Publications by authors named "Satoshi Tamada"

53 Publications

Pembrolizumab plus axitinib versus sunitinib in metastatic renal cell carcinoma: outcomes of Japanese patients enrolled in the randomized, phase III, open-label KEYNOTE-426 study.

Int J Clin Oncol 2021 Nov 20. Epub 2021 Nov 20.

Kindai University, 3 Chome-4-1 Kowakae, Higashiosaka, Osaka, 577-8502, Japan.

Background: In the phase III open-label KEYNOTE-426 (NCT02853331) study, first-line pembrolizumab and axitinib improved overall survival (OS) and progression-free survival (PFS) versus sunitinib for metastatic renal cell carcinoma (mRCC). KEYNOTE-426 evaluated patients enrolled from 25 sites in Japan.

Methods: Patients enrolled in Japan were included in this post hoc subgroup analysis. Adults with clear cell mRCC were randomly assigned 1:1 to receive intravenous pembrolizumab 200 mg every 3 weeks plus oral axitinib 5 mg twice daily or oral sunitinib 50 mg once daily (4 weeks on/2 weeks off). Dual primary endpoints were OS and PFS as assessed by blinded independent central review. Objective response rate (ORR) and safety were secondary endpoints.

Results: The Japanese subgroup comprised 94 patients (pembrolizumab-axitinib, n = 44; sunitinib, n = 50; 11% of the intent-to-treat population). Median time from randomization to data cutoff (January 6, 2020) was 29.5 months (range 24.6-37.3). Consistent with the intent-to-treat population, the OS, PFS, and ORR suggested improvement with pembrolizumab-axitinib versus sunitinib in the Japanese subgroup. Grade ≥ 3 treatment-related adverse events (TRAEs) occurred in 70% of patients receiving pembrolizumab-axitinib versus 78% receiving sunitinib; 11 (25%) patients receiving pembrolizumab-axitinib and 13 (27%) patients receiving sunitinib discontinued the study medication due to AEs. TRAEs led to the discontinuation of pembrolizumab, axitinib, pembrolizumab-axitinib, or sunitinib in 32%, 34%, 14%, and 20%, respectively. No deaths from TRAEs occurred.

Conclusions: Efficacy outcomes for the Japanese subgroup were consistent with those of the global population. Safety in Japanese patients was consistent with the results from the global population.
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http://dx.doi.org/10.1007/s10147-021-02014-7DOI Listing
November 2021

Pembrolizumab plus axitinib versus sunitinib monotherapy as first-line treatment of advanced renal cell carcinoma (KEYNOTE-426): extended follow-up from a randomised, open-label, phase 3 trial.

Lancet Oncol 2020 12 23;21(12):1563-1573. Epub 2020 Oct 23.

Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.

Background: The first interim analysis of the KEYNOTE-426 study showed superior efficacy of pembrolizumab plus axitinib over sunitinib monotherapy in treatment-naive, advanced renal cell carcinoma. The exploratory analysis with extended follow-up reported here aims to assess long-term efficacy and safety of pembrolizumab plus axitinib versus sunitinib monotherapy in patients with advanced renal cell carcinoma.

Methods: In the ongoing, randomised, open-label, phase 3 KEYNOTE-426 study, adults (≥18 years old) with treatment-naive, advanced renal cell carcinoma with clear cell histology were enrolled in 129 sites (hospitals and cancer centres) across 16 countries. Patients were randomly assigned (1:1) to receive 200 mg pembrolizumab intravenously every 3 weeks for up to 35 cycles plus 5 mg axitinib orally twice daily or 50 mg sunitinib monotherapy orally once daily for 4 weeks per 6-week cycle. Randomisation was done using an interactive voice response system or integrated web response system, and was stratified by International Metastatic Renal Cell Carcinoma Database Consortium risk status and geographical region. Primary endpoints were overall survival and progression-free survival in the intention-to-treat population. Since the primary endpoints were met at the first interim analysis, updated data are reported with nominal p values. This study is registered with ClinicalTrials.gov, NCT02853331.

Findings: Between Oct 24, 2016, and Jan 24, 2018, 861 patients were randomly assigned to receive pembrolizumab plus axitinib (n=432) or sunitinib monotherapy (n=429). With a median follow-up of 30·6 months (IQR 27·2-34·2), continued clinical benefit was observed with pembrolizumab plus axitinib over sunitinib in terms of overall survival (median not reached with pembrolizumab and axitinib vs 35·7 months [95% CI 33·3-not reached] with sunitinib); hazard ratio [HR] 0·68 [95% CI 0·55-0·85], p=0·0003) and progression-free survival (median 15·4 months [12·7-18·9] vs 11·1 months [9·1-12·5]; 0·71 [0·60-0·84], p<0·0001). The most frequent (≥10% patients in either group) treatment-related grade 3 or worse adverse events were hypertension (95 [22%] of 429 patients in the pembrolizumab plus axitinib group vs 84 [20%] of 425 patients in the sunitinib group), alanine aminotransferase increase (54 [13%] vs 11 [3%]), and diarrhoea (46 [11%] vs 23 [5%]). No new treatment-related deaths were reported since the first interim analysis.

Interpretation: With extended study follow-up, results from KEYNOTE-426 show that pembrolizumab plus axitinib continues to have superior clinical outcomes over sunitinib. These results continue to support the first-line treatment with pembrolizumab plus axitinib as the standard of care of advanced renal cell carcinoma.

Funding: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.
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http://dx.doi.org/10.1016/S1470-2045(20)30436-8DOI Listing
December 2020

Editorial Comment to Efficacy and safety of first-line nivolumab plus ipilimumab in patients with metastatic renal cell carcinoma: A multicenter retrospective study.

Authors:
Satoshi Tamada

Int J Urol 2020 12 1;27(12):1100-1101. Epub 2020 Oct 1.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

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http://dx.doi.org/10.1111/iju.14383DOI Listing
December 2020

Cabozantinib in advanced renal cell carcinoma: A phase II, open-label, single-arm study of Japanese patients.

Int J Urol 2020 11 12;27(11):952-959. Epub 2020 Aug 12.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Objectives: To evaluate the efficacy and safety of cabozantinib, through a bridging study to METEOR, in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.

Methods: This phase II, open-label, single-arm study (ClinicalTrials.gov registration number: NCT03339219) included adult Japanese patients with advanced renal cell carcinoma and measurable disease who had received one or more tyrosine kinase inhibitors. Patients received cabozantinib 60 mg orally once daily while there was clinical benefit, or until unacceptable toxicity or disease progression. The primary end-point was objective response rate per Response Evaluation Criteria in Solid Tumors Version 1.1. Secondary end-points included clinical benefit rate (complete or partial response, or ≥8-week stable disease), progression-free survival, overall survival and safety.

