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Background: In the THOR trial (NCT03390504) Cohort 1, erdafitinib demonstrated significantly prolonged overall survival (OS) (median 12.1 versus 7.8 months) and reduced risk of death by 36% (hazard ratio 0.64, P = 0.005) compared with chemotherapy in metastatic urothelial carcinoma (mUC) patients with FGFR alterations who progressed after ≥ 1 prior treatments, including anti-PD-(L)1. There have been no reports of the Japanese subgroup results yet., Methods: THOR Cohort 1 randomized patients to erdafitinib once daily or docetaxel/vinflunine once every 3 weeks. Primary endpoint was OS. Secondary endpoints included progression-free survival (PFS) and objective response rate (ORR). No specific statistical power was set for this Japanese subgroup analysis., Results: Of 266 patients randomized, 27 (14 erdafitinib; 13 chemotherapy) were Japanese. Baseline characteristics were generally similar between treatments and to the overall population, except for more males, lower body weight, and more upper tract primary tumors among Japanese patients. Compared with chemotherapy, erdafitinib showed improved OS (median 25.4 versus 12.4 months), PFS (median 8.4 versus 2.9 months) and ORR (57.1% versus 15.4%). Any grade treatment-related adverse events (AEs) occurred in all patients from both arms but Grade 3/4 AEs and AEs leading to discontinuation were lower in the erdafitinib arm. No new safety signals were observed in the Japanese subgroup., Conclusion: In the Japanese subgroup, erdafitinib showed improved survival and response compared to chemotherapy, with no new safety concerns. These results support erdafitinib as a treatment option for Japanese mUC patients with FGFR alterations, and early FGFR testing after diagnosis of mUC should be considered., (© 2024. The Author(s).)

Objectives: To compare the efficacy and safety of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with gemcitabine-based regimens for neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients treated in Japan., Methods: Data for MIBC patients who received NAC-dd-MVAC followed by a radical cystectomy from June 2019 to May 2023 performed at our hospital were analyzed. For comparisons, data for MIBC patients who received NAC gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) therapy between January 2010 and March 2019 were also obtained. Rates of ypT1N0 or less, progression-free survival (PFS), overall survival (OS), and NAC adverse effects were compared between the GC/GCarbo and dd-MVAC regimens., Results: Results for 32 patients who received dd-MVAC and 30 who received GC/GCarbo NAC therapy were analyzed. ypT1N0 or less was noted in 40.7% of the dd-MVAC and 40.0% of the GC/GCarbo groups, while ypT0N0 rates were 25% and 10%, respectively, with no statistical differences noted. However, Kaplan-Meier analysis of the total cohort demonstrated that dd-MVAC was associated with significantly better PFS and OS rates than GG/GCarbo (hazard ratios: 0.33, p = 0.0237, and 0.23, p = 0.0127, respectively). Propensity-matched models also showed similar results for both PFS and OS. Adverse effects of dd-MVAC were acceptable and the incidence of hematologic toxicity was lower as compared with GC/GCarbo therapy., Conclusion: The present study is the first to show that dd-MVAC as NAC can provide better survival as compared with a gemcitabine-based regimen for patients with MIBC treated in Japan., (© 2024 The Japanese Urological Association.)

Objectives: The JAVELIN Bladder 100 phase 3 trial showed that avelumab first-line maintenance + best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with advanced urothelial carcinoma who were progression-free following first-line platinum-based chemotherapy. We report findings from J-AVENUE (NCT05431777), a real-world study of avelumab first-line maintenance therapy in Japan., Methods: Medical charts of patients with advanced urothelial carcinoma without disease progression following first-line platinum-based chemotherapy, who received avelumab maintenance between February and November 2021, were reviewed. Patients were followed until June 2022. The primary endpoint was patient characteristics; secondary endpoints included time to treatment failure and progression-free survival., Results: In 79 patients analyzed, median age was 72 years (range, 44-86). Primary tumor site was upper tract in 45.6% and bladder in 54.4%. The most common first-line chemotherapy regimen was cisplatin + gemcitabine (63.3%). Median number of chemotherapy cycles received was four. Best response to chemotherapy was complete response in 10.1%, partial response in 58.2%, and stable disease in 31.6%. Median treatment-free interval before avelumab was 4.9 weeks. With avelumab first-line maintenance therapy, the disease control rate was 58.2%, median time to treatment failure was 4.6 months (95% CI, 3.3-6.4), and median progression-free survival was 6.1 months (95% CI, 3.6-9.7)., Conclusions: Findings from J-AVENUE show the effectiveness of avelumab first-line maintenance in patients with advanced urothelial carcinoma in Japan in clinical practice, with similar progression-free survival to JAVELIN Bladder 100 and previous real-world studies, supporting its use as a standard of care., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Objective: To analyse the impact of histological discordance of subtypes (subtypes or divergent differentiation [DD]) in specimens from transurethral resection (TUR) and radical cystectomy (RC) on the outcome of the patients with bladder cancer receiving RC., Patients and Methods: We analysed data for 2570 patients from a Japanese nationwide cohort with bladder cancer treated with RC between January 2013 and December 2019 at 36 institutions. The non-urinary tract recurrence-free survival (NUTR-FS) and overall survival (OS) stratified by TUR or RC specimen histology were determined. We also elucidated the predictive factors for OS in patients with subtype/DD bladder cancer., Results: At median follow-up of 36.9 months, 835 (32.4%) patients had NUTR, and 691 (26.9%) died. No statistically significant disparities in OS or NUTR-FS were observed when TUR specimens were classified as pure-urothelial carcinoma (UC), subtypes, DD, or non-UC. Among 2449 patients diagnosed with pure-UC or subtype/DD in their TUR specimens, there was discordance between the pathological diagnosis in TUR and RC specimens. Histological subtypes in RC specimens had a significant prognostic impact. When we focused on 345 patients with subtype/DD in TUR specimens, a multivariate Cox regression analysis identified pre-RC neutrophil-lymphocyte ratio and pathological stage as independent prognostic factors for OS (P = 0.016 and P = 0.001, respectively). The presence of sarcomatoid subtype in TUR specimens and lymphovascular invasion in RC specimens had a marginal effect (P = 0.069 and P = 0.056, respectively)., Conclusion: This study demonstrated that the presence of subtype/DD in RC specimens but not in TUR specimens indicated a poor prognosis. In patients with subtype/DD in TUR specimens, pre-RC neutrophil-lymphocyte ratio and pathological stage were independent prognostic factors for OS., (© 2024 BJU International.)

