with increasing incidence in most countries. Interestingly, RCC incidence is significantly lower in Asian countries relative to other regions, which is attributed to environmental and genetic influences. Additionally, it has been demonstrated that different ethnic groups differ in their RCC characteristics which might lead to varied responses to therapy. In this review, physicians drawn from countries across the Asia-Pacific region--China, Japan, Taiwan, Republic of Korea, and Australia--take all available data into consideration to develop the first opinion statement on treatment of advanced RCC in the region. We have sought to determine what factors influence treatment patterns and availability of therapeutic agents in our respective countries, discussed whether these factors are fully justified or should be modified, and considered what additional efforts should be undertaken to optimize treatment outcomes in RCC. Additionally, we have addressed the limitations on treatment of RCC in the region, capturing the restrictive situations of targeted therapy use in the Asia-Pacific region, mainly because of drug availability and treatment reimbursement. Often this illustrates the gap between Western and regional or even among local guidelines, the opinions of leading physicians regarding the treatment, and the realistic access to agents for most patients. Proposals made in this document are based on clinical experience and data from clinical trials of RCC therapies in which Asian patients have been included.
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• URETERO-EXTERNAL ILIAC ARTERY FISTULA WITH LONGTERM INDWELLING OF URETERAL STENT, Mamoru Hashimoto, Nobutaka Shimizu, Shingo Toyoda, Yoshitaka Saito, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 60(6), 269 - 273, Jun. 2014
  Summary:We report a case of a patient with a fistula between the right ureter and external iliac artery. The patient was a 75-year-old woman who had undergone abdominal radical hysterectomy for uterine cancer, and whole pelvis radiotherapy for right external iliac lymph node metastasis. Her post-operative course was complicated by hydronephrosis of the right kidney, which was treated by the insertion of a double-J stent. While removing the frequently obstructed double-J stent after percutaneous nephrostomy, arterial hemorrhage occurred from the external urethral meatus. Computed tomographic scan demonstrated right ureteral external iliac artery fistula formation located adjacent to the pseudoaneurysm. The patient was treated successfully with endovascular stent grafting and has showed no episode of hematuria since then.
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• Osteopontin knockdown in the kidneys of hyperoxaluric rats leads to reduction in renal calcium oxalate crystal deposition., Hidenori Tsuji, Nobutaka Shimizu, Masahiro Nozawa, Tohru Umekawa, Kazuhiro Yoshimura, Marco A De Velasco, Hirotsugu Uemura, Saeed R Khan, Urolithiasis, Urolithiasis, 42(3), 195 - 202, Jun. 2014 , Refereed
  Summary:Osteopontin (OPN) expression is increased in kidneys of rats with ethylene glycol (EG) induced hyperoxaluria and calcium oxalate (CaOx) nephrolithiasis. The aim of this study is to clarify the effect of OPN knockdown by in vivo transfection of OPN siRNA on deposition of CaOx crystals in the kidneys. Hyperoxaluria was induced in 6-week-old male Sprague-Dawley rats by administering 1.5% EG in drinking water for 2 weeks. Four groups of six rats each were studied: Group A, untreated animals (tap water); Group B, administering 1.5% EG; Group C, 1.5% EG with in vivo transfection of OPN siRNA; Group D, 1.5% EG with in vivo transfection of negative control siRNA. OPN siRNA transfections were performed on day 1 and 8 by renal sub-capsular injection. Rats were killed at day 15 and kidneys were removed. Extent of crystal deposition was determined by measuring renal calcium concentrations and counting renal crystal deposits. OPN siRNA transfection resulted in significant reduction in expression of OPN mRNA as well as protein in group C compared to group B. Reduction in OPN expression was associated with significant decrease in crystal deposition in group C compared to group B. Specific suppression of OPN mRNA expression in kidneys of hyperoxaluric rats leads to a decrease in OPN production and simultaneously inhibits renal crystal deposition.
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• Identification of erythropoietin receptor-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from HLA-A24(+) patients with renal cell carcinoma., Takafumi Minami, Tomoko Minami, Nobutaka Shimizu, Yutaka Yamamoto, Marco De Velasco, Masahiro Nozawa, Kazuhiro Yoshimura, Nanae Harashima, Mamoru Harada, Hirotsugu Uemura, International immunopharmacology, International immunopharmacology, 20(1), 59 - 65, May 2014 , Refereed
  Summary:Molecular targeting therapy with anti-angiogenic agents, including sunitinib and sorafenib, has been proven to be the first- and second-line standard treatments for metastatic renal cell carcinoma (mRCC) worldwide. Despite their significant antitumor effects, most of the patients with mRCC have not been cured. Under such circumstances, anti-cancer immunotherapy has been considered as a promising treatment modality for mRCC, and cytotoxic T lymphocytes (CTLs) are the most powerful effectors among several immune cells and molecules. Therefore, we previously conducted anti-cancer vaccine therapy with peptides derived from carbonic anhydrase-9 and vascular endothelial growth factor receptor-1 as phase-I/II trials for mRCC patients and reported their clinical benefits. Alternatively, up-regulated expression of erythropoietin (Epo) and its receptor (EpoR) in RCC has been reported, and their co-expression is involved in tumorigenesis. In order to increase options for peptide-based vaccination therapy, we searched for novel EpoR-peptides for HLA-A24(+) RCC patients. Among 5 peptides derived from EpoR, which were prepared based on the binding motif to the HLA-A24 allele, EpoR52-60 peptide had the potential to induce peptide-specific CTLs from peripheral blood mononuclear cells of HLA-A24(+) RCC patients. Cytotoxicity toward HLA-A24(+) and EpoR-expressing RCC cells was ascribed to peptide-specific CD8(+) T cells. These results indicate that the EpoR52-60 peptide could be a promising candidate for a peptide-based anti-cancer vaccine for HLA-A24(+) mRCC patients.
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• Peptide vaccines with low-dose dexamethasone versus dexamethasone alone for chemotherapy-naive castration resistant prostate cancer: A randomized phase II study, Uemura, Hirotsugu, Kimura, Takahiro, Minami, Takafumi, Yoshimura, Kazuhiro, Nozawa, Masahiro, Egawa, Shin, Fujimoto, Hiroyuki, Yamada, Akira, Itoh, Kyogo, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 32(4), Feb. 2014 , Refereed
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• Favorable outcome in elderly Asian patients with metastatic renal cell carcinoma treated with everolimus: the Osaka Urologic Oncology Group., Teruo Inamoto, Haruhito Azuma, Norio Nonomura, Tatsuya Nakatani, Tadashi Matsuda, Masahiro Nozawa, Takeshi Ueda, Hidefumi Kinoshita, Kazuo Nishimura, Hiro-Omi Kanayama, Tsuneharu Miki, Yoshihiko Tomita, Toshiaki Yoshioka, Masao Tsujihata, Hirotsugu Uemura, Asian Pacific journal of cancer prevention : APJCP, Asian Pacific journal of cancer prevention : APJCP, 15(4), 1811 - 5, 2014 , Refereed
  Summary:BACKGROUND: In clinical trials with no upper age limit, the proportion of older patients is usually small, probably reflecting the more conservative approach adopted by clinicians when treating the elderly. An exploratory analysis of elderly patients in the RECORD-1 Trial showed that patients ≥ 65 y.o. had superior median PFS than overall RECORD-1 population (5.4 months and 4.9 months, respectively). We investigated the efficacy, relative benefit and safety of Everolimus (EVE) as sequential therapy after failure of VEGFr-TKI therapy for older patients with metastatic renal cell cancer (mRCC), in daily practice. MATERIALS AND METHODS: 172 consecutive IRB approved patients with mRCC (median age 65, M:F 135/37, 78% clear cell) who received salvage EVE at 39 tertiary institutions between October 2009 and August 2011 were included in this analysis. Some 31% had progressed on sunitinib, 22% on sorafenib, 1% on axitinib, 41% on sequential therapy, and 5% had received other therapy. Patients with brain metastases were not included and 95% of the patients had a ECOG (Eastern Cooperative Oncology Group) performance status (PS) of 0 or 1. Previous radiotherapy was an exclusion criterion, but prior chemotherapy was permitted. Adequate organ function and hematologic parameters were mandatory. EVE administration was approved by the institutional review board at each participating institution and signed informed consent was obtained from all patients. RESULTS: Median time of the whole cohort to last follow-up was 3.5 months (range 0.4-15.2 months). Forty four percent were continuing to take EVE at last follow- up. There were 86 (50%) patients ≥ 65 y.o. and 86 (50%) <65 y.o. The percentage of patients who showed PR/ SD was higher in the older group than in the younger one (5.9%/61.2% vs 1.2%/46.5%, respectively). Median survival of older patients was also significantly longer (3.5 +/- 0.31 vs 3.1 +/- 0.34, hazard ratio=0.45, CI; 0.255- 0.802). Analysis using Cox regression model adjusted for gender, PS, number of metastases, site of metastases, histology, smoking history and age detected an association between age and PFS (p=0.011). The frequency of adverse events in elderly patients treated with EVE was no greater than that in younger patients, although such toxicity may have had a greater impact on their quality of life. CONCLUSIONS: Older patients should not generally be excluded from accepted therapies (mTOR inhibitors after failure of VEGFr-TKI therapy) for mRCC.
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• Effects of the Rho kinase inhibitor, hydroxyfasudil, on bladder dysfunction and inflammation in rats with HCl-induced cystitis., Nobutaka Shimizu, Marco A De Velasco, Tohru Umekawa, Hirotsugu Uemura, Kazuhiro Yoshikawa, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 20(11), 1136 - 43, Nov. 2013 , Refereed
  Summary:OBJECTIVE: To evaluate the effect of the Rho kinase inhibitor, hydroxyfasudil, on bladder function in a rat model of HCl-induced chemical cystitis, and to elucidate the possible mechanisms associated with its therapeutic effect. METHODS: Female Sprague-Dawley rats with HCl-induced cystitis were given hydroxyfasudil (10 mg/kg, i.p.) for 7 days. Treatment efficacy was determined by comparing bladder function and histopathology to sham and untreated control rats. Bladder function was determined by cystometric analysis. Rho kinase activity was determined by quantitative reverse transcription polymerase chain reaction and signal inhibition of downstream Ras homolog member A/Rho kinase signaling molecules by western blot and immunohistochemistry. RESULTS: Treatment with hydroxyfasudil significantly improved bladder intercontraction intervals. Rats treated with hydroxyfasudil also showed a significant reduction of histopathological features associated with cystitis. Western blot and immunohistochemistry findings showed that hydroxyfasudil inhibited downstream molecules of Rho kinase that ameliorated changes associated with HCl-induced chemical cystitis, such as inflammatory cell recruitment and smooth muscle cell proliferation. CONCLUSION: The findings from the present study suggest a promising therapeutic role for hydroxyfasudil in bladder inflammation associated with cystitis.
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• Adverse event profile and dose modification of everolimus for advanced renal cell carcinoma in real-world Japanese clinical practice., Masahiro Nozawa, Norio Nonomura, Takeshi Ueda, Kazuo Nishimura, Hiro-Omi Kanayama, Tsuneharu Miki, Tatsuya Nakatani, Yoshihiko Tomita, Haruhito Azuma, Toshiaki Yoshioka, Masao Tsujihata, Hirotsugu Uemura, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 43(11), 1132 - 8, Nov. 2013 , Refereed
  Summary:OBJECTIVE: The aim of the study was to assess the safety and efficacy of everolimus therapy for advanced renal cell carcinoma in Japanese patients receiving real-world care. METHODS: Patients who had been treated with everolimus for advanced renal cell carcinoma at 39 Japanese medical centers between January 2010 and November 2011 were retrospectively investigated to assess adverse events and the time to treatment failure. RESULTS: A total of 180 patients were identified. Their median age was 65 years (range 23-93). The median time to treatment failure was 2.9 months (95% confidence interval 2.4-3.4). The median time to treatment failure was significantly longer in patients with dose modification (4.2 months; 95% confidence interval 3.4-5.0) than in patients without dose modification (1.7 months; 95% confidence interval 1.0-2.3; P < 0.01) after experiencing adverse events. Stomatitis (44%) was the most frequent adverse event, followed by thrombocytopenia (31%), anemia (22%), interstitial pneumonia (22%) and hyperglycemia (17%). Interstitial pneumonia was the most frequent cause of discontinuation in patients who discontinued everolimus due to intolerability regardless of the dose modification status. None of the patients with dose modification of everolimus discontinued everolimus due to thrombocytopenia or leukopenia. CONCLUSIONS: The adverse event profile of everolimus may differ between Japanese and Caucasian patients. Dose modification of everolimus might be associated with longer treatment duration in patients with advanced renal cell carcinoma. Further studies are required to clarify this association. Interstitial pneumonia may be difficult to overcome by dose modification.
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• [A case of a nonseminomatous germ cell tumor responding to MEA therapy]., Yasuharu Nagai, Takafumi Minami, Yoshitaka Itami, Yasuyuki Kobayashi, Nobutaka Shimizu, Yutaka Yamamoto, Taiji Hayashi, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 59(10), 693 - 7, Oct. 2013 , Refereed
  Summary:We experienced a case of testicular cancer that was successfully treated by salvage chemotherapy comprised of methotrexate, actinomycin D and etoposide (MEA). A 25-year-old man was admitted to our hospital with a diagnosis of stage III B2 (JUA classification) testicular cancer. The patient had multiple lung metastases, and underwent a left orchiectomy. A histopathological examination revealed a choriocarcinoma, embryonal carcinoma, mature teratoma, and a yolk sac tumor. Tumor marker levels were elevated ; human chorionic gonadotropin β was 46 mIU/ml and alpha fetoprotein was 437 ng/ml. Although he was treated post-operatively with two courses of bleomycin, etoposide and cisplatin therapy, four courses of high-dose carboplatin, etoposide and iphosphamide (VIP) therapy, and two courses of CPT-11＋ cisplatin therapy, tumor maker levels remained elevated and lung metastases were stable. Accordingly, he received three courses of MEA therapy. MEA therapy is regimen used to treat gestational trophoblastic neoplasia. After MEA therapy, levels of the tumor markers normalized. He then underwent a partial resection of lung and enucleation of lung metastasis by the video assisted thoracoscopic surgery method. Histopathological examination of the lung metastasis revealed only necrotic tissue. Tumor recurrence has not been observed in the 14 months since the MEA therapy.
• Pazopanib versus sunitinib in metastatic renal-cell carcinoma., Robert J Motzer, Thomas E Hutson, David Cella, James Reeves, Robert Hawkins, Jun Guo, Paul Nathan, Michael Staehler, Paul de Souza, Jaime R Merchan, Ekaterini Boleti, Kate Fife, Jie Jin, Robert Jones, Hirotsugu Uemura, Ugo De Giorgi, Ulrika Harmenberg, Jinwan Wang, Cora N Sternberg, Keith Deen, Lauren McCann, Michelle D Hackshaw, Rocco Crescenzo, Lini N Pandite, Toni K Choueiri, The New England journal of medicine, The New England journal of medicine, 369(8), 722 - 31, Aug. 22 2013 , Refereed
  Summary:BACKGROUND: Pazopanib and sunitinib provided a progression-free survival benefit, as compared with placebo or interferon, in previous phase 3 studies involving patients with metastatic renal-cell carcinoma. This phase 3, randomized trial compared the efficacy and safety of pazopanib and sunitinib as first-line therapy. METHODS: We randomly assigned 1110 patients with clear-cell, metastatic renal-cell carcinoma, in a 1:1 ratio, to receive a continuous dose of pazopanib (800 mg once daily; 557 patients) or sunitinib in 6-week cycles (50 mg once daily for 4 weeks, followed by 2 weeks without treatment; 553 patients). The primary end point was progression-free survival as assessed by independent review, and the study was powered to show the noninferiority of pazopanib versus sunitinib. Secondary end points included overall survival, safety, and quality of life. RESULTS: Pazopanib was noninferior to sunitinib with respect to progression-free survival (hazard ratio for progression of disease or death from any cause, 1.05; 95% confidence interval [CI], 0.90 to 1.22), meeting the predefined noninferiority margin (upper bound of the 95% confidence interval, <1.25). Overall survival was similar (hazard ratio for death with pazopanib, 0.91; 95% CI, 0.76 to 1.08). Patients treated with sunitinib, as compared with those treated with pazopanib, had a higher incidence of fatigue (63% vs. 55%), the hand-foot syndrome (50% vs. 29%), and thrombocytopenia (78% vs. 41%); patients treated with pazopanib had a higher incidence of increased levels of alanine aminotransferase (60%, vs. 43% with sunitinib). The mean change from baseline in 11 of 14 health-related quality-of-life domains, particularly those related to fatigue or soreness in the mouth, throat, hands, or feet, during the first 6 months of treatment favored pazopanib (P<0.05 for all 11 comparisons). CONCLUSIONS: Pazopanib and sunitinib have similar efficacy, but the safety and quality-of-life profiles favor pazopanib. (Funded by GlaxoSmithKline Pharmaceuticals; COMPARZ ClinicalTrials.gov number, NCT00720941.).
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• Role of vaccine therapy for renal cell carcinoma in the era of targeted therapy., Kazuhiro Yoshimura, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 20(8), 744 - 55, Aug. 2013 , Refereed
  Summary:Renal cell carcinoma is the most common malignant tumor originating from the kidney. Compared with other solid tumors, it does not respond to traditional management modalities, such as chemotherapy and radiotherapy. However, it is well known that renal cell carcinoma represents one of the most immune-responsive cancers and several immunotherapeutic strategies have been investigated in the management of renal cell carcinoma with variable degrees of success. The development of immunotherapy with α-interferon or high-dose interleukin-2 is the best established treatment, and is associated with durable disease control. Although the lack of defined antigens in renal cell carcinoma has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of renal cell carcinoma for more than 30 years. At present, there are three types of cell-based vaccines in renal cell carcinoma treatment: autologous tumor-cell vaccines, genetically modified tumor vaccines and dendritic cell-based vaccines. A further type is peptide-based vaccination with tumor-associated antigens as possible targets, such as carbonic anhydrase IX, survivin and telomerase that are overexpressed in renal cell carcinoma. In the present article, we review data from completed clinical trials of vaccine therapy, and discuss future trials to assess the current knowledge and future role of vaccine therapy for renal cell carcinoma in the era of recently developed targeted therapy.
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• INTERIM ANALYSIS ON THE EFFECT OF TADALAFIL ON SEXUAL FUNCTION IN PATIENTS TREATED WITH BRACHYTHERAPY, Nagai, Yasuharu, Shimizu, Nobutaka, Minami, Takafumi, Yamamoto, Yutaka, Hayashi, Taiji, Tsuji, Hidenori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Ishii, Tokumi, Uemura, Hirotsugu, JOURNAL OF SEXUAL MEDICINE, JOURNAL OF SEXUAL MEDICINE, 10, 244 - 244, Jun. 2013 , Refereed
• INFLUENCE OF ORAL ADMINISTRATION OF A1-AR ANTAGONISTS ON SEXUAL FUNCTION FOR PATIENTS RECEIVING BRACHYTHERAPY, Shimizu, Nobutaka, Minami, Takafumi, Nagai, Yasuharu, Yamamoto, Yutaka, Hayashi, Taiji, Tsuji, Hidenori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Ishii, Tokumi, Uemura, Hirotsugu, JOURNAL OF SEXUAL MEDICINE, JOURNAL OF SEXUAL MEDICINE, 10, 243 - 243, Jun. 2013 , Refereed
• Efficacy and safety of axitinib versus sorafenib in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from the global randomized Phase 3 AXIS trial., Takeshi Ueda, Hirotsugu Uemura, Yoshihiko Tomita, Taiji Tsukamoto, Hiroomi Kanayama, Nobuo Shinohara, Jamal Tarazi, Connie Chen, Sinil Kim, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 43(6), 616 - 28, Jun. 2013 , Refereed
  Summary:OBJECTIVE: Axitinib is a potent and selective second-generation inhibitor of vascular endothelial growth factor receptors 1, 2 and 3. The efficacy and safety of axitinib in Japanese patients with metastatic renal cell carcinoma were evaluated. METHODS: A subgroup analysis was conducted in Japanese patients enrolled in the randomized Phase III trial of axitinib versus sorafenib after failure of one prior systemic therapy for metastatic renal cell carcinoma. RESULTS: Twenty-five (of 361) and 29 (of 362) patients randomized to the axitinib and sorafenib arms, respectively, were Japanese and included in this analysis. Median progression-free survival in Japanese patients was 12.1 months (95% confidence interval 8.6 to not estimable) for axitinib and 4.9 months (95% confidence interval 2.8-6.6) for sorafenib (hazard ratio 0.390; 95% confidence interval 0.130-1.173; stratified one-sided P = 0.0401). The objective response rate was 52.0% for axitinib and 3.4% for sorafenib (P = 0.0001). The common all-causality adverse events (all grades) in Japanese patients were dysphonia (68%), hypertension (64%), hand-foot syndrome (64%) and diarrhea (56%) for axitinib, and hand-foot syndrome (86%), hypertension (62%) and diarrhea (52%) for sorafenib. The safety profiles of axitinib and sorafenib in Japanese patients were generally similar to those observed in the overall population, with the exceptions of higher incidences of hypertension, dysphonia, hand-foot syndrome, hypothyroidism and stomatitis. CONCLUSIONS: Axitinib is efficacious and well tolerated in Japanese patients with previously treated metastatic renal cell carcinoma, consistent with the results in the overall population, providing a new targeted therapy for these Japanese patients.
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• Clinical utility of the prostate cancer gene 3 (PCA3) urine assay in Japanese men undergoing prostate biopsy., Atsushi Ochiai, Koji Okihara, Kazumi Kamoi, Takehiro Oikawa, Toru Shimazui, Shin-Ichiro Murayama, Kyoichi Tomita, Tohru Umekawa, Hirotsugu Uemura, Tsuneharu Miki, BJU international, BJU international, 111(6), 928 - 33, May 2013 , Refereed
  Summary:UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: It is known that a prostate cancer gene 3 (PCA3) urine assay is superior to serum PSA level or PSA-related indices for predicting a positive biopsy result in European and US men. This is the first report on PCA3 in a large cohort of Japanese men. The diagnostic value of the PCA3 score in Japanese men was similar to those reported in European and US men. The study concludes that a combination of PSA density and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy. OBJECTIVE: To examine the diagnostic performance of the prostate cancer gene 3 (PCA3) score for prostate cancer in Japanese men undergoing prostate biopsy. PATIENTS AND METHODS: This Japanese, multicentre study included 647 Asian men who underwent extended prostate biopsy with elevated prostate-specific antigen (PSA) and/or abnormal digital rectal examination (DRE). Urine samples were collected after DRE. The PCA3 score was determined using a PROGENSA PCA3 assay and correlated with biopsy outcome. Its diagnostic accuracy was compared with that of serum PSA level, prostate volume (PV), PSA density (PSAD), and free/total PSA ratio (f/t PSA). RESULTS: A total of 633 urine samples were successfully analysed (the informative rate was 98%). Median PSA was 7.6 ng/mL. Biopsy revealed cancer in 264 men (41.7%). The PCA3 score for men with prostate cancer was significantly higher than that for men with negative biopsies (median PCA3 score: 49 vs. 18; P < 0.001). The rate of positive biopsy was 16.0% in men with a PCA3 score of <20 and 60.6% in those with a PCA3 score of ≥50. Using a PCA3 score threshold of 35, sensitivity and specificity were 66.5 and 71.6%, respectively. The area under the curve of the PCA3 score was significantly higher than that of the f/t PSA in men with PSA 4-10 ng/mL (0.742 vs 0.647; P < 0.05). In men with PSAD < 0.15 and PCA3 < 20, only three (4.2%) out of 72 men had prostate cancer. CONCLUSIONS: The PCA3 score was significantly superior to f/t PSA in predicting a positive biopsy result for prostate cancer in Japanese men with PSA 4-10 ng/mL. The combination of PSAD and PCA3 score may be useful for selecting patients who could avoid an unnecessary biopsy.
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• STAT3 polymorphism can predict the response to interferon-α therapy in patients with metastatic renal cell carcinoma., Masatoshi Eto, Tomomi Kamba, Hideaki Miyake, Masato Fujisawa, Takao Kamai, Hirotsugu Uemura, Taiji Tsukamoto, Haruhito Azuma, Akio Matsubara, Kazuo Nishimura, Tsuyoshi Nakamura, Osamu Ogawa, Seiji Naito, European urology, European urology, 63(4), 745 - 52, Apr. 2013 , Refereed
  Summary:BACKGROUND: In our 2007 retrospective study, we reported that single nucleotide polymorphisms (SNPs) in the signal transducer and activator of transcription 3 (acute-phase response factor) (STAT3) gene were significantly associated with better response to interferon (IFN)-α in patients with metastatic renal cell carcinoma (mRCC). OBJECTIVE: To prospectively confirm those results, the Japan Immunotherapy SNPs-Study Group for Kidney Cancer conducted this trial. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter, prospective study, 203 eligible patients were enrolled. We evaluated the correlation between the antitumor effects of IFN-α and 11 SNPs (STAT3-2, STAT3-0, SOCS3-1, IL4R-34, PTGS1-3, PTGS1-4, PTGS1-5, PTGS2-12, IRF2-67, ICSBP-38, and TAP2-5) in eight genes in 180 patients who received IFN-α for >12 wk. INTERVENTIONS: Patients were treated with three doses per week of IFN-α 5 million IU. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We analyzed the association of response to IFN-α and overall survival (OS) with genetic polymorphisms using a chi-square test and a logistic regression model. RESULTS AND LIMITATIONS: The response rate of IFN-α was 13.8% (28 of 203 patients; 9 complete responses [CRs], 19 partial responses [PRs]). The CR rate of 4.4% was higher than we expected. Response to IFN-α was not associated with any of the 11 SNPs examined. However, when we assessed patients with CR, PR, and stable disease >24 wk as a group representing those with clinical response, a significant association was observed between STAT3-2 (rs1905341) and the clinical response of IFN-α (p=0.039). Namely, C/C genotype of STAT3-2 was significantly associated with the clinical response of IFN-α and OS. These results were generated in Japanese patients and should be studied in other ethnic groups. CONCLUSIONS: This is the first prospective study demonstrating that a STAT3 polymorphism can be a predictive marker for treatment with IFN-α for patients with mRCC.
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• Systemic transduction of p16INK4A antitumor peptide inhibits the growth of MBT-2 mouse bladder tumor cell line grafts., Toru Shimazui, Kazuhiro Yoshikawa, Jun Miyazaki, Takahiro Kojima, Hiromu Inai, Satoshi Ando, Hirotsugu Uemura, Kazuhiko Uchida, Hiroyuki Nishiyama, International journal of oncology, International journal of oncology, 42(2), 543 - 8, Feb. 2013 , Refereed
  Summary:p16(INK4a) (p16), a key molecule in bladder tumor development, inhibits the activities of cyclin-dependent kinases (CDKs) and maintains the retinoblastoma protein (pRb) in its active hypophosphorylated state. Following the finding that the p16 antitumor peptide dramatically inhibits the growth of aggressive leukemia/lymphoma through the restoration of p16 function using the Wr-T peptide transporter system, in this study, we developed a systemic therapy using mouse‑p16 peptide (m‑p16) in subcutaneous p16‑null mouse bladder tumors. In vitro analysis showed that the growth of p16‑null bladder tumor cells and the hyperphosphorylation of their pRbs were inhibited by p16 transduction in a concentration‑dependent manner. In an animal model, p16‑null MBT‑2 cells were injected subcutaneously into KSN/SKC nude mice. The systemic delivery of the m‑p16 peptide using Wr‑T by cardiac injection significantly inhibited the growth of solid MBT‑2 tumors compared with the control phosphate‑buffered saline (PBS) injection. Histological examination by TUNEL staining revealed that apoptosis was increased and pRb phosphorylation was inhibited. Thus, the systemic peptide delivery of p16 restores the hypophosphorylation of pRb and may be a useful tool for the treatment of bladder tumors.
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• Survey on lower urinary tract symptoms and sleep disorders in patients treated at urology departments., Nobutaka Shimizu, Yasuharu Nagai, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Takashi Oki, Koichi Sugimoto, Kazuhiro Nose, Tsukasa Nishioka, Nature and science of sleep, Nature and science of sleep, 5, 7 - 13, 2013 , Refereed
  Summary:OBJECTIVES: This study examined the association between sleep disorders and lower urinary tract symptoms in patients who had visited urology departments. METHODS: This was an independent cross-sectional, observational study. Outpatients who had visited the urology departments at the Kinki University School of Medicine or the Sakai Hospital, Kinki University School of Medicine, between August 2011 and January 2012 were assessed using the Athens Insomnia Scale and the International Prostate Symptom Score. RESULTS: In total, 1174 patients (mean age, 65.7 ± 13.7 years), with 895 men (67.1 ± 13.2 years old) and 279 women (61.4 ± 14.6 years old), were included in the study. Approximately half of these patients were suspected of having a sleep disorder. With regard to the International Prostate Symptom Score subscores, a significant increase in the risk for suspected sleep disorders was observed among patients with a post-micturition symptom (the feeling of incomplete emptying) subscore of ≥1 (a 2.3-fold increase), a storage symptom (daytime frequency + urgency + nocturia) subscore of ≥5 (a 2.7-fold increase), a voiding symptom (intermittency + slow stream + hesitancy) subscore of ≥2 (a 2.6-fold increase), and a nocturia subscore of ≥2 (a 1.9-fold increase). CONCLUSION: The results demonstrated that the risk factors for sleep disorders could also include voiding, post-micturition, and storage symptoms, in addition to nocturia.
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• Clinical outcome of incidentally discovered small renal cell carcinoma after delayed surgery., Koichi Sugimoto, Nobutaka Shimizu, Takashi Oki, Kazuhiro Nose, Tsukasa Nishioka, Shogo Adomi, Takayuki Ohzeki, Atsunobu Esa, Hirotsugu Uemura, Cancer management and research, Cancer management and research, 5, 85 - 9, 2013 , Refereed
  Summary:BACKGROUND: This study was undertaken to investigate the growth rate and clinical outcome of patients with a small renal mass (SRM) after delayed surgery. METHODS: We reviewed the clinical records of 34 patients with SRMs ≤ 4 cm at diagnosis, who underwent delayed surgical intervention during surveillance from January 2000 to December 2011. Radiographic evaluations using computed tomography (CT) scan and magnetic resonance imaging (MRI) were performed at least every 6 months, and the tumor size was determined at least twice. RESULTS: The mean follow-up time was 26.6 ± 18.6 months and mean tumor doubling time was 23.4 ± 16.0 months. Histopathological analysis revealed that 32 of the 34 patients were malignant in pT1aN0M0. Only one patient showed tumor recurrence, who subsequently died due to tumor progression. CONCLUSION: The growth rate of the small renal mass was slow in the majority of our patients. Delayed intervention does not have a detrimental effect on cancer-specific outcomes.
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• Clinical Outcome of Small Renal Cell Carcinoma after Delayed Surgery versus Immediate Surgery., Koichi Sugimoto, Nobutaka Shimizu, Kazuhiro Nose, Hideo Tahara, Masaaki Imanishi, Tsukasa Nishioka, Atsunobu Esa, Hiroshi Kajikawa, Hirotsugu Uemura, Journal of Cancer, Journal of Cancer, 4(6), 514 - 8, 2013 , Refereed
  Summary:BACKGROUND: This study was undertaken to investigate the growth rate and clinical outcome of patients with a small renal mass (SRM) after delayed surgery versus immediate surgery. METHODS: We reviewed the clinical records of 328 patients with SRM ≦ 4cm at diagnosis, who underwent delayed or immediate surgical intervention from January 2000 to December 2011. Radiographic evaluation using CT scan and MRI were performed at least every 6 months and the tumor size was determined at least twice in the delayed surgery group. RESULTS: A total of 292 RCC patients with pT1aN0M0 were identified; among them, 32 patients had been managed with delayed surgery intervention. No statistically significant difference was observed in overall survival rate (OSR) and cancer recurrence-free rate (CRFR). But cancer-specific survival rate (CSSR) was significantly lower in the delayed surgery group (p=0.0002). CONCLUSIONS: The overall survival rate of delayed surgery was not inferior compared with that after immediate surgery. Delayed surgery intervention for SRMs is a treatment option in the current study.
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• Procalcitonin as a useful marker to decide upon intervention for urinary tract infection., Koichi Sugimoto, Nobutaka Shimizu, Naoki Matsumura, Takashi Oki, Kazuhiro Nose, Tsukasa Nishioka, Hirotsugu Uemura, Infection and drug resistance, Infection and drug resistance, 6, 83 - 6, 2013 , Refereed
  Summary:BACKGROUND: Because the use of procalcitonin has been advocated as a marker of bacterial infection, this study was carried out to determine the usefulness of serum PCT as an early marker to decide upon intervention for urinary tract infection. METHODS: The subjects were 68 patients with urinary tract infection (UTI) in whom we measured serum procalcitonin concentration at the start of treatment. RESULTS: There were 47 patients with nonobstructed UTI and 21 with obstructed UTI. All patients with obstructed UTI were subjected to intervention. There were significant differences in procalcitonin, white blood cells, and creatinine levels between patients with nonobstructed and obstructed UTI (P < 0.05). CONCLUSION: Although this retrospective study comprised a small number of patients, we found that procalcitonin was a useful marker to decide upon urinary intervention.
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• Therapeutic efficacy and anti-inflammatory effect of ramelteon in patients with insomnia associated with lower urinary tract symptoms., Nobutaka Shimizu, Masahiro Nozawa, Koichi Sugimoto, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Research and reports in urology, Research and reports in urology, 5, 113 - 9, 2013 , Refereed
  Summary:OBJECTIVES: This study was conducted to examine the therapeutic efficacy and anti-inflammatory effect of ramelteon in elderly patients with insomnia associated with lower urinary tract symptoms (LUTS), who visited our urology department. METHODS: The study included 115 patients (102 men, 13 women) who scored ≥4 on the Athens Insomnia Scale and who wished to receive treatment. The assessment scales for therapeutic efficacy included the International Prostate Symptom Score (IPSS) for LUTS and the Insomnia Severity Index (ISI) for sleep disorders. The high-sensitivity C-reactive protein (hs-CRP) test was used to an objective assessment. The patients were treated with ramelteon (8 mg/day) for an average of 10 weeks and were then reexamined using the questionnaires and hs-CRP test to evaluate therapeutic efficacy. RESULTS: IPSS total scores declined significantly from 11.39 ± 8.78 to 9.4 ± 7.72. ISI total scores improved significantly from 11.6 ± 5.2 to 9.2 ± 5.3 (P < 0.0001). The levels of hs-CRP decreased significantly from 0.082 (standard deviation [SD] upper limit, 0.222; SD lower limit, -0.059) to 0.06 (SD upper limit, 0.152; SD lower limit, -0.032). The ISI scores ≥ 10 (n = 51) showed a weak correlation with the hs-CRP levels. CONCLUSION: Ramelteon had a systemic anti-inflammatory effect and improved sleep disorders and LUTS, suggesting that it may be a useful treatment for patients with LUTS-associated insomnia.
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• Sorafenib rechallenge in patients with metastatic renal cell carcinoma., Masahiro Nozawa, Yutaka Yamamoto, Takafumi Minami, Nobutaka Shimizu, Yuji Hatanaka, Hidenori Tsuji, Hirotsugu Uemura, BJU international, BJU international, 110(6 Pt B), E228-34 - 34, Sep. 2012 , Refereed
  Summary:UNLABELLED: What's known on the subject? and What does the study add? Targeted agents with a similar or different target molecule are often used sequentially in the treatment of metastatic RCC. Two tyrosine kinase inhibitors, sorafenib and sunitinib, have been reported to show little cross-resistance, when used sequentially. In addition, a recent report showed that sunitinib rechallenge could potentially benefit selected patients. This case series shows that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment. Outcomes of the sorafenib rechallenge were not significantly affected by the response to the initial sorafenib treatment or by the duration of intervening treatments between first sorafenib and rechallenge. OBJECTIVE: To investigate clinical outcomes of sorafenib rechallenge during sequential therapy for patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with metastatic RCC who received sorafenib rechallenge after failed treatment first with sorafenib and subsequently with other agents, were retrospectively reviewed for patient characteristics, best response, progression-free survival (PFS), and adverse events (AEs). RESULTS: Of the 14 patients who received sorafenib rechallenge, 12 were evaluable for response. Eleven patients had previously undergone nephrectomy, and 10 had previously received systemic therapy, mostly interferon-α (nine patients) and interleukin-2 (six patients), with a median duration of 9 months. The best responses after the first sorafenib therapy were partial response (PR) in two patients, stable disease (SD) in seven, and progressive disease (PD) in two. The median PFS was 5.7 months. Initial sorafenib therapy was discontinued because of PD in eight patients and AEs in four patients. Rechallenge with sorafenib was undertaken after a 7.6 month median interval from the initial sorafenib challenge. Eight patients achieved SD on sorafenib rechallenge and median PFS was 5.4 (95% confidence interval, 3.8-7.0) months. The outcome of the sorafenib rechallenge was not significantly affected by the response to the initial sorafenib treatment or by the duration of treatments received between first sorafenib and rechallenge. No severe AE was newly observed on the rechallenge. CONCLUSION: In the systemic treatment of advanced RCC, it was suggested that patients once refractory to sorafenib could regain disease control on rechallenge with sorafenib during sequential treatment.
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• The 7th American Urological Association and the Japanese Urological Association international affiliate society meeting., Homma Y, Kakizaki H, Smith JA Jr, Namiki S, Arai Y, Tomita Y, Uzzo R, Tsuchiya N, Takahashi M, Ichikawa T, Quek ML, Uemura H, Mizokami A, Kakizaki H, Steers WD, Gotoh M, Ogawa T, Chancellor MB, Yamamoto S, Takahashi S, Ichihara K, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 19(4), 374 - 385, Apr. 2012 , Refereed
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• Preclinical Remodeling of Human Prostate Cancer through the PTEN/AKT Pathway., Marco A De Velasco, Hirotsugu Uemura, Advances in urology, Advances in urology, 2012, 419348 - 419348, 2012 , Refereed
  Summary:Knowledge gained from the identification of genetic and epigenetic alterations that contribute to the progression of prostate cancer in humans is now being implemented in the development of functionally relevant translational models. GEM (genetically modified mouse) models are being developed to incorporate the same molecular defects associated with human prostate cancer. Haploinsufficiency is common in prostate cancer and homozygous loss of PTEN is strongly correlated with advanced disease. In this paper, we discuss the evolution of the PTEN knockout mouse and the cooperation between PTEN and other genetic alterations in tumor development and progression. Additionally, we will outline key points that make these models key players in the development of personalized medicine, as potential tools for target and biomarker development and validation as well as models for drug discovery.
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• Personalized cancer therapy for urological cancers: from bench to bedside and back., Hirotsugu Uemura, Colleen Nelson, Jack A Schalken, Laurence Klotz, Advances in urology, Advances in urology, 2012, 298105 - 298105, 2012 , Refereed
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• Comparative effectiveness of axitinib versus sorafenib in advanced renal cell carcinoma (AXIS): a randomised phase 3 trial., Brian I Rini, Bernard Escudier, Piotr Tomczak, Andrey Kaprin, Cezary Szczylik, Thomas E Hutson, M Dror Michaelson, Vera A Gorbunova, Martin E Gore, Igor G Rusakov, Sylvie Negrier, Yen-Chuan Ou, Daniel Castellano, Ho Yeong Lim, Hirotsugu Uemura, Jamal Tarazi, David Cella, Connie Chen, Brad Rosbrook, Sinil Kim, Robert J Motzer, Lancet (London, England), Lancet (London, England), 378(9807), 1931 - 9, Dec. 03 2011 , Refereed
  Summary:BACKGROUND: The treatment of advanced renal cell carcinoma has been revolutionised by targeted therapy with drugs that block angiogenesis. So far, no phase 3 randomised trials comparing the effectiveness of one targeted agent against another have been reported. We did a randomised phase 3 study comparing axitinib, a potent and selective second-generation inhibitor of vascular endothelial growth factor (VEGF) receptors, with sorafenib, an approved VEGF receptor inhibitor, as second-line therapy in patients with metastatic renal cell cancer. METHODS: We included patients coming from 175 sites (hospitals and outpatient clinics) in 22 countries aged 18 years or older with confirmed renal clear-cell carcinoma who progressed despite first-line therapy containing sunitinib, bevacizumab plus interferon-alfa, temsirolimus, or cytokines. Patients were stratified according to Eastern Cooperative Oncology Group performance status and type of previous treatment and then randomly assigned (1:1) to either axitinib (5 mg twice daily) or sorafenib (400 mg twice daily). Axitinib dose increases to 7 mg and then to 10 mg, twice daily, were allowed for those patients without hypertension or adverse reactions above grade 2. Participants were not masked to study treatment. The primary endpoint was progression-free survival (PFS) and was assessed by a masked, independent radiology review and analysed by intention to treat. This trial was registered on ClinicalTrials.gov, number NCT00678392. FINDINGS: A total of 723 patients were enrolled and randomly assigned to receive axitinib (n=361) or sorafenib (n=362). The median PFS was 6·7 months with axitinib compared to 4·7 months with sorafenib (hazard ratio 0·665; 95% CI 0·544-0·812; one-sided p<0·0001). Treatment was discontinued because of toxic effects in 14 (4%) of 359 patients treated with axitinib and 29 (8%) of 355 patients treated with sorafenib. The most common adverse events were diarrhoea, hypertension, and fatigue in the axitinib arm, and diarrhoea, palmar-plantar erythrodysaesthesia, and alopecia in the sorafenib arm. INTERPRETATION: Axitinib resulted in significantly longer PFS compared with sorafenib. Axitinib is a treatment option for second-line therapy of advanced renal cell carcinoma. FUNDING: Pfizer Inc.
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• Effect of tamsulosin on bladder blood flow and bladder function in a rat model of bladder over distention/emptying induced bladder overactivity., Hiroko Okutsu, Seiji Matsumoto, Akiyoshi Ohtake, Masanori Suzuki, Shuichi Sato, Masao Sasamata, Hirotsugu Uemura, The Journal of urology, The Journal of urology, 186(6), 2470 - 7, Dec. 2011 , Refereed
  Summary:PURPOSE: Decreased bladder blood flow was the subject of a recent study as a pathophysiological cause of bladder overactivity. We developed a rat model of bladder over distention/emptying induced bladder overactivity and investigated the effect of the α(1)-adrenoceptor antagonist tamsulosin on bladder blood flow and bladder function in this model. MATERIALS AND METHODS: The bladder was distended with 2 ml saline using anesthesia for 2 hours (over distention) and then emptied. Bladder blood flow was measured using a perfusion imager. Micturition behavior and parameters were observed using a metabolic cage and a cystometry method, respectively, from 2 hours after bladder emptying. After model establishment was confirmed we examined the participation of afferent C-fibers and the effects of tamsulosin in rats pretreated with capsaicin (Sigma-Aldrich®) (125 mg/kg) and tamsulosin (1 μg/kg per hour), respectively, using a metabolic cage. RESULTS: Decreased bladder blood flow was observed upon over distention with partial recovery at emptying. Bladder over distention/emptying increased micturition frequency and decreased mean voided volume in the micturition recording study, and decreased the intercontraction interval and voided volume without affecting micturition pressure, threshold pressure or post-void residual volume in the cystometry study. Capsaicin pretreatment did not affect bladder overactivity. However, 1-week continuous treatment with tamsulosin increased bladder blood flow after bladder emptying, resulting in decreased micturition frequency and increased voided volume. CONCLUSIONS: Bladder over distention/emptying induced bladder blood flow decrease/partial recovery and caused bladder overactivity via a mechanism other than capsaicin sensitive C-fiber activation. Findings in tamsulosin treated rats confirmed the potency of tamsulosin to increase bladder blood flow and ameliorate bladder overactivity.
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• Key predictive factors of axitinib (AG-013736)-induced proteinuria and efficacy: a phase II study in Japanese patients with cytokine-refractory metastatic renal cell Carcinoma., Yoshihiko Tomita, Hirotsugu Uemura, Hiroyuki Fujimoto, Hiro-omi Kanayama, Nobuo Shinohara, Hayakazu Nakazawa, Keiji Imai, Yoshiko Umeyama, Seiichiro Ozono, Seiji Naito, Hideyuki Akaza, European journal of cancer (Oxford, England : 1990), European journal of cancer (Oxford, England : 1990), 47(17), 2592 - 602, Nov. 2011 , Refereed
  Summary:BACKGROUND: Axitinib (AG-013736) is an oral, selective and potent inhibitor of vascular endothelial growth factor receptors (VEGFR)-1, 2 and 3. This phase II study investigated axitinib efficacy, safety and biomarkers in Japanese patients with cytokine-refractory metastatic renal cell carcinoma (mRCC). PATIENTS AND METHODS: In an open-label, multicentre study, 64 patients received an axitinib starting dose of 5mg twice daily. RESULTS: Objective response rate (ORR) was 50.0% and median progression-free survival (PFS) was 11.0 months per independent review committee. Common treatment-related adverse events were hypertension (84%; 70% grade ≥3), hand-foot syndrome (75%; 22% grade ≥3) and diarrhoea (64%; 5% grade ≥3). Eighteen patients (28%) developed proteinuria ≥2g/24h and required dose reduction or treatment interruption/discontinuation. Proteinuria was a major cause for treatment discontinuation. Baseline urine protein levels were associated with development of proteinuria ≥2g/24h (hazard ratio [HR]=5.457, P=0.0035 in patients with baseline proteinuria ≥1+ versus <1+). Baseline urine protein levels correlated more strongly with axitinib-related proteinuria than other baseline renal function test values or blood pressure. Patients with greater decreases in soluble VEGFR-2 concentrations had significantly higher ORR and longer PFS than those with smaller decreases (ORR: 64.5% versus 37.5%, P=0.045; median PFS: 12.9 months versus 9.2 months, HR=0.42, P=0.01). CONCLUSIONS: Axitinib showed significant antitumour activity and was well tolerated in Japanese mRCC patients. Baseline proteinuria and soluble VEGFR-2 levels may be key indicators of axitinib-induced proteinuria and efficacy, respectively.
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• A new molecular targeted therapeutic approach for renal cell carcinoma with a p16 functional peptide using a novel transporter system., Kenji Zennami, Kazuhiro Yoshikawa, Eisaku Kondo, Kogenta Nakamura, Yoshiaki Upsilonamada, Marco A De Velasco, Motoyoshi Tanaka, Hirotsugu Uemura, Toru Shimazui, Hideyuki Akaza, Shinsuke Saga, Ryuzo Ueda, Nobuaki Honda, Oncology reports, Oncology reports, 26(2), 327 - 33, Aug. 2011 , Refereed
  Summary:Molecular targeting agents have become formidable anticancer weapons showing much promise against refractory tumors and functional peptides and are among the more desirable of these nanobio-tools. Intracellular delivery of multiple functional peptides forms the basis for a potent, non-invasive mode of delivery, providing distinctive therapeutic advantages. We examine the growth suppression efficiency of human renal cell carcinoma (RCC) by single-peptide targeting. We simultaneously introduced p16INK4a tumor suppressor peptides by Wr-T-mediated peptide delivery. Wr-T-mediated transport of p16INK4a functional peptide into 10 RCC lines, lacking expression of the p16INK4a molecule, reversed the specific loss of p16 function, thereby drastically inhibiting tumor growth in all but 3 lines by >95% within the first 96 h. In vivo analysis using SK-RC-7 RCC xenografts in nude mice demonstrated tumor growth inhibition by the p16INK4a peptide alone, however, inoculation of Wr-T and the p16INK4a functional peptide mixture, via the heart resulted in complete tumor regression. Thus, restoration of tumor suppressor function with Wr-T peptide delivery represents a powerful approach, with mechanistic implications for the development of efficacious molecular targeting therapeutics against intractable RCC.
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• Maintenance therapy with bacillus Calmette-Guérin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer., Shiro Hinotsu, Hideyuki Akaza, Seiji Naito, Seiichiro Ozono, Yoshiteru Sumiyoshi, Sumio Noguchi, Akito Yamaguchi, Satoshi Nagamori, Akito Terai, Yasutomo Nasu, Haruki Kume, Yoshihiko Tomita, Yoshinori Tanaka, Shoji Samma, Hirotsugu Uemura, Hirofumi Koga, Tomoyasu Tsushima, BJU international, BJU international, 108(2), 187 - 95, Jul. 2011 , Refereed
  Summary:OBJECTIVE: • To confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guérin (BCG) maintenance therapy for non-muscle-invasive bladder cancer. PATIENTS AND METHODS: • The enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT). • The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS). RESULTS: • Efficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients. • At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively. • The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P= 0.0190). CONCLUSION: • BCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.
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• A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A24-positive patients with castration-resistant prostate cancer., Masanori Noguchi, Hirotsugu Uemura, Seiji Naito, Hideyuki Akaza, Akira Yamada, Kyogo Itoh, The Prostate, The Prostate, 71(5), 470 - 9, Apr. 2011 , Refereed
  Summary:BACKGROUND: To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC). METHODS: In a phase I dose-escalation study, four peptides showing the highest levels of peptide-specific immunoglobulin G (IgG) to 14 vaccine candidates (ITK-1) were subcutaneously injected every week in three different dose settings (1, 3, and 5 mg per peptide) for 6 weeks with a low dose of EMP, and the patients were followed by maximum 2 years extension study either weekly or bi-weekly six times PPV as one course with a low dose of EMP. RESULTS: Fifteen patients were enrolled in the phase I study. No serious treatment-related adverse events were observed. The most common adverse events were grade 2 skin reactions at the injection sites. The maximum acceptable dose of ITK-1 was 8.643 mg. There were no treatment-related systemic adverse events of grade 3 or more, and maximum tolerated dose could not be determined. Cytotoxic T lymphocyte responses measured by interferon-γ release assay were boosted in 10 of 15 (67%) patients, and IgG responses were boosted in 7 of 15 (47%) patients. Twelve patients proceeded to the extension study, and the median survival time was 23.8 months during a median follow-up of 23.8 months. CONCLUSIONS: PPV treatment for HLA-A24 positive patients with CRPC could be recommended for further stages of clinical trials because of its safety and the higher frequency of boosting immune responses.
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• EFFICACY OF alpha 1-AR ANTAGONISTS IN PATIENTS UNDERGOING PROSTATE (125)vertical bar BRACHYTHERAPY FOR PROSTATE CARCINOMA: A RANDOMIZED TRIAL INVOLVING PRESSURE FLOW STUDY, Shimizu, Nobutaka, Saito, Yoshitaka, Minami, Takafumi, Hayashi, Taiji, Tsuji, Hidenori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Ishii, Tokumi, Uemura, Hirotsugu, Nakamatsu, Kiyoshi, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 185(4), E865 - E865, Apr. 2011 , Refereed
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• A PHASE I TRIAL OF VEGFR1 PEPTIDE VACCINES FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA, Uemura, Hirotsugu, De Velasco, Marco, Yoshimura, Kazuhiro, Nozawa, Masahiro, Minami, Takafumi, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 185(4), E710 - E710, Apr. 2011 , Refereed
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• Phase III trial of everolimus in metastatic renal cell carcinoma: subgroup analysis of Japanese patients from RECORD-1., Taiji Tsukamoto, Nobuo Shinohara, Norihiko Tsuchiya, Yasuo Hamamoto, Masayuki Maruoka, Hiroyuki Fujimoto, Masashi Niwakawa, Hirotsugu Uemura, Michiyuki Usami, Akito Terai, Hiro-omi Kanayama, Yoshiteru Sumiyoshi, Masatoshi Eto, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 41(1), 17 - 24, Jan. 2011 , Refereed
  Summary:OBJECTIVE: To assess the efficacy and safety of everolimus in Japanese patients with metastatic renal cell carcinoma. METHODS: A subgroup analysis of the pivotal Phase III, randomized, double-blind, placebo-controlled trial of everolimus 10 mg/day in patients with disease progression after treatment with sorafenib, sunitinib or both assessed outcomes in Japanese participants. Results were compared with those for the overall study population. RESULTS: The final trial analysis included 24 Japanese patients (everolimus, n= 15; placebo, n = 9). Median progression-free survival in the Japanese subpopulation was 5.75 months (95% confidence interval, 4.90 months to not reached) with everolimus and 3.61 months (95% confidence interval, 1.91-9.03 months) with placebo (hazard ratio, 0.19; 95% confidence interval, 0.05-0.83). Median overall survival was not reached with everolimus and was 14.9 months (95% confidence interval, 11.0-16.8 months) with placebo (hazard ratio, 0.30; 95% confidence interval, 0.07-1.27). Overall, efficacy and safety were similar when comparing the Japanese and overall populations. In the Japanese subpopulation, the most common adverse events with everolimus were stomatitis, infections and rash. Four Japanese subjects (27%) developed Grade 1 (n = 2) or 2 (n = 2) pneumonitis (all reversible and allowing for continuation of therapy, after interruption, steroids and dose reduction for both Grade 2 cases), with a lower pneumonitis incidence of 14% in the overall population (albeit associated with a Grade 3 incidence of 4%). CONCLUSIONS: These findings suggest that the demonstrated benefits of everolimus in the overall trial population are similar in Japanese patients with metastatic renal cell carcinoma.
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• Assessment of immunological biomarkers in patients with advanced cancer treated by personalized peptide vaccination., Masanori Noguchi, Takashi Mine, Nobukazu Komatsu, Shigetaka Suekane, Fukuko Moriya, Kei Matsuoka, Shigeru Yutani, Shigeki Shichijo, Akira Yamada, Uhi Toh, Kouichiro Kawano, Kouichi Azuma, Hirotsugu Uemura, Kiyotaka Okuno, Kazumasa Matsumoto, Hiroaki Yanagimoto, Ryuya Yamanaka, Masaaki Oka, Satoru Todo, Tetsuro Sasada, Kyogo Itoh, Cancer biology & therapy, Cancer biology & therapy, 10(12), 1266 - 79, Dec. 15 2010 , Refereed
  Summary:To investigate immunological biomarkers to predict overall survival of advanced cancer patients under treatment with personalized peptide vaccination, correlations between overall survival and biomarkers, including cytotoxic T lymphocyte (CTL) and immunoglobulin G (IgG) responses to the vaccinated peptides, were investigated in 500 advanced cancer patients who received personalized peptide vaccination from October 2000 to October 2008. The best clinical response was assessed for in 436 patients, 43 patients (10%) had partial response, 144 patients (33%) had stable disease and 249 patients (57%) had progressive, with a median overall survival of 9.9 months. Both lymphocyte counts prior to the vaccination (P = 0.0095) and increased IgG response (P = 0.0116) to the vaccinated peptides, along with performance status (P < 0.0001), well correlated with overall survival. To confirm the superiority of IgG response to CTL response, the samples from advanced castration-resistant prostate cancer patients who survived more than 900 days (n=20) and those who died within 300 days (n=23) were analyzed further. As a result, both the numbers of peptides, to which increased IgG responses were observed, and the fold increases in IgG levels were significantly higher in long-term survivors (P = 0.000282 and P = 0.00045). In contrast, CTL responses were not statistically different between the two groups. Both lymphocyte numbers and IgG response were thus suggested to be biomarkers of cancer vaccine for advanced cancer patients.
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• Overall survival and updated results from a phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma., Yoshihiko Tomita, Nobuo Shinohara, Takeshi Yuasa, Hiroyuki Fujimoto, Masashi Niwakawa, Soichi Mugiya, Tsuneharu Miki, Hirotsugu Uemura, Norio Nonomura, Masayuki Takahashi, Yoshihiro Hasegawa, Naoki Agata, Brett Houk, Seiji Naito, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 40(12), 1166 - 72, Dec. 2010 , Refereed
  Summary:BACKGROUND: In a phase II, open-label, multicentre Japanese study, sunitinib demonstrated antitumour activity and acceptable tolerability in metastatic renal cell carcinoma patients. Final survival analyses and updated results are reported. METHODS: Fifty-one Japanese patients with a clear-cell component of metastatic renal cell carcinoma (25 treatment-naïve; 26 cytokine-refractory) received sunitinib 50 mg orally, once daily (Schedule 4/2). Overall and progression-free survivals were estimated by the Kaplan-Meier method. Objective response rate (per Response Evaluation Criteria in Solid Tumours) and safety were assessed with an updated follow-up. RESULTS: First-line and pretreated patients received a median 6.0 and 9.5 treatment cycles, respectively. Investigator-assessed, end-of-study objective response rate was 52.0, 53.8 and 52.9% in first-line, pretreated and overall intent-to-treat populations, respectively. The median progression-free survival was 12.2 and 10.6 months in first-line and pretreated patients, respectively. Fourteen patients per group died (56 and 54%), and the median overall survival was 33.1 and 32.5 months, respectively. The most common treatment-related Grade 3 or 4 adverse events and laboratory abnormalities were fatigue (24%), hand-foot syndrome (18%), decreased platelet count (55%), decreased neutrophil count (53%) and increased lipase (49%). No Grade 5 treatment-related adverse events occurred. Forty patients (78%) required dose reduction, and 13 (25%) discontinued, due to treatment-related adverse events. CONCLUSIONS: With the median overall survival benefit exceeding 2.5 years, and acceptable tolerability, in first-line and pretreated Japanese metastatic renal cell carcinoma patients with Eastern Cooperative Oncology Group performance status 0/1, sunitinib showed a favourable risk/benefit profile, similar to Western studies. However, there was a trend towards greater efficacy and more haematological adverse events in Japanese patients.
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• Kidney Cancer Working Group report., Seiji Naito, Yoshihiko Tomita, Sun Young Rha, Hirotsugu Uemura, Mototsugu Oya, He Zhi Song, Li Han Zhong, Mohamed Ibrahim Bin A Wahid, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 40 Suppl 1(1), i51-56 - i56, Sep. 2010 , Refereed
  Summary:UNLABELLED: 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. High-dose 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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• Effect of Partial Bladder Outlet Obstruction on the Morphology of Elastin in Rabbit Bladder Smooth Muscle., Koichi Sugimoto, Seiji Matsumoto, Hiroyuki Ito, Hirotsugu Uemura, Lower urinary tract symptoms, Lower urinary tract symptoms, 2(2), 71 - 5, Sep. 2010 , Refereed
  Summary:OBJECTIVES: Elastin, in association with collagen, allows the body's organs to stretch and relax. Collagen and elastin, the major components of connective tissue, are present throughout the bladder wall and are intimately related to bladder compliance. The present study was undertaken to evaluate elastin morphologically using immunostaining and electron microscopy in the rabbit model of partial bladder outlet obstruction (PBOO). METHODS: Four groups of Japanese white rabbits underwent either PBOO by mild ligation of the urethra (2- and 4-week PBOO) or no obstruction (2- and 4-week sham). Histopathological examination was performed by Elastica van Gieson staining, scanning electron microscopy, transmission electron microscopy, and ultra-high voltage electron microscopy. The number of pixels representing elastin fibers in computerized images was analyzed using Adobe Photoshop Version 2.0. RESULTS: Bladder weight significantly increased after PBOO. Increase in the thickness of the bladder wall was observed after obstruction on histopathological examination. On scanning electron microscopy, elastin was very thick and was found in large configurations. 3-D analysis using electron microscopic tomography revealed that elastic fibers in the bladder had a coil-like appearance in the muscle layer, with each fiber composed of several fibrils. Such structures may be closely related to the physiological function of the bladder. CONCLUSION: Elastin in the bladder assumes the form of a coil during micturition. We examined that the increase in elastin makes it difficult for elastin to stretch linearly resulting in reduced elasticity. This change may be one of the factors involved in the decrease in compliance mediated by PBOO.
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• Noninfectious pneumonitis after everolimus therapy for advanced renal cell carcinoma., Dorothy A White, Philippe Camus, Masahiro Endo, Bernard Escudier, Emiliano Calvo, Hideyuki Akaza, Hirotsugu Uemura, Euloge Kpamegan, Andrea Kay, Matthew Robson, Alain Ravaud, Robert J Motzer, American journal of respiratory and critical care medicine, American journal of respiratory and critical care medicine, 182(3), 396 - 403, Aug. 01 2010 , Refereed
  Summary:RATIONALE: Noninfectious pneumonitis is a known class effect of mammalian target of rapamycin (mTOR) inhibitors. OBJECTIVES: To assess the incidence, radiographic patterns, management, and outcome of pneumonitis in patients with advanced renal cell carcinoma receiving everolimus. METHODS: Clinical study data from 416 patients, randomized to receive everolimus versus placebo, were analyzed for adverse events of pneumonitis. Radiographic studies performed every 8 weeks were subject to a prospective, independent, blinded central review for the presence of findings indicative of pneumonitis. MEASUREMENTS AND MAIN RESULTS: Of 274 patients receiving everolimus, clinical pneumonitis was suspected for 37 patients (13.5%) (none with placebo). Nine cases (3.3%) were grade 1 (asymptomatic), 18 (6.6%) were grade 2 (not interfering with daily living), and 10 (3.6%) were grade 3 (interfering with daily living or oxygen indicated). No grade 4 (life-threatening) pneumonitis was observed. Of the 10 patients with grade 3 pneumonitis, 5 had baseline radiological evidence of pneumonitis before everolimus therapy. Twenty of the 37 cases (54.0%) were reversible within the follow-up period; resolution followed dose reduction for 20 patients and treatment discontinuation in 10 patients. Corticosteroid therapy was initiated in 16 cases. Dedicated radiological review of available serial radiographic studies (245 patients receiving everolimus and 132 receiving placebo) found a higher percentage of new radiographic findings even in patients without a diagnosis of clinical pneumonitis who were receiving everolimus versus placebo (38.9 vs. 15.2%). CONCLUSIONS: Early recognition, prompt intervention, and a conservative approach are important in managing the risk associated with noninfectious pneumonitis in association with everolimus. Clinical trial registered with www.clinicaltrials.gov (NCT 00410124).
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• A randomized phase II trial of personalized peptide vaccine plus low dose estramustine phosphate (EMP) versus standard dose EMP in patients with castration resistant prostate cancer., Masanori Noguchi, Tatsuyuki Kakuma, Hirotsugu Uemura, Yasutomo Nasu, Hiromi Kumon, Yasuhiko Hirao, Fukuko Moriya, Shigetaka Suekane, Kei Matsuoka, Nobukazu Komatsu, Shigeki Shichijo, Akira Yamada, Kyogo Itoh, Cancer immunology, immunotherapy : CII, Cancer immunology, immunotherapy : CII, 59(7), 1001 - 9, Jul. 2010 , Refereed
  Summary:Personalized peptide vaccination (PPV) combined with chemotherapy could be a novel approach for many cancer patients. In this randomized study, we evaluated the anti-tumor effect and safety of PPV plus low-dose estramustine phosphate (EMP) as compared to standard-dose EMP for HLA-A2- or -A24-positive patients with castration resistant prostate cancer. Patients were randomized into groups receiving either PPV plus low-dose EMP (280 mg/day) or standard-dose EMP (560 mg/day). After disease progression, patients were switched to the opposite regime. The primary end point was progression-free survival (PFS). We randomly assigned 28 patients to receive PPV plus low-dose EMP and 29 patients to receive standard-dose EMP. Nineteen events in the PPV group and 20 events in the EMP group occurred during the first treatment. Median PFS for the first treatment was 8.5 months in the PPV group and 2.8 months in the EMP group with a hazard ratio (HR) of 0.28 (95% CI, 0.14-0.61; log-rank P = 0.0012), while there was no difference for median PFS for the second treatment. The HR for overall survival was 0.3 (95% CI, 0.1-0.91) in favor of the PPV plus low-dose EMP group (log-rank, P = 0.0328). The PPV plus low-dose EMP was well tolerated without major adverse effects and with increased levels of IgG and cytotoxic-T cell responses to the vaccinated peptides. PPV plus low-dose EMP was associated with an improvement in PSA-based PFS as compared to the standard-dose EMP alone.
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• Molecular genetic events associated with renal cell carninoma and its implication to treatment by molecular target therapy., Takeshi Kishida, Masahiro Yao, Hirotsugu Uemura, Carsten Ohlmann, Yoshihiko Tomita, Ronald M Bukowski, Sei Naito, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 17(3), 198 - 205, Mar. 2010 , Refereed
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• A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety., Hirotsugu Uemura, Nobuo Shinohara, Takeshi Yuasa, Yoshihiko Tomita, Hiroyuki Fujimoto, Masashi Niwakawa, Soichi Mugiya, Tsuneharu Miki, Norio Nonomura, Masayuki Takahashi, Yoshihiro Hasegawa, Naoki Agata, Brett Houk, Seiji Naito, Hideyuki Akaza, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 40(3), 194 - 202, Mar. 2010 , Refereed
  Summary:OBJECTIVE: This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). METHODS: Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. RESULTS: In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). CONCLUSIONS: In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.
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• A case of Fournier's gangrene in which Flexi-Seal was effective for evacuation management, Takayuki Ohzeki, Taiji Hayashi, Tadashi Hanai, Hirotsugu Uemura, Acta urologica Japonica, Acta urologica Japonica, 56(3), 181 - 184, Mar. 2010
  Summary:A 67-year-old male was referred to our hospital with septicemia from necrotizing fasciitis of the genitalia of unknown origin. He had a history of diabetes and cerebral infarction. Extensive debridement of necrotizing tissue was performed over an area extending from the lower abdomen to the light inguinal,scrotal and perianal regions. At a suitable point,Flexi-Seal TM was applied to the wound as a preventive measure against infection. There was no contamination of perianal wounds,allowing them to be closed without infection. The Flexi-SealTM was successfully removed after around 3 weeks. This is the second case in which Flexi-SealTM was used in Japan to treat Fourier's gangrene.