Results: Of the 35 patients enrolled, 68.6%, 22.9% and 8.6% had previously received one, two and three prior tyrosine kinase inhibitors, respectively. The median duration of cabozantinib exposure was 27.0 weeks (range 5.1-43.0 weeks). The objective response rate was 20.0% (90% confidence interval 9.8-34.3%), and the clinical benefit rate was 85.7% (95% confidence interval 69.7-95.2%). The 6-month estimated progression-free survival was 72.3% (95% confidence interval 53.3-84.6%); the median progression-free survival and overall survival were not reached. All patients reported adverse events, which were manageable by supportive treatment or dose modification; two patients (5.7%) discontinued therapy due to adverse events.

Conclusions: The results showed that findings from METEOR can be extrapolated, and that cabozantinib 60 mg/day is a viable treatment option in Japanese patients with advanced renal cell carcinoma who had progressed after prior tyrosine kinase inhibitor therapy.
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http://dx.doi.org/10.1111/iju.14329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7689847PMC
November 2020

Myeloid-derived suppressor cells are essential partners for immune checkpoint inhibitors in the treatment of cisplatin-resistant bladder cancer.

Cancer Lett 2020 06 19;479:89-99. Epub 2020 Mar 19.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan. Electronic address:

Myeloid-derived suppressor cells (MDSCs) are one of the key players that contribute to immune evasion. The purpose of the present study was to investigate whether MDSCs could be a novel target for the treatment of cisplatin-resistant bladder cancer. We established cisplatin-resistant bladder cancer cell lines (MB49R, MBT-2R, and T24R) and evaluated chemokine expression and MDSC expansion. We also assessed the antitumor effect by depleting MDSCs with or without a α-PD-L1 antibody using MB49R xenograft models. The chemokine expression of CXCL1, CXCL2, and CCL2 increased in cisplatin-resistant cells compared to those in their parent strains. Monocytic MDSCs (Mo-MDSCs) were observed more frequently compared to polymorphonuclear MDSCs (PMN-MDSCs) in MB49R tumors. The immunosuppressive genes arginase 1 and iNOS were comparably expressed in each MDSC subtype. In vivo, combination therapy targeting both PMN- and Mo-MDSCs using α-Gr1 and α-Ly6C antibodies significantly reduced tumor volume with increased infiltration of CD8 T cells in the tumor. Finally, co-targeting pan-MDSCs and PD-L1 remarkably reduced the tumor growth. These findings suggest that targeting MDSCs might enhance the therapeutic effect of immune checkpoint inhibitors in cisplatin-resistant bladder cancers.
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http://dx.doi.org/10.1016/j.canlet.2020.03.013DOI Listing
June 2020

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: the OCUU-CRPC study.

Int J Clin Oncol 2020 Mar 28;25(3):486-494. Epub 2019 Sep 28.

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.

Background: Before the androgen target therapy era, flutamide was widely used for castration-resistant prostate cancer in Japan. Enzalutamide is currently the recommended treatment; however, the efficacy and safety of enzalutamide and flutamide after combined androgen blockade therapy with bicalutamide, has not been compared.

Methods: Patients with castration-resistant prostate cancer who received combined androgen blockade therapy with bicalutamide were randomly assigned to receive either enzalutamide or flutamide. The primary endpoint for efficacy was the 3-month prostate-specific antigen response rate. This trial is registered with ClinicalTrials.gov (NCT02346578) and the University hospital Medical Information Network (UMIN000016301).

Results: Overall, 103 patients were enrolled. The 3- (80.8% vs. 35.3%; p < 0.001) and 6-month (73.1% vs. 31.4%; p < 0.001) prostate-specific antigen response rates were higher in the enzalutamide than in the flutamide group. The 3-month disease progression rates (radiographic or prostate-specific antigen progression) were 6.4% and 38.8% in the enzalutamide and flutamide groups, respectively [hazard ratio (HR): 0.16; 95% confidence interval (CI): 0.05-0.47; p < 0.001]; the 6-month rates were 11.4% and 51.1%, respectively (HR 0.22; 95% CI 0.09-0.50; p < 0.001). Enzalutamide provided superior prostate-specific antigen progression-free survival compared with flutamide (HR 0.29; 95% CI 0.15-0.54; p < 0.001). Median time to prostate-specific antigen progression-free survival was not reached and was 6.6 months in the enzalutamide and flutamide groups, respectively.

Conclusions: As an alternative anti-androgen therapy in patients with castration-resistant prostate cancer who fail bicalutamide-combined androgen blockade therapy, enzalutamide provides superior clinical outcomes compared with flutamide. Enzalutamide should be preferred over flutamide in these patients.
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http://dx.doi.org/10.1007/s10147-019-01554-3DOI Listing
March 2020

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: study protocol for a multicenter randomized phase II trial (the OCUU-CRPC study).

BMC Cancer 2019 Apr 11;19(1):339. Epub 2019 Apr 11.

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.

Background: Enzalutamide is an oral androgen receptor targeted agent that has been shown to improve survival in PREVAIL trials and has been approved for patients with chemo-naïve metastatic castration-resistant prostate cancer (CRPC). Meanwhile, flutamide is a non-steroidal oral anti-androgen that was commonly used before the approval of bicalutamide. The objective of the OCUU-CRPC study is to compare the efficacy and safety between second-line hormonal therapy of enzalutamide and flutamide as alternative anti-androgen therapy (AAT) after combined androgen blockade (CAB) therapy that included bicalutamide in patients with CRPC.

Methods: A total of 100 patients with CRPC with or without distant metastases after disease progression who received CAB therapy with bicalutamide were randomly assigned at a 1:1 ratio according to distant metastases to the enzalutamide (160 mg/day, 4 × 40 mg capsules once daily) and flutamide (375 mg/day; 3 × 125 mg tablets thrice daily) groups. The primary endpoint for the drug efficacy is the response rate of prostate-specific antigen (PSA) (i.e., the ratio of patients whose PSA declined by ≥50% from baseline) at 3 months. Meanwhile, the secondary endpoints are PSA progression rate at 3 and 6 months, PSA response rate at 6 months, change in quality of life, PSA progression-free survival, and safety. The patient registration started in January 2015 and will end in March 2018, and the follow-up period is 6 months after the last patient registration. The main result will be reported in March 2019.

Discussion: In the OCUU-CRPC study, we compare the efficacy and safety of enzalutamide or alternative AAT with flutamide in participants with CRPC who were previously treated with a CAB therapy with bicalutamide. The expected results of this study will be that enzalutamide is superior to flutamide in terms of PSA response. A longer time to disease progression with enzalutamide over flutamide may translate to better overall survival. However, flutamide may be more accessible for patients owing to its lower cost than enzalutamide.