Objectives: Evaluate real-world epidemiologic trends and treatment patterns in newly diagnosed patients with locally advanced or metastatic urothelial carcinoma (la/mUC) in Japan., Methods: This retrospective analysis included adults with newly diagnosed la/mUC in Japan (January 2015-December 2019) from a nationwide-linked electronic medical record Diagnostic Procedure Combination claims dataset. Outcomes included epidemiologic trends (incidence and prevalence), baseline demographics, clinical characteristics, and treatment patterns in newly diagnosed patients with la/mUC before (2015-2017) and after (2018-2019) approval of pembrolizumab in Japan., Results: Of 975 patients included, 76.4% were men; 71.6% were aged 70 years or older. Most cases (70.5%) were of the bladder. Between 2015 and 2019, the annual age-adjusted incidence increased from 6.8 to 12.4 per 100 000; the annual age-adjusted period prevalence increased from 13.0 to 25.2 per 100 000; and 307 (31.5%) and 668 (68.5%) patients were diagnosed from 2015 to 2017 and 2018 to 2019, respectively. Overall, 731 (75%) patients received systemic anticancer therapy; all received 1 line and 50.2% received 2 lines of therapy; 78.3% of patients received gemcitabine plus platinum-based therapy and 2.2% received pembrolizumab as first-line treatment. First-line treatment rates increased from 69.4% to 77.5% after pembrolizumab approval. Of 367 patients who received second-line treatment, 22.3% received gemcitabine plus platinum-based therapy; 14.7% received pembrolizumab., Conclusions: In the Japanese regions considered, incidence and prevalence of newly diagnosed la/mUC increased over time and first-line treatment with pembrolizumab increased after approval., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Objective: In December 2021, enfortumab vedotin (EV), an antibody-drug conjugate directed against nectin-4, was approved in Japan as a new treatment after platinum-containing chemotherapy and PD-1/PD-L1 inhibitors. This study evaluated, using real-world data, the efficacy and safety of EV therapy in patients with metastatic urothelial carcinoma (mUC)., Materials and Methods: Fifty-five patients with mUC who discontinued pembrolizumab therapy due to disease progression between June 2018 and April 2023 at Yokohama City University Hospital were evaluated retrospectively. Of the 55 patients, 25 received EV therapy (EV group) and 30 did not (non-EV group). All patients who underwent EV therapy were diagnosed with disease progression after the approval of EV in Japan., Results: The median (range) follow-up period after pembrolizumab discontinuation was 6.3 (0.7-31.1) months. There were eight (32.0%) deaths due to cancer in the EV group and 27 (90.0%) in the non-EV group. The overall survival (OS) after pembrolizumab discontinuation was not reached in the EV group versus 2.6 months in the non-EV group (p < 0.001). A multivariate analysis revealed that EV therapy (EV vs. non-EV group; hazard ratio 0.26; 95% confidence interval 0.16-0.41; p < 0.001) was an independent prognostic factor for OS., Conclusion: EV prolonged OS in mUC following pembrolizumab therapy in real-world data., (© 2024 The Japanese Urological Association.)

Objectives: Immune checkpoint inhibitors and enfortumab vedotin have opened new avenues for sequential treatment strategies for locally advanced/metastatic urothelial carcinoma (la/mUC). In the pre-enfortumab vedotin era, many patients could not receive third-line treatment owing to rapid disease progression and poor general status. This study aimed to analyze real-world sequential treatment practices for la/mUC in Japan, with a focus on patients who do not receive third-line treatment., Methods: We analyzed data for 1023 la/mUC patients diagnosed between January 2020 and December 2021 at 54 institutions from a Japanese nationwide cohort., Results: At the median follow-up of 28.5 months, the median overall survival from first-line initiation for 905 patients who received systemic anticancer treatment was 19.1 months. Among them, 81% and 32% received second- and third-line treatment. Notably, 52% had their treatment terminated before the opportunity for third-line treatment. Multivariate logistic regression analysis revealed that low performance status (≥1), elevated neutrophil-to-lymphocyte ratio (≥3), and low body mass index (<21 kg/m 2 ) at the start of first-line treatment were independent risk factors for not proceeding to third-line treatment (p = 0.0024, 0.0069, and 0.0058, respectively). In this cohort, 33% had one of these factors, 36% had two, and 15% had all three., Conclusions: This study highlights the high frequency of factors associated with poor tolerance to anticancer treatment in la/mUC patients. The findings suggest the need to establish optimal sequential treatment strategies, maximizing efficacy within time and tolerance constraints, while concurrently providing strong supportive care, considering immunological and nutritional aspects., (© 2024 The Authors. International Journal of Urology published by John Wiley & Sons Australia, Ltd on behalf of The Japanese Urological Association.)