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• Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer., Hirotsugu Uemura, Kiyohide Fujimoto, Takashi Mine, Shigeya Uejima, Marco A de Velasco, Yoshihiko Hirao, Nobukazu Komatsu, Akira Yamada, Kyogo Itoh, Cancer science, Cancer science, 101(3), 601 - 8, Mar. 2010 , Refereed
  Summary:We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (CRPC) patients. In the present study, PPV monotherapy was given to CRPC patients. Twenty-three patients with metastatic CRPC were treated with PPV without any additional treatment modalities, including LH-RH analogs. Samples were analyzed for peptide-specific cytotoxic T-lymphocyte (CTL) precursor analysis and peptide-reactive IgG. Toxicity and immunological and clinical responses were assessed on a three-monthly basis. Seventeen patients were available for immunological and clinical evaluation. The vaccines were well tolerated, with grade 3 erythema at injection sites in only one patient. Augmentation of CTL or IgG responses to at least one of the peptides was observed in six of 17 (35%) and 15 of 17 (88%) patients tested, respectively. Among 57 peptides used, 9 and 36 peptides induced CTL and IgG responses, respectively. Delayed-type hypersensitivity reaction was observed in eight of 17 patients. More than 30% prostate-specific antigen (PSA) decline was observed in four of 17 patients. Of these, one patient achieved a complete PSA response and another patient showed a partial PSA response with profound shrinking of lymph node metastases and prostate. The overall median survival time was 24 months (range, 5-37 months). These results suggest that PPV monotherapy appears to be safe and capable of inducing peptide-specific immune responses and clinical responses in CRPC patients. This trial was registered with University Hospital Medical Information Network (UMIN) number R000003339.
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• Prognosis of Japanese metastatic renal cell carcinoma patients in the cytokine era: a cooperative group report of 1463 patients., Sei Naito, Naoki Yamamoto, Tatsuya Takayama, Masatoshi Muramoto, Nobuo Shinohara, Kenryu Nishiyama, Atsushi Takahashi, Ryo Maruyama, Takashi Saika, Senji Hoshi, Kazuhiro Nagao, Shingo Yamamoto, Issei Sugimura, Hirotsugu Uemura, Shigehiko Koga, Masayuki Takahashi, Fumio Ito, Seiichiro Ozono, Toshiro Terachi, Seiji Naito, Yoshihiko Tomita, European urology, European urology, 57(2), 317 - 25, Feb. 2010 , Refereed
  Summary:BACKGROUND: Incidence rate of renal cell carcinoma (RCC) differs among countries. The rates of Asian countries are lower than those of countries in North America or Europe but are exceptionally high in Japanese males. Approximately 30% of patients with RCC have metastasis at initial diagnosis, and another 30% have metastasis after nephrectomy. Clinical studies of risk factors in patients with metastatic RCC (mRCC) are mainly based on data from non-Asian patients. OBJECTIVES: We aimed to investigate the prognosis of Japanese patients and their prognostic factors. DESIGN, SETTING, AND PARTICIPANTS: The subjects of this study were 1463 patients who were clinically diagnosed with RCC with metastasis in 40 Japanese hospitals between January 1988 and November 2002. MEASUREMENTS: The primary end point was overall survival calculated from first diagnosis of mRCC to death or last follow-up. We also investigated the relationship between survival and clinical features. RESULTS AND LIMITATIONS: The median overall survival time was 21.4 mo. The estimated survival rates at 1, 3, 5, and 10 yr were 64.2%, 35.2%, 22.5%, and 9.1%, respectively; they contrasted with data from the United States of 54%, 19%, 10%, and 6%, respectively for the same periods. A high percentage of patients had undergone nephrectomy (80.5%) and metastasectomy (20.8%), both of which were shown to prolong survival. CONCLUSIONS: The median survival time in the present study was approximately twice as long as that of previous studies from North America or Europe. Early diagnosis of metastasis, nephrectomy, metastasectomy, and cytokine-based therapy seemed to improve the prognosis of RCC patients in the present study.
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• Primary Synovial Sarcoma of the Kidney., Kawahara T, Sekiguchi Z, Makiyama K, Nakayama T, Nagashima Y, Kita K, Namura K, Itou H, Sano F, Hayashi N, Nakaigawa N, Ogawa T, Uemura H, Yao M, Kubota Y, Case reports in oncology, Case reports in oncology, 2(3), 189 - 193, Oct. 2009 , Refereed
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• Superoxide from NADPH oxidase as second messenger for the expression of osteopontin and monocyte chemoattractant protein-1 in renal epithelial cells exposed to calcium oxalate crystals., Tohru Umekawa, Hidenori Tsuji, Hirotsugu Uemura, Saeed R Khan, BJU international, BJU international, 104(1), 115 - 20, Jul. 2009 , Refereed
  Summary:OBJECTIVE To test the hypothesis that exposure of a renal epithelial cell line, NRK52E, to calcium oxalate monohydrate crystals (COM) would up-regulate NADPH oxidase subunit p47(phox), enhance superoxide production and increase monocyte chemoattractant protein-1 (MCP-1) and osteopontin mRNA levels. MATERIALS AND METHODS Confluent cultures of NRK52E cells were exposed to COM (66.7 microg/cm(2)) with or with no pretreatment with diphenileneiodium chloride (DPI, 10 x 10(-6)m) an inhibitor for NADPH oxidase, under serum-free conditions. The conditioned medium was collected and total cellular RNA isolated from the cells, and subjected to enzyme-linked immunosorbent assay and real-time polymerase chain reaction (PCR). Production of reactive oxygen species (ROS) was estimated by dihydroethidium (DHE) staining using a fluorescence microscope. Immunohistochemistry and real-time PCR were used to analyse p47(phox) in NRK52E cells. RESULTS In COM treated NRK52E cells there was enhanced expression of p47(phox) and production of superoxide. COM-induced production of MCP-1 and osteopontin was significantly reduced after treatment with DPI. CONCLUSIONS While the generation of a lot of ROS might play a major role in tissue injury or death, the regulated generation of low concentration of ROS, possibly by NADPH oxidase, may represent a second messenger system for generation of COM-induced MCP-1 and osteopontin production in the renal tubules.
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• Change of lower urinary tract symptoms during pregnancy and after delivery: investigations using IPSS/QOL and Urinary Incontinence Questionnaires, Shigeki Horikawa, Seiji Matsumoto, Tadashi Hanai, Toshiya Yamamoto, Tomomi Kishimoto, Hirotsugu Uemura, Acta urologica Japonica, Acta urologica Japonica, 55(6), 311 - 314, Jun. 2009
  Summary:Using International Prostate Symptom Score (IPSS)/Quality of life (QOL) and Urinary Incontinence Questionnaires,we collected a total of 89 questionnaires from 48 pregnant women (average age of 31.4± 3.42) and data 4 times during each pregnancy (during the 14th,26th and 36th weeks of pregnancy) and 1 month after delivery. We examined whether there was a relationship between the number of incontinence incidences listed in the questionnaires and other parameters : the body mass index (BMI),previous deliveries, the weight of the baby delivered,the use of episiotomy,etc. The average IPSS score was 5.84±4.65,5.33± 2.73,7.35 ±4.51 for the 14,26 and 36th week,respectively and 1.82±1.76 one month after delivery. The major symptom reported was storage symptom and the scores increased as the pregnancy progressed and recovered by one month after delivery. The average score on the Urinary Incontinence Questionnaires was 3.32±2.69,5.05 ±3.02,6.15 ±2.89 for the 14,26 and 36th week,respectively and 1.59±2.03 one month after delivery. The major symptom reported was stress incontinence. The scores increased significantly as the pregnancy progressed and,one month after delivery,returned to the level at the 14th week of pregnancy. We found a positive correlation between the number of incidences of incontinence at the 36th week and the subject's BMI. Among the lower urinary tract symptoms,storage symptom and stress incontinence were found in the early stage of pregnancy. Storage symptom disappeared after delivery,but stress incontinence was reduced only to the level in the early stage of pregnancy.
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• Tumor thrombus arising from the superior vena cava and extending into the right atrium in a patient with advanced testicular germ cell tumor, Makito Miyake, Kiyohide Fujimoto, Chie Matsushita, Yoshitomo Chihara, Masahiro Tanaka, Akihide Hirayama, Yoshihiko Hirao, Hirotsugu Uemura, Acta urologica Japonica, Acta urologica Japonica, 55(6), 371 - 375, Jun. 2009
  Summary:A 24-year-old man was referred to our hospital with a painless mass on the left side of his neck. Ultrasonographydetected right testicular tumor and computerized tomographyscanning revealed a left supraclavicular lymph node mass and bulky retroperitoneal lymph node mass. He initially underwent right high orchiectomy, combination chemotherapy and retroperitoneal lymph node dissection for advanced testicular non-seminomatous germ cell tumor. Six years later, late relapse was detected in the lung. After complete remission of the lung metastasis with chemotherapy, the serum alpha-fetoprotein began to increase because of superior vena caval thrombus extending into the right atrium. Emergencysurgical excision was performed successfullyusing extracorporeal circulation to prevent pulmonaryembolism and the resected specimen pathologicallyrevealed adenocarcinoma interpreted as teratoma malignant transformation. Adjuvant chemotherapyconsisting of paclitaxel, ifosfamide and nedaplatin were administered for subsequent slight elevation of serum F-human chorionic gonadotropin β, resulting in successful normalization again. Later, he suddenlydied of cerebral infarction without anyevidence of recurrence 138 months after his initial presentation. We report herein an extremelyuncommon case of advanced testicular germ cell tumor with development of superior vena caval thrombus extending into the right atrium.
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• Bladder outlet obstruction accelerates bladder carcinogenesis., Seiji Matsumoto, Nobutaka Shimizu, Tadashi Hanai, Hirotsugu Uemura, Robert Levin, BJU international, BJU international, 103(10), 1436 - 9, May 2009 , Refereed
  Summary:OBJECTIVE: To examine the correlation between partial bladder outlet obstruction (PBOO) and bladder carcinogenesis. MATERIALS AND METHODS: Female Wistar rats (6 weeks old) were divided into three groups of 10 each: group 1 was exposed to n-butyl-n-butanol nitrosamine (BBN, a carcinogen) in drinking water for 8 weeks; group 2 had PBOO induced surgically after exposure to BBN for 8 weeks; group 3 had a sham operation and the rats drank normal water (control group). After 20 weeks, all of the rats were killed humanely and their bladders analysed. RESULTS: There were no significant differences in body weight among the groups. The bladder weight of group 2 was significantly greater than either group 1 or group 3. Histopathologically, bladder smooth muscle hypertrophy was the major cause of the increased bladder weight for group 2. In group 2 there were increases in bladder wall thickness and many nipple-shaped urothelial tumours. Basic fibroblast growth factor and hypoxia-inducible factor-1alpha expression were significantly greater in group 2 than in groups 1 and 3. CONCLUSIONS: Exposure of the bladder to carcinogens during bladder hyperplasia and hypertrophy induced by PBOO results in a greater incidence of superficial bladder carcinoma.
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• The Changes of Prostate Specific Antigen (PSA) after Treatment with Alpha 1-Adorenergic Receptor Antagonists in Men with 4.0-9.9 ng/ml PSA Level: A Study for Comparison of Benign Prostatic Hyperplasia/Lower Urinary Tract Symptom (BPH/LUTS) and Prostate Cancer, Tadashi Hanai, Seiji Matsumoto, Sunao Shouji, Yukio Usui, Xian Yan Tang, Yoshinari Kato, Masanori Iguchi, Hirotsugu Uemura, Toshirou Terachi, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 55(4), 187 - 191, Apr. 2009
  Summary:The aims of this study were to define the relationships between prostate-specific antigen (PSA) and alpha 1-adrenergic receptor antagonist (alpha 1 blocker). A prospective clinical study of 48 male patients examined between May 2004 and December 2007 was performed. 4.0-9.9 ng/ml PSA level who had no notable clinical findings of urinary retention, urinary tract infections and prostate cancer (PC) received tamusulosin 0.2 mgonce daily for 3 months, and then received prostate biopsy. We divided the patients into two groups : PC and benign prostate hyperplasia (BPH)/lower urinary tract symptom (LUTS) group. In total, the PSA level showed no significant change after treatment. In the PC group, PSA significantly increased after treatment. However, PSA decreased in the BPH/LUTS group. The alpha 1 blocker significantly improved urination status (the subjective symptoms and urodynamics parameters) in the BPH/LUTS group. In two groups, prostate volume showed no significant difference. Among those patients in the BPH/LUTS group, their urination status was significantly improved with alpha 1 blocker and their PSA level dropped slightly. On the other hand, the PSA level was significantly increased in the PC group. This study shows that by usingan alpha 1 blocker, it may be possible to avoid conductingthe prostate biopsy at an early stage or indeed one may not be needed at all for patients with only slight increases in PSA.
• Effects of chronic treatment with vardenafil, a phosphodiesterase 5 inhibitor, on female rat bladder in a partial bladder outlet obstruction model., Seiji Matsumoto, Tadashi Hanai, Hirotsugu Uemura, Robert M Levin, BJU international, BJU international, 103(7), 987 - 90, Apr. 2009 , Refereed
  Summary:OBJECTIVES: To investigate whether vardenafil, a phosphodiesterase 5 (PDE-5) inhibitor, would protect the bladder from decompensatory changes in a 4-week rat bladder outlet obstruction (BOO) model, as evidence has been accumulating that PDE-5 inhibitors improve lower urinary tract symptoms (LUTS) in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: In all, 50 12-week-old female Sprague-Dawley rats were divided into five equal groups; group 1, sham operated vehicle control rats; group 2, BOO vehicle rats; group 3-5, BOO rats given oral vardenafil at 5, 20, 80 mg/L, respectively. Vardenafil was given in drinking water from the day of surgery. At 4-weeks after the introduction of BOO, vardenafil was washed-out by giving water for 24-48 h, and then the bladder was excised and dissected into four longitudinal strips for isometric organ-bath assay. Contractile responses of bladder strips to electrical field stimulation (EFS), carbachol and KCl was determined for each group. RESULTS: BOO induced a significant increase in bladder weight in group 2 compared with group 1. Bladder weights of groups 3-5 were not significantly different from that of group 2. The contractile forces in response to EFS, carbachol and KCl in group 2 were 30.7-51.7% of those in group 1. Vardenafil treatment in groups 3-5 generally did not block the BOO-induced reduction of contractile force in the bladder strips. However, treatment with a high dose of vardenafil resulted in a significant increase in the contractile response to carbachol (78.4% group 5 vs 51.7% group 2). CONCLUSION: Chronic treatment with a high dose of vardenafil protected the rat bladder from BOO-induced contractile dysfunction to carbachol.
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• GFP image analysis in the mouse orthotopic bladder cancer model., Marco A De Velasco, Motoyoshi Tanaka, Satoshi Anai, Atsushi Tomioka, Kazuto Nishio, Hirotsugu Uemura, Oncology reports, Oncology reports, 20(3), 543 - 7, Sep. 2008 , Refereed
  Summary:Precise and objective measurements of tumor response have yet to be standardized in the mouse orthotopic bladder cancer model. In this study, we used image analysis and green fluorescent protein (GFP) to objectively measure tumor size in response to chemotherapy. KU-7 human bladder cancer cells transfected with GFP were intravesically inoculated into 8-week-old female nude mice. Fourteen days after tumor cell inoculation, the mice were assigned into a control (PBS) group or a doxorubicin (conc. 1.0 mg/ml) treatment group and received a single instillation of treatment. Fourteen days after treatment, the bladders were surgically exposed and fluorescent images were captured and later analyzed using image analysis. Bladders were processed for histological examination. Tumor incidence determined by GFP expression and histology was 100 and 80%, respectively, in the doxorubicin treatment group. A 9-fold (histology) vs. 12-fold (GFP expression) difference in tumor regression measured by tumor area (P<0.05) and a 5-fold (histology) vs. 9-fold (GFP expression) difference in tumor regression measured by the percent of tumor area in the bladder (P<0.001) were observed in the doxorubicin treatment group. Our findings suggest that using image analysis provides a precise, sensitive and objective means to measure tumor growth and treatment response in the mouse orthotopic bladder cancer model in lieu of histological methods. Consequently, the number of mice required in an experiment can be reduced since tissue samples are not needed for histology, thus making tissue samples readily available for additional assays in both a labor-effective and cost-effective manner.
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• Delivery of PTEN via a novel gene microcapsule sensitizes prostate cancer cells to irradiation., Atsushi Tomioka, Motoyoshi Tanaka, Marco A De Velasco, Satoshi Anai, Satoshi Takada, Toshihiro Kushibiki, Yasuhiko Tabata, Charles J Rosser, Hirotsugu Uemura, Yoshihiko Hirao, Molecular cancer therapeutics, Molecular cancer therapeutics, 7(7), 1864 - 70, Jul. 2008 , Refereed
  Summary:The tumor suppressor gene MMAC/PTEN located on chromosome10q23.3 has dual phosphatase activity in the phosphoinositide-3-kinase signaling pathway and inhibits Akt activation, a serine-threonine kinase, which is involved in proliferative and antiapoptotic pathways. Furthermore, MMAC/PTEN is frequently inactivated in a variety of tumors including prostate cancer. In this study, we generated a new type of gene transfer drug, GelaTen, which is a microsphere of cationized gelatin hydrogels incorporating PTEN plasmid DNA. Using our previously reported radiation-resistant PC3-Bcl-2 human prostate cancer cells (PTEN deleted), we examined the efficacy of GelaTen to force the expression of PTEN in vivo to inhibit tumor growth after intratumoral injection alone or with irradiation. Combinational therapy with GelaTen and irradiation improved both the in vitro and in vivo efficacy of growth inhibition compared with GelaTen or irradiation alone. These data show that GelaTen gene therapy, enabling radiosensitization, can potentially treat prostate cancers that have MMAC/PTEN gene alterations associated with radioresistance.
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• Tumor vaccines in renal cell carcinoma., Hirotsugu Uemura, Marco A De Velasco, World journal of urology, World journal of urology, 26(2), 147 - 54, Apr. 2008 , Refereed
  Summary:INTRODUCTION: Although most vaccines target foreign infectious agents, therapeutic cancer vaccines target both well-established and metastatic tumor cells expressing tumor antigens. Active immunotherapy is intended to enhance or activate the immunosurveillance of an individual through a therapeutic vaccine. Renal cell carcinoma (RCC) is one of the most immunoresponsive cancers in humans, which in turn makes it an ideal candidate for immune based therapies. METHOD: Several types of therapeutic vaccines have been tested and applied in the clinical setting and can be divided into cell-based vaccines including direct application of inactivated autologous tumor cells, gene modified tumor cell-based, dendritic cell-based (expressing RCC derived tumor antigens), and non-cell-based vaccines. This review will examine the current status of cell-based vaccine immunotherapy and focuses on non-cell-based vaccine strategies. CONCLUSION: Recent advances in molecular targeting therapy have introduced a battery receptor tyrosine kinase (RTK) and mTOR inhibitors that provide promising treatment options, however, the tolerability of tumor vaccines and the success of clinical effectiveness in selected populations combined with recent advances in cellular therapies warrant the continued exploration of novel methods of tumor vaccine therapies in the clinical setting.
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• Effects of deep brain stimulation on urodynamic findings in patients with Parkinson's disease, Nobutaka Shimizu, Seiji Matsumoto, Yasunori Mori, Nobuhiro Yoshioka, Hirotsugu Uemura, Naoki Nakano, Mamoru Taneda, Acta urologica Japonica, Acta urologica Japonica, 53(9), 609 - 612, Sep. 2007
  Summary:Electric stimulation therapy is one of the surgical treatments for Parkinson's disease whereby a chronic stimulating electrode is placed on the subthalmic nucleus (STN). Because medical treatments centered around L-dopa have limitations in severe Parkinson's disease, electric stimulation therapy is regarded as an appropriate treatment modality. Most Parkinson's disease patients experience lower urinary tract disorders such as urgency, daytime frequency or nocturia, due to detrusor overactivity. We conducted an International Prostate Symptom Score (IPSS) analysis and a pressure flow study (PFS) on 6 patients before and after a chronic stimulating electrode was placed on the STN and evaluated how the subjective symptoms and bladder functions changed. As a result, the IPSS total value, involuntary detrusor contraction threshold volume and maximum bladder capacity were all found to significantly improve (P<0.05). The average IPSS decreased from 11.2 to 7.0. The average involuntary detrusor contraction threshold volume increased from 90.7 ml to 172.7 ml. The average maximal bladder capacity increased from 104.0 ml to 177.2 ml. These findings suggest that the STN the positively contributes to an improvement in urinary function.
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• STAT3 polymorphism predicts interferon-alfa response in patients with metastatic renal cell carcinoma., Noriyuki Ito, Masatoshi Eto, Eijiro Nakamura, Atsushi Takahashi, Taiji Tsukamoto, Hiroshi Toma, Hayakazu Nakazawa, Yoshihiko Hirao, Hirotsugu Uemura, Susumu Kagawa, Hiroomi Kanayama, Yoshiaki Nose, Naoko Kinukawa, Tsuyoshi Nakamura, Nobuyoshi Jinnai, Toyokazu Seki, Masanobu Takamatsu, Yoshihiro Masui, Seiji Naito, Osamu Ogawa, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 25(19), 2785 - 91, Jul. 01 2007 , Refereed
  Summary:PURPOSE: To clarify the effect of genetic polymorphisms on the response to interferon alfa (IFN-alpha) for metastatic renal cell carcinoma (MRCC), and to find a reliable molecular marker to select those patients with MRCC who would benefit from IFN-alpha immunotherapy. PATIENTS AND METHODS: We carried out an association study in which 463 single nucleotide polymorphisms (SNPs) in 33 candidate genes were genotyped in 75 Japanese patients who had received IFN-alpha for MRCC. RESULTS: After adjusting for lung metastasis, stepwise logistic regression analysis revealed that the SNPs in signal transducer and activator 3 (STAT3) were most significantly associated with better response to IFN-alpha. Linkage disequilibrium mapping revealed that the SNP in the 5' region of STAT3, rs4796793, was the most significant predictor of IFN-alpha response (odds ratio [OR] = 2.73; 95% CI, 1.38 to 5.78). The highest OR was shown in the CC genotype at rs4796793 compared to the GG + GC genotypes (OR = 8.38, 95% CI, 1.63 to 42.96). Genotype-dependent expressions of STAT3 in B lymphocyte cell lines and the enhanced growth inhibitory effects of IFN- by STAT3 suppression in an RCC cell line supported the results of the present association study. CONCLUSION: The present study suggested that the STAT3 polymorphism is a useful diagnostic marker to predict the response to IFN-alpha therapy in patients with MRCC. An efficient response marker for IFN-alpha needs to be utilized to establish individual optimal treatment strategies, even when newer drug therapies are used as first line treatments for MRCC.
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• Identification of SART3-derived peptides having the potential to induce cancer-reactive cytotoxic T lymphocytes from prostate cancer patients with HLA-A3 supertype alleles., Takafumi Minami, Satoko Matsueda, Hiroko Takedatsu, Masahiro Tanaka, Masanori Noguchi, Hirotsugu Uemura, Kyogo Itoh, Mamoru Harada, Cancer immunology, immunotherapy : CII, Cancer immunology, immunotherapy : CII, 56(5), 689 - 98, May 2007 , Refereed
  Summary:SART3-derived peptides applicable to prostate cancer patients with HLA-A3 supertype alleles were identified in order to expand the possibility of an anti-cancer vaccine, because the peptide vaccine candidates receiving the most attention thus far have been the HLA-A2 and HLA-A24 alleles. Twenty-nine SART3-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11, -A31, and -A33) were first screened for their recognizability by immunoglobulin G (IgG) of prostate cancer patients and subsequently for the potential to induce peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-A3 supertype(+) prostate cancer patients. As a result, five SART3 peptides were frequently recognized by IgG, and two of them-SART3 (511-519) and SART3 (734-742)-efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity toward prostate cancer cells was ascribed to peptide-specific and CD8(+) T cells. These results indicate that these two SART3 peptides could be promising candidates for peptide-based immunotherapy for HLA-A3 supertype(+) prostate cancer patients.
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• A phase I trial of vaccination of personalized peptides for HLA-A2/A24 positive patients with hormone-refractory prostate cancer, Uemura, Hirotsugu, Tanaka, Motoyoshi, Uejima, Shigeya, Minami, Takafumi, Fujimoto, Kiyohide, Hirao, Yoshihiko, Itoh, Kyogo, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 177(4), 202 - 202, Apr. 2007 , Refereed
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• Pregnancy in chronic dialysis and after renal transplantation, Acta urologica Japonica, Acta urologica Japonica, 52(12), 915 - 917, Dec. 2006
  Summary:A female patient gave birth to a child while receiving hemodialysis, six years later, she gave birth to another child after cadavatic renal transplantation. Both children showed normal growth without any congenital defects. During the term of pregnancy after renal transplantation, there was no significant rejection episode, and graft function was stable. It seems rare for a patient to bear children during dialysis and after renal transplantation.
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• Pulmonary metastasis of renal cell carcinoma 20 years after nephrectomy, Acta urologica Japonica, Acta urologica Japonica, 52(12), 929 - 931, Dec. 2006
  Summary:A 70-year-old man underwent right nephrectomy for clear cell renal carcinoma in 1985. After nephrectomy, he was routinely followed up as an outpatient. Solitary chest tumor was detected on pulmonary CT in 2005. A wedge resection of pulmonary tumor was performed under diagnosis of primary lung cancer. The histological feature was not of primary lung cancer, but the previous nephrectomised specimen, i.e., clear cell renal carcinoma.
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• Left renal pelvic tumor 32 years after calyco-ileo-vesiconeostomy, Acta urologica Japonica, Acta urologica Japonica, 52(11), 871 - 873, Nov. 2006
  Summary:This is a case report of left renal pelvic tumor found 32 years after left calico-ileo-vesiconeostomy. The patient has undergone right nephrectomy for absence of renal function at 26 years-old and left urinary reconstruction was performed using the intestine for pyelo-ureteral junction obstruction at 28 years old because of bilateral congenital hydronephrosis. Later he was treated for recurrent left renal stone with percutaneous nephrolithotripsy, nephrolithotomy and extracorporeal shock wave lithotripsy. When he was 56 years old, macrohematuria appeared. He received left nephrectomy under the diagnosis of left renal pelvic tumor.
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• A phase I trial of vaccination of CA9-derived peptides for HLA-A24-positive patients with cytokine-refractory metastatic renal cell carcinoma., Hirotsugu Uemura, Kiyohide Fujimoto, Motoyoshi Tanaka, Motoyoshi Yoshikawa, Yoshihiko Hirao, Shigeya Uejima, Kazuhiro Yoshikawa, Kyogo Itoh, Clinical cancer research : an official journal of the American Association for Cancer Research, Clinical cancer research : an official journal of the American Association for Cancer Research, 12(6), 1768 - 75, Mar. 15 2006 , Refereed
  Summary:PURPOSE: A phase I peptide vaccination trial was done in patients with progressive cytokine-refractory metastatic renal cell carcinoma (RCC) to assess both the toxicity and capability to induce immune responses of three peptides (CA9p219-227, p288-296, and p323-331) derived from CA9, a tumor-associated antigen ubiquitously expressed in RCC. EXPERIMENTAL DESIGN: Twenty-three patients positive for human leukocyte antigen (HLA)-A24 with histologically confirmed RCC were enrolled. Eligibility included progressive disease after standard cytokine therapy with interleukin-2 and/or IFN-alpha. Patients were vaccinated s.c. with the three peptides emulsified in incomplete Freund's adjuvant at 2-week intervals. Pre- and post-vaccination blood samples were obtained for toxicity assessment and immunologic studies. Patients were monitored for clinical responses on a 3-monthly basis. RESULTS: Vaccinations were well tolerated without any major adverse event. Most of the patients developed peptide-specific CTLs and/or immunoglobulin G reactive to the peptides after the 6th or 9th vaccination, followed by a gradual increase in both CTL frequency and levels of peptide-reactive serum IgG. Three patients with multiple lung metastases showed partial responses with disappearance and shrinking of metastatic lesions. Additionally, stable disease for >6 months was observed in six patients (median duration, 12.2 months). Moreover, the median survival time of all patients who were progressive at trial enrollment after failing immunotherapy was 21.0 months (5-35 months). CONCLUSIONS: These results suggest that vaccination of these peptides is safe and recommended for further trials for HLA-A24-positive metastatic RCC patients.
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• Bladder leiomyosarcoma in a boy., Seiji Matsumoto, Nobutaka Shimizu, Naohiko Moriguchi, Makoto Yagi, Hirotsugu Uemura, International urology and nephrology, International urology and nephrology, 38(3-4), 549 - 51, 2006 , Refereed
  Summary:Leiomyosarcoma of the urinary bladder in childhood is uncommon. We reported bladder leiomyosarcoma in a 10-year-old boy. He had underwent the extirpation of the tumor and performed adjuvant chemotherapy in combination with radiotherapy according to the Intergroup Rhabdomyosarcoma Study-4 regimens. He had no evidence of recurrence of disease after 3 years.
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• A malignant Leydig cell tumor of the testis., Koichi Sugimoto, Seiji Matsumoto, Kazuhiro Nose, Takashi Kurita, Hirotsugu Uemura, Young-Chol Park, June Hanai, International urology and nephrology, International urology and nephrology, 38(2), 291 - 2, 2006 , Refereed
  Summary:A 40-year-old man was referred to our hospital with gynecomastia and painless swelling of the right scrotum. Ultrasonography revealed a 15 x 10 mm mass with low echogenicity of the right testis. We performed right high orchiectomy. Histologically, Reinke's crystals and capsular invasion by tumor cells were found. Final diagnosis, the tumor was a malignant Leydig cell tumor of the testis.
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• Medial prefrontal cortex lesions inhibit reflex micturition in anethetized rats., Seiji Matsumoto, Tadashi Hanai, Nobuhiro Yoshioka, Nobutaka Shimizu, Takahide Sugiyama, Hirotsugu Uemura, Neuroscience research, Neuroscience research, 54(1), 66 - 70, Jan. 2006 , Refereed
  Summary:The medial prefrontal cortex is thought to participate in the control of micturition and urinary continence, based on evidence from clinical reports, but its exact role is not fully understood. This study investigated whether ibotenic acid lesions of the medial prefrontal cortex would influence volume-evoked micturition in urethane-anesthetized rats. The incidence and amplitude of bladder contractions were recorded during continuous saline infusion (0.1 ml/min) immediately before and 1 week after ibotenic acid (0.5 microg) or vehicle (0.5 microl) was injected into the medial prefrontal cortex. Vehicle injection did not change the incidence or amplitude of bladder contractions compared to pre-injection values. Ibotenic acid lesions prolonged the time interval between bladder contractions significantly although it did not affect the amplitude of bladder contractions. Histological analysis revealed that ibotenic acid lesions were restricted primarily to the anterior cingulate and prelimbic cortices. Larger ibotenic acid lesions extending ventrally into the infralimbic cortex produced a variable response but did not change the overall incidence or amplitude of bladder contractions significantly. These data indicate that the medial prefrontal cortex influences the timing of bladder contractions but does not affect contraction amplitudes.
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• Edaravone protects against ischemia/reperfusion-induced functional and biochemical changes in rat urinary bladder., Seiji Matsumoto, Tadashi Hanai, Nobuhiro Yoshioka, Nobutaka Shimizu, Takahide Sugiyama, Hirotsugu Uemura, Robert M Levin, Urology, Urology, 66(4), 892 - 6, Oct. 2005 , Refereed
  Summary:OBJECTIVES: To investigate the effects of edaravone on ischemia/reperfusion (I/R) injury in the rat bladder. Increasing evidence has shown that I/R are major etiologic factors in the progression of bladder dysfunction induced by partial outlet obstruction, and that part of the damage is due to the generation of free radicals. Edaravone is a newly developed radical scavenging agent that has been used for protection against I/R injury in patients with cerebral infarction. METHODS: Thirty-five adult male rats were divided into five groups. Groups 1 to 4 underwent 1 hour of ischemia followed by 1 hour of reperfusion. Groups 1 to 3 were treated with edaravone at 1, 3, or 10 mg/kg body weight and group 4 with saline. Group 5 consisted of age-matched control rats. In vivo ischemia was created by clamping the vesical arteries for 1 hour. Reperfusion was accomplished by removing the clips and also lasted for 1 hour. Edaravone or saline was administered into the femoral artery after reperfusion for 30 minutes. After reperfusion, the bladder was excised and separated. The responses to electrical field stimulation, carbachol, and KCl were recorded. Other materials were analyzed for malondialdehyde as a measure of lipid peroxidation. RESULTS: Edaravone administration resulted in protection of the contractile responses to both field stimulation and carbachol, although the responses to KCl were not affected. I/R resulted in an increase in malondialdehyde, which was reduced to control levels by edaravone. CONCLUSIONS: These results suggest that edaravone has a potential protective effect against I/R-induced damage in the rat bladder.
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• Diphenyleneiodium (DPI) reduces oxalate ion- and calcium oxalate monohydrate and brushite crystal-induced upregulation of MCP-1 in NRK 52E cells., Tohru Umekawa, Karen Byer, Hirotsugu Uemura, Saeed R Khan, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association, 20(5), 870 - 8, May 2005 , Refereed
  Summary:BACKGROUND: Our earlier studies have demonstrated upregulation of monocyte chemoattractant protein-1 (MCP-1) in NRK52E rat renal epithelial cells by exposure to oxalate (Ox) ions and crystals of calcium oxalate monohydrate (COM) or the brushite (Br) form of calcium phosphate. The upregulation was mediated by reactive oxygen species (ROS). This study was performed to investigate whether NADPH oxidase is involved in ROS production. METHODS: Confluent cultures of NRK52E cells were exposed to Ox ions or COM and Br crystals. They were exposed for 1, 3, 6, 12, 24 and 48 h for isolation of MCP-1 mRNA and 24 h for enzyme-linked immunosorbent assay (ELISA) to determine the secretion of protein into the culture medium. We also investigated the effect of free radical scavenger, catalase, and the NADPH oxidase inhibitor diphenyleneiodium (DPI) chloride, on the Ox- and crystal-induced expression of MCP-1 mRNA and protein. The transcription of MCP-1 mRNA in the cells was determined using real-time polymerase chain reaction. Hydrogen peroxide and 8-isoprostane were measured to investigate the involvement of ROS. RESULTS: Exposure of NRK52E cells to Ox ions as well as the crystals resulted in increased expression of MCP-1 mRNA and production of the chemoattractant. Treatment with catalase reduced the Ox- and crystal-induced expression of both MCP-1 mRNA and protein. DPI reduced the crystal-induced gene expression and protein production but not Ox-induced gene expression and protein production. CONCLUSIONS: Exposure to Ox ions, and COM and Br crystals stimulates a ROS-mediated increase in MCP-1 mRNA expression and protein production. Reduction in ROS production, lipid peroxidation, low-density lipoprotein release, and inducible MCP-1 gene and protein in the presence of DPI indicates an involvement of NADPH oxidase in the production of ROS.
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• Analysis of bone mineral density in urolithiasis patients., Hidenori Tsuji, Tohru Umekawa, Takashi Kurita, Hirotsugu Uemura, Masanori Iguchi, Kokai Kin, Kazuhiro Kushida, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 12(4), 335 - 9, Apr. 2005 , Refereed
  Summary:BACKGROUND: The association between hypercalciuria and bone mineral density (BMD) has been already recognized. The aim of the present study is to relate BMD to age and sex and to evaluate the calcium metabolism and hypercalciuria-defined dietary or non-dietary category in patients with urolithiasis. METHODS: The BMI of the L2-L4 lumbar vertebrae was measured in 310 renal stone patients (191 men and 119 women). Percent age matched score (%AMS), which is the percent ratio of measured BMD to the mean BMD of age-matched control subjects, was utilized for the appraisal of BMD. Low BMD groups were defined by lower than 90% of %AMS. RESULTS: Low BMD was observed in 27.7% of urinary stone patients, which was not a significant difference to that of control subjects (23.5%) who were measured in the health examination. In male patients with urolithiasis, the frequency of patients in whom BMD had been apt to decrease since youth was high, but there was not a proven significant difference among the three age groups (20-39 years old, 40-59 years old and 60 years old or older). In contrast, for female stone patients, the frequency of low BMD markedly increased in patients aged 40 years or older, when menopause occurs. Furthermore, in female stone patients with hypercalciuria, the frequency of reduced BMD reached more than 40%. When the cause was non-dietary hypercalciuria (classified mainly on the daily amount of urinary calcium excretion after ingestion of calculus test diet), the frequency of reduced BMD reached 65% (P < 0.01). CONCLUSIONS: In case female stone patients with non-dietary hypercalciuria become menopausal, not only the risk of recurrent lithiasis increases, but the possibility of developing osteopenia in the future also increases. Appropriate treatments for prophylactic effects on urolithiasis or osteopenia should be considered, as judged from BMD, diet, sex, urinary calcium excretion and other factors synthetically.
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• The level of cadherin-6 mRNA in peripheral blood is associated with the site of metastasis and with the subsequent occurrence of metastases in renal cell carcinoma., Toru Shimazui, Kazuhiro Yoshikawa, Hirotsugu Uemura, Yoshihiko Hirao, Shinsuke Saga, Hideyuki Akaza, Cancer, Cancer, 101(5), 963 - 8, Sep. 01 2004 , Refereed
  Summary:BACKGROUND: To evaluate the significance of the presence of circulating renal cell carcinoma (RCC) cells in the development of metastases, the authors extended a previous study to quantify cadherin-6 mRNA levels in association with the pattern of metastasis. METHODS: Cadherin-6 mRNA levels were measured in peripheral blood samples from 66 patients with RCC, including 55 patients who had newly diagnosed RCC (43 without metastases and 12 with metastases) and 11 patients who had recurrent RCC. For quantitative polymerase chain reaction analysis, a cutoff value was determined in blood samples from 25 healthy volunteers and was verified in samples from 5 healthy controls and from 10 patients who had other malignancies. The correlation between the site of metastases and the cadherin-6 mRNA level was analyzed, and a follow-up study (median, 39 months) to track subsequent metastases was performed after patients underwent nephrectomy. RESULTS: Cadherin-6 was found in 69.9% of patients with metastases and in 34.9% of patients without apparent metastases (P = 0.0099). In the group of patients with recurrent RCC, patients who had only pulmonary metastases had a significantly lower positivity rate (25.0%) compared with patients who had distant metastases (85.7%; P = 0.044). Among 43 patients with newly diagnosed RCC, 5 of 15 patients who were positive for cadherin-6 had metastases after nephrectomy, whereas only 2 of the 28 patients with negative cadherin-6 status had recurrent disease (P = 0.0398). In addition, the recurrence-free survival of patients who were positive for cadherin-6 was poorer compared with the survival of patients who were negative for cadherin-6 (P = 0.062). CONCLUSIONS: The quantification of cadherin-6 mRNA in peripheral blood may be a significant predictive marker for current and future metastases. However, subsequent metastases did not always correlate with levels of cadherin-6 mRNA. This may have been due either to the small numbers of circulating tumor cells or to the low levels cadherin-6 mRNA in circulating tumor cells.
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• OAB, 7(*), 769 - 775, Jul. 2004
• A case of retrovesical leiomyoma, Mitsuhiro Tambo, Kiyohide Fujimoto, Fumiaki Hoshiyama, Michimasa Nakanishi, Takeshi Inoue, Akihide Hirayama, Hirotsugu Uemura, Yoshihiko Hirao, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 50(7), 497 - 499, Jul. 2004
  Summary:We herein report a rare case of leiomyoma in the retroperitoneal space posterior to the urinary bladder. A 61-year-old man came to our department complaining of lower abdominal discomfort. Abdominal and pelvic computed tomographic scan revealed a retrovesical solid tumor on the cranial side to the left seminal vesicle. Diagnostic imaging suggested that the retrovesical tumor was a benign tumor such as leiomyoma or fibroma, and he underwent simple resection of this retrovesical tumor via reroperitoneal approach. Histopathological diagnosis was well compatible with image diagnosis of leiomyoma. He has been followed up for 6 months without recurrence.
• Long-term results of transurethral microwave thermotherapy, Jpn J Endurol ESWL, Jpn J Endurol ESWL, 17, 225 - 228, 2004
• Detection of cadherin-6 mRNA by nested RT-PCR as a potential marker for circulating cancer cells in renal cell carcinoma., Toru Shimazui, Kazuhiro Yoshikawa, Hirotsugu Uemura, Risa Kawamoto, Koji Kawai, Katsunori Uchida, Yoshihiko Hirao, Shinsuke Saga, Hideyuki Akaza, International journal of oncology, International journal of oncology, 23(4), 1049 - 54, Oct. 2003 , Refereed
  Summary:To detect circulating RCC cells, we established a nested RT-PCR system for cadherin-6 mRNA, which is specifically expressed in RCC. A total of 121 samples of peripheral blood (34 healthy volunteers and 87 patients with RCC) were analyzed in this study. Total RNA of the monocyte fraction of the blood was extracted, then nested RT-PCR using specific primers was performed to detect mRNA of N-cadherin or cadherin-6. Nested RT-PCR revealed that expression of cadherin-6 mRNA was not present in the blood of most healthy volunteers (absent in 32/34), but positive expression was observed in the blood at concentrations of 10 cells/ml or greater of the SKRC-33 RCC cell line, which is a strong expresser of cadherin-6. In peripheral blood from patients with metastatic disease, cadherin-6 mRNA was detected in 70.4% (19/27). Messenger RNA of cadherin-6 was detectable in 45.0% (27/60) of patients with localized tumors. The PCR-based detection system for peripheral blood samples from patients with metastatic disease could reveal the presence of circulating RCC cells in the blood. Detection of cadherin-6 mRNA in non-metastatic presurgical RCC patients suggests that careful follow-up study is necessary in these patients.
• [Investigation of 14 renal cell carcinoma cases with tumor thrombus in the inferior vena cava]., Tajiri T, Noguchi K, Kishida T, Uemura H, Saito K, Yao M, Takeda M, Kubota Y, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 49(8), 457 - 461, Aug. 2003 , Refereed
• A case of primary transitional cell carcinoma of the prostate, Hiroshi Morikawa, Masaki Cho, Satoshi Takada, Kiyohide Fujimoto, Hirotsugu Uemura, Seiichiro Ozono, Yoshihiko Hirao, Osamu Natsume, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 49(6), 357 - 360, Jun. 2003
  Summary:A 77-year-old man was referred to our hospital with a complaint of dysuria and right ischiodynia. He had had a hemi-thyroidectomy for thyroid cancer and right cervical lymphadenectomy three years and one year, respectively, before this visit. Prostate cancer was strongly suspected by transrectal examination with prostate specific antigen (PSA) elevated to 77.8 ng/ml. Pathological diagnosis of prostate biopsy specimen was transitional cell carcinoma with grade 3 malignancy and negative staining for PSA. Endoscopic examination showed a normal appearance of bladder and prostatic urethral epithelium. Urine cytology showed no malignant cells. However, immunostaining for PSA revealed that the cervical lymph node specimen resected before was moderately differentiated adenocarcinoma of prostate. He had multiple metastases to mediastinal and retroperitoneal lymph nodes and right ischium. Endocrine therapy (goserelin acetate depot, bicalutamide) and systemic chemotherapy (methotrexate, epirubicin, cisplatin) were performed combined with irradiation to right ischium metastasis. Two months later, he showed a complete response in PSA and partial response in lymph node metastases, but died of cancer 13 months later.
• Clinicopathological significance of neoadjuvant hormonal therapy prior to radical prostatectomy: whole section analysis, Hirotsugu Uemura, Masaki Cho, Yoshihiko Hirao, Noboru Konishi, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 48(11), 719 - 723, Nov. 2002
  Summary:We investigated whether the histopathological effect (cell viability) of neoadjuvant hormonal treatment before radical prostatectomy for clinically localized prostate cancer is involved in the biochemical outcome, i.e., androgen independency. Non-randomized prospective trial was carried out between September 1996 and April 2001 involving the patients with clinical stage T1-3 prostate cancer, including 62 who underwent radical prostatectomy after receiving neoadjuvant hormonal treatment for an average of 6.3 months and 76 who underwent radical prostectomy only. All resected specimens were histopathologically diagnosed by whole section analysis. The patients receiving neoadjuvant hormonal treatment were categorized into 4 groups according to the histological change in the resected prostate. There were 8 patients in G0 (all viable cells), 11 patients in G1 (more than 50% viable cells), 26 patients G2 (more than 50% non-viable cells) and 17 patients in G3 (no cancer cells). No difference in the patient background (prostate specific antigen, stage, Gleason score, positive core Nr, duration of neoadjuvant therapy) was observed in any group, except for the duration of (p < 0.05). Multivariate hazards analyses revealed that only the duration of neoadjuvant hormonal treatment was independently associated with excellent responders with grade 3 histological effect. Neoadjuvant hormonal therapy prior to radical operation resulted in various histopathological changes in the prostate, but it is not clear whether the histological effects of hormonal treatment might be involved in the outcome. A longer follow-up randomized prospective trial is necessary.
• Renal cell carcinoma-associated G250 methylation and expression: in vivo and in vitro studies., Karin Grabmaier, Mirjam de Weijert, Hirotsugu Uemura, Jack Schalken, Egbert Oosterwijk, Urology, Urology, 60(2), 357 - 62, Aug. 2002 , Refereed
  Summary:OBJECTIVES: In renal cell carcinoma (RCC) cell lines, expression of the RCC-associated antigen G250 correlates with hypomethylation of the investigated CpG dinucleotides in the G250 promoter region, despite the absence of a CpG island. To gain insight into the molecular mechanism leading to G250 expression in vivo, we ascertained whether this correlation between G250 gene expression and the methylation status of the G250 gene also existed in primary RCC and normal kidney tissue. METHODS: G250 mRNA and protein expression was determined by reverse transcriptase-polymerase chain reaction, fluorescence activated cell sorting analysis, and immunohistochemistry in 15 RCC cell lines and 13 paired primary RCC/normal kidney tissue specimens. The methylation status of the G250 gene was determined by bisulfite genomic sequencing. RESULTS: RCC cell lines revealed a clear correlation between G250 expression and hypomethylation. In contrast, no hypomethylation was observed in primary RCC compared with normal kidney tissue. The CpG dinucleotides investigated were generally completely methylated in RCC, as well as in normal kidney tissue. Furthermore, a primary culture of RCC tissue revealed increasing hypomethylation of the G250 gene in successive passages, suggesting that the G250 hypomethylation observed in vitro is tissue culture induced. CONCLUSIONS: The methylation status of the G250 gene correlated with G250 expression in vitro but not in vivo.
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• Non-ischemic nephron-sparing surgery for small renal cell carcinoma: complete tumor enucleation using a microwave tissue coagulator., Yoshihiko Hirao, Kiyohide Fujimoto, Masahito Yoshii, Nobumichi Tanaka, Yoshiki Hayashi, Hitoshi Momose, Shoji Samma, Eijiro Okajima, Hirotsugu Uemura, Katsunori Yoshida, Seiichiro Ozono, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 32(3), 95 - 102, Mar. 2002 , Refereed
  Summary:OBJECTIVE: To determine the methodological usefulness of non-ischemic complete enucleation for small renal cell carcinomas (RCC) using a microwave tissue coagulator (MTC). METHODS: Fifty-nine patients (61 kidneys) underwent non-ischemic complete tumor enucleation by MTC. Of the 59 patients, 46 had an elective indication and 15 kidneys of 13 patients had an imperative indication. RCC was exposed with minimal peri-renal detachment. The demarcation line, 7-10 mm from the tumor, was coagulated at 8-10 mm intervals with a microwave antenna needle for 30-40 s at 50-60 W. The renal tumor was excised along the coagulated zone with normal surrounding tissue. The enucleation bed was covered with fibrin glue or fat tissue without approximation. RESULTS: The operations were successfully completed in all intended cases. The mean operation time was 160 +/- 43 (median: 160) min and the mean blood loss was 313 +/- 370 (median: 158) ml. No major bleeding or urine leakage from the enucleation bed was observed in 62.2 and 88.5% of cases, respectively. The minor bleeding and urine leakage were controlled easily with absorbable sutures. None of the cases presented with postoperative bleeding or urine leakage from the enucleation bed. Severe impairment of the renal function was not observed in any case evaluated by means of serum creatinine, creatinine clearance and radioisotope examination. The 5-year overall survival rate was 87% without recurrence up to 23.1 +/- 19.5 months of the mean follow-up. CONCLUSION: Non-ischemic complete tumor enucleation using MTC constitutes a simple, reliable and less invasive alternative to ordinary nephron-sparing surgeries for small RCC.
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• Clinical aspects of renal cell carcinoma., UEMURA Hirotsugu, Oosterwijk E, Debruyne FMJ, Revista Romana de Urol., Revista Romana de Urol., 1, 81 - 88, 1994 , Refereed
• Induction of nephrosis by .BETA.-cyclodextrin in Beagles., Tabata Shoichi, Kitahori Yoshiteru, Hiasa Yoshio, Ozono Seiichiro, Yamaguchi Hisako, Kitagawa Hisayo, Uemura Hirotsugu, Matsuki Hisashi, Samma Shoji, Hirao Yoshihiko, Okajima Eigoro, Journal of Toxicologic Pathology, Journal of Toxicologic Pathology, 4(1), 67 - 73, 1991
  Summary:The present study was conducted to examine nephrotoxicity of β-cyclodextrin (β-C) in dogs. Five female Beagle dogs were divided into 3 groups: Group 1 (2 dogs treated with 0.9g/kg of β-C), Group 2 (2 dogs treated with 0.45g/kg of β-C), and Group 3 (1 dog treated with saline). Durations of β-C injection were 7 and 10 consecutive days in Groups 1 and 2. Histopathological and histo-chemical examinations of the kidney were performed. Following 0.9g/kg or long-term 0.45g/kg treatment with β-C, the animals showed marked fatigue and elevated BUN and Cr. Histopathologically, β-C treatment resulted in vacuolation, necrosis, and regeneration in the proximal tubules. Activities of succinic dehydrogenase, β-glucuronidase, and glucose-6-phosphatase decreased histochemically after β-C treatment. Because signs of nephrotoxicity represented were noted in dogs after β-C treatment, as has been reported in rats, it seems likely that dogs also can serve as a model of nephrosis. If this model is to be applied to the study of renal carcinogenesis, the present study suggests the optimum dosing regimen for β-C to be 7-day 0.45g/kg treatment.
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• TUMOR MARKERS IN RATS WITH RENAL TUMOR INDUCED BY N-ETHYL-N-HYDROXYETHYLNITROSAMINE, Yamaguchi Hisako, Kitahori Yoshiteru, Hiasa Yoshio, Ozono Seiichiro, Kitagawa Hisayo, Uemura Hirotsugu, Tabata Shoichi, Matsuki Hisashi, Samma Shoji, Hirao Yoshihiko, Okajima Eigoro, Journal of Toxicologic Pathology, Journal of Toxicologic Pathology, 3(2), 239 - 243, 1990
  Summary:Renal carcinomas were induced by N-ethyl-N-hydroxyethylnitrosamine (EHEN) followed by trisodium nitrilotriacetate monohydrate (NTA) in Wistar rats. In these rats, various parameters which are clinically used as tumor markers were examined. Renal tumors developed in 6 (37.5%) of 16 rats treated with EHEN alone and in 14 (82.4%) of 17 rats treated with EHEN and subsequently with NTA. When various parameters were compared between these two groups and the control group, RBC, Hb Al-P, LDH, BUN, Cr, and Ca in the former two groups differed significantly from those values of the untreated controls. In the EHEN-treated rats (Group 1 and 2), erythropoietin (EP) was higher in the tumor-bearing group than in the tumor-free group (p<0.025), although no other significant difference was observed. As compared to the untreated controls, tumor-bearing rats showed significant elevation in RBC (p<0.005). Cr (p<0.005), and EP (p<0.05) and significant reduction in Hb (p<0.005). Al-P (p<0.005), and LDH (p<0.05). Therefore, the significant difference in RBC, Hb, Al-P, LDH, and Cr seems to be attributable to the effect of EHEN and NTA. These results suggest that EP is specifically elevated in rats with renal tumor.
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• A multicenter retrospective study of nivolumab monotherapy in previously treated metastatic renal cell carcinoma patients: interim analysis of Japanese real-world data., Nobuyuki Hinata, Junji Yonese, Satoru Masui, Yasutomo Nakai, Suguru Shirotake, Katsunori Tatsugami, Teruo Inamoto, Masahiro Nozawa, Kosuke Ueda, Toru Etsunaga, Takahiro Osawa, Motohide Uemura, Go Kimura, Kazuyuki Numakura, Kazutoshi Yamana, Hideaki Miyake, Satoshi Fukasawa, Kenya Ochi, Hirokazu Kaneko, Hirotsugu Uemura, International journal of clinical oncology, International journal of clinical oncology, Jun. 09 2020 , Refereed
  Summary:BACKGROUND: In a phase III clinical trial, CheckMate 025, treatment of metastatic renal cell carcinoma (mRCC) with nivolumab demonstrated superior efficacy over everolimus. However, as the clinical trial excluded patients with specific complications and poor performance status (PS), the effectiveness and safety of nivolumab in clinical practice, in which patients with various clinical complications are treated, is unclear. This study explored real-world nivolumab treatment in Japanese mRCC patients. METHODS: This is an interim analysis of a multicenter, non-interventional, medical record review study (minimum follow-up: 9 months). All eligible Japanese mRCC patients who first received nivolumab between February and October 2017 were included; data cut-off was April 2019. We analyzed nivolumab treatment patterns, efficacy (including overall survival, progression-free survival, objective response rate, and duration of response) and safety (including immune-related adverse events). RESULTS: Of 208 evaluable patients, 31.7% received nivolumab as fourth- or later line of treatment. At data cut-off, 26.9% of patients were continuing nivolumab treatment. The major reason for discontinuation was disease progression (n = 100, 65.8%). Median overall survival was not reached; the 12-month survival rate was 75.6%. Median progression-free survival was 7.1 months, the objective response rate was 22.6%, and median duration of response was 13.3 months. Patients who were excluded or limited in number in CheckMate 025, such as those with non-clear cell RCC or poor PS, also received benefits from nivolumab treatment. Immune-related adverse events occurred in 27.4% of patients (grade ≥ 3, 10.1%). CONCLUSION: Nivolumab was effective and well-tolerated in real-world Japanese mRCC patients. TRIAL REGISTRATION: UMIN000033312.
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• Editorial Comment from Dr Adomi et al. to Frailty is significantly associated with the type of urinary diversion in patients with muscle-invasive bladder cancer., Shogo Adomi, Kazutoshi Fujita, Kazuhiro Yoshimura, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, Jun. 04 2020 , Refereed
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• A randomized, double-blind, comparison of radium-223 and placebo, in combination with abiraterone acetate and prednisolone, in castration-resistant metastatic prostate cancer: subgroup analysis of Japanese patients in the ERA 223 study., Nobuaki Matsubara, Go Kimura, Hiroji Uemura, Hirotsugu Uemura, Motonobu Nakamura, Satoshi Nagamori, Atsushi Mizokami, Hiroaki Kikukawa, Makoto Hosono, Seigo Kinuya, Heiko Krissel, Jonathan Siegel, Yoshiyuki Kakehi, International journal of clinical oncology, International journal of clinical oncology, 25(4), 720 - 731, Apr. 2020 , Refereed
  Summary:BACKGROUND: ERA 223 compared concurrent abiraterone acetate/prednisolone (AAP) plus radium-223 with AAP plus placebo in men with chemotherapy-naïve asymptomatic or mildly symptomatic metastatic castration-resistant prostate cancer (mCRPC) and bone metastases. We report data from a subgroup of Japanese patients in ERA 223. METHODS: Patients were randomized to radium-223 (55 kBq/kg) or placebo once every 4 weeks (max. 6 cycles), and also received oral abiraterone acetate 1000 mg once daily plus prednisone/prednisolone 5 mg twice daily during and after radium-223/placebo treatment, until a symptomatic skeletal event (SSE). The primary endpoint was SSE-free survival (SSE-FS); overall survival (OS) was a secondary endpoint. RESULTS: Of 806 patients randomized in ERA 223, 114 patients (57 per arm) were enrolled in Japan. SSE-FS was not improved significantly in the radium-223 arm [25.5 months, 95% CI 20.6-not estimated (NE)] compared with the placebo arm (28.7 months, 95% CI 19.7-NE) (HR = 0.907, 95% CI 0.501-1.642). OS and other secondary endpoints were not improved significantly in the radium-223 arm. The incidence of fracture was 23% and 11% in the radium-223 and placebo arms, respectively. The incidence of death was 32% and 36%, respectively. CONCLUSIONS: In the Japanese ERA 223 subgroup, concurrent treatment with AAP and radium-223 did not significantly improve SSE-FS and increased the incidence of fracture, similar to outcomes achieved in the overall population, while an increased incidence of death was not evident. The combination of radium-223 with AAP is not recommended in Japanese patients with asymptomatic or mildly symptomatic mCRPC and bone metastases. CLINICAL TRIAL REGISTRATION: Clinical trial registration no: NCT02043678.
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• Chemopreventive effects of nanoparticle curcumin in a mouse model of Pten-deficient prostate cancer, Marco A. De Velasco,, Yan Lu, Yurie Kura, Toshiyuki China, Yasuyuki Inou, Akinori Nakayama, Hiroshi Okada, Shigeo Horie, Hirotsugu Uemura, Hisamitsu Ide, Human Cell, Human Cell, Mar. 2020 , Refereed
• Mixed 20-peptide cancer vaccine in combination with docetaxel and dexamethasone for castration-resistant prostate cancer: a randomized phase II trial., Masanori Noguchi, Gaku Arai, Shin Egawa, Chikara Ohyama, Seiji Naito, Kazumasa Matsumoto, Hirotsugu Uemura, Masayuki Nakagawa, Yasutomo Nasu, Masatoshi Eto, Shigetaka Suekane, Tetsuro Sasada, Shigeki Shichijo, Akira Yamada, Tatsuyuki Kakuma, Kyogo Itoh, Cancer immunology, immunotherapy : CII, Cancer immunology, immunotherapy : CII, Feb. 05 2020 , Refereed
  Summary:A novel cancer vaccine consisting of 20 mixed peptides (KRM-20) was designed to induce cytotoxic T lymphocytes (CTL) against twelve different tumor-associated antigens. The aim of this phase II trial was to examine whether KRM-20 in combination with docetaxel and dexamethasone enhances the antitumor effects in patients with castration-resistant prostate cancer (CRPC). In this double-blind, placebo-controlled, randomized phase II study, we enrolled chemotherapy-naïve patients with CRPC from ten medical centers in Japan. Eligible patients were randomly assigned 1:1 centrally to receive either KRM-20 combined with docetaxel and dexamethasone (n = 25) or placebo with docetaxel and dexamethasone (n = 26). The primary endpoint was the difference in prostate-specific antigen (PSA) decline between each treatment. The rates of > 50% PSA decline in the two arms were similar (56.5% versus 53.8%; P = 0.851). Human leukocyte antigen (HLA)-matched peptide-specific immunoglobulin G (P = 0.018) and CTL (P = 0.007) responses in the KRM-20 arm significantly increased after treatment. The addition of KRM-20 did not increase toxicity. There were no between-group differences in progression-free or overall survival (OS). The addition of KRM-20 was safe, and similar PSA decline and HLA-matched peptide-specific CTL and IgG responses increased in combination with docetaxel and dexamethasone in CRPC patients. Subgroup analysis suggested that this treatment is favorable for CRPC patients with ≥ 26% lymphocytes or PSA levels of < 11.2 ng/ml, but further clinical trials comparing OS are required.
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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, Japanese journal of clinical oncology, 50(1), 12 - 19, Jan. 24 2020 , Refereed
  Summary: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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• Role of p38 MAP kinase signaling pathways in storage and voiding dysfunction in mice with spinal cord injury., Nobutaka Shimizu, Naoki Wada, Takahiro Shimizu, Takahisa Suzuki, Masahiro Kurobe, Anthony J Kanai, William C de Groat, Mamoru Hashimoto, Akihide Hirayama, Hirotsugu Uemura, Naoki Yoshimura, Neurourology and urodynamics, Neurourology and urodynamics, 39(1), 108 - 115, Jan. 2020 , Refereed
  Summary:AIM: To investigate the role of p38 MAP kinase in lower urinary tract dysfunction in mice with spinal cord injury (SCI). METHODS: Cystometry and external urethral sphincter-electromyography were performed under an awake condition in 4-week SCI female mice. Two weeks after SCI, a catheter connected to an osmotic pump filled with a p38 mitogen-activated protein kinase (MAPK) inhibitor or artificial cerebrospinal fluid (CSF) was implanted into the intrathecal space of L6-S1 spinal cord for continuous intrathecal instillation at infusion rate of 0.51 μL/h for 2 weeks before the urodynamic study. L6 dorsal root ganglia were then removed from CSF and p38 MAPK inhibitor-treated SCI mice as well as from CSF-treated normal (spinal intact) mice to evaluate the levels of transient receptor potential cation channel subfamily V member 1 (TRPV1), tumor necrosis factor-α (TNF-α), and inducible nitric oxide synthase (iNOS) transcripts by real-time polymerase chain reaction. RESULTS: In p38 MAPK inhibitor-treated SCI mice, nonvoiding contractions during bladder filling, bladder capacity, and post-void residual volume were significantly reduced while micturition pressure and voiding efficiency were significantly increased in comparison to these measurements in CSF-treated SCI mice. The expression of TRPV1, TNF-α, and iNOS messenger RNA was increased in SCI mice compared with expression in spinal intact mice and significantly decreased after p38 MAPK inhibitor treatment. CONCLUSIONS: The p38 MAPK signaling pathway in bladder sensory neurons or in the spinal cord plays an important role in storage and voiding problems such as detrusor overactivity and inefficient voiding after SCI.
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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, Cancer science, Dec. 28 2019 , Refereed
  Summary: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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• United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia., Hirotsugu Uemura, Dingwei Ye, Ravindran Kanesvaran, Edmund Chiong, Bannakij Lojanapiwat, Yeong-Shiau Pu, Sudhir Kumar Rawal, Azad Hassan Abdul Razack, Hao Zeng, Byung Ha Chung, Noor Ashani Md Yusoff, Chikara Ohyama, Choung Soo Kim, Sunai Leewansangtong, Yuh-Shyan Tsai, Yanfang Liu, Weiping Liu, Maximiliano van Kooten Losio, Marxengel Asinas-Tan, BJU international, BJU international, Dec. 23 2019 , Refereed
  Summary:OBJECTIVES: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry. PATIENTS AND METHODS: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017. RESULTS: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy). CONCLUSION: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.
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• Reactivation of latent tuberculosis infection induced by cabazitaxel in a patient with prostate cancer: A case report., Mamoru Hashimoto, Takafumi Minami, Mamoru Hamaguchi, Saizo Fujimoto, Tomoki Takahashi, Takashi Kikuchi, Shogo Adomi, Eri Banno, Takayuki Ohzeki, Nobutaka Shimizu, Yasunori Mori, Masahiro Nozawa, Kazuhiro Nose, Kazuhiro Yoshimura, Hirotsugu Uemura, Medicine, Medicine, 98(51), e18436, Dec. 2019 , Refereed
  Summary:RATIONALE: Latent tuberculosis infection (LTBI) describes the dormant state of tuberculosis (TB), in which persistent immune-related interaction between TB and T-cells maintain its state. Cabazitaxel (CBZ) is reported to improve overall survival in patients with castration-resistant prostate cancer (CRPC) after progression observed in regimens including docetaxel. CBZ is known for severe myelosuppression; however there is no recommendation for the treatment of LTBI before CBZ treatment. To the authors' knowledge, this is the first report to describe reactivation of LTBI induced by CBZ. PATIENT CONCERNS: A 75-year-old Japanese male with a medical history of TB since 16 years of age had been treated for prostate cancer (PC) (initial prostate-specific antigen 532 ng/ml; cT4N1M1b; Gleason score4+4) with androgen deprivation therapy, abiraterone, and docetaxel. Calcified nodules and radiological findings of LTBI were present in the upper right lobe since the diagnosis of PC. After progression was observed during these treatments, CBZ was administered combined with pegfilgrastim, long-acting granulocyte colony-stimulating factor (G-CSF). Seven days after the third course of CBZ, he was admitted to the authors' hospital to treat febrile neutropenia (FN). High fever persisted even after myelosuppression had recovered. Computed tomography (CT) revealed distribution of small nodules in the bilateral lungs, for which miliary TB was included in the differential diagnosis. T-Spot, interferon-gamma-release assay, and bronchoscopy yielded no significant findings; however, sputum and urine culture confirmed the diagnosis of TB. DIAGNOSIS: CT, sputum and urine culture confirmed the diagnosis of miliary TB. INTERVENTIONS: The patient was treated with anti-bacterial therapy (cefepime) on hospital admission, which was not effective. After the diagnosis of miliary TB was confirmed, anti-TB drugs, including isoniazid, rifampicin, pyrazinamide and ethambutol, were administered. OUTCOMES: Despite anti-TB therapy, high fever persisted and radiological findings worsened. Fifty days after the third course of CBZ, the patient died of respiratory dysfunction caused by progression of miliary TB. LESSONS: Management of LTBI is needed in cases of radiographic findings of LTBI and medical history of TB before CBZ treatment, despite the rarity of LTBI reactivation in patients with PC.