Trial Registration: The OCUU-CRPC study was prospectively registered at clinicaltrials.gov ( NCT02346578 , January 2015) and University Hospital Medical Information Network ( UMIN000016301 , January 2015).
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http://dx.doi.org/10.1186/s12885-019-5526-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6458677PMC
April 2019

Pembrolizumab plus Axitinib versus Sunitinib for Advanced Renal-Cell Carcinoma.

N Engl J Med 2019 03 16;380(12):1116-1127. Epub 2019 Feb 16.

From the Cleveland Clinic Taussig Cancer Institute, Cleveland (B.I.R.); Fox Chase Cancer Center, Philadelphia (E.R.P.); Dnipropetrovsk Medical Academy of Ministry of Health of Ukraine (V.S.) and Dnipropetrovsk Medical Academy (I.B.), Dnipro, Sumy State University, Sumy Regional Oncology Center, Sumy (I.V.), and Ivano-Frankivsk National Medical University, Ivano-Frankivsk (A.K.) - all in Ukraine; the Russian Scientific Center of Roentgen Radiology (R.G.), Central Clinical Hospital with Outpatient Clinic (D.N.), and Hertzen Moscow Cancer Research Institute (B.A.), Moscow; the Christie NHS Foundation Trust, Manchester (R.H.), and Barts Health and the Royal Free NHS Trusts, Barts Cancer Institute, and Queen Mary University of London, London (T.P.) - all in the United Kingdom; Centre Hospitalier Universitaire (CHU) de Québec and Université Laval, Quebec, QC (F.P.), and CHU de Montréal, Montreal (D.S.) - both in Canada; Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic (B.M.); Hospital de Clínicas de Porto Alegre, Porto Alegre, Brazil (S.J.A.); Centre Antoine Lacassagne, Université Côte d'Azur, Nice (D.B.), and Hôpitaux Universitaires de Lyon, Lyon (S. Tartas) - both in France; Military Institute of Medicine, Warsaw, Poland (C.S.); Rocky Mountain Cancer Center, Colorado Springs, CO (M.M.); Adelaide and Meath Hospital and University College Dublin, Dublin (R.S.M.); the Department of Urology, Eberhard-Karls University Tübingen, Tübingen, Germany (J.B.); Taipei Veterans General Hospital, Taipei, Taiwan (Y.-H.C.); Osaka City University Hospital, Osaka, Japan (S. Tamada); MSD China, Beijing (Q.S.); Merck, Kenilworth, NJ (R.F.P., M.C.); and Georgetown Lombardi Comprehensive Cancer Center, Washington, DC (M.B.A.).

Background: The combination of pembrolizumab and axitinib showed antitumor activity in a phase 1b trial involving patients with previously untreated advanced renal-cell carcinoma. Whether pembrolizumab plus axitinib would result in better outcomes than sunitinib in such patients was unclear.

Methods: In an open-label, phase 3 trial, we randomly assigned 861 patients with previously untreated advanced clear-cell renal-cell carcinoma to receive pembrolizumab (200 mg) intravenously once every 3 weeks plus axitinib (5 mg) orally twice daily (432 patients) or sunitinib (50 mg) orally once daily for the first 4 weeks of each 6-week cycle (429 patients). The primary end points were overall survival and progression-free survival in the intention-to-treat population. The key secondary end point was the objective response rate. All reported results are from the protocol-specified first interim analysis.

Results: After a median follow-up of 12.8 months, the estimated percentage of patients who were alive at 12 months was 89.9% in the pembrolizumab-axitinib group and 78.3% in the sunitinib group (hazard ratio for death, 0.53; 95% confidence interval [CI], 0.38 to 0.74; P<0.0001). Median progression-free survival was 15.1 months in the pembrolizumab-axitinib group and 11.1 months in the sunitinib group (hazard ratio for disease progression or death, 0.69; 95% CI, 0.57 to 0.84; P<0.001). The objective response rate was 59.3% (95% CI, 54.5 to 63.9) in the pembrolizumab-axitinib group and 35.7% (95% CI, 31.1 to 40.4) in the sunitinib group (P<0.001). The benefit of pembrolizumab plus axitinib was observed across the International Metastatic Renal Cell Carcinoma Database Consortium risk groups (i.e., favorable, intermediate, and poor risk) and regardless of programmed death ligand 1 expression. Grade 3 or higher adverse events of any cause occurred in 75.8% of patients in the pembrolizumab-axitinib group and in 70.6% in the sunitinib group.

Conclusions: Among patients with previously untreated advanced renal-cell carcinoma, treatment with pembrolizumab plus axitinib resulted in significantly longer overall survival and progression-free survival, as well as a higher objective response rate, than treatment with sunitinib. (Funded by Merck Sharp & Dohme; KEYNOTE-426 ClinicalTrials.gov number, NCT02853331.).
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http://dx.doi.org/10.1056/NEJMoa1816714DOI Listing
March 2019

Enzalutamide versus flutamide for castration-resistant prostate cancer after combined androgen blockade therapy with bicalutamide: a retrospective study.

Int J Clin Oncol 2019 Jul 11;24(7):848-856. Epub 2019 Feb 11.

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan.

Background: Alternative anti-androgen therapy (AAT) with flutamide after combined androgen blockade (CAB) therapy with bicalutamide for metastatic prostate cancer is common. However, no studies have compared enzalutamide without AAT with enzalutamide after AAT with flutamide as treatment for castration-resistant prostate cancer (CRPC). We aimed to compare the efficacies of flutamide and enzalutamide for CRPC.

Methods: In our hospital, 55 patients were diagnosed with CRPC after CAB therapy and administered flutamide or enzalutamide between May 2014 and December 2017. Patients with flutamide failure were administered enzalutamide. We evaluated the (1) prostate-specific antigen (PSA) best response with initial therapy, (2) PSA progression-free survival with initial therapy (PSA-PFS), (3) PSA best response with enzalutamide therapy, (4) PSA-PFS of enzalutamide therapy, and (5) overall survival (OS).

Results: As first-line therapy, patients were administered enzalutamide (n = 29) or flutamide (n = 26). In the flutamide group, 18 patients showed disease progression and were administered enzalutamide. PSA best response was statistically higher in the enzalutamide group. PSA-PFS was significantly longer in the enzalutamide group [hazard ratio (HR) 0.42, 95% confidence interval (CI) 0.19-0.92, p = 0.024]. However, there was no significant difference in PSA best response with enzalutamide therapy and PSA-PFS between the first- and second-line enzalutamide therapies (HR 0.80, 95% CI 0.33-1.94, p = 0.62). There was no significant difference in OS between enzalutamide and flutamide groups (HR 1.85, 95% CI 0.53-6.42, p = 0.33).