Objective: Real-world evidence regarding enfortumab vedotin for unresectable or metastatic urothelial carcinoma is scarce, particularly in Japan. We investigated real-world data focusing on patient background, previous treatments, response, survival and adverse events in patients receiving enfortumab vedotin., Methods: A multicentre database was used to register 556 patients diagnosed with metastatic urothelial carcinoma from 2008 to 2023; 34 patients (6.1%) treated with enfortumab vedotin were included. Best radiographic objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (v1.1) during treatments. Overall survival and progression-free survival were estimated (Kaplan-Meier method). Toxicities were reported according to the Common Terminology Criteria for Adverse Events, version 5.0. The relative dose intensity, which could impact oncological outcomes, was calculated., Results: The median number of enfortumab vedotin therapy cycles was 5. The best objective response to enfortumab vedotin was partial response, stable disease and progressive disease in 19 (56%), 5 (15%) and 10 (29%) patients, respectively. The median overall survival and progression-free survival after the first enfortumab vedotin dose were 16 and 9 months, respectively. No significant relationship was observed between survival outcomes after enfortumab vedotin initiation and the enfortumab vedotin relative dose intensity. The median overall survival from first-line platinum-based chemotherapy initiation was 42 months. Twenty-six (76%) patients experienced any grade of enfortumab vedotin-related toxicities; eight (24%) experienced Grades 3-4 toxicities, the most common being skin toxicity (any grade, 47%; Grades 3-4, 12%)., Conclusions: Here, we report real-world evidence for enfortumab vedotin therapy in Japan. Tumour responses and safety profiles were comparable with those of clinical trials on this novel treatment., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Background: Photodynamic diagnosis-assisted transurethral resection of bladder tumor (PDD-TURBT) showed improvement of diagnostic accuracy and treatment efficacy compared to white light TURBT (WL-TURBT). While PDD-TURBT is highly effective, PDD-TURBT requires the use of PDD device and light-sensitive substance precursor, which increases the medical cost compared to WL-TURBT. In this study, the impact on health care economic costs were examined between PDD-TURBT and WL-TURBT., Methods: Of the total 265 patients, 88 patients for WL-TURBT and 105 patients for PDD-TURBT were available for analysis. Costs were also examined between 34 patients without false-positives and 36 patients with false-positives with a follow-up period of at least 200 days. To compare costs between the two treatments, we calculated the cost/person/year of TURBT using Japanese Diagnosis Procedure Combination and Per-Diem Payment System (DPC/PDPS)., Results: The total number of surgeries including the first TURBT was 135 (47 recurrences) in the WL-TURBT group and 133 (28 recurrences) in the PDD-TURBT group. The cost per person for hospitalization and surgery was 366,310 Japanese yen (JPY) for the WL-TURBT and 501,930 JPY for the PDD-TURBT. The cost per person per year was 491,622 JPY in the WL-TURBT group and 506,405 JPY in the PDD-TURBT group. Regarding false-positives, the cost per person per year was 494,544 JPY in the group without false-positives and 328,086 JPY in the group with false-positives., Conclusions: Although PDD-TURBT is cost more than WL-TURBT for one surgical hospitalization, the cost per person per year for PDD-TURBT and WL-TURBT is cost-neutral., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023. Published by Elsevier B.V.)

Although recent clinical trials of new therapeutic agents for metastatic urothelial carcinoma have shown prolonged overall survival, there are few real-world evidence. To assess the impact of new therapeutic agents, we performed retrospective analysis for consecutive 158 metastatic urothelial carcinoma patients who performed systemic therapy in our institution between May 2008 and August 2023. We defined a period from May 2008 to December 2017, when pembrolizumab was first introduced to the clinical setting in the new therapeutic agents for metastatic urothelial carcinoma in Japan, as "pre new drug era" and a period from January 2018 to August 2023 as "post new drug era". We compared overall survival between pre- and post- new drug era using Kaplan-Meier method with log rank test. Median overall survival of pre- and post- new drug era were 14.5 months (95% confidence intervals: 11.6-16.7) and 23.1 months (95% confidence intervals: 14.5-NA), respectively (p < 0.001). Five-year survival rate of pre- and post- new drug era was 7.0% (95% confidence intervals: 2.3-15.3) and 36.3% (95% confidence intervals: 21.4-51.5), respectively. Multivariable Cox proportional hazards regression analysis of factors associated with overall survival showed that enfortumab vedotin administration, administration of second-line or more systemic therapy, best overall response of SD, PR and CR in first-line systemic therapy, higher serum albumin and lower CRP were factors for overall survival prolongation. Introduction of new therapeutic agents for metastatic urothelial carcinoma contributed to the improvement of overall survival in comparison with the era without these agents., (© 2023. Springer Nature Limited.)

Objective: To investigate the involvement of pretreatment C-reactive protein (CRP) and neutrophil-to-lymphocyte ratio (NLR) in the prognosis of patients who underwent intravesical bacillus Calmette-Guérin (BCG) therapy for non-muscle invasive bladder cancer (NMIBC)., Methods: The clinicopathological data of 1709 patients with NMIBC who underwent initial intravesical BCG therapy after transurethral resection of bladder tumor were retrospectively analyzed to evaluate the outcome of intravesical BCG therapy in a multicenter study conducted by the Japan Urological Oncology Group. The prognoses of these patients were analyzed to determine whether the biomarkers (CRP and NLR) could predict the efficacy of intravesical BCG therapy. Patients were divided into two groups according to the pretreatment CRP and NLR, with cutoff values defined as CRP ≥ 0.5 mg/dl and NLR ≥ 2.5, based on several previous reports., Results: In the univariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence, cancer-specific survival, and bladder cancer (BC) progression, while NLR ≥ 2.5 was not significantly associated with patient prognosis. In the multivariable analysis, CRP ≥ 0.5 mg/dl was significantly associated with intravesical recurrence and BC progression. The concordance index was used to examine the accuracy in predicting recurrence and progression events. While CRP was slightly, though not statistically significant, inferior to the European Association of Urology risk classification, the combination of them showed improved predictive accuracy., Conclusion: This study suggests that CRP can be a prognostic factor after intravesical BCG therapy and may provide useful data for determining treatment and follow-up strategies for patients with NMIBC., (© 2022 The Japanese Urological Association.)