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• Health-related quality of life after apalutamide treatment in patients with metastatic castration-sensitive prostate cancer (TITAN): a randomised, placebo-controlled, phase 3 study., Neeraj Agarwal, Kelly McQuarrie, Anders Bjartell, Simon Chowdhury, Andrea J Pereira de Santana Gomes, Byung Ha Chung, Mustafa Özgüroğlu, Álvaro Juárez Soto, Axel S Merseburger, Hirotsugu Uemura, Dingwei Ye, Robert Given, David Cella, Ethan Basch, Branko Miladinovic, Lindsay Dearden, Kris Deprince, Vahid Naini, Angela Lopez-Gitlitz, Kim N Chi, The Lancet. Oncology, The Lancet. Oncology, 20(11), 1518 - 1530, Nov. 2019 , Refereed
  Summary:BACKGROUND: In the phase 3 TITAN study, the addition of apalutamide to androgen deprivation therapy (ADT) significantly improved the primary endpoints of overall survival and radiographic progression-free survival in patients with metastatic castration-sensitive prostate cancer. We aimed to assess health-related quality of life (HRQOL) in TITAN, including pain and fatigue. METHODS: In this randomised, placebo-controlled, double-blind, phase 3 study, patients with metastatic castration-sensitive prostate cancer (defined as not receiving ADT at the time of metastatic disease progression) aged 18 years and older, receiving continuous ADT (selected at the investigator's discretion), and with an Eastern Cooperative Oncology Group performance status score of 0 or 1 were randomly assigned (1:1), using an interactive web response system, to receive oral apalutamide (four 60 mg tablets, once daily) or matching placebo. Previous localised disease treatment or previous docetaxel for metastatic castration-sensitive prostate cancer were allowed. Randomisation was stratified by Gleason score at diagnosis, region, and previous docetaxel treatment. Randomisation was done using randomly permuted blocks (block size of four). Investigators, research staff, sponsor study team, and patients were masked to the identities of test and control treatments. Patient-reported outcomes were prespecified exploratory endpoints and were the Brief Pain Inventory-Short Form (BPI-SF), Brief Fatigue Inventory (BFI), Functional Assessment of Cancer Therapy-Prostate (FACT-P), and EuroQoL 5D questionnaire 5 level (EQ-5D-5L). BPI and BFI were completed for 7 consecutive days (days -6 to 1 inclusive of each cycle visit), then at months 4, 8, and 12 in follow-up. FACT-P and EQ-5D-5L were completed during cycles 1-7, then every other cycle until the end of treatment, and at months 4, 8, and 12 in follow-up. Analyses were based on the intention-to-treat population. Missing patient-reported outcome assessments were calculated as the expected number of assessments for a visit minus the actual number of assessments received for that visit. For time-to-event endpoints, when median values could not be calculated because less than 50% of patients had degradation, 25th percentiles were compared. This study is registered with ClinicalTrials.gov, number NCT02489318, and is ongoing. FINDINGS: Between Dec 9, 2015, and July 25, 2017, 1052 eligible patients were enrolled randomly assigned to apalutamide (n=525) or placebo (n=527). Data cutoff for this analysis of patient-reported outcomes was Nov 23, 2018. Median follow-up for time to pain-related endpoints ranged from 19·4 to 22·1 months. Patients were mostly asymptomatic at baseline: on the BPI-SF pain severity scale of 0-10, median pain scores (indicating worst pain in the past 24 h) were 1·14 (IQR 0-3·17) in the apalutamide group and 1·00 (0-2·86) in the placebo group, and median worst fatigue scores on the BFI were 1·29 (IQR 0-3·29) in the apalutamide group and 1·43 (0·14-3·14) in the placebo group. Patient experience of pain and fatigue (intensity and interference) did not differ between the groups for the duration of treatment. Median time to worst pain intensity progression was 19·09 months (95% CI 11·04-not reached) in the apalutamide group versus 11·99 months (8·28-18·46) in the placebo group (HR 0·89 [95% CI 0·75-1·06]; p=0·20). Median time to pain interference progression was not reached in either group (95% CI 28·58-not reached in the apalutamide group; not reached-not reached in the placebo group). 25th percentiles for time to pain interference progression were 9·17 months (5·55-11·96) in the apalutamide group and 6·24 months (4·63-7·43) in the placebo group (HR 0·90 [95% CI 0·73-1·10]; p=0·29). FACT-P total scores and EQ-5D-5L data showed preservation of HRQOL in both groups. The median time to deterioration as determined by FACT-P total score was 8·87 months (95% CI 4·70-11·10) in the apalutamide group and 9·23 months (7·39-12·91) in the placebo group (HR 1·02 [95% CI 0·85-1·22]; p=0·85). INTERPRETATION: Apalutamide with ADT is a well-tolerated and effective option for men with metastatic castration-sensitive prostate cancer. The combination significantly improves survival outcomes compared with ADT alone while maintaining HRQOL despite additive androgen blockade. FUNDING: Janssen Research & Development.
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• 抗癌剤治療による筋肉量減少が腎盂または尿管癌の予後に与える影響, 橋本 士, 藤本 西蔵, 浜口 守, 高橋 智輝, 菊池 尭, 安富 正悟, 大關 孝之, 清水 信貴, 森 康範, 南 高文, 野澤 昌弘, 能勢 和宏, 吉村 一宏, 植村 天受, 日本癌治療学会学術集会抄録集, 日本癌治療学会学術集会抄録集, 57回, P42 - 7, Oct. 2019 , Refereed
• 転移性尿路上皮癌に対するペムブロリズマブの使用経験, 山本 豊, 西本 光寿, 野澤 昌弘, 明石 泰典, 喜馬 啓介, 橋本 士, 菊池 尭, 大関 孝之, 清水 信貴, 森 康範, 南 高文, 能勢 和宏, 吉村 一宏, 平山 暁秀, 植村 天受, 日本癌治療学会学術集会抄録集, 日本癌治療学会学術集会抄録集, 57回, P97 - 3, Oct. 2019 , Refereed
• 高リスク前立腺癌に対する永久挿入密封小線源療法とロボット支援前立腺全摘術の比較, 南 高文, 藤本 西蔵, 浜口 守, 高橋 智輝, 橋本 士, 菊池 堯, 安富 正悟, 大關 孝之, 清水 信貴, 森 康範, 能勢 和宏, 野澤 昌弘, 吉村 一宏, 植村 天受, 日本癌治療学会学術集会抄録集, 日本癌治療学会学術集会抄録集, 57回, P108 - 6, Oct. 2019 , Refereed
• Targeting castration-resistant prostate cancer with androgen receptor antisense oligonucleotide therapy., Marco A De Velasco, Yurie Kura, Kazuko Sakai, Yuji Hatanaka, Barry R Davies, Hayley Campbell, Stephanie Klein, Youngsoo Kim, A Robert MacLeod, Koichi Sugimoto, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, JCI insight, JCI insight, 4(17), Sep. 05 2019 , Refereed
  Summary:Sustained therapeutic responses from traditional and next-generation antiandrogen therapies remain elusive in clinical practice due to inherent and/or acquired resistance resulting in persistent androgen receptor (AR) activity. Antisense oligonucleotides (ASO) have the ability to block target gene expression and associated protein products and provide an alternate treatment strategy for castration-resistant prostate cancer (CRPC). We demonstrate the efficacy and therapeutic potential of this approach with a Generation-2.5 ASO targeting the mouse AR in genetically engineered models of prostate cancer. Furthermore, reciprocal feedback between AR and PI3K/AKT signaling was circumvented using a combination approach of AR-ASO therapy with the potent pan-AKT inhibitor, AZD5363. This treatment strategy effectively improved treatment responses and prolonged survival in a clinically relevant mouse model of advanced CRPC. Thus, our data provide preclinical evidence to support a combination strategy of next-generation ASOs targeting AR in combination with AKT inhibition as a potentially beneficial treatment approach for CRPC.
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• Prostate cancer in Asia: design of a patient registry to inform real-world treatments, outcomes, and quality of life., Yanfang Liu, Hirotsugu Uemura, Dingwei Ye, Ji Y Lee, Edmund Chiong, Yeong-S Pu, Azad H A Razack, Choosak Pripatnanont, Sudhir Rawal, Grace K M Low, Hong Qiu, Weng H Chow, Maximiliano Van Kooten Losio, Prostate international, Prostate international, 7(3), 108 - 113, Sep. 2019 , Refereed
  Summary:Background: The incidence of prostate cancer (PC) in Asian countries is increasing for reasons that are not clear. Data describing how PC is diagnosed and treated are fragmented across Asia, with marked intercountry and intracountry differences in outcome and knowledge gaps in clinical diagnostic and treatment practices. To address these knowledge gaps, we have established a PC disease registry with the aim of providing a comprehensive picture of PC diagnosis, prognosis, treatment and outcome, population characteristics, and comorbidities in real-world clinical practice in Asia. Methods: This is a multinational, multicenter, longitudinal, and observational registry of PC patients presenting to participating tertiary-care hospitals in eight Asian countries (www.clinicaltrials.gov NCT02546908. Registry Identifier: NOPRODPCR4001). Approximately 3500-4000 eligible patients with existing or newly diagnosed high-risk localized PC (cohort 1), nonmetastatic biochemically recurrent PC (cohort 2), or metastatic PC (cohort 3) will be consecutively enrolled and followed-up for 5 years. An enrollment cap of 600 patients each will be applied to cohorts 1 and 2. Disease status is collected at enrollment, and outcome variables captured at 3-monthly intervals include diagnostic/staging, treatments including reason for change, laboratory results, comorbidities, and concomitant medications. Treatments and survival outcomes will be captured real time until study end. Patient-reported quality-of-life will be measured every 6 months, and medical resource utilization summarized at study end. Data analysis will include exploratory analyses of potential associations between multiple risk factors and socioeconomic variables with disease progression and evaluation of various treatments for PC including novel therapies on clinical outcome and health-related quality-of-life outcomes. Results: 3636 men with PC were enrolled until July 2018; 416 in cohort 1, 399 in cohort 2 and 2821 in cohort 3. Discussion: A total of 3636 patients were enrolled until July 2018. The prospective disease registry will provide comprehensive and wide-ranging real-world information on how PC is diagnosed and treated in Asia. Such information can be used to inform policy development for best practice and direct clinical study design evaluating new treatments.
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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, Japanese journal of clinical oncology, 49(8), 766 - 771, Aug. 01 2019 , Refereed
  Summary: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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• Apalutamide reworks the immune composition of prostate tumors, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sato, Noriko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 79(13), Jul. 2019 , Refereed
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• A real-time PCR-based approach to quantitatively assess tumor immune profiles and immune responses, De Velasco, Marco A., Kura, Yurie, Sato, Noriko, Ando, Naomi, Sakai, Kazuko, Mori, Yasunori, Davies, Barry R., Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 79(13), Jul. 2019 , Refereed
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• Immunomodulation of the multi-tyrosine kinase inhibitor TAS-115 in a mouse model of prostate cancer, De Velasco, Marco A., Kura, Yurie, Sato, Noriko, Ando, Naomi, Sakai, Kazuko, Yoshimura, Kazuhiro, Nozawa, Masahiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 79(13), Jul. 2019 , Refereed
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• Dietary isoflavone decreases prostate cancer progression and improves survival in conditional Pten/Trp53-deficient mice, Mon, Yasunori, De Velasco, Marco A., Kura, Yurie, Benno, Eh, Ando, Naomi, Sato, Noriko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 79(13), Jul. 2019 , Refereed
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• Interrogating genetically engineered mouse models of prostate cancer to aid in immunotherapy development, De Velasco, Marco A., Kura, Yurie, Mori, Yasunori, Shimizu, Nobutaka, Ozeki, Takayuki, Sakai, Kazuko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 386 - 386, Dec. 2018 , Refereed
• Identification of a gene set associated with poor clinical outcomes in prostate cancer patients, Hashimoto, Mamoru, De Velasco, Marco A., Kura, Yurie, Sakai, Kazuko, Shimizu, Nobutaka, Mori, Yasunori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 534 - 534, Dec. 2018 , Refereed
• Preclinical activity of apalutamide (ARN-509) in genetically engineered mouse models of Pten-deficient prostate cancer, Mori, Yasunori, De Velasco, Marco A., Kura, Yurie, Ozeki, Takayuki, Shimizu, Nobutaka, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 211 - 211, Dec. 2018 , Refereed
• PIM inhibition reduces tumor growth and improves survival in mouse advanced castration-resistant prostate cancer, Kura, Yurie, De Velasco, Marco A., Mori, Yasunori, Shimizu, Nobutaka, Ozeki, Takayuki, Sakai, Kazuko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 230 - 230, Dec. 2018 , Refereed
• Preclinical evaluation of the multi tyrosine kinase inhibitor TAS-115 in mouse Pten-deficient prostate cancer, Nozawa, Masahiro, De Velasco, Marco A., Kura, Yurie, Shimizu, Nobutaka, Mori, Yasunori, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 231 - 231, Dec. 2018 , Refereed
• Effect of abiraterone therapy on anti-tumor immunity in a mouse Pten-deficient prostate cancer model, Shimizu, Nobutaka, De Velasco, Marco A., Kura, Yurie, Ozeki, Takayuki, Mori, Yasunori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 1117 - 1117, Dec. 2018 , Refereed
• The relationship of testosterone and lower urinary tract symptoms after withdrawing dutasteride, Hashimoto, Mamoru, Shimizu, Nobutaka, Sugimoto, Koichi, Minami, Takafumi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Tahara, Hideo, Uemura, Hirotsugu, Hirayama, Akihide, INTERNATIONAL JOURNAL OF UROLOGY, INTERNATIONAL JOURNAL OF UROLOGY, 25, 203 - 203, Oct. 2018 , Refereed
• Influence of abiraterone therapy on anti-tumor immunity in genetically engineered mouse prostate cancer models, Banno, Eri, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sato, Noriko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 78(13), Jul. 2018 , Refereed
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• Treatment-dependent effects of androgen receptor signaling suppression on immune modulation in mouse Pten-deficient prostate cancer, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sakai, Kazuko, Davies, Barry R., Kim, Youngsoo, MacLeod, A. Robert, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 78(13), Jul. 2018 , Refereed
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• Preclinical evaluation of the multi tyrosine kinase inhibitor TAS-115 in genetically engineered mouse models of prostate cancer, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sato, Noriko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 78(13), Jul. 2018 , Refereed
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• Apalutamide (ARN-509) demonstrates therapeutic efficacy in genetically engineered mouse models of Pten-deficient prostate cancer, De Velasco, Marco A., Nozawa, Masahiro, Kura, Yurie, Ando, Naomi, Sato, Noriko, Yoshimura, Kazuhiro, Sakai, Kazuko, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 78(13), Jul. 2018 , Refereed
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• Targeting PIM and AKT kinases impairs tumor growth and improves overall survival in a murine model of advanced castration-resistant prostate cancer, De Velasco, Marco A., Kura, Yurie, Ando, Naomi Ando, Sato, Noriko, Davies, Barry R., Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, CANCER RESEARCH, 78(13), Jul. 2018 , Refereed
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• Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type-specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190-201]., Nobutaka Shimizu, Mark F Doyal, William F Goins, Katsumi Kadekawa, Naoki Wada, Anthony J Kanai, William C de Groat, Akihide Hirayama, Hirotsugu Uemura, Joseph C Glorioso, Naoki Yoshimura, Neuroscience, Neuroscience, 381, 161 - 161, Jun. 15 2018 , Refereed
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• Successful low-dose IVIG with desensitization therapy in three DSA-positive kidney trasplantation cases: Case report, Kazuhiro Nose, Yoshitaka Saito, Yasunori Mori, Kazuhiro Yoshimura, Hirotsugu Uemura, Takashi Kikuchi, Taiji Hayashi, Tsukasa Nishioka, Transplantation Reports, Transplantation Reports, 3(2), 13 - 15, Jun. 01 2018 , Refereed
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• Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: A phase III study, Seiichiro Ozono, Taiji Tsukamoto, Seiji Naito, Shigeo Horie, Yasuo Ohashi, Hiroji Uemura, Yumiko Yokomizo, Satoshi Fukasawa, Hidehito Kusuoka, Rio Akazawa, Masako Saito, Hideyuki Akaza, Cancer Science, Cancer Science, 109(6), 1920 - 1929, Jun. 01 2018 , Refereed
  Summary:Non-inferiority in the cumulative castration rate of the 3-month formulation of degarelix compared with the 3-month formulation of goserelin was evaluated in subjects with prostate cancer. A phase III, open-label, parallel-arm study was carried out. An initial dose of 240 mg degarelix or 3.6 mg goserelin was given s.c. after day 28, a maintenance dose of 480 mg degarelix or 10.8 mg goserelin was given once every 84 days. Non-inferiority in castration rate and safety of degarelix to goserelin were evaluated. The primary end-point was the cumulative castration rate from day 28 to day 364 and the non-inferiority margin was set to be 10%. A total of 234 subjects with prostate cancer were randomized to the degarelix group (n = 117) and the goserelin group (n = 117). The cumulative castration rate was 95.1% in the degarelix group and 100.0% in the goserelin group. As there were no events in the goserelin group, an additional analysis was carried out using 95% confidence intervals of the difference in the proportion of subjects with castration. Analyses indicated the non-inferiority of the 3-month formulation of degarelix to goserelin. Degarelix showed more rapid decreases in testosterone, luteinizing hormone, follicle stimulating hormone, and prostate-specific antigen levels compared with goserelin. The most common adverse events in the degarelix group were injection site reactions. Non-inferiority of the 3-month formulation of degarelix to goserelin was shown for testosterone suppression. The 3-month formulation of degarelix was also found to be tolerated as an androgen deprivation therapy for patients with prostate cancer. This trial was registered with ClinicalTrials.gov (identifier NCT01964170).
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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., Jun Guo, Jie Jin, Mototsugu Oya, Hirotsugu Uemura, Shunji Takahashi, Katsunori Tatsugami, Sun Young Rha, Jae-Lyun Lee, Jinsoo Chung, Ho Yeong Lim, Hsi Chin Wu, Yen Hwa Chang, Arun Azad, Ian D Davis, Marlene J Carrasco-Alfonso, Bhupinder Nanua, Jackie Han, Qasim Ahmad, Robert Motzer, Journal of hematology & oncology, Journal of hematology & oncology, 11(1), 69 - 69, May 22 2018 , Refereed
  Summary: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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• Primary amelanotic malignant melanoma of the male urethra with inguinal lymph node metastasis successfully controlled by nivolumab: A case report, Takashi Tokita, Takashi Kawahara, Yusuke Ito, Sohgo Tsutsumi, Koichi Abe, Kazuhiro Namura, Futoshi Sano, Koichi Shioi, Daiji Takamoto, Yasushi Yumura, Noboru Nakaigawa, Masahiro Yao, Hiroji Uemura, Hidefumi Wada, Yukio Tsuura, Kazuki Kobayashi, Urology Case Reports, Urology Case Reports, 18, 54 - 56, May 01 2018 , Refereed
  Summary:We report a rare case of primary amelanotic malignant melanoma of the male urethra. A 65-year-old man with a urethral mass was referred to our hospital. A pathological diagnosis of a biopsy specimen revealed malignant melanoma. Thereafter, the patient underwent partial penectomy. The histopathological diagnosis was amelanotic malignant melanoma of the urethra. The patient had received DAV-Feron in an adjuvant setting however, PET-CT revealed multiple metastasis. After receiving more than 10 cycles of nivolumab, the accumulation of FDG was no longer observed on PET-CT. The patient is currently free from recurrence at 20 months after nivolumab treatment.
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• The half-loop transurethral incision technique for bilateral ureterocele in adult, Sahoko Ninomiya, Takashi Kawahara, Taku Mochizuki, Masahiro Yao, Jun-ichi Teranishi, Hiroji Uemura, Urology Case Reports, Urology Case Reports, 18, S50 - S50, May 01 2018 , Refereed
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• Apalutamide treatment and metastasis-free survival in prostate cancer, Matthew R. Smith, Fred Saad, Simon Chowdhury, Stéphane Oudard, Boris A. Hadaschik, Julie N. Graff, David Olmos, Paul N. Mainwaring, Ji Youl Lee, Hiroji Uemura, Angela Lopez-Gitlitz, Géralyn C. Trudel, Byron M. Espina, Youyi Shu, Youn C. Park, Wayne R. Rackoff, Margaret K. Yu, Eric J. Small, New England Journal of Medicine, New England Journal of Medicine, 378(15), 1408 - 1418, Apr. 12 2018 , Refereed
  Summary:BACKGROUND Apalutamide, a competitive inhibitor of the androgen receptor, is under development for the treatment of prostate cancer. We evaluated the efficacy of apalutamide in men with nonmetastatic castration-resistant prostate cancer who were at high risk for the development of metastasis. METHODS We conducted a double-blind, placebo-controlled, phase 3 trial involving men with nonmetastatic castration-resistant prostate cancer and a prostate-specific antigen doubling time of 10 months or less. Patients were randomly assigned, in a 2:1 ratio, to receive apalutamide (240 mg per day) or placebo. All the patients continued to receive androgen-deprivation therapy. The primary end point was metastasis-free survival, which was defined as the time from randomization to the first detection of distant metastasis on imaging or death. RESULTS A total of 1207 men underwent randomization (806 to the apalutamide group and 401 to the placebo group). In the planned primary analysis, which was performed after 378 events had occurred, median metastasis-free survival was 40.5 months in the apalutamide group as compared with 16.2 months in the placebo group (hazard ratio for metastasis or death, 0.28 95% confidence interval [CI], 0.23 to 0.35 P< 0.001). Time to symptomatic progression was significantly longer with apalutamide than with placebo (hazard ratio, 0.45 95% CI, 0.32 to 0.63 P< 0.001). The rate of adverse events leading to discontinuation of the trial regimen was 10.6% in the apalutamide group and 7.0% in the placebo group. The following adverse events occurred at a higher rate with apalutamide than with placebo: rash (23.8% vs. 5.5%), hypothyroidism (8.1% vs. 2.0%), and fracture (11.7% vs. 6.5%). CONCLUSIONS Among men with nonmetastatic castration-resistant prostate cancer, metastasis-free survival and time to symptomatic progression were significantly longer with apalutamide than with placebo. (Funded by Janssen Research and Development SPARTAN ClinicalTrials.gov number, NCT01946204.)
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• Comprehensive analyses of tumor immunity in PTEN-deficient mouse models of prostate cancer, De Velasco, Marco A., Kura, Yurie, Sakai, Kazuko, Sugimoto, Kouichi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 281 - 281, Jan. 2018 , Refereed
• STAT3 activity in human prostate cancer, Mori, Yasunori, De Velasco, Marco A., Hatanaka, Yuji, Kura, Yurie, Sugimoto, Kouichi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 1075 - 1075, Jan. 2018 , Refereed
• Targeting AKT and Pim kinases improves treatment responses in preclinical models of PTEN-deficient prostate cancer, Kura, Yurie, De Velasco, Marco A., Sugimoto, Kouichi, Sakai, Kazuko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 568 - 568, Jan. 2018 , Refereed
• PD-L1 immune checkpoint blockade in genetically engineered mouse models of prostate cancer, Shimizu, Nobutaka, De Velasco, Marco A., Kura, Yurie, Sakai, Kazuko, Sugimoto, Kouichi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 292 - 292, Jan. 2018 , Refereed
• Targeting prostate cancer with next generation antisense oligonucleotide against androgen receptor and AKT inhibition, Sugimoto, Kouichi, De Velasco, Marco A., Kura, Yurie, Sakai, Kazuko, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER SCIENCE, CANCER SCIENCE, 109, 357 - 357, Jan. 2018 , Refereed
• Comprehensive preclinical assessment of novel compounds using genetically engineered mouse models of prostate cancer, Uemura, Hirotsugu, Kura, Yurie, Sugimoto, Kouichi, Mori, Yasunori, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, De Velasco, Marco A., CANCER SCIENCE, CANCER SCIENCE, 109, 897 - 897, Jan. 2018 , Refereed
• Serious Hypokalemia Associated with Abiraterone Acetate in Patients with Castration-Resistant Prostate Cancer., Yutaka Yamamoto, Yasunori Akashi, Takahumi Minami, Masahiro Nozawa, Keisuke Kiba, Motokiyo Yoshikawa, Akihide Hirayama, Hirotsugu Uemura, Case reports in urology, Case reports in urology, 2018, 1414395 - 1414395, 2018 , Refereed
  Summary:Introduction: The treatment strategy for castration-resistant prostate cancer (CRPC) has changed with the approval of several new agents. In 2011, abiraterone acetate was approved for the treatment of metastatic CRPC; however abiraterone is known to cause mineralocorticoid excess syndrome characterized by hypokalemia, fluid retention, and hypertension. We experienced two cases of grade 4 hypokalemia associated with abiraterone treatment. Case Presentation: Case 1: a 71-year-old male with metastatic CRPC presented with convulsive seizures two weeks after receiving abiraterone plus prednisone. The serum potassium level was 2.1mEq/l. We determined that convulsive seizure was caused by hypokalemia associated with abiraterone. Case 2: a 68-year-old male with metastatic CRPC presented with severe lethargy one month after receiving abiraterone plus prednisone. The serum potassium level was 1.7mEq/l and we concluded that severe lethargy was caused by hypokalemia associated with abiraterone. They were treated with potassium supplementation and increased prednisone following withdrawal of abiraterone. Discussion: The two patients had been on glucocorticoid therapy before abiraterone therapy. Prolonged administration of exogenous glucocorticoid can lead adrenocortical insufficiency and consequently reduce endogenous glucocorticoid production. This situation may increase the risk of abiraterone-induced mineralocorticoid excess. To reduce the risk of abiraterone-induced hypokalemia, evaluation of adrenocortical insufficiency is required.
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• The treatment patterns of castration-resistant prostate cancer in Japan, including symptomatic skeletal events and associated treatment and healthcare resource use, Hiroji Uemura, Marco DiBonaventura, Ed Wang, Dianne Athene Ledesma, Kristen Concialdi, Yasuko Aitoku, Expert Review of Pharmacoeconomics and Outcomes Research, Expert Review of Pharmacoeconomics and Outcomes Research, 17(5), 511 - 517, Sep. 03 2017 , Refereed
  Summary:Background: Real-world treatment patterns of bone metastatic castration-resistant prostate cancer (mCRPC) in Japan were examined, focusing on treatment patterns and resource use differences attributed to symptomatic skeletal events (SSEs). Methods: Urologists (N = 176) provided retrospective chart data for patients with mCRPC (N = 445) via online surveys. Descriptive analyses and chi-square tests evaluated treatment patterns and their differences by SSE presence generalized linear mixed models examined healthcare resource utilization differences as a function of SSEs. Results: Patients were on average 73.6 years old (SD = 8.3), diagnosed with prostate cancer 5.1 years (SD = 6.2), castration-resistant 2.3 years (SD=2.0), and had 7.9 bone metastases sites (SD=12.4). Novel anti-hormones showed increased adoption as mCRPC treatment. Simultaneously, luteinizing hormone-releasing hormone (LHRH) agonist/antagonist use was common (43.6% of patients in 1st line), even as CRPC treatment had started. SSEs were uncommon (2–3% per treatment line 5% at any time), but were associated with increased opioids, strontium-89, bisphosphonates, and NSAIDs use, plus increased healthcare visits (all p < .05). Conclusions: LHRH agonist/antagonist treatment combinations remain the mCRPC treatment mainstay in Japan. However, novel anti-hormone therapies are becoming well-accepted in practice. SSEs were associated with increased healthcare resource and analgesic use, highlighting the need for efficient symptom management.
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• Efficacy of Adding Dutasteride to α-Blocker Therapy Treated Benign Prostatic Hyperplasia Patients with Small Volume Prostate (<30 mL)., Mamoru Hashimoto, Nobutaka Shimizu, Koichi Sugimoto, Sachiko Hongoh, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Akihide Hirayama, Hideo Tahara, Hirotsugu Uemura, Lower urinary tract symptoms, Lower urinary tract symptoms, 9(3), 157 - 160, Sep. 2017 , Refereed
  Summary:OBJECTIVES: To assess the efficacy of dutasteride add-on therapy for patients with benign prostatic hyperplasia (BPH) and lower urinary tract symptoms (LUTS) with small prostates who have been treated with α-blocker therapy for >3 months. METHODS: A total of 110 men with clinical BPH were enrolled. There were 17 and 93 subjects with a prostate volume (PV) <30 and ≥30 mL, respectively. All subjects had been treated with α-blocker therapy for >3 months. Subjective and objective clinical variables were assessed using the total International Prostate Symptom Score (IPSS-T), IPSS quality of life (IPSS-QoL), IPSS voiding subscore (IPSS-V), IPSS storage subscore (IPSS-S), overactive bladder symptom score (OABSS), PV, prostate specific antigen (PSA) level, post-void residual (PVR), and maximum flow rate (Qmax). These variables were assessed at baseline and every 3 months for 1 year. RESULTS: In the small prostate group, IPSS-T and IPSS-V showed improvements from baseline at 6 and 9 months, storage subscore at 6 months, and OABSS at 3 months, but no sustained improvements were observed. During the study period, only the IPSS QoL scores did not show any improvement. Conversly, dutasteride was significantly effective at improving IPSS-T, IPSS-V, IPSS-S, and IPSS-QoL scores throughout the study period in the large prostate BPH group. PSA levels and PV significantly decreased in both groups throughout the study. CONCLUSIONS: Benign prostatic hyperplasia in LUTS patients with small prostates did not show a sustainable benefit from the addition of dutasteride to α-blocker therapy.
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• Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study, Yoshihiko Tomita, Satoshi Fukasawa, Nobuo Shinohara, Hiroshi Kitamura, Mototsugu Oya, Masatoshi Eto, Kazunari Tanabe, Go Kimura, Junji Yonese, Masahiro Yao, Robert J. Motzer, Hirotsugu Uemura, M. Brent McHenry, Elmer Berghorn, Seiichiro Ozono, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 47(7), 639 - 646, Jul. 2017 , Refereed
  Summary: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). 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. 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. 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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• Overall survival of first-line axitinib in metastatic renal cell carcinoma: Japanese subgroup analysis from phase II study, Mototsugu Oya, Yoshihiko Tomita, Satoshi Fukasawa, Nobuo Shinohara, Tomonori Habuchi, Brian I. Rini, Yosuke Fujii, Yoichi Kamei, Yoshiko Umeyama, Angel H. Bair, Hirotsugu Uemura, CANCER SCIENCE, CANCER SCIENCE, 108(6), 1231 - 1239, Jun. 2017 , Refereed
  Summary:Subgroup analyses of a randomized global phase II study of axitinib showed objective response rate of 66% and median progression-free survival of 27.6months in treatment-naive 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 33months, fewer than half (16 of 44) of the Japanese patients had died and median OS was not reached (95% confidence interval [CI], 38.8months-not estimable), whereas 107 of 169 (63%) non-Japanese patients had died and median OS was 33.9months (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-naive Japanese patients with metastatic RCC, with an acceptable toxicity profile.
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• Erratum to: Patient preferences for treatment of castration-resistant prostate cancer in Japan: A discrete-choice experiment (BMC Urol. (2016) 16 (63) DOI: 10.1186/s12894-016-0182-2), Hiroji Uemura, Nobuaki Matsubara, Go Kimura, Akito Yamaguchi, Dianne Athene Ledesma, Marco DiBonaventura, Ateesha F. Mohamed, Enrique Basurto, Ian McKinnon, Ed Wang, Kristen Concialdi, Aya Narimatsu, Yasuko Aitoku, BMC Urology, BMC Urology, 16(1), 1 - 10, Mar. 28 2017 , Refereed
  Summary:Background: Up to a fifth of patients diagnosed with prostate cancer (PC) will develop castration-resistant prostate cancer (CRPC), which has been associated with a poor prognosis. The aim of this study was to consider the patient perspective as part of the overall treatment decision-making process for CRPC, given that an alignment between patient preference and prescribing has been shown to benefit patient outcomes. This study examines preferences of patients with CRPC in Japan for treatment features associated with treatments like RA-223, abiraterone, and docetaxel and to examine the extent to which treatment preferences may vary between symptomatic and asymptomatic patients. Methods: A two-phase research approach was implemented. In Phase 1, N = 8 patients with CRPC were recruited from a single hospital to complete a qualitative interview to provide feedback on the draft survey. In Phase 2, N = 134 patients with CRPC were recruited from five hospitals to complete a paper survey. The survey included 6 treatment choice questions, each asking patients to choose between two hypothetical treatments for their CRPC. Each treatment alternative was defined by the following attributes: length of overall survival (OS), time to a symptomatic skeletal event (SSE), method of administration, reduction in the risk of bone pain, treatment-associated risk of fatigue and lost work days. A hierarchical Bayesian logistic regression was used to estimate relative preference weights for each attribute level and mean relative importance. Results: A total of N = 133 patients with CRPC completed the survey and were included in the final analysis. Patients had a mean age of 75.4 years (SD = 7.4) and had been diagnosed with PC a mean of 6.5 years prior (SD = 4.4). Over the attribute levels shown, fatigue (relative importance [RI] = 24.9 %, 95 % CI: 24.7 %, 25.1 %) was the most important attribute, followed by reduction in the risk of bone pain (RI = 23.2 %, 95 % CI: 23.0 %, 23.5 %), and OS (RI = 19.2 %, 95 % CI: 19.0 %, 19.4 %). Although symptomatic patients placed significantly more importance on delaying an SSE (p < .05), no other preference differences were observed. Conclusions: CRPC patients were more concerned about reduced quality of life from side effects of treatment rather than extension of survival, which may have implications for shared decision-making between patients and physicians.
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• Foreign body in the bladder: A case report, Kota Shimokihara, Takashi Kawahara, Yutaro Hayashi, Sohgo Tsutsumi, Daiji Takamoto, Taku Mochizuki, Yusuke Hattori, Jun-ichi Teranishi, Yasuhide Miyoshi, Yasushi Yumura, Masahiro Yao, Hiroji Uemura, International Journal of Surgery Case Reports, International Journal of Surgery Case Reports, 32, 22 - 24, 2017 , Refereed
  Summary:Foreign bodies are occasionally reported in the bladder. In most cases, the foreign body is removed via the transurethral approach. A 57-year-old male patient was referred to our hospital to undergo the retrieval of a foreign body from his bladder. However, the foreign body had become severely calcified and could not be removed transurethrally. Thus, an open bladder wall incision was necessary to remove it. We herein report a case of a foreign body in the bladder that had become calcified and which was successfully removed using a higher bladder incision approach. A careful preoperative examination should be performed to detect the characteristics of the foreign body and avoid the risk of bladder wall perforation.
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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., Brian I Rini, Yoshihiko Tomita, Bohuslav Melichar, Takeshi Ueda, Viktor Grünwald, Mayer N Fishman, Hirotsugu Uemura, Mototsugu Oya, Angel H Bair, Glen I Andrews, Brad Rosbrook, Eric Jonasch, Clinical genitourinary cancer, Clinical genitourinary cancer, 14(6), 499 - 503, Dec. 2016 , Refereed
  Summary:BACKGROUND: In a randomized phase II trial in metastatic renal cell carcinoma (mRCC), objective response rate was significantly higher with axitinib versus placebo titration (54% vs. 34%; 1-sided P = .019). PATIENTS AND METHODS: Treatment-naive patients with mRCC (n = 213) received axitinib 5 mg twice per day (b.i.d.) for 4 weeks. Patients meeting dose titration criteria were randomized to receive axitinib 5 mg b.i.d. with axitinib or placebo titration (n = 56 each); 91 patients ineligible for randomization continued axitinib 5 mg b.i.d.; 10 discontinued before randomization. RESULTS: Median overall survival (95% confidence interval [CI]) was 42.7 months (24.7-not estimable) with axitinib titration versus 30.4 months (23.7-45.0) with placebo titration (stratified hazard ratio, 0.785; 95% CI, 0.485-1.272; 1-sided P = .162), and 41.6 months (95% CI, 33.0-not estimable) in nonrandomized patients. Safety data were consistent with previous reports. CONCLUSION: Median overall survival was numerically longer in patients with first-line mRCC who received axitinib versus placebo titration. No new safety signal was observed after long-term axitinib treatment in first-line mRCC.
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• Ductal adenocarcinoma of the prostate: A case report, Yutaro Hayashi, Takashi Kawahara, Hiromichi Iwashita, Kota Shimokihara, Sohgo Tsutsumi, Daiji Takamoto, Taku Mochizuki, Yusuke Hattori, Jun-Ichi Teranishi, Yasuhide Miyoshi, Yasushi Yumura, Masahiro Yao, Yoshiaki Inayama, Hiroji Uemura, Case Reports in Oncology, Case Reports in Oncology, 9(3), 802 - 805, Sep. 13 2016 , Refereed
  Summary:Ductal adenocarcinoma is an unusual variant of adenocarcinoma of the prostate. A 73-year-old male was referred to our hospital for the further examination of an elevated prostate-specific antigen level of 23.4 ng/mL. Radical prostatectomy (RP) was performed based on the diagnosis obtained by a prostate needle biopsy. The RP specimen revealed ductal adenocarcinoma of the prostate with positive capsular penetration. We herein report a rare case of ductal adenocarcinoma of the prostate.
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• HERPES SIMPLEX VIRUS (HSV) VECTOR-MEDIATED TRACING AND LABELLING OF DIFFERENT POPULATIONS OF BLADDER AFFERENT NEURONS IN NORMAL AND SPINAL CORD INJURED MICE, N. Shimizu, W. Goins, S. Takai, T. Shimizu, N. Wada, A. Hirayama, H. Uemura, P. Tyagi, J. Glorioso, N. Yoshimura, NEUROUROLOGY AND URODYNAMICS, NEUROUROLOGY AND URODYNAMICS, 35, S115 - S116, Aug. 2016 , Refereed
• A multicenter phase I/II study of enzalutamide in Japanese patients with castration-resistant prostate cancer., Hideyuki Akaza, Hirotsugu Uemura, Taiji Tsukamoto, Seiichiro Ozono, Osamu Ogawa, Hideki Sakai, Mototsugu Oya, Mikio Namiki, Satoshi Fukasawa, Akito Yamaguchi, Hiroji Uemura, Yasuo Ohashi, Hideki Maeda, Atsushi Saito, Kentaro Takeda, Seiji Naito, International journal of clinical oncology, International journal of clinical oncology, 21(4), 773 - 782, Aug. 2016 , Refereed
  Summary: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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• Increased neutrophil-to-lymphocyte ratio is associated with disease-specific mortality in patients with penile cancer, Jun Kasuga, Takashi Kawahara, Daiji Takamoto, Sachi Fukui, Takashi Tokita, Tomoyuki Tadenuma, Masaki Narahara, Syusei Fusayasu, Hideyuki Terao, Koji Izumi, Hiroki Ito, Yusuke Hattori, Jun-Ichi Teranishi, Takeshi Sasaki, Kazuhide Makiyama, Yasuhide Miyoshi, Masahiro Yao, Yasushi Yumura, Hiroshi Miyamoto, Hiroji Uemura, BMC Cancer, BMC Cancer, 16(1), 396, Jul. 07 2016 , Refereed
  Summary:Background: The neutrophil-to-lymphocyte ratio (NLR), a simple marker of the systemic inflammatory response, has been demonstrated to correlate with patient outcomes for various solid malignancies. We investigated the utility of the pretreatment NLR as a prognosticator in patients who presented with penile cancer. Methods: A total of 41 patients who underwent complete blood count with differential and subsequent radical penectomy from 1988 to 2014 were analyzed. We assessed the correlation between the NLR and the prognosis of penile cancer. Results: The median and mean (± SD) NLRs in 41 penile cancer patients were 3.42 and 5.03 ± 4.99, respectively. Based on the area under receiver operator characteristic curve, the cut-off value of NLR was determined to be 2.82. Patients with a high NLR (≥2.82) showed a significantly poorer cancer-specific survival (p = 0.023) than those with a low NLR. Conclusions: The pretreatment NLR may function as a biomarker that precisely predicts the prognosis in patients with penile cancer.
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• The Jak1/2 inhibitor AZD1480 suppresses tumor growth and metastasis in genetically engineered mouse models of PTEN-deficient prostate cancer, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Barry R. Davies, Dennis Huszdar, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 76, Jul. 2016 , Refereed
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• Effects of oral chloroquine administration on a preclinical mouse model of PTEN/p53-deficient prostate cancer, Marco A. De Velasco, Koichi Sugimoto, Yurie Kura, Yuji Hatanaka, Yutaka Yamamoto, Takashi Oki, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 76, Jul. 2016 , Refereed
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• Effects of increased dietary fat consumption on prostate cancer progression in genetically engineered mice, Marco A. De Velasco, Yurie Kura, Yuji Hatanaka, Takashi Oki, Yutaka Yamamoto, Koichi Sugimoto, Yasunori Mori, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 76, Jul. 2016 , Refereed
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• Prognosis of metastatic renal cell carcinoma with first-line interferon-α therapy in the era of molecular-targeted therapy., Yoshiaki Kawano, Wataru Takahashi, Masatoshi Eto, Tomomi Kamba, Hideaki Miyake, Masato Fujisawa, Takao Kamai, Hirotsugu Uemura, Taiji Tsukamoto, Haruhito Azuma, Akio Matsubara, Kazuo Nishimura, Tsuyoshi Nakamura, Osamu Ogawa, Seiji Naito, Cancer science, Cancer science, 107(7), 1013 - 7, Jul. 2016 , Refereed
  Summary:The RCC-SELECT study showed the correlation between single nucleotide polymorphisms (SNP) in STAT3 gene and survival in metastatic renal cell carcinoma (mRCC) patients with first-line interferon-α (IFN-α). In that study, even patients with STAT3 SNP linked to shorter overall survival (OS) exhibited remarkably improved prognosis. All 180 patients evaluated in the above study were further analyzed for correlation between OS and demographics/clinicopathological parameters. OS was estimated using the Kaplan-Meier method. Associations between OS and potential prognostic factors were assessed using the log-rank test and the Cox proportional hazards model. The median OS was 42.8 months. Univariate analysis showed that worse Eastern Cooperative Oncology Group-performance status (ECOG-PS), high T stage, regional lymph node metastasis, distant metastasis, higher grade, infiltrative growth pattern, the presence of microscopic vascular invasion (MVI), hypercalcemia, anemia, thrombocytopenia and elevated C-reactive protein were significantly associated with OS. Multivariate analysis revealed that ECOG-PS (hazard ratio [HR] = 3.665, P = 0.0004), hypercalcemia (HR = 6.428, P = 0.0005) and the presence of MVI (HR = 2.668, P = 0.0109) were jointly significant poor prognostic factors. This is the first study analysing prognostic factors of mRCC patients with first-line IFN-α using large cohort of the prospective study. The present study suggests that first-line IFN-α is still a useful therapy for mRCC even in the era of molecular targeted therapy.
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• Predicting the mineral composition of ureteral stone using non-contrast computed tomography, Takashi Kawahara, Hiroshi Miyamoto, Hiroki Ito, Hideyuki Terao, Manabu Kakizoe, Yoshitake Kato, Hitoshi Ishiguro, Hiroji Uemura, Masahiro Yao, Junichi Matsuzaki, UROLITHIASIS, UROLITHIASIS, 44(3), 231 - 239, Jun. 2016 , Refereed
  Summary:We investigated the correlation between computed tomography (CT) density of ureteral stones and their mineral composition. A total of 346 patients who underwent ureteroscopic lithotripsy for calculi all fragments of which were acquired at a single institution from 2009 to 2011 were analyzed. The maximum and mean CT densities were measured preoperatively. A mineral analysis revealed calcium oxalate in 203 (58.7 %), mixed calcium oxalate and calcium phosphate in 78 (23.0 %), calcium phosphate in 18 (5.2 %), uric acid in 8 (2.3 %), struvite in 3 (0.9 %), and cysteine in 5 (1.4 %). The mean Hounsfield units (HUs) of the CT density were 1046 HUs in calcium oxalate, 1101 HUs in mixed calcium oxalate and calcium phosphate, 835 HUs in calcium phosphate, 549 HUs in uric acid, 729 HUs in struvite, and 698 HUs in cystine. The HUs in calcium oxalate were significantly higher than those in uric acid (p < 0.01) and struvite (p < 0.01). Those in monohydrate stones were significantly higher, compared with dehydrate stones (p < 0.05). We analyzed the largest number of stones than each published study to correlate their mineral composition and CT density. Calcium component stones showed significantly higher CT densities than other types.
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• [Immunotherapy]., Kazuhiro Yoshimura, Hirotsugu Uemura, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 74 Suppl 3, 238 - 43, May 20 2016 , Refereed
• [Sequential therapy for castration-resistant prostate cancer]., Masahiro Nozawa, Hirotsugu Uemura, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 74 Suppl 3, 644 - 8, May 20 2016 , Refereed
• A rat model to study the effects of diet-induced obesity on radiation-induced mammary carcinogenesis, Tatsuhiko Imaoka, Mayumi Nishimura, Kazuhiro Daino, Takamitsu Morioka, Yukiko Nishimura, Hiroji Uemura, Kenta Akimoto, Yuki Furukawa, Masahiro Fukushi, Keiji Wakabayashi, Michihiro Mutoh, Yoshiya Shimada, Radiation Research, Radiation Research, 185(5), 505 - 515, May 01 2016 , Refereed
  Summary:A detailed understanding of the relationship between radiation-induced breast cancer and obesity is needed for appropriate risk management and to prevent the development of a secondary cancer in patients who have been treated with radiation. Our goal was to develop an animal model to study the relationship by combining two existing Sprague-Dawley rat models of radiation-induced mammary carcinogenesis and diet-induced obesity. Female rats were fed a high-fat diet for 4 weeks and categorized as obesity prone or obesity resistant based on their body weight at 7 weeks of age, at which time the rats were irradiated with 4 Gy. Control rats were fed a standard diet and irradiated at the same time and in the same manner. All rats were maintained on their initial diets and assessed for palpable mammary cancers once a week for the next 30 weeks. The obesity-prone rats were heavier than those in the other groups. The obesity-prone rats were also younger than the other animals at the first detection of mammary carcinomas and their carcinoma weights were greater. A tendency toward higher insulin and leptin blood levels were observed in the obesity-prone rats compared to the other two groups. Blood angiotensin II levels were elevated in the obesity-prone and obesity-resistant rats. Genes related to translation and oxidative phosphorylation were upregulated in the carcinomas of obesity-prone rats. Expression profiles from human breast cancers were used to validate this animal model. As angiotensin is potentially an important factor in obesity-related morbidities and breast cancer, a second set of rats was fed in a similar manner, irradiated and then treated with an angiotensin-receptor blocker, losartan and candesartan. Neither blocker altered mammary carcinogenesis analyses of losartan-treated animals indicated that expression of renin in the renal cortex and of Agtr1a (angiotensin II receptor, type 1) in cancer tissue was significantly upregulated, suggesting the presence of compensating mechanisms for blocking angiotensin-receptor signaling. Thus, obesity-related elevation of insulin and leptin blood levels and an increase in available energy may facilitate sustained protein synthesis in cancer cells, which is required for rapid cancer development.
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• Diversity in treatment modalities of Stage II/III urothelial cancer in Japan: sub-analysis of the multi-institutional national database of the Japanese Urological Association., Takuya Koie, Chikara Ohyama, Hiroyuki Fujimoto, Hiroyuki Nishiyama, Jun Miyazaki, Shiro Hinotsu, Eiji Kikuchi, Mizuaki Sakura, Junichi Inokuchi, Tomohiko Hara, Chikara Ohyama, Hiroyuki Nishiyama, Masato Fujisawa, Hirotsugu Uemura, Hiroyuki Fujimoto, Kazuhiro Suzuki, Masatoshi Eto, Isao Hara, Akio Matsubara, Norio Nonomura, Hiroyuki Nakanishi, Takuya Koie, Hiroomi Kanayama, Tsuneharu Miki, Tomoharu Fukumori, Seiji Naito, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 46(5), 468 - 74, May 2016 , Refereed
  Summary:OBJECTIVE: We aimed to survey treatment modalities for the patients with Stage II/III urothelial cancer in Japan. METHODS: We used the multi-institutional national database of the Japanese Urological Association from 348 Japanese institutions, in which a total of 3707 patients with muscle-invasive bladder cancer and 1538 with upper urinary tract urothelial carcinoma were registered in 2008 and 2011, respectively. Primary treatment was classified as surgery alone, surgery with chemotherapy, surgery with radiation, radiation alone, chemotherapy alone, combination of radiation and chemotherapy and observation. Overall and cancer-specific survivals were examined using the Kaplan-Meier method, and survival in the subgroups was analyzed using the log-rank test. RESULTS: In Stage II/III bladder cancer patients, 49.7% of those were treated with radical operation and 22.3% received observation only. A total 97.2% of Stage II/III upper urinary tract urothelial carcinoma patients treated with radical surgery. A total 30.4% of Stage II/III bladder cancer patients received chemotherapy. Majority of the patients received cisplatin-based regimen, however, regimens of chemotherapy was rich in variety up to 13 regimens. Chemotherapy regimens for the patients with upper urinary tract urothelial carcinoma were also various up to eight regimens. Overall and cancer-specific survivals were statistically significantly stratified according to the clinical stage. The upper urinary tract urothelial carcinoma patients diagnosed with clinical stage T3 had significantly poor prognosis compared with those diagnosed with clinical stage T2. CONCLUSIONS: This study demonstrated the variety of treatments used for Japanese patients with Stage II/III urothelial cancer. Treatment standardization for these entities may be necessary.
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• [The Influence of Change in Body Water Distribution Caused by Changing Position Upon Nocturia in Older Men]., Keisuke Kiba, Akihide Hirayama, Motokiyo Yoshikawa, Yutaka Yamamoto, Kazumasa Torimoto, Kiyohide Fujimoto, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 62(5), 243 - 8, May 2016 , Refereed
  Summary:A total of 29 men 60 years and older (mean age 74 years) who complained at least once about nocturnal voiding and were diagnosed with nocturnal polyuria in the frequency volume chart (FVC) were enrolled in this study. Body water was measured by bioelectric impedance analysis just after lying down at 4 pm and after raising legs 30 minutes later. Nocturnal urine production was measured by FVC, and urine production per unit of time at first nocturnal voiding (urine volume at first nocturnal voiding/hours of undisturbed sleep (HUS) : UFN/HUS), urine production per unit of time during sleep (total nocturnal urine volume/hours of sleep : TNV/HS), etc was evaluated. Extra cellular water (ECW) of 0.19 l (4.0%) in legs was reduced caused by body position changing. There was a significant positive correlation between the amount of ECW in legs and UFN/HUS, TNV/HS (r＝0. 57, p＝0.001 ; r＝0. 38, p＝0.042, respectively). Moreover, UFN/HUS had a significant correlation with soft lean mass in legs, ECW in legs and daytime water intake. This study suggested that a change in leg fluids caused by a change in position results in increased urine production and decreased HUS.
• Effective Treatment with Everolimus for Recurrent Granulomatous Interstitial Nephritis in a Renal Transplant Recipient: A Case Report, J. Teranishi, Y. Hattori, T. Mochizuki, T. Kawahara, K. Makiyama, H. Uemura, Transplantation Proceedings, Transplantation Proceedings, 48(3), 946 - 948, Apr. 01 2016 , Refereed
  Summary:Background Granulomatous interstitial nephritis (GIN) is a rare renal disease, and its etiology remains unknown. We report recurrent GIN in renal allograft successfully treated with everolimus (EVR). Case Report A 22-year-old man with GIN received a kidney from his mother. On follow-up 8 months later, his serum creatinine level was increased, from 1.3 mg/dL to 1.7 mg/dL, and he had microhematuria and proteinuria. A protocol graft biopsy at 1 year after transplantation showed epithelioid granuloma with multinucleated giant cells. He received steroid pulse therapy for recurrent GIN twice, but he developed allograft dysfunction, hematuria, and proteinuria. EVR was started in combination with maintenance immunosuppressants at 28 months after transplantation. Thereafter, the serum creatinine level decreased, from 2.1 mg/dL to 1.6 mg/dL, and microhematuria and proteinuria were stable despite reduction of steroid dose. Conclusions Maintenance immunosuppressive therapy combined with EVR may be effective for the recurrence of idiopathic GIN in renal allograft.
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• Expression of androgen receptor in non-muscle-invasive bladder cancer predicts the preventive effect of androgen deprivation therapy on tumor recurrence., Koji Izumi, Yusuke Ito, Hiroshi Miyamoto, Yasuhide Miyoshi, Junichi Ota, Masatoshi Moriyama, Tetsuo Murai, Hiroyuki Hayashi, Yoshiaki Inayama, Kenichi Ohashi, Masahiro Yao, Hiroji Uemura, Oncotarget, Oncotarget, 7(12), 14153 - 60, Mar. 22 2016 , Refereed
  Summary:Our recent retrospective study revealed a significantly reduced risk of bladder cancer (BC) recurrence in men who received androgen deprivation therapy (ADT) for their prostate cancer. However, whether androgen receptor (AR) signals contributed to the preventive effect of ADT remained unclear because ADT could reduce serum estrogens as well. The purpose of this study is to investigate the associations between the expression of AR/estrogen receptors (ERs) and BC recurrence in patients treated with ADT. We immunohistochemically stained 72 BCs and 42 corresponding normal urothelial tissues. AR/ERα/ERβ were positive in 44(61%)/22(31%)/39(54%) tumors and 35(83%)/24(57%)/34(81%) corresponding normal urothelial tissues, respectively. There were no statistically significant correlations between AR/ERα/ERβ expression and clinicopathological features of BC. With a median follow-up of 31.3 months, 12 (43%) of 28 patients with AR-negative tumor versus 11 (23%) of 44 patients with AR-positive tumor experienced BC recurrence. Thus, patients with AR-positive tumor had a significantly lower risk of BC recurrence (P=0.031), compared with those with AR-negative tumor. Meanwhile, the expression of ERα/ERβ in tumors and that of AR/ERα/ERβ in normal urothelial tissues were not significantly correlated with BC recurrence. A multivariate analysis revealed AR positivity in tumors as an independent prognosticator (hazard ratio: 0.27; 95% confidence interval: 0.11-0.67) for BC recurrence. These results indicate that ADT prevents BC recurrence via the AR pathway, but not via the ERα/ERβ pathways.
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• Pharmacotherapies for renal cell carcinoma in Japan., Kazuhiro Yoshimura, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 23(3), 194 - 202, Mar. 2016 , Refereed
  Summary:The standard treatment for advanced renal cell carcinoma has changed dramatically in the past decade, from cytokine therapy to targeted therapy. Since sorafenib was approved in April 2008, four tyrosine kinase inhibitors and two mammalian target of rapamycin inhibitors have become available in Japan. Most Japanese renal cell carcinoma patients are treated by urologists who are involved in not only kidney surgeries, but also targeted therapy using tyrosine kinase inhibitors, as well as mammalian target of rapamycin inhibitors. Optimal treatment methods are selected from theoretically-based global recommendations, such as the National Comprehensive Cancer Network and European Society for Medical Oncology guidelines; however, real-world clinical practice might be different from that in non-Asian countries. This might be because of different practical conditions; for example, different adverse events and efficacy profiles, different healthcare system, and so on. In the present review, we examine current pharmacotherapy for renal cell carcinoma from evidence-based global data, and compare the reality of Japanese clinical practice to explore the importance of individualized patient therapy.
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• Degarelix/bicalutamide combination versus degarelix alone as initial androgen-deprivation therapy, Masahiro Nozawa, Koichi Sugimoto, Yasuharu Nagai, Takahide Sugiyama, Yuji Hatanaka, Takashi Oki, Hideo Tahara, Hisao Matsuda, Yutaka Yamamoto, Hirotsugu Uemura, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 34(2), Jan. 2016 , Refereed
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• Predictors of poor response to secondary alternative antiandrogen therapy with flutamide in metastatic castration-resistant prostate cancer, Masato Yasui, Koichi Uemura, Shuko Yoneyama, Takashi Kawahara, Yusuke Hattori, Jun-Ichi Teranishi, Masahiro Inoue, Jun-Ichi Ohta, Yumiko Yokomizo, Masahiro Yao, Hiroji Uemura, Yasuhide Miyoshi, Japanese Journal of Clinical Oncology, Japanese Journal of Clinical Oncology, 46(11), 1042 - 1046, 2016 , Refereed
  Summary:Objective: In Japan, flutamide had been commonly used as second-line alternative antiandrogen hormonal therapy for metastatic castration-resistant prostate cancer that relapses after initial hormone therapy before new androgen pathway inhibitors became available. In this study, we attempted to identify predictive factors for efficacy of alternative antiandrogen as second-line hormone therapy. Methods: We identified consecutive 65 patients with metastatic castration-resistant prostate cancer who were treated with alternative antiandrogen as second-line hormonal therapy (bicalutamide to flutamide). All patients were treated with combined androgen blockade initially. We analyzed correlations between progression-free survival of alternative antiandrogen and clinicopathological characteristics, including patients' ages, initial prostate-specific antigen levels, prostate-specific antigen levels at flutamide induction, Gleason scores, T stage, N stage, extent of disease grades on bone scan and previous duration of prostate cancer response to combined androgen blockade. Results: In univariate analysis, T stage, N stage and previous duration of response to combined androgen blockade were correlated with shorter progression-free survival. We found four significant risk factors for shorter progression-free survival in multivariate analysis: initial prostatespecific antigen level, clinical N stage, extent of disease grades and previous duration of response to combined androgen blockade. Conclusions: Initial prostate-specific antigen, N stage, extent of disease grades on bone scan and previous duration of response to combined androgen blockade were the significant predictors for efficacy of alternative antiandrogen as second-line hormone therapy in patients with metastatic castration-resistant prostate cancer. These findings might support that decision-making of when to start the new androgen receptor pathway inhibitors.
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• Zoledronic acid combined with androgen-deprivation therapy may prolong time to castration-resistant prostate cancer in hormone-naïve metastatic prostate cancer patients - A propensity scoring approach., Kazuhiro Nagao, Hideyasu Matsuyama, Masahiro Nozawa, Isao Hara, Tsukasa Nishioka, Takahiro Komura, Atsunobu Esa, Shigeya Uejima, Masaaki Imanishi, Yasunari Uekado, Takatoshi Ogawa, Hiroshi Kajikawa, Hirotsugu Uemura, Asian journal of urology, Asian journal of urology, 3(1), 33 - 38, Jan. 2016 , Refereed
  Summary:Objective: To clarify the oncological benefit of zoledronic acid for hormone-naïve metastatic prostate cancer, patient outcome of androgen deprivation therapy with zoledronic acid (ADT + Z) and androgen deprivation therapy alone (ADT) was compared. Methods: Fifty-two patients with pathologically confirmed metastatic prostate cancer were prospectively enrolled and treated with combined androgen blockade (goserelin and bicalutamide) with zoledronic acid (4 mg every 4 weeks for 24 months). A propensity score-match with logistic regression analysis was applied to select 50 pair-matched cohorts (both from ADT + Z and from historical control cohorts who had undergone ADT alone), and patient outcomes were compared. Results: Patients with ADT + Z had significantly longer time to progression (TTP) than those with ADT (median TTP; 24.2 vs. 14.0 months, p = 0.0092), while no significant difference of overall survival between two groups (p = 0.1502). Multivariate analysis for biochemical recurrence revealed treatment with ADT was the sole independent prognostic factor (HR: 1.724, 95% CI: 1.06-2.86, p = 0.0297). Conclusion: Combination of zoledronic acid with ADT may prolong time to castration resistant prostate cancer.
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• Association Study of a Functional Variant on ABCG2 Gene with Sunitinib-Induced Severe Adverse Drug Reaction., Siew-Kee Low, Koya Fukunaga, Atsushi Takahashi, Koichi Matsuda, Fumiya Hongo, Hiroyuki Nakanishi, Hiroshi Kitamura, Takamitsu Inoue, Yoichiro Kato, Yoshihiko Tomita, Satoshi Fukasawa, Tomoaki Tanaka, Kazuo Nishimura, Hirotsugu Uemura, Isao Hara, Masato Fujisawa, Hideyasu Matsuyama, Katsuyoshi Hashine, Katsunori Tatsugami, Hideki Enokida, Michiaki Kubo, Tsuneharu Miki, Taisei Mushiroda, PloS one, PloS one, 11(2), e0148177, 2016 , Refereed
  Summary:Sunitinib is a tyrosine kinase inhibitor and used as the first-line treatment for advanced renal cell carcinoma (RCC). Nevertheless, inter-individual variability of drug's toxicity was often observed among patients who received sunitinib treatment. This study is to investigate the association of a functional germline variant on ABCG2 that affects the pharmacokinetics of sunitinib with sunitinib-induced toxicity of RCC patients in the Japanese population. A total of 219 RCC patients were recruited to this pharmacogenetic study. ABCG2 421C>A (Q141K) was genotyped by using PCR-Invader assay. The associations of both clinical and genetic variables were evaluated with logistic regression analysis and subsequently receiver operating characteristic (ROC) curve was plotted. About 43% (92/216) of RCC patients that received sunitinib treatment developed severe grade 3 or grade 4 thrombocytopenia according to the National Cancer Institute-Common Terminology Criteria for Adverse Events version 3.0, the most common sunitinib-induced adverse reaction in this study. In the univariate analysis, both age (P = 7.77x10(-3), odds ratio (OR) = 1.04, 95%CI = 1.01-1.07) and ABCG2 421C>A (P = 1.87x10(-2), OR = 1.71, 95%CI = 1.09-2.68) showed association with sunitinib-induced severe thrombocytopenia. Multivariate analysis indicated that the variant ABCG2 421C>A is suggestively associated with severe thrombocytopenia (P = 8.41x10(-3), OR = 1.86, 95% CI = 1.17-2.94) after adjustment of age as a confounding factor. The area under curve (AUC) of the risk prediction model that utilized age and ABCG2 421C>A was 0.648 with sensitivity of 0.859 and specificity of 0.415. Severe thrombocytopenia is the most common adverse reaction of sunitinib treatment in Japanese RCC patients. ABCG2 421C>A could explain part of the inter-individual variability of sunitinib-induced severe thrombocytopenia.
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• [The Effect of Tadalafil on Sexual Function, Urinary Function and Health-Related Quality of Life in Patients Treated with Brachytherapy]., Yasuharu Nagai, Nobutaka Shimizu, Takafumi Minami, Shingo Toyoda, Mamoru Hashimoto, Mitsuhisa Nishimoto, Takashi Kikuti, Yoshitaka Saitou, Yutaka Yamamoto, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 61(10), 383 - 7, Oct. 2015 , Refereed
  Summary:OBJECTIVES: We compared sexual function by the expanded prostate cancer index composite (sexual domains of EPIC), health-related quality of life (SF-8), and International Prostate Symptom Score (I-PSS) inpatients using tadalafil after prostate brachytherapy (PB). Forty-five patients who underwent PB between April 2011 and January 2014 were included in this study. Patients were divided into the tadalafil (20 mg,once/week or once/two weeks) treated and non-treated (NT) groups. Sexual function was assessed prior to PB treatment and followed up to 24 weeks after PB. SF-8, sexual domains of EPIC, IPSS and subjective symptoms were assessed pre-PB and at 4, 8, 16, and 24 weeks post-PB. Patients in the tadalafil group achieved higher sexual function scores compared to NT group at all time points. For SF8, the patients in the tadalafil group significantly improved in mental health by the eighth week, and significantly worsened in the NT group (8 w ; p = 0.04). The voiding domains of EPIC score were found to worsen significantly after 4 weeks from PB in both groups, but the score tended to improve over 24 weeks. There was no significant difference between two groups. The I-PSS total score was found to worsen significantly in both groups post-PB, but the tadalafil group had a tendency to worsen less. PB treatment of localized prostate cancer is preferred for the preservation of sexual function. Management of sexual dysfunction with tadalafil after PB does not worsen sexual functions. We concluded that tadalafil might be applicable to mental health care in the treatment of patients with a high interest in sexual function before PB.
• Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer, Masahiro Nozawa, Hirofumi Mukai, Shunji Takahashi, Hiroji Uemura, Takeo Kosaka, Yusuke Onozawa, Jun Miyazaki, Kazuhiro Suzuki, Koji Okihara, Yoichi Arai, Tomomi Kamba, Masashi Kato, Yasutomo Nakai, Hiroshi Furuse, Haruki Kume, Hisamitsu Ide, Hiroshi Kitamura, Akira Yokomizo, Takahiro Kimura, Yoshihiko Tomita, Keiji Ohno, Yoshiyuki Kakehi, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, INTERNATIONAL JOURNAL OF CLINICAL ONCOLOGY, 20(5), 1026 - 1034, Oct. 2015 , Refereed
  Summary:We previously reported the pharmacokinetic profile and preliminary tolerability of cabazitaxel in a phase I study in Japanese patients with metastatic castration-resistant prostate cancer (mCRPC). Here we report the final safety profile and anti-tumor activity of cabazitaxel in a larger population, including all patients enrolled in the expansion cohort of the study. Japanese patients with mCRPC previously treated with docetaxel received cabazitaxel intravenously every 3 weeks plus daily prednisolone. In patients treated with the maximum tolerated dose of 25 mg/m(2) we evaluated adverse events including treatment-related neutropenia, prostate-specific antigen (PSA) response and objective response. In total, 44 patients were treated with the maximum tolerated dose. The most frequent adverse events (any grade) were neutropenia (100 %), febrile neutropenia (54.5 %), fatigue (54.5 %), nausea (52.3 %) and diarrhea (50.0 %). There were no deaths due to treatment-related adverse events. Neutropenia with prior docetaxel did not appear to influence the probability of febrile neutropenia with cabazitaxel. Most patients received therapeutic granulocyte colony-stimulating factor (G-CSF; cycle 1: 86.4 %; cycle 2 or later: 81.8 %). In the efficacy population, two of 12 patients with measurable disease had partial response (objective response rate: 16.7 %), while 10 had stable disease. PSA response rate was 29.3 % (12/41 patients). Median time to PSA progression was 3.68 months (95 % confidence interval 1.35-4.63). In this heavily pretreated Japanese population, the occurrence of neutropenia and febrile neutropenia was high, suggesting G-CSF prophylaxis may be required as part of toxicity management. However, the efficacy of cabazitaxel was consistent with global studies. ClinicalTrials.gov identifier: NCT01324583.
