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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• 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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• 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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• 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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• 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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• 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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• Article Navigation Nivolumab versus everolimus in advanced renal cell carcinoma: Japanese subgroup analysis from the CheckMate 025 study, Yoshihiko Tomita, Japanese Journal of Clinical Oncology, Japanese Journal of Clinical Oncology, 47(7), 639 - 646, Jul. 2017 , Refereed
• 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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• Evaluation of in vivo responses of sorafenib therapy in a preclinical mouse model of PTEN-deficient of prostate cancer, Yutaka Yamamoto, Journal of Translational Medicine, Journal of Translational Medicine, May 2015 , Refereed
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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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• Japanese phase I study of cabazitaxel in metastatic castration-resistant prostate cancer., Nozawa M, Mukai H, Takahashi S, Uemura H, Kosaka T, Onozawa Y, Miyazaki J, Suzuki K, Okihara K, Arai Y, Kamba T, Kato M, Nakai Y, Furuse H, Kume H, Ide H, Kitamura H, Yokomizo A, Kimura T, Tomita Y, Ohno K, Kakehi Y, Int J Clin Oncol., Int J Clin Oncol., 20(5), 1026 - 1034, 2015 , Refereed
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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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• A phase 2 study of abiraterone acetate in Japanese men with metastatic castration-resistant prostate cancer who had received docetaxel-based chemotherapy., Satoh T, Uemura H, Tanabe K, Nishiyama T, Terai A, Yokomizo A, Nakatani T, Imanaka K, Ozono S, Akaza H, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 44(12), 1206 - 1215, Dec. 2014 , Refereed
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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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• Cutaneous angiosarcoma at an interval of thirty-six years from radiation for a testicular germ cell tumor., Kato M, Oiso N, Nishimoto M, Mori Y, Katoh Y, Uemura H, Kawada A, European journal of dermatology : EJD, European journal of dermatology : EJD, 24(5), 622 - 623, Sep. 2014 , Refereed
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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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• Examination of the effect of changing to azilsartan from candesartan in renal transplant patients., Ishii T, Yasuda M, Saito Y, Mori Y, Hayashi T, Uemura H, Nose K, Nishioka T, Transplant Proc., Transplant Proc., 46(2), 492 - 495, 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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• 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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• 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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• Phase I clinical trial of human vascular endothelial growth factor receptor 1 peptide vaccines for patients with metastatic renal cell carcinoma., Yoshimura K, Minami T, Nozawa M, Uemura H, Br J Cancer., Br J Cancer., 108(6), 1260 - 1266, 2013 , Refereed
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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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• A phase I study of personalized peptide vaccination using 14 kinds of vaccine in combination with low-dose estramustine in HLA-A-24-positive patients with castration-resistant prostate cancer, The Prostate, The Prostate, 71, 470 - 479, 2011
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• Basic research in kidney cancer, Eur.Urol., Eur.Urol., 60, 622 - 633, 2011