Backgrounds and Objectives: To overcome the piecemeal nature of bladder tumor resection, en bloc resection of bladder tumor (ERBT) has been introduced. ERBT is difficult for surgeons to perform using the currently available system because it has only one arm. Herein, we aimed to develop a new transurethral surgical system to facilitate two-arm ERBT and to report the results of preclinical experiments using tumor phantoms. Methods: Initially, we aimed to develop a brand-new surgical system for ERBT but, after trial and error, we redirected our development to the creation of three elements: the left arm to grasp the tumor; the right arm to cut the tumor; and the system to operate the arms that can be attached to the existing surgical system (UES-40 SurgMaster ® [Olympus Co. Ltd., Tokyo, Japan]). The current system was evaluated by performing simulated ERBTs using tumor phantoms made from konjac jelly. Results: Following the assembly of developed arms into the UES-40 SurgMaster, we conducted preliminary ERBTs. After performing several resections, we adopted a basket-shaped forceps as the left arm instead of grasping forceps and an arched electrode as the right arm. The two arms and single endoscope were placed in an equilateral triangle. We performed ERBT for the tumor phantoms that ranged from 0.5 to 2.0 cm without major redo. Conclusion: Herein, we introduced our development for two-arm ERBT. The current concept of "two-hand transurethral surgery" has the potential to be developed in future in vivo and clinical trials.

Objective: To compare the therapeutic effect of Bacille Calmette-Guérin (BCG) intravesical instillation in older and younger patients with high-risk non-muscle-invasive bladder cancer. The comparison was performed with propensity score matching (PSM) without terminating the death of the older patients using relatively large-scale retrospective data from multiple institutes in Japan., Materials and Methods: Overall, 3283 patients diagnosed with non-muscle-invasive bladder cancer treated with intravesical BCG instillation during 2000-2018 in 31 institutes were examined; 1437 and 602 patients with high-grade T1 and Tis tumors were divided into those aged ≥75 and <75 years. Multivariate analysis using the Fine-Gray competing risks regression model before PSM and survival analysis using the cumulative incidence method after PSM were performed., Results: In the pre-PSM series of high-grade T1 tumors, age ≥75 years was an independent prognostic factor for both recurrence and progression in multivariate analysis (P = .015 and P = .013). In the pre-PSM series with Tis tumor, no variables to predict recurrence and progression was found. In the post-PSM series of 870 high-grade T1 tumors, cumulative probability of recurrence after BCG intravesical instillation were significantly higher in patients aged ≥75 years than in those aged <75 years (P = .008). The frequency of discontinuation of BCG instillation in patients aged ≥75 years with high-grade T1 and Tis was not significantly different from those in patients aged <75 years (P = .564 and P = .869)., Conclusion: The cumulative probability of recurrence after intravesical BCG instillation was significantly higher in older than in younger patients with high-grade T1 bladder cancer., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aim: The optimal timing of switching from platinum-based chemotherapy to pembrolizumab in patients with advanced urothelial carcinoma (UC) remains unclear., Patients and Methods: Thirty-four patients who received pembrolizumab as second-line treatment after first-line platinum-based chemotherapy were retrospectively evaluated., Results: According to overall survival (OS) from pembrolizumab, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (7.0 and 25.5 months, p=0.034), but not between ≤6 and >6 cycles (11.3 and 6.6 months, p=0.658). According to the Cox proportional hazards regression model, the number of chemotherapy cycles was not correlated with better OS in pembrolizumab-treated patients. According to the OS from the first-line treatment, there was a significant difference between ≤4 and >4 prior chemotherapy cycles (17.3 and 37.1 months, p<0.001), but not between ≤6 and >6 cycles (18.6 and 27.3 months, p=0.276)., Conclusion: The optimal timing of switching from platinum-base chemotherapy to pembrolizumab in advanced UC is around six cycles., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Objectives: The US Food and Drug Administration recently defined the clinical term "bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer" as a disease state resistant to adequate bacillus Calmette-Guérin therapy. There is a significant lack of prognostication for this disease even in patients who have undergone early radical cystectomy. This study aimed to identify the clinical outcomes and prognostic factors in Japanese patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer who underwent early radical cystectomy., Methods: Data from a large-scale multicenter retrospective study included 2879 patients with highest-risk or high-risk non-muscle-invasive bladder cancer who received intravesical bacillus Calmette-Guérin induction therapy between January 2000 and December 2019. A total of 141 patients (4.3%) met the criteria for bacillus Calmette-Guérin-unresponsive disease, of whom 47 (33.3%) underwent early radical cystectomy. Prognostic factors for three clinical endpoints, namely, unresectable lesion-free survival, cancer-specific survival, and overall survival, were identified., Results: The highest-risk status at induction bacillus Calmette-Guérin was associated with short unresectable lesion-free survival (hazard ratio 7.85; P < 0.05), cancer-specific survival (hazard ratio 12.24; P < 0.05), and overall survival (hazard ratio 9.25; P < 0.01). Moreover, extravesical tumors (pathological T3 or T4) on the radical cystectomy specimens were associated with poor prognosis and were found at a higher rate in patients with the highest-risk status at induction bacillus Calmette-Guérin than in those with high-risk status (35.7% vs 21.2%)., Conclusions: The highest-risk status among the pre-bacillus Calmette-Guérin factors was associated with upstaging to extravesical tumors and poor prognosis despite early radical cystectomy procedures. Appropriate decision-making and the correct timing of radical cystectomy are vital to avoid treatment delays and improve outcomes., (© 2021 The Japanese Urological Association.)