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• Chloroquine demonstrates limited effectiveness in an autochthonous preclinical model of prostate cancer, Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Barry R. Davies, Dennis Huzdar, Yutaka Yamamoto, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 75, Aug. 2015 , Refereed
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• Evaluation of Pim-1 kinase inhibition in a preclinical model of mouse prostate cancer, Marco A. De Velasco, Takashi Oki, Yurie Kura, Naomi Ando, Emiko Fukushima, Barry R. Davies, Dennis Huszar, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 75, Aug. 2015 , Refereed
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• Preclinical activity of the AKT inhibitor AZD5363 in PTEN-deficient mouse models of prostate cancer, Marco A. De Velasco, Yuji Hatanaka, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry R. Davies, Yutaka Yamamoto, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 75, Aug. 2015 , Refereed
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• Preclinical effects of dual AKT/MAPK inhibition in PTEN-deficient prostate cancer, Marco A. De Velasco, Yutaka Yamamoto, Yurie Kura, Emiko Fukushima, Naomi Ando, Barry Davies, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 75, Aug. 2015 , Refereed
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• Inhibition of mouse PTEN-deficient prostate cancer with next generation antisense oligonucleotide targeting the androgen receptor, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Barry R. Davies, Hayley Campbell, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 75, Aug. 2015 , Refereed
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• [Cases of Fournier's Gangrene in Kinki University]., Shingo Toyoda, Takafumi Minami, Mamoru Hashimoto, Mitsutaka Saito, Nobutaka Shimizu, Yutaka Yamamoto, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 61(6), 223 - 6, Jun. 2015 , Refereed
  Summary:The aim of our study was to identify risk factors that may influence outcomes for patients presenting with Fournier gangrene. Twelve patients hospitalized and treated between August 2007 and August 2013 were included in this study. Distinct features were noted after one or two weeks of hospitalization. We did not observe a significant correlation between death risk and the extent of necrosis in this patient set. However, the extent of necrosis tended to correlate with the duration of hospitalization in the survivors. We also compared the results of blood biochemical analyses between the surviving and non-surviving groups. A significant difference was noted in the levels of glucose (Glu) after two weeks. In the non-surviving group, Glu levels were increased. These findings suggest a relationship between glycemic control after the initiation of therapy and death. We also examined the results of blood biochemical analyses according to the duration of hospitalization. The lactate dehydrogenase (LDH) levels at admission and LDH levels after two weeks were significantly higher in the patients with a duration of hospitalization longer than the median duration of 61.5 days. These findings suggest a relationship between the duration of hospitalization and the extent of necrosis at diagnosis.
• Phase II study of degarelix/bicalutamide combination for prostate cancer., Masahiro Nozawa, Takahide Sugiyama, Koichi Sugimoto, Tasuharu Nagai, Yuji Hatanaka, Takashi Oki, Hideo Tahara, Hisao Matsuda, Hirotsugu Uemura, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 33(15), May 2015 , Refereed
• Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer, Yamamoto, Yutaka, De Velasco, Marco A., Kura, Yurie, Nozawa, Masahiro, Hatanaka, Yuji, Oki, Takashi, Ozeki, Takayuki, Shimizu, Nobutaka, Minami, Takafumi, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, JOURNAL OF TRANSLATIONAL MEDICINE, JOURNAL OF TRANSLATIONAL MEDICINE, 13, May 2015 , Refereed
  Summary:Background: Despite recent advances in the treatment for advanced prostate cancer, outcomes remain poor. This lack of efficacy has prompted the development of alternative treatment strategies. In the present study we investigate the effects of the multikinase inhibitor sorafenib in a genetically engineered mouse model of prostate cancer and explore the rational combination with the mTOR inhibitor everolimus.Methods: Conditional prostate specific PTEN-deficient knockout mice were utilized to determine the pharmacodynamic and chemopreventive effects of sorafenib. This mouse model was also used to examine the therapeutic efficacy of sorafenib alone or in combination with everolimus. Preclinical efficacy was assessed by comparing the reduction of tumor burden, proliferation, angiogenesis and the induction of apoptosis. Molecular responses were assessed by immunohistochemical, TUNEL and western blot assays.Results: Pharmacodynamic analysis revealed that a single dose of sorafenib decreased activation of the PI3K/AKT/mTOR signaling axis at doses of 30-60 mg/kg, but activated JAK/STAT3 signaling. Levels of cleaved casapase-3 increased in a dose dependent manner. Chemoprevention studies showed that chronic sorafenib administration was capable of inhibiting tumor progression through the reduction of cancer cell proliferation, angiogenesis and the induction of apoptosis. In intervention models of established castration-naive and castration-resistant prostate cancer, treatment with sorafenib provided modest but statistically insignificant reduction in tumor burden. However, sorafenib significantly inhibited cancer cell proliferation and MVD but had minimal effects on the induction of apoptosis. Interestingly, the administration of sorafenib increased the expression levels of the androgen receptor, p-GSK3 beta and p-ERK1/2 in castration-resistant prostate cancers. In both intervention models, combination therapy demonstrated a clear tendency of enhanced antitumor effects over monotherapy. Notably, the treatment combination of sorafenib and everolimus overcame therapeutic escape from single agent therapy in castration-resistant prostate cancers.Conclusions: In summary, we provide insights into the molecular responses of sorafenib therapy in a clinically relevant model of prostate cancer and present preclinical evidence for the development of targeted treatment strategies based on the use of multikinase inhibitors in combination with mTOR inhibitors for the treatment of advanced prostate cancer.
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• Ureteroscopy-assisted retrograde nephrostomy (UARN) without ureteral access sheath (UAS), Takashi Kawahara, Hiroki Ito, Hideyuki Terao, Hiroji Uemura, Masahiro Yao, Junichi Matsuzaki, International Journal of Surgery Case Reports, International Journal of Surgery Case Reports, 10, 56 - 58, 2015 , Refereed
  Summary:Introduction We previously described ureteroscopy assisted retrograde nephrostomy (UARN). In UARN, it is possible to continuously visualize the dilation of the ureter from puncture to insertion of the nephroaccess sheath with minimal complication. But in the course of making nephrostomy, UARN requires ureteral access sheath (UAS). UAS has a potential risk of ureteral stricture. Herein, we report the first case of UARN without the use of UAS. Presentation of case A 53-year-old female was referred to our hospital for treatment of her right renal stone. Because her stone burden was 27 mm, we planned to perform percutaneous nephrolithotomy (PCNL) using UARN without UAS. Discussion UAS facilitates a decrease in the intrarenal pressure due to irrigation, and it makes controlling the URS easier. However, in terms of the risk of ureteral stricture, unnecessary insertion of a UAS should be avoided. Conclusion We describe the first case of a renal stone successfully treated by PCNL using the UARN method without the use of a UAS.
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• A pilot study of acotiamide hydrochloride hydrate in patients with detrusor underactivity., Koichi Sugimoto, Takahiro Akiyama, Nobutaka Shimizu, Naoki Matsumura, Taiji Hayashi, Tsukasa Nishioka, Hirotsugu Uemura, Research and reports in urology, Research and reports in urology, 7, 81 - 3, 2015 , Refereed
  Summary:AIM: To investigate the clinical efficacy of acotiamide hydrochloride hydrate in patients with detrusor underactivity. METHODS: We measured the post-void residual urinary volume in 19 patients with underactive bladders. All these patients had been under treatment with distigmine bromide and were prescribed acotiamide hydrochloride hydrate at a dose of 100 mg three times daily for 2 weeks. RESULTS: Compared with the post-void residual urinary volume value at baseline (161.4±90.0 mL) a statistically significant reduction was observed at the end of treatment (116.3±63.1 mL) (P=0.006). The drug was generally well tolerated by the majority of patients. CONCLUSION: Maybe, acotiamide hydrochloride hydrate showed clinical efficacy in patients with underactive bladders and may, therefore, be used alternatively in patients who do not respond sufficiently to distigmine bromide.
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• Axitinib as first-line therapy in metastatic renal cell carcinoma, Masahiro Nozawa, Hirotsugu Uemura, TRANSLATIONAL CANCER RESEARCH, TRANSLATIONAL CANCER RESEARCH, 3(6), 555 - 557, Dec. 2014 , Refereed
  Summary:Axitinib is a highly potent and selective VEGF receptor inhibitor. Previous trials suggested a significant advantage of axitinib versus sorafenib in progression-free survival (PFS) of patients with metastatic renal cell carcinoma (RCC) treated with prior cytokine therapy. Recently an important negative study was reported, which evaluated the PFS with axitinib and with sorafenib in treatment-naive metastatic RCC. This study was underpowered but conveyed an important message on the limit of current VEGF signal targeted drugs as a first-line therapy. In the future, more emphasis should be put on arrangement of dosing and scheduling of drugs already approved as well as development of new agents targeting novel molecules in this disease.
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• A Phase 2 Study of Abiraterone Acetate in Japanese Men with Metastatic Castration-resistant Prostate Cancer Who Had Received Docetaxel-based Chemotherapy, Takefumi Satoh, Hiroji Uemura, Kazunari Tanabe, Tsutomu Nishiyama, Akito Terai, Akira Yokomizo, Tatsuya Nakatani, Keiichiro Imanaka, Seiichiro Ozono, Hideyuki Akaza, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 44(12), 1206 - 1215, Dec. 2014 , Refereed
  Summary:In this Phase 2 multicenter study the efficacy and safety of oral abiraterone acetate (1000 mg/once daily) plus prednisolone (5 mg/twice daily) was evaluated in metastatic castration-resistant prostate cancer patients from Japan who had previously received docetaxel-based chemotherapy. Men (aged a parts per thousand yen20 years) with metastatic castration-resistant prostate cancer (prostate-specific antigen levels: a parts per thousand yen5 ng/ml), who had received 1 or 2 cytotoxic chemotherapies (with a parts per thousand yen1 regimen being docetaxel) for prostate cancer, were enrolled in this open-label, single-arm study. Primary efficacy endpoint was proportion of patients achieving a a parts per thousand yen50% prostate-specific antigen decline from baseline (prostate-specific antigen response rate) after 12-week treatment. Safety and pharmacokinetics were also assessed. Confirmed prostate-specific antigen response rate by Week 12 was 28.3% (90% confidence interval: 17.6%; 41.1%) or 13 out of 46 (full analysis set) treated patients. However, total prostate-specific antigen response rate including confirmed and unconfirmed responses was 34.8% (90% confidence interval: 23.2%; 47.9%). Secondary efficacy endpoints and outcomes were: improvement in Eastern Cooperative Oncology Group performance status score by a parts per thousand yen1 unit: 7/16 patients (43.8%); objective radiographic response: complete response, partial response and stable disease in 0, 1/22 (4.5%) and 9/22 (40.9%) patients, respectively; pain palliation response: 9/16 (56.3%) patients. The most common adverse events (> 20% patients) were upper respiratory tract infection (13/47, 27.7% patients) and hepatic function abnormal (10/47, 21.3% patients, Grade 3: 8.5%). All mineralocorticoid-related toxicities were Grade 1/2. Abiraterone acetate plus prednisolone showed favorable efficacy in metastatic castration-resistant prostate cancer Japanese patients who had received chemotherapy. Abiraterone acetate plus prednisolone had an acceptable safety profile. NCT01795703.
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• Phase-1 study of abiraterone acetate in chemotherapy-naive Japanese patients with castration-resistant prostate cancer, Nobuaki Matsubara, Hiroji Uemura, Iwao Fukui, Masashi Niwakawa, Akito Yamaguchi, Koho Iizuka, Hideyuki Akaza, CANCER SCIENCE, CANCER SCIENCE, 105(10), 1313 - 1320, Oct. 2014 , Refereed
  Summary:Persistent androgen synthesis under castration status in adrenal gland, testes and tumor cells is thought to be one of the major causes of development and progression of castration-resistant prostate cancer (CRPC). Abiraterone acetate (AA), the prodrug of abiraterone, which is an inhibitor of androgen synthesis enzymes, was evaluated for pharmacokinetics, pharmacodynamics, preliminary efficacy and safety in Japanese patients with CRPC in a phase-1, open-label and dose-escalation study. Chemotherapy-naive Japanese CRPC patients (N=27) received one of four AA daily doses (250mg [n=9], 500mg [n=6], 1000[1h premeal] mg [n=6] and 1000 [2h postmeal] mg [n=6]) continuously through 28-day treatment cycles. In the first cycle, AA monotherapy was given on days1-7 for pharmacokinetics, and AA plus prednisone (5mg twice daily) from days8 to 28. Of 27 patients, 9 continued treatment with AA until the data cut-off date (18 July 2013). Over the evaluated dose range, plasma abiraterone concentrations increased with dose, with median t(max) 2-3h. At each dose level, mean serum corticosterone concentrations increased, while testosterone and dehydroepiandrosterone sulfate concentrations rapidly decreased following a single AA dose and were further reduced to near the quantification limit on day8 regardless of the dose. At least 3 patients from each dose-group experienced 50% prostate-specific antigen reduction, suggesting clinical benefit from AA in Japanese CRPC patients. AA was generally well-tolerated, and, therefore, the recommended AA dosage regimen in Japanese CRPC patients is 1000mg oral dose under modified fasting conditions (at least 1h premeal or 2h postmeal). This study is registered at : NCT01186484.
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• Expression of lumican is negatively associated with the risk of biochemical recurrence in human prostate cancer, Marco A. De Velasco, Yuji Hatanaka, Takashi Oki, Yurie Kura, Yutaka Yamamoto, Kazuhiro Yoshimura, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• The role of autophagy in prostate tumorigenesis and its therapeutic implications, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• Co-targeting the PI3K and androgen receptor signal pathways in castration resistant prostate cancer, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• Functional evaluation of synchronous inactivation of PTEN and P53 in a murine model of prostate cancer, Hirotsugu Uemura, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• Combining PI3K and 5alpha-reductase inhibitors improves the treatment response in a mouse model of PTEN-deficient prostate cancer, Yurie Kura, Marco A. De Velasco, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• Establishment and characterization of cell lines derived from a murine model of PTEN-deficient prostate cancer, Kazuhiro Yoshikawa, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 74(19), Oct. 2014 , Refereed
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• High testosterone levels in prostate tissue obtained by needle biopsy correlate with poor-prognosis factors in prostate cancer patients, Yasuhide Miyoshi, Hiroji Uemura, Susumu Umemoto, Kentaro Sakamaki, Satoshi Morita, Kazuhiro Suzuki, Yasuhiro Shibata, Naoya Masumori, Tomohiko Ichikawa, Atsushi Mizokami, Yoshiki Sugimura, Norio Nonomura, Hideki Sakai, Seijiro Honma, Masaoki Harada, Yoshinobu Kubota, BMC Cancer, BMC Cancer, 14(1), Sep. 26 2014 , Refereed
  Summary:Background: There is currently no consensus on the correlations between androgen concentrations in prostate tissue and blood and stage and pathological grade of prostate cancer. In this study, we used a newly-developed ultra-sensitive liquid-chromatography tandem mass spectrometry method to measure testosterone (T) and dihydrotestosterone (DHT) concentrations in blood and needle biopsy prostate specimens from patients with prostate cancer.Methods: We analyzed androgen levels in 196 men diagnosed with prostate cancer. All patients had undergone systematic needle biopsy, and an additional needle biopsy from the peripheral zone was conducted for the simultaneous determination of T and DHT. We analyzed the relationships between T and DHT levels in tissue and blood and Gleason score, clinical stage, and percentage of positive biopsy cores, using multivariate analysis. Results: The median T and DHT levels in blood were 3551.0 pg/mL and 330.5 pg/mL, respectively. There was a strong correlation between serum T and DHT. The median T and DHT levels in prostate tissue were 0.5667 pg/mg and 7.0625 pg/mg, respectively. In multivariate analysis, serum prostate-specific antigen and tissue T levels were significantly associated with poor prognosis high T levels in prostate tissue were significantly related to high Gleason score (p = 0.041), advanced clinical stage (p = 0.002), and a high percentage of positive biopsy cores (p = 0.001). Conclusions: The results of this study indicate that high T levels in prostate tissue are related to high Gleason score, advanced clinical stage, and a high percentage of positive biopsy cores in patients with prostate cancer. T level in needle biopsy specimens may therefore be a useful prognostic factor in prostate cancer patients.
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• Cutaneous angiosarcoma at an interval of thirty-six years from radiation for a testicular germ cell tumor, Maiko Kato, Naoki Oiso, Mitsuhisa Nishimoto, Yasunori Mori, Yoshinari Katoh, Hirotsugu Uemura, Akira Kawada, EUROPEAN JOURNAL OF DERMATOLOGY, EUROPEAN JOURNAL OF DERMATOLOGY, 24(5), 622 - 623, Sep. 2014 , Refereed
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• Successful ABO-incompatible living-donor renal transplant without splenectomy for renal coloboma syndrome: a case report., Yasuyuki Kobayashi, Taiji Hayashi, Tokumi Ishii, Hirotsugu Uemura, Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation, Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation, 12(2), 162 - 4, Apr. 2014 , Refereed
  Summary:To our knowledge, this is the first report of an ABO-incompatible living-donor renal transplant without a splenectomy performed in a patient with renal coloboma syndrome, a rare disorder caused by PAX2 gene mutations, and that presents with renal and optic nerve hypodysplasia and disorders of the central nervous system. Many patients with renal coloboma syndrome develop end-stage renal disease requiring renal replacement therapy. Few reports of a well-defined course of renal transplant for coloboma syndrome have been published. We treated a 22-year-old man who had end-stage renal disease from renal coloboma syndrome. We performed an ABO-incompatible living-donor renal transplant with a kidney donated by his father. Two years after the transplant, the patient has good preserved renal function, and his compliance with the immunosuppressive regimen was good.
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• Examination of the Effect of Changing to Azilsartan From Candesartan in Renal Transplant Patients, T. Ishii, M. Yasuda, Y. Saito, Y. Mori, T. Hayashi, H. Uemura, K. Nose, T. Nishioka, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 46(2), 492 - 495, Mar. 2014 , Refereed
  Summary:Background. Azilsartan, an angiotensin receptor blocker (ARB), was administered to renal transplant recipients to investigate the safety and antihypertensive effect in addition to its ARB-characteristic organ-protective effect. Methods. The subjects were 20 patients (18 males, 2 females; baseline serum creatinine 2.39 +/- 1.33 mg/dL) responding poorly to candesartan, who suffered albuminuria (>0.3 g/g creatinine) and hypertension (>140/90 mm Hg) following renal transplantation. Three months after candesartan was switched to azilsartan 20 mg/d, blood pressure, creatinine-corrected urinary albumin excretion, urinary L-type acid binding protein, urinary 8-hydroxydeoxyguano-sine, serum creatinine, and estimated glomerular filtration rate were evaluated. Thirteen patients received cyclosporine (65.0%) and 7 received tacrolimus (35.0%). Another hypertensive (calcium antagonist) agent was combined in 7 (35.0%). Results. Systolic blood pressure significantly decreased from 139.5 mm Hg (baseline) from 128.7 mm Hg (at 3 months), whereas no significant changes were observed for diastolic blood pressure. The percentage of patients achieving the target level of antihypertensive effect (blood pressure < 130/80 mm Hg) significantly improved from 30.0% (baseline) to 70.0% (at 3 months). No significant changes were observed in renal graft function, oxidative stress marker level, or biochemical examination findings. Conclusion. Sufficient antihypertensive effect was demonstrated soon after switching to azilsartan. However, no significant change was found in renal damage markers. Long-term study must be conducted to confirm the protective effect azilsartan on the transplanted kidney, as found with candesartan. The safety of azilsartan was demonstrated. If the transplanted kidney protection is demonstrated, this drug is expected to contribute to the improved long-term prognosis of renal transplant recipients.
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• Proposal of "cyclic therapy", a novel treatment strategy with targeted agents for advanced renal cell carcinoma., Masahiro Nozawa, Hirotsugu Uemura, Translational andrology and urology, Translational andrology and urology, 2(4), 324 - 7, Dec. 2013 , Refereed
  Summary:The number of molecular targeted agents for advanced renal cell carcinoma (RCC) has gradually increased, but evidence on the optimal order of selection for such agents has not yet caught up with this trend. In addition, timing of switching molecular targeted drugs may also become an important issue for controlling the disease as types of these drugs grow in number. Based on the fact that the efficacy of a rechallenge of the drug previously used suggests the recovery of the sensitivity, a cyclic therapy in which drugs are changed before exacerbation to repeatedly administer several drugs in a rotated manner, may also be an effective sequential therapy.
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• [A case of testicular tumor of ovarian epithelial type]., Mitsuhisa Nishimoto, Nobutaka Shimizu, Takashi Kikuchi, Yasuyuki Kobayashi, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 59(11), 753 - 7, Nov. 2013 , Refereed
  Summary:Testicular tumors of ovarian epithelial types are rare, and their etiology is unknown. Moreover, a clear treatment policy has not become settled. Under the diagnosis of a testicular tumor, this patient underwent a high orchiectomy, and the pathology revealed testicular tumor of ovarian epithelial type. CA125 was elevated for three years post-operatively and a recurrence was discovered in the left inguinal region by positron emission tomography-computed tomography. Therefore, tumor extirpation was performed. The pathology result confirmed the recurrence of testicular tumor of ovarian epithelial type. After the surgery, the patient was given combined therapy with paclitaxel and carboplatin, which is a regimen of ovarian cancer, on a triweekly basis. After five courses of this therapy, the patient remains in remission.
• Angiotensin receptor blockers and risk of prostate cancer among united states veterans, Gowtham A. Rao, Joshua R. Mann, Matteo Bottai, Hiroji Uemura, James B. Burch, Charles Lee Bennett, Kathlyn Sue Haddock, James R. Hébert, Journal of Clinical Pharmacology, Journal of Clinical Pharmacology, 53(7), 773 - 778, Jul. 2013 , Refereed
  Summary:To address concerns regarding increased risk of prostate cancer (PrCA) among angiotensin receptor blocker (ARB) users, we used national retrospective data from the Department of Veterans Affairs (VA) through the Veterans Affairs Informatics and Computing Infrastructure. We identified a total of 543,824 unique Veterans who were classified into either ARB treated or not-treated in 1:15 ratio. The two groups were balanced using inverse probability of treatment weights. A double-robust cox-proportional hazards model was used to estimate the hazard ratio for PrCA incidence. To evaluate for a potential Gleason score stage migration, we conducted weighted Cochrane-Armitage test. Post weighting, the rates of PrCA in treated and not-treated groups were 506 (1.5%) and 8,269 (1.6%), respectively representing a hazard ratio of (0.91, p-value .049). There was no significant difference in Gleason scores between the two groups. We found a small, but statistically significant, reduction in the incidence of clinically detected PrCA among patients assigned to receive ARB with no countervailing effect on degree of differentiation (as indicated by Gleason score). Findings from this study support Food and Drug Administration's recent conclusion that ARB use does not increase risk of incident PrCA. © The Author(s) 2013.
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• Zoledronic acid for hormone-naive prostate cancer with bone metastasis., Masahiro Nozawa, Isao Hara, Kazuhiro Nagao, Hideyasu Matsuyama, Hirotsugu Uemura, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 31(15), May 2013 , Refereed
• Efficacy of Ramelteon in Patients with Insomnia and Nocturia., Nobutaka Shimizu, Koichi Sugimoto, Masahiro Nozawa, Yasuyuki Kobayashi, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Kazuhiro Nose, Tsukasa Nishioka, Lower urinary tract symptoms, Lower urinary tract symptoms, 5(2), 69 - 74, May 2013 , Refereed
  Summary:OBJECTIVES: To study the efficacy of ramelteon for patients with insomnia and nocturia. METHODS: Forty-nine patients experiencing insomnia and two or more nocturnal voids were included. The degree of lower urinary tract symptoms and sleep disorders was evaluated using the International Prostate Symptom Score (IPSS), Pittsburg Sleep Quality Index (PSQI)(1) score, and frequency/volume chart (FVC). The patients were treated with ramelteon (8 mg) for four weeks and then reexamined by questionnaire and FVC to evaluate the therapeutic efficacies. RESULTS: The mean IPSS score was 16.1 ± 6.9 at baseline and 12.4 ± 7.1 at four weeks. The subject scores for the number of nocturnal voids also decreased significantly from 3.3 ± 0.9 to 2.9 ± 1.0. In addition, PSQI scores improved significantly from 7.4 ± 2.9 to 5.4 ± 2.8. According to the FVC, the number of nocturnal voids decreased significantly from 3.1 ± 1.2 at baseline to 2.2 ± 1.1 at four weeks, and nighttime bladder capacity improved significantly from 181.4 ± 79.9 to 201.1 ± 93.7 mL. CONCLUSION: Ramelteon alleviated nocturia and disturbed sleep in patients with insomnia and nocturia and led to increased nighttime bladder capacity.
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• [Penile metastasis from esophageal cancer: a case report]., Yasuyuki Kobayashi, Masahiro Nozawa, Takashi Kikuchi, Mitsuhisa Nishimoto, Nobutaka Shimizu, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Hidenori Tsuji, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 59(5), 315 - 8, May 2013 , Refereed
  Summary:A 61-year-old man visited our department with the complaint ofa palpable hard mass in the penile shaft which showed a significant uptake on fluorodeoxyglucose positron emission tomography-computed tomography (FDG PET-CT). He had undergone a surgery for local invasive esophageal cancer and had received adjuvant chemotherapy. Open biopsy revealed metastases in the carvenous body and the glans of the penis from esophageal squamous cell carcinoma. He died from the cancer 5 months after the biopsy in spite of additional chemotherapy.
• Leptin contributes to prostate cancer progression., Marco A. De Velasco, Yutaka Yamamoto, Yuji Hatanaka, Yurie Kura, Naomi Ando, Emiko Fukushima, Masahiro Nozawa, Nobutaka Shimizu, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 73(8), Apr. 2013 , Refereed
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• Autophagy is required for prostate cancer progression, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yuji Hatanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 73(8), Apr. 2013 , Refereed
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• Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma, K. Yoshimura, T. Minami, M. Nozawa, H. Uemura, BRITISH JOURNAL OF CANCER, BRITISH JOURNAL OF CANCER, 108(6), 1260 - 1266, Apr. 2013 , Refereed
  Summary:Background: It is well known that renal cell carcinoma (RCC) represents one of the most immune-responsive cancers. Although the lack of defined antigens in RCC has hindered more specific vaccine development, research regarding vaccination therapy has been of special interest for the treatment of RCC for more than 30 years. Methods: To evaluate the safety of the vascular endothelial growth factor receptor 1 (VEGFR1) peptide vaccination and its clinical outcomes, data from 18 metastatic RCC (mRCC) patients treated with VEGFR1 vaccine were collected. Toxicity assessments were performed. Clinical outcomes included assessment using CT scanning, magnetic resonance imaging or X-ray examination in accordance with the WHO Response Evaluation Criteria in Solid Tumors. Results: No patient showed any toxicities of grade 3 or greater. Of the 18 patients, 2 patients showed a partial response during treatment. Stable disease for more than 5 months was observed in eight patients with a median duration of 16.5 months (4-32 months). At the time of the analysis in this study, six patients were alive with a median follow-up of 30 months (26-36 months). Conclusion: These results suggest that VEGFR1 peptide vaccine is safe and is recommended for further trials for patients with mRCC.
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• Difference in adverse-event profiles between mTOR inhibitors, temsirolimus, and everolimus for advanced renal cell carcinoma, Masahiro Nozawa, Takashi Kikuchi, Mitsutoshi Nishimoto, Yasuyuki Kobayashi, Hirotsugu Uemura, JOURNAL OF CLINICAL ONCOLOGY, JOURNAL OF CLINICAL ONCOLOGY, 31(6), Feb. 2013 , Refereed
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• Comparison of the loss of renal function after cold ischemia open partial nephrectomy, warm ischemia laparoscopic partial nephrectomy and laparoscopic partial nephrectomy using microwave coagulation, Takashi Kawahara, Ryoko Sakata, Kimiko Kawahara, Hiroki Ito, Yasuhide Miyoshi, Futoshi Sano, Noboru Nakaigawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Kazuhide Makiyama, Current Urology, Current Urology, 6(3), 118 - 123, Jan. 2013 , Refereed
  Summary:Purpose: Nephron sparing surgery is an effective surgical option in patients with renal cell carcinoma. Laparoscopic partial nephrectomy involves clamping and unclamping techniques of the renal vasculature. This study compared the postoperative renal function of partial nephrectomy using an estimation of the glomerular filtration rate (eGFR) for a Japanese population in 3 procedures open partial nephrectomy in cold ischemia (OPN), laparoscopic partial nephrectomy in warm ischemia (LPN), and microwave coagulation using laparoscopic partial nephrectomy without ischemia (MLPN). Materials and Methods: A total of 57 patients underwent partial nephrectomy in Yokohama City University Hospital from July 2002 to July 2008. 18 of these patients underwent OPN, 17 patients received MLPN, and 22 patients had LPN. The renal function evaluation included eGFR, as recommended by The Japanese Society of Nephrology. Results: There was no significant difference between the 3 groups in the reduction of eGFR. eGFR loss in the OPN group was significantly higher in patients that experienced over 20 minutes of ischemia time. eGFR loss in LPN group was significantly higher in patients that experienced over 30 minutes of ischemia time. Conclusion: This study showed that all 3 procedures for small renal tumor resection were safe and effective for preserving postoperative renal function. © 2012 S. Karger AG, Basel.
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• Continuous or intermittent? On the dosing schedule of sunitinib for advanced renal cell carcinoma., Masahiro Nozawa, Hirotsugu Uemura, Translational andrology and urology, Translational andrology and urology, 1(4), 202 - 3, Dec. 2012 , Refereed
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• [Adverse event profile of new targeted agents for renal cell carcinoma]., Masahiro Nozawa, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 58(11), 655 - 7, Nov. 2012 , Refereed
  Summary:Targeted therapy has survival benefit for patients with advanced renal cell carcinoma. However, intolerability often causes discontinuation of treatment. Therefore management of adverse events and maintenance of treatment duration as long as possible are absolutely essential for patient care. Hypertension is a common adverse event of vascular endothelial growth factor receptor (VEGFR) inhibitors. General symptoms such as fatigue or asthenia and gastrointestinal disorders including diarrhea, nausea, and anorexia are also frequently produced by VEGFR inhibitors as well as other targeted agents under development. Development of a new drug which does not cause any severe adverse event may be an ultimate strategy against adverse events of current targeted agents. Here we review the adverse-event profiles of targeted therapies being developed, including axitinib, tivozanib, dovitinib, AS1411, vorinostat, AMG386, BMS-936558, carfilzomib, IMA901, and AGS-003, for renal cell carcinoma.
• [Era of molecular targeting therapy in RCC]., Hirotsugu Uemura, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 70 Suppl 8, 480 - 5, Nov. 2012 , Refereed
• 食事誘導性レプチンは前立腺癌の進行に寄与する(Diet-induced leptin contributes to prostate cancer progression), De Velasco Marco A., Hatanaka Yuji, Yamamoto Yutaka, Yoshimura Kazuhiro, Shimizu Nobutaka, Nozawa Masahiro, Yoshikawa Kazuhiro, Nishio Kazuto, Uemura Hirotsugu, 日本癌学会総会記事, 日本癌学会総会記事, 71回, 430 - 430, Aug. 2012 , Refereed
• [A case of prostatic cancer with a low PSA level accompanied with cystic formation requiring differentiation from adenocarcinoma of the seminal vesicle]., Yoshitaka Itami, Yasuharu Nagai, Yasuyuki Kobayashi, Nobutaka Shimizu, Yutaka Yamamoto, Takafumi Minami, Taiji Hayashi, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 58(7), 349 - 53, Jul. 2012 , Refereed
  Summary:A 70-year-old man with the complaint of macrohematuria and hematospermia was admitted to our hospital for further examination of a cystic formation of the right seminal vesicle, 3.6 cm in diameter, detected by magnetic resonance imaging(MRI). Cystoscopy revealed no remarkable change, but urine cytology was class III. The serum concentration of prostate specific antigen (PSA) was within the normal range of 1.83 ng/ml. Transperineal needle biopsy of the prostate and cystic tumor of the seminal vesicle revealed adenocarcinoma of the prostate and seminal vesicle, but immunostaining for PSA was negative, so we diagnosed the case as primary adenocarcinoma of the seminal vesicle. Bloody fluid of the cyst was obtained by transperineal aspiration, but no cancer cells were detected by cytological examination. Total prostatectomy was performed, and pathological findings was infiltration of prostate cancer into the seminal vesicle (pT3b) because immunostaining of the PSA was positive.
• Long-Term Renoprotective Effect of Candesartan in Renal Transplant Patients, T. Ishii, M. Yasuda, Y. Itami, T. Hayashi, H. Uemura, K. Nose, T. Nishioka, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 44(3), 638 - 641, Apr. 2012 , Refereed
  Summary:Background. The renoprotective effects of angiotensin II type 1 receptor blockers (ARBs) have been demonstrated in a number of clinical studies, but there are few evaluations of long-term ARB treatment. We measured blood pressure, urine protein, and estimated glomerular filtration rate (eGFR) among patients under long-term (up to 9 years) treatment with candesartan cilexetil to evaluate its safety and effectiveness to protect renal graft function. Methods. This study of 41 patients (31 male and 10 female) who presented with proteinuria and hypertension (blood pressure >140/90 mm Hg) after receiving a renal graft. Their serum creatinine level at baseline was 1.51 +/- 0.53 mg/dL. Cyclosporine or tacrolimus were concomitantly prescribed for 18 (43.9%) and 22 (53.7%) subjects, respectively. The ARB treatment period was >= 12 months (up to 9 years, mean 4.8 years). Combination with other antihypertensive drugs (calcium antagonists) was necessary in 14/41 subjects (34.1%). Results. Significant declines in blood pressure were observed during the treatment period; blood pressure reduction target (blood pressure <130/80 mm Hg) was met in 56.1% for systolic and 68.3% for diastolic pressure. No significant increase in serum creatinine level or eGFR was observed. Urinary protein was reduced to negative or marginal in 63.4% of the subjects, demonstrating a significant decrease. Conclusions. Candesartan cilexetil was considered to be safe even for long-term treatment in renal transplant patients, and effective to protect renal graft function.
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• Use of a novel synthetic biomaterial to induce mild whole body hyperthermia for the treatment of cancer in a preclinical model, Mitsuyama Kodama, Marco A. De Velasco, Yutaka Yamamoto, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 72, Apr. 2012 , Refereed
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• Enhanced anti-tumor effects using a combinatorial targeted treatment strategy in a preclinical model of prostate cancer, Yutaka Yamamoto, Marco A. De Velasco, Yuji Hatanaka, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Mitsumasa Kodama, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 72, Apr. 2012 , Refereed
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• A preclinical model to evaluate the risk of increased dietary fat consumption and prostate cancer progression, Yasuyuki Kobayashi, Marco A. De Velasco, Yuji Hatanaka, Yutaka Yamamoto, Motoyoshi Tanaka, Nozawa Masahiro, Nobutaka Shimizu, Kazuhiro Yoshimura, Mitsuyama Kodama, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 72, Apr. 2012 , Refereed
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• Evaluation of lumican expression profiles in prostate cancer, Kazuhiro Yoshimura, Marco A. De Velasco, Yuji Hatanaka, Yutaka Yamamoto, Mitsumasa Kodama, Motoyoshi Tanaka, Nobutaka Shimizu, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 72, Apr. 2012 , Refereed
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• PROGNOSTIC IMPACT OF ZOLEDRONIC ACID ON BIOCHEMICAL RELAPSE IN TREATMENT-NAIVE PATIENTS WITH BONE-METASTATIC PROSTATE CANCER, Hideyasu Matsuyama, Masahiro Nozawa, Takeshi Inagaki, Kazuhiro Nagao, Isao Hara, Hirotsugu Uemura, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 187(4), E312 - E312, Apr. 2012 , Refereed
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• HOXA10 expression profiles in prostate cancer, Yuji Hatanaka, Marco A. De Velasco, Yurie Kura, Yuji Yamamoto, Mitsumasa Kodama, Masahiro Nozawa, Nobutaka Shimizu, Kazuhiro Yoshimura, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 72, Apr. 2012 , Refereed
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• [A case of primary urotherial carcinoma with glandular differentiation of the renal pelvis with high serum level of carbohydrate antigen 19-9 (CA19-9)]., Yoshitaka Itami, Nobutaka Shimizu, Taiji Hayashi, Yasuharu Nagai, Yasuyuki Kobayashi, Yutaka Yamamoto, Takafumi Minami, Masahiro Nozawa, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 58(4), 203 - 7, Apr. 2012 , Refereed
  Summary:A 63-year-old man visited our hospital with body weight loss. Laboratory examination revealed a high serum level of carbohydrate antigen 19-9 (CA19-9) and LDH. There were no abnormal findings in the gastrointestinal tract. Enhanced abdominal computed tomography (CT) revealed a renal tumor, 5×3 cm in diameter, in the right lower pole and multiple lymph node swelling. The right renal tumor was not a typical renal cell carcinoma, so we considered the presence of bellini duct carcinoma and renal pelvis carcinoma, we performed right nephroureterectomy. Histopathological diagnosis was urothelial carcinoma with glandular differentiation of the renal pelvis. Post operation chemotherapy with GC (gemcitabine/cisplatin: 3-cycle), MVAC (methotrexate/vinblastine/doxorubicin/cisplatin: 1-cycle), TS-1 + CBDCA (tegafur-gimeracil-oteracil potassium/carboplatin: 3-cycle) was performed for lymph node metastasis, but he died of cachexia 18 months after operation.
• Laparoscopic Donor Nephrectomy: Single-Center Experience, T. Hayashi, K. Nose, M. Nozawa, T. Nishioka, K. Yoshimura, T. Ishii, H. Uemura, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 44(1), 30 - 31, Jan. 2012
  Summary:Objective. Laparoscopic living donor nephrectomy (LLDN) has become the standard procedure for renal transplantation. This technique is considered less invasive for the donor, allowing lower postoperative analgesic requirements and a faster return to daily activities. In Japan, 1123 renal transplantation were performed in 2009. And, almost 83% were living related procedures. The aim of this study was a retrospective assessment of the safety and outcomes of LLDN on renal transplantations. Material and methods. We retrospectively analyzed the intraoperative data and surgical complications for 21 patients who underwent retroperitoneoscopic living donor nephrectomy between June 2009 and March 2011. Results. LLDN was successfully completed in all patients, without conversion to open surgery. Mean operative time was 243.5 +/- 46.0 minutes with an average blood loss of 46.0 +/- 46.1 mL. Warm ischemic time was 2.1 +/- 0.62 minutes. Hospital stay was 11.1 +/- 2.7 days. There were no major donor complications. One patient presented a wound infection responding to conservative treatment. Conclusions. LLDN is a safe effective procedure. The vascular stapler is useful to manage the renal vessels.
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• [Analysis of prognostic factor in 52 castration-resistant prostate cancer treated with docetaxel]., Yoshitaka Saitou, Yuji Hatanaka, Masaaki Imanishi, Takayuki Ohzeki, Kiyoshi Hashimoto, Koichi Sugimoto, Atsunobu Esa, Hiroshi Kajikawa, Muneo Yasuda, Yutaka Yamamoto, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 58(1), 7 - 11, Jan. 2012 , Refereed
  Summary:The prognostic factor was retrospectively analyzed in 52 castration-resistant prostate cancer treated with docetaxel (DTX) in our institutions from April, 2006 to August, 2009. The treatment outcomes were decided with prostate specific antigen (PSA) progression-free survival and overall survival. These were calculated by Kaplan-Meier methods and tested with Log-rank test. Median PSA progression-free survival was 8.8 months and median overall survival was 24.1 months. Prognostic factors on PSA progression were PSA value before DTX treatment and rate of PSA decrement after DTX treatment. Prognostic factors on overall survival were Gleason score (GS), PSA value before DTX treatment, rate of PSA decrement after DTX treatment and positive of bone metastasis in Log-rank test. Odds ratio of PSA ≧20 ng/ml before DTX treatment was 2.99 and PSA decreasing rate < 30% was 3.65. These were statistically significant (p < 0.001) risk factors in the overall survival.
• CLINICAL STATISTICS OF LAPAROSCOPIC DONOR NEPHRECTOMY, Taiji Hayashi, Masahiro Nozawa, Kazuhiro Nose, Kazuhiro Yoshimura, Tokumi Ishii, Hirotsugu Uemura, JOURNAL OF ENDOUROLOGY, JOURNAL OF ENDOUROLOGY, 25, A214 - A214, Nov. 2011 , Refereed
• BMI AS A PREDICTOR OF INTRAOPERATIVE BLOOD LOSS IN LAPAROSCOPIC RADICAL NEPHRECTOMY, Masahiro Nozawa, Yasuharu Nagai, Yoshitaka Itami, Yasuyuki Kobayashi, Taiji Hayashi, Kazuhiro Yoshimura, Hirotsugu Uemura, JOURNAL OF ENDOUROLOGY, JOURNAL OF ENDOUROLOGY, 25, A217 - A217, Nov. 2011 , Refereed
• CLINICAL EVALUATION OF LAPAROSCOPIC ADRENALECTOMY AT OUR INSTITUTE, Kobayashi, Yasuyuki, Shimizu, Nobutaka, Yamamoto, Yutaka, Minami, Takafumi, Hayashi, Taiji, Nozawa, Masahiro, Yoshimura, Kazuhiro, Ishii, Tokumi, Uemura, Hirotsugu, JOURNAL OF ENDOUROLOGY, JOURNAL OF ENDOUROLOGY, 25, A205 - A205, Nov. 2011 , Refereed
• Basic Research in Kidney Cancer, Egbert Oosterwijk, W. Kimryn Rathmell, Kerstin Junker, A. Rose Brannon, Frederic Pouliot, David S. Finley, Peter F. A. Mulders, Ziya Kirkali, Hirotsugo Uemura, Arie Belldegrun, EUROPEAN UROLOGY, EUROPEAN UROLOGY, 60(4), 622 - 633, Oct. 2011
  Summary:Context: Advances in basic research will enhance prognosis, diagnosis, and treatment of renal cancer patients. Objective: To discuss advances in our understanding of the molecular basis of renal cancer, targeted therapies, renal cancer and immunity, and genetic factors and renal cell carcinoma (RCC). Evidence acquisition: Data on recently published (2005-2011) basic science papers were reviewed. Evidence synthesis: Advances in basic research have shown that renal cancers can be subdivided based on specific genetic profiles. Now that this molecular basis has been established, it is becoming clear that additional events play a major role in the development of renal cancer. For example, aberrant chromatin remodelling appears to be a main driving force behind tumour progression in clear cell RCC. A large number of potential biomarkers have emerged using various high-throughput platforms, but adequate biomarkers for RCC are still lacking. To bring the potential biomarkers and biomarker profiles to the clinical arena is a major challenge for the field. The introduction of tyrosine kinase inhibitors (TKIs) for therapy has shifted the interest away from immunologic approaches. Nevertheless, a wealth of evidence supports immunotherapy for RCC. Interestingly, studies are now appearing that suggest a combination of TKI and immunotherapy may be beneficial. Thus far, little attention has been paid to patient-specific differences. With high-throughput methods becoming cheaper and with the advances in sequencing possibilities, this situation is expected to change rapidly. Conclusions: Great strides have been made in the understanding of molecular mechanisms of RCC. This has led this field to the enviable position of having a range of molecularly targeted therapies. Large sequencing efforts are now revealing more and more genes responsible for tumour development and progression, offering new targets for therapy. It is foreseen that through integration of high-throughput platforms, personalised cancer treatment for RCC patients will become possible. (C) 2011 European Association of Urology. Published by Elsevier B.V. All rights reserved.
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• [Prostate cancer in a young adult : a case report]., Muneo Yasuda, Naoki Matsumura, Yasuto Okuda, Nobutaka Shimizu, Yutaka Yamamoto, Takahumi Minami, Taiji Hayashi, Hidenori Tsuji, Masahiro Nozawa, Tokumi Ishii, Kazuhiro Yoshimura, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 57(10), 585 - 8, Oct. 2011 , Refereed
  Summary:We report a case of prostate cancer in a 41-year-old male. The patient initially visited another institution with a chief complaint of left breech pain. He was referred to our hospital for further investigation. Serum level of PSA was 267ng/ml and multiple bone metastases were found on bone scintigram. Digital rectal examination revealed a stony-hard prostate. Computed tomography showed multiple lung and lymph node metastases. Transperineal needle biopsy of the prostate revealed moderately differentiated adenocarcinoma (Gleason score 4＋5) frombilateral lobes (the 3th Edition). The patient was diagnosed with cT4N1M1c prostate cancer and maximal androgen blockade therapy was commenced.
• Maintenance therapy with bacillus Calmette-Guerin Connaught strain clearly prolongs recurrence-free survival following transurethral resection of bladder tumour for non-muscle-invasive bladder cancer, Shiro Hinotsu, Hideyuki Akaza, Seiji Naito, Seiichiro Ozono, Yoshiteru Sumiyoshi, Sumio Noguchi, Akito Yamaguchi, Satoshi Nagamori, Akito Terai, Yasutomo Nasu, Haruki Kume, Yoshihiko Tomita, Yoshinori Tanaka, Shoji Samma, Hirotsugu Uemura, Hirofumi Koga, Tomoyasu Tsushima, BJU INTERNATIONAL, BJU INTERNATIONAL, 108(2), 187 - 195, Jul. 2011
  Summary:OBJECTIVE To confirm the recurrence-preventing efficacy and safety of 18-month bacillus Calmette-Guerin (BCG) maintenance therapy for non-muscle-invasive bladder cancer. PATIENTS AND METHODS The enrolled patients had been diagnosed with recurrent or multiple non-muscle-invasive bladder cancer (stage Ta or T1) after complete transurethral resection of bladder tumours (TURBT). The patients were randomized into three treatment groups: a maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks as induction therapy, followed by three once-weekly instillations at 3, 6, 12 and 18 months after initiation of the induction therapy), a non-maintenance group (BCG, 81 mg, intravesically instilled once weekly for 6 weeks) and an epirubicin group (epirubicin, 40 mg, intravesically instilled nine times). The primary endpoint was recurrence-free survival (RFS). RESULTS Efficacy analysis was performed for 115 of the full-analysis-set population of 116 eligible patients, including 41 maintenance group patients, 42 non-maintenance group patients and 32 epirubicin group patients. At the 2-year median point of the overall actual follow-up period, the final cumulative RFS rates in the maintenance, non-maintenance and epirubicin groups were 84.6%, 65.4% and 27.7%, respectively. The RFS following TURBT was significantly prolonged in the maintenance group compared with the non-maintenance group (generalized Wilcoxon test, P = 0.0190). CONCLUSION BCG maintenance therapy significantly prolonged the post-TURBT RFS compared with BCG induction therapy alone or epirubicin intravesical therapy.
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• [Application of basic research to the treatment of prostate cancer]., Kazuhiro Yoshimura, Hirotsugu Uemura, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 5, 19 - 24, Jun. 2011 , Refereed
• [Peptide vaccine therapy]., Kazuhiro Yoshimura, Hirotsugu Uemura, Nihon rinsho. Japanese journal of clinical medicine, Nihon rinsho. Japanese journal of clinical medicine, 69 Suppl 5, 174 - 8, Jun. 2011 , Refereed
• A Phase I Study of Personalized Peptide Vaccination Using 14 Kinds of Vaccine in Combination With Low-Dose Estramustine in HLA-A24-Positive Patients With Castration-Resistant Prostate Cancer, Masanori Noguchi, Hirotsugu Uemura, Seiji Naito, Hideyuki Akaza, Akira Yamada, Kyogo Itoh, PROSTATE, PROSTATE, 71(5), 470 - 479, Apr. 2011
  Summary:BACKGROUND. To evaluate the safety, tolerability, immune response, and antitumor activity of a combination of personalized peptide vaccination (PPV) and estramustine phosphate (EMP) in patients with castration-resistant prostate cancer (CRPC). METHODS. In a phase I dose-escalation study, four peptides showing the highest levels of peptide-specific immunoglobulin G(IgG) to 14 vaccine candidates (ITK-1) were subcutaneously injected every week in three different dose settings (1, 3, and 5 mg per peptide) for 6 weeks with a low dose of EMP, and the patients were followed by maximum 2 years extension study either weekly or bi-weekly six times PPV as one course with a low dose of EMP. RESULTS. Fifteen patients were enrolled in the phase I study. No serious treatment-related adverse events were observed. The most common adverse events were grade 2 skin reactions at the injection sites. The maximum acceptable dose of ITK-1 was 8.643 mg. There were no treatment-related systemic adverse events of grade 3 or more, and maximum tolerated dose could not be determined. Cytotoxic T lymphocyte responses measured by interferon-gamma release assay were boosted in 10 of 15 (67%) patients, and IgG responses were boosted in 7 of 15 (47%) patients. Twelve patients proceeded to the extension study, and the median survival time was 23.8 months during a median follow-up of 23.8 months. CONCLUSIONS. PPV treatment for HLA-A24 positive patients with CRPC could be recommended for further stages of clinical trials because of its safety and the higher frequency of boosting immune responses. Prostate 71: 470-479, 2011. (C) 2010 Wiley-Liss, Inc.
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• Sorafenib inhibits tumor development and growth in a transgenic mouse model of prostate cancer, Hirotsugu Uemura, Yuji Hatanaka, Ayaka Izumi, Erina Okazaki, Makiko Doi, Motoyoshi Tanaka, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Marco A. De Velasco, CANCER RESEARCH, CANCER RESEARCH, 71, Apr. 2011 , Refereed
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• Increased consumption of dietary fat contributes to increased prostate cancer-specific mortality in a transgenic mouse model of prostate cancer, Yuji Hatanaka, Marco A. De Velasco, Motoyoshi Tanaka, Makiko Doi, Erina Okazaki, Ayaka Izumi, Yutaka Yamamoto, Nobutaka Shimizu, Kazuhiro Yoshimura, Masahiro Nozawa, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, CANCER RESEARCH, 71, Apr. 2011 , Refereed
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• Intravesical bacillus calmette-guerin therapy for grade 3 non-muscle invasive bladder cancer: Results of six or eight successive instillations, Koichi Sugimoto, Hiroyuki Koike, Kiyoshi Hashimoto, Atsunobu Esa, Yoshitaka Saitou, Yuji Hatanaka, Masaaki Imanishi, Nobutaka Shimizu, Hideo Taharac, Marco De Velasco, Hirotsugu Uemura, Current Urology, Current Urology, 5(1), 41 - 45, Apr. 2011 , Refereed
  Summary:Background: Bacillus Calmette-Guerin (BCG) instillation has been considered to be the most effective method of treatment for non-muscle invasive bladder cancer. The objective of the study was to evaluate the efficacy of between 6 and 8 intravesical BCG instillations after transurethral resection of bladder tumor (TUR-Bt) for Grade 3 nonmuscle invasive bladder cancer. Methods: Between January 2000 and December 2007, a total of 68 cases (58 males and 10 females) with nonmuscle invasive bladder cancer (pTa-1 G3, without carcinoma in situ) were used in the study. After TUR-Bt, patients were divided into a non-infusion group (group A) and BCG (Tokyo 172 strain BCG, 80 mg in 40 ml saline or Connaught BCG, 81 mg in 40 ml saline) infusion groups administered weekly for 6 (group B) and 8 weeks (group C). Recurrence rates were used as endpoints for this study. Also, a single variable and multivariable analysis in a T classification (Ta or T1), tumor multiplicity, tumor size (diameter) and presence or absence of concomitant carcinoma in situ was conducted. Results: In group A, one-year recurrence free survival was 59.1%, and three-year recurrence free survival was 45.2%. In group B, one-year recurrence free survival was 63.6%, and three-year recurrence free survival was 53%. In group C, one-year recurrence free survival was 81%, and three-year recurrence free survival was 72%. Conclusion: This study showed that there may be an increased advantage from adjuvant treatment therapy consisting of 8 weekly intravesical administrations of BCG following TUR-Bt for patients suffering from grade 3 non-muscle invasive bladder cancer. © 2011 S. Karger AG, Basel.
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• [Multifunctional character of osteopontin and strategy for clinical applications]., Hidenori Tsuji, Tohru Umekawa, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 57(1), 49 - 54, Jan. 2011 , Refereed
  Summary:Osteopontin (OPN) is the major constituent of calcium-containing urinary stones and is involved in the inhibition of nucleation and aggregation of calcium oxalate (CaOx) crystals, promotion of the adherence of CaOx crystals to cultured renal epithelial cells, and regulation of inflammatory cells as chemokine. OPN has different effects (inhibitor and promoter) at each stage of stone formation in vitro and these multifunctional actions of OPN have not been fully elucidated. We developed a modified crystal method using collagen granules (CG) and immobilized OPN. OPN had strong inhibitory activity on the aggregation/growth of CaOx crystals, but the inhibitory activity decreased by use of OPN-immobilized CG. OPN is also a critical promoter of adherence for CaOx crystals to cultured renal epithelial cells in an in vitro experimental system. We examined the effect of OPN in vivo, by OPN siRNA transfection in rats. Hydrodynamic intravenous and renal subcapsular injections with lipofection were performed on days 1 and 8. The calcium concentration in the kidney was significantly lower and the frequency of CaOx crystal deposits in the tubules was lower in the OPN siRNA transfection group (drinking 1.5% ethylene glycol (EG)), than in the EG drinking group (sham operation) at day 15. We examined the effect of candesartan, an angiotensin II (Ang II) type 1 receptor blockers (ARB) in hyperoxaluric rats. ARB reduced crystal formation and calcium concentrations in the whole kidney. Hyperoxaluria leads to CaOx crystallization and the development of tubulointerstitial lesions in the kidney. AngII mediates OPN synthesis, which is involved in both macrophage recruitment and CaOx crystallization. OPN synthesis and production increased with hyperoxaluria but to a lesser extent in ARB-treated hyperoxaluric rats. These results show that oxalate can activate the renal renin-angiotensin system and that oxalate-induced upregulation of OPN is in part mediated via the renal renin-angiotensin system.
• Carvedilol protects tubular epithelial cells from ischemia-reperfusion injury by inhibiting oxidative stress., Taiji Hayashi, Marco Antonio De Velasco, Yoshitaka Saitou, Kazuhiro Nose, Tsukasa Nishioka, Tokumi Ishii, Hirotsugu Uemura, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 17(12), 989 - 95, Dec. 2010 , Refereed
  Summary:OBJECTIVES: Renal ischemia-reperfusion injury (IRI), leading to acute kidney injury, is a frequent complication with renal transplantation and it is associated with graft function. Its pathogenesis involves ischemia, vascular congestion and reactive oxygen metabolites. Carvedilol is an antihypertensive drug with potent anti-oxidant properties. In this study we investigated the protective effects of carvedilol in a rat renal IRI model. METHODS: Twenty-four rats were randomized into sham, untreated control and carvedilol (2 mg/kg 30 min before surgery and 12 hr after reperfusion) treatment groups and were subjected to 60 min of left renal ischemia followed by reperfusion at 24, 48, 96 and 168 hr. RESULTS: Treatment with carvedilol significantly decreased plasma creatinine levels after IRI (up to 168 hr) compared to controls (P < 0.001), suggesting an improvement in renal function. Histopathological analysis revealed decreased IRI-induced damage in kidneys from carvedilol-treated rats. A significant increase in the expression levels of Cu/Zn superoxide dismutase and reduction of 8-hydroxydeoxyguanosine and apoptosis levels (P < 0.005) suggested a protective effect after treatment with carvedilol. CONCLUSIONS: Our findings suggest that carvedilol ameliorates IRI resulting in improved renal function.
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• がんの予防・化学予防 前立腺癌に対する酢酸クロルマジノンの術前化学予防効果(Cancer prevention and chemoprevention Pre-clinical chemopreventive efficacy of chlormadinone acetate against prostate cancer), Koike Hiroyuki, De Velasco Marco A., Shimada Keiji, Yoshikawa Kazuhiro, Arao Tokuzu, Nishio Kazuto, Konishi Noboru, Uemura Hirotsugu, 日本癌学会総会記事, 日本癌学会総会記事, 69回, 234 - 234, Aug. 2010 , Refereed
• ドラッグデリバリーシステム、その他 前臨床マウスモデル系における前立腺癌に対するeverolimusと酢酸クロルマジノンの抗腫瘍作用(Drug delivery system, others Anti-tumor effects of everolimus and chlormadinone acetate against prostate cancer in a pre-clinical mouse model), De Velasco Marco A., Koike Hiroyuki, Shimada Keiji, Yoshikawa Kazuhiro, Konishi Noboru, Arao Tokuzu, Nishio Kazuto, Uemura Hirotsugu, 日本癌学会総会記事, 日本癌学会総会記事, 69回, 424 - 424, Aug. 2010 , Refereed
• Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer, Hirotsugu Uemura, Kiyohide Fujimoto, Takashi Mine, Shigeya Uejima, Marco A. de Velasco, Yoshihiko Hirao, Nobukazu Komatsu, Akira Yamada, Kyogo Itoh, CANCER SCIENCE, CANCER SCIENCE, 101(3), 601 - 608, Mar. 2010
  Summary:We previously reported that personalized peptide vaccine (PPV) therapy in combination with leutenizing hormone-releasing hormone (LH-RH) analog and estramustine phosphate in certain cases is safe and capable of inducing both immune responses and clinical responses for metastatic castration-resistant prostate cancer (CRPC) patients. In the present study, PPV monotherapy was given to CRPC patients. Twenty-three patients with metastatic CRPC were treated with PPV without any additional treatment modalities, including LH-RH analogs. Samples were analyzed for peptide-specific cytotoxic T-lymphocyte (CTL) precursor analysis and peptide-reactive IgG. Toxicity and immunological and clinical responses were assessed on a three-monthly basis. Seventeen patients were available for immunological and clinical evaluation. The vaccines were well tolerated, with grade 3 erythema at injection sites in only one patient. Augmentation of CTL or IgG responses to at least one of the peptides was observed in six of 17 (35%) and 15 of 17 (88%) patients tested, respectively. Among 57 peptides used, 9 and 36 peptides induced CTL and IgG responses, respectively. Delayed-type hypersensitivity reaction was observed in eight of 17 patients. More than 30% prostate-specific antigen (PSA) decline was observed in four of 17 patients. Of these, one patient achieved a complete PSA response and another patient showed a partial PSA response with profound shrinking of lymph node metastases and prostate. The overall median survival time was 24 months (range, 5-37 months). These results suggest that PPV monotherapy appears to be safe and capable of inducing peptide-specific immune responses and clinical responses in CRPC patients. This trial was registered with University Hospital Medical Information Network (UMIN) number R000003339. (Cancer Sci 2010; 101: 601-608)
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• Chronic treatment with a PDE5 inhibitor increases contractile force of normal bladder in rats., Seiji Matsumoto, Tadashi Hanai, Hirotsugu Uemura, International urology and nephrology, International urology and nephrology, 42(1), 53 - 6, Mar. 2010 , Refereed
  Summary:OBJECTIVES: We have previously shown that a phosphodiesterase 5 (PDE5) inhibitor, vardenafil, possesses bladder protective effects in bladder outlet obstruction (BOO) rats by preserving contractile force. In this study, we examined the effects of vardenafil to obtain clues for further research elucidating the mechanism of action of vardenafil on rat normal bladder. MATERIALS AND METHODS: In all, twenty 12-week-old female Sprague-Dawley rats were divided into two equal groups: group 1, water-treated rats; and group 2, vardenafil-treated rats. Vardenafil (8 mg/kg/day) was given by drinking water. Four weeks after, vardenafil was washed out by giving water for 24-48 h, and then bladder was excised and dissected into four longitudinal strips for isometric organ bath assay. Contractile profile of bladder strips to electrical field stimulation (EFS), carbachol, and potassium chloride (KCl) was investigated. RESULTS: Vardenafil had no effect on body and bladder weight. Contractile forces to EFS, carbachol, and KCl were all increased significantly in group 2 by chronic vardenafil treatment. CONCLUSION: These effects were consistent with those observed in BOO rats for carbachol response, suggesting that effects of vardenafil are not limited to diseased condition, but also apply in normal condition. Chronic treatment with vardenafil increased contractile force of rat normal bladder strips.
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• A Phase II Study of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma: Insights into the Treatment, Efficacy and Safety, Hirotsugu Uemura, Nobuo Shinohara, Takeshi Yuasa, Yoshihiko Tomita, Hiroyuki Fujimoto, Masashi Niwakawa, Soichi Mugiya, Tsuneharu Miki, Norio Nonomura, Masayuki Takahashi, Yoshihiro Hasegawa, Naoki Agata, Brett Houk, Seiji Naito, Hideyuki Akaza, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 40(3), 194 - 202, Mar. 2010 , Refereed
  Summary:This study aims to assess the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (RCC). Fifty-one Japanese patients with prior nephrectomy, 25 treatment-naive patients (first-line group) and 26 cytokine-refractory patients (pretreated group) were enrolled in this phase II trial. Patients received sunitinib 50 mg orally, once daily, in repeated 6-week cycles (4 weeks on treatment, 2 weeks off). The primary endpoint was RECIST-defined objective response rate (ORR) with tumour assessments every 6 weeks via computed tomography or magnetic resonance imaging. Toxicity was assessed regularly. In the primary efficacy analysis of the intent-to-treat (ITT) population, ORR and 95% confidence interval were calculated based on independent review. Secondary time-to-event endpoints, such as progression-free survival (PFS), were estimated using the Kaplan-Meier method. In the ITT population, ORR was 48.0% in the first-line group (after a median 4 cycles), 46.2% in the pretreated group (5 cycles) and 47.1% overall, with median times to tumour response of 7.1, 10.7 and 10.0 weeks, respectively. Median PFS was 46.0, 33.6 and 46.0 weeks, respectively. The most common treatment-related grade 3/4 adverse events and laboratory abnormalities were fatigue (20%), hand-foot syndrome (14%) and hypertension (12%), decreased platelet count (55%), decreased neutrophil count (51%), increased lipase (39%) and decreased lymphocyte count (33%). In Japanese patients with RCC, sunitinib is consistently effective and tolerable with similar risk/benefit as that in Western patients, though there was a trend toward greater antitumour efficacy and higher incidence of haematological adverse events in Japanese patients.
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• Eviprostat suppresses urinary oxidative stress in a rabbit model of partial bladder outlet obstruction and in patients with benign prostatic hyperplasia., Seiji Matsumoto, Tadashi Hanai, Takahiro Matsui, Michiko Oka, Mitsushi Tanaka, Hirotsugu Uemura, Phytotherapy research : PTR, Phytotherapy research : PTR, 24(2), 301 - 3, Feb. 2010 , Refereed
  Summary:Eviprostat is a phytotherapeutic agent that has been used widely for more than 40 years in the treatment of benign prostatic hyperplasia (BPH) in Japan and Germany, and is known to have antioxidant activity. The present study investigated the effect of Eviprostat on the levels of the urinary oxidative stress marker 8-hydroxy-2'-deoxyguanosine (8-OHdG) in a rabbit model of surgical partial bladder outlet obstruction (PBOO) and in patients with lower urinary tract symptoms (LUTS) associated with BPH. In the rabbit model, 8-OHdG levels in urine collected after 3 weeks of PBOO were 3.8-fold higher than in the urine of sham-operated rabbits. When twice-daily Eviprostat was administered orally throughout the 3-week PBOO period, the increase in urinary 8-OHdG levels was suppressed by 70%. In the clinical study, nine patients who received Eviprostat for 4 weeks showed 2.5-fold lower urinary 8-OHdG levels than before treatment. During Eviprostat treatment, the total International Prostate Symptom Score (IPSS) decreased from 16.56 +/- 2.74 to 13.67 +/- 2.30 and the quality of life score from 4.22 +/- 0.40 to 3.22 +/- 0.46. The findings provide evidence that the antioxidant activity of Eviprostat is responsible for its beneficial effects in the treatment of BPH.
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• Neuroendocrine carcinoma of the bladder, Takashi Kawahara, Shoji Yamanaka, Hisashi Ohshiro, Zenkichi Sekiguchi, Kazuhiro Namura, Hiroki Itou, Futoshi Sano, Kaoru Kita, Narihiko Hayashi, Kazuhide Makiyama, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Case Reports in Oncology, Case Reports in Oncology, 3(1), 54 - 58, 2010 , Refereed
  Summary:The case was a 67-year-old male who visited our hospital with a major complaint of macroscopic hematuria. A bladder tumor was found. When a transurethral resection of the bladder tumor was performed, the histopathological diagnosis was neuroendocrine bladder cancer. After chemotherapy with cisplatin and etoposide a partial shrinkage of the tumor was observed however, the patient expired 7 months after the first visit. Copyright © 2010 S. Karger AG.