Conclusions: AAT with subsequent flutamide after CAB therapy with bicalutamide may be suitable for some CRPC patients.
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http://dx.doi.org/10.1007/s10147-019-01413-1DOI Listing
July 2019

Second-line treatment after sunitinib therapy in patients with renal cell carcinoma: a comparison of axitinib and mammalian target of rapamycin inhibitors.

Oncotarget 2018 Dec 11;9(97):37017-37025. Epub 2018 Dec 11.

Department of Urology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.

This retrospective study compared the outcomes of sequential therapy using sunitinib followed by axitinib or the mammalian target of rapamycin (mTOR) inhibitors (everolimus or temsirolimus). Among 234 patients treated with molecular-targeted drugs for metastatic renal cell carcinoma, we selected 137 patients treated with sunitinib as the first-line therapy. We then compared patients treated with axitinib (n = 52) or mTOR inhibitors (n = 31), as the second-line treatment, and investigated the progression-free survival (PFS) and overall survival (OS). The PFS of axitinib-treated patients (median 8.7 months) was superior to that of mTOR inhibitors-treated patients (median 3.4 months; P = 0.001). Additionally, the OS from baseline of axitinib-treated patients (median 69 months) was superior to that of mTOR inhibitors-treated patients (median 33.4 months; P = 0.034). A multivariate analysis was performed with the following factors: the drugs used for the second-line treatment, the Memorial Sloan Kettering Cancer Center risk classification during the initial treatment, whether the discontinuation of the first-line treatment was due to adverse events, and whether the duration of response of the first-line treatment was less than 6 or 12 months. Importantly, the drugs used for the second-line treatment and Memorial Sloan Kettering Cancer Center risk classification were independent factors. Our findings suggest that axitinib works better than mTOR inhibitors after the first-line treatment with sunitinib.
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http://dx.doi.org/10.18632/oncotarget.26439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319347PMC
December 2018

Time to progression to castration-resistant prostate cancer after commencing combined androgen blockade for advanced hormone-sensitive prostate cancer.

Oncotarget 2018 Dec 11;9(97):36966-36974. Epub 2018 Dec 11.

Department of Urology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.

Purpose: The aim of our retrospective study was to determine the time to progression to castration-resistant prostate cancer (CRPC) in prostate cancer patients who undergo combined androgen blockade (CAB), as well as their prognoses.

Materials And Methods: We examined the overall survival (OS) and disease-specific survival rates, as well as the time to CRPC development, in 387 patients who were treated with CAB for prostate cancer. The disease-specific survival rate and time to CRPC were stratified by prostate-specific antigen (PSA) levels, Gleason score (GS), and presence of metastasis at diagnosis. We designated high-risk patients as those satisfying at least two of the following three criteria: extent of disease of bone metastasis grade ≥2, presence of metastasis at diagnosis, and a GS ≥8.

Results: The 10- and 15-year OS rates were 74.0% and 50.4%, respectively, while the corresponding disease-specific survival rates were both 86.8%. Metastasis at diagnosis was an independent prognostic factor for disease-specific survival. The median time to CRPC development was 140.7 months. A PSA level ≥20 ng/mL, a GS ≥8, and the presence of metastasis at diagnosis were independent predictors of a shorter time to CRPC development. The 10-year disease-specific survival rate in the high-risk group was significantly lower than that in the low-risk group (approximately 74% vs. 98%), and the time to CRPC development was significantly shorter (median: 20.5 months vs. not reached).

Conclusions: The time to CRPC development was shorter in high-risk prostate cancer patients with metastases. Such patients require alternative novel treatment modalities.
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http://dx.doi.org/10.18632/oncotarget.26426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6319345PMC
December 2018

Near infrared fluorescence imaging system for laparoscopic partial nephrectomy.

Can J Urol 2018 12;25(6):9606-9613

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Introduction: Recently, the use of indocyanine green (ICG) with near infrared fluorescence (NIRF) imaging has emerged as an alternative technique for the real-time delineation of resection margins during partial nephrectomy (PN). We aimed to assess the feasibility of using NIRF imaging with ICG during laparoscopic partial nephrectomy (LPN) to delineate the margin between normal renal parenchyma and renal cortical tumors.

Materials And Methods: A retrospective comparison of real-time tumor margin identification and operative outcomes was conducted for 83 patients who underwent LPN with NIRF imaging (IMAGE1 system) and 74 patients who did not.

Results: Tumor margins were identified in 82% of cases in the NIRF group, with a rate of 79% for the clear cell renal carcinoma cases only. Volume of blood loss was higher for the NIRF than normal imaging group (p = 0.015), while the warm ischemia time was significantly shorter (p < 0.01) for the NIRF group. There was no significant difference in the pre to postoperative change in estimated glomerular filtration rate (p = 0.38) or rate of severe complications (Clavien grade ≥ 3; p = 0.88). The rate of positive surgical margins was comparable between the groups (3%; p = 0.91).

Conclusions: NIRF imaging with ICG during LPN was safe and feasible, although the surgical outcomes with NIRF alone was not significantly superior to the ones with conventional methods.
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December 2018

Steroid sulfatase promotes invasion through epithelial-mesenchymal transition and predicts the progression of bladder cancer.

Exp Ther Med 2018 Dec 21;16(6):4463-4470. Epub 2018 Sep 21.

Department of Pathology, Osaka City University Graduate School of Medicine, Osaka 545-8585, Japan.

Androgen signal has been recently suggested to be associated with the progression of bladder cancer. Steroid sulfatase (STS) is a steroid sulfate activation enzyme, considered to be one of the key enzymes in the androgen signaling pathway. However, the role of STS in bladder cancer has not been elucidated. The purpose of the present study was to determine the clinical and functional significance of STS in bladder cancer. Immunohistochemical analysis of surgical specimens obtained by radical cystectomy (n=114) demonstrated that overexpression of STS was associated with the invasion of bladder cancer, as evidenced by the incidence of STS-positive cancers (11.5 and 37.1% in non-muscle invasive and muscle invasive bladder cancers, respectively; P=0.003). STS-positive cancer demonstrated shorter recurrence-free survival and cancer-specific survival (P=0.0027 and 0.0030, respectively). Furthermore, knockdown of STS significantly reduced cell migration and invasion capacities of bladder cancer cells (P<0.001 and P=0.005, respectively), accompanied by the upregulation of E-cadherin and downregulation of vimentin. In summary, the present study demonstrated that STS promotes the invasion capability of bladder cancer via regulation of the epithelial-mesenchymal transition, and may be a useful marker for predicting the progression of bladder cancers.
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http://dx.doi.org/10.3892/etm.2018.6787DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6257456PMC
December 2018

Androgen Receptor Splice Variant 7 Drives the Growth of Castration Resistant Prostate Cancer without Being Involved in the Efficacy of Taxane Chemotherapy.