Background: Intravesical bacillus Calmette-Guérin (BCG) fails in a considerable proportion of non-muscle invasive bladder cancer (NMIBC) patients despite treatment per recommended protocol. This real-world study aimed to understand the current patterns of treatment and disease management for the broad BCG-unresponsive NMIBC patient population, alongside collecting sufficient data on patients who do not undergo cystectomy., Methods: This was a multicenter, retrospective survey of physicians treating BCG-unresponsive NMIBC patients. Data were collected in eight countries - France, Germany, Spain, Italy, United Kingdom, United States, China, and Japan - between January and May 2019. The study consisted of a short online physician survey and a retrospective chart review of eligible BCG-unresponsive NMIBC patients. Physicians abstracted chart data for the last 10 (five patients in Japan) eligible BCG-unresponsive NMIBC patients meeting the inclusion criteria, and the data were analysed for all countries combined using descriptive statistics. Country-specific analyses were also carried out, as appropriate., Results: Overall, 508 physicians participated in the study. Almost one-quarter (22.9%) of physicians' current NMIBC patient caseload was BCG-unresponsive, whereby BCG therapy was no longer considered an option. Half of physicians (49.4%) did not regularly use biomarker tests in their practice, with particularly few physicians undertaking biomarker testing in Spain and Japan. Biomarker testing varied considerably, with the proportions of physicians selecting 'none' ranging from 11.4% in China to 70.3% in Japan. Physicians reported transurethral resection of the bladder tumor (TURBT) and BCG as the most common current treatments received by their patients. Chemotherapy and anti-PD-L1 treatment options were considered impactful new therapies by 94.7% and 90.0% of physicians surveyed in this study, respectively., Conclusions: The most common treatments received by patients in this study were TURBT and BCG. Emerging new treatments are driven by exploring biomarkers, but in real-world clinical practice only half of physicians or fewer regularly tested their NMIBC patients for biomarkers; PD-1/PD-L1 was the most common biomarker test used. Most physicians reported that, in addition to chemotherapy, anti-PD-L1 was an impactful new therapy., (© 2022. The Author(s).)

Background: To explore possible solutions to overcome chronic Bacillus Calmette-Guérin (BCG) shortage affecting seriously the management of non-muscle invasive bladder cancer (NMIBC) in Europe and throughout the world, we investigated whether non-maintenance eight-dose induction BCG (iBCG) was comparable to six-dose iBCG plus maintenance BCG (mBCG)., Methods: This observational study evaluated 2669 patients with high- or highest-risk NMIBC who treated with iBCG with or without mBCG during 2000-2019. The patients were classified into five groups according to treatment pattern: 874 (33%) received non-maintenance six-dose iBCG (Group A), 405 (15%) received six-dose iBCG plus mBCG (Group B), 1189 (44%) received non-maintenance seven-/eight-dose iBCG (Group C), 60 (2.2%) received seven-/eight-dose iBCG plus mBCG, and 141 (5.3%) received only ≤5-dose iBCG. Recurrence-free survival (RFS), progression-free survival, and cancer-specific survival were estimated and compared using Kaplan-Meier analysis and the log-rank test, respectively. Propensity score-based one-to-one matching was performed using a multivariable logistic regression model based on covariates to obtain balanced groups. To eliminate possible immortal bias, 6-, 12-, 18-, and 24-month conditional landmark analyses of RFS were performed., Results: RFS comparison confirmed that mBCG yielded significant benefit following six-dose iBCG (Group B) in recurrence risk reduction compared to iBCG alone (groups A and C) before (P < 0.001 and P = 0.0016, respectively) and after propensity score matching (P = 0.001 and P = 0.0074, respectively). Propensity score-matched sequential landmark analyses revealed no significant differences between groups B and C at 12, 18, and 24 months, whereas landmark analyses at 6 and 12 months showed a benefit of mBCG following six-dose iBCG compared to non-maintenance six-dose iBCG (P = 0.0055 and P = 0.032, respectively). There were no significant differences in the risks of progression and cancer-specific death in all comparisons of the matched cohorts., Conclusions: Although non-maintenance eight-dose iBCG was inferior to six-dose iBCG plus mBCG, the former might be an alternative remedy in the BCG shortage era. To overcome this challenge, further investigation is warranted to confirm the real clinical value of non-maintenance eight-dose iBCG.

As part of the recent series of articles to create a comprehensive description of the radiation risks of solid cancer incidence after ionizing radiation exposure, based on the atomic bomb survivors' Life Span Study (LSS), this work focuses on the risks of urinary tract cancer (UTC) and kidney cancer. Analyses covered a 52-year period of follow-up, through 2009, among 105,444 eligible survivors who were alive and cancer free in 1958. This represents an additional 11 years of follow-up since the last comprehensive report, with a total of 3,079,502 person-years. We observed 790 UTC and 218 kidney cancer cases. Adjusted for smoking, there was a strong linear radiation dose response for UTC. The sex-averaged excess relative risk per 1 Gy (ERR/Gy) was 1.4 (95% confidence interval, CI: 0.82 to 2.1). Both males and females showed significantly increased ERRs/Gy with female point estimates at a factor of 3.4 (95% CI: 1.4 to 8.6) greater than male estimates. UTC radiation risks were largely unmodified by age at exposure or attained age. The attributable fraction of UTC to radiation exposure was approximately 18% while that attributed to smoking was 48%. Kidney cancer showed an increased ERR due to smoking (0.56 per 50 pack-years; 95% CI -0.007 to 1.6; P = 0.054), but we did not observe any strong associations of kidney cancer with radiation exposure, although sex-specific dose responses were found to be statistically different., (©2021 by Radiation Research Society. All rights of reproduction in any form reserved.)