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• Chemotherapy with low-dose docetaxel and estramustine phosphate in patient with liver dysfunction due to liver metastases of hormone-refractory prostate cancer: A case report, Miki Miyake, Noboru Nakaigawa, Kaoru Kita, Masahiro Yanagisawa, Hideyuki Terao, Futoshi Sano, Takayuki Murakami, Kazuhide Makiyama, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 56(1), 45 - 48, Jan. 2010 , Refereed
  Summary:A 82-year-old man was referred to our hospital for treatment of hormone-refractory prostate cancer with liver metastases. The obstruction of intrahepatic bile ducts due to the rapid growth of liver metastases induced liver dysfunction. We administered 25 mg/m2 docetaxel on dayl and 280 mg/body estramustine phosphate on day 1 to day 3, every 4 weeks. After two courses of this combined chemothrapy, the liver metastases were markedly reduced in size with the rapid improvement of liver function.
• Gallbladder metastasis from renal cell carcinoma, Takashi Kawahara, Hisashi Ohshiro, Zenkichi Sekiguchi, Mitsuko Furuya, Kazuhiro Namura, Hiroki Itoh, Futoshi Sano, Kaoru Kawaji, Narihiko Hayashi, Kazuhide Makiyama, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Case Reports in Oncology, Case Reports in Oncology, 3(1), 30 - 34, 2010 , Refereed
  Summary:A 73-year-old female was operated with radical nephrectomy and cholecystectomy for renal cell carcinoma and suspected gallstones after 9 courses of sunitinib treatment. Gallbladder specimen showed gallbladder metastasis originating from the renal cell carcinoma. Gallbladder metastasis from renal cell carcinoma is rare. Here, we discuss a case of gallbladder metastasis from renal cell carcinoma. Copyright © 2010 S. Karger AG.
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• ATM is the predominant kinase involved in the phosphorylation of histone H2AX after heating., Akihisa Takahashi, Eiichiro Mori, Xiaoming Su, Yosuke Nakagawa, Noritomo Okamoto, Hirokazu Uemura, Natsuko Kondo, Taichi Noda, Atsushi Toki, Yosuke Ejima, David J Chen, Ken Ohnishi, Takeo Ohnishi, Journal of radiation research, Journal of radiation research, 51(4), 417 - 22, 2010 , Refereed
  Summary:Heating induces histone H2AX phosphorylation at serine 139 (gammaH2AX). Phosphorylated H2AX subsequently forms foci in numerous mammalian cell lines. The aim of this study was to clarify details in the mechanisms involved in the phosphorylation of H2AX after heating. The cell lines used were DNA-PKcs knockout cells, ATM knockout cells, and their parental cell lines. To elucidate mechanisms of induction of phosphorylation of H2AX after heating, ATM/ATR inhibitor (CGK733) and DNA-PK inhibitor (NU7026) were used. The intensity of gammaH2AX signals was assayed with flow cytometry. The thermal dose-response curve for the fluorescence intensity of gammaH2AX appearance in DNA-PKcs-/- cells during the heating period was similar to that observed in DNA-PKcs+/+ cells. On the other hand, the slope of thermal dose-response curve for them in ATM-/- cells was lower than that in ATM+/+ cells. Phosphorylation of H2AX after heating was suppressed by a combination of CGK733 and NU7026 in the culture medium in DNA-PKcs-/- cells, ATM-/- cells and in their parental cells. Although the phosphorylation of H2AX after heating was not suppressed by NU7026 in their parental cells, such phosphorylation was suppressed by CGK733 in their parental cells. These results indicate that ATM is the predominant protein which is active in the phosphorylation of histone H2AX after heating.
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• Effects of tamsulosin on bladder blood flow and bladder function in rats with bladder outlet obstruction., Hiroko Okutsu, Seiji Matsumoto, Tadashi Hanai, Yukiko Noguchi, Noriko Fujiyasu, Akiyoshi Ohtake, Masanori Suzuki, Shuichi Sato, Masao Sasamata, Hirotsugu Uemura, Takashi Kurita, Urology, Urology, 75(1), 235 - 40, Jan. 2010 , Refereed
  Summary:OBJECTIVES: To investigate the mechanism underlying the ameliorating effect of tamsulosin, an alpha(1)-adrenoceptor antagonist, on storage symptoms associated with benign prostatic hyperplasia, the effects of tamsulosin on bladder blood flow (BBF) and bladder function was evaluated in rats with bladder outlet obstruction (BOO). METHODS: BOO was produced by partial ligature of the proximal urethra, which was maintained for 2 weeks. Tamsulosin was subcutaneously administered via an osmotic pump for 2 weeks immediately after the BOO surgery. The BBF in the sham-operated rats, the control BOO rats, and the tamsulosin-treated BOO rats was measured using the fluoromicrosphere method. Each rat was kept in a metabolic cage for observation of micturition behavior. Expression of the alpha(1)-adrenoceptor subtype mRNA in the vesical artery was measured by reverse transcriptase-polymerase chain reaction. RESULTS: BBF was significantly reduced in BOO rats compared with sham-operated rats, and tamsulosin significantly increased the BBF in BOO rats. Tamsulosin ameliorated the decrease in mean voided volume in BOO rats with bladder masses < 500 mg. Expression of the alpha(1)-adrenoceptor subtype in the vesical artery was alpha(1a)- > alpha(1d)-adrenoceptors; almost no expression was observed of alpha(1b)-adrenoceptors in either sham-operated or BOO rats. CONCLUSIONS: Tamsulosin increased BBF in BOO rats via an antagonistic effect, presumably on the alpha(1A)- and/or alpha(1D)-adrenoceptor in the vesical artery mainly, and improved the decrease in mean voided volume. Therefore, the results of this study suggest that tamsulosin improves bladder overactivity via improvement of BBF.
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• Effect of Edaravone on Ischemia Reperfusion Injury in Rat Urinary Bladder - Changes in Smooth Muscle Cell Phenotype and Contractile Function, S. Matsumoto, T. Hanai, N. Shimizu, K. Sugimoto, H. Uemura, AKTUELLE UROLOGIE, AKTUELLE UROLOGIE, 41, S46 - S49, Jan. 2010 , Refereed
  Summary:Edaravone is a newly developed radical scavenging agent that has been widely used for protection against ischemia/reperfusion (I / R) injury in patients with cerebral infarction. The present study investigated the effects of edaravone on the I / R injury in rat urinary bladder. Adult male rats were divided in the four groups: groups 1-3 received 1 hour of ischemia followed by 1 hour of reperfusion with saline and with edaravone (1 and 3 mg/kg body weight), and group 4 were age-matched control rats. The in vivo ischemia was created by clamping the vesical arteries for 1 hour and reperfusion was accomplished by removing the clips and lasted for 1 hour. Edaravone or saline were administered after reperfusion for 30 min. Following reperfusion, the bladder was excised and separated. Bladder smooth muscle cell (SMC) phenotypic expression was investigated in the electron microscope. The number of contractile and non-contractile bladder SMC phenotype according to the morphological criteria was counted and the ratio of non-contractile to contractile phenotype was calculated. The responses to electrical field stimulation and carbachol were recorded. Edaravone administration resulted in the protection of the morphological changes and contractile responses to both EFS and carbachol that were affected by the agent. Our findings demonstrate that edaravone has a potentially protective effect on I / R-induced damage in the rat bladder.
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• 個別化治療マウスモデルにおける抗腫瘍薬の薬効測定におけるヒト腫瘍移植片の利用(Use of human tumor explants for the determination of anti-tumor drug efficacy in a personalized medicine mouse model), Yoshimura Kazuhiro, De Velasco Marco A., Tanaka Motoyoshi, Nishio Kazuto, Uemura Hirotsugu, 日本癌学会総会記事, 日本癌学会総会記事, 68回, 188 - 188, Aug. 2009 , Refereed
• 遺伝子改変マウスにおける近赤外蛍光画像による腫瘍量の測定(Use of near infrared fluorescence imaging to determine tumor burden in genetically engineered mice), Uemura Hirotsugu, Yoshikawa Kazuhiro, Tanaka Motoyoshi, Nishio Kazuto, De Velasco Marco A., 日本癌学会総会記事, 日本癌学会総会記事, 68回, 457 - 457, Aug. 2009 , Refereed
• Laparoscopic right partial nephrectomy in the presence of riedel's lobe of the liver, Miki Miyaké, Kazuhide Makiyama, Noboru Nakaigawa, Yasuhide Miyoshi, Futoshi Sano, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 55(8), 509 - 511, Aug. 2009 , Refereed
  Summary:A 54-year-old woman consulted our hospital for further evaluation of an incidentally detected small renal mass. Abdominal computed tomography (CT) and other imaging showed a right renal mass adjacent to the Riedel's lobe. Laparoscopic right partial nephrectomy was performed under a diagnosis of suspected renal cell carcinoma. Riedel's lobe is an anatomic variant, which is a caudal extension of the right lobe of the liver. Riedel's lobe presented an obstruction during right renal surgery, but we performed the procedure successfully because we retracted the lobe medially. This procedure yielded a clear surgical field, allowing us to perform this delicate operation safely.
• Mixed epithelial and stromal tumor of kidney: A case report, Hideyuki Terao, Kazuhide Makiyama, Masahiro Yanagisawa, Miki Miyake, Futoshi Sano, Kaoru Kita, Takayuki Murakami, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Yoshiaki Inayama, Yoii Nagashima, Acta Urologica Japonica, Acta Urologica Japonica, 55(8), 495 - 498, Aug. 2009 , Refereed
  Summary:Mixed epithelial and stromal tumor of kidney (MEST-K) is a rare benign renal tumor that was first described by Michal and Syrucek in 1998. Its frequency is 0.2-0.28% of all the renal tumors. Here, we report an additional case of MEST-K occurring in a 28-year-old woman. The patient visited a hospital with complaints of lumbago and fever caused by pyelonephritis. The computed tomography revealed hydronephrosis and a cystic tumor in the right kidney, and laparoscopic right nephrectomy was performed. The resected kidney contained a cystic lesion with a grayish-white mural nodule, in the lower portion. The entire lesion measured 5 cm in diameter, and the mural nodule 2.5 cm in diameter. Histologically, the cyst was lined with tall columnar and transitional epithelia. The mural nodule showed microcystic architectures lined with tall columnar and transitional epithelia, scattered in a compact stroma. Immunohistochemically, spindle cells in the stroma were positive for smooth muscle-specific actin, and estrogen and progesterone receptors (ER and PR). Based on these findings, the tumor was diagnosed as MEST-K. MEST-K was newly introduced to the WHO classification of renal tumors, with a pathogenesis related to long-term estrogen exposure, because of ER and PR expression in the stroma. It is important to consider the possibility of this tumor when encountering cases of cystic tumor in middle-aged and older women, and men with a previous history of estrogen administration.
• A case of adult-onset idiopathic hypogonadotropic hypogonadism presenting with infertility, Hideyuki Terao, Takehiko Ogawa, Masahiro Yanagisawa, Miki Miyake, Futoshi Sano, Kaoru Kita, Takayuki Murakami, Kazuhide Makiyama, Noboru Nakaigawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 55(7), 437 - 439, Jul. 2009 , Refereed
  Summary:A 28-year-old man with adult-onset idiopathic male hypogonadotropic hypogonadism (MHH) is reported. He had been delivered normally and had normal puberty. He was referred to our hospital with a chief complaint of infertility. Serum levels of testosterone, luteinizing hormone, and follicle stimulating hormone (FSH) were low. Semen analysis demonstrated azoospermia. Pituitary hypofunction was suggested by gonadotropin releasing hormone (GnRH) loading test. Magnetic resonance images did not detect any abnormalities in the hypothalamic-pituitary region. After a diagnosis of adult-onset hypogonadotropic hypogonadism was established, the patient received human chorionic gonadotropin (hCG) and recombinant FSH treatment. After 5 months, his sperm count reached 6.9 X 10 6 per ml and his wife became pregnant. Adult-onset HH in most cases is caused by tumors and trauma. To our knowledge 17 cases of adult-onset idiopathic HH have been reported, and there were only 3 cases that were caused by pituitary dysfunction. This report showed that r-FSH and hCG therapy was effective in promoting fertility in a patient with adult-onset idiopathic MHH.
• A case of upper urinary tract metastases from sigmoid colon cancer, Mitsuru Komeya, Noboru Nakaigawa, Futoshi Sano, Masayo Kagota, Takayuki Murakami, Kazuhide Makiyama, Yasuhide Miyoshi, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoji Nagashima, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 55(6), 339 - 343, Jun. 2009 , Refereed
  Summary:We report a case of colorectal cancer with metastasis to the upper urinary tract. A 56-year-old man had left flank pain. Ultrasonography and computed tomographic (CT) examination demonstrated left hydronephroureter and a soft-tissue structure within the left ureter. Urinary cytology of the left ureter showed class IIIb. We diagnosed him with ureteral cancer and performed left nephroureterectomy. Microscopic examination demonstrated adenocarcinoma located in ureteral and pelvic wall, especially in blood vessels, with intact mucosa and similar to adenocarcinoma of colon cancer. Therefore metastatic upper urinary tract tumor was suspected. Barium enema and positron emission tomography-CT demonstrated sigmoid colon cancer. Biopsy specimen of colon cancer demonstrated adenocarcinoma, which was consistent with the ureteral tumor. Finally we diagnosed him with metastatic upper urinary tract tumor of sigmoid colon cancer. (Hinyokika Kiyo 55 : 339-343, 2009).
• A case of sarcomatoid renal cell carcinoma developed in the chalked kidney (Putty Kidney), Mitsuru Komeya, Futoshi Sano, Masayo Kagota, Takayuki Murakami, Kazuhide Makiyama, Yasuhide Miyoshi, Noboru Miyoshi, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Hisashi Ooshiro, Yoji Nagashima, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 55(5), 253 - 257, May 2009 , Refereed
  Summary:A 66-year-old woman, who developed pulmonary tuberculosis at 17 years old, had a high fever in December, 2006. Computed tomographic (CT) scan showed a tumor in the left chalked kidney, which measured 7 cm in diameter with very low enhancement. Laboratory data showed the rise of acute phase reactants (erythrocyte sedimentation rate and c-reactive protein) and severe anemia. The cultures of sputum and urine revealed no Mycobacterium tuberculosis. With the diagnosis of left renal cell carcinoma in the chalked kidney, we performed left radical nephrectomy. Histopathological diagnosis was sarcomatoid renal cell carcinoma. Although sarcomatoid renal cell carcinoma is highly malignant and its prognosis is poor, her post-operative condition has been good without any adjuvant treatments and there have been no recurrent or metastatic lesions for 9 months. The supervention of renal cell carcinoma on renal tuberculosis is rare. The possible effects of tuberculous lesions on the development and progression of renal cell carcinoma are discussed. (Hinyokika Kiyo 55 : 253-257, 2009).
• Free PSA/Total PSA Ratio Increases the Detection Rate of Prostate Cancer in Twelve-Core Biopsy, Yumiko Yokomizo, Yasuhide Miyoshi, Noboru Nakaigawa, Kazuhide Makiyama, Takehiko Ogawa, Masahiro Yao, Yoshinobu Kubota, Hiroji Uemura, UROLOGIA INTERNATIONALIS, UROLOGIA INTERNATIONALIS, 82(3), 280 - 285, 2009 , Refereed
  Summary:Background: In the present study, we compared 12-with 8-core biopsy in patients with prostate-specific antigen (PSA) levels of 4.0-20.0 ng/ml. We also examined whether the free/total (F/T) PSA ratio is useful for cancer detection in 12-core biopsy. Methods: A total of 419 men with PSA level between 4.0 and 20.0 ng/ml underwent transrectal ultrasound-guided transperineal needle biopsies of the prostate. Of these men, 235 underwent 8-core biopsy and 184 underwent 12-core biopsy. We compared the cancer detection rate between the 8- and 12-core biopsy groups by analyzing the PSA value, and especially the F/T PSA ratio. Results: The cancer detection rate in the 12-core group (35.9%) was significantly higher than in the 8-core group (23.8%). In cases of PSA level of 4.0-20.0 ng/ml with F/T PSA ratio less than 0.11, the cancer detection rate was 53.1% in the 12-core biopsy group. Performing 12-core biopsy resulted in a marked difference of cancer detection rate between men with F/T PSA ratio less than 0.11 and those with more than 0.12 in gray zone PSA (48.2% and 17.5%, respectively). Conclusions: Twelve-core biopsy can achieve a higher detection rate of prostate cancer than 8-core biopsy using F/T PSA ratio. Copyright (C) 2009 S. Karger AG, Basel
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• (Selectivity): Silodosin early effectiveness and safety multi center trial in Yokohama multi-center trial on the early effects of silodosin on lower urinary tract symptoms associated with benign prostatic hyperplasia, Takehiko Ogawa, Hirqji Uemura, Futoshi Sano, Kouji Hoshino, Kaoru Kita, Narihiko Hayashi, Masayo Kagota, Takayuki Murakami, Kazuhide Makiyama, Yasuhide Miyoshi, Noboru Nakaigawa, Masahiro Yao, Hidetoshi Shimura, Akihiko Furuhata, Naoya Fujikawa, Koichi Shioi, Teiichiro Ueki, Yoshinori Hara, Kiyoshi Saitou, Satoshi Kawakami, Yoshiaki Satomi, Yusuke Hattori, Junichi Teranishi, Keiichi Kondo, Takeshi Kishida, Kazuo Saito, Kazumi Noguchi, Hiroshi Fujii, Toyoaki Yamaguchi, Yuzo Kinoshita, Sakae Nomura, Minoru Yoshida, Naoki Sakai, Hideyuki Terao, Tatsuya Matsumoto, Susumu Umemoto, Yoshiharu Ogo, Kazuki Kobayashi, Sumio Noguchi, Tomoyuki Asakura, Teruo Kohdaira, Kozue Iguchi, Koji Izumi, Masami Hirano, Hitomi Kanno, Toshihiro Takahashi, Fumihiko Nukui, Yasuhiro Mokuo, Kentaro Muraoka, Yutaka Osada, Makoto Funahashi, Kazuo Kitami, Shimpei Sugiura, Junichi Ohta, Takeshi Miura, Yoshio Ishibashi, Mitsunobu Masuda, Atsushi Komiya, Yutaka Suwa, Takafumi Hashiba, Kunihisa Mitaka, Masataka Kobayashi, Kimito Ohsaka, Tetsuzo Takano, Futoshi Tsuchiya, Akira Iwasaki, Yuzo Yamashita, Junichi Matsuzaki, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 54(12), 757 - 764, Dec. 2008 , Refereed
  Summary:Silodosin (URIEF®), a new so-called 3rd generation alpha-1 blocker, is widely expected to be effective and useful for lower urinary tract symptoms (LUTS) associated with benign prostatic hyperplasia (BPH), due to its high specificity to alpha-1 A receptor. We evaluated the efficacy of Silodosin, on 187 males 50 years old or over with the diagnosis of BPH. Silodosin significantly improved the International Prostate Symptom Score (IPSS) and quality of life (QOL) score from the day after administration was started. Among 166 patients whose data were available for the analysis of efficacy of Silodosin, 77.5% showed apparent subjective improvement. Eighty three patients, who had been taking another alpha-1 blocker but without satisfactory effects, showed almost the same improvements in IPSS and QOL score after switching to Silodosin as the remaining 83 patients who had no preceding treatment with an alpha-1 blocker. The improvements were not only in voiding symptoms but also in storage symptoms. The patients, who had serious storage symptoms, responded rather well to Silodosin and showed significant improvement. Taken together, Silodosin showed a quick effect for improving subjective symptoms and QOL, and was found to be useful for the management of LUTS with BPH.
• [Investigation of lower urinary tract symptoms in urological outpatients using original IPSS plus post micturition dribble questionnaire]., Tadashi Hanai, Seiji Matsumoto, Nobutaka Shimizu, Hirotsugu Uemura, Takahide Sugiyama, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, 99(7), 723 - 8, Nov. 2008 , Refereed
  Summary:OBJECTIVES: At present, there are almost no report concerning post micturition dribble (PMD) in lower urinary tract symptoms (LUTS). PMD may have a negative effect on the quality of life (QOL) of afflicted patients. However, question concerning PMD are not included in the International Prostate Symptom Score (IPSS) questionnaire, and a number of questions about PMD remain to be addressed, such as the correlation between PMD and QOL. Therefore, we investigated PMD using an original question form (IPSS added PMD) we created. METHODS: Between June 2006 and March 2007, the self-administered modified IPSS (IPSS with new questions included concerning PMD) was 5 obtained from 621 outpatients (394 men and 227 women) visiting our hospital. RESULTS: The PMD scores were 1.2 +/- 1.7 in men, and 0.6 +/- 1.2 in women, and thus we see that the men had a significantly higher than the women. Men's PMD scores rise from age 50 and reach a peak in the 70's. On the other hand, there is no significant change for women from the 20s and thereafter. Those with higher PMD scores were male patients with benign prostatic hyperplasia (BPH) and females with stress urinary incontinence. In BPH group, the average PMD score was higher than patients with another urological disease. The PMD scores were appreciably high at 1.59 +/- 1.90 for the LUTS group, and had the lower value of 0.36 +/- 0.90 for the non-LUTS group. Therefore, the LUTS group was found to have a significantly higher PMD score. Men in the LUTS group (especially those with BPH) had a positive correlation between their QOL scores and PMD scores. CONCLUSION: The following points may be revealed from the present study. In patients with LUTS (especially BPH), PMD score is higher and may impair their QOL. Even women and youth may experience PMD. A more detailed evidence concerning PMD will be needed.
• Efficacy of carvedilol for ischemia/reperfusion-induced oxidative renal injury in rats, T. Hayashi, Y. Saitou, K. Nose, T. Nishioka, T. Ishii, H. Uemura, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 40(7), 2139 - 2141, Sep. 2008
  Summary:In renal transplantation, ischemia/reperfusion (I/R) injury is related to production of reactive oxygen species. In addition to its anti hypertensive action due to nonselective beta-adrenergic blocking activity, carvedilol has potent antioxidant activity. This study was designed to investigate the effects of carvedilol on I/R injury in rats. On postoperative days 2 and 4, serum creatinine levels were higher among the control and the metoprolol treatment groups compared with the carvedilol treatment group (P < .005). However, there were no significant differences on postoperative day 7. In conclusion, increased antioxidant modulation by carvedilol attenuated renal I/R injury.
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• [Examination of the mechanism of ameliorating effect of alpha 1-blocker on storage symptoms associated with benign prostatic hyperplasia]., Seiji Matsumoto, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 54(6), 453 - 6, Jun. 2008 , Refereed
  Summary:To investigate the mechanism of the ameliorating effect of alpha1-blocker on storage symptoms associated with benign prostatic hyperplasia (BPH), we evaluated the effect of tamsulosin on the bladder blood flow in rats with bladder outlet obstruction (BOO). BOO was produced by ligature in the part around a proximal urethra and kept for 2 weeks. Tamsulosin was subcutaneously administered with an osmotic pump for 2 weeks immediately after the BOO operation. Bladder blood flow in the sham-operated rats, the control BOO rats and the tamsulosin-treated BOO rats was measured by the fluoro-microsphere method. Bladder blood flow was significantly reduced in BOO rats compared with sham-operated rats, and tamsulosin significantly increased the bladder blood flow in BOO rats. The present results suggest that the increase in bladder blood flow by tamsulosin contributes to the improvement of storage symptoms associated with BPH.
• [Distribution of elastic fiber on prostate]., Koichi Sugimoto, Seiji Matsumoto, Hirotsugu Uemura, Hiroyuki Ito, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 54(5), 321 - 4, May 2008 , Refereed
  Summary:We examined prostate specimens from 5 patients (median age; 71.8 years, range 57-83), with benign prostatic hyperplasia (BPH) removed during surgery, and 4 autopsied cadavers (median age at death; 68.8 years, range 46-92) who had either obstructive or neurogenic voiding dysfunction. The prostate specimens were severed anatomically into samples of the base, middle, and apex of the prostate. They served as samples for a comparative study of the distribution of elastin fibers by means of a pathology study, using the Elastica Van Gieson (EV) staining method. The number of pixels representing elastin fibers in computerized images was analyzed using Adobe Photoshop Ver. 2.0. There was a larger proportion of elastin in the area of the urethra and at the base of prostate than in the remainder of the organ. The percentage of elastin at the base of the prostate was significantly greater among BPH patients than cadavers. Thus, it was demonstrated that elastin a stromal component was increased in BPH patients.
• ラット膀胱虚血・再還流モデルにおける膀胱平滑筋細胞の形態学的Phenotypeと膀胱機能の検討(CHANGES IN SMOOTH MUSCLE CELL PHENOTYPE AND CONTRACTILE FUNCTION FOLLOWING ISCHEMIA-REPERFUSION INJURY IN THE RAT URINARY BLADDER), 松本 成史, 花井 禎, 清水 信貴, 植村 天受, 泌尿器科紀要, 泌尿器科紀要, 54(3), 179 - 184, Mar. 2008
  Summary:目的:下部尿路閉塞による膀胱機能低下には膀胱虚血・再還流が一要因であるという報告が増加している。今回、ラット膀胱虚血・再還流モデルを用いて膀胱平滑筋細胞における形態学的phenotypeの変化と膀胱機能の関係を検討した。方法:28匹のSD雄ラットを用いて膀胱虚血・再還流(I-R)モデルを作製し、1時間虚血単独群、1時間虚血・1時間再還流群、1時間虚血・4時間再還流群、コントロール群に分類し、透過型電子顕微鏡による膀胱平滑筋細胞におけるphenotypeの比率および経壁電気刺激とKClに対する等尺性収縮力を測定し、検討を行った。結果:コントロールにおける膀胱平滑筋細胞の収縮型と非収縮型の比率(nc/c比)は0.169、虚血単独群はnc/c比は0.991,1時間I-R群、4時間I-Rのnc/c比はそれぞれ0.865,1.601であった。経壁電気刺激とKClに対する等尺性収縮力はI-R群で減少していた。考察:膀胱平滑筋細胞のnc/c比の結果より虚血単独群でも、非収縮型細胞が増加し、I-Rによりさらに非収縮型細胞が増加することが示された。膀胱平滑筋収縮力は虚血単独群でもI-R群でも減少したが、収縮反応は膀胱平滑筋細胞のphenotypeの変化とは対応しなかった。(著者抄録)
• 前立腺癌 PTENの前立腺特異的欠失による前立腺癌モデルの作製(Prostate Cancer A Prostate Cancer Model by the Prostate Specific Deletion of PTEN), Tomioka Atsushi, Tanaka Motoyoshi, Anai Satoshi, Ikeda Tomohiro, Shimada Keiji, Velasco Marco, Saito Keigo, Hirao Yoshihiko, Uemura Hirotsugu, 日本泌尿器科学会雑誌, 日本泌尿器科学会雑誌, 99(2), 149 - 149, Feb. 2008 , Refereed
• [Tumor inhibitory factors in urologic malignancies]., Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 54(1), 49 - 52, Jan. 2008 , Refereed
  Summary:In this review, pathogenesis and genetic alterations of urologic malignancies and their therapeutic target molecule are summarized briefly. In bladder cancer, only a little has been revealed. Loss of heterozygosity of 9p/q is frequently observed in low grade, low stage tumors. In invasive or carcinoma in situ tumors, alteration of p53 and Rb tumor suppressor gene is frequently found. In prostate cancer, the process of carcinogenesis from normal epithelium to cancer hypothesized by Nelson et al. (N Engl J Med 24; 349 : 366-381) seems to be logic. Androgen independency of tumor cells is associated with androgen receptor gene mutation and amplification, however, the mechanism is not well clarified. It is a turning point, therapeutic strategy is changing from cytokine immunotherapy to molecular targeting therapy in metastatic renal cell carcinoma. The pathway from growth factors such as vascular endothelial growth factor and platelet derived growth factor, and their receptors to mTOR is a central controller of tumor angiogenesis and proliferation.
• Urinary concentration of osteopontin and association with urinary supersaturation and crystal formation., Hidenori Tsuji, Umekawa Tohru, Uemura Hirotsugu, Iguchi Masanori, Hatanaka Yuji, Kurita Takashi, International journal of urology : official journal of the Japanese Urological Association, International journal of urology : official journal of the Japanese Urological Association, 14(7), 630 - 4, Jul. 2007 , Refereed
  Summary:OBJECTIVE: In this study, we measured urinary osteopontin (OPN) concentrations in urolithiasis patients as well as in healthy volunteers, and investigated the relationship between urinary excretion of OPN and urinary supersaturation level. METHODS: Supersaturation levels (AP indexes) were determined by using Tiselius's index. Crystals with a maximum diameter of 12 ìm or larger and less than 5 ìm were counted by scanning electron microscopy. A sum of cross-sectional areas of crystals was also calculated as the total crystal volume (VT). RESULTS: Urinary OPN concentrations in the group with no urinary stone were significantly higher than that in the urolithiasis patients with a tendency toward stone enlargement. AP indexes were observed to be significantly higher in patients with stone enlargement, whereas urinary OPN concentrations bore no definite relation to the urinary supersaturation levels. VT and number of large crystals (12 ìm or larger) in patients with a tendency toward stone enlargement were higher than healthy volunteers, but no differences were found between the number of micro-crystal with the diameter of less than 5 ìm. On the basis of the plots of VT and OPN concentrations, regression analysis revealed that VT and log OPN had a significant correlation. CONCLUSION: Urinary OPN tended to be lower in cases with larger crystal volumes and is potentially associated with crystal growth for inhibitory effect.
• Intravesical instillation of liposomal doxorubicin nanoparticles in mouse superficial bladder cancer., Satoshi Anai, Atsushi Tomioka, Yoshihiko Hirao, Ikumi Sugiyama, Yasuyuki Sadzuka, Motoyoshi Tanaka, Marco DeVelasco, Hirotsugu Uemura, JOURNAL OF UROLOGY, JOURNAL OF UROLOGY, 177(4), 293 - 293, Apr. 2007 , Refereed
• A case of laparoscopic heminephroureterectomy for ureter cancer in a horseshoe kidney, Takayuki Murakami, Kazuhide Makiyama, Yasuhide Miyoshi, Yusuke Ito, Kozue Iguchi, Futoshi Sano, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Japanese Journal of Urology, Japanese Journal of Urology, 98(6), 786 - 789, 2007 , Refereed
  Summary:We reported a case of laparoscopic heminephroureterectomy for ureter cancer in a horseshoe kidney. A 59-year-old woman presented with frequency and diagnosed as left lower ureter cancer with a horseshoekidney. We performed transperitoneal laparoscopic nephroureterectomy. Feeding vessels were four arteries and two veins. Isthmus of the horseshoe kidney was divided using LCS and hemostasis was made using monopolar shears. Operating time was 300 minutes. Total Blood loss was 400 ml. Laparoscopic pyeloplasty or ishmusectomy to benign disease of the horseshoe kidney is often reported, but that of heminephrectomy to malignancy is seldom reported. Laparoscopic Heminephectomy for a horseshoe kidney is difficult surgery for aberrant vessels and isthmus, so it tends to be avoided for safety. But if anatomical consideration about aberrant vessels etc is well done and we operate carfully, so we will be able to do it for safety and small invasive opration.
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• [Pregnancy in chronic dialysis and after renal transplantation]., Taiji Hayashi, Yasunori Mori, Seiji Matsumoto, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 52(12), 915 - 7, Dec. 2006 , Refereed
  Summary:A female patient gave birth to a child while receiving hemodialysis, six years later, she gave birth to another child after cadavatic renal transplantation. Both children showed normal growth without any congenital defects. During the term of pregnancy after renal transplantation, there was no significant rejection episode, and graft function was stable. It seems rare for a patient to bear children during dialysis and after renal transplantation.
• [Pulmonary metastasis of renal cell carcinoma 20 years after nephrectomy]., Miho Kaneko, Seiji Matsumoto, Hideo Tahara, Tokumi Ishii, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 52(12), 929 - 31, Dec. 2006 , Refereed
  Summary:A 70-year-old man underwent right nephrectomy for clear cell renal carcinoma in 1985. After nephrectomy, he was routinely followed up as an outpatient. Solitary chest tumor was detected on pulmonary CT in 2005. A wedge resection of pulmonary tumor was performed under diagnosis of primary lung cancer. The histological feature was not of primary lung cancer, but the previous nephrectomised specimen, i.e., clear cell renal carcinoma.
• [Clinical study of acute urinary retention]., Nobutaka Shimizu, Seiji Matsumoto, Nobuhiro Yoshioka, Tadashi Hanai, Takahide Sugiyama, Hirotsugu Uemura, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, 97(7), 839 - 43, Nov. 2006 , Refereed
  Summary:PURPOSE: Clinical study of acute urinary retention seen by this department. MATERIALS AND METHODS: Subjects were 206 cases seen during office hours and during after-hours emergency care by the department of Urology at the Kinki University Hospital for acute urinary retention for the 12-year-period from April 1993 to April 2005. RESULTS: By gender, the 206 cases of acute urinary retention included 175 men (85%) and 31 women (15%). The ratio of men to women was 5.6:1, with a markedly larger number of male cases. Ages of the 206 cases overall were distributed from 6 to 93 years old and the mean age was 66 years old. In male cases, the mean age was 69.6 years old while in female cases it was 46.3 years old. With regard to the cause, bladder outlet obstruction (BOO) accounted for 123 (70.3%) of the 175 male cases; benign prostatic hyperplasia (BPH) was noted in 92 cases and accounted for 52.6%of the total. Detrusor Weakness (DW) was noted in 35 cases (20%). DW was most prevalent in women, being noted in 20 cases (64.5%). With regard to treatment, in male cases surgery was performed for BOO in 69 (56%) of 123 cases; surgery was performed for BPH in 56 (60.8%) of 92 cases, drug therapy was used in 19 cases, and 3 cases were observed. In female cases, 10 cases were able to urinate on their own through treatment of the causative disorder. With regard to outcome, ultimately a total of 139 cases (67.5%), 125 men and 14 women, were able to urinate on their own. CONCLUSIONS: 1. 85% of acute urinary retention cases were men. Of these, 70% were caused by some form of BOO. DW due to a cause other than obstruction accounted for about 70% of the remaining 30%. 2. Overall, 70% of cases were able to urinate on their own after treatment while 30% required catheterization. 3. After the cause of BOO was eliminated, cases were likely to be able to urinate on their own; CIC (clean intermittent catheterization) was frequently used in treatment of causes other than BOO. 4.15% of acute urinary retention cases were women.
• [Left renal pelvic tumor 32 years after calyco-ileo-vesiconeostomy]., Miho Kaneko, Seiji Matsumoto, Koichi Sugimoto, Shigeya Uejima, Hirotsugu Uemura, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 52(11), 871 - 3, Nov. 2006 , Refereed
  Summary:This is a case report of left renal pelvic tumor found 32 years after left calico-ileo-vesiconeostomy. The patient has undergone right nephrectomy for absence of renal function at 26 years-old and left urinary reconstruction was performed using the intestine for pyelo-ureteral junction obstruction at 28 years old because of bilateral congenital hydronephrosis. Later he was treated for recurrent left renal stone with percutaneous nephrolithotripsy, nephrolithotomy and extracorporeal shock wave lithotripsy. When he was 56 years old, macrohematuria appeared. He received left nephrectomy under the diagnosis of left renal pelvic tumor.
• Creatol, an oxidative product of creatinine in kidney transplant patients, as a useful determinant of renal function: A preliminary study, S. Matsumoto, T. Hanai, T. Matsuura, H. Uemura, T. Nishioka, T. Akiyama, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 38(7), 2009 - 2011, Sep. 2006
  Summary:Creatol (CTL, 5-hydroxycreatinine) is a creatinine (Cr) oxidative metabolite, which was originally isolated from the urine of patients with chronic renal failure, representing a candidate for a uremic toxin. The effectiveness of CTL as an indicator of oxidative stress after kidney transplantation has not been reported. Therefore, we examined the relation between the change in oxidative stress (using CTL) in renal transplant patients and their change in renal function (using Cr). The serum Cr and serum and urine CTL were examined in five renal transplant patients. Serum CTL closely correlated with serum Cr. Serum CTL also correlated with urine CTL, but in some cases there was a time lag. Both the ratio of CTL/(Cr) and serum CTL observed in patient 2 were slow to improve after transplantation. The process through which oxidative stress was reduced was shown by the index of renal damage correlated with kidney function oxidative stress (using serum CTL) after transplantation. Our data suggested that CTL/Cr may be a good indicator of graft prognosis.
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• Can monitoring of serum 8-OHdG level for 2 hours after renal transplantation predict prognosis of the graft?, S. Matsumoto, T. Hanai, T. Matsuura, H. Uemura, T. Nishioka, T. Akiyama, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 38(7), 2014 - 2015, Sep. 2006
  Summary:8-Hydroxy-2'-deoxyguanosine (8-OHdG) is an oxidant of deoxyguanosine, a base in the construction of DNA. We examined the extent of DNA damage to the graft through oxidative stress after renal transplantation. Seven renal transplant patients were enrolled in this study. Before reperfusion of the grafts, the level of serum 8-OHdG was measured using enzyme-linked immunosorbent assay. No relationship was found between the level of serum 8-OHdG just before reperfusion and the postoperative course. In all cases, the level of serum 8-OHdG increased after reperfusion and decreased within 2 hours. In six cases, it remained almost the same as the preoperative level. A faster rate of decrease from the first peak of serum 8-OHdG was associated with a lower nadir serum creatinine and reduced occurrence of acute rejection. This study suggested that immediate calming of the oxidative stress following reperfusion may potentially have a positive influence on graft prognosis. In addition, biomarkers of oxidative stress may predict graft prognosis.
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• Experience with laparoscopic splenectomy for ABO-incompatible living renal transplantation without plasmapheresis, T. Hayashi, H. Tahara, Y. Hara, T. Ishii, H. Uernura, TRANSPLANTATION PROCEEDINGS, TRANSPLANTATION PROCEEDINGS, 38(7), 1985 - 1986, Sep. 2006
  Summary:A 25-year-old male, blood type A, was admitted to our hospital for renal transplantation from his father of AB blood type. Before transplant, we performed laparoscopic splenectomy. The serum anti-B antibody titer fell from 1:8 to 1:2. Therefore, plasmapheresis was not performed. The total ischemic time was 80 minutes. Five immunosuppressive agents, including tacrolimus, mycophenolate mofetil, prednisolone, basiliximab, and deoxyspergualine, were administered in the initial period. On the 47th day, value of cytomegalovirus antibody, which was routinely measured, became positive. Hence, we administered ganciclovir, with a fall in antibody. Sixty-five days after transplant, he was discharged with a serum creatinine of 1.0 mg/dL. We concluded that it was possible to perform ABO-incompatible renal transplantation with no need for plasmapheresis or rituximab.
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• Oxalate ions and calcium oxalate crystal-induced up-regulation of osteopontin and monocyte chemoattractant protein-1 in renal fibroblasts., Tohru Umekawa, Masanori Iguchi, Hirotsugu Uemura, Saeed R Khan, BJU international, BJU international, 98(3), 656 - 60, Sep. 2006 , Refereed
  Summary:OBJECTIVE: To examine the responses of renal fibroblasts to high oxalate (Ox) and calcium Ox (CaOx) crystals, as the latter are found in the renal interstitium of patients with primary or enteric hyperoxaluria, and in animals with experimental CaOx nephrolithiasis, and are associated with tubulointerstitial inflammation (TI). TI might begin with the production of chemoattractants by the renal epithelial cells exposed to high Ox and/or CaOx crystals; as Ox levels are also high in the renal interstitium and crystal deposition in nephrolithiasis might start in the interstitium, we hypothesized that renal fibroblasts might also be involved in the development of TI. MATERIALS AND METHODS: We exposed renal fibroblast cells of line NRK 49F in vitro to Ox ions (500 micromol/L) or CaOx monohydrate crystals (67 microg/cm(2)). We assessed the production of osteopontin and monocyte chemoattractant protein-1 (MCP-1), and expression of their mRNA, in the cells. We also determined the cellular malondialdehyde content as a marker of reactive oxygen species (ROS)-induced lipid peroxidation, and Trypan blue staining and the release of lactate dehydrogenase as markers of injury. RESULTS: Similar to renal epithelial cells, renal fibroblasts were stimulated by exposure to Ox and CaOx crystals. They showed signs of injury and ROS-induced lipid peroxidation. The mRNA expression and production of osteopontin and MCP-1 increased significantly. CONCLUSIONS: These results indicate that fibroblasts respond to high Ox and CaOx crystals by up-regulating specific pathways producing pro-inflammatory conditions. Migration of monocytes/macrophages to sites of interstitial crystal deposits can lead to localized interstitial inflammation and fibrosis.
• Propiverine hydrochloride improved correlatively subjective QOL and objective findings in Japanese patients with urinary frequency and/or incontinence, Kazumi Noguchi, Takuya Yamagishi, Kotaro Suzuki, Keiichi Kondo, Takeshi Kishida, Kazuo Saito, Yuki Sekiguchi, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Masaki Kawai, Kazuto Okajima, Kazuki Kobayashi, Masatoshi Moriyama, Yuzo Kinoshita, Kunihisa Mikata, Kazuo Kitami, Mitsunobu Masuda, Ryuichi Saito, Tetsuo Murai, Takeshi Tomoda, Sumio Noguchi, Naoki Sakai, Atsushi Hamano, Sakae Nomura, Kazuhiko Sato, Acta Urologica Japonica, Acta Urologica Japonica, 52(5), 343 - 348, May 2006 , Refereed
  Summary:To investigate how urinary frequency and incontinence affect the patient's subjective quality of life (QOL) and whether an improvement in objective findings by medical treatment affects his/her subjective QOL, a voiding diary using the King's Health Questionnaire (KHQ) and International Consultation on Incontinence Questionnaire-Short Form (ICIQ-SF) was delivered to patients with urinary frequency and/or incontinence before and after treatment with propiverine hydrochloride for 8 weeks. Sixty-eight patients completed the diary and the questionnaires. Objective symptoms decreased significantly with respect to the mean frequency of urination and to the mean incidence of urinary incontinence. The KHQ and ICIQ-SF scores improved significantly with respect to all domains except personal relationships in the KHQ. In the KHQ, furthermore, a significant correlation was found between decreased incidence of urinary incontinence and improvement in role limitations and between decreased incidence of urinary incontinence and improvement in emotional problems. In the ICIQ-SF, a significant correlation was found between decreased incidence of urinary frequency and subjective improvement in quantity of leakage, between decreased incidence of urinary frequency and improvement in subjective QOL scores, between decreased incidence of urinary frequency and improvement in the total ICIQ-SF score, and between decreased incidence of urinary incontinence and improvement in subjective QOL scores. Thirty-two episodes of adverse reactions were observed. None of them were serious. These results suggest that an improvement in objective symptoms with propiverine hydrochloride favorably improves subjective QOL of the patient, and provide further evidence about the safety and efficacy of propiverine hydrochloride.
• A phase I trial of vaccination of CA9-derived peptides for HLA-A24-positive patients with cytokine-refractory metastatic renal cell carcinoma, H Uemura, K Fujimoto, M Tanaka, M Yoshikawa, Y Hirao, S Uejima, K Yoshikawa, K Itoh, CLINICAL CANCER RESEARCH, CLINICAL CANCER RESEARCH, 12(6), 1768 - 1775, Mar. 2006
  Summary:Purpose: A phase I peptide vaccination trial was done in patients with progressive cytokine-refractory metastatic renal cell carcinoma (RCC) to assess both the toxicity and capability to induce immune responses of three peptides (CA9p219-227, p288-296, and p323-331) derived from CA9, a tumor-associated antigen ubiquitously expressed in RCC. Experimental Design: Twenty-three patients positive for human leukocyte antigen (HLA) -A24 with histologically confirmed RCC were enrolled. Eligibility included progressive disease after standard cytokine therapy with interleukin-2 and/or IFN-alpha. Patients were vaccinated s.c. with the three peptides emulsified in incomplete Freund's adjuvant at 2-week intervals. Pre- and post-vaccination blood samples were obtained for toxicity assessment and immunologic studies. Patients were monitored for clinical responses on a 3-monthly basis. Results: Vaccinations were well tolerated without any major adverse event. Most of the patients developed peptide-specific CTLs and/or immunoglobulin G reactive to the peptides after the 6th or 9th vaccination, followed by a gradual increase in both CTL frequency and levels of peptide-reactive serum IgG. Three patients with multiple lung metastases showed partial responses with disappearance and shrinking of metastatic lesions. Additionally, stable disease for >6 months was observed in six patients (median duration, 12.2 months). Moreover, the median survival time of all patients who were progressive at trial enrollment after failing immunotherapy was 21.0 months (5-35 months). Conclusions: These results suggest that vaccination of these peptides is safe and recommended for further trials for HLA-A24-positive metastatic RCC patients.
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• A case of salvage combination chemotherapy of gemcitabine plus nedaplatin for squamous cell carcinoma of the ureter, Susumu Umemoto, Yasuhide Miyoshi, Yumiko Yokomizo, Shinpei Sugiura, Kazuhide Makiyama, Noboru Nakaigawa, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 52(1), 35 - 39, Jan. 2006 , Refereed
  Summary:A 46-year-old man complained of lower abdominal pain, and his abdominal and pelvic computed tomographic scan revealed left hydronephrosis and a huge tumor (9 × 9 cm) in the left distal ureter involving the left iliac vessel that was considered unresectable. Histological diagnosis showed squamous cell carcinoma, and histoculture drug response assay (HDRA) suggested the effectiveness of gemcitabine and nedaplatin. A cycle of adjuvant chemotherapy consisting of MEG (methotrexate 30 mg/m 2: day 1 and 15, epirubicin 50 mg/m 2: day 1, and cisplatin 50 mg/m 2: day 2 and 3) was performed as a first line chemotherapy, but the size of the ureteral tumor did not change. He was treated with 3 cycles of systematic combination chemotherapy consisting of gemcitabine (1,000 mg/m 2: day 1 and 8) and nedaplatin (80 mg/m 2: day 1). After 2 courses of chemotherapy, the tumor size was reduced by 50% (PR RECIST guidelines) and the tumor markers (SCC, CYFRA, NSE, CEA, and CA19-9) dropped to within the normal range. There were no serious adverse events except for grade 3 neutropenia which spontaneously recovered. However, because the tumor size was not reduced after the third cycle of chemotherapy, we applied external beam radiation to the primary lesion and the metastatic retroperitoneal lymph node site. No evidence of residual tumor progression has been found for 6 months after radiation therapy. We concluded that GN chemotherapy may be useful for patients with squamous cell carcinoma of the ureter.
• [Pharmacological evaluation of efficacy and safety of propiverine hydrochloride in patients of overactive bladder--relationship between urodynamic observation and propiverine pharmacokinetics--]., Takahide Sugiyama, Nobutaka Shimizu, Kiyoshi Hashimoto, Nobuhiro Yoshioka, Tadashi Hanai, Seiji Matsumoto, Hirotsugu Uemura, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, 96(7), 670 - 7, Nov. 2005 , Refereed
  Summary:PURPOSE: The clinical benefit of propiverine hydrochloride against overactive bladder was evaluated, and the relationships between urinary voiding functions and the pharmacokinetics were investigated by means of clinical pharmacology with PK/PD approach. PATIENTS AND METHODS: Total 7 patients suffering urgency with urinary frequency and incontinence received propiverine hydrochloride in doses of 10 mg qd or 20 mg qd for 4 weeks, and then the doses were switched in cross-over manner to continue the treatment for further 4 weeks. The urodynamic measurements as well as pharmacokinetic samplings were done before the medication, 4 weeks and 8 weeks after the starting medication, to examine the dose-response and concentration-response relationships. RESULTS: The volume at first desire to void increased according to dose increased, and the volume at first involuntary contraction tended to increase according to both dose and drug concentration in plasma. However, no apparent dose-response relationships were observed for maximum urinary flow rate and the detrusor pressure at the maximum urinary flow rate. The PK/PD analysis using Emax model suggested that, approximately 75 ng/mL of the propiverine concentration in plasma allowed the increase in the volume at first involuntary contraction for 50%. The urinary residual volume increased in dose-dependent manner only in the patients with severe grade of lower urinary tract obstruction, but scarcely increased in the patients with moderate grade or below. CONCLUSION: Propiverine hydrochloride improved the urinary voiding functions with a tendency to depend on both dose and concentration in plasma. After the administration of propiverine hydrochloride, the concentration in plasma will immediately reach the level at which the drug can increase in the volume at first involuntary contraction for 50%, and then the concentration level will sustain the effect ranging from 10% to 50% increase in bladder volume. Furthermore, the lower urinary tract obstruction will be a predictor of increase in urinary residual volume.
• Two cases of testicular tumors with high α-fetoprotein levels: A case report, Makoto Funahashi, Futoshi Tuchiya, Kazuhide Makiyama, Shinpei Sugiura, Yasuhide Miyoshi, Takeshi Kishida, Takehiko Ogawa, Hiroji Uemura, Masahiro Yao, Yoshinobu Kubota, Acta Urologica Japonica, Acta Urologica Japonica, 51(2), 133 - 137, Feb. 2005 , Refereed
  Summary:Two patients with testicular tumors whose serum α-fetoprotein (AFP) persisted to show an abnormally high concentration are reported. Case 1 : A 42-year-old male who had been suffering from chronic hepatitis, underwent left high orchiectomy for a left testicular tumor in 1998. Diagnosis was an authentic stage I seminoma. In 2002, chemotherapy was performed for a metastatic seminoma revealed as a solitary mass in the mediastinum by radiographic studies, and histologically confirmed to be a metastatic seminoma. Although lymph nodes were gradually reduced in size, the serum AFP and transaminase levels remained at an abnormally high concentration. The subfraction profile with lens culinaris hemagglutinin (LCA) revealed elevation of only peak 1 which implied that the chronic hepatitis was due to liver dysfunction. After a 10-month follow-up the levels of both AFP and transaminase decreased, and the patient was disease-free. Case 2: In 2002, a 30-year-old male underwent left high orchiectomy for a left testicular tumor, and histological examination revealed seminoma, immature and mature teratoma, embryonal carcinoma. The serum AFP was elevated to 45 ng/ml. Diagnosis was authentic stage I. After 2 courses of chemotherapy, the serum AFP remained at an abnormally high concentration. However, there were no new lesions. The serum AFP level was not elevated in any of the family members. The subfraction profile with LCA revealed elevation of only peak 1, which implied that there were no viable lesions. After a 24-month follow-up AFP was about 20 ng/ml and the patient was disease-free.
• [A case of intrapelvic retroperitoneal ganglioneuroma]., Mitsuhiro Tambo, Kiyohide Fujimoto, Takeshi Inoue, Motoyoshi Tanaka, Akihide Hirayama, Hirotsugu Uemura, Katsunori Yoshida, Yoshihiko Hirao, Kunio Ichijima, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, Nihon Hinyokika Gakkai zasshi. The japanese journal of urology, 95(7), 809 - 12, Nov. 2004 , Refereed
  Summary:A 61-year-old man presented with an asymptomatic intrapelvic retrovesical tumor, measuring 8.5 cm in maximum diameter, which was revealed by preoperative diagnostic imaging for transverse colon cancer. When he was referred to our department one year after hemi-colectomy, this tumor showed no change in size, but there was some suspicion of concomitant malignancy because of large tumor size and contrast enhancement in a region adherent to the right seminal vesicle. En-bloc resection of the tumor along with the right seminal vesicle was performed retroperitoneally. The tumor was diagnosed histopathologically as retroperitoneal ganglioneuroma. Herein, we report this rare case of intrapelvic retroperitoneal ganglioneuroma, and present a brief review of the relevant literature including the present case.
• Brain metastases from urachal carcinoma., Takanobu Kaido, Hirotsugu Uemura, Yoshihiko Hirao, Ryunosuke Uranishi, Noriyuki Nishi, Toshisuke Sakaki, Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia, 10(6), 703 - 5, Nov. 2003 , Refereed
  Summary:We present a case of brain metastases of the urachal carcinoma, which is extremely rare and malignant. Contrast-enhanced MRI was employed to detect them. A large mass was removed surgically and 4 other small metastases were treated by gamma knife radiosurgery. Six weeks after radiosurgery, the 4 lesions had disappeared on MRI. We emphasise the importance of early diagnosis using MRI and treatment by radiosurgery for this rare condition.
• Induction of antigen specific cellular immunity by vaccination with peptides from MN/CA IX in renal cell carcinoma, K Shimizu, H Uemura, M Yoshikawa, K Yoshida, Y Hirao, K Iwashima, S Saga, K Yoshikawa, ONCOLOGY REPORTS, ONCOLOGY REPORTS, 10(5), 1307 - 1311, Sep. 2003 , Refereed
  Summary:We investigated the induction of the specific immunity for renal cell carcinomas (RCC) using MN/CA IX, a tumor-associated antigen frequently expressed in RCC. We have generated 9-mer peptide derived from MN/CA IX and examined the antigenicity as a vaccine to induce specific immunity for RCC. To use mouse syngeneic system, we transfected human MN/CA9 cDNA into RenCa and BALB-3T3 cells originally from BALB/c mouse, and established MN/CA IX expressing mouse cell lines, i.e., MN-RenCa and MN-3T3. The immunization of BALB/c mouse with MN-RenCa cells resulted in the induction of cytotoxic T lymphocytes (CTL) against MN/CA IX expressing cells and the CTL clone was established from bulked CTL. This CTL clone specifically lyzed MN-3T3 cells, but not parental cells. To identify the targeted epitope binding to H=2K(d) antigen, three 9-mer peptides (A, B, C-peptide) of human MN/CA IX compatible with the H-2K(d) as well as HLA-A24 binding motif was synthesized. The cloned CTL targeted the B-peptide pulsed BALB-3T3 cells as well as MN-3T3 cells. Furthermore, spleen cells from BALB/c mouse immunized with B-peptide reacted against MN-RenCa cells. These results suggest that the peptides derived from MN/CA IX containing HLA-A24 binding motif may be useful as a potent tumor vaccine for the treatment of human RCC, and in mouse models.
• Detection of circulating MN/CA9 positive renal cell carcinoma cells during operationl, H Uemura, Y Nakagawa, A Iwai, E Okajima, E Okajima, K Yoshikawa, Y Hirao, AKTUELLE UROLOGIE, AKTUELLE UROLOGIE, 34(4), 270 - 272, Jul. 2003
  Summary:Our previous study demonstrated the clear detection of MN/CA9 mRNA in peripheral blood samples from RCC patients. However, approximately 30% of control blood samples from healthy volunteers showed MN/CA9 expression. We have developed a new primer set and optimized the PCR conditions, now resulting in a specificity of 100%. In tissue samples, all clear cell type carcinomas but none of the spindle cell type and pleomorphic cell type tumors expressed the MN/CA9 message. Analysis of MN/CA9 messages in peripheral blood samples from RCC patients gave positive results for 0/2, 1/9, 0/4 and 4/12 of stage I, II, III and IV cases, respectively. RT-PCR analysis using preoperative renal venous blood samples resulted in clear detection of MN/CA9 positive cells in 2/4, 3/13, 2/6 and 1/1 of stage I, II, III and IV cases, respectively. Our results suggest that assessment of MN/CA9 expression by RT-PCR is a promising method for detecting cancer cells in the circulation of patients with RCC.
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• Expression of cyclooxygenase-2 in primary superficial bladder cancer tissue may predict risk of its recurrence after complete transurethral resection, E. Okajima, H. Uemura, S. Ohnishi, M. Tanaka, M. Ohta, M. Tani, K. Fujimoto, S. Ozono, E. Okajima, Yoshihiko Hirao, Aktuelle Urologie, Aktuelle Urologie, 34(4), 256 - 258, Jul. 2003 , Refereed
  Summary:A new modality is necessary to prevent recurrence of superficial bladder cancer after complete transurethral resection (TUR) because of the high recurrence rate even with current prophylaxis protocols. Prostaglandins (PGs) are known to be produced more in transitional cell carcinoma, and etiologically bladder cancer risk is negatively associated with the intake of non-steroidal anti-inflammatory drugs (NSAIDs), which inhibit cyclooxygenase (COX), the rate-limiting enzyme of the PG production. We have shown the chemopreventive effect of piroxicam, an NSAID, on the N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN)-induced rat bladder cancer model. To avoid gastrointestinal side effects of regular NSAIDs, we also showed the chemopreventive effect of nimesulide, a selective inhibitor of the second isoform of COX, COX-2, which does not affect COX-1 house-keeping activity in gastrointestinal mucosa on the same model. We also observed induction of COX-2 protein in the rat bladder tumor. In this study, we screened COX-2 protein expression in primary superficial bladder cancer tissues, to elucidate if COX-2 selective inhibitors can be a candidate chemopreventive agent for bladder cancer recurrence. Five and 6 samples of superficial bladder cancer cases with and without recurrence after complete TUR were examined by immunohistochemical analysis. We found more COX-2 protein positive samples in the cases with recurrence than in cases without recurrence. Even though the number of cases examined is small, this result supports our hypothesis that COX-2 contributes to superficial bladder cancer recurrence, thus, selective COX-2 inhibitors can be a candidate chemopreventive agent for the recurrence.
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• [Clinical significance for detection of circulating cancer cells in renal cell carcinoma]., Hirotsugu Uemura, Yoshihiko Hirao, Gan to kagaku ryoho. Cancer & chemotherapy, Gan to kagaku ryoho. Cancer & chemotherapy, 29(10), 1712 - 8, Oct. 2002 , Refereed
  Summary:Renal cell carcinoma has a very poor prognosis since various therapeutic modalities other than radical operation are not effective. Early detection and treatment are of considerable importance to cure the patients; however, early diagnosis of renal cell carcinoma is not easy because no specific tumor marker, like PSA for prostate cancer, is available. MN/CA9 is considered to be one of the carbonic anhydrase isoenzymes, and is expressed in approximately 90% of renal cell carcinomas. Expression of MN/CA9 in normal tissues is very limited. Using optimal RT-PCR with specific primers, MN/CA9 positive cells were clearly detected in the blood. The sensitivity and specificity were found to be approximately 40% and 90% respectively. The detection of circulating renal cell carcinoma cells using RT-PCR for MN/CA9 mRNA is useful for diagnosis of the presence of renal cell carcinomas. This RT-PCR assay may also be able to provide information with which to predict the prognosis of the patients.
• Serum neopterin monitoring and vitamin E-modified, regenerated hemodialyzer membrane influence on biocompatibility., Katsunori Yoshida, Takanori Kitauchi, Shouki Kimura, Tatsuo Yoneda, Hirotsugu Uemura, Seiichirou Ozono, Yoshihiko Hirao, Artificial organs, Artificial organs, 26(1), 54 - 7, Jan. 2002 , Refereed
  Summary:The exposure of blood to hemodialysis membranes results in numerous phenomena and/or complications in hemodialyzed patients, which have an influence on the quality of life (QOL) of those patients. A vitamin E-modified regenerated cellulose membrane (E-membrane) was developed to act as a scavenger for reactive oxygen species causing complications in hemodialysis patients. Neopterin (NEOP) is a metabolite derived from guanosine triphosphate with the production and release of NEOP being induced in monocytes and macrophages by cytokines such as interferon-gamma (IFN-gamma). Serum neopterin levels are shown to be a reactive marker of bioincompatibility of dialysis membranes in hemodialysis patients. The following report evaluates the usefulness of serum NEOP as a marker for the biocompatibility of the E-membrane hemodialyzer in a clinical study. In the clinical study, where extracorporeal ultrafiltration strategies with E-membranes were employed, the serum levels of NEOP were lower than those in patients using cellulose triacetate membranes (C-membranes). In the long-term evaluation of the biocompatibility of E- and C-membranes, the increase of serum neopterin levels in the C-membrane was higher than those in the E-membrane. In conclusion, the evaluation of serum neopterin levels during hemodialysis shows that the E-membrane has a good biocompatibility in hemodialyzed patients.
• Aberrations of the p14(ARF) and p161(INK4a) genes in renal cell carcinomas, Y Kawada, M Nakamura, E Ishida, K Shimada, E Oosterwijk, H Uemura, Y Hirao, KS Chul, N Konishi, JAPANESE JOURNAL OF CANCER RESEARCH, JAPANESE JOURNAL OF CANCER RESEARCH, 92(12), 1293 - 1299, Dec. 2001 , Refereed
  Summary:The INK4a/ARF locus on chromosome 9p21, which encodes two distinct genes, p14(ARF) and p16(INK4a), is frequently altered in human neoplasms. To investigate the potential roles of p14ARF and p16(INK4a) genes in human renal cell carcinomas (RCCs), we analyzed 6 human RCC cell lines and 91 primary RCCs for homozygous deletion, promoter hypermethylation and expression of the p14(ARF) and p16(INK4a) gene products using differential PCR, methylation-specific PCR, and immunohistochemistry, respectively. Five cell lines showed homozygous co-deletion of both genes and one demonstrated promoter hypermethylation of the p16(INK4a) gene only. Eight of 91 RCCs showed aberrations of p14(ARF) or p16(INK4a) status and six of these featured gross extension into the renal vein. The results suggest that p14(ARF) and p16(INK4a) aberrations may play roles in the relatively late stage of renal tumorigenesis associated with tumor progression.
• Hypomethylation of the MN/CA9 promoter and upregulated MN/CA9 expression in human renal cell carcinoma, M Cho, H Uemura, SC Kim, Y Kawada, K Yoshida, Y Hirao, N Konishi, S Saga, K Yoshikawa, BRITISH JOURNAL OF CANCER, BRITISH JOURNAL OF CANCER, 85(4), 563 - 567, Aug. 2001 , Refereed
  Summary:MN/CA9 is a cancer-related gene, frequently activated in human renal cell carcinomas (RCCs). To reveal the activation mechanism, we investigated the relationship between methylation status of the MN/CA9 promoter region and gene expression using 13 human RCCs, and examined the effect of in vitro CpG methylation on the MN/CA9 promoter activity using a human RCC cell line (SK-RC-44), expressing MN/CA9. MN/CA9 expression was evaluated by RT-PCR and observed in 10 of 13 RCCs (77%). A total of 9 out of 10 MN/CA9-positive RCCs (90%) contained clear cell components. Methylation status of 6 CpGs in the MN/CA9 promoter region was decided by using the bisulfite genomic sequencing protocol. Out of 13 RCCs 9 (69%) showed partial hypomethylation of the CpG at -74 bp, while the other 4 RCCs and 3 normal kidney tissue samples showed complete methylation. Hypomethylation of the CpG at -74 bp was strongly correlated with MN/CA9 expression. Luciferase assay revealed that the MN/CA9 promoter activity was strongly suppressed by methylation of the CpG at -74 bp. These findings suggest that hypomethylation of the CpG at -74 bp in the MN/CA9 promoter region might play an important role in this gene activation of human RCC. (C) 2001 Cancer Research Campaign http://www.bjcancer.com.
• PTEN/MMAC1/TEP1 mutations in human primary renal-cell carcinomas and renal carcinoma cell lines, Kei-Ichi Kondo, Masahiro Yao, Kazuki Kobayashi, Shinsuke Ota, Minoru Yoshida, Shigeki Kaneko, Masaya Baba, Naoki Sakai, Takeshi Kishida, Satoshi Kawakami, Hiroji Uemura, Yoji Nagashima, Yukio Nakatani, Masahiko Hosaka, International Journal of Cancer, International Journal of Cancer, 91(2), 219 - 224, Jan. 15 2001 , Refereed
  Summary:Extensive allelotyping studies have implicated several tumor-suppressor loci on chromosomes 3p, 5q, 6q, 8p, 9pq, 10q, 11q, 14q, 17p, 18q and 19p in human kidney tumorigenesis. The PTEN (also called MMACI and TEPI) gene, a candidate tumor suppressor located at chromosome 10q23.3, is mutated in a variety of sporadic malignancies as well as in patients with Cowden disease. To investigate the potential role of the PTEN gene in renal tumorigenesis, we searched for abnormalities of the gene in 68 primary renal-cell carcinomas (RCCs) as well as in 17 renal carcinoma-derived cell lines, using DNA-SSCP, sequencing and microsatellite analysis. Five of 68 (7.5%) primary RCCs exhibited intragenic mutations (3 missense, 1 deletion and 1 splice-site), and 1 of 17 (5.9%) cell lines had an insertion mutation. Loss of heterozygosity of the PTEN gene occurred in 25% of primary RCCs, including the 3 cases with intragenic mutation and the 1 PTEN-mutated cell line. Clinical and histopathological examinations revealed that 4 of the 5 primary tumors with PTEN mutation were high-grade, advanced clear-cell RCCs with distant metastases or renal vein tumor invasions, resulting in poor prognostic courses. The other was a low-stage papillary/chromophilic RCC. Our data suggest that PTEN mutation is observed in a subset of RCCs and that, especially in clear-cell RCCs, it occurs as a late-stage event and may contribute to the invasive and/or metastatic tumor pheno-type. © 2001 Wiley-Liss, Inc.