J Clin Med 2018 Nov 16;7(11). Epub 2018 Nov 16.

Department of Urology, Graduate School of Medicine, Osaka City University, Osaka 545-8585, Japan.

Expression of androgen receptor (AR) splice variant 7 (AR-V7) has been identified as the mechanism associated with the development of castration-resistant prostate cancer (CRPC). However, a potential link between AR-V7 expression and resistance to taxanes, such as docetaxel or cabazitaxel, has not been unequivocally demonstrated. To address this, we used LNCaP95-DR cells, which express AR-V7 and exhibit resistance to enzalutamide and docetaxel. Interestingly, LNCaP95-DR cells showed cross-resistance to cabazitaxel. Furthermore, these cells had increased levels of P-glycoprotein (P-gp) and their sensitivity to both docetaxel and cabazitaxel was restored through treatment with tariquidar, a P-gp antagonist. Results generated demonstrated that P-gp mediated cross-resistance between docetaxel and cabazitaxel. Although the LNCaP95-DR cells had increased expression of AR-V7 and its target genes (UBE2C, CDC20), the knockdown of AR-V7 did not restore sensitivity to docetaxel or cabazitaxel. However, despite resistance to docetaxel and carbazitaxel, EPI-002, an antagonist of the AR amino-terminal domain (NTD), had an inhibitory effect on the proliferation of LNCaP95-DR cells, which was similar to that achieved with the parental LNCaP95 cells. On the other hand, enzalutamide had no effect on the proliferation of either cell line. In conclusion, our results suggested that EPI-002 may be an option for the treatment of AR-V7-driven CRPC, which is resistant to taxanes.
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http://dx.doi.org/10.3390/jcm7110444DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262607PMC
November 2018

Treatment outcomes of ureteral stenting for malignant extrinsic ureteral obstruction: a comparison between polymeric and metallic stents.

Cancer Manag Res 2018 28;10:2977-2982. Epub 2018 Aug 28.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan,

Purpose: To compare treatment outcomes, more specifically patency rate, of polymeric and metallic stents for malignant ureteral obstruction.

Patients And Methods: Between August 2007 and September 2017, we retrospectively analyzed the data of 92 patients (126 ureters) having a diagnosis of malignant extrinsic ureteral obstruction treated with indwelling ureteral stents (polymeric and full-length metallic stents). Of these patients, 35 (54 ureters) were treated with polymeric stents and 57 (72 ureters) with a Resonance® metallic stent. The observation period was censored to 1 year. Survival rate in cases of malignant ureteral obstruction was calculated, and the relationship between the causes of ureteral obstruction, the stent type, and the patency rate was evaluated.

Results: The median observation period was 145 days, with a median survival time of 258 days. The stent patency rate was 70.9% at 1 year, regardless of stent type. Stent occlusion was observed in 20 patients (33 ureters). According to stent type, occlusion of the polymeric and metallic stents was identified in 12 (22%) and 8 (11%) cases, respectively. The clinical features associated with stent failure were assessed. In univariate analysis, the patency rate was significantly better for the metallic stent than for the polymeric stent (1-year patency rate; 78.4%, 61.1%, respectively, HR, 2.15; 95% CI, 1.07-4.33; =0.031). However, the patency rate among patients with abdominal dissemination, lymph node metastasis, and direct compression by tumor was not significantly different.

Conclusion: Indwelling ureteral stents, particularly metallic stents, are effective for the treatment of malignant ureteral obstruction.
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http://dx.doi.org/10.2147/CMAR.S172283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6118249PMC
August 2018

A change from gonadotropin releasing hormone antagonist to gonadotropin releasing hormone agonist therapy does not affect the oncological outcomes in hormone sensitive prostate cancer.

Basic Clin Androl 2018 18;28. Epub 2018 Jul 18.

1Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585 Japan.

Background: The aim of our retrospective study was to evaluate the 5-year survival and time to castration resistant prostate cancer in patients with hormone sensitive prostate cancer treated with the gonadotropin releasing hormone antagonist, degarelix. Another aim was to evaluate the effects of changing the treatment from degarelix to a gonadotropin releasing hormone agonist after achieving stable disease control, on the clinical and oncological outcomes.

Results: Our analysis was based on the data of 108 patients with prostate cancer who were treated with degarelix. Of these, the treatment was changed from degarelix to a gonadotropin releasing hormone agonist in 57 patients (changed group), and the treatment with degarelix was continued in the other 51 (continued group). The overall 5-year survival was statistically superior in the changed (96.6%) group than that in the continued (74.1%) group ( = 0.006). The 5-year cancer-specific survival was also superior in the changed (100%) group than that in the continued (84.6%) group ( = 0.027). The average time to castration resistant prostate cancer was comparable in both the changed (43.3 months) and continued (35.2 months) groups ( = 0.117). Lower serum levels of prostate specific antigen and alkaline phosphatase were maintained after changing the therapy from degarelix to a gonadotropin releasing hormone agonist.

Conclusions: Degarelix is effective in the treatment of prostate cancer. Degarelix therapy can also be safely changed to a gonadotropin releasing hormone agonist without any adverse clinical or oncological effects.
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http://dx.doi.org/10.1186/s12610-018-0074-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6050721PMC
July 2018

The difference in the survival rate of patients with metastatic renal cell carcinoma in the intermediate-risk group of the Memorial Sloan Kettering Cancer Center criteria.

Oncotarget 2018 Jun 12;9(45):27752-27759. Epub 2018 Jun 12.

Department of Urology, Osaka City University Graduate School of Medicine, Abeno-ku, Osaka 545-8585, Japan.

Objectives: To investigate the necessity of stratifying patients in the intermediate-risk group of the Memorial Sloan Kettering Cancer Center (MSKCC) criteria in a real-world population of patients with metastatic renal cell carcinoma.

Patients And Methods: We retrospectively analyzed 234 consecutively treated patients who had received molecular targeted drugs. We examined the difference between progression-free survival and overall survival among patients in the intermediate-risk group of MSKCC criteria. We divided the intermediate group into two subgroups as follows: patients positive for only one risk factor (Int-1) and those positive for two risk factors (Int-2) including performance status, serum hemoglobin level, time from diagnosis to treatment, and corrected calcium and lactate dehydrogenase levels. Next, we evaluated the association between the number of metastatic organs, the presence of pancreatic metastasis, Int-1 or Int-2 grouping, and overall survival.