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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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• A phase II study of sunitinib in Japanese patients with metastatic renal cell carcinoma: insights into the treatment, efficacy and safety., Uemura H, Shinohara N, Yuasa T, Tomita Y, Fujimoto H, Niwakawa M, Mugiya S, Miki T, Nonomura N, Takahashi M, Hasegawa Y, Agata N, Houk B, Naito S, Akaza H, Japanese journal of clinical oncology, Japanese journal of clinical oncology, 40(3), 194 - 202, Mar. 2010 , Refereed
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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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• 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., BJU Iit, BJU Iit, 108, 187 - 195, 2010
• efficacy of Carvedilol for ischemia/reperfusion-induced oxidative renal injury in rats, transplantation proceeedings, transplantation proceeedings, 40, 2139 - 2141, 2010
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• Effect of Edaravone on Ischemia/Reperfusion Injury in Rat Urinary Bladder-Changes in Smooth Muscle Cell Phenotype and Contractile Function., Matsumoto S, Hanai T, Shimizu N, Sugimoto K, Uemura H, Aktuelle Urol., Aktuelle Urol., 41, S46 - S49, 2010 , Refereed
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• [Mixed epithelial and stromal tumor of kidney: a case report]., Terao H, Makiyama K, Yanagisawa M, Miyake M, Sano F, Kita K, Murakami T, Nakaigawa N, Ogawa T, Uemura H, Yao M, Kubota Y, Inayama Y, Nagashima Y, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 55(8), 495 - 498, Aug. 2009 , Refereed
• 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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• [Case of sarcomatoid renal cell carcinoma developed in the chalked kidney (putty kidney)]., Komeya M, Sano F, Kagota M, Murakami T, Makiyama K, Miyoshi Y, Nakaigawa N, Ogawa T, Uemura H, Yao M, Ooshiro H, Nagashima Y, Kubota Y, Hinyokika kiyo. Acta urologica Japonica, Hinyokika kiyo. Acta urologica Japonica, 55(5), 253 - 257, May 2009 , Refereed
• 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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• Immunological evaluation of personalized peptide vaccination monotherapy in patients with castration-resistant prostate cancer, Cancer Science, Cancer Science, 101(3), 601 - 608, 2009
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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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• 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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• Creatol, an oxidative product of creatinine in kidney transplant patients, as a useful determinant of renal function: a preliminary study., Transplantation Proceedings, Transplantation Proceedings, 38(7), 2009 - 2011, Sep. 2006
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• Can Monitoring of Serum 8-OHdG Level for 2 Hours After Renal Transplantation Predict Prognosis of the Graft?, Transplantation Proceedings, Transplantation Proceedings, 38(7), 2014 - 2015, Sep. 2006
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• Experience with lapalroscopic splenelectomy for ABO-incompatible living renal transplantation, Transplantation proceedings, Transplantation proceedings, (38), 1985 - 1986, Jun. 2006
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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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• A phase I trial of vaccination of CA9-derived peptides for HLA-A24-positive patients with cytokine-refractory metastatic renal cell carcinoma, Clinical Cancer Research, Clinical Cancer Research, 12(6), 1768 - 1775, Mar. 2006
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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.
• Induction of antigen specific cellular immunity by vaccination with peptides from MN/CA IX in renal cell carcinoma., Shimizu K, Uemura H, Yoshikawa M, Yoshida K, Hirao Y, Iwashima K, Saga S, Yoshikawa K, Oncology reports, Oncology reports, 10(5), 1307 - 1311, Sep. 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.
• Detection of circulating MN/CA9 positive renal cell carcinoma cells during operation., Aktuel. Urol., Aktuel. Urol., 34, 270 - 272, 2003
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• 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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• Aberrations of the p14ARF and p16INK4a genes in renal cell carcinomas., Kawada Y, Nakamura M, Ishii E, Shimada K, Oosterwijk E, Uemura H, Hirao Y, Kim SC, Konishi N, J. Cancer Res., J. Cancer Res., 92, 1293 - 1299, 2001 , Refereed