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• Expression of MN antigen in urologic cancer: Potential tool as a therapeutic target, H Uemura, Y Nakagawa, Y Hirao, E Okajima, K Yoshikawa, E Oosterwijk, AKTUELLE UROLOGIE, AKTUELLE UROLOGIE, 31, 52 - 54, Sep. 2000 , Refereed
  Summary:In the present study, we investigated MN/G250 expression with immunohistochemistry and RT-PCR in urologic cancers. in addition, we applied PCR technology to detect circulating MN/G250-positive cells in patient blood samples. Frozen specimens of 92 RCC, 54 bladder carcinoma (BT) 42 prostate carcinoma (PCa), and 19 germ cell tumor (GCT) were studied by immunohistochemistry with MAbG250 as well as RT-PCR analysis with primers derived from cDNA sequence of MN/G250 antigen, in RCC, 81 of 92 (88%) specimens showed strong and homogeneous MN/G250 expression, in accordance with our previous studies. PCR analysis resulted in clear detection of WIN mRNA signals in 86 RCC (93%), more than protein lever. All 81 positive staining RCC showed MN/CA9 gene expression. No correlation between MNG250 expression and tumor stage was observed, however, tumor grade significantly correlated with MN expression, i.e., high grade tumors showed the decrease of MN expression (5/16, only 31 %). in BT, 21 of 54 (39 %) primary tumors showed MN expression. Comparing to RCC, immunostaining pattern of BT demonstrated heterogeneous and weak. MN expression in BT appeared to correlate with tumor grade, i.e., low grade and papillary tumor had positive immunoreactivity with MAbG250 but not in high grade, invasive cases. In contrast, no MN expression was observed in PCa, GCT specimens and other normal tissues. For molecular detection of circulating cancer cells, one third of blood samples from RCC patients demonstrated MN/G250 mRNA. Our findings suggest that MN/G250 antigen may be potential target molecule in RCC.
• Aortic calcification index (ACI): A parameter to predict renal function following nephrectomy; A preliminary reports, Y Hirao, M Yoshi, S Tsujimoto, H Uemura, K Yoshida, S Ozono, E Okajima, AKTUELLE UROLOGIE, AKTUELLE UROLOGIE, 31, 2 - 3, Sep. 2000 , Refereed
• Activation of the MN/CA9 gene is associated with hypomethylation carcinoma cell lines, M Cho, K Grabmaier, Y Kitahori, Y Hiasa, Y Nakagawa, H Uemura, Y Hirao, T Ohnishi, K Yoshikawa, E Ooesterwijk, MOLECULAR CARCINOGENESIS, MOLECULAR CARCINOGENESIS, 27(3), 184 - 189, Mar. 2000 , Refereed
  Summary:The MN/CA9 (G250) gene expressed in the normal alimentary tract in a tissue-specific manner is often activated in renal cell carcinomas. To cast light on the activation mechanism, we examined the methylation status of this gene in seven human renal cell carcinoma cell lines (SKRC-01, -06, -10, -12, -14, -44, and -59) and three normal kidney tissue samples by using the bisulfite genomic sequencing protocol. CpG methylation was measured at seven locations in the MN/CA9 5' region. MN/CA9 transcripts were detected by reverse transcription-polymerase chain reaction in five of the renal cell carcinoma cell lines (SKRC-01, -06, -10, -44, and -59). These MN/CA9 positive cell lines showed hypomethylation, whereas the remaining two cell lines (SKRC-12, and -14), and three normal kidney tissue samples without transcripts demonstrated hypermethylation. Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in activation of the MN/CA9 gene in the negative cell lines (SKRC-12 and -14). These data suggest that hypomethylation in the 5' region may have a major role in expression of the MN/CA9 gene in renal cell carcinoma cells. Mol. Carcinog. 27:184-189, 2000. (C) 2000 Wiley-Liss, Inc.
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• MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas, H Uemura, Y Nakagawa, K Yoshida, S Saga, K Yoshikawa, Y Hirao, E Oosterwijk, BRITISH JOURNAL OF CANCER, BRITISH JOURNAL OF CANCER, 81(4), 741 - 746, Oct. 1999
  Summary:The monoclonal antibody G250 (mAbG250) raised against a human renal cell carcinoma (RCC) has been shown to react with a large number of RCCs. Recently G250 antigen was isolated and found to be homologous to the MN/CA9 gene originally identified in HeLa cells. To determine whether G250 antigen (MN/CA IX/G250) could be a potential therapeutic target and a tumour marker, a total of 147 cases of RCC were investigated immunohistochemically as well as by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, total RNAs extracted from patients' peripheral blood samples were analysed for MN/CA9/G250 mRNA signals. Immunohistochemistry demonstrated strong expression in 128/147 (87.1%) of RCCs, in contrast to the lack of expression observed in normal tissues. RT-PGR analyses of frozen specimens resulted in the clear detection of MN/CA9/G250 mRNA signals in 137/147 (93.2%), and despite subtle differences the results were almost identical to those for immunohistochemistry. Although high-grade and -stage tumours exhibited significantly lower expression than low-grade and -stage tumours, a large proportion of tumours expressed MN/G250 protein as well as mRNA. RT-PCR analysis of patients' blood samples revealed the presence of circulating MN/CA9/G250 expressing cells. These findings suggest that this antigen may be a potential therapeutic target as well as diagnostic marker for RCCs. (C) 1999 Cancer Research Campaign.
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• Immunohistochemical analysis of Midkine expression in human prostate carcinoma, Noboru Konishi, Mitsutoshi Nakamura, Shingo Nakaoka, Yoshio Hiasa, Masaki Cho, Hirotsugu Uemura, Yoshihiko Hirao, Takashi Muramatsu, Kenji Kadomatsu, Oncology, Oncology, 57(3), 253 - 257, Oct. 1999 , Refereed
  Summary:Midkine (MK) is a growth/differentiation factor frequently expressed at high levels in some types of human malignancies. To investigate whether MK is a useful marker in prostate carcinogenesis, immunohistochemical analysis was performed on samples of both latent and clinical prostate cancers of various stages, as well as on specimens of normal gland and prostatic intraepithelial neoplasia (PIN). Of the 80 clinical cancers examined, 69 specimens (86.3%) were immunoreactive for MK, with metastatic lesions generally showing higher expression than the corresponding primaries normal prostate tissues were negative or showed only weak staining. Midkine was also detected in 12 of 15 latent cancers (80%) and in 12 of 16 cases of PIN (75%). In sections of whole prostate, MK showed variable expression through tumorous sections, probably in reflection of heterogeneous cell populations. The results demonstrate the possible value of MK as a marker for early and latent disease, as well as for more advanced clinical stages of prostate cancer.
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• MN/CA IX/G250 as a potential target for immunotherapy of renal cell carcinomas, H Uemura, Y Nakagawa, K Yoshida, S Saga, K Yoshikawa, Y Hirao, E Oosterwijk, BRITISH JOURNAL OF CANCER, BRITISH JOURNAL OF CANCER, 81(4), 741 - 746, Oct. 1999 , Refereed
  Summary:The monoclonal antibody G250 (mAbG250) raised against a human renal cell carcinoma (RCC) has been shown to react with a large number of RCCs. Recently G250 antigen was isolated and found to be homologous to the MN/CA9 gene originally identified in HeLa cells. To determine whether G250 antigen (MN/CA IX/G250) could be a potential therapeutic target and a tumour marker, a total of 147 cases of RCC were investigated immunohistochemically as well as by reverse transcriptase polymerase chain reaction (RT-PCR) analysis. In addition, total RNAs extracted from patients' peripheral blood samples were analysed for MN/CA9/G250 mRNA signals. Immunohistochemistry demonstrated strong expression in 128/147 (87.1%) of RCCs, in contrast to the lack of expression observed in normal tissues. RT-PGR analyses of frozen specimens resulted in the clear detection of MN/CA9/G250 mRNA signals in 137/147 (93.2%), and despite subtle differences the results were almost identical to those for immunohistochemistry. Although high-grade and -stage tumours exhibited significantly lower expression than low-grade and -stage tumours, a large proportion of tumours expressed MN/G250 protein as well as mRNA. RT-PCR analysis of patients' blood samples revealed the presence of circulating MN/CA9/G250 expressing cells. These findings suggest that this antigen may be a potential therapeutic target as well as diagnostic marker for RCCs. (C) 1999 Cancer Research Campaign.
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• E-cadherin and alpha-, beta- and gamma-catenin expression in prostate cancers: correlation with tumour invasion, N Morita, H Uemura, K Tsumatani, M Cho, Y Hirao, E Okajima, N Konishi, Y Hiasa, BRITISH JOURNAL OF CANCER, BRITISH JOURNAL OF CANCER, 79(11-12), 1879 - 1883, Apr. 1999 , Refereed
  Summary:The E-cadherin-catenin complex plays an important role in establishing and maintaining intercellular connections and morphogenesis and reduced expression of its constituent molecules is associated with invasion and metastasis. in the present study, we examined E-cadherin and alpha-, beta- and gamma-catenin levels in tumour tissues obtained by radical prostatectomy in order to investigate the relationship with histopathological tumour invasion. Immunohistochemical findings for 45 prostate cancer specimens demonstrated aberrant expression of each molecule to be associated with dedifferentiation and, in addition, alteration of staining patterns for the three types of catenin was significantly correlated with capsular but not lymphatic or vascular invasion. The data thus suggest that three types of catenin may be useful predictive markers for biological aggressiveness of prostate cancer.
• Expression of pepsinogen II with androgen and estrogen receptors in human prostate carcinoma, Noboru Konishi, Shingo Nakaoka, Kyoichi Matsumoto, Mitsutoshi Nakamura, Shin-Ichi Kuwashima, Yoshio Hiasa, Masaki Cho, Hirotsugu Uemura, Yoshihiko Hirao, Pathology International, Pathology International, 49(3), 203 - 207, 1999 , Refereed
  Summary:The expression of pepsinogen II (PG II), an aspartyl proteinase usually involved in the digestion of proteins in the stomach, was immunohistochemically investigated in conjunction with androgen (AR) and estrogen receptor (ER) status in prostate adenocarcinomas. Of a total of 38 samples obtained from radical prostatectomies, 23 tumors (60.5%) were positive for PG II and there was a significant positive correlation to the expression of AR but not to ER. Cells positive for PG II were localized mainly to the peripheral zones of tumorous glands which, in normal prostate, are negative, and in areas also expressing AR. In addition, a significant correlation between AR and ER was detected in the prostate carcinomas examined, which suggests a hormone-dependent status. On the basis of these results, PG II expression might be closely related to hormonal alterations associated with the development of prostate tumors.
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• Genomic aberrations in renal cell carcinomas detected by restriction landmark genomic scanning, M Cho, N Konishi, K Yamamoto, T Inui, Y Kitahori, Y Nakagawa, H Uemura, Y Hirao, Y Hiasa, EUROPEAN JOURNAL OF CANCER, EUROPEAN JOURNAL OF CANCER, 34(13), 2112 - 2118, Dec. 1998 , Refereed
  Summary:In order to reveal and characterise genetic events occurring in renal tumorigenesis, samples of sporadic renal cell carcinomas (RCCs) were examined using restriction landmark genomic scanning (RLGS), an electrophoretic separation technique which detects gene amplification and deletion. We were able to find two fragments frequently amplified and 10 others commonly showing reduced signal intensity within the 16 tumour samples analysed. These altered spots were located on chromosomes 2, 3, 9-12, 16, 17 and 18 according to chromosomal assigned RLGS;. A subset of reduced fragments appeared to be correlated to tumour type and were located within a new chromosomal region, suggesting genetic specificity within the process of renal carcinogenesis. (C) 1998 Elsevier Science Ltd. All rights reserved.
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• Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13, Y Nakagawa, H Uemura, Y Hirao, K Yoshida, S Saga, K Yoshikawa, GENOMICS, GENOMICS, 53(1), 118 - 119, Oct. 1998 , Refereed
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• Detection of DNA amplification in human renal cell carcinoma cell lines using restriction landmark genomic scanning, M Cho, N Konishi, Y Kitahori, Y Hiasa, YI Nakagawa, H Uemura, Y Hirao, E Oosterwijk, CELLULAR AND MOLECULAR BIOLOGY, CELLULAR AND MOLECULAR BIOLOGY, 44(6), 913 - 918, Sep. 1998 , Refereed
  Summary:Gene amplification, which has often been observed in various human cancers, appears to be associated with the development and progression of malignant phenotypes. However, in renal cell carcinoma (RCC), conventional analytic methods requiring specific primers and probes have revealed infrequent amplification of known oncogenes. We attempted to determine if gene amplification was truly uncommon in RCC. The genomic DNAs extracted from 5 human RCC cell lines were examined by restriction landmark genomic scanning (RLGS), a two-dimensional gel analysis which allows evaluation of approximately 2,000 radiolabelled DNA fragments. By this method, we detected 24 distinct spots commonly amplified in at least 2 RCC cell lines compared to normal kidneys. Comparing the present results with chromosomal assigned-RLGS, approximately one half of these DNA fragments proved to be located on chromosome 2, 5 or 7. Our data suggest that amplification of unknown genes is likely to occur in RCC cell lines.
• A histopathological mapping study of the urinary bladder tumors induced by N-butyl-N(4-hydroxybutyl)nitrosamine in dogs, Eigoro Okajima, Seiichiro Ozono, Katsunori Yoshida, Shoji Samma, Hitoshi Momose, Akio Iwai, Hirotsugu Uemura, Shoichi Tabata, Kenichi Tsumatani, Yoshihiko Hirao, Kunihiko Tsunemi, Urological Research, Urological Research, 25(5), 315 - 323, Oct. 1997 , Refereed
  Summary:Bladder tumors were induced by N-butyl-N(4-hydroxybutyl)nitrosamine (BBN) in five Beagles and four mongrel dogs. The tumors were observed for long periods and the tumor progression was traced using histopathological mapping. The results indicated (1) that low-dose BBN over a long period induced multiple low-grade (G1-2) and low-stage (pTa-1) papillary tumors, resembling superficial bladder cancer in humans (2) that high-dose BBN over a short period induced high-grade (G2-3) and high-stage (pT3b) nonpapillary tumors and carcinoma in situ (CIS) resembling invasive cancer and CIS in humans (3) that beagle dogs required longer periods and higher total doses of BBN as compared with mongrel dogs (4) that the tumors induced by low- dose BBN in beagles were observed without BBN as long as the animals lived, and neither increasing numbers of tumors nor malignant features such as deep infiltration and metastasis was observed and (5) that low-dose BBN seems to induce mild dysplasia, which is followed by Brunn's nest-like proliferation in the lamina propria and nodular change, eventually leading to the development of papillary noninvasive transitional cell carcinoma (TCC) and that high-dose BBN seems to induce severe dysplasia which leads to CIS and nonpapillary invasive TCC. These results may contribute to clarifying the natural history of human bladder cancer.
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• Experimental model of renal tumors in polycystic kidneys: Effects of long-term 2-amino-4,5-diphenylthiazole administration in rats treated with N-ethyl-N-hydroxyethylnitrosamine, K Tsumatani, Y Nakagawa, Y Kitahori, N Konishi, H Uemura, S Ozono, Y Hirao, E Okajima, K Hirao, Y Hiasa, TOXICOLOGIC PATHOLOGY, TOXICOLOGIC PATHOLOGY, 25(4), 363 - 371, Jul. 1997 , Refereed
  Summary:We previously reported that treatment of Fischer-344 rats with 2-amino-4,5-diphenylthiazole (DPT) results in renal cystic changes. The present study was undertaken to examine the effects of long-term DPT treatment after initiation of kidney carcinogenesis with N-ethyl-N-hydroxyethylnitrosoamine (EHEN) in Wistar rats. One hundred forty-four 6-wk-old male Wistar rats were divided into 6 equal receiving groups: 1000 ppm EHEN or normal tap water for 2 wk followed by 1.06% DPT or basal diet for the subsequent 14 or 30 wk. Controls were maintained without treatment throughout. Subgroups of 6 animals from each group were sacrificed after 8, 16, 24, and 32 wk for histopathological assessment of lesion development in the kidneys and liver. Animals treated with DPT first developed cystic changes of the kidneys (primarily at the corticomedullary border) after 8 wk of treatment, and these changes progressed with time thereafter. In the groups in which DPT treatment was discontinued after 14 wk, cysts then gradually decreased in size. All tumors detected in the kidneys were histopathologically diagnosed as renal cell adenomas. The tumor multiplicity after 32 wk of treatment was significantly higher in Group I, receiving EHEN + DPT for 30 wk (6.33 +/- 4.36), and Group III, receiving EHEN + DPT for 14 wk (3.83 +/- 1.57), than in Group V, EHEN alone (1.00 +/- 0.58) (p < 0.05). Renal cell tumors within cysts were only seen in Groups I and III. The general bromodeoxyuridine labeling indices for the kidneys at week 32 were significantly higher in Group I (55.94 +/- 21.08 cells/mm(2)) and Group III (53.75 +/- 12.38 cells/mm(2)) than in Group V (22.38 +/- 6.98 cells/mm(2)) (p < 0.05). In conclusion, DPT caused cystic changes in rat kidneys, which, however, gradually decreased in size after the treatment was discontinued, suggesting a reversible nature. DPT clearly also promotes renal tumor development after EHEN initiation, and this effect persists, to a certain extent, even after the insult is removed.
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• Telomerase activity in primary prostate cancer, Yi Lin, Hiroji Uemura, Kiyoshi Fujinami, Masahiko Hosaka, Masaoki Harada, Yoshinobu Kubota, Journal of Urology, Journal of Urology, 157(3), 1161 - 1165, 1997 , Refereed
  Summary:Purpose: Telomerase activity has been detected in a wide variety of human tumor types. We analyzed the telomerase activity in association with the acquisition of prostate cancer. Materials and Methods: Telomerase activity in prostate tissues was examined by PCR-based telomeric repeat amplification protocol (TRAP) assay. Results: Among 31 primary prostate cancers, 28 tissue samples (90%) displayed telomerase activity. The relative level of telomerase activity was associated with the pathological differentiation. High levels of telomerase activity were more frequently detected in poorly differentiated prostate cancer. None of the 10 samples taken from prostates with benign prostatic hyperplasia (BPH) or normal prostates expressed telomerase activity. In another 10 BPH samples obtained from prostate tissue adjacent to cancerous tissue, one of 10 samples (10%) showed weak telomerase activity. Furthermore, we investigated this activity in human prostate cancer cell lines (PC-3, LNCaP, and DU145) and all showed very high activity compared to normal human tissue samples. Four lymph nodes and one bone metastasis also exhibited extremely high telomerase activity. Conclusions: The present results indicate that telomerase activity might be a marker for detecting malignancy of the prostate and evaluating the malignant potential of prostate cancer.
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• Non-ischemic enucleation of small renal cell carcinoma using microwave tissue coagulator, Y Hirao, H Uemura, K Fujimoto, K Yoshida, S Ozono, E Okajima, AKTUELLE UROLOGIE, AKTUELLE UROLOGIE, 27, 17 - 19, Apr. 1996 , Refereed
  Summary:Non-ischemic enucleation of small renal cell carcinoma using microwave tissue coagulator was performed on 13 kidneys of 12 patients (average 64.2 years old) at Nara Medical University Hospital and its affiliated hospitals between September 1993 and June 1995. The indication for nephron-sparing surgery were elective in 8 cases and imperative in 5 kidneys of 4 cases. The renal cell carcinoma size was on average 36.8 mm (20-50 mm). The demarcation line, 7-10 mm apart from the tumor margin, was defined under ultrasonography, and was coagulated at every 8-10 mm interval along the demarcation line with the microwave monopolar antenna needle. The renal tumor was excised along the middle of coagulated zone with scissors and blunt dissection. The operation time was on average 174.2 minutes, and perioperative bleeding was average 249.5 ml, excluding case 2 who underwent partial hepatectomy for metastatic rectal cancer simultaneously. No major complication was encountered. Local recurrence and severe impairment of the remaining kidney were not observed in all cases at the median 9.6 months of follow-up. In situ non-ischemic tumor enucleation using microwave tissue coagulator constitutes a simple, reliable, and less invasive alternative to ordinary nephron-sparing surgery, and is indicated for small asymptomatic renal cell carcinoma.
• Effects of Long Term Administration of 2-Amino-4,5-Diphenylthiazole on Kidneys in Rats and N-Ethyl-N-Hydroxyethylnitrosamine-Treated Rats, Kenichi Tsumatani, Seiichiro Ozono, Hirotsugu Uemura, Hisako Yamaguchi, Yoshihiko Hirao, Yoshihiro Motomiya, Eigoro Okajima, Yoshiteru Kitahori, Yoshio Hiasa, Hiroaki Okabe, Yoshinori Uji, Journal of Toxicologic Pathology, Journal of Toxicologic Pathology, 9(2), 151 - 159, 1996 , Refereed
  Summary:Changes in the kidneys were studied histopathologically and biochemically in F344 rats treated for long periods with 2-amino-4, 5-diphenylthiazole (DPT), with and without prior application of the renal carcinogen N-ethyl-N-hydroxyethylnitrosamine (EHEN).Experiment I: A total of 45 male 6-week-old F344 rats were divided into two groups one receiving DPT at 1.06% in the diet (n=30) and the other being untreated (n=15). The observation period was 52 weeks. DPT caused cystic changes in the corticomedullary border, which were seen from the 4th week, progressed with time. Urine osmolarity began to decrease from the 6th week, however no biochemical signs of renal failure were noted before the 32nd week. High-performance liquid chromatography (HPLC) revealed 6 fractions, representing metabolites of DPT, in urine from DPT-treated rats. Experiment II: A total of 132 male 6-week-old F344 rats were divided into four groups: Group 1 (2-weeks 1,000 ppm EHEN treatment followed by 1.06% DPT treatment), Group 2 (1.06% DPT treatment), Group 3 (2-weeks 1,000 ppm EHEN treatment), and Group 4 (untreated controls). They were observed for 60 weeks. Cystic changes in the kidneys, as seen in Experiment I, were noted in Groups 1 and 2. Preneoplastic changes were seen only in Group 1, at incidences of 20% and 75% at weeks 48 and 60, respectively. Adenomas were seen in Groups 1 and 3, at incidences of 20% and 0%, and 25% and 20% at weeks 48 and 60, respectively. A carcinoma was diagnosed in 1 (20%) of the 5 rats from Group 1 in the 48th week. These results suggest that the DPT-treated rat can serve as a valid experimental model of congenital cystic kidney disease and chronic renal failure, and that DPT may promote EHEN-induced renal carcinogenesis. © 1996, JAPANESE SOCIETY OF TOXICOLOGIC PATHOLOGY. All rights reserved.
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• Induction of tumor regression by passive transfer of antibody from mice vaccinated with anti-idiotype antibodies resembling a human renal cell carcinoma-associated antigen, Hirotsugu Uemura, Eigoro Okajima, Frans M.J. Debruyne, Egbert Oosterwijk, Urologic Oncology: Seminars and Original Investigations, Urologic Oncology: Seminars and Original Investigations, 1(2), 73 - 79, 1995 , Refereed
  Summary:We have shown that six different internal image antiidiotype antibodies (Ab2) raised against the combining site of the murine monoclonal antibody G250 (MAbG250 Abl), which specifically reacts with a human renal cell carcinoma (RCC)-associated antigen, induce antigen specific humoral and cellular responses in mice. These six Ab2 can be divided into four mutually exclusive groups: (1) NUH31 and NUH51, (2) NUH44 and NUH82, (3) NUH71, and (4) NUH91. Immunization with NUH82 or NUH91 resulted in Ab3 sera that gave complete protection against tumor challenge. In this study, we tested the antitumor efficacy of NUH82- and NUH91-induced mouse sera (Ab3 sera Ab3-82 and Ab3-91) in mice with established subcutaneous human RCC xenografts. Mice were treated 3 times per week by intraperitoneal injection of Ab3 sera (0.2 ml) or MAbG250 (250 μg) for 6 weeks. Treatment of NU12 human RCC xenografts of approximately 20 mm3 expressed as tumor size index (TSI) with NUH-Ab3 sera or MAbG250 resulted in significant tumor growth inhibition compared with tumors treated with Ab3 sera from mice immunized with control immunoglobulin (Ab3-MOPC). In all Ab3-NUH treated mice, tumors stabilized or disappeared completely. In contrast, Ab3-MOPC treatment did not result in any antitumor effects. Tumor remnants in Ab3-NUH treated animals contained viable tumor cells surrounded by infiltrating mouse cells, whereas no infiltration was observed in control tumors. These findings demonstrate that Ab3 sera obtained from NUH82- or NUH91-immunized mice are very effective in eradicating established RCC [i.e., Ab2 vaccination may be able to eradicate (minimal) residual disease in RCC patients]. © 1995.
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• IMMUNIZATION WITH ANTIIDIOTYPE MONOCLONAL-ANTIBODIES BEARING THE INTERNAL IMAGE OF THE RENAL-CELL CARCINOMA-ASSOCIATED ANTIGEN G250 INDUCES SPECIFIC CELLULAR IMMUNE-RESPONSES, H UEMURA, E OKAJIMA, FMJ DEBRUYNE, E OOSTERWIJK, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF CANCER, 59(6), 802 - 807, Dec. 1994 , Refereed
  Summary:We have previously isolated and characterized 6 anti-idiotype antibodies (Ab2s) directed against monoclonal antibody G250 (MAbG250) which reacts with a tumor-associated antigen (TAA) expressed in a large proportion of human renal-cell carcinomas (RCC). These 6 Ab2s (NUH31, 51, 71, 82, 91: IgG(1), NUH44: IgG(2a)) showed MAbG250 binding site specificity and induction of anti-TAA antibody resembling MAbG250 (so-called Ab1') in rabbits, indicating that they are internal image antibodies. To investigate whether these Ab2s could induce G250-TAA-specific cell-mediated immunity, delayed-type hypersensitivity (DTH) tests were carried out with G250 antigen-positive and/or -negative cells in the ears of BALB/c mice. Mice primed with Ab2 showed antigen-specific DM responses, whereas no significant DTH response was observed with G250-negative cells. This antigen-specific DTH could be transferred to naive mice by lymphocytes harvested from Ab2-sensitized mice. In addition to the classical DTH responses observed 24 and 48 hr after tumor challenge, an early-phase antigen-specific hypersensitivity response was seen 2 hr after challenge. This early component of the specific hypersensitivity reaction but not the classical DTH could be transferred to naive mice by serum from Ab2-sensitized mice, indicating that the early reaction was due to serum factors. These findings demonstrate that all AbZs induced tumor-specific cellular immune responses directed against human RCC, and suggest that they may be useful as RCC-TAA surrogates, i.e., as tumor vaccines for RCC patients. (C) 1994 Wiley-Liss, Inc.
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• VACCINATION WITH ANTIIDIOTYPE ANTIBODIES MIMICKING A RENAL-CELL CARCINOMA-ASSOCIATED ANTIGEN INDUCES TUMOR-IMMUNITY, H UEMURA, AJMC BENIERS, E OKAJIMA, FMJ DEBRUYNE, E OOSTERWIJK, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF CANCER, 58(4), 555 - 561, Aug. 1994 , Refereed
  Summary:We have previously isolated and characterized 6 different internal image mouse monoclonal anti-idiotype antibodies (Ab2) directed against the paratope of mouse monoclonal antibody G250 (MAbG250, Ab1), which specifically reacts with human renal cell carcinoma (RCC). These Ab2s (NUH31, 44, 51, 71, 82 and 91) demonstrated specificity for the combining site of Ab1, and appeared to recognize 2 partly overlapping idiotopes on Ab1. In this study. we further characterize the fine specificity of the Ab2, investigate whether the immunogenicity of Ab2 could be enhanced by conjugation to a carrier and investigate the anti-tumor efficacy of Ab3 sera in mice challenged with RCC. Immunization of animals with Ab2 conjugated to keyhole limpet hemocyanin as carrier protein resulted in a 2-fold increase in antigen-specific anti-anti-idiotype antibodies (Ab3) as compared with immunization using Ab2 alone. Specific reactivity was observed with antigen-positive cell lysates, and all Ab3 sera contained immunoglobulin resembling Ab1 (Ab1'), as shown by competitive Ab1-antigen binding assays. Fine-specificity studies of Ab3 sera revealed that the Ab2s can be divided into 4 mutually exclusive groups, showing that the 6 Ab2s recognize 4 slightly different idiotopes in the Ab1 binding pocket. Treatment of RCC-challenged mice with Ab3 sera resulted in significant tumor growth inhibition and lower tumor take rates as compared with control groups. Ab3 sera obtained from NUH-91-immunized animals showed superior characteristics as compared to the other Ab3 sera: no tumors remained after 5 weeks of Ab3-NUH91 treatment. Our findings indicate that the Ab2 elicit powerful anti-tumor effects in immune-competent animals. (C) 1994 Wiley-Liss, Inc.
  DOI
• DNA Polymerase β Gene Mutation in Human Prostate Cancer, Yasushi Dobashi, Taro Shuin, Hiromichi Tsuruga, Hiroji Uemura, Soichiro Torigoe, Yoshinobu Kubota, Cancer Research, Cancer Research, 54(11), 2827 - 2829, Jun. 01 1994 , Refereed
  Summary:DNA polymerase β is a nuclear protein essential to DNA repair in mammalian cells. A high frequency of mutations in this gene has been reported in colorectal cancers. To clarify the tumorigenesis steps of human prostate cancers in the molecular basis, we examined the entire coding region of the human DNA polymerase β gene in human prostate cancer tissues using polymerase chain reaction, single-strand conformational polymorphism analysis of RNA, and sequencing analysis. Consequently, we detected DNA polymerase 0 gene mutations in 2 of 12 cases (17%). The first case is an A to G transition at nucleotide 893, resulting in a substitution of the amino add from tyrosine to cysteine. In the second case, we found an A to G transition at nucleotide 305, a T deletion at nucleotide 569, and an A insertion into the 6 repeats of A from nucleotide 612 to 617. This T deletion shifted the subsequent reading frame and resulted in the premature termination at codon 163 instead of 336. The two cases were advanced grade and stage. Present results suggest that polymerase 0 gene mutations, although they occurred at relatively low frequency, are involved in certain cases of human prostate carcinogenesis. © 1994, American Association for Cancer Research. All rights reserved.
• INTERNAL IMAGE ANTIIDIOTYPE ANTIBODIES RELATED TO RENAL-CELL CARCINOMA-ASSOCIATED ANTIGEN G250, H UEMURA, E OKAJIMA, FMJ DEBRUYNE, E OOSTERWIJK, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF CANCER, 56(4), 609 - 614, Feb. 1994 , Refereed
  Summary:The potential usefulness of internal-image anti-idiotype antibodies (Ab2s) in modulating hosts' immune responses to tumor-associated antigen (TAA) have stimulated considerable interest in the development and characterization of Ab2s. Six different mouse monoclonal Ab2s (NUH31, 44, 51, 71, 82 and 91) were generated against murine monoclonal antibody G250 (MAbG250) which recognizes a human renal-cell carcinoma-associated antigen. All 6 Ab2s showed specificity for the MAbG250 paratope in Western-blot analysis. In inhibition assays, all Ab2s were able to compete with the nominal antigen, albeit with differing efficiency. Based on cross-blocking studies for idiotope mapping, the Ab2s could be divided into 2 groups (group I; NUH31, 51, 71, group 2; NUH44, 82, 91). However, cross-reactivity between these 2 groups was observed, indicating that they recognized partly overlapping epitopes on the paratope of MAbG250. Sera from rabbits immunized with Ab2s showed reactivity with G250 antigen-positive cell lysates, but not with antigen-negative cell lysates. Additional studies revealed that all Ab2s were able to induce anti-anti-idiotype antibodies resembling MAbG250 (Ab 1'). These findings suggest that the Ab2s functionally mimic the original G250 antigen and may be of use in the immunotherapy of human renal-cell carcinoma. (C) 1994 Wiley-Liss, Inc.
  DOI
• A case report of synchronous triple cancer resected simultaneously, Eijiro Okajima, Seiichiro Ozono, Junichi Nagayoshi, Hirotsugu Uemura, Yoshihiko Hirao, Yoshiyuki Nakajima, Hiroshige Nakano, Masumi Yoshida, Masahito Sugimura, Eigoro Okajima, Japanese Journal of Clinical Oncology, Japanese Journal of Clinical Oncology, 24(3), 166 - 170, 1994 , Refereed
  Summary:We report a unique case of a patient with synchronous renal cell carcinoma, hepatocellular carcinoma and squamous cell carcinoma of the oral floor. All three tumors were resected during a single operation. The patient was a 75-year-old man with masses in the liver and right kidney discovered by ultrasound examination during a routine checkup. Further examination also revealed a squamous cell carcinoma of the oral floor. The patient underwent a simultaneous radical nephrectomy, enucleation of the liver tumor and resection of the tumor of the oral floor. The diagnoses were histopathologically confirmed. The number of patients with multiple cancers has recently been increasing. The possibility of a second or third malignant lesion should be considered, not only in patients with a known malignancy but also in those without malignancy. The importance of screening procedures in the early detection of malignancy before the appearance of clinical symptoms should be emphasized. © 1994 Oxford University Press.
  DOI
• THERAPEUTIC EFFECTS OF MONOCLONAL-ANTIBODY G250, INTERFERONS AND TUMOR-NECROSIS-FACTOR, IN MICE WITH RENAL-CELL CARCINOMA XENOGRAFTS, J VANDIJK, H UEMURA, AJMC BENIERS, WP PEELEN, ST ZEGVELD, GJ FLEUREN, SO WARNAAR, E OOSTERWIJK, INTERNATIONAL JOURNAL OF CANCER, INTERNATIONAL JOURNAL OF CANCER, 56(2), 262 - 268, Jan. 1994 , Refereed
  Summary:Because renal-cell carcinoma (RCC) is considered relatively resistant to radio- and chemotherapy, RCC patients may benefit from new treatment modalities, e.g. immunotherapy. In vitro and in vivo studies suggest that combinations of cytokines such as interferon gamma or interferon alpha (IFN-gamma, IFN-alpha) and tumor necrosis factor alpha (TNF-alpha) may act synergistically. In this study we tested whether a monoclonal antibody (MAb) G250, reactive with a RCC-associated antigen, showed anti-tumor effects in vivo in nude mice with established s.c. human RCC xenografts, and also whether this MAb could enhance the anti-tumor effect of combinations of IFNs and TNF-alpha. Treatment with combinations of IFN-alpha/TNF-alpha or IFN-gamma/TNF-alpha, or with MAb G250 alone, resulted in a significant inhibition of tumor growth. Treatment with MAb G250, in combination with IFN-gamma/TNF-alpha, did not result in an improve anti-tumor effect as compared to that of either treatment alone. In contrast, MAb G250 combined with IFN-alpha/TNF-alpha resulted in a significantly enhanced anti-tumor response. In one experiment, 3 out of 10 mice showed complete tumor regression, with no recurrence after 90 days. Large numbers of infiltrating macrophages were found surrounding viable and necrotic tumor tissue after treatment with G250 combined with IFN-alpha/TNF-alpha. These results suggest that combination therapy, consisting of IFN-alpha, TNF-alpha and MAbs, may have therapeutic value in the treatment of RCC. (C) 1994 Wiley-Liss, Inc.
  DOI
• A pathological study of incidental carcinoma of the prostate. Pathological study of age-groups, H. Uemura, K. Fujimoto, C. Kawasaki, H. Fujii, Y. Kinoshita, M. Hosaka, T. Miura, I. Kondo, M. Harada, S. Fukushima, K. Miyai, E. Ishizuka, H. Fukuoka, K. Sasaki, Japanese Journal of Urology, Japanese Journal of Urology, 83(1), 48 - 52, 1992 , Refereed
  DOI
• TUMOR THROMBUS AND MICROVASCULAR INVASION AS PROGNOSTIC FACTORS IN RENAL-CELL CARCINOMA, S SAMMA, K YOSHIDA, S OZONO, S OHARA, Y HAYASHI, S TABATA, H UEMURA, A IWAI, A HIRAYAMA, Y HIRAO, E OKAJIMA, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 21(5), 340 - 345, Oct. 1991 , Refereed
  Summary:The significance of two types of vascular invasion (macroscopic tumor thrombus into the renal vein or vena cava inferior and microvascular invasion) as prognostic factors in renal cell carcinoma is analyzed in 121 patients treated at the Department of Urology, Nara Medical University. The data indicate there to be close correlations between tumor thrombus, microvascular invasion and distant metastasis. In patients with tumor thrombus, however, the prognosis is not as poor when surgical removal of the tumor thrombus is successfully performed as when it is not. In contrast, the prognosis of patients with positive microvascular invasion is significantly worse than that of those with a negative finding. Microvascular invasion appears to be a significant prognostic factor in renal cell carcinoma in addition to well-known factors such as tumor stage, tumor grade, tumor thrombus and distant metastasis. To detect microvascular invasion, the histological examination should be extended to give as much detail as possible.
• Prostate Cancer: Retrospective Study of Long-Term Follow-up Cases Is it Possible to Discontinue Hormonal Medications?, Hiroji Uemura, Yoshiaki Satomi, Toshimichi Sugawara, Toyoaki Yamaguchi, Takeshi Kishida, Katsuo Ishibashi, Masaoki Harada, Japanese Journal of Urology, Japanese Journal of Urology, 82(2), 260 - 267, 1991 , Refereed
  Summary:We reviewed retrospectively the medical records of 70 patients treated for prostate cancer who were followed for more than 10 years or until they died. All patients were treated by hormonal therapy and 54 of 70 patients (77 per cent) were combined with castration. Of 70 patients 10 (14.3 per cent) are alive now with an average follow up for 180.5 months. Of 60 patients with stage A and B only 3 died of the tumor. Of 56 patients with stage C and D, 10 and 18 patients died of the tumor, respectively. From the point of pathology, none of the patients with well differentiated adenocarcinoma died of the tumor. And in patients with stage A and B, pathologically well and moderately differentiated adenocarcinoma, there were no cancer death. On the other hand, a group of patients of poorly differentiated adenocarcinoma had a poor prognosis. In cases with well differentiated adenocarcinoma who discontinued hormonal medication (diethylstibestrol diphosphate) no patients died of the tumor. From these observations we consider that, after long term hormonal medication, we can stop the hormonal medication for patients who have no positive prostate biopsy results for 4 years with well differentiated adenocarcinoma of stage A and B. © 1991, THE JAPANESE UROLOGICAL ASSOCIATION. All rights reserved.
  DOI
• Rapid induction of carcinoma in situ in dog urinary bladder by sequential treatment with N-methyl-N'-nitrosourea and N-butyl-N-(4-hydroxybutyl)-nitrosamine, S. Samma, H. Uemura, S. Tabata, A. Iwai, F. Nakatsuji, H. Matsuki, K. Babaya, Y. Hirao, E. Okajima, Gann, The Japanese Journal of Cancer Research, Gann, The Japanese Journal of Cancer Research, 75(5), 385 - 387, 1984 , Refereed
  Summary:A highly atypical intraepithelial proliferation, which was interpreted as carcinoma in situ, developed in the urinary bladder of 2 beagle dogs after repeated intravesical instillations of N-methyl-N'-nitrosourea followed by oral administration of N-butyl-N-(4-hydroxybutyl)nitrosamine. The latent period was 37 weeks. The technique may provide a useful model to study the natural history of bladder cancer, particularly carcinoma in situ.

Books etc

• Anti-idiotype antibodies resembling the renal cell carcinoma-associated antiggen development. in Idiotypes in Medicine. Autoimmunity, UEMURA Hirotsugu, Infection and Cancer, Elsevier Science,   1997
  Summary:Uemura H and Oosterwjik E.
• Tools for vaccination and immunotherapy; (internal image anti-idiotype antibodies resembling the renal cell carcinoma-associated antigen development). in ;Complementary Research on Renal Cell Carcinoma, UEMURA Hirotsugu, Springer-Verlag,   1995
  Summary:Uemura H, Oosterwjik E, Deburyne FMJ.

Conference Activities & Talks

• New therapies for kidney cancer, 植村 天受, C2 Retreat 2011,   2011 11 , C2 Retreat 2011
• Use of prostate-specific PTEN conditional knockout mice in prostate cancer prevention and intervention research, 植村 天受, 田中 基幹, 小池 浩之, 山本 豊, 畑中 祐二, 王 一, 清水 信貴, 野澤 昌弘, 吉村 一宏, 西尾 和人, デベラスコ マルコ アントニオ, 第70回日本癌学会総会,   2011 10 , 第70回日本癌学会総会
• Lumican expression prostate cancer, 植村 天受, デベラスコ マルコ アントニオ, 畑中 祐二, 山本 豊, 田中 基幹, 清水 信貴, 児玉 光正, 荒尾 徳三, 西尾 和人, 医学部泌尿器科学教室, 第70回日本癌学会学術総会,   2011 10 , 第70回日本癌学会学術総会
• Systemic transduction of p16 INK4A anti-tumor peptide inhibits growth of mbt-2 bladder tumor cell line graft in mice, 植村 天受, Tsukuba, Aichi, Hitachi, Tsukuba, Nasushiobara, Nagoya, AUA Annual Meeting,   2011 05 , AUA Annual Meeting
• A phase I trial of vegfr1 peptide vaccines for patients with metastatic renal cell carcinoma, 植村 天受, デベラスコ マルコ アントニオ, 吉村 一宏, 野澤 昌弘, 南 高文, AUA Auual Meeting,   2011 05 , AUA Auual Meeting
• Sorafenib inhibits tumor development and growth in a transgenic mouse model of prostate cancer, 植村 天受, 畑中 祐二, 泉 あやか, 岡崎 絵莉奈, 土井 万貴子, 田中 基幹, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 西尾 和人, デベラスコ マルコ アントニオ, 102nd Auual Meeting AACR,   2011 04 , 102nd Auual Meeting AACR
• Experience sharing for sequential use of targeted agents and AE management in mRCC, 植村 天受, Asia-Pacific Uro-Oncology Summit 2011,   2011 01 , Asia-Pacific Uro-Oncology Summit 2011
• Anti-cancer effect of zoledronic acid in prostate cancer, 植村 天受, Asia-Pacific Uro-Oncology Summit 2011,   2011 01 , Asia-Pacific Uro-Oncology Summit 2011
• Breast and renal cell carcinomas; Improving outcomes by targeting shared signaling pathways., 植村 天受, 浜松オンコロジーセンター, San Camillo Forlanini, 第48回日本癌治療学会学術集会,   2010 10 , 第48回日本癌治療学会学術集会
• Systemic transduction of p16INK4A anti-tumor peptide inhibits growth of MBT-2 bladder tumor cell line graft in mice, 植村 天受, 筑波大学医学部泌尿器科学, 愛知医科大学臨床試験センター, 日立総合病院泌尿器科, 筑波大学医学部泌尿器科学, 第69回日本癌学会学術総会,   2010 09 , 第69回日本癌学会学術総会
• The inhibitory effect of renal stone formation by osteopontin siRNA transfection, 辻 秀憲, 清水 信貴, 梅川 徹, 植村 天受, 第98回日本泌尿器科学会総会,   2010 04 , 第98回日本泌尿器科学会総会
  Summary:【目的】オステオポンチン(OPN)は尿路結石形成に対して重要な働きをもつが、その作用はin vitroでは多機能性を有する。今回、結石形成ラット腎にin vivo OPNsiRNA transfectionを行い、結石形成への影響をみた。【方法】target sequenceは、5’AAGGCGCATTACAGCAAACAC3’(5’167―185 3’)。A:コントロール群, B:1.5％エチレングリコール（EG）投与群, C:ラットの尾静脈よりリポフェクションにてOPNsiRNAをtransfectionさせた群, D:腎被膜下にAteloGeneTMを用いてOPNsiRNAを注入した群 を作成。C,D群は1週毎の投与で、3週目に摘出腎のOPN mRNA/OPNタンパク質レベルをリアルタイムPCRにより測定した。尿細管内の結晶沈着と腎組織のカルシウム含有量を原子吸光分析で計測した。【結果・考察】OPNの発現はmRNAで＆＆蛋白で＆＆＆。尿細管内の結晶沈着はC,D群で有意な減少を認めた。カルシウム含有量はB群:0.143±0.036,C群:0.077±0.003,D群:0.065±0.021でOPNsiRNA transfection群では有意に減少した。OPNはin vivoで全体としては結石形成に促進的に作用
• Use of nesr infrared fluorescence imaging to determine tumor burden in genetically engineered mice, 植村 天受, デベラスコ マルコ アントニオ, 西尾 和人, 愛知医科大学臨床試験センター, 中外製薬, 近畿大学農学部, 近畿大学農学部, 近畿大学農学部, 101th Annunal Meeting of the American for Cancer Research,   2010 04 , 101th Annunal Meeting of the American for Cancer Research
• The effects of whole body hyperthermia on tumor growth by a novel far infrared emitter, 植村 天受, デベラスコ マルコ, アントニオ, 近畿大学農学部, 近畿大学農学部, 近畿大学農学部, 愛知医科大学臨床試験センター, 101st Annual Meeting of American for Cancer Research,   2010 04 , 101st Annual Meeting of American for Cancer Research
• Asian experience with the use of novel agents for the treatement of mRCC, 植村 天受, 8th Asia Pacific Oncology Summit,   2010 03 , 8th Asia Pacific Oncology Summit
• A phase II study of VEGFR1 peptide vaccines for metastatic renal cell carcinoma, 植村 天受, デベラスコ マルコ アントニオ, 野澤 昌弘, 南 高文, 吉村 一宏, 2010 ASCO-GU,   2010 03 , 2010 ASCO-GU
• A phase I/II study of personalized peptide vaccination therapy for castration resistant prostate cancer, 植村 天受, 南 高文, デベラスコ マルコ アントニオ, 上島 成也, 奈良県立医科大学泌尿器科, 奈良県立医科大学泌尿器科, 久留米大学免疫学, URS 25th Annual Meeting,   2009 08 , URS 25th Annual Meeting
• Insights into treatment efficacy in Japanese patients with metastatic renal cell carcinoma, 植村 天受, 24th Annual EAU Congress,   2009 03 , 24th Annual EAU Congress
• A phase II study of carbonic anhydrase 9 peptide vaccines with interferon-alfa in advanced renal cell carcinoma, 植村 天受, 上島 成也, 田中 基幹, 南 高文, 2009 Genitourinary Cancers Symposium,   2009 02 , 2009 Genitourinary Cancers Symposium
• A phase II study of the efficacy and safety of sunitinib in Japanese patients with metastatic renal cell carcinoma (mRCC), 植村 天受, 北海道大学医学部泌尿器科, 九州大学医学部泌尿器科, 筑波大学医学部泌尿器科, Urological Research Society,   2008 09 , Urological Research Society
• Using targeted treatments: case discussions, 植村 天受, 5th Asia Pacific Urology Summit,   2008 08 , 5th Asia Pacific Urology Summit
• Phase I/II study of individualized peptide vaccines for HLA-A2/A24 positive patients with hormonerefractory prostate cancer, 植村 天受, 南 高文, 田中 基幹, 上島 成也, 奈良県立医科大学泌尿器科, 奈良県立医科大学泌尿器科, 久留米大学免疫学, ASCO 2008 Annual Meeting,   2008 05 , ASCO 2008 Annual Meeting
• Hypertension Promotes BBN-induced Bladder Carcinogenesis in Spontaneously Hypertensive Rat, 松本 成史, 田中 基幹, 上島 成也, 植村 天受, 第66回日本癌学会総会,   2007 10 , 第66回日本癌学会総会
• Phase I/II study if CA9 peptide vaccination with interferon-alpha in cytokine refractory renal cancer patients, 植村 天受, 田中 基幹, 野澤 昌弘, 松本 成史, 上島 成也, 66th Annual Meeting of the Japanese Cancer Association,   2007 10 , 66th Annual Meeting of the Japanese Cancer Association
• CA9 peptide vaccination in combination with interferon-alpha in HLA-A24 positive patients with cytokine refractory renal cell carcinoma, 植村 天受, 上島 成也, 清水 信貴, 田中 基幹, 奈良県立医科大学泌尿器科, 奈良県立医科大学泌尿器科, 23rd Annual Meeting Urological Research Society,   2007 10 , 23rd Annual Meeting Urological Research Society
• The Role of Elastin Fibers in the Bladder and Bladder Functions - Related with Bladder Outlet Obstruction -, 松本 成史, 杉本 公一, 花井 禎, 植村 天受, 伊藤 浩行, 37th Annual Meeting of the International Continence Society (ICS),   2007 08 , 37th Annual Meeting of the International Continence Society (ICS)
• PDE5 inhibitor (vardenafil) protects rat bladder from partial outlet obstruction-induced contractile dysfunction, 松本 成史, 花井 禎, 清水 信貴, 杉本 公一, 渡邊 絵美, 植村 天受, 37th Annual Meeting of the International Continence Society (ICS),   2007 08 , 37th Annual Meeting of the International Continence Society (ICS)
• Effects of deep brain stimulation on urodynamic findings in patients with Parkinson's disease, 松本 成史, 清水 信貴, 花井 禎, 植村 天受, 中野 直樹, 37th Annual Meeting of the International Continence Society (ICS),   2007 08 , 37th Annual Meeting of the International Continence Society (ICS)
• A Correlative study on the effect of Eviprostat between the clinical parameters and oxidative stress (urinary 8-OHdG) in the treatment of the lower urinary tract symptoms associated with BPH (BPH/LUTS) and on urinary 8-OHdG content in rabbit BOO model, 松本 成史, 花井 禎, 堀川 重樹, 植村 天受, Matsui T Oka, M, Tanaka M, 37th Annual Meeting of the International Continence Society (ICS),   2007 08 , 37th Annual Meeting of the International Continence Society (ICS)
• Distribution of elastin fiber in prostate, 杉本 公一, 松本 成史, 花井 禎, 伊藤 浩行, 植村 天受, 102th Annual Meeting of American Urological Association (AUA),   2007 05 , 102th Annual Meeting of American Urological Association (AUA)
• Bladder protective effects of PDE5 inhibitor -Efficacy of vardenafil on rat bladder with outlet obstruction-, 松本 成史, 渡邊 絵美, 中田 裕佳, 杉本 公一, 清水 信貴, 花井 禎, 植村 天受, 102th Annual Meeting of American Urological Association (AUA),   2007 05 , 102th Annual Meeting of American Urological Association (AUA)
• A phase I traial of vaccination of personalized peptides for HLA-A2/A24 positive patients with hormone-refractory prostate cancer, 植村 天受, 田中 基幹, 上島成也, 南 高文, 藤本 清秀, 平尾, 伊東 恭悟, AUA 2007,   2007 05 , AUA 2007
• Edaravone protects against ischemia / reperfusion-induced morphological and functional changes in rat urinary bladder, 松本 成史, 花井 禎, 吉岡 伸浩, 清水 信貴, 植村 天受, 8th Triennial Meeting of the German-Japanese Confederation of Urology,   2007 03 , 8th Triennial Meeting of the German-Japanese Confederation of Urology
• CA9 peptide vaccination as a new therapeutic strategy for advanced renal cancer, 植村 天受, 上島成也, 南 高文, 藤本 清秀, 平尾, The 8th Triennial Meeting of the German-Japanese Confederation of Urology,   2007 03 , The 8th Triennial Meeting of the German-Japanese Confederation of Urology
• Effect of alpha-blocker before TURP in terms of its dosing period, 吉岡 伸浩, 松本 成史, 清水 信貴, 花井 禎, 植村 天受, 36th Annual Meeting of the International Continence Society (ICS),   2006 11 , 36th Annual Meeting of the International Continence Society (ICS)
• Edaravone protects against ischemia / reperfusion-induced morphological and functional changes in rat urinary bladder, 松本 成史, 花井 禎, 吉岡 伸浩, 清水 信貴, 植村 天受, 36th Annual Meeting of the International Continence Society (ICS),   2006 11 , 36th Annual Meeting of the International Continence Society (ICS)
• Distribution of elastin fiber in prostate, 松本 成史, 杉本 公一, 清水 信貴, 花井 禎, 植村 天受, 36th Annual Meeting of the International Continence Society (ICS),   2006 11 , 36th Annual Meeting of the International Continence Society (ICS)
• Bladder outlet obstruction (BOO) promotes BBN-induced bladder carcinogenesis in rat, 松本 成史, 田中 基幹, 上島 成也, 植村 天受, 第65回日本癌学会総会,   2006 09 , 第65回日本癌学会総会
• Effect of Edaravone on ischemia/reperfusion injury in rat urinary bladder -Changes in smooth muscle cell phenotype and contractile function-, 松本 成史, 花井 禎, 吉岡 伸浩, 堀川 重樹, 清水 信貴, 植村 天受, The 23rd Japan Korea Urological Congress,   2006 09 , The 23rd Japan Korea Urological Congress
• A phase I trial of vaccination of tailor-made peptides for HLA-A2/A24 positive patients with hormone-refractory prostate cancer, 植村 天受, Urological Research Society,   2006 09 , Urological Research Society
• Bladder Outlet Obstruction Promotes BBN - induced Bladder Carcinogenesis in Rat, 松本 成史, 清水 信貴, 土手 健作, 花井 禎, 田中 基幹, 伊藤 浩行, 植村 天受, 8th Asian Congress of Urology,   2006 08 , 8th Asian Congress of Urology
• Novel gene transduction technology by Credia TF, 田中 基幹, 植村 天受, 外崎 円, 梅影, 政文, 小中, 富雄, 池田 寿文, The 9th Annual Meeting of the American Society of Gene Therapy,   2006 05 , The 9th Annual Meeting of the American Society of Gene Therapy
• Phase-1 syudy of carbonic anhydrase 9 peptide vaccines in patients with metastatic renal cell carcinoma, 植村 天受, 田中 基幹, 上島 成也, 平尾 佳彦, 伊東 恭悟, Annual EAU Congress,   2006 04 , Annual EAU Congress
• Novel gene transduction technology by Credia TF, 田中 基幹, 植村 天受, 外崎 円, 梅影, 政文, 小中, 富雄, 辻, 良平, 池田 寿文, The 97th Annual Meeting, American Association for Cancer Research,   2006 03 , The 97th Annual Meeting, American Association for Cancer Research
• Phase-I/II trial of CA9 peptide vaccines in HLA-A24 positive patients with cytokine refractory renal cell carcinoma, 植村 天受, Urological Research Society,   2005 11 , Urological Research Society
• Creatol, an Oxidative Product of Creatinine in Kidney Tansplant Patients, as a Useful Determinant of Renal Function; A Preliminary Study, 松本 成史, 花井 禎, 松浦 健, 植村 天受, 西岡 伯, 秋山 ?弘, 9th Congress of the Asian Society of Transplantation,   2005 11 , 9th Congress of the Asian Society of Transplantation
• Can monitoring of serum 8-OHdG level for two hours after renal transplantation predict prognosis of the graft?, 松本 成史, 花井 禎, 松浦 健, 植村 天受, 西岡 伯, 秋山 ?弘, 9th Congress of the Asian Society of Transplantation,   2005 11 , 9th Congress of the Asian Society of Transplantation
• Bladder outlet obstruction accelerates carcinogenesis of the bladder, 松本 成史, 植村 天受, Robert M. Levin, 21th Urological Research Society,   2005 11 , 21th Urological Research Society
• 前立腺癌におけるPTEN癌抑制遺伝子の役割, 田中 基幹, 植村 天受, 冨岡 厚志, 高田, 聡, 穴井, 智, 平尾 佳彦, 第16回前立腺癌ワークショップ,   2005 09 , 第16回前立腺癌ワークショップ
• Inductive Coupling Wireless Sensor-Transmitter for Continuous Monitoring of Intra-Bladder Pressure for Unconstrained Urodynamic Study, 松本 成史, 植村 天受, Nakazono K, Takeuchi Y, 5th International Workshop on Biosignal Interpretation (BSI 2005),   2005 09 , 5th International Workshop on Biosignal Interpretation (BSI 2005)
• 8OHdG before and after TUR, 花井 禎, 松本 成史, 杉山 高秀, 植村 天受, 35th International Continence Society,   2005 08 , 35th International Continence Society
• Phase-I study of CA9 peptide vaccines in patients with stage IV renal cell carcinoma, 植村 天受, 上島成也, 中西 まこ, 藤本清秀, 平尾佳彦, AUA 2005,   2005 05 , AUA 2005
• Enhanced efficacy of radiation sensitivity by controlled gene delivery of PTEN expression vector conjugated with cationized gelatin in prostate cancer cells, 田中 基幹, 植村 天受, 高田 聡, 冨岡, 厚志, 松村, 善昭, 平尾 佳彦, The 100th Annual Meeting, American Urological Association, Inc.,   2005 05 , The 100th Annual Meeting, American Urological Association, Inc.
• Bladder smooth muscle cell phenotypic changes and detrusor functional changes on ischemia-reperfusion injury in the rat urinary bladder, 松本 成史, 清水 信貴, 杉山 高秀, 植村 天受, 吉岡 伸浩, 花井 禎, Robert M. Levin, 100th American Urological Association,   2005 05 , 100th American Urological Association
• Enhanced efficacy of radiation sensitivity by controlled gene delivery of PTEN expression vector conjugated with cationized gelatin in prostate cancer cells, 田中 基幹, 植村 天受, 穴井 智, 高田, 聡, 松村, 善昭, 冨岡, 厚志, 平尾 佳彦, The 96th Annual Meeting, American Association for Cancer Research,   2005 04 , The 96th Annual Meeting, American Association for Cancer Research
• Prostate cancer detected from multiple pulmonary metastases: A case report., 杉本 公一, 松本 成史, 田原 秀男, 松浦 健, 植村 天受, 第190回日本泌尿器科学会関西地方会,   2005 02 , 第190回日本泌尿器科学会関西地方会
  Summary:55才、男性。健診にて胸部異常陰影を指摘され精査施行。CTガイド下針生検にてPSA染色陽性腺癌を認め当科紹介。前立腺生検にて確定診断となった。MAB+PE療法にて転移性肺腫瘍は縮小した。
• Changes in surgery for female stress urinary incontinence over 20 years at this hospital, 清水 信貴, 松本 成史, 吉岡 伸浩, 杉山 高秀, 植村 天受, 4th International congress of the Egyptian society of Uro-gynaecology and Pelvic Floor Studies(ESUG),   2005 02 , 4th International congress of the Egyptian society of Uro-gynaecology and Pelvic Floor Studies(ESUG)
  Summary:Efforts to resolve female stress urinary incontinence spread in the latter half of the 1980s, fueled by the introduction of the Stamey procedure. Afterwards, various techniques to treat stress urinary incontinence were developed and attempted. However, the decline in long-term results with needle bladder neck suspension and anterior colporrhaphy has been criticized in recent years, and the first choice for treatment is shifting to urethral sling surgery with a TVT procedure. Thus, we studied the changes in surgery for female stress urinary incontinence at this hospital. Subjects were diagnosed with stress urinary incontinence by the Urology Department of the Kinki University School of Medicine from 1984-2004 and underwent surgery. Until the early half of the 1990s, Stamey, Raz, and Gittes suspensions and later Vesica and collagen injection were attempted, although TVT was used in all cases starting in the latter half of the 1990s.