Results: The median overall survival was 41.2 months. The median overall survival of the favorable-, intermediate-, and poor-risk groups of the MSKCC criteria were 91.0, 33.6, and 15.2 months, respectively. Patient characteristics were similar between the Int-1 and Int-2 groups. Increased positivity for risk factors of MSKCC classification between the two groups was for performance status and serum hemoglobin level. Progression-free survival and overall survival of the Int-1 group were significantly higher than those of the Int-2 group. In Cox proportional stepwise multivariate analysis, the Int-1 and Int-2 classification was an independent risk factor for overall survival.

Conclusion: Patients in the intermediate-risk group had different prognoses depending on the number of positive risk factors.
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http://dx.doi.org/10.18632/oncotarget.25554DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6021254PMC
June 2018

Kamikihito improves cancer-related fatigue by restoring balance between the sympathetic and parasympathetic nervous systems.

Prostate Int 2018 Jun 6;6(2):55-60. Epub 2017 Dec 6.

RIKEN Center for Life Science Technologies, Kobe, Japan.

Background: Cancer-related fatigue is one of the most prevalent symptoms that patients with cancer experience, but the mechanisms underlying it are unknown. We aimed to quantify and mechanistically evaluate the improvement in fatigue related to administration of the Kampo medicine, Kamikihito.

Materials And Methods: Initially, we recruited outpatients with urological diseases and compared fatigue levels of 37 patients with cancer with a control group of 23 volunteers who had recovered completely from cancer or who were being treated for dysuria. Fatigue level was estimated using an autonomic function analyzer. Then, Kamikihito was administered to another 35 patients treated with hormone or antitumor therapy for prostate cancer and metastatic renal cell cancer. Subjective fatigue and other problems of the patients were assessed using the Chalder fatigue scale, the Center for Epidemiologic Studies Depression scale, and the Epworth sleepiness scale. Serum levels of derivatives of reactive oxygen species and biological antioxidant potential were also measured.

Results: Patients in the cancer treatment group experienced more fatigue compared with the control patients when evaluated using an autonomic function analyzer. The group of 35 patients who were administered Kamikihito showed improved scores for fatigue, depression, and sleepiness. Autonomic nervous system balance was also improved with Kamikihito administration. The Kamikihito group also had significantly lower reactive oxygen species metabolite levels and significantly higher antioxidant potential.

Conclusions: Fatigue was more serious in patients with cancer than in control patients. Kamikihito rescued this fatigue and improved anxiety and sleepiness. It restored autonomic nervous system balance and antioxidant function.
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http://dx.doi.org/10.1016/j.prnil.2017.11.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6004623PMC
June 2018

Oncological outcomes classified according to metastatic lesions in the era of molecular targeted drugs for metastatic renal cancer.

Mol Clin Oncol 2018 Jun 24;8(6):791-796. Epub 2018 Apr 24.

Department of Urology, Osaka University Graduate School of Medicine, Osaka 545-8585, Japan.

Since the introduction of molecular targeted agents for the treatment of metastatic renal cell cancer (mRCC), several treatment outcomes, including those from our facilities, have been reported. However, the outcome of these drugs, classified by the metastatic organs, is not well known. The present study reported the treatment results of molecular-targeted agents as classified by the metastatic organ at Osaka City University Graduate School of Medicine. A total of 180 consecutively treated patients who had received molecular targeted agents for metastatic renal cancer for 3 or more months were retrospectively analyzed. The overall survival was calculated and compared according to the Memorial Sloan-Kettering Cancer Center (MSKCC) criteria, the number of metastatic organs, and metastatic lesions. The median overall survival of patients with mRCC treated by molecular targeted agents was 34 months. A significant difference in survival rate between groups was found according to the MSKCC criteria. Patients with single metastatic organ lived significantly longer compared with those with metastases in multiple organs. Patients with pancreatic metastasis had a good response to molecular targeted drugs. Pancreatic metastasis, the number of metastatic organs, and MSKCC criteria were independent risk factors for overall survival. Treatment of mRCC by molecularly targeted agents did not show any difference by metastatic organs except for the pancreas, although its efficacy depends on the number of metastatic organs and the MSKCC classification.
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http://dx.doi.org/10.3892/mco.2018.1614DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5958790PMC
June 2018

Comparison of efficacy and toxicity of second-line combination chemotherapy regimens in patients with advanced urothelial carcinoma.

Int J Clin Oncol 2018 Oct 21;23(5):944-950. Epub 2018 May 21.

Department of Urology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahimachi, Abeno, Osaka, 545-8585, Japan.

Background: The aim of this study was to evaluate the efficacy and toxicities of second-line chemotherapy regimens with docetaxel and gemcitabine (GD), or paclitaxel and gemcitabine (GP) for advanced or metastatic urothelial carcinoma (UC) that did not respond to first-line platinum-based chemotherapy.

Methods: From 2002 to 2017, 78 patients with metastatic UCs that progressed after platinum-based chemotherapy were treated with either GD (n = 41) or GP (n = 37). We compared these two different regimens by analyzing their efficacy and toxicities in a retrospective manner.

Results: Of the 78 patients enrolled in this study, it was possible to determine treatment efficacy in 70; the proportion of patients with objective response and disease control were 8.6 (9/70) and 54.3% (38/70), respectively. The median progression-free survival and overall survival in the total population (GP and GD) were 3.5 (95% CI 0.6-53.3) and 9.6 months (95% CI 1.2-53.3), respectively. There was no significant difference between the two regimens (GD or GP) regarding survival outcomes. Treatment-related adverse events were mostly manageable, but one patient died as a result of febrile neutropenia. The presence of liver metastasis and anemia (Hb < 10.0 g/dl) was prognostic factors for worse survival.

Conclusions: Combination chemotherapy with either GP or GD was a favorable and well-tolerated second-line treatment regimen for patients with advanced or metastatic UC following the failure of a platinum-based regimen. Further study using a large prospective cohort is needed to identify patients who will benefit from second-line combination therapy.
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http://dx.doi.org/10.1007/s10147-018-1288-1DOI Listing
October 2018

Notch Signaling Enhances Stemness by Regulating Metabolic Pathways Through Modifying p53, NF-κB, and HIF-1α.

Stem Cells Dev 2018 07 30;27(13):935-947. Epub 2018 May 30.