In Japan, a study using population-based cancer registry data from six prefectures revealed a difference in bladder cancer survival between men and women. However, the period of the study was limited to 1993-2006. The recent introduction of immune checkpoint inhibitors, which have proved to be effective for the treatment for bladder cancer, has led to a rising demand for analysis of long-term trends in net survival in order to accurately assess the effect of the new treatment. The aim of the present study was to examine long-term trends in sex difference in bladder cancer net survival using large-scale population-based cancer registry data from Osaka, Japan (17,500 cases from 1975 to 2009). We also evaluated sex difference in bladder cancer survival after adjustment for stage, histologic type, and other prognostic factors. We showed the long-term trend of five-year net survival for each stage and found that women had poorer five-year net survival than men for the whole study period. The risk of death from bladder cancer was higher among men than women even after adjusting for period at diagnosis, histologic type, stage, age group, and treatment (Excess hazard ratios: 1.17; 95% Confidence interval: 1.10-1.25)., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objectives: To identify the prognosis of pure non-urothelial carcinoma (non-UC) of bladder and to compare them with those of pure urothelial carcinoma (UC)., Methods: We used Japan's nationwide hospital-based cancer registry data to extract histologically confirmed pure non-UC and UC cases of bladder diagnosed in 2008-2009. We estimated the 5-year overall survival (OS) by a Kaplan-Meier analysis., Results: A total of 8094 patients with confirmed histological subtypes of bladder cancer were identified. The most common pure non-UC was squamous cell carcinoma (SQ, n = 192, 2.4%) followed by adenocarcinoma (AC, n = 138, 1.7%) and small cell neuroendocrine carcinoma (SmC, n = 54, 0.7%). The proportion of female patients (48%) was significantly higher in the SQ group compared with the pure UC group (P < 0.001). The 5-year OS rate of the non-UC patients was significantly worse than that of the UC patients (40 vs. 61%, P < 0.001). According to stages, the 5-year OS rates of the stage I and III non-UC patients were significantly worse than those of the UC patients (P = 0.001). Considering histologic subtypes and stages, the 5-year OS rates of the stage I SQ patients were worse than those of the AC and SmC patients (46, 68 and 64%, respectively)., Conclusion: The prognosis of pure non-UC was worse than that of pure UC, especially in the stage I and III non-UC patients. To improve these patients' oncologic outcomes, a more aggressive surgical approach may be necessary in stage I patients with non-UC, especially in pure SQ., (© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permission@oup.com.)

Purpose: The incidence of prostate cancer is increasing in Asian countries. Studies using prostatectomy specimens have reported a racial difference in tumor location within the prostate, with a greater incidence of transition zone cancer in Asian men compared with Caucasian men. However, there may be potential biases in studies based on surgical specimens. We describe the pathological features of subclinical prostate cancer, such as latent cancer and incidental cancer, to elucidate tumor location of contemporary Japanese patients. We also compare the prevalence of latent and incidental prostate cancer to determine whether the incidence of prostate cancer is higher in patients with bladder cancer., Materials and Methods: Overall 182 men autopsied and 148 who underwent cystoprostatectomy for bladder cancer were included in the study. Each prostate gland was fixed and sliced in step sections. Histological evaluation was performed by a single genitourinary pathologist. The index tumor location was categorized into transition zone or peripheral zone., Results: Prostate cancer was found in 39.0% of the autopsy specimens and 31.6% of the cystoprostatectomy specimens. The prevalence and pathological characteristics were not significantly different between latent and incidental cancer. The prevalence of transition zone cancer was 39.0% (46 of 118). In elderly men peripheral zone cancer was more frequently diagnosed than transition zone cancer (p=0.049). The pathological characteristics of transition and peripheral zone cancers were similar except for the pT stage., Conclusions: Transition zone cancer was prevalent in contemporary Japanese men. The incidence of prostate cancer in men with bladder cancer might not be higher than that in healthy men.

Background: A previous comparative study in Japan has demonstrated that the two consecutive UroVysion tests are useful tools to detect the presence of bladder cancer during follow-up after transurethral resection, but they also presented their high rates of false-positive results. Here, we aimed to evaluate the relationship between the UroVysion tests and subsequent intravesical recurrence., Methods: In the previous study, patients without bladder cancer during the first analysis showed the same examination set repeated 3 months later as the second analysis. In this follow-up study, 326 patients showed negative findings confirmed on cystoscopy during the second UroVysion test. Recurrence-free survival was assessed using a median follow-up of 27 months., Results: In the two consecutive UroVysion tests, 214 patients (65.6%) showed negative UroVysion results in both tests, whereas 91 presented a positive result on either tests and 21 patients presented positive results in both tests. During the follow-up, 40 patients (12.3%) had an intravesical recurrence with non-muscle-invasive bladder cancer. The recurrence rates in patients with negative results in both tests, those with one positive result in either tests, and those with positive results in both tests were 8.4%, 16.5%, and 33.3%, respectively. The multivariate analysis indicated that the history of bladder cancer and the consecutive UroVysion test pattern were independent risk factors for recurrence., Conclusions: Our data confirmed the effectiveness of two consecutive UroVysion tests in predicting intravesical recurrence after TURBT. Further prospective studies would help determine an appropriate interval for cystoscopy follow-up.

Background: The open-label, randomized, active-controlled KEYNOTE-045 study (NCT02256436) showed that second-line pembrolizumab significantly improved overall survival (OS) of patients with advanced/metastatic urothelial cancer (UC) that progressed after first-line platinum-containing chemotherapy, compared with standard chemotherapy (paclitaxel, docetaxel, or vinflunine). Pembrolizumab is approved for patients with bladder cancer in Japan., Patients and Methods: Analysis was performed in the subgroup of Japanese patients enrolled in the KEYNOTE-045 study. Coprimary end points were OS and progression-free survival (PFS). Objective response rate (ORR) and safety were secondary end points., Results: Fifty-two Japanese patients (pembrolizumab, n = 30; chemotherapy, n = 22) were followed up for a median of 26.1 months. Patients who received pembrolizumab compared with chemotherapy had a 19% lower risk for death (hazard ratio [HR] 0.81, 95% CI 0.44-1.50); after adjusting for baseline covariates, the HR for OS was 0.61 (95% CI 0.32-1.15). The 24-month OS rate was higher with pembrolizumab (26.9% vs 14.3%). PFS was 2.0 and 4.9 months for pembrolizumab and chemotherapy, respectively (HR 1.71, 95% CI 0.95-3.08). ORR was similar for pembrolizumab and chemotherapy (20.0% vs 18.2%); durability of response was higher with pembrolizumab: 67% and 33% of patients, respectively, maintained a response for > 12 months. Treatment-related adverse events, including grade 3-5 events, occurred less frequently with pembrolizumab., Conclusions: Pembrolizumab provided durable antitumor activity in patients with locally advanced/metastatic UC that progressed after platinum-containing chemotherapy in the overall population and in the Japanese subgroup; safety profile was consistent with that previously observed for pembrolizumab.