• Drug-induced interstitial pneumonia after post-living renal transplantation, 杉本 公一, 松本 成史, 能勢 和宏, 田原 秀男, 原 靖, 松浦 健, 植村 天受, 第38回日本臨床腎移植学会,   2005 01 , 第38回日本臨床腎移植学会
  Summary:28歳、男性.2002年より慢性腎不全にて腹膜透析導入。2004年5月19日母親（55歳）をドナ−とした生体腎移植術を施行いあた。HLA:A、B；1ミスマッチ、DR;0ミスマッチ、また血液型はドナ−A型、レシピエントAB型の血液型不一致であった。初期免疫抑制はタクロリムス、ミゾリビン、プレドニゾロンおよびバシリキシマブの4剤であった。術後経過は良好であったが、3日目より急に呼吸困難が出現し、間質性肺炎象を認めた。薬剤性間質性肺炎の診断下に免疫抑制剤を変更(Tac→CyA、Mz中止)し、ステロイドパルス療法施行後、肺炎像は軽快し、呼吸困難も改善した。今回われわれは薬剤性間質性肺炎の1例を経験したので若干の文献的考察を加えて報告した。
• Induction of anti-tumor responses in patients with metastatic renal cell caricinoma by vaccination with peptides-a phase I study, 植村 天受, Fujimoto K, Tanaka M, Yoshikawa M, Nakanishi M, Hirao Y, 27th Congress of the Societe Internatiolale d'Urologie,   2004 10 , 27th Congress of the Societe Internatiolale d'Urologie
• Controlled gene delivery of PTEN expression vector conjugated with cationized gelatin in prostate cancer cells, 田中 基幹, 植村 天受, 穴井 智, 高田, 聡, 松村, 善昭, 冨岡, 厚志, 平尾 佳彦, The 27th Congress of International Society of Urology,   2004 10 , The 27th Congress of International Society of Urology
• 徐放性PTEN遺伝子薬を用いた、前立腺癌における放射線感受性増強効果, 田中 基幹, 植村 天受, 高田 聡, 冨岡, 厚志, 平尾佳彦, 田畑 泰彦, 第63回日本癌学会総会,   2004 09 , 第63回日本癌学会総会
• Patients-oriented vaciene tehrapy for hormone refractory prostate cancer, 植村 天受, Fujimoto K, Tanaka M, Tanaka N, Okajima E, Hirao Y, 20th urological Research Society Meeting,   2004 09 , 20th urological Research Society Meeting
• Tailor-made peptide vaccines for hormone refractory prostate cancer patients, 植村 天受, Fujimoto K, Tanaka M, Tanaka N, Okajima E, Hirao H, 7th Triennial Meeting of the German-Japanese Confederation of Urology,   2004 06 , 7th Triennial Meeting of the German-Japanese Confederation of Urology
• VHL-dependent and independent regulation of MN/CA9 in renal fell carcinoma cell lines, 植村 天受, Kawada Y, Hirao Y, 第６回VHL国際シンポジウム,   2004 05 , 第６回VHL国際シンポジウム
• Sensitization of radiotherapy by PTEN gene microcapsule in prostate cancer, 田中 基幹, 植村 天受, 穴井 智, 高田, 聡, 松村, 善昭, 平尾 佳彦, Charles J Rosser, H Barton Grossman, The 95th Annual Meeting, American Association for Cancer Research,   2004 03 , The 95th Annual Meeting, American Association for Cancer Research
• The development of anti-tumour vaccines derived from MN/CA9 in renal cell carcinoma, 植村 天受, K Shimizu, M Yoshikawa, M Tanaka, Y Hirao, K Yoshikawa, 18th Annual Meeting of European Association of Urology,   2003 , 18th Annual Meeting of European Association of Urology
• Early phase ? trial with MN/CA9 antigen peptide vaccines restricted to HLA-A24 in renal cell carcinomas, 植村 天受, M Tanaka, M Cho, M Yoshikawa, Y Hirao, 94th Annual Meeting of American Association for Cancer Research,   2003 , 94th Annual Meeting of American Association for Cancer Research
• Detection of circulating RCC cells in the renal vein during radical nephrectomy, 植村 天受, M Cho, Y Hirao, K Yoshikawa, 18th Urological Research Society Annual Meeting,   2001 , 18th Urological Research Society Annual Meeting
• Cancer vaccines targeting MN/CA? antigen for renal cell carcinoma, 植村 天受, K Shimizu, M Cho, Eijiro Okajima, Y Hirao, S Saga, K Yoshikawa, 92th Annual Meeting of American Association for Cancer Research,   2001 , 92th Annual Meeting of American Association for Cancer Research
• Vaccination of antigen peptide derived from MN/CA? induces specific immunity, 植村 天受, K Shimizu, M Cho, Y Hirao, K Yoshikawa, International Symposium Cancer Research Institute Tumor Vaccines 2000,   2000 , International Symposium Cancer Research Institute Tumor Vaccines 2000
• Peptide vaccination of MN/CA? antigen induces specific tumor immunity, 植村 天受, K Shimizu, M Cho, M Yoshikawa, Y Hirao, K Yoshikawa, E Oosterwijk, 91th Annual Meeting of American Association for Cancer Research,   2000 , 91th Annual Meeting of American Association for Cancer Research
• MN/CA? as a potential therapeutic target for active specific immunotherapy of renal cell carcinoma, 植村 天受, M Cho, H Shimizu, Y Nakagawa, K Yoshida, Y Hirao, K Yoshikawa, E Oosterwijk, 15th Congress of the European Association of Urology,   2000 , 15th Congress of the European Association of Urology
• Active specific immunotherapy for RCC ?Vaccination of MN/CA? Ag peptide induces specific tumor immunity-, 植村 天受, K Shimizu, M Cho, M Yoshikawa, Y Hirao, K Yoshikawa, 17th Urological Research Society Annual Meeting,   2000 , 17th Urological Research Society Annual Meeting
• G250 antigen as a potential target for immunotherapy of renal cell carcinomas, 植村 天受, Y Nakagawa, Y Hirao, K Yoshikawa, F Debruyne, E Oosterwijk, 14th Congress of the European Association of Urology,   1999 , 14th Congress of the European Association of Urology

Misc

• 遺伝子改変前立腺癌マウスモデルにおけるapalutamide(ARN-509)の治療効果, 森 康範, でべらすこ・まるこ, 倉 由吏恵, 清水 信貴, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本泌尿器科学会総会, 107回, OP, 083,   2019 04
• 遺伝子改変前立腺癌マウスモデルにおけるアビラテロンの抗腫瘍免疫に対する影響, 清水 信貴, 倉 由吏恵, でべらすこ・まるこ, 森 康範, 南 高文, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本泌尿器科学会総会, 107回, PP1, 004,   2019 04
• 日本の転移性腎細胞癌患者を対象としたニボルマブの有効性と安全性の検討 メディカルチャートレビューによる後方視的観察研究 第1回調査結果, 植村 天受, 日向 信之, 越智 研也, 金子 裕和, 中井 康友, 日本泌尿器科学会総会, 107回, OP, 456,   2019 04
• Nocturia, 73, 3, 210, 218,   2019 03 , http://id.ndl.go.jp/bib/029540711
• 進行腎細胞癌に対する術前分子標的療法 日本人集団における長期臨床成績(Presurgical targeted molecular therapy for advanced renal cell carcinoma: Long-term clinical outcomes in a Japanese population), Ohzeki Takayuki, Hashimoto Mamoru, Shimizu Nobutaka, Minami Takafumi, Nozawa Masahiro, Nose Kazuhiro, Yoshimura Kazuhiro, Uemura Hirotsugu, Acta Medica Kinki University, 43, 2, 69, 74,   2018 12
  Summary:腫瘍切除術前に分子標的療法を受けた腎細胞癌患者についてレトロスペクティブに検討した。2008年7月から2014年2月までに11名(男9名、女2名、40〜77歳)が分子標的療法後に切除術を受けた。切除不能癌の患者1名を除き、転移を伴う局所進行癌の全例に開腹手術を行った。原発巣および転移巣の腫瘍縮小率はそれぞ-14.9%(範囲-47%〜+18%)および-35.7%(範囲-100%〜+40%)であった。癌関連死は原発巣の縮小が少ない患者に多くみられた。患者2名に軽度の周術期合併症(創傷治癒遅延、感染症)がみられた。全例の病理組織学的診断が明細胞癌であった。以上より、大部分の患者において、分子標的療法後の腎細胞癌の外科的切除は施行可能と考えられた。
• 癌治療-Made in Japan 世界にはばたく日本発の癌治療-次世代を担う免疫療法を目指して 個別化ペプチドワクチンによるがんの最適治療を目指す3つの臨床的アプローチ, 伊東 恭悟, 野口 正典, 由谷 茂, 七條 茂樹, 山田 亮, 笹田 哲朗, 成田 善孝, 寺崎 瑞彦, 植村 天受, 末金 茂高, 唐 宇飛, 内藤 雅康, 河野 光一郎, 吉山 康一, 坂本 信二郎, 日本癌治療学会学術集会抄録集, 56回, SSY7, 1,   2018 10
• 去勢抵抗性前立腺がんに対する20種混合ペプチドワクチンの有効性の検討, 野口 正典, 新井 学, 頴川 晋, 大山 力, 内藤 誠二, 松本 和将, 植村 天受, 中川 昌之, 那須 保友, 江藤 正俊, 末金 茂高, 笹田 哲朗, 山田 亮, 角間 辰之, 伊東 恭悟, 日本癌治療学会学術集会抄録集, 56回, O43, 1,   2018 10
• 下部尿路症状を有する患者に対するUDSを用いたアコチアミド塩酸塩水和物追加投与の検討, 秋山隆弘, 杉本公一, 西野安紀, 松村直紀, 清水信貴, 南高文, 能勢和宏, 上島成也, 西岡泊, 植村天受, 日本排尿機能学会誌, 29, 1, 245, 245,   2018 09 , http://jglobal.jst.go.jp/public/201802229384576998
• イミダフェナシン投与後の夜間多尿改善と尿濃縮効果の関係について, 橋本士, 清水信貴, 國重玲紋, 豊田信吾, 西本光寿, 大關孝之, 南高文, 野澤昌弘, 吉村一宏, 田原秀男, 平山暁秀, 植村天受, 日本排尿機能学会誌, 29, 1, 230, 230,   2018 09 , http://jglobal.jst.go.jp/public/201802284959998465
• T1b腎細胞癌に対する手術療法 T1b腎細胞癌に対する腹腔鏡下腎摘除術, 野澤 昌弘, 植村 天受, 日本泌尿器科学会総会, 106回, DB2, 4,   2018 04
• 転移性腎細胞がん患者を対象とした薬物治療の後方視的観察研究, 野澤 昌弘, 植村 元秀, 大澤 崇宏, 原田 健一, 山名 一寿, 木村 剛, 立神 勝則, 野々村 祝夫, 篠原 信雄, 藤澤 正人, 冨田 善彦, 近藤 幸尋, 江藤 正俊, 越智 研也, 穴澤 嘉雄, 植村 天受, RCC retrospective chart review study group, 日本泌尿器科学会総会, 106回, OP, 471,   2018 04
• ラジウム223使用症例における予後予測因子,6回完遂可能因子の検討, 堤壮吾, 堤壮吾, 三好康秀, 河原崇司, 横溝由美子, 林成彦, 矢尾正祐, 上村博司, 松村直樹, 大関孝之, 南高文, 野澤昌弘, 吉村一宏, 植村天受, 日本泌尿器科学会総会(Web), 106th, ROMBUNNO.OP‐135 (WEB ONLY), 135,   2018 04 , http://jglobal.jst.go.jp/public/201802275528390918
• 限局性前立腺癌に対する放射線療法後膀胱癌発症例の検討, 南高文, 橋本士, 松村直紀, 大關孝之, 本郷祥子, 杉本公一, 清水信貴, 森康範, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会総会(Web), 106th, ROMBUNNO.PP1‐212 (WEB ONLY), 212,   2018 04 , http://jglobal.jst.go.jp/public/201802217554289999
• MRIを用いた健常女性骨盤底の検討, 本郷祥子, 本郷祥子, 橋本士, 松村直紀, 大関孝之, 杉本公一, 清水信貴, 森康範, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 上島成也, 上島成也, 日本泌尿器科学会総会(Web), 106th, ROMBUNNO.OP‐429 (WEB ONLY), 429,   2018 04 , http://jglobal.jst.go.jp/public/201802250950332314
• 腎細胞癌に対する免疫チェックポイント阻害薬, 野澤昌弘, 植村天受, 日本老年泌尿器科学会プログラム・抄録集, 31st, 31,   2018 , http://jglobal.jst.go.jp/public/201802224443523454
• 腸腰筋面積と下部尿路症状との関係, 橋本士, 清水信貴, 浜口守, 國重玲紋, 豊田信吾, 西本光寿, 大關孝之, 南高文, 野澤昌弘, 吉村一宏, 平山暁秀, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 227,   2018 , http://jglobal.jst.go.jp/public/201802226675273543
• 近畿大学におけるBrachytherapyの検討, 南高文, 國重玲紋, 浜口守, 豊田信吾, 橋本士, 西本光寿, 大關孝之, 清水信貴, 森康範, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 296,   2018 , http://jglobal.jst.go.jp/public/201802250401130179
• 当院におけるホルモン療法未治療前立腺癌(HNPC)に対するアビラテロンとプレドニゾロン併用療法の初期経験, 豊田信吾, 浜口守, 國重玲紋, 橋本士, 西本光寿, 大関孝之, 清水信貴, 森康範, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 212,   2018 , http://jglobal.jst.go.jp/public/201802253237435579
• 下部尿路症状を有する患者に対するUDSを用いたアコチアミド塩酸塩水和物追加投与の検討, 杉本公一, 秋山隆弘, 西野安紀, 松村直紀, 清水信貴, 南高文, 能勢和宏, 上島成也, 西岡伯, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 222,   2018 , http://jglobal.jst.go.jp/public/201802258934936187
• High risk前立腺癌の手術, 野澤昌弘, 國重玲紋, 浜口守, 豊田信吾, 橋本士, 西本光寿, 大關孝之, 清水信貴, 森康範, 南高文, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 142,   2018 , http://jglobal.jst.go.jp/public/201802270918434995
• 進行腎細胞癌に対する分子標的薬によるPRESURGICAL療法長期成績の検討, 大関孝之, 浜口守, 國重玲紋, 豊田信吾, 橋本士, 西本光寿, 清水信貴, 森康範, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 68th, 174,   2018 , http://jglobal.jst.go.jp/public/201802279224989764
• Foresight in drug therapy for renal cell carcinoma, 72, 1, 76, 79,   2018 01 , http://id.ndl.go.jp/bib/028759459
• Prospect in targeted therapy for renal cell carcinoma, 6, 6, 488, 492,   2017 12 , http://id.ndl.go.jp/bib/028732174
• ラジウム223使用症例における予後予測因子の検討, 堤 壮吾, 野澤 昌弘, 三好 康秀, 河原 崇司, 横溝 由美子, 林 成彦, 矢尾 正祐, 吉村 一宏, 上村 博司, 植村 天受, 日本癌治療学会学術集会抄録集, 55回, O6, 6,   2017 10
• PTENノックアウト前立腺癌マウスモデルにおける腫瘍免疫の包括的分析, De Velasco Marco A, 倉 由吏恵, 坂井 和子, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1222,   2017 09
• 遺伝子改変前立腺癌マウスモデルにおけるPD-L1免疫チェックポイント阻害薬について, 清水 信貴, De Velasco Marco A, 倉 由吏恵, 坂井 和子, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1246,   2017 09
• アンドレゲンレセプターを標的とした次世代アンチセンスオリゴヌクレオチドとAKT阻害薬併用療法の治療効果について, 杉本 公一, De Velasco Marco A, 倉 由吏恵, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1376,   2017 09
• AKTおよびPimキナーゼをターゲットにした治療戦略はPTEN欠出前立腺癌前臨床動物モデルにおいて治療効果改善を示す, 倉 由吏恵, De Velasco Marco A, 杉本 公一, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, J, 2099,   2017 09
• 遺伝子改変マウス前立腺癌モデルを用いた新規化合物の包括的前臨床評価について, 植村 天受, 倉 由吏恵, 杉本 公一, 森 康範, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, De Velasco Marco A, 日本癌学会総会記事, 76回, J, 3121,   2017 09
• ヒト前立腺癌におけるSTAT3について, 森 康範, De Velasco Marco A, 畑中 祐二, 倉 由吏恵, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 3215,   2017 09
• 前立腺特異的PTENノックアウトマウスを用いたJak1/2阻害薬であるAZD1480による抗腫瘍効果および転移抑制についての検討, 倉 由吏恵, 吉村 一宏, 野澤 昌弘, 南 高文, 杉本 公一, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 植村 天受, 日本泌尿器科学会総会, 105回, OP42, 6,   2017 04
• PTEN/p53ダブルノックアウト前立腺癌マウスモデルにおけるAutophagy阻害薬クロロキンの治療効果について, 杉本 公一, 吉村 一宏, 野澤 昌弘, 南 高文, 清水 信貴, 倉 由吏恵, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 植村 天受, 日本泌尿器科学会総会, 105回, PP16, 07,   2017 04
• 遺伝子改変前立腺癌マウスモデルにおける高脂肪食摂取による腫瘍増殖について, 森 康範, デベラスコ・マルコ, 倉 由吏恵, 沖 貴士, 杉本 公一, 畑中 祐二, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本泌尿器科学会総会, 105回, PP16, 10,   2017 04
• Renal dysfunction with molecular targeted agents, 5, 3, 306, 311,   2017 03 , http://id.ndl.go.jp/bib/028067768
• 「転移性腎癌治療戦略」薬物療法(I‐O drug), 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 67th, 137,   2017 , http://jglobal.jst.go.jp/public/201802258559074686
• 献腎移植後に可逆性白質脳症症候群(PRES)と考えられた1例, 齋藤允孝, 大森直美, 桑原賢, 安富正悟, 大関孝之, 本郷祥子, 杉本公一, 清水信貴, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本臨床腎移植学会プログラム・抄録集, 50th, 155,   2017 , http://jglobal.jst.go.jp/public/201702263703139604
• 当院における進行性腎細胞癌に対するパゾパニブ使用成績の検討, 大関孝之, 橋本士, 松村直紀, 本郷祥子, 杉本公一, 清水信貴, 森康範, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 67th, 239,   2017 , http://jglobal.jst.go.jp/public/201802241938720071
• PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討, 倉 由吏恵, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 1029,   2016 10
• PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 1073,   2016 10
• PTENノックアウト前立腺癌マウスモデルにおけるJAK1/2阻害による腫瘍増殖及び転移抑制効果の検討, 植村 天受, 倉 由吏恵, 森 康範, 畑中 祐二, 沖 貴士, 杉本 公一, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 日本癌学会総会記事, 75回, E, 2085,   2016 10
• PTEN/p53ダブルノックアウト前立腺癌マウスモデルにおけるクロロキン経口による治療効果, 杉本 公一, デベラスコ・マルコ, 倉 由吏恵, 森 康範, 畑中 祐二, 沖 貴士, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 3065,   2016 10
• 遺伝子改変と前立腺癌マウスモデルにおける高脂肪食摂取による腫瘍増殖について, 森 康範, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 沖 貴士, 杉本 公一, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, P, 3348,   2016 10
• がん治療が変わる―免疫チェックポイント阻害剤の与えるインパクト―先行する癌腫における治療成績 腎細胞癌, 野澤昌弘, 植村天受, 肝胆膵, 73, 3, 375‐380,   2016 09 28 , http://jglobal.jst.go.jp/public/201602288793139911
• 前立腺癌マウスモデルを用いたAKT阻害薬AZD5363の抗腫瘍効果の検討, 植村 天受, 吉村 一宏, 野澤 昌弘, 南 高文, 杉本 公一, 倉 由吏恵, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 植村 天受, 日本泌尿器科学会総会, 104回, OP, 228,   2016 04
• 前立腺癌におけるAKT/PI3KおよびMAPK経路阻害による治療相互作用について, 山本 豊, 吉村 一宏, 野澤 昌弘, 南 高文, 杉本 公一, 倉 由吏恵, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 植村 天受, 日本泌尿器科学会総会, 104回, PP3, 265,   2016 04
• 去勢抵抗性前立腺癌におけるPim-1キナーゼ阻害薬AZD1208の治療効果, 杉本 公一, 吉村 一宏, 野澤 昌弘, 南 高文, 倉 由吏恵, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 植村 天受, 日本泌尿器科学会総会, 104回, PP3, 266,   2016 04
• 献腎移植後に可逆性白質脳症症候群(PRES)と考えられた1例, 齋藤允孝, 大森直美, 桑原賢, 安富正悟, 大関孝之, 本郷祥子, 杉本公一, 清水信貴, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 66th, 178,   2016 , http://jglobal.jst.go.jp/public/201602213310869277
• ペプチドワクチン療法の有用性と今後の展望, 吉村一宏, 南高文, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 66th, 114,   2016 , http://jglobal.jst.go.jp/public/201602223227701086
• CRPCに対するタキサン系薬剤の位置付け, 野澤昌弘, 大森直美, 桑原賢, 安富正悟, 大関孝之, 本郷祥子, 齋藤允孝, 杉本公一, 清水信貴, 南高文, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 66th, 105,   2016 , http://jglobal.jst.go.jp/public/201602240054701402
• 前立腺癌に対するデガレリクス/ビカルタミド併用療法, 野澤昌弘, 杉山高秀, 杉本公一, 永井康晴, 畑中祐二, 沖貴士, 田原秀男, 松田久雄, 吉川元清, 植村天受, 日本臨床腫瘍学会学術集会(CD-ROM), 13th, ROMBUNNO.O3-11-4,   2015 , http://jglobal.jst.go.jp/public/201502209361544516
• 高齢患者に対する薬剤選択, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 65th, 115,   2015 , http://jglobal.jst.go.jp/public/201602217195782268
• 転移性腎癌に対するパゾパニブの使用経験, 杉本公一, 野澤昌弘, 藤島一樹, 高橋智輝, 西野安紀, 安富正悟, 大關孝之, 本郷祥子, 齋藤允孝, 清水信貴, 南高文, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 65th, 161,   2015 , http://jglobal.jst.go.jp/public/201602200610416051
• 当院におけるタダラフィルの使用経験, 松村直紀, 杉本公一, 菊池尭, 大關孝之, 齋藤允孝, 本郷祥子, 清水信貴, 南高文, 林泰司, 野澤昌弘, 能勢和宏, 吉村一宏, 西岡伯, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 65th, 173,   2015 , http://jglobal.jst.go.jp/public/201602208318122404
• 去勢抵抗性前立腺癌に対する免疫療法, 吉村一宏, 南高文, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 65th, 87,   2015 , http://jglobal.jst.go.jp/public/201602212647428929
• 高齢前立腺癌患者における好中球/リンパ球比(NLR)と予後との関連, 安富正悟, 杉本公一, 高橋智輝, 藤島一樹, 西野安紀, 大關孝之, 本郷祥子, 齋藤允孝, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 65th, 152,   2015 , http://jglobal.jst.go.jp/public/201602213449648022
• 「進行腎癌に対する治療戦略」分子標的薬によるプレサージカル療法の検討, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 64th, 75,   2014 , http://jglobal.jst.go.jp/public/201502232128509698
• カバジタキセルの使用経験, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 64th, 103,   2014 , http://jglobal.jst.go.jp/public/201502287754205942
• 近畿大学医学部附属病院における高齢者前立腺癌患者に対するbrachytherapyの検討, 南高文, 清水信貴, 野沢昌弘, 吉村一宏, 植村天受, 日本老年泌尿器科学会プログラム・抄録集, 27th, 150,   2014 , http://jglobal.jst.go.jp/public/201402239744585249
• 献腎移植後27年目にMDSを発症しアザシチジンを使用した1例, 齋藤允孝, 橋本士, 豊田信吾, 清水信貴, 山本豊, 南高文, 林泰司, 辻秀憲, 野澤昌弘, 吉村一宏, 石井徳味, 植村天受, 森田泰慶, 日本臨床腎移植学会プログラム・抄録集, 47th, 161,   2014 , http://jglobal.jst.go.jp/public/201502218490978033
• 腎癌に対する分子標的薬によるPresurgical療法の検討, 大関孝之, 明石泰典, 橋本士, 安富正悟, 齋藤允孝, 清水信貴, 山本豊, 南高文, 野澤昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 64th, 124,   2014 , http://jglobal.jst.go.jp/public/201502241609789332
• 精巣腫瘍と精巣原発悪性リンパ腫の検討, 松村直紀, 杉本公一, 林泰司, 西岡伯, 清水信貴, 南高文, 山本豊, 野沢昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 64th, 152,   2014 , http://jglobal.jst.go.jp/public/201502249215955840
• 転移性腎癌に対する新規分子標的薬パゾパニブの使用経験, 山本豊, 橋本士, 安富正悟, 大関孝之, 斎藤允孝, 清水信貴, 南高文, 野沢昌弘, 能勢和宏, 吉村一宏, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 64th, 116,   2014 , http://jglobal.jst.go.jp/public/201502262955594570
• 当科におけるフルニエ壊疽症例の検討, 豊田信吾, 山本豊, 橋本士, 齋藤允孝, 清水信貴, 南高文, 林泰司, 辻秀憲, 野沢昌弘, 吉村一宏, 石井徳味, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 63rd, 149,   2013 , http://jglobal.jst.go.jp/public/201302219177294108
• 精巣原発悪性リンパ腫の8例, 松村直紀, 杉本公一, 能勢和宏, 西岡伯, 清水信貴, 南高文, 山本豊, 林泰司, 辻秀憲, 野沢昌弘, 吉村一宏, 石井徳味, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 63rd, 164,   2013 , http://jglobal.jst.go.jp/public/201302257863345745
• α1遮断薬投与中の30g未満の前立腺肥大症患者に対するデュタステリド追加投与の検討, 橋本士, 清水信貴, 南高文, 辻秀憲, 野沢昌弘, 吉村一宏, 植村天受, 杉本公一, 能勢和宏, 西岡伯, 田原秀男, 畑中祐二, 今西正昭, 江左篤宣, 日本泌尿器科学会中部総会プログラム・抄録集, 63rd, 141,   2013 , http://jglobal.jst.go.jp/public/201302297510286372
• TKI Failureとなった高齢者mRCCに対するエベロリムスの治療効果, 稲元輝生, 東治人, 野々村祝夫, 仲谷達也, 松田公志, 野沢昌弘, 植田健, 木下秀文, 西村和郎, 金山博臣, 三木恒治, 冨田善彦, 辻畑正雄, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 63rd, 138,   2013 , http://jglobal.jst.go.jp/detail.php?from=API&JGLOBAL_ID=201302202242511553
• エベロリムスは高齢進行性腎癌に有効である, 稲元輝生, 東治人, 野々村祝夫, 仲谷達也, 松田公志, 野澤昌弘, 植田健, 木下秀文, 西村和郎, 金山博臣, 三木恒治, 冨田善彦, 吉岡俊昭, 辻畑正雄, 植村天受, 日本癌治療学会学術集会(CD-ROM), 51st, ROMBUNNO.OS10-3,   2013 , http://jglobal.jst.go.jp/detail.php?from=API&JGLOBAL_ID=201302249081566510
• 近畿大学泌尿器科におけるゾレドロン酸使用の実際, 南高文, 山本豊, 野澤昌弘, 菊池尭, 西本光寿, 小林泰之, 清水信貴, 林泰司, 辻秀憲, 吉村一宏, 石井徳味, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 62nd, 163,   2012 , http://jglobal.jst.go.jp/public/201302266119616667
• 尿膜管癌の臨床的検討, 松村直紀, 橋本潔, 加藤良成, 井口正典, 小林泰之, 清水信貴, 山本豊, 南高文, 林泰司, 野澤昌弘, 吉村一宏, 石井徳味, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 62nd, 151,   2012 , http://jglobal.jst.go.jp/public/201302266802649570
• 腎被膜原発のSclerosing PEComaの1例, 小林泰之, 菊池尭, 西本光寿, 清水信貴, 山本豊, 南高文, 林泰司, 辻秀憲, 野澤昌弘, 吉村一宏, 石井徳味, 筑後孝章, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 62nd, 140,   2012 , http://jglobal.jst.go.jp/public/201302294132841142
• 進行性・転移性腎癌に対するPresurgical療法, 吉村一宏, 野澤昌弘, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 61st, 69,   2011 , http://jglobal.jst.go.jp/public/201202224439590427
• 当院における急性陰嚢症の経験, 永井康晴, 伊丹祥隆, 小林泰之, 清水信貴, 山本豊, 南高文, 林泰司, 辻秀憲, 野澤昌弘, 吉村一宏, 石井徳味, 植村天受, 日本泌尿器科学会中部総会プログラム・抄録集, 61st, 158,   2011 , http://jglobal.jst.go.jp/public/201202217203665896
• 当院での前立腺癌骨転移症例に対するストロンチウム‐89(Sr‐89)治療の臨床評価, 伊丹祥隆, 清水信貴, 林泰司, 永井康晴, 小林泰之, 山本豊, 南高文, 野澤昌弘, 吉村一宏, 石井徳味, 植村天受, 沖貴士, 吉岡伸浩, 日本泌尿器科学会中部総会プログラム・抄録集, 61st, 167,   2011 , http://jglobal.jst.go.jp/public/201202234805136594
• Immunochemotherapy with interferon-α, interleukin-2, 5-fluorouracil, and cimetidine for patients with advanced renal cell carcinoma, Makito Miyake, Kiyohide Fujimoto, Masahiro Tanaka, Yoshihiko Hirao, Hirotsugu Uemura, Takeshi Otani, Masahito Yoshii, Journal of Nara Medical Association, 60, 37, 47,   2009 04 01 , https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=68549101622&origin=inward
  Summary:Introduction. We prospectively evaluated the efficacy and safety of immunochemotherapy using INF-α, IL-2, 5-fluorouracil (5-FU), and cimetidine in patients with metastatic renal cell carcinoma (RCC). Patients and Methods. Twenty-two patients with metastatic RCC were given 4 weeks of initial therapy consisting of IFN-α- (3-6x106IU/day 3 times/week), IL-2 (0.7-1.4x106JRU/day for 5 consecutive days/week), 5-FU (150 mg/m2/day for 5 consecutive days/week), and Cimetidine (800 mg/day), followed by maintenance therapy with IFN-α, IL-2, and Cimetidine. The response rate, overall and progression-free survivals, and adverse events were analyzed. Results. The median periods of therapy and follow-up were 4.4 months (range: 0.4-33) and 28.8 months (range: 1-65), respectively. The early anti-tumor effect was a complete response in one (4.5%), a partial response in 3 (13.6%), no change in 9 (40.9%), and progressive disease in 9 (40.9%). The 2-year progression-free and overall survival rates were 31% and 76%, respectively. The overall survival of cytokine-naïve group was higher than that of cytokine-resistant group (p<0.032). Adverse events of grade ≤3 occurred in 5 patients, and 9 discontinued this therapy due to adverse events. Conclusion. The present regimen had a low response rate despite the high incidence of adverse events and should be limited to patients with cytokine-naïve metastatic RCC.
• 近畿大学附属病院におけるTESE/MESA症例の検討, 林泰司, 大関孝之, 吉川元清, 中川勝弘, 南高文, 辻秀憲, 野澤昌弘, 梅川徹, 田中基幹, 石井徳味, 植村天受, 辻勲, 星合昊, 日本アンドロロジー学会総会記事, 27th, 178,   2008 06 13 , http://jglobal.jst.go.jp/public/200902240480919745
• 膀胱癌におけるVEGFR2発現の検討, 野澤昌弘, 有馬良一, 植村天受, 日本臨床腫瘍学会学術集会プログラム・抄録集, 6th, 288,   2008 , http://jglobal.jst.go.jp/public/201502263016676713
• 不妊治療中に診断された腸管子宮内膜症の2症例, 椎名昌美, 小池英爾, 梅本雅彦, 金村和美, 岡田紀久子, 上田和毅, 南高文, 今本治彦, 石井徳味, 塩田充, 奥野清隆, 植村天受, 星合昊, エンドメトリオーシス研究会プログラム・講演抄録集, 29th, 84,   2008 , http://jglobal.jst.go.jp/public/200902270757238798
• Effect of stimulated effect for urinary disorder in Parkinson’s disease using urodynamics., 46, 1, 68, 69,   2007 05
• Inductive Coupling Wireless Sensor-Transmitter for Continuous Monitoring of Intra-Bladder Pressure for Unconstrained Urodynamic Study, Proceedings of 5th International Workshop on Biosignal Interpretation, 193, 194,   2005 09
• 当科および当科関連施設における夫婦間移植8例の検討, 南高文, 森康範, 森本康裕, 能勢和宏, 田原秀男, 原靖, 石井徳味, 松浦健, 植村天受, 永野哲郎, 西岡伯, 秋山隆弘, 江左篤宣, 日本臨床腎移植学会プログラム・抄録集, 38th, 106,   2005 , http://jglobal.jst.go.jp/public/200902269559991032
• The role of MN/CA IX antigen in carcinogenesis and metastasis of renal cell carcinoma, 47, 11, 809, 814,   2001 11 , http://hdl.handle.net/2433/114641
  Summary:MN/CA IX is a carbonic anhydrase (CA) isoenzyme expressed in normal alimentary tract in a tissue-specific manner. This antigen is activated in the majority of renal cell carcinomas (RCC) but not in normal kidney tissues. Although the exact role of CA activity in carcinogenesis and metastasis has not been established, MN/CA9 has been suggested to be implicated in acidification of extracellular milieu surrounding the cancer cells and thus create a microenvironment conductive to tumor growth and spread. Mutations in the von Hippel-Lindau (VHL) gene cause the familial syndrome and are also found in the majority of sporadic RCC. Wild-type VHL was recently described to down-regulate MN/CA9 in RCC cell lines, and the molecular mechanism of MN/CA9 and VHL in renal carcinogenesis is of interest. To investigate the mechanism of MN/CA9 activation in RCC, we examined the methylation status of this gene in RCC cell lines and human tissue samples and found that hypomethylation in the promoter region may play an important role in the expression of MN/CA9. RT-PCR analysis of blood samples from RCC patients revealed the presence of circulating MN-positive cells in the blood. This antigen may be a potential therapeutic target as well as diagnostic marker for RCC. Therefore, we are currently investigating whether or not MN/CA IX peptide could be an appropriate molecule for use antigen specific immunotherapy on RCC patients.
• A case of prostate cancer with cyst formation, 47, 9, 653, 656,   2001 09 , http://hdl.handle.net/2433/114602
  Summary:A 73-year-old man with the complaint of dysuria of 2 years' standing was admitted to our hospital for further examination of an intrapelvic cystic mass, 8.6 cm in diameter, detected incidentally by abdominal ultrasonography. The serum concentration of prostate specific antigen (PSA) was elevated to 44.9 ng/ml. Pelvic computed tomography (CT) and magnetic resonance imaging (MRI) revealed a cystic mass with an irregular thick cyst wall posterior to the urinary bladder originating from the prostate. Transrectal needle biopsy presented a moderately differentiated adenocarcinoma of the prostate. The bloody fluid of the cyst obtained by transperineal aspiration contained a significantly increased level of PSA, but no cancer cells were detected by cytological examination. Total prostatectomy was performed under the diagnosis of clinical stage C (cT3N0M0) prostate cancer. Pathological diagnosis was that cancer cells were present in the prostate tissue and had partly infiltrated the cyst wall. These results suggest that the present cyst was associated with the development of prostate cancer as a pseudocyst without an epithelial lining. The patient has remained free from the disease for over ten months. We review 56 cases of this rare condition that have been reported in Japan.
• MN/CA IX antigen as a potential target for renal cell carcinoma, 46, 10, 745, 748,   2000 10 , http://hdl.handle.net/2433/114377
  Summary:MN/CA IX is considered as a carbonic anhydrase isoenzyme expressed in the normal alimentary tract in a tissue-specific manner. This antigen is activated in the majority of renal cell carcinomas (RCC) but not in the normal kidney tissues. Our previous study revealed that increase of malignant potential is related to down-regulation of MN/CA9. To investigate the mechanism of MN activation in RCC, we examined the methylation status of this gene (MN/CA9) in RCC cell lines (SKRC-1, 6, 10, 12, 14, 44, 59). Moreover, we analyzed the circulating blood of patients for the presence of RCC cells by RT-PCR, to determine whether detection of circulating RCC cells could be useful as a biomarker. CpG methylation was investigated at 7 CpG sites in the MN/CA9 5' region. Clear mRNA signals were observed in 5 cell lines (SKRC-1, 6, 10, 44, 59), e.g., MN/CA9 positive. These 5 MN-positive cell lines showed hypomethylation in the 5' region. In contrast, all CpG sites were methylated in the remaining 2 lines and 3 normal kidney tissue samples. These results suggest that hypomethylation in the 5' region may play an important role in the expression of MN/CA9 in RCC. RT-PCR analysis of blood samples from RCC patients revealed the presence of circulating MN-positive cancer cells in the blood. Although a significant correlation with tumor stage and grade was not observed, the analysis of blood samples from patients with metastases resulted in a high detection rate of 82%. These findings suggest the usefulness of MN/CA IX as a potential diagnostic marker for detection of RCC.
• A case of psoas cold abscess in a young tuberculosis patient, 46, 9, 619, 622,   2000 09 , http://hdl.handle.net/2433/114364
  Summary:A 28-year-old man was referred to our hospital with a complaint of painful induration of right epididymis accompanied with right back pain and persistent low-grade fever. He was finally diagnosed with tuberculosis by sputum culture. Abdominal computed tomography (CT) revealed right psoas abscess and vertebral caries. He underwent a percutaneous drainage of the abscess followed by multidrug (streptomycin, pyrazinamide, refanpicin, isoniazide) combination therapy. Immediately after the drainage, symptoms began to improve with these therapies. However, four months later, abdominal CT showed a worsening of the abscess. Recently there is a stagnation in the decline of incidence of tuberculosis. It is still necessary to examine young people carefully bearing urogenital tuberculosis in mind. The pathogenesis and management of this rare condition are discussed.
• A CASE OF GUNSHOT WOUND BY 0.38 INCH LOW-VELOCITY BULLET, Journal of Nara Medical Association, 50, 5, 442, 446,   1999 10 , http://hdl.handle.net/10564/546
  Summary:A case of gunshot wound by 0.38 inch low-velocity bullet is reported. A 41 -year-old man was admitted to our hospital due to gunshot wounds. Three open wounds were recognized in the hip, right femoral region, and right lower leg on arrival. Also subcutaneous hematoma was found in the right femoral region. X-ray films on admission revealed a bullet in the right femoral region and injury of the femur bone. Pelvic CT scan revealed hematoma in the bladder and bullet fragments; however, no more associated injury was detected. Then, we diagnosed as non-penetrating wound through pelvic cavity and penetrating wound, entered from femoral region through lower leg. We removed the bullet and made debridement. The patient was discharged from our hospital on the 12th postoperative day and his postoperative course was uneventful. Since the bullet in this case was a 0.38 inch low-velocity bullet, it seemed that the degree of injury was not severe. Gunshot wound victims have been rarely seen in Japan, however, the system such as Advanced Trauma Life Support (ALTS) in the U.S.A should be established in Japan. Emergency physicians should know ballistics and gunshot wound management.
• Molecular detection of circulating cancer cells in patients with renal cell carcinoma, 45, 8, 571, 575,   1999 08 , http://hdl.handle.net/2433/114096
  Summary:We have developed a highly sensitive technique to detect circulating renal cell carcinoma (RCC) cells in the blood using the reverse transcriptase-polymerase chain reaction (RT-PCR) with primers specific for the MN/CA9 gene. RT-PCR analysis of RCC specimens resulted in the clear detection of MN/CA9 mRNA signal in 93%. In contrast, no expression of MN/CA9 was observed in normal kidney specimens. Highly sensitive RT-PCR analysis of blood samples from RCC patients revealed the presence of circulating MN-positive cancer cells in the blood. Fifty samples obtained from the patients with RCC and 31 samples from healthy donors were investigated. The sensitivity and specificity of this RT-PCR analysis were 72% and 78%, respectively. These findings suggest that the MN antigen may be a potential diagnostic biomarker for early detection of RCC.
• The role of prostate specific antigen in diagnosis of localized adenocarcinoma of the prostate. Nara Uro-Oncology Research Group, 42, 10, 795, 804,   1996 10 , http://hdl.handle.net/2433/115820
  Summary:The number of cases of prostate carcinoma (PCA) is steadily inceasing in Japan. The clinical application of a reliable tumor marker, prostate specific antigen (PSA) for the diagnosis, as well as the increasing elderly population in Japan may account for this increase. The subjects were patients at the Nara Medical University and its affiliated hospitals; 1) 687 cases without PCA were evaluated for age-specific PSA and the incidence of abnormal PSA following urological manipulations, 2) 135 cases with histological proven BPH by transurethral resection of prostate (TUR-P) were examined for PSA density (PSAD) and positive PSA rate in BPH, 3) 135 cases receiving a needle biopsy with suspicion of PCA were examined for the efficacy of PSA and PSAD and other parameters, and 4) 459 PCA cases treated between 1988 and 1994, were examined for specific PSA and PSAD values by stage and degree of cell differentiation. The PSA assay used in this study was MARKIT-M PA (normal range < or = 3.6 ng/ml). The PSA was decreased gradually with age in non-PCA patients, and abnormal PSA was found in 5.5% of these patients following manipulations. The average PSA was 2.95 +/- 2.03 ng/ml in 130 BPH patients (mean age: 71.1 +/- 7.0 years old. and average prostate volume: 32.9 +/- 16.1 ml). And abnormal PSA level (more than 3.61 ng/ml) was found in 22.3%. The mean PSAD was 0.1.0 +/- 0.06, and PSAD was below 0.15 in 86.1% of these BPH cases. Among the 135 cases receiving a needle biopsy, 33 cases had PSA values between 3.61 and 10.0 ng/ml. Of these cases, PCA was found in 18.5% of the 27 cases with a PSAD below 1.5, and in 33.3% of the 6 cases with a PSAD over 1.5. PSA and PSAD were proportionally increased with stage, and a significant difference in the PSA value was observed between stage B1 and B2, and stage C and D (P < 0.05). However, PSA and PSAD values were not significantly correlated with the cell differentiation in PCA stage A2-C. In total, PSA was 18.1 ng/ml in well, 23.9 ng/ml in moderately and 35.9 ng/ml in poorly differentiated type PCA. The positive rate of PSA was 22.3, 65.4 and 83.5%, that of prostate acid phosphatase (PAP) was 10.0, 17.8 and 45.8%, and that of GSM was 25.0, 14.7 and 68.4%, in BPH, stage A PCA and stage BPCA, respectively. In conclusion, PSA is the most reliable tool in the diagnosis of localized PCA. However, the differential diagnosis of BPH and localized PCA is difficult when the PSA value is between 3.61 and 10.0 ng/ml, and accurate staging of localized PCA is difficult with PSA or PSAD alone. At present, it is necessary to use all possible tools for the early detection of localized PCA, and to perform the needle biopsy in all PCA-suspicious cases.
• POTENTIAL TOOLS OF ANTI-IDIOTYPE ANTIBODIES FOR ACTIVE SPECIFIC IMMUNOTHERAPY IN HUMAN RENAL CELL CARCINOMA, 47, 1, 76, 87,   1996 02 , http://hdl.handle.net/10564/700
• CLINICAL STATISTICS ON OUTPATIENTS, INPATIENTS AND OPERATIONS IN THE DEPARTMENT OF UROLOGY, NARA MEDICAL UNIVERSITY, 1992, 46, 3, 209, 215,   1995 06 30 , http://hdl.handle.net/10564/819
  Summary:Clinical statistics in 1992 on outpatients, inpatients and operations in the Department of Urology, Nara Medical University, are reported in this paper. The total number of outpatients was 2,990, and inpatients numbered 336. Among these inpatients, urological tumors were most frequent (146 cases, 43 %), followed by renal failure (51 cases, 15 %), urolithiasis (44 cases, 13 %) and others. Totally 345 operations were performed.
• CLINICAL STATISTICS ON OUTPATIENTS, INPATIENTS AND OPERATIONS IN THE DEPARTMENT OF UROLOGY, NARA MEDICAL UNIVERSITY, 1990, 46, 3, 195, 201,   1995 06 30 , http://hdl.handle.net/10564/817
  Summary:Clinical statistics in 1990 on outpatients, inpatients and operations in the Department of Urology, Nara Medical University, are reported in this paper. The total number of outpatients was 3,645 and inpatients numbered 343. Among these inpatients, urological tumors were most frequent (178 cases, 51.9 %), followed by urolithiasis (57 cases, 16.6 %), renal failure (43 cases, 12.5 %), and others. Totally 444 operations were performed.
• CLINICAL STATISTICS ON OUTPATIENTS, INPATIENTS AND OPERATIONS IN THE DEPARTMENT OF UROLOGY, NARA MEDICAL UNIVERSITY, 1993, 46, 3, 216, 222,   1995 06 30 , http://hdl.handle.net/10564/820
  Summary:Clinical statistics in 1993 on outpatients, inpatients and operations in the Department of Urology, Nara Medical University, are reported in this paper. The total number of outpatients was 2,785 and inpatients numbered 329. Among these inpatients, urological tumors were most frequent (148 cases, 44.7 %), followed by renal failure (74 cases, 22.5 %), urolithiasis (36 cases, 10.9 %), and others. Totally 320 operations were performed.
• CLINICAL STATISTICS ON OUTPATIENTS, INPATIENTS AND OPERATIONS IN THE DEPARTMENT OF UROLOGY, NARA MEDICAL UNIVERSITY, 1991, 46, 3, 202, 208,   1995 06 30 , http://hdl.handle.net/10564/818
  Summary:Clinical statistics in 1991 on outpatients, inpatients and operations in the Department of Urology, Nara Medical University, are reported in this paper. The total number of outpatients was 3,457, and inpatients numbered 310. Among these inpatients, urological tumors were most frequent (174 cases, 56.1 %), followed by renal failure (45 cases, 14.2 %), urolithiasis (27 cases, 8.7 %), and others. Totally 361 operations were performed.
• A case of patent urachus, 41, 5, 395, 398,   1995 05 , http://hdl.handle.net/2433/115494
  Summary:A case of congenital patent urachus is reported. A 12-month-old boy was referred to our outpatient clinic with the complaint of watery discharge from the navel. A cystography revealed the communication between the dome of the urinary bladder and the umbilicus. Excretion from the umbilicus of indigocarmine solution instilled into the urinary bladder was recognized. There were no complicated abnormalities in other organs. The patient underwent radical operation. Herein, we collected 164 cases of urachal disorders reported in Japan and reviewed the incidence, clinical symptoms, diagnosis and treatment. The classifications of the disease were briefly discussed.
• A CASE OF NON-SPECIFIC INFLAMMATORY GRANULOMA OF THE URINARY BLADDER ASSOCIATING WITH OSTEOLYTIC CHANGE OF THE PUBIC BONE, 46, 1, 7, 12,   1995 02 , http://hdl.handle.net/10564/792
  Summary:A case of non-specific inflammatory granuloma of the urinary bladder is reported. A 16-year-old high school student visited our outpatient clinic with the com- plaints of fever and severe perineal discomfort after a 3-week medication. Diagnostic imagings showed a mass formation at the anterior wall of the urinary bladder extending to the surrounding tissue, and an osteolytic change of the pubic bone was recognized. The first two biopsies by a needle and TUR failed to diagnose. A sufficient amount of tissue obtained by an open biopsy finally led to the diagnosis of non-specific inflammatory granulation. The patient received treatment with an antibiotic and 10 mg/day of p. o. predonisolone, which resulted in a 60% reduction of the mass in a week and its complete disappearance in two months. The steroid therapy was terminated after 3 months. We collected only 9 cases of non-specific inflammatory granuloma of the urinary bladder in the Japanese literature. Classifications, diagnosis and treatments of the disease are briefly discussed.
• A case of retroperitoneal extramedullary plasmacytoma, 39, 7, 639, 643,   1993 07 , http://hdl.handle.net/2433/117884
  Summary:Extramedullary plasmacytoma (EMP) is a very rare disease and mainly arises in the head and neck area. We herein reported a case of EMP arising in the retroperitoneal space. A 46-year-old man was referred to our outpatient clinic in November 1989 with the complaint of flank pain on the left side. Radiological examinations showed a tumor formation in the retroperitoneal space, which involved the left kidney, spleen and pancreas. Immunoelectrophoresis showed an elevation of serum IgG level and a spike of M-protein was detected in the serum protein electrophoresis. No bone lesions were detected, and bone marrow aspiration showed no abnormal cells. US-guided needle biopsy of the tumor led to the histological diagnosis as plasmacytoma of the IgG-kappa type. Following three cycles of preoperative chemotherapy (a THP-COP regimen), which resulted in a size reduction of the tumor by 40%, extensive resection of the tumor including extirpation of the left kidney, spleen, and tail of pancreas was performed. Because of tumor extension into the posterior wall of the stomach, however, the surgery resulted in incomplete resection. A total of 11 cycles of postoperative chemotherapy (THP-COP) was performed periodically for the residual tumor in the stomach. Rapid tumor spreading in addition to re-elevation of the serum IgG level, however, developed after the 11th postoperative chemotherapy, which extensively involved the stomach and intestines. The patient died of the disease 33 months after the initiation of treatment.
• A case of retroperitoneal ganglioneuroma, 37, 4, 369, 372,   1991 04 , http://hdl.handle.net/2433/117161
  Summary:A 41-year-old female patient with a right retroperitoneal tumor for more than thirty years was referred to our department. Exploration was done through a transperitoneal approach and the tumor was removed. A ganglioneuroma was diagnosed histopathologically. There have been 99 reported cases with retroperitoneal ganglioneuroma including our present case in Japan and we discuss the pathogenesis and treatment of this rare disease.
• INVESTIGATION OF POSTOPERATIVE ADJUVANT CHEMOTHERAPY FOR PATIENTS WITH TRANSITIONAL CELL CARCINOMA OF THE UPPER UROTHELIUM, Uemura Hirotsugu, Yoshikawa Motoyoshi, Morita Noboru, Yoshida Kojiro, Watanabe Shuji, Hiramatsu Tadashi, Ikuma Shoichiro, Yamada Kaoru, Babaya Katsuhiro, Shiomi Tsutomu, Kubota Kazuo, Ozono Seiichiro, Maruyama Yoshio, Hayashi Yoshiki, Hirao Yoshihiko, Okajima Eigoro, Aoyoma Hideo, Sasaki Kenji, Ohara Soichi, Hashimoto Masayoshi, The Japanese Journal of Urology, 82, 8, 1273, 1280,   1991 , 10.5980/jpnjurol1989.82.1273
  Summary:During the 5 years from January, 1985 to December, 1989, 88 patients with transitional cell carcinoma of the renal pelvis and/or ureter were operated curatively in the Department of Urology, Nara Medical University and the affiliated hospitals. There were 66 males and 22 females (3:1) and the mean age was 66.0 years old ranging from 34 to 82. Staging of the renal pelvic and ureteral cancer of each patient was determined by General Rule for Clinical and Pathological Studies on Renal Pelvic and Ureteral Cancer established jointly by Japanese Urological Association and The Japanese Society of Pathology in 1990. The over-all survival rates at 1 and 3 years were 91.2% and 74.0%, respectively. The 3 year survival rates of TS and TE were 80.5% and 41.7%. As for grading, the 3-year survival rates were 75.0% for G1, 70.1% for G2, and 75.2% for G3, respectively. The stage of the tumors affected the prognosis. Of 88 patients 26 (Group 1) received cisplatin based combination chemotherapy as a postoperative adjuvant therapy, and the remaining 62 (Group 2) received no such cytotoxic adjuvant chemotherapy. The 3-year survival rates were 63.3% in Group 1 and 78.9% in Group 2, however mean age of Group 1 was significantly younger than that of Group 2. In spite of the age matched trial, there were no significant differences in survival rates between both groups. Adverse effects of cisplatin based combination chemotherapy included gastrointestinal symptom, fatigue, alopecia and leukopenia, however no serious toxicity was seen. These results suggest that prospective randomized trial would be clarified the efficacy of postoperative adjuvant chemotherapy for patients with renal pelvic and/or ureteral cancer.
• THE URINARY OXALATE DETERMINATION USING HIGH PERFORMANCE LIQUID CHROMATOGRAPHY, Ikuma Shoichiro, Yoshida Katsunori, Kihoin Kunihiko, Hirao Yoshihiko, Okajima Eigoro, Motomiya Yoshihiro, Tsunemi Kunihiko, Hirata Naoya, Tsumatani Kenichi, Morita Noboru, Uemura Hirotsugu, Kaneko Yoshiteru, Moriya Alira, The Japanese Journal of Urology, 79, 5, 903, 909,   1988 , 10.5980/jpnjurol1928.79.5_903
  Summary:A procedure has been newly developed, with which urinary oxalate may be determined through an electroconductivity detector, whenerver sample urine is transfused into the high performance liquid chromatography through a dispo-typed column. The procedure features a measuring range from 1 to 100mg/l; a variation factor as reproducibility determinant of 2.0±0.9% on the basis of triplicate assay; and a recovery rate of 102.3±3 9%. The mean urinary oxalate excretion of normal subjects (n=10) was 25.6±4.7mg/day.
• Usefulness of computed tomography and ultrasonography for the early detection of renal cell carcinoma, 33, 7, 998, 1004,   1987 07 , http://hdl.handle.net/2433/119207
  Summary:Eighty-three cases of renal cell carcinomas admitted to Nara Medical University and its related hospitals from August, 1962 through July, 1984 were reviewed. We have been using computed tomography (CT) and ultrasonography (US) for early detection of renal cell carcinomas since 1980. Thereafter the number of patients with low stage renal cell carcinoma was significantly increased. Furthermore 6 carcinomas were incidentally detected by CT and/or US examination for checkup of other diseases. We believe that CT and US may be valuable as a screening modality for early detection of renal cell carcinoma.
• MEDULLARY SPONGE KIDNEY ASSOCIATED WITH RENAL CELL CARCINOMA:REPORT OF A CASE, Uemura Hirotsugu, Futami Takashi, Yoshikawa Motoyoshi, Yamamoto Masashi, Babaya Katsuhiro, Hirao Yoshihiko, Okajima Eigoro, The Japanese Journal of Urology, 77, 1, 140, 144,   1986 01 , 10.5980/jpnjurol1928.77.1_140
  Summary:A case of medullary sponge kidney associated with right renal cell carcinoma is reported. The patient was a 64-year-old man, who was admitted to our hospital on February 3 1983, with the complaint of asymptomatic grosshematuria. He was diagnosed as bilateral medullary sponge kidney on the basis of radiological findings by excretory urography and retrograde pyelography which showed fanlike images and grape-like clusters in 1976. The diagnosis of right renal tumor was established by CT scan and selective renal angiography in 1983. Right radical nephrectomy was done in February 15, 1983. Histological diagnosis was renal cell carcinoma. Japanese cases of medullary sponge kidney were reviewed and complication of medullarv sponge kidney was discussed.
• Experience of renal autotransplantation, 30, 11, 1565, 1578,   1984 11 , http://hdl.handle.net/2433/118334
  Summary:We present 2 cases with renovascular hypertension treated by renal autotransplantation and 3 cases with extensive renal calculi treated by renal bench surgery and autotransplantation. The cases with renovascular hypertension were due to fibromuscular dysplasia in the trunk of renal artery, and return to normotension and improvement of renal function were obtained within a few days after the operation. In 2 of the cases with extensive renal calculi, the contralateral kidney was contracted. In all cases, the stones were removed completely and urinary tract infection persisting before operation was eradicated. The postoperative renal function was well preserved and no recurrence of renal calculi was observed throughout the follow up period. The indication of renal bench surgery and autotransplantation was discussed both for renal calculi and renovascular hypertension.
• A clinical observation on pyeloplasty in obstruction of the ureteropelvic junction. Special consideration on Anderson-Hynes pyeloplasty, 30, 10, 1393, 1404,   1984 10 , http://hdl.handle.net/2433/118307
  Summary:Thirty-three patients (thirty-five kidneys) underwent pyeloplasty for hydronephrosis due to obstruction of ureteropelvic junction between 1963 and 1982 in our department. Renal function was judged to have improved in 68 and 67% of the patients from the radiogram and radioisotope renogram, respectively, Anderson-Hynes pyeloplasty was performed on 27 kidneys. In these kidneys, the improvement of renal function as judged from the radiogram and radioisotope renogram was 74 and 71%, respectively. Postoperative results were compared according to age, preoperative urinary tract infection (UTI), indwelling periods of nephrostomy and splint catheter, and duration of postoperative UTI. In addition the relationship between indwelling periods of nephrostomy catheter and the duration of postoperative UTI are discussed. Infants under 10 years old had the best improvement. Preoperative UTI and indwelling periods of nephrostomy and splint catheter were not directly related with post operative results. The cases with nephrostomy catheter which could be removed within the 16th day after operation had excellent improvement on UTI and also in renal function.