1 Pharmaceutical Research and Technology Institute, Kindai University , Osaka, Japan .

Human adipose-derived mesenchymal stromal cells (hASCs) are attractive for regenerative medicine, but their limited in vitro life span limits their therapeutic applicability. Recent data demonstrate that hypoxia may benefit the ex vivo culture of stem cells. Such cells exhibit a high level of glycolytic metabolism under hypoxic conditions. However, the physiological role of glycolytic activation and its underlying regulatory mechanism are incompletely understood. We have shown that when activated under conditions of 5% O, Notch signaling dramatically increases the rate of glycolysis, improves proliferation efficiency, prevents senescence, and maintains the multipotency of hASCs. In the present study, we found that activated Notch1 enhanced nuclear p65 levels, resulting in an increase in glucose metabolism through the upregulation of glycolytic factors, including GLUT3. Notch signaling was also involved in glucose metabolism through p53 inactivation. We also found that NF-κB signaling was regulated by p53. These data suggest that Notch-HES1 signaling enhances the glycolytic pathway through p53 and NF-κB. Our data also revealed that activated Notch1 markedly increased the transcriptional activity of hypoxia-inducible factor 1 (HIF-1). Knockdown of HIF-1α significantly attenuated glycolysis induced by activated Notch1, indicating that the glycolysis pathway is regulated by the coordination of Notch signaling and HIF. Overall, our observations provide new regulatory mechanisms for the glycolysis by Notch signaling to maintain the stemness of hASCs.
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http://dx.doi.org/10.1089/scd.2017.0260DOI Listing
July 2018

Transarterial chemoembolization of liver metastasis from renal cell carcinoma.

Urol Case Rep 2018 Mar 28;17:79-81. Epub 2018 Jan 28.

Department of Urology, Osaka City University Graduate School of Medicine, Japan.

A 73-year-old woman with chief complaint of macroscopic hematuria was diagnosed as having left renal tumor with pancreatic invasion. Nephrectomy was performed. Pathological diagnosis was clear cell carcinoma, pT3a. Three months after the operation, liver metastasis appeared and sunitinib was started. Most of the liver metastases disappeared; however, a new lesion appeared, and sunitinib was switched to axitinib, which was effective on the residual lesion, but the new lesion had poor response. Transarterial chemoembolization was performed to treat the liver metastases, and all metastatic lesions disappeared. There was no recurrence at 2 years, and axitinib was discontinued.
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http://dx.doi.org/10.1016/j.eucr.2018.01.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849875PMC
March 2018

Outcomes of indwelling metallic stents for malignant extrinsic ureteral obstruction.

Int J Urol 2018 03 30;25(3):258-262. Epub 2017 Nov 30.

Department of Urology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Objectives: To report the treatment outcomes of patients with extrinsic ureteral obstruction treated with metallic stents and to identify the factors predicting stent failure.

Methods: A total of 52 patients with extrinsic ureteral obstruction as a result of malignancy (66 ureters) were treated with metallic stents (Resonance ) and included in the study. The median observation period was 118 days.

Results: The median survival time of these patients was 210 days, and the stent patency rate was 86.0% at 6 months and 60.0% at 1 year. Eight (15.4%) patients underwent nephrostomy as a result of stent failure. The occlusion rate of bilateral ureteral obstructed cases was significantly higher than that of unilateral cases. There was no correlation between the preoperative serum creatinine level, causes of ureteral occlusions (compression by tumor, lymph node metastasis, peritoneal dissemination), obstructed site (upper, middle, lower ureter) and stent failure.

Conclusions: Metallic stents are excellent in maintaining patency compared with the conventional stents. Therefore, they can be used as first-line treatment of malignant ureteral obstructions.
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http://dx.doi.org/10.1111/iju.13500DOI Listing
March 2018

Heat shock protein 70 inhibitors suppress androgen receptor expression in LNCaP95 prostate cancer cells.

Cancer Sci 2017 Sep 12;108(9):1820-1827. Epub 2017 Aug 12.

Department of Pharmacology, Osaka City University Medical School, Osaka, Japan.

Androgen deprivation therapy is initially effective for treating patients with advanced prostate cancer; however, the prostate cancer gradually becomes resistant to androgen deprivation therapy, which is termed castration-resistant prostate cancer (CRPC). Androgen receptor splice variant 7 (AR-V7), one of the causes of CRPC, is correlated with resistance to a new-generation AR antagonist (enzalutamide) and poor prognosis. Heat shock protein 70 (Hsp70) inhibitor is known to decrease the levels of full-length AR (AR-FL), but little is known about its effects against CRPC cells expressing AR-V7. In this study, we investigated the effect of the Hsp70 inhibitors quercetin and VER155008 in the prostate cancer cell line LNCaP95 that expresses AR-V7, and explored the mechanism by which Hsp70 regulates AR-FL and AR-V7 expression. Quercetin and VER155008 decreased cell proliferation, increased the proportion of apoptotic cells, and decreased the protein levels of AR-FL and AR-V7. Furthermore, VER155008 decreased AR-FL and AR-V7 mRNA levels. Immunoprecipitation with Hsp70 antibody and mass spectrometry identified Y-box binding protein 1 (YB-1) as one of the molecules regulating AR-FL and AR-V7 at the transcription level through interaction with Hsp70. VER155008 decreased the phosphorylation of YB-1 and its localization in the nucleus, indicating that the involvement of Hsp70 in AR regulation might be mediated through the activation and nuclear translocation of YB-1. Collectively, these results suggest that Hsp70 inhibitors have potential anti-tumor activity against CRPC by decreasing AR-FL and AR-V7 expression through YB-1 suppression.
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http://dx.doi.org/10.1111/cas.13318DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5581527PMC
September 2017

Comparative effectiveness of radical prostatectomy and curative radiotherapy in localized prostate cancer: long-term follow-up.

J Radiat Res 2017 Jul;58(4):552-558

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahi-machi, Abeno-ku, Osaka545-8585, Japan.

We sought to investigate the long-term outcomes after radical prostatectomy (RP) and external-beam radiation therapy (EBRT) for the treatment of localized prostate cancer in Japanese patients. RP and radiation therapy are curative treatments for localized prostate cancer. However, there is controversy around which treatment is superior in Japanese patients. The aim of our retrospective study was to compare the long-term clinical outcomes of each treatment. We retrospectively evaluated the overall survival (OS), cancer-specific survival (CSS) and biochemical failure-free survival (BFS) for patients who had been diagnosed with localized prostate cancer and treated with RP (n = 248) or conventional 2D or 3D-CRT EBRT (n = 182) between 1995 and 2009. The median OS was superior in the RP group compared with that in EBRT group (P < 0.001), although CSS was comparable for both treatment groups; BFS was superior for the EBRT group compared with that for the RP group (P = 0.04). Univariate analysis identified a prostate-specific antigen count (PSA)of ≥20 vs <20 mg/ml, clinical T-stage of the tumor and Gleason score as predictors for CSS. However, multivariate analysis did not identify a factor for CSS. Subgroup analysis was also performed based on clinical T stage, PSA and Gleason score, but there was no difference in each subgroup between RP and EBRT. Both treatments provided satisfactory clinical outcomes in terms of disease control in localized prostate cancer.
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http://dx.doi.org/10.1093/jrr/rrw119DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5570081PMC
July 2017

Carbonic anhydrase 2 is a novel invasion-associated factor in urinary bladder cancers.