Purpose: We investigated the impact of previous, simultaneous or subsequent bladder cancer on the clinical outcomes of upper urinary tract urothelial carcinoma., Materials and Methods: We retrospectively collected data on 2,668 patients who underwent radical nephroureterectomy of nonmetastatic upper urinary tract urothelial carcinoma in 1995 to 2009. We evaluated the impact of bladder cancer on overall mortality and the factors predictive of subsequent bladder cancer., Results: A total of 631 patients (23.7%) had previous or simultaneous bladder cancer. Patients with previous or simultaneous bladder cancer had significantly shorter overall survival than patients without previous or simultaneous bladder cancer (HR 1.29, 95% CI 1.09-1.53, p=0.0026). Of the 2,037 patients without previous or simultaneous bladder cancer 683 (33.5%) subsequently had bladder cancer after radical nephroureterectomy. Of patients with pT0-2 disease those with subsequent bladder cancer had significantly shorter overall survival than patients without subsequent bladder cancer (HR 1.81, 95% CI 1.23-2.67, p=0.0025). In patients with pT3-4 disease subsequent bladder cancer was not associated with worse overall survival. On multivariable analyses independent predictors of subsequent bladder cancer were gender, preoperative urine cytology and clinical node status in the preoperative setting, and gender, adjuvant chemotherapy and pathological node status in the postoperative setting., Conclusions: Bladder cancer was significantly associated with worse clinical outcomes after radical nephroureterectomy of upper urinary tract urothelial carcinoma. Preventing subsequent bladder cancer in patients with pT0-2 upper urinary tract urothelial carcinoma may lead to better prognosis in those who undergo radical nephroureterectomy.

Objectives: To investigate the treatment pattern of non-muscle invasive bladder cancer patients among urologists in Japan, Korea and Taiwan, with emphasis on compliance with important treatment guidelines., Methods: A Web-based questionnaire survey was conceived by representative members of each country's urological oncology society and was open from June 2016 to February 2017 to each society's members. Descriptive statistics and multinomial logistic regression analysis were used., Results: A total of 2334 urologists were invited and 701 responded to the survey with a response rate of 30.0%. Instruments used during transurethral resection of bladder cancer varied significantly between countries and depended on their availability. The re-transurethral resection rate for pT1 or high-grade disease >50% of the time was significantly higher in Japan than in the other two countries, but the collective rate was just 49%. The frequency of intravesical therapy in intermediate- to high-risk disease was generally consistent across countries. However, the choice of agent between chemotherapy and bacillus Calmette-Guérin was significantly different between countries. Maintenance bacillus Calmette-Guérin was used <10% of the time by 45% of respondents, the most important reasons being fear of side-effects, followed by a lack of efficacy and shortage of drug supply., Conclusions: There are significant differences between Japan, Korea and Taiwan in the management of intermediate- to high-risk non-muscle invasive bladder cancer. The results of this survey can serve as the basis for joint efforts to develop common clinical guidelines., (© 2019 The Japanese Urological Association.)

Background: To determine the peri-operative safety and oncological value of robotic-assisted radical cystectomy (RARC) for older and younger patients in an initial Japanese RARC series., Methods: We retrospectively analyzed the demographics, complications, peri-operative and oncological outcomes of 253 consecutive patients with bladder cancer who underwent RARC at 34 institutions in Japan between April 2009 and March 2017. The patients were assigned to groups according to ages at surgery of < 70 (younger; n = 125) and ≥ 70 (older; n = 128) years., Results: Mean Charlson comorbidity index (p = 0.045) and the incidence of a history of previous abdominal surgery (p = 0.002) were significantly higher, whereas a history of neoadjuvant chemotherapy (p = 0.028) and neobladder (p < 0.001) were significantly lower in the older group. Mean total operative time was significantly shorter (p = 0.019) and mean estimated blood loss (p = 0.013) was significantly lower in the older group. Post-operative Grade ≥ II complications were comparable at 0-30, 31-90 and 91 days after surgery despite urinary tract associations. Rates of positive surgical margins and mean numbers of removed lymph nodes were comparable between the two groups. Although 5-year overall survival rates were significantly lower (p = 0.03) for older patients, 5-year cancer-specific (p = 0.10) and recurrence-free survival rates were comparable (p = 0.20) between the groups., Conclusion: Using RARC potentially allows the application of less invasive procedures and cancer control for septuagenarian patients that are equivalent to those for younger patients.

Backgrounds: This study aimed to describe the morbidity and mortality in older patients undergoing laparoscopic radical cystectomy (LRC) and compare the outcomes of LRC between octogenarians and younger patients (< 80 years) in a Japanese multicenter cohort., Methods: We identified 433 patients (80 octogenarians) who underwent LRC in a retrospective multicenter database from 10 institutions. The perioperative outcomes and the 90-day and late (> 90-day) complications according to the Clavien-Dindo classification were compared between the octogenarians and younger patients. Recurrence-free survival (RFS), overall survival (OS), and cancer-specific survival (CSS) were measured by the Kaplan-Meier method., Results: Compared with the younger group, the octogenarian group included a significantly higher proportion of women, patients with a lower body mass index, patients with a lower preoperative albumin level, and patients with a history of abdominal surgery. The 90-day rates of all complications and major complications (grades III-V) were 50.0% and 20.0% among octogenarians and 54.7% and 16.4% among younger patients. The 90-day mortality rate among octogenarians was 3.8%. The 2-year RFS, CSS, and OS rates for octogenarians stratified by pathological stage was 95.2, 100, and 100% for ≤ pT1; 50.7, 76.6, and 56.1% for pT2; 33.6, 82.5, and 72.6% for ≥ pT3; and 23.1, 42.2, and 37.5% for pN + or distant metastasis, respectively. There was significant difference between octogenarians and younger patients only in 2-year OS for pT2 (56.1% vs 87.7%, p = 0.03)., Conclusions: This study revealed that LRC can be performed for selected octogenarians with a complication rate similar to that of younger patients. Appropriate risk evaluation and modification of surgical procedures are necessary for octogenarians.