• Expression of MN antigen in urologic cancer: potential tool as a therapeutic target, UEMURA Hirotsugu, Nakagawa Y, Hirao Y, Okajima E, Yoshikawa K, Oosterwijk E, Aktuel Urol., Aktuel Urol., 31, 52 - 54, 2000 , Refereed
• Aortic calcification index(ACI): A parameter to predict renal function following nephrectomy; A preliminary reports, HiraoY, Yoshii M, Tsujimoto S, Uemura H, Yoshida K, Ozono S, Okajima E, Aktuel Urol, Aktuel Urol, 31, 2 - 3, 2000 , Refereed
• ctivation of the MN/CA9 is associated with hypomethylation in humanrenal cell carcinomas., Cho M, Grabmaier K, Kitahori Y, Hiasa Y, Nakagawa Y, Uemura H, Hirao Y, Ohnishi T, Yoshikawa K, Ooesterwijk E, Mol.Carcinogenesis, Mol.Carcinogenesis, 27, 184 - 189, 2000 , Refereed
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• MN/CA IX/G250 as potential target for immunotherapy of renal cell carcinomas, British Journal of Cancer, British Journal of Cancer, 81, 741 - 746, 1999
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• MN/CA /G250 as a potential target for immunotherapy of renal cell carcinomas., UEMURA Hirotsugu, Nakagawa Y, Yoshida K, Saga S, Yoshikawa K, Hirao Y, Oosterwijk E, Brit.J.Cancer, Brit.J.Cancer, 81, 741 - 746, 1999 , Refereed
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• Genomic aberrations in renal cell carcinomas detected by restriction landmark genomic scanning., Cho M, Konishi N, Yamamoto K, Inui T, Kitahori Y, Nakagawa Y, Uemura H, Hirao Y, Hiasa Y, Eur.J.Cancer, Eur.J.Cancer, 34(13), 2112 - 2118, 1998 , Refereed
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• Detection of DNA amplification in human renal cell carcinoma cell lines using restriction landmark genomic scanning., Cho M, Konishi N, Kitahori Y, Hiasa Y, Nakagawa Y, Uemura H, Hirao Y, Oosterwijk E, Cell.mol.Biol., Cell.mol.Biol., 44, 913 - 918, 1998 , Refereed
• Radiation hybrid mapping of the human MN/CA9 locus to chromosome band 9p12-p13., Nakagawa Y, Uemura H, Hirao Y, Yoshida K, Saga S, Yoshikawa K, Genomics, Genomics, 53, 118 - 119, 1998 , Refereed
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• Experimental model of renal tumors in polycystic kidney: effects of long-term 2-amino-4,5-diphenylthiazole administration in rats treated with N-ethyl-N-hydroxyelnitrosamine., Tsumatani K, Nakagawa Y, Kitahori Y, Konishi N, Uemura H, Ozono S, Hirao Y, Okajima E, Hirao K, Hiasa Y, Toxicol. Pathol., Toxicol. Pathol., 25, 363 - 371, 1997 , Refereed
  DOI
• Induction of tumor regression by passive transfer of antibody from mice vaccinated with anti-idiotype antibodies resembling a human renal cell carcinoma-associated antigen, UEMURA Hirotsugu, Okajima E, Deburyne FMJ, Oosterwijk E, Urol. Oncol., Urol. Oncol., 1, 73 - 79, 1995 , Refereed
• Immunization with anti-idiotype monoclonal antibodies bearing the internal image of the renal cell carcinoma-associated antigen G250 induces specific cellular immune responses., UEMURA Hirotsugu, Okajima E, Deburyne FMJ, Oosterwijk E, Int. J. Cancer, Int. J. Cancer, 59, 802 - 807, 1994 , Refereed
  DOI
• Vaccination with anti-idiotype antibodies mimicking a renal cell carcinoma-associated antigen induces tumor immunity., UEMURA Hirotsugu, Beniers AJMC, Okajima E, Deburyne FMJ, Oosterwijk E, Int. J. Cancer, Int. J. Cancer, 58, 555 - 561, 1994 , Refereed
  DOI
• 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
• Internal image antiidiotype antibodies related to renal cell carcinoma-associated antigen G250, UEMURA Hirotsugu, Okajima E, Deburyne FMJ, Oosterwjik E, Int. J. Cancer, Int. J. Cancer, 56, 609 - 614, 1994 , Refereed
  DOI
• Therapeutic effects of monoclonal antibody G250, interferons and tumor necrosis factor, in mice with renal cell carcinoma xenografts., van Dijk J, Uemura H, Beniers AJMC, Peelen WP, Zegveld ST, Fleuren GJ, Warnaar SO, Oosterwjik E, Int. J. Cancer, Int. J. Cancer, 56, 262 - 268, 1994 , Refereed
  DOI
• 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.
  DOI
• 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.
  DOI

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

• 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
• 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
• 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
• 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
• 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
• 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
• 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.
• 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
• 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.

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.