Cancer Sci 2017 Mar;108(3):331-337

Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Rat bladder cancer is nearly always papillary non-invasive urothelial carcinoma (UC). To establish an animal model mimicking invasive UC that arises from papillary non-invasive UC in the bladder, male human c-Ha-ras proto-oncogene transgenic rats (Hras128) were treated with 0.05% N-butyl-N-(hydroxybutyl)nitrosameine (BBN) in their drinking water and/or 0.1% phenylethyl isothiocyanate (PEITC) in their diet as follows: BBN (8 weeks)→PEITC (8 weeks); PEITC (8 weeks)→BBN (8 weeks); BBN alone (16 weeks); PEITC alone (16 weeks); and no treatment. At the end of week 16, the highest incidence of invasive UC was observed in the BBN→PEITC group. Therefore, we used Hras128 rats treated with BBN followed by PEITC as a model of invasive bladder cancer to identify invasion-associated proteins. Proteome analysis was performed to compare the protein profiles of invasive and non-invasive UC in Hras128 rats. We identified 49 proteins that were either overexpressed or underexpressed in invasive UC but not in non-invasive UC. Immunohistochemical analysis of carbonic anhydrase 2 (CA2), an overexpressed protein, showed that the relative number of CA2-positive UC was significantly higher for invasive UC compared to non-invasive UC in rats. Moreover, the incidence of CA2-positive cancers was also significantly higher for human muscle-invasive bladder cancer (MIBC) compared to non-MIBC (NMIBC) and was positively associated with the progression of NMIBC. Our findings indicate that CA2 is an invasion-associated factor and suggest that it could serve as a potential therapeutic molecular target for bladder cancers.
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http://dx.doi.org/10.1111/cas.13143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5378286PMC
March 2017

Anti-PD-L1 treatment enhances antitumor effect of everolimus in a mouse model of renal cell carcinoma.

Cancer Sci 2016 Dec 13;107(12):1736-1744. Epub 2016 Dec 13.

Department of Molecular Pathology, Osaka City University Graduate School of Medicine, Osaka, Japan.

Immunotherapy based on blockade of the programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) axis has shown promising clinical activity for renal cell carcinoma (RCC) patients; however, the most effective use of these agents in combination with conventional targeted therapy remains to be resolved. Here we evaluated the therapeutic efficacy of the combination of the mTOR inhibitor everolimus (EVE) and anti-PD-L1 using an immunocompetent mouse model of RCC. We first assessed the in vitro effect of EVE on PD-L1 expression in the human 786-O and mouse RENCA RCC cell lines and found that EVE upregulated PD-L1 expression in these RCC cell lines. We then treated RENCA tumor-bearing mice with EVE and found that PD-L1 expression was also increased in tumor cells after EVE treatment. To determine the antitumor effects of EVE alone, anti-PD-L1 alone, and EVE in combination with anti-PD-L1, we evaluated their antitumor effects on RENCA tumor-bearing mice. A significant decrease in the tumor burden was observed in the EVE alone but not in the anti-PD-L1 alone treatment group compared with the control group. Importantly, the combination of EVE with anti-PD-L1 significantly reduced tumor burden compared with the EVE alone treatment, increasing tumor infiltrating lymphocytes (TILs) and the ratio of cytotoxic CD8 T cells to TILs. The results of the present study demonstrated that anti-PD-L1 treatment enhanced the antitumor effect of EVE in a mouse model, supporting a direct translation of this combination strategy to the clinic for the treatment of RCC.
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http://dx.doi.org/10.1111/cas.13099DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5198964PMC
December 2016

A Case of Metastatic Urachal Carcinoma Treated With FOLFIRI (irinotecan and 5-Fluorouracil/leucovorin) Plus Bevacizumab.

Urol Case Rep 2015 Mar 23;3(2):9-11. Epub 2014 Dec 23.

Department of Urology, Osaka City University Graduate School of Medicine, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan.

A 68-year-old man was introduced to our hospital for the treatment of lung and mediastinum lymph node metastases that originated from an urachal carcinoma 4 years after a partial cystectomy. First-line chemotherapy with an S-1 and cisplatin combination was ineffective. The patient received FOLFIRI plus bevacizumab chemotherapy as salvage chemotherapy. Stability was achieved after eight cycles of FOLFIRI plus bevacizumab therapy. We conducted a biopsy of the metastatic tumor, and the pathology of the biopsy tissue was partially necrotic. To our knowledge, this case represents the first report of a metastatic urachal carcinoma treated with FOLFIRI plus bevacizumab.
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http://dx.doi.org/10.1016/j.eucr.2014.11.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4714276PMC
March 2015

Association of MnSOD AA Genotype with the Progression of Prostate Cancer.

PLoS One 2015 6;10(7):e0131325. Epub 2015 Jul 6.

Department of Urology, SUNY Upstate Medical University, Syracuse, New York, United States of America.

Purpose: To investigate whether manganese superoxide dismutase (MnSOD) genetic polymorphism is associated with the clinical significance of prostate cancer.

Materials And Methods: Prostates were obtained from 194 deceased men 45 years or older who did not have a history of prostate cancer. Serial sections and histological examinations of the prostate were performed. The MnSOD genotypes of the specimens were determined by polymerase chain reaction restriction fragment length polymorphism analysis.

Results: Of the 194 men, 31 and 26 had clinically insignificant and significant prostate cancer. Clinically significant cancer comprised 29% and 58% of the cancers in men <70 and >70 years old, respectively. The age-specific proportion of significant cancer significantly increased with the advance of age (p<0.001). MnSOD AA, as compared with the other genotypes (VA and VV together), was associated with significant prostate cancer across all ages, odds ratio (OR) 2.34, 95% confidence interval (CI) 0.99-5.49, and in men older than 69 years (OR 4.89, 95% CI 1.51-15.8), but not in men younger than 70 years. The genotype was not associated with clinically insignificant cancer regardless of age. The comparison between significant and insignificant cancer, the OR (95% CI) for MnSOD AA was 5.04 (1.05-24.2) (sensitivity 0.57, specificity 0.78, positive predictive value 0.78) in men older than 69 years.

Conclusions: MnSOD polymorphism is strongly associated with the clinical significance of prostate cancer in men older than 69 years, but not in men younger than 70 years suggesting that oxidative stress may be involved in the progression of the disease. MnSOD may be a clinically useful marker to predict the potential of progression of prostate cancer.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0131325PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4492976PMC
March 2016
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