Objective: To investigate the impact of sex on the prognosis of bladder cancer in Japan., Methods: In total, 18 728 patients diagnosed as having bladder cancer from 1993 to 2006 were registered in population-based cancer registries of six prefectures in Japan. We estimated relative survival by sex, age, clinical stage at initial diagnosis and pathology., Results: Patients included 14 203 men (75.8%) and 4525 women (24.2%). The stage at initial diagnosis in women was significantly higher than in men (P < 0.0001). Pathologically, women were more likely to have non-urothelial cancer than men (women 18.0%, men 9.5%, P < 0.0001). The 5-year relative survival was 80.3% for men and 67.7% for women. The 5-year relative survival was 93.0% for men and 87.7% for women in the localized cancer group, 34.8% for men and 23.9% for women in the locally advanced cancer group, and 7.1% for men and 8.3% for women in the metastatic cancer group. The relative survival of women was worse than that of men in the localized cancer group (hazard ratio 1.29, 95% confidence interval 1.05-1.57; P = 0.0145) and locally advanced cancer group (hazard ratio 1.32, 95% confidence interval 1.15-1.52; P = 0.0001), but not different in the metastatic cancer group (hazard ratio 1.04, 95% confidence interval 0.87-1.25; P = 0.6555)., Conclusions: Population-based registry data in Japan show that the cancer stage at initial diagnosis is higher in women than in men, and women with localized or locally advanced bladder cancer have a worse prognosis compared with men., (© 2019 The Japanese Urological Association.)

Background: Non-muscular invasive bladder cancer (NMIBC) has a high risk of recurrence. As androgen receptor (AR) reportedly affects bladder cancer, we assessed the correlation between NMIBC recurrence and tumor AR expression in Japanese patients., Methods: We retrospectively reviewed 53 specimens of non-metastatic NMIBC, with recurrence-free survival (RFS) as the primary endpoint. We used real-time quantitative polymerase chain reaction to quantify AR mRNA expression. Kaplan-Meier product-limit estimators were used to assess RFS distribution, log-rank tests to analyze differences in RFS between high- and low-risk groups; and multivariate analyses of AR mRNA expression and other clinicopathological factors to predict independent factors for RFS., Results: The high AR mRNA-expressing group (n = 43) tended to have a longer median RFS (not reached) than did the low-AR group (n = 10; 9.04 months; P = 0.112). Multivariate analysis showed female sex (hazard ratio [HR]: 7.360, 95% CI: 1.649-32.856, P = 0.009), tumor size ≥3 cm (HR: 23.697, 95% CI: 4.383-128.117, P < 0.001) and low AR mRNA expression (HR: 0.202, 95% CI: 0.048-0.841, P = 0.028) to be independent predictors of shorter RFS., Conclusion: Our study showed that low AR mRNA expression level is an independent risk factor for RFS in Japanese patients with NMIBC. Further studies are necessary but AR expression might be a new indicator of recurrence of NMIBC.

Objectives: To describe the complications and their surgical management after laparoscopic radical cystectomy in a Japanese multicenter cohort., Methods: The participants were drawn from a retrospective multicenter study at 10 institutions. We identified 436 patients who underwent laparoscopic radical cystectomy with no robot assistance. Early and late complications were graded according to their Clavien-Dindo classification. The records of all patients who underwent surgical interventions for laparoscopic radical cystectomy-specific complications were also reviewed. Kaplan-Meier curves were used to describe the time to surgical intervention., Results: The 90-day rates for overall complications, high-grade complications (Clavien-Dindo classification III-V) and mortality were 53%, 17% and 1.4%, respectively. Gastrointestinal (25%), infectious (22%) and abdominal wall-related (9%) complications were the most common. The late complication rate was 18%, and a total of 81 patients (19%) underwent surgical intervention during the median follow-up period of 22 months. The reoperation rate was 25% at 5 years. Gastrointestinal complications in the early postoperative period and abdominal wall-related complications in the late postoperative period were the main reasons for reoperation. Seven (7%) out of 100 female patients underwent emergent surgical reoperation for transvaginal bowel evisceration as a result of vaginal dehiscence., Conclusions: Early and late postoperative complications and surgical reoperations are notable after laparoscopic radical cystectomy. Abdominal wall-related complications including vaginal dehiscence are common, and they represent the main indication for reoperation during long-term follow up., (© 2019 The Japanese Urological Association.)

Background: We evaluated the use of UroVysion fluorescence in situ hybridization tests to detect the intravesical recurrence of bladder cancer during follow-up after a transurethral resection of bladder tumor (TURBT)., Methods: In this prospective, blinded, comparative study, 486 patients treated by TURBT within the prior 2 years were registered at 12 centers. Urine cytology and UroVysion tests were performed once or twice at a central testing laboratory. For the patients with no suspicious findings of bladder cancer in the first analysis, the same examination set was repeated 3 months later as the second analysis. Totals of 468 and 399 patients were eligible for the first and second analyses, respectively. We determined the sensitivity and specificity of two consecutive UroVysion tests., Results: Bladder cancers were identified in 44 patients at the first analysis. The UroVysion test had 50.0% (95% CI 35.2-64.8%) sensitivity and 72.4% (68.3-76.8%). Urine cytology had 4.5% (0.0-10.7%) sensitivity and 99.8% (99.3-100.0%) specificity. The concordant rate of the first and second UroVysion test results was 72% (kappa coefficient 0.157). Interestingly, the patients with two consecutive positive UroVysion test results had the highest cancer detection rate (14.8%), which is greater than those of the patients with a positive result in either (7.2%) or neither (1.2%) of the two tests at the 3-month follow-up., Conclusions: The UroVysion test provided higher sensitivity than urine cytology to detect bladder cancer during post-TURBT follow-up. Two consecutive UroVysion tests might be a better indicator to predict intravesical recurrence.

Background: There is growing evidence suggesting that soy isoflavones play a protective role in the development of cancer. However, few epidemiological studies have investigated the association between soy isoflavone intake and bladder cancer. Methods: We evaluated