• 腫瘍免疫環境プロファイルと抗腫瘍免疫反応(Profiling the tumor immune milieu to assess and predict immune responses), デベラスコ・マルコ, 倉 由吏恵, 森 康範, 清水 信貴, 大關 孝之, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 78回, E, 2067,   2019 09
• アパルタミドによる前立腺腫瘍内の免疫環境の変化(Apalutamide reworks the tumor immune microenvironment of prostate tumors), 清水 信貴, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 78回, P, 2267,   2019 09
• TAS-115マルチキナーゼ阻害薬のマウス前立腺癌モデルにおける免疫調整について(Immunomodulation of the multi-tyrosine kinase inhibitor TAS-115 in a mouse Pten-deficient prostate cancer), 倉 由吏恵, デベラスコ・マルコ, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 78回, P, 2360,   2019 09
• イソフラボン摂取はマウス前立腺癌転移モデルにおいて癌の進行を抑制し生存期間を延長させる(Chemopreventive effects of dietary isoflavone in conditional Pten/Trp53-deficient mouse model of prostate cancer), 森 康範, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 78回, J, 3030,   2019 09
• リアルタイムPCRを用いた腫瘍免疫プロファイルと免疫反応性の評価について(A real-time PCR-based approach to quantitatively assess tumor immune profiles and immune responses), 野澤 昌弘, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 78回, J, 3035,   2019 09
• アンドロゲン受容体標的治療は前立腺癌の腫瘍微小免疫環境を変化させる(Targeting the androgen receptor to remodel the tumor immune microenvironment of prostate cancers), 植村 天受, デベラスコ・マルコ, 日本癌学会総会記事, 78回, P, 3272,   2019 09
• 脊髄損傷(SCI)したマウスの下部尿路機能障害(LUTD)に対するPDE9阻害薬の治療効果(Therapeutic effects of PDE9 inhibitor on lower urinary tract dysfunction(LUTD) in mice with spinal cord injury(SCI)), 清水 信貴, 鈴木 孝尚, 高岡 栄一郎, 清水 孝洋, 平山 暁秀, 植村 天受, 吉村 直樹, 日本泌尿器科学会総会, 107回, ISP, 32,   2019 04
• 骨転移を有する去勢抵抗性前立腺癌患者を対象とした塩化ラジウム-223の使用成績調査(中間解析結果), 絹谷 清剛, 筧 善行, 舛森 直哉, 高橋 俊二, 細野 眞, 平野 和史, 松葉 康浩, 砂谷 敏行, 植村 天受, 核医学, 55, Suppl., S189, S189,   2018 11
• 癌治療-Made in Japan 世界にはばたく日本発の癌治療-次世代を担う免疫療法を目指して 個別化ペプチドワクチンによるがんの最適治療を目指す3つの臨床的アプローチ, 伊東 恭悟, 野口 正典, 由谷 茂, 七條 茂樹, 山田 亮, 笹田 哲朗, 成田 善孝, 寺崎 瑞彦, 植村 天受, 末金 茂高, 唐 宇飛, 内藤 雅康, 河野 光一郎, 吉山 康一, 坂本 信二郎, 日本癌治療学会学術集会抄録集, 56回, SSY7, 1,   2018 10
• 軟部組織肉腫-原発巣に応じた外科的アプローチの多様性- 悪性軟部腫瘍の治療 泌尿器科の立場から, 野澤 昌弘, 植村 天受, 日本癌治療学会学術集会抄録集, 56回, PD12, 2,   2018 10
• 腎細胞癌に対するNivolumab+IpilimumabとSunitinib比較試験(CheckMate214) 日本人解析, 冨田 善彦, 近藤 恒徳, 木村 剛, 井上 高光, 和久本 芳彰, 矢尾 正祐, 杉山 貴之, 大家 基嗣, 藤井 靖久, 小原 航, Mekan Sabeen, Mchenry Brent, Doan Justin, Motzer Robert, 植村 天受, 日本癌治療学会学術集会抄録集, 56回, O42, 1,   2018 10
• 去勢抵抗性前立腺がんに対する20種混合ペプチドワクチンの有効性の検討, 野口 正典, 新井 学, 頴川 晋, 大山 力, 内藤 誠二, 松本 和将, 植村 天受, 中川 昌之, 那須 保友, 江藤 正俊, 末金 茂高, 笹田 哲朗, 山田 亮, 角間 辰之, 伊東 恭悟, 日本癌治療学会学術集会抄録集, 56回, O43, 1,   2018 10
• 骨転移を有するCRPC患者を対象とした塩化ラジウム-223の使用成績調査 中間解析結果, 舛森 直哉, 植村 天受, 絹谷 清剛, 高橋 俊二, 平野 和史, 松葉 康浩, 砂谷 敏行, 筧 善行, 日本癌治療学会学術集会抄録集, 56回, P46, 5,   2018 10
• 遺伝子改変Ptenノックアウトマウス前立腺癌モデルにおけるApalutamideの有効性についての検討(Preclinical activity of apalutamide (ARN-509) in genetically engineered mouse models of Pten-deficient prostate cancer), 森 康範, デベラスコ・マルコ, 倉 由吏恵, 大關 孝之, 清水 信貴, 野澤 昌弘, 吉村 一宏, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 179, 179,   2018 09
• Pimキナーゼ阻害薬は去勢抵抗性マウス前立腺癌モデルにおいて腫瘍増殖を抑制し生存期間を延長する(PIM inhibition reduces tumor growth and improves survival in mouse advanced castration-resistant prostate cancer), 倉 由吏恵, デベラスコ・マルコ, 森 康範, 清水 信貴, 大關 孝之, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 264, 264,   2018 09
• Ptenノックアウトマウス前立腺癌モデルにおけるマルチキナーゼ阻害薬TAS-115の有効性についての検討(Preclinical evaluation of the multi tyrosine kinase inhibitor TAS-115 in mouse Pten-deficient prostate cancer), 野澤 昌弘, デベラスコ・マルコ, 倉 由吏恵, 清水 信貴, 森 康範, 吉村 一宏, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 265, 265,   2018 09
• 免疫療法開発における遺伝子改変マウス前立腺癌モデルの有用性について(Interrogating genetically engineered mouse models of prostate cancer to aid in immunotherapy development), デベラスコ・マルコ, 倉 由吏恵, 森 康範, 清水 信貴, 大關 孝之, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 414, 414,   2018 09
• 前立腺癌患者の予後不良に関わる遺伝子群の同定(Identification of a gene set associated with poor clinical outcomes in prostate cancer patients), 橋本 士, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 清水 信貴, 森 康範, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 792, 792,   2018 09
• 前立腺癌における遺伝子改変マウスモデル ヒトからマウスへ マウスからヒトへ(Genetically engineered mouse models of prostate cancer: from man to mouse and back), 植村 天受, デベラスコ・マルコ, 日本癌学会総会記事, 77回, 1150, 1150,   2018 09
• Ptenノックアウトマウス前立腺癌モデルを用いたアビラテロンによる抗腫瘍免疫効果に関する検討(Effect of abiraterone therapy on anti-tumor immunity in a mouse Pten-deficient prostate cancer model), 清水 信貴, デベラスコ・マルコ, 倉 由吏恵, 大關 孝之, 森 康範, 野澤 昌弘, 吉村 一宏, 坂井 和子, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 77回, 1792, 1792,   2018 09
• PTENノックアウト前立腺癌マウスモデルにおける腫瘍免疫の包括的分析, De Velasco Marco A., 倉 由吏恵, 坂井 和子, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1222,   2017 09
• 遺伝子改変前立腺癌マウスモデルにおけるPD-L1免疫チェックポイント阻害薬について, 清水 信貴, De Velasco Marco A., 倉 由吏恵, 坂井 和子, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1246,   2017 09
• HLA-A24陽性腎細胞癌患者におけるcancer-reactive cytotoxic T lymphocytesを誘導しうるHIF-1α由来ペプチドの同定, 南 高文, 杉本 公一, 清水 信貴, デベラスコ・マルコ, 野澤 昌弘, 吉村 一宏, 原嶋 奈々江, 原田 守, 植村 天受, 日本癌学会総会記事, 76回, P, 1325,   2017 09
• アンドレゲンレセプターを標的とした次世代アンチセンスオリゴヌクレオチドとAKT阻害薬併用療法の治療効果について, 杉本 公一, De Velasco Marco A., 倉 由吏恵, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 1376,   2017 09
• AKTおよびPimキナーゼをターゲットにした治療戦略はPTEN欠失前立腺癌前臨床動物モデルにおいて治療効果改善を示す, 倉 由吏恵, De Velasco Marco A., 杉本 公一, 坂井 和子, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, J, 2099,   2017 09
• 遺伝子改変マウス前立腺癌モデルを用いた新規化合物の包括的前臨床評価について, 植村 天受, 倉 由吏恵, 杉本 公一, 森 康範, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, De Velasco Marco A., 日本癌学会総会記事, 76回, J, 3121,   2017 09
• ヒト前立腺癌におけるSTAT3について, 森 康範, De Velasco Marco A., 畑中 祐二, 倉 由吏恵, 杉本 公一, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 76回, P, 3215,   2017 09
• Therapeutic potential of combination therapy using a next generation antisense oligonucleotide targeting the androgen receptor and AKT inhibition with AZD5363 in genetically engineered mouse models of prostate cancer, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sugimoto, Koichi, Sakai, Kazuko, Davies, Barry R., Kim, Youngsoo, MacLeod, A. Robert, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, 77,   2017 07 , 10.1158/1538-7445.AM2017-1582
• Characterization of STAT3 activation in human prostate cancer, De Velasco, Marco A., Hatanaka, Yuji, Kura, Yurie, Ando, Naomi, Sakai, Kazuko, Sugimoto, Koichi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, 77,   2017 07 , 10.1158/1538-7445.AM2017-751
• Co-targeting of AKT and Pim kinases in mouse PTEN-deficient prostate cancer, De Velasco, Marco A., Sugimoto, Koichi, Kura, Yurie, Ando, Naomi, Sato, Noriko, Sakai, Kazuko, Davies, Barry R., Huszar, Dennis, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, 77,   2017 07 , 10.1158/1538-7445.AM2017-1096
• PD-L1 blockade in preclinical models of PTEN-deficient prostate cancer, De Velasco, Marco A., Kura, Yurie, Ando, Naomi, Sato, Noriko, Sakai, Kazuko, Davies, Barry R., Sugimoto, Koichi, Nozawa, Masahiro, Yoshimura, Kazuhiro, Yoshikawa, Kazuhiro, Nishio, Kazuto, Uemura, Hirotsugu, CANCER RESEARCH, 77,   2017 07 , 10.1158/1538-7445.AM2017-4702
• First-line avelumab plus axitinib therapy in patients (pts) with advanced renal cell carcinoma (aRCC): Results from a phase Ib trial., Toni K. Choueiri, James M. G. Larkin, Mototsugu Oya, Fiona C. Thistlethwaite, Marcella Martignoni, Paul D. Nathan, Thomas Powles, David F. McDermott, Paul B. Robbins, David D. Chism, Daniel C. Cho, Michael B. Atkins, Michael S. Gordon, Sumati Gupta, Hirotsugu Uemura, Yoshihiko Tomita, Anna Compagnoni, Alessandra Di Pietro, Brian I. Rini, JOURNAL OF CLINICAL ONCOLOGY, 35,   2017 05 , 10.1200/JCO.2017.35.15_suppl.4504
• Avelumab plus axitinib vs sunitinib as first-line treatment of advanced renal cell carcinoma: Phase 3 study (JAVELIN Renal 101), Toni K. Choueiri, Brian I. Rini, James M. G. Larkin, Georg A. Bjarnason, Gwenaelle Gravis, Howard Gurney, Jae-Lyun Lee, Daniel Keizman, John B. A. G. Haanen, Yoshihiko Tomita, Hirotsugu Uemura, Laurence Albiges, Manuela Schmidinger, Michael B. Atkins, Mariangela Mariani, Michael Shnaidman, Alessandra Di Pietro, Robert J. Motzer, JOURNAL OF CLINICAL ONCOLOGY, 35,   2017 05 , 10.1200/JCO.2017.35.15_suppl.TPS4594
• EFFECTS OF NERVE GROWTH FACTOR (NGF) NEUTRALIZATION ON TRP CHANNEL EXPRESSION IN LASER-CAPTURED BLADDER AFFERENT NEURONS OF MICE WITH SPINAL CORD INJURY (SCI), Nobutaka Shimizu, Shun Takai, Naoki Wada, Takahisa Suzuki, Ei-ichiro Takaoka, Takahiro Shimizu, Akihide Hirayama, Hirotsugu Uemura, Anthony J. Kanai, Naoki Yoshimura, JOURNAL OF UROLOGY, 197, 4, E1353, E1354,   2017 04
• PTENノックアウトマウス前立腺癌におけるノンコーディングRNAの検討, 倉 由吏恵, デベラスコ・マルコ, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 1029,   2016 10
• PTENノックアウトマウス前立腺癌において選択的スプライシングは頻繁に認められる, デベラスコ・マルコ, 倉 由吏恵, 坂井 和子, 藤田 至彦, 冨樫 庸介, 寺嶋 雅人, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 1073,   2016 10
• PTENノックアウト前立腺癌マウスモデルにおけるJAK1/2阻害による腫瘍増殖及び転移抑制効果の検討, 植村 天受, 倉 由吏恵, 森 康範, 畑中 祐二, 沖 貴士, 杉本 公一, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 日本癌学会総会記事, 75回, E, 2085,   2016 10
• PTEN/p53ダブルノックアウト前立腺癌マウスモデルにおけるクロロキン経口による治療効果, 杉本 公一, デベラスコ・マルコ, 倉 由吏恵, 森 康範, 畑中 祐二, 沖 貴士, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, E, 3065,   2016 10
• 遺伝子改変と前立腺癌マウスモデルにおける高脂肪食摂取による腫瘍増殖について, 森 康範, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 沖 貴士, 杉本 公一, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 75回, P, 3348,   2016 10
• Analysis of noncoding RNA expression in a mouse model of PTEN-deficient prostate cancer, Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yuji Hatanaka, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, 76,   2016 07 , 10.1158/1538-7445.AM2016-954
• Alternative splicing is a frequent event in mouse PTEN-deficient prostate cancer, Marco A. De Velasco, Yurie Kura, Kazuko Sakai, Yoshihiko Fujita, Yosuke Togashi, Masato Terashima, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, 76,   2016 07 , 10.1158/1538-7445.AM2016-2014
• Phase II clinical study of radium-223 chloride (BAY 88-8223) in Japanese patients with symptomatic castration-resistant prostate cancer (CRPC) with bone metastases., Hiroji Uemura, Satoshi Nagamori, Yoshiaki Wakumoto, Hirotsugu Uemura, Go Kimura, Akira Yokomizo, Hiroaki Kikukawa, Atsushi Mizokami, Takeo Kosaka, Naoya Masumori, Yoshihide Kawasaki, Junji Yonese, Yasutomo Nasu, Satoshi Fukasawa, Takayuki Sugiyama, Motohide Uemura, Iku Yamaguchi, Hirokazu Tsutsui, Eisuke Matsunaga, Nobuaki Matsubara, JOURNAL OF CLINICAL ONCOLOGY, 34, 2,   2016 01
• マウス前立腺癌モデルを用いたAKT阻害薬AZD5356の抗腫瘍効果, 植村 天受, 倉 由吏恵, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, De Velasco Marco A., 日本癌学会総会記事, 74回, E, 1099,   2015 10
• 去勢抵抗性前立腺癌に対するPim-1キナーゼ阻害薬AZD1208の治療効果, 倉 由吏恵, De Velasco Marco A., 沖 貴士, 山本 豊, 畑中 祐二, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 74回, E, 1100,   2015 10
• PTEN欠損前立腺癌マウスモデルにおけるオートファジー阻害薬CQによる長期治療効果について, 杉本 公一, De Velasco Marco A., 倉 由吏恵, 山本 豊, 畑中 祐二, 沖 貴士, 清水 信貴, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 74回, P, 1039,   2015 10
• 前立腺癌におけるAkt/P13KおよびMAPK経路阻害の治療相乗効果について, 山本 豊, De Velasco Marco A., 倉 由吏恵, 畑中 祐二, 沖 貴士, 清水 信貴, 野澤 昌弘, 吉川 和宏, 吉村 一宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 74回, E, 1340,   2015 10
• 前立腺癌に対するオートファジー阻害薬CQと分子標的薬の併用療法について, 畑中 祐二, De Velasco Marco A., 倉 由吏恵, 山本 豊, 沖 貴士, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 74回, E, 1341,   2015 10
• アンドロゲン受容体に対する次世代アンチセンスオリゴヌクレオチドを用いた前立腺癌治療, De Velasco Marco A., 倉 由吏恵, 畑中 祐二, 山本 豊, 吉川 和宏, 清水 信貴, 野澤 昌弘, 吉村 一宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 74回, P, 3355,   2015 10
• Safety and efficacy of radium-223 dichloride (BAY 88-8223) in Japanese patients with castration-resistant prostate cancer and bone metastases, Hirotsugu Uemura, Hiroji Uemura, N. Matsubara, M. Kaneko, T. Doi, EUROPEAN JOURNAL OF CANCER, 51, S489, S489,   2015 09
• Effects of long-term chloroquine chemotherapy in a preclinical model of PTEN-deficient prostate cancer, Kazuhiro Yoshikawa, Marco A. De Velasco, Yurie Kura, Naomi Ando, Emiko Fukushima, Yutaka Yamamoto, Yuji Hatanaka, Takashi Oki, Nobutaka Shimizu, Kazuhiro Yoshimura, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, 75,   2015 08 , 10.1158/1538-7445.AM2015-1857
• Overall survival analysis from a randomized phase II study of axitinib with or without dose titration for first-line metastatic renal cell carcinoma., Brian I. Rini, Yoshihiko Tomita, Bohuslav Melichar, Takeshi Ueda, Viktor Gruenwald, Mayer N. Fishman, Hirotsugu Uemura, Mototsugu Oya, A. H. Bair, Glen Andrews, Dmitri Pavlov, Eric Jonasch, JOURNAL OF CLINICAL ONCOLOGY, 33, 15,   2015 05
• Treatment of castrate-resistant prostate cancer - What is the best management?, Hirotsugu Uemura, Robert Reiter, INTERNATIONAL JOURNAL OF UROLOGY, 22, 4, 427, 427,   2015 04
• オートファジーと前立腺癌発生-進展に関する関係について、PTEN/Atg-7ダブルKO前立腺癌マウスを作製し、検討した(Autophagy in Prostate Tumorigenesis and Its Clinical Implications), デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, J, 2002,   2014 09
• 去勢抵抗性前立腺癌においてアンドロゲン受容体およびmTORの抑制によって、抗腫瘍効果は増強する(Improved antitumor effects of androgen receptor and mTOR inhibition in castration resistant prostate cancer), 倉 由吏恵, デベラスコ・マルコ, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, E, 3064,   2014 09
• 前立腺癌自然発生マウスモデルPTEN KOマウスより、PTEN/p53ダブルKOマウスを確立し、その有用性について報告する(Development of a Lethal Genetically Engineered Mouse Model of Prostate Cancer for Survival Studies and End-stage Cancer), 植村 天受, 倉 由吏恵, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 日本癌学会総会記事, 73回, P, 2023,   2014 09
• 前立腺癌マウスモデルにおけるPI3K/mTORシグナル阻害の効果(Dual targeting of the PI3K/mTOR and AR pathways in a mouse model of PTEN-deficient prostate cancer), 山本 豊, ベデラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 清水 信貴, 南 高文, 野沢 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, P, 2117,   2014 09
• PTEN欠損マウス前立腺がん由来細胞株の樹立(Establishment and characterization of cell lines derived from mouse PTEN-deficient prostate cancer), 吉川 和宏, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, P, 3172,   2014 09
• HOXA10の発現異常が前立腺全摘出術後の再発を予測する可能性の検討(Aberrantly Expressed HOXA10 Could Possibly Predict Recurrence after Radical Prostatectomy), 畑中 祐二, マルコ・デベラスコ, 沖 貴士, 倉 由吏恵, 山本 豊, 吉村 一宏, 清水 信貴, 野沢 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, P, 1303,   2014 09
• ヒト前立腺癌におけるLumicanの発現についての検討(Expression of Lumican in Human Prostate Cancer), 沖 貴士, デベラスコ・マルコ, 畑中 祐二, 倉 由吏恵, 山本 豊, 吉村 一宏, 清水 信貴, 野澤 昌弘, 吉川 和弘, 西尾 和人, 植村 天受, 日本癌学会総会記事, 73回, P, 1313,   2014 09
• EFFECTS OF ANTICHOLINERGIC AGENT ON AUTONOMIC NERVOUS SYSTEM (ANS) FUNCTION OF OVERACTIVE BLADDER SYNDROME PATIENTS, N. Shimizu, K. Sugimoto, Y. Yamamoto, T. Minami, M. Nozawa, K. Yoshimura, H. Uemura, A. Hirayama, NEUROUROLOGY AND URODYNAMICS, 33, 6, 1016, 1018,   2014 08
• Randomized phase II study of personalized peptide vaccination in patients isith advanced bladder cancer progressing after chernotherapy, Masanori Noguchi, Umasa Matsumoto, Hirotsugu Uemura, Gaku Arai, Masatoshi Eto, Seiji Nalto, Chlkara Ohyama, Yasutomo Nasu, Masatoshl Tanaka, Fukuko Moriya, Shigetaka Suekano, Satoko Matsueda, Nobukazu Komatsu, -Mauro Nada, Akira Yamada, Kyogo Koh, JOURNAL OF CLINICAL ONCOLOGY, 32, 15,   2014 05
• Development and analysis of androgen receptor (AR) axis biomarkers of circulating tumor cells (CTCs) in. Japanese metastatic castration-resistant prostate cancer (mCRPC) patients (pts) treated iii abiraterone acetate (AA), Weimin Li, Hideyuki Akaza, Tsutomu Nishiyama, Takefumi Satoh, Hiroji Uemura, Denis Smirnov, Willem Talloen, Brad Foulk, Jaymala Patel, Kathy Zellnsky, Deborah Sokol Ricci, Makio Kamida, Kazushiro Kawaguchi, Koho Iizuka, JOURNAL OF CLINICAL ONCOLOGY, 32, 15,   2014 05
• Phase I clinical study of cabazitaxel plus prednisolone for the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a Japanese population., Shunji Takahashi, Hirofumi Mukai, Hirotsugu Uemura, Hiroji Uemura, Takeo Kosaka, Hiroyuki Nishiyama, Kazuhiro Suzuki, Yoshiyuki Kakehi, Koji Okihara, Shunichi Namiki, Osamu Ogawa, Masashi Kato, Yasutomo Nakai, Keiji Ohno, JOURNAL OF CLINICAL ONCOLOGY, 32, 4,   2014 02
• がん免疫療法 臨床研究から学ぶヒト腫瘍免疫学 CTLエピトープワクチン療法(Cancer Immunotherapy: Bedside to Bench Recent advances of cancer vaccines with CTL epitope peptides), 伊東 恭悟, 山田 亮, 植村 天受, 笹田 哲朗, 野口 正典, 日本癌学会総会記事, 72回, 55, 55,   2013 10
• PTENノックアウト前立腺癌マウスにおけるMAPKシグナル抑制と抗腫瘍効果(Tumor responses to MAPK signal inhibition in a preclinical model of PTEN deficient prostate cancer), 山本 豊, デベラスコ・マルコ, 倉 由吏恵, 安藤 直美, 福島 恵美子, 畑中 祐二, 清水 信貴, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 72回, 197, 197,   2013 10
• STAT3転写活性の抑制による前立腺癌治療(Targeting Prostate Cancer Through Inhibition of STAT3 Transcriptional Activation), 倉 由吏恵, デベラスコ・マルコ, 安藤 直美, 福島 恵美子, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 72回, 197, 197,   2013 10
• オートファジーと前立腺癌(Autophagy and prostate cancer), デベラスコ・マルコ, 倉 由吏恵, 安藤 直美, 福島 恵美子, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 72回, 227, 227,   2013 10
• 前立腺癌のPTEN・P53ダブルノックアウトによる相乗効果(Synchronous inactivation of PTEN and P53 accelerates prostate cancer), 植村 天受, 倉 由吏恵, 安藤 直美, 福島 恵美子, 畑中 祐二, 山本 豊, 清水 信貴, 吉村 一宏, 野澤 昌弘, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 日本癌学会総会記事, 72回, 232, 232,   2013 10
• 前立腺癌におけるHOXA10の発現異常について(HOXA10 is aberrantly expressed in prostate cancer), 畑中 祐二, デベラスコ・マルコ, 倉 由吏恵, 清水 信貴, 山本 豊, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 72回, 308, 308,   2013 10
• Importance of performance status, corrected calcium, and microvascular invasion in predicting overall survival in patients with metastatic renal cell carcinoma at the era of molecular targeted therapy, Masatoshi Eto, Tomomi Kamba, Hideaki Miyake, Masato Fujisawa, Takao Kamai, Hirotsugu Uemura, Taiji Tsukamoto, Haruhito Azuma, Akio Matsubara, Kazuo Nishimura, Tsuyoshi Nakamura, Osamu Ogawa, Seiji Naito, JOURNAL OF CLINICAL ONCOLOGY, 31, 15,   2013 05
• CLINICAL UTILITY OF PCA3 URINE ASSAY IN JAPANESE MEN UNDERGOING PROSTATE BIOPSY, Atsushi Ochiai, Koji Okihara, Kazumi Kamoi, Takehiro Oikawa, Toru Shimazui, Shinichiro Murayama, Kyoichi Tomita, Tohru Umekawa, Hirotsugu Uemura, Tsuneharu Miki, JOURNAL OF UROLOGY, 189, 4, E915, E915,   2013 04
• 前立腺がんに対するStat3を標的とした阻害の治療の有効性(The potential of targeted Stat3 inhibition for prostate cancer), デ・ベラスコ・マルコ, 倉 由吏恵, 小林 泰之, 畑中 祐二, 山本 豊, 吉村 一宏, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本泌尿器科学会雑誌, 104, 2, 412, 412,   2013 03
• ヒト前立腺がんにおけるルミカンの発現(Expression of lumican in human prostate adenocarcinoma), 倉 由吏恵, デベラスコ・マルコ, 畑中 祐二, 山本 豊, 吉村 一弘, 清水 信貴, 野澤 昌弘, 吉川 和弘, 西尾 和人, 植村 天受, 日本泌尿器科学会雑誌, 104, 2, 416, 416,   2013 03
• レプチンは前立腺がんの進行に寄与する(Leptin contributes to drive prostate cancer progression), 吉村 一宏, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 山本 豊, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本泌尿器科学会雑誌, 104, 2, 416, 416,   2013 03
• Comparison of PFS and safety for Asian compared to North American and European populations in the phase III trial of pazopanib versus sunitinib in patients with treatment-naive RCC (COMPARZ), Jun Guo, Jie Jin, Yiran Huang, Jin-Wan Wang, Ho Yeong Lim, Hirotsugu Uemura, Sun Young Rha, Hsi Chin Wu, Rocco Crescenzo, Keith C. Deen, Lauren McCann, Robert John Motzer, JOURNAL OF CLINICAL ONCOLOGY, 31, 6,   2013 02
• THE CLINICAL ROLE OF PEPTIDE VACCINES FOR CASTRATION-RESISTANT PROSTATE CANCER, T. Minami, T. Kimura, M. Nozawa, K. Yoshimura, T. Nakagawa, A. Yamada, K. Itoh, H. Fujimoto, S. Egawa, H. Uemura, ANNALS OF ONCOLOGY, 23, 96, 96,   2012 10
• Phase II Study of Zoledronic Acid Concomitant with Androgen Deprivation Therapy for Patients with Treatment-Naive Bone-Metastatic Prostate Cancer: An Interim Analysis, Hara, I, M. Nozawa, K. Nagao, T. Nishioka, T. Komura, A. Esa, M. Kitagawa, T. Inagaki, H. Matsuyama, H. Uemura, UROLOGY, 80, 3, S275, S275,   2012 09
• Difference in Adverse Events of mTOR Inhibitors, Everolinus and Temsirolimus, in Metastatic Renal Cell Carcinoma Patients, M. Nozawa, N. Shimizu, Y. Yamamoto, T. Minami, T. Hayashi, K. Yoshimura, T. Ishii, H. Uemura, UROLOGY, 80, 3, S94, S94,   2012 09
• 転移性腎がんに対するMHCクラスIペプチドワクチン療法の役割(Clinical role of MHC-class I peptide vaccines for metastatic renal cell carcinoma), 植村 天受, 吉村 一宏, 南 高文, デベラスコ・マルコ, 日本癌学会総会記事, 71回, 146, 146,   2012 08
• HLA-A24陽性腎細胞癌患者におけるcancer-reactive CTLsを誘導し得るEpoR抗原由来ペプチドの同定(Identification of EpoR-derived peptides having the potential to induce cancer-reactive CTLs from HLA-A24+RCC patients), 南 高文, 南 知子, 大関 孝之, デベラスコ・マルコ, 清水 信貴, 山本 豊, 辻 秀憲, 野澤 昌弘, 吉村 一宏, 植村 天受, 日本癌学会総会記事, 71回, 151, 151,   2012 08
• ヒト前立腺癌におけるルミカンの発現について(Expression of Lumican in Human Prostate Adenocarcinoma), 吉村 一宏, デベラスコ・マルコ, 畑中 祐二, 倉 由吏恵, 山本 豊, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 71回, 293, 293,   2012 08
• 前立腺特異的PTENノックアウトマウスにおけるSTAT3の転写活性に関する検討(Stat3 Transcriptional Activation in a Pten-mutant Mouse Model of Prostate Cancer), 小林 泰之, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 山本 豊, 吉村 一宏, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 71回, 437, 437,   2012 08
• 前立腺癌マウスモデルに対する分子標的治療薬の抗腫瘍効果の検討(Preclinical evaluation of combined targeted therapy for the treatment of prostate cancer), 山本 豊, デベラスコ・マルコ, 倉 由吏恵, 畑中 祐二, 吉村 一宏, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 71回, 437, 437,   2012 08
• ヒト前立腺癌の進展におけるHOXA10の発現異常について(Deregulation of HOXA10 is Associated with Progression of Human Prostate Cancer), 畑中 祐二, デベラスコ・マルコ, 倉 由吏恵, 山本 豊, 吉村 一宏, 清水 信貴, 野澤 昌弘, 吉川 和宏, 西尾 和人, 植村 天受, 日本癌学会総会記事, 71回, 519, 519,   2012 08
• Efficacy and safety of sunitinib (SU) in patients (pts) with metastatic renal cell carcinoma (mRCC) and lung metastases (mets) only at baseline, Nobuo Shinohara, Hideyuki Akaza, Yoshihiko Tomita, Takeshi Yuasa, Hiroyuki Fujimoto, Masashi Niwakawa, Seiichiro Ozono, Soichi Mugiya, Tsuneharu Miki, Hirotsugu Uemura, Norio Nonomura, Masayuki Takahashi, Yoshihiro Hasegawa, Eiji Ueda, Atsushi Shibata, Norisuke Kawai, Seiji Naito, JOURNAL OF CLINICAL ONCOLOGY, 30, 15,   2012 05
• Use of STAT3 polymorphisms to predict overall survival in patients treated with interferon-alpha for metastatic renal cell carcinoma., Masatoshi Eto, Tomomi Kamba, Hideaki Miyake, Masato Fujisawa, Takao Kamai, Hirotsugu Uemura, Taiji Tsukamoto, Haruhito Azuma, Akio Matsubara, Kazuo Nishimura, Tsuyoshi Nakamura, Osamu Ogawa, Seiji Naito, JOURNAL OF CLINICAL ONCOLOGY, 30, 15,   2012 05
• Role of Stat3 transcriptional activation in a preclinical mouse model of prostate cancer and potential as a therapeutic target, Marco A. De Velasco, Motoyoshi Tanaka, Kaori Fujimoto-Ouchi, Yoichiro Moriya, Yurie Kura, Yasuki Kobayashi, Yutaka Yamamoto, Yuji Hatanaka, Hiroyuki Kato, Kazuhiro Yoshikawa, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, 72,   2012 04 , 10.1158/1538-7445.AM2012-3876
• Efficacy and safety of sequential usage of everolimus in Asian patients with metastatic renal cell carcinoma (mRCC): Cooperative results from Osaka Urologic Oncology Group (OUOG)., Teruo Inamoto, Hirotsugu Uemura, Norio Nonomura, Tatsuya Nakatani, Tadashi Matsuda, Haruhito Azuma, JOURNAL OF CLINICAL ONCOLOGY, 30, 5,   2012 02
• Efficacy of alpha 1-AR antagonists in patients undergoing prostate 125I brachytherapy for prostate carcinoma: A randomized trial involving pressure flow study, N. Shimizu, M. Yasuda, Y. Yamamoto, T. Minami, T. Hayashi, M. Nozawa, K. Yoshimura, T. Ishii, H. Uemura, K. Nakamatsu, EUROPEAN UROLOGY SUPPLEMENTS, 11, 1, E732, U557,   2012 02
• Effect of zoledronic acid and biochemical relapse in treatment-naive patients with bone-metastatic prostate cancer., Hideyasu Matsuyama, Masahiro Nozawa, Takeshi Inagaki, Kazuhiro Nagao, Isao Hara, Hirotsugu Uemura, JOURNAL OF CLINICAL ONCOLOGY, 30, 5,   2012 02
• 前立腺癌におけるルミカン発現(Lumican expression in prostate cancer), 王 一, デベラスコ・マルコ, 畑中 祐二, 山本 豊, 田中 基幹, 清水 信貴, 児玉 光正, 吉川 和宏, 荒尾 徳三, 西尾 和人, 植村 天受, 日本癌学会総会記事, 70回, 69, 69,   2011 09
• PTENコンディショナルノックアウト前立腺癌マウスモデルを用いた新規バイオマーカの同定(Use of the prostate-specific PTEN conditional knockout mouse model to Identify prognostic biomarkers in prostate cancer), デベラスコ・マルコ, 田中 基幹, 畑中 祐二, 山本 豊, 清水 信貴, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 荒尾 徳三, 植村 天受, 西尾 和人, 日本癌学会総会記事, 70回, 69, 70,   2011 09
• Ptenノックアウト前立腺癌モデルにおけるsorafenibの治療効果(Pre-clinical efficacy of sorafenib on a Pten knockout mouse prostate cancer model), 山本 豊, デベラスコ・マルコ, 王 一, 畑中 祐二, 田中 基幹, 清水 信貴, 児玉 光正, 吉川 和宏, 荒尾 徳三, 西尾 和人, 植村 天受, 日本癌学会総会記事, 70回, 70, 70,   2011 09
• 高脂肪食摂取量の増大と前立腺癌の進行の関係に関するリスク評価のための臨床前モデル(A preclinical model to evaluate the risk of increased dietary fat consumption and prostate cancer progression), 吉村 一宏, デベラスコ・マルコ, 畑中 祐二, 田中 基幹, 山本 豊, 王 一, 清水 信貴, 野澤 昌弘, 荒尾 徳三, 西尾 和人, 植村 天受, 日本癌学会総会記事, 70回, 101, 101,   2011 09
• 前立腺特異的PTENノックアウトマウスモデルを用いた前立腺癌におけるChemopreventionおよびInterventionに関する研究(Use of prostate-specific PTEN conditional knockout mice in prostate cancer prevention and intervention research), 植村 天受, 田中 基幹, 小池 浩之, 山本 豊, 畑中 祐二, 王 一, 清水 信貴, 野澤 昌弘, 吉村 一宏, 吉川 和宏, 西尾 和人, デベラスコ・マルコ, 日本癌学会総会記事, 70回, 161, 161,   2011 09
• HOXA10 expression in prostate cancer(HOXA10 is aberrantly expressed in prostate cancer), 畑中 祐二, デベラスコ・マルコ, 王 一, 山本 豊, 田中 基幹, 清水 信貴, 児玉 光正, 吉川 和宏, 荒尾 徳三, 西尾 和人, 植村 天受, 日本癌学会総会記事, 70回, 439, 439,   2011 09
• SYSTEMIC TRANSDUCTION OF P16(INK4A) ANTI-TUMOR PEPTIDE INHIBITS GROWTH OF MBT-2 BLADDER TUMOR CELL LINE GRAFT IN MICE, Toru Shimazui, Kazuhiro Yoshikawa, Takahiro Kojima, Jun Miyazaki, Hiromu Inai, Hirotsugu Uemura, Eisaku Kondo, JOURNAL OF UROLOGY, 185, 4, E428, E429,   2011 04
• Activity of retreatment with sorafenib for metastatic renal cell carcinoma, M. Nozawa, N. Matsumura, M. Yasuda, Y. Okuda, H. Uemura, JOURNAL OF CLINICAL ONCOLOGY, 29, 7,   2011 03
• ACTIVITY OF SUNITINIB AS THIRD-LINE TREATMENT OF METASTATIC RENAL CELL CARCINOMA (MRCC) (JAPAN), M. Nozawa, Y. Mochida, K. Nishigaki, S. Nagae, H. Uemura, JAPANESE JOURNAL OF CLINICAL ONCOLOGY, 41, 3, I11, I11,   2011 03
• 前立腺がんの基礎・臨床研究の最前線 前立腺特異的PTENコンディショナルノックアウトマウスモデルによるヒト前立腺癌への応用(Front line of basic and clinical researches of prostate cancer The prostate-specific PTEN conditional knockout mouse as a model for human prostate cancer), デベラスコ・マルコ, 小池 浩之, 吉川 和宏, 荒尾 徳三, 西尾 和人, 植村 天受, 日本癌学会総会記事, 69回, 363, 363,   2010 08
• p16INK4A抗腫瘍ペプチドの全身投与によるマウスのMBT-2移植膀胱腫瘍に対する増殖抑制効果(Systemic transduction of p16INK4A anti-tumor peptide inhibits growth of MBT-2bladder tumor cell line graft in mice), 島居 徹, 吉川 和宏, 小島 崇宏, 宮崎 淳, 稲井 広夢, 植村 天受, 日本癌学会総会記事, 69回, 472, 472,   2010 08
• Targeting prostate cancer chemoprevention via the androgen receptor in a preclinical mouse model, Hiroyuki Koike, Marco A. De Velasco, Yuka Miyazaki, Chiori Asahi, Hiroshi Ushida, Keiji Shimada, Kazuhiro Yoshikawa, Kazuto Nishio, Noboru Konishi, Hirotsugu Uemura, CANCER RESEARCH, 70,   2010 04 , 10.1158/1538-7445.AM10-956
• DELIVERY OF PTEN VIA A NOVEL GENE MICRO-CAPSULE SENSITIZES PROSTATE CANCER CELLS TO IRRADIATION, Marco DeVelasco, Motoyoshi Tanaka, Atsushi Tomioka, Satoshi Anai, Hirotsugu Uemura, JOURNAL OF GENE MEDICINE, 11, 12, 1182, 1182,   2009 12
• A NOVEL PTEN FUNCTIONAL PEPTIDE THERAPY FOR PROSTATE CANCER, Motoyoshi Tanaka, Satoshi Anai, Marco DeVelasco, Keigo Saito, Atsushi Tomioka, Kazuhiro Yoshikawa, Hirotsugu Uemura, JOURNAL OF GENE MEDICINE, 11, 12, 1183, 1183,   2009 12
• RADIOSENSITIZATION BY A NOVEL P16 FUNCTIONING PEPTIDE THERAPY IN PROSTATE CANCER, Satoshi Anai, Motoyoshi Tanaka, Marco De Velasco, Keigo Saito, Atsushi Tomioka, Kazuhiro Yoshikawa, Toru Shimazhui, Eisaku Kondo, Yoshihiko Hirao, Hirotsugu Uemura, JOURNAL OF GENE MEDICINE, 11, 12, 1181, 1181,   2009 12
• Tolerability and adverse events of sunitinib in Japanese patients with advanced renal cell carcinoma, M. Nozawa, T. Oki, Y. Okuda, T. Minami, T. Hayashi, S. Nagae, K. Nishigaki, Y. Mochida, H. Uemura, EJC SUPPLEMENTS, 7, 2, 430, 431,   2009 09
• 血清セレン濃度と前立腺癌リスクの検討(Serum selenium and risk of prostate cancer in Japanese men), 野澤 昌弘, 吉田 宗弘, 齋藤 允孝, 大関 孝之, 中川 勝弘, 南 高文, 林 泰司, 植村 天受, 日本癌学会総会記事, 68回, 504, 504,   2009 08
• Chemopreventive efficacy of meloxicam against prostate tumor growth and progression in the prostate-specific PTEN conditional gene knockout mouse model, Motoyoshi Tanaka, Marco De Velasco, Keiji Shimada, Hirotsugu Uemura, CANCER RESEARCH, 69,   2009 05
• Serum selenium and risk of prostate cancer in Japanese men, M. Nozawa, M. Yoshida, Y. Saito, M. Nakagawa, T. Ozeki, M. Yoshikawa, Y. Aono, H. Uemura, JOURNAL OF CLINICAL ONCOLOGY, 27, 15,   2009 05
• Tumor explant animal model: Moving towards tailor-made therapy of renal cell carcinoma, Marco De Velasco, Motoyoshi Tanaka, Kazuto Nishio, Hirotsugu Uemura, CANCER RESEARCH, 69,   2009 05
• EXPRESSION OF CADHERIN-6 MRNA IS POOR PROGNOSTIC FACTOR FOR PATIENTS WITH T1-T3 RENAL CELL CARCINOMA, Toru Shimazui, Kazuhiro Yoshikawa, Hirotsugu Uemura, Yoshihiko Hirao, Hideyuki Akaza, JOURNAL OF UROLOGY, 181, 4, 216, 217,   2009 04
• CHRONIC TREATMENT WITH A PDE5 INHIBITOR INCREASED CONTRACTILE FORCE OF NORMAL BLADDER IN RATS, Seiji Matsumoto, Tadashi Hanai, Hirotsugu Uemura, JOURNAL OF UROLOGY, 181, 4, 151, 151,   2009 04
• EFFECT OF PARTIAL BLADDER OUTLET OBSTRUCTION ON THE MORPHOLOGY OF ELASTIN IN RABBIT BLADDER SMOOTH MUSCLE, Koichi Sugimoto, Seiji Matsumoto, Hiroyuki Itoh, Hirotsugu Uemura, JOURNAL OF UROLOGY, 181, 4, 502, 503,   2009 04
• 腫瘍移植モデルを用いたRCC化学療法に対するテーラーメイドアプローチ(Tailor-made approach to RCC chemotherapy using the tumor explant model), マルコ・デベラスコ, 田中 基幹, 植村 天受, 日本泌尿器科学会雑誌, 100, 2, 341, 341,   2009 02
• Role of renin-angiotensin system in prostate cancer, Hiroji Uemura, Yoshinobu Kubota, Japanese Journal of Cancer and Chemotherapy, 36, 8, 1228, 1233,   2009
  Summary:Although a low prevalence of cancer in hypertensive patients receiving angiotensin converting enzyme inhibitors was reported, the molecular mechanisms have not been elucidated. It is known that the Angiotensin-II (Ang-II) plays a fundamental role not only as a vasoconstrictor in controlling blood pressure and electrolyte/fluid homeostasis, but also as a mitogenic factor through the Ang-II type-1 (AT1) receptor in cardiovascular cells. Recently, there has been increasing evidence that the renin-angiotensin system (RAS) is implicated in the development of various cancers. Ang-II has been demonstrated to be a cytokine, especially acting as a growth factor. Of interest, the physiological function of Ang-II seems to be similar in prostate cancer and stromal cells as we previously reported. AT1 receptor blockers (ARBs), a class of antihypertensive agent, have the potential to inhibit the growth of prostate cancer cells and tumors through the AT1 receptor. We conducted a pilot clinical study to examine whether ARBs were able to elicit an antiproliferative effect on prostate cancer clinically, resulting in a PSA decline of hormone refractory cancer or delaying PSA progression after radical prostatectomy. As a number of investigators have clarified that Ang-II induces oxidative stress in vascular cells, we reported the hypothesis that Ang-II generated in the prostate gland may be a cause of oxidative stress linked to prostatic carcinogenesis. This review provides an insight into the key role of Ang-II and AT1 receptor, and the possibility of ARBs for molecular targeting of mitogenesis and angiogenesis in prostate cancer.
• Prostate cancer mouse model derived by pten conditional gene targeting: Towards pre-clinical applications, Motoyoshi Tanaka, Marco de Velasco, Hirotsugu Uemura, UroToday International Journal, 1, 3,   2008 09 , 10.3834/uij.1939.4810.2008.09.07
• UIJ-A phase ii study of the Efficacy and Safety of Sunitinib in Japanese Patients with Metastatic Renal Cell Carcinoma (mRCC), Peter J. Goebell, H. Uemura, N. Shinohara, S. Naito, H. Akaza, UroToday International Journal, 1, 3,   2008 09 , 10.3834/uij.1939.4810.2008.09.12
• 腎細胞癌における、テーラーメイド医療に向けた動物モデル(Tumor explant animal model: aiming towards tailor-made therapy of renal cell carcinoma), デベラスコ・マルコ, 田中 基幹, 吉川 元清, 穴井 智, 西尾 和人, 植村 天受, 日本癌学会総会記事, 67回, 183, 183,   2008 09
• リポソーム化ドキソルビシン膀胱内注入によるマウス膀胱癌モデルでの検討(Intravesical administration of liposomal doxorubicin in mouse orthotopic bladder cancer model), 吉川 元清, デベラスコ・マルコ, 田中 基幹, 佐塚 泰之, 穴井 智, 植村 天受, 日本癌学会総会記事, 67回, 356, 356,   2008 09
• マウス膀胱癌(MBT-2)皮下移植モデルにおけるp16INK4Aペプチド導入の抗腫瘍効果(P16INK4A anti-tumor peptide transduction inhibits growth of MBT-2 mouse bladder tumor cell line graft in mice), 稲井 広夢, 島居 徹, 小島 崇宏, 吉川 和宏, 田中 基幹, 穴井 智, 植村 天受, 赤座 英之, 日本癌学会総会記事, 67回, 366, 366,   2008 09
• Pten機能性ペプチドによる前立腺癌治療の試み(Pten functional peptide therapy in prostate cancer), 田中 基幹, 穴井 智, デベラスコ・マルコ, 吉川 和宏, 植村 天受, 日本癌学会総会記事, 67回, 370, 370,   2008 09
• テーラーメイド癌ペプチドワクチン臨床試験の生存解析 475症例でのアップデート(Survival benefit of personalized peptide vaccine for advanced cancer patients: Up date of enrolled 475 cases), 峯 孝志, 野口 正典, 藤堂 省, 柳本 泰明, 植村 天受, 山中 龍也, 嘉村 敏治, 岡 正朗, 奥野 清隆, 松本 和将, 山田 亮, 伊東 恭悟, 日本癌学会総会記事, 67回, 490, 490,   2008 09
• A novel p16 peptide therapy radiosensitizes prostate cancer, Satoshi Anai, Motoyoshi Tanaka, Marco De Velasco, Keigo Saito, Atsushi Tomioka, Tomohiro Ikeda, Kazuhiro Yoshikawa, Toru Shimazui, Eisaku Kondo, Yoshihiko Hirao, Hirotsugu Uemura, JOURNAL OF UROLOGY, 179, 4, 228, 229,   2008 04
• Effects of tamsulosin on bladder blood flow and bladder function in rats with bladder outlet obstruction, Akiyoshi Ohtake, Hiroko Okutsu, Seiii Matsumoto, Tadashi Hanai, Yukiko Noguchi, Masanori Suzuki, Masao Sasamata, Hirotsugu Uemura, Takashi Kurita, JOURNAL OF UROLOGY, 179, 4, 452, 452,   2008 04
• Functional peptide therapy with PTEN in prostate cancer, Motoyoshi Tanaka, Satoshi Anai, Keigo Saito, Marco De Velasco, Atsushi Tomioka, Kazuhiro Yoshikawa, Hirotsugu Uemura, JOURNAL OF UROLOGY, 179, 4, 224, 224,   2008 04
• 前立腺特異的PTEN欠損マウスにおける前立腺発癌(Cancer development in the mouse by prostate specific deletion of PTEN), 冨岡 厚志, 田中 基幹, 穴井 智, De Velasco Marco, 植村 天受, 平尾 佳彦, 日本癌学会総会記事, 66回, 117, 117,   2007 08
• マウス同所性膀胱癌モデルにおける画像解析を用いた評価法(Use of Image Analysis of Treatment Response in Mouse Orthotopic Bladder Cancer Model), デベラスコ・マルコ, 田中 基幹, 穴井 智, 冨岡 厚志, 杉山 育美, 佐塚 泰之, 西尾 和人, 植村 天受, 日本癌学会総会記事, 66回, 121, 121,   2007 08
• サイトカイン抵抗性腎臓癌患者に対するインターフェロンα併用のCA9ペプチドワクチンの第I/II相試験(Phase I/II study of CA9 peptide vaccination with interferon-alpha in cytokine refractory renal cancer patients), 植村 天受, 田中 基幹, 野澤 昌弘, 松本 成史, 上島 成也, 日本癌学会総会記事, 66回, 240, 240,   2007 08
• 膀胱癌におけるp16機能性ペプチド導入による増殖抑制効果(Efficacy of p16 anti-tumor peptide into bladdertumor cell lines using a novel transpoeter system), 島居 徹, 吉川 和宏, 田中 基幹, 穴井 智, 小島 崇宏, 植村 天受, 佐賀 信介, 上田 龍三, 赤座 英之, 日本癌学会総会記事, 66回, 532, 532,   2007 08
• Distribution of elastin fiber in prostate, Sugimoto Koichi, Seiji Matsumoto, Tadashi Hanai, Hiroyuki Ito, Hirotsugu Uemura, JOURNAL OF UROLOGY, 177, 4, 448, 448,   2007 04
• The role of PTEN in hormone independent prostate cancer derived by prostate specific deletion of PTEN., Atsushi Tomioka, Satoshi Anai, Yoshihiko Hirao, Keiji Shimada, Marco DeVelasco, Motoyoshi Tanaka, Hirotsugu Uemura, JOURNAL OF UROLOGY, 177, 4, 218, 219,   2007 04
• Bladder protective effects of PDE5 inhibitor - Efficacy of vardenafil on rat bladder with outlet obstruction, Seiji Matsumoto, Emi Watanabe, Yuka Nakata, Kouichi Sugimoto, Nobutaka Shimizu, Tadashi Hanai, Hirotsugu Uemura, JOURNAL OF UROLOGY, 177, 4, 446, 446,   2007 04
• Phase-I/II trial of CA9 peptide vaccination in combination with interferon-alpha in HLA-A24 positive patients with cytokine refractory renal cell carcinoma., Motoyoshi Tanaka, Shigeya Uejima, Hirotsugu Uemura, Kiyohide Fujimoto, Yoshihiko Hirao, JOURNAL OF UROLOGY, 177, 4, 303, 303,   2007 04
• Credia TFを用いた遺伝子導入(Novel gene transduction technology by Credia TF), 田中 基幹, 外崎 円, 梅影 雅史, 池田 寿文, 植村 天受, 日本癌学会総会記事, 65回, 507, 507,   2006 09
• 徐放性PTEN遺伝子薬を用いた,前立腺癌における放射線感受性増強効果(Increased Efficacy of Radiation Sensitivity by Controlled Gene Delivery of PTEN with Cationized Gelatin Hydrogel in Prostate Cancer Cells), 田中 基幹, 高田 聡, 冨岡 厚志, 穴井 智, 松村 善昭, 櫛引 俊宏, 田畑 泰彦, 植村 天受, 平尾 佳彦, 日本癌学会総会記事, 63回, 516, 516,   2004 09
• PTENによる,前立腺癌細胞の増殖抑制及び化学・放射線療法感受性の誘導(PTEN SUPPRESSES CELL GROWTH AND ACTS AS CHEMO- AND RADIO- SENSITIZERS IN PROSTATE CANCER), 田中 基幹, 植村 天受, 穴井 智, 高田 聡, 平尾 佳彦, 日本癌学会総会記事, 62回, 419, 419,   2003 08
• Messenger RNA level of cadherin-6 in peripheral blood is associated with site of metastasis and occurrence of future meastasis in renal cell carcinoma, T Shimazui, K Yoshikawa, H Uemura, Y Hirao, S Saga, H Akaza, JOURNAL OF UROLOGY, 169, 4, 207, 208,   2003 04
• MN as a potential target in renal cell carcinoma, Y Nakagawa, H Uemura, Y Hirao, E Okajima, K Yoshikawa, S Saga, E Oosterwijk, JOURNAL OF UROLOGY, 159, 5, 187, 187,   1998 05
• MN target immunotherapy for renal cell carcinoma, H Uemura, Y Nakagawa, E Okajima, Y Hirao, K Yoshikawa, S Saga, E Oosterwijk, JOURNAL OF UROLOGY, 159, 5, 188, 188,   1998 05

Research Grants & Projects

• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Development of PSA-conditional PTEN/p53 double knockout mouse prostate cancer model, We have previously developed a PTEN flox/PSA-Cre transgenic mouse prostate cancer model. In the current research, we focused on p53 (Trp53) to establish a more aggressive metastatic prostate cancer model. Using the same gene engineering method, we established a PSA-conditional PTEN/p53 double knockout (PTEN/p53 DKO) mouse prostate cancer model. Mice with DKO homo-deletion develop an aggressive phenotype characterized by a higher incidence of metastasis, including multiple metastases to lungs, liver, lymph nodes and other distant organs, and decreased survival (median overall survival, 55 weeks of the age), enabling us to use the PTEN/p53 DKO mouse model to evaluate the therapeutic efficacy in a ramdomised controlled studies with similar end points of PFS and OS to a human phase-3 trial. These findings demonstrate the usefulness of the PTEN/p53 DKO mouse prostate cancer model for the preclinical development of novel treatment strategies for prostate cancer.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Exploratory Research, Functional analysis of autophagy in PTEN/Atg7 double knockout mouse prostate cancer, We had previously developed a conditional knockout mouse model in which homozygous deletion of PTEN lead to the stage-specific development of invasive adenocarcinoma. To determine the effect of defective autophagy on prostate cancer progression, we generated prostate-specific conditional double knockout mice harboring both inactivated PTEN and ATG7, a key regulator for the formation of autophagosomes. We show that inhibition of autophagy by the conditional inactivation of ATG7, a gene essential for autophagosome formation, does not contribute to tumor initiation. We also show that simultaneous inactivation of ATG7 significantly suppresses PTEN-deficient prostate cancer progression and improves survival.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Development of multi-peptide tumor vaccine for renal cell carcinoma, We have been working on the development of new MHC-class-I restricted peptide vaccines for five independent therapeutic targets and have identified a significant candidate EPOR, PDL1 and HIF1. We made the application of patents for EPOR and PDL1 peptide vaccine and are preparing the application for HIF1. Together with CA9 and VEGFR1 previously developed peptide vaccines, we established multi-peptide vaccination system using these five peptide vaccines.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Identification of cancer-derived peptides as potential candidates for the development of anti-cancer vaccines for prostate cancer patients, EZH2-derived peptides applicable to prostate cancer patients with HLA-A3 supertype alleles were identified in order to expand the possibility of an anti-cancer vaccine, because the peptide vaccine candidates receiving the most attention thus far have been the HLA-A2 and HLA-A24 alleles. Five EZH2-derived peptides that were prepared based on the binding motif to the HLA-A3 supertype alleles (HLA-A11,-A31, and -A33) were screened for the potential to induce peptide-specific cytotoxic T lymphocytes (CTLs) from HLA-A3 supertype+ prostate cancer patients. As a result, EZH2733-741 efficiently induced peptide-specific and cancer-reactive CTLs. Their cytotoxicity toward prostate cancer cells was ascribed to peptide-specific and CD8+ T cells. These results indicate that the EZH2733-741 peptide could be promising candidates for peptide-based immunotherapy for HLA-A3 supertype+ prostate cancer patients.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Development of tailor made peptide vaccines for renal cell carcinoma, e have been working on the development of new MHC-class-I restricted peptide vaccines for five independent therapeutic targets and have identified a significant candidate EPORxx. We are preparing the application of a patent for this particular peptide vaccine. We also carried out phase-I/II clinical study with VEGFR1 peptide vaccines for 18 patients with disseminated renal cell carcinoma, and showed the safty and efficacy of the vaccination treatment.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Pre-clinical applications using PTEN-knockout prostate cancer mouse model, To better understand the disease process of prostate cancer, we have developed a prostate-specific conditional knockout mouse model that targets the PTEN tumor suppressor gene. Our model is based on PSA-Cre recombinase driven inactivation of Pten to alter PI3K/Akt/mTOR signaling specific to the prostate, resulting in a stage-specific development and progression of cancer that mimics humans recapitulating various stages of disease progression ranging from precancerous PIN lesions to castration resistant prostate cancer. We performed several experiments that demonstrate the versatility and usefulness of this model for validation of preclinical targeted intervention, biomarker discovery (leptin, lumican and HOXA10) and characterizing lifestyle behavior effects on cancer progression.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Development of tailor-madepeptide vaccines for renal eell carcinoma
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Novel molecular therapeutic strategies in prostate cancer
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Molecular Therapy Targeting PTEN-Akt Signaling Pathway in Prostate Cancer., 1. Exploration of molecular markers for prostate cancer : To evaluate the new molecular marker of prostate cancer, we examined the expression of PTEN, phospho-Akt, Bcl-2, and VEGF as down stream of Akt-PTEN signaling pathway in prostate cancer specimens from the operation by immunohistochemistry. These molecules expression status revealed as a possible prognostic or response marker of chemotherapy, radiotherapy, or hormone therapy. 2. Sleeping beauty transposon plasmid vector as drug design : Sleeping beauty (SB) transposon is a system to integrate the gene into choromosome. We designed a cationized hydrogelatin conjugated with SB aiming for slow releasing compound, which can last long term gene expression in vivo, and observed successful gene transduction of SB vector system in mouse system. 3. Molecular therapy with transporter protein or peptide : We developed a transporter system of antibody and functional peptide in treating prostate cancer. P16 and p14 functional peptides were shown to inhibit tumor cell growth of prostate cancer cells in vitro. Antibody of p-Akt as protein was also shown to work in vitro for the treatment of prostate cancer cells. 4. In vivo experiment : Subcutaneous tumor model in nude mice were examined if we can treat with conjugation of cationized gelatin and SB or peptide. P16 and p14 functional peptide treatment showed a significant tumor growth inhibition in nude mice and sensitized radiotherapy combination. Now we are repeating these animal experiment.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Development new generation peptides derived from CA9 as tailar-made vaccines for renal cell carcinoma, We have previously developed 3 CA9-derived peptide vaccines (CA9p219, p288, p323) having the ability to induce HLA-A2402 restricted CA9 specific CTL. Recently a phase-I peptide vaccination trial was carried out in 23 patients with cytokine refractory RCC patients, and resulted in promising efficacy without any major adverse events. However, more than 3 months were needed for induction of specific CTL and more than 6 months were needed for clinical responses. This may be due to relatively low immunogenic peptides. The aim of our study is to develop more immunogenic new peptide vaccines having the higher ability to induce CA9-specific CTL response. We made 25 kinds of CA9 9mer peptides including modified peptides of CA9p219 and CA9p288, and checked their affinity to HLA-A24 molecule by MHC stabilization assay. Surprisingly, CA9p219 had a low affinity although it has high affinity estimation by the computer software and actually had the highest ability of CTL induction in the clinical trial, indicating that real affinity is not associated with the affinity estimation. Based on these data, we screened all peptide made in this study whether these peptides could induce CA9 specific CTL responses. We found several peptides have the higher ability to induce CA9 specific CTL responses. We are currently investigating direct killing capability to CA9 positive cancer cells (SW620) of these peptides.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Application for PTEN Gene Therapy in Prostate Cancer, We have demonstrated that an adenoviral gene therapy of PTEN can effectively treat bladder and prostate cancers, and can be effectively treated tumors which exhibit drug or radiation resistance associated with expression of phosphorylated Akt in combination with chemotherapy or radiotherapy. PTEN is well known as a tumor suppressor gene and has a phosphatase activity in the phosphatidylinositol 3'-kinase mediated signal transduction pathway and inhibits the activation of Akt, a serine-threonine kinase involved in proliferative and anti-apoptotic pathways. These days, using virus vector for cancer gene therapy is controversial, and non-viral gene transfer is a future promising procedure but several problems need to be cleared, such as transduction efficacy. We have developed non-viral compound conjugated with cationized gelatin microsphere and plasmid DNA, which is a new type of gene transfer drug and designed to release plasmid DNA and last the gene expression continuously for a long period in vivo. In this study, we originally generated the GelaTen, which is a conjugate with cationized gelatin microsphere (2 mg) and PTEN expression vector (100 μg), and examined the efficacy of GelaTen as a combination therapy with radiation in prostate cancer. Single direct injection of GelaTen into established subcutaneous bcl-2-overexpressing PC3 prostate cancer tumors (PTEN deleted, up-regulation of phosphorylated Akt and Bcl-2) in nude mice, which reached approximately 5-7mm in diameter, resulted in significantly decreased growth compared to the conjugate with ss-gal plasmid (control) or PBS treated tumors. Immunohistochemical analysis showed that tumors inducted with GelaTen expressed PTEN and exhibited decreased amounts of phosphorylated Akt, whereas tumors treated with CTL or PBS were negative for PTEN and diffusely positive for phosphorylated Akt. Since PTEN downregulates phosphorylated Akt and Bcl-2 and increases sensitivity to radiation, we explored combination therapy with GelaTen and radiation in vivo. Combination therapy with GelaTen and 5 Gy irradiation (5 days after GelaTen injection) improved the in vivo efficacy of tumor growth compared to the GelaTen monotherapy alone in these tumors. These data demonstrate that PTEN gene therapy with gene drug GelaTen can effectively treat prostate cancers that have genomic alterations in PTEN. Furthermore, tumors that exhibit radiation resistance associated with expression of phosphorylated Akt and Bcl-2 can be effectively treated with GelaTen and radiotherapy.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), MN/CA9 expression and VHL regulation in renal cell carcinoma, The von Hippel-Lindaw (VHL) gene is a well-known tumor suppressor gene interacting with the hypoxia inducible factor (HIF), which associates with a variety of gene expressions in normal and cancer cells. Frequent gene alterations of the VHL gene, such as deletions or mutations, have been reported in sporadic renal cell carcinoma (RCC), suggesting one of major cause of RCC development. MN/CA9, which is one of the isoenzymes of the carbonic anhydrase family, is frequently over-expressed and considered as a tumor-associated antigen in RCCs. We have previously demonstrated that the RCC cell lines with wild-type VHL gene expression have undetectable or extremely low expressions of MN/CA9 so that the VHL gene alterations may have a role for the MN/CA9 constitutive expression in RCCs. Since the fact that the MN/CA9 expression was induced by hypoxic condition, the VHL-HIF pathway may associate with the MN/CA9 gene regulation in RCCs. To investigate the role of MN/CA9 in VHL-HIF pathway, 6 RCC cell lines were analyzed for MN/CA9 mRNA expression. Despite all these cell lines have the VHL gene alterations, 3 of 6 lines have no expression of MN/CA9. We used other 3 cell lines expressing MN/CA9 for further analysis of VHL-related hypoxia. In nonnoxic condition, the transfectants with the VHL expression vector in these 3 cell lines showed down-regulation of MN/CA9 expression compared to the transfectants with control vector or parental cells. In hypoxic condition, however theMN/CA9 expression was induced in these transfectants with the VHL gene, but not in the control transfectants or parental cells. Furthermore, we used MN/CA9-negative cell line SK-RC 14, which has the VHL gene deletion, to investigate whether MN/CA9-negative cell line can induce MN/CA9 expression in either normoxic or hypoxic condition through VHL dependent pathway. SK-RC14 did not show any induction of MN/CA9. This study demonstrates that regulation of MN/CA9 is not exactly associated with pVHL.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Active specific immunotherapy with MN\CA IX antigen peptide vaccines for renal cell carcinoma, MN/CA IX antigen is a tumor-associated antigen expressed in approximately 90 % of renal cell carcinomas (RCQ). We have synthesized 9mer antigen peptides restricted to HLA-A24 and employed them as tumor vaccines to investigate the ability to induce this antigen specific responses in mouse syngeneic ROC model. Antigen specific CTL was induced by immunization of MN/CA9 9mer peptide vaccine in mouse system. This finding suggests that vaccination with MN/CA9 antigen peptides may be potential therapeutic approach for RCC patients. We also have investigated the capacity of CTL induction using RCC patient lymphocytes in vitro. In addition, presence of CTL precursor was investigated using PBMC from the patients with metastatic RCC patients. Stimulation of patient lymphocytes with autologons dendritic cell loaded MN/CA9 peptides resulted in antigen specific CTL induction. Based on these pie-clinical data, we started a phase-I study to investigate MN/CA9 peptide vaccines by subcutaneous administration in patients with disseminated renal cell carcinoma since July 2002. Patients with distant metastases received three sets of MN/CA9 9-mer peptide vaccines 6 times at 2-week intervals. Primary end points of this study are to evaluate the toxicity and immunogenicity of these antigen peptide vaccines. Six patients finished the protocol until now and only low grade toxicities such as fever, pruritus and local reaction (swelling, pain) were observed. Antigen specific cell-mediated cytotoxicity was induced in some patients. In addition, antibodies (IgG) against MN/CA9 peptides vaccines were detected in some patients. These findings suggest that our MN/CA9 peptide vaccines may be safe and applicable for HLA-A24 positive RCC patients. Moreover; we are currently investigating the generation of modified peptide vaccines to obtain more powerful antigenicity.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Search for new target antigens of cancer by the SEREX method using cancer patient's serum containing antibodies, The SEREX method is a system to identify unique antibodies and antigens for cancer patients using autologouse cancer tissue and serum and many researchers had found many unique antigens. These results showed that many of these antigens detected expressed in Testis. So, these antigens were named Cancer testis (CT) antigen. These antigens are useful targets to induce cellular immunity to treat cancers, since, on the Spermatogenic cells surface, HLA-class I antigen is not expressed. In this study, we collected cancer tissues and autologouse serums of a prostate and 5 renal cancer, and serums of 3 prostate and 10 renal cancers. We tried to make an expression libraries using mRNAs from prostate cancer tissues and we found that the titer of these libraries were 2.5x10^6 pfu. And we made an expression library using one tissue of two testis obtained. We tested the usefulness of this testis library using cancer serum, which was confirmed to contained some antibodies reacted to cancer tissues, and could get many positive cloned. We determined nucleotide sequences of cDNA fragments in positive clones and found that we got 7 unique clones and many positive clones were same clones. Now, we can't open the name of unique genes which contained come antigens detected in auto-immune disease. These results showed that the our original libraries were useful tools to detect antigens recognized with cancer patients serum. So, we continue to screen the library using several cancer serums.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B), Clinical Significance for detection of circulating renal cancer cells in the blood by RT-PCR, Renal cell carcinoma is considered as a very poor prognostic disease due to absence of specific tumor marker and effective therapeutic modalities. Conventional treatments such as chemotherapy and radiotherapy are not useful at all. We are previously investigating to detect circulating renal cancer cells in the patient's blood and established RT-PCR assay to detect MN/CA9 positive cells in the peripheral blood. The blood-based RT-PCR resulted in detection of MN/CA9 mRNA in 76% of RCC patients. However; detection of MN/CA9 positive cells was observed in 30% of healthy volunteers (false positive). This may be because the skin expresses MN/CA9 antigen and aspiration of MN/CA9 positive cell when taking the blood via skin. Considering this situation, we try to use blood sample from renal vein during radical nephrectomy. To optimize PCR condition, we investigated 96 sets of PCR primers, and were able to set up blood-based RT-PCR with approximately 70 % sensitivity and 90 % specificity. We expected such high detection rates and no correlation with prognostic factors such as stage, grade and metastases, was observed. Based on these findings, we focused on cadherin-6 as an additional targeting molecule. Cadherin-6 is cell-cell adhesional molecule and considered as an as an important biomarker in renal cell carrinomas. We set up blood-based RT-PCR double assay targeting to MN/CA9 and Cadherin-6. Prospective study with blood samples from renal vein during radical nephrectomy revealed that significantly high detection rate of MN/CA9 and/or Cadherin-6 positive cells was observed in RCC patients with metastasis. This finding suggests that our double assay may be useful for diagnosis of RCC as well as early detection of metastasis.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Elucidation of activation mechanism of MN/CA9 in human renal cell carcinomas, Correlation between MN/CA9 expression and hypomethylation of MN/CA9 5'flanking region in human renal cell carcinomas Hypomethylation of the CpG at -74 bp of MN/CA9 was strongly correlated with MN/CA9 expression in both human renal cell carcinoma (RCC) cell lines and human RCC tissues. Methylation status was examined by bisulfite genomic sequencing protocol. MN/CA9 expression was examined by RT-PCR. Induction of MN/CA9 expression by treatment with a demethylating agent Treatment with the demethylating agent 5-aza-2'-deoxycytidine resulted in activation of the MN/CA9 gene in MN/CA9 negative RCC cell lines. Identification of MN/CA9 promoter region DNAs of MN/CA9 5' flanking region (-1246 / +42 bp) were ligated into luciferase reporter plasmids. Deletion analyses revealed that 5' end of minimal MN/CA9 promoter was located between -158 bp and -58 bp. Effect of in vitro DNA methylation on promoter activity MN/CA9 promoter (-158 / +42 bp) / luciferase reporter plasmids were treated with CpG methylases (SssI or HhaI) and transfected into MN/CA9 positive RCC cell lines. All CpGs of MN/CA9 promoter were methylated by SssI, and only CpG at -74 bp was specifically methylated by HhaI.Activity of MN/CA9 promoter was strongly suppressed by treatment with both SssI and HhaI. These data suggest that hypomethylation of the CpG at -74bp in MN/CA9 promoter may have a major role in MN/CA9 expression in human renal cell carcinomas.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Specific immunotherapy targeting MN/CA9 tumor-associated antigen for renal cell carcinoma, MN/CA IX antigen is a plasma membrane glycoprotein expressed in several types of malignancies. Our previous study revealed that majority of renal cell carcinomas (RCC) express this antigen. We have synthesized 9mer antigen peptides and employed them as tumor vaccines to investigate the ability to induce this antiger specific responses. MN-RenCa and MN-3T3, MN/CA9 transfectant mouse renal cell carcinoma and embryofibroblast cell lines, have been established in our laboratory. Using these cell lines, we examined whether vaccination with the antigen peptides could induce specific CTL.Vaccines were made with HLA-A24 as well as H-2K^d restricted immunodominant peptides, and administrated into BALB/c mice with IFA every week. After the fourth vaccination, MN specific CTL activity was tested by TNF release assay and LDH release assay against MN-3T3. Furthermore, therapeutic efficacy of vaccination with the antigen peptides was investigated in syngeneic animal model. Spleen cells derived from BALB/c mouse vaccinated with antigen peptides showed reactivity against MN-RenCa and MN-3T3 cells, i.e., vaccination with MN antigen peptides resulted in the induction of MN specific CD8+ CTL precursor. This CTL precursor were transferred into naive mice after MN-RenCa inoculation and significantly low tumor-take was observed in these mice compared to control mice. These findings suggest that vaccination with MN antigen peptides may be potential therapeutic approach for RCC.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Establishment of diagnosis and therapy in renal cell carcinomas by MN/CAIX antibody, MN/CA9 expression renal cell carcinoma cell line : This plasmid ligated MN/CA9 cDNA and BCMGSNeo vector introduced into RenCa cell, i.e.mouse rental cell carcinoma(RCC) cell line. Transfected RenCa cell clones were selected by growth in the presence of antibiotics G418 and expression of MN/CA9 was examined with mixed hemadsorption method. MN/CA9 expression mouse RCC model. MN/CA9 expression RenCa cells were injected BALB/c mouse subcutaneously. The MN/CA9 expression of grown tumors was stained immunohistochemically with G250 antibody (G250 is already established MN/CA9 antibody). MN/CA9 recombinant antigen : Specific regions of MN/CA9 DNA dissimilar to other antigen by amino acid homology comparisons was amplified by Polymerase chain reaction. The specific region joined expression vector PET32c and transformed E.coli. The protein produced in E.coli was analyzed by SDS-PAGE and western blotting and the examination displayed MN/CAIX expression of the protein. Polyclonal antibody :. For production of polyclonal antibody, rabbit was immunized with synthesized MN/CAIX antigen emulsified with incomplete Freund adjuvant. The binding of antiserum with MN/CAIX antigen was measured in ELISA. Now antibody is isolated from the antiserum using affinity chromatography. Monoclonal antibody : Hybridoma for monoclonal antibody was made using SP2/0 cells and spleen cells from mice immunized with cell lysate of RenCa cell expressed MN/CAIX. Specificity of monoclonal antibody was analyzed by using immunohistochemistry and confirmed to be similar to G250 antibody. Single chain antibody : DNA of monoclonal antibody was cut in hybridoma gene and recombinant DNA molecule transferred to E.coli. E.coli made protein of single chain antibody. Specific single chain antibody is isolated from the protein and the affinity is analyzed. Furthermore, examination of single chain antibody for clinical use is now in progress.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Molecular detection of circulating renal cell carcinoma cells by RT-PCR, A murine monoclonal antibody G250 (MAbG25O) raised against human renal cell carcinoma (RCC)(Oosterwijk, et al, 1986) has been known to react with a large proportion of RCC, but not with the norma1 kidney tissue. The antigen recognized by MAbG25O is present in the plasma membrane and expresses in several types of malignancies. Recently, G250 antigen gene has been isolated (Oosterwijk et al. 1995), and database analysis revealed that G250 antigen is identical to MN/CA IX originally deribed from Hela cell (Pastorek et al, 1994). To determine whether G250 antigen (MN/CA IX/G250) could be a potential therapeutic target and a tumor marker, a total of 147 cases of RCC were investigated immunohistochemically as well as, by reverse transcriptase polymerase chain reaction (RT-PCR) anilysis. In addition, total RNAs extracted from patients' peripheral blood samples were analyzed for MN/CA9/G250 mRNA signals. Immunohistochenistry resulted in strong expression in 128/147 (87.1%) of RCC, in contrast to the lack of expression observed in normal tissues. RT-PCR analyses of frozen specimens resulted in the clear detection of MN/CA9/G25OmRNA signals in 137/147 (93.2 %), and despite of the subtle differences, the results were almost identical to those for immunohistochemistry. Although high grade and stage tumors exhibited significaitly lower expression than low grade and stage tumors, a large proportion of tumors expressed MN/CA9 IX/G250 protein as well as mRNA.RT-PCR analysis of patients' blood samples revealed the presence of circulating MN/CA9/G25O expressing cells. These findings suggest that this antigen may be a potential therapeutic target as well as diagnostic marker for RCCs.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), A tumor-associated antigen MN/G250 in urologic malignancies ; potetial therapeutic target, A murine monoclonal antibody MAbG250 is known to react with the majority of renal cell carcinomas (RCC) whereas reactivity with normal tissues is restricted to gastric mucosal cells and large blle duct cells. Recently, the G250 antigen has been identified (Oosterwijk et al.1995). Sequence analysis and database searching revealed that G250 antigen is identical to MN,a human tumor-associated antigen identified in cervical carcinoma (Pastorek et al, 1994). This antigen (G250, MN) is a transmembrane glycoprotein of 54 kDa and detectable in several types of malignancies but not in corresponding normal tissues. In the present study, we investigate MN/G250 expression with immunohistochemistry and RT-PCR in urologic cancers. MATERIAL & METHODS : Frozen specimens of bladder carcinoma (BT)(n=61), prostate carcinoma (PCa)(n=46), RCC (n=147) and germ cell tumor (GCT)(n=19)were studied for MN/G250 antigen peptide and gene expression. In addition, 17 RCC cell lines and 8 bladder carcinoma cell lines, and 3 PCa cell lines were studied. Cell lines were tested for MN/G250 expression by MHA and RT-PCR analysis with primers derived from cDNA sequence of MN/G250 antigen. RESULTS : In RCC,128/147 (87%) tissue specimens showed strong and homogeneous MN/G250 expression, in accordance with previous studies. Tumor grade and cell type appeared to correlate inversely with MN/G250 expression, i.e., high grade and sarcomatoid type showed significantly low expression as compared to the others. 6 of 17 (35%) RCC cell lines were G250 positive. In bladder carcinoma, 20/61(33%)primary tumors showed MN/G250 expression heterogeneously and 1/8(13%)cell lines were G250 positive. In contrast, no G250 expression was observed in PCa and GCT specimens and the other normal normal tissues. Based, on these results describe above, we cariied out therapeutic experiments in mice with RCC xenograft. Briefly, small pieces of NUR-2 RCC were transplanted into the right flank of male nu/nu BALB/c mice. A couple of weeks after transplantation, mice were randomized and divided into each groups (n=6-7). Mice carrying NUR-2 human RCC xenografts (MN/G250^+,20mm^3) were treated by peri-tumor injection of MAbG250 and/or cytokines (m-IFN/IL-2/MCSF) or 0.2 ml of Ab3 sera with/without MCSF.Mice were treated 5 times a week for 6 weeks. Control mice were treated with 0.1 ml medium alone (RPMl 1640) or sera from MOPC21 immunized mice (Ab3-MOPC). The tumor-take rates and tumor growth were determined every week. RESULTS : All mice showed 100% tumor take after 4 weeks. However, the tumor volume in IFN or IL-2 therapy as well as MAbG250 treated animals were significantly lower as compared to control animals (p<0.01). Treatment with MCSF resulted in tumor growth inhibition but not significant. Combination of MAbG250 with cytokines resulted in increased anti-tumor effects as compared to MAbG250 or cytokine monotherapy. IL-2/IFN/MAbG250 therapy showed significant tumor growth Inhibition as compared to MAbG250 or cytokine monotherapy (p<0.05), however the other combination therapy were not significant. Moreover, Ab3-based (Ab2-induced) immunotherapy resulted in tremendous tumor growth inhibition as compared to MAbG250 or the other cytokine combination therapies (p<0.001). CONCLUSIONS : Our findings suggest that MN/G250 antigen may be potential therapeutic target for RCC immunotherapy.
• Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C), Tools for active specific immunotherapy with anti-idiotype antibodies in human renal cell carcinoma, In apite of the increasing success in the management of urological malignancies, curative treatment of renal cell carcinoma (RCC) patients with metastatic disease still remains extremely difficult. Even with the multitude of therapeutic strategies, almost no improvement of the survival for these patients has been established in the last decade. It is well known that RCC is relatively resistant to conventional therapies and immunotherapy seems to be the most promising treatment for disseminated RCC.Obviously, the development of new therapeutic approach is necessary. We have developed internal image anti-idhiotype antibodies (Ab2) raised against MAbG250 which recognizes a large proportion of RCC,and also have shown that Ab2 vaccination resulted in the destruction of established tumor in mice. In the present study, we investigate therapeutic effects of MAbG250 immunotherapy in combination with cytokines (exp.1) and internal image Ab2 induced antisera (Ab3-82)(exp.2) in mice with RCC xenografts. Method : exp.1) Nu-nu BALB/c mice with approximately 20mm NUR2 human RCC xenografts were divided into 10 groups, i.e., gr.1 : control.gr.2 : IL-2, gr.3 : rm-IFN,gr.4 : MCSF,gr.5 : MAbG250, gr.6 : IL-2/MAbG250, gr. 7 : rm-IFN/MAbG250, gr.8 : MCSF/MAbG250, gr.9 : IL-2/IFN,gr.10 : IL-2/rm-IFN/MAbG250. Mice were treated with peri-tumor injection of 200 U/g mouse cytokines 5 days a week for 6 weeks. exp.2) Nu/nu mice with NUR2 xenografts were divided into 4 groups and treated with the following schedule for 6 weeks ; gr.1 : NMS (control)(0.2ml, i.p.3/week), gr.2 : MAbG250/IL-2/rm-IFN,gr.3 : Ab3-82 (0.2ml, i.p.3/week), gr.4 : Ab3-82+MCSF.Results : (exp.1) Treatment of NUR2 with IFN,IL-2, MAbG250, MCSF or IL-2/MAbG250 resulted in significant tumor growth inhibition (p<0.05) as compared to control group. In the remaining 3 groups, i.e., IL-2/IFN,IFN/MAbG250, IL-2/IFN/MAbG250, the tumor growth inhibition was greater than in the previous groups. (exp.2) Treatment of NUR2 RCC xenografts with IL-2/IFN/MAbG250, Ab3 based immunotherapy resulted in significant tumor growth inhibition compared to control group (gr.2,3 : p<0.01, gr.4 : p<0.0001). These findings suggest that Ab2 vaccination might be useful for specific immunotherapy in RCC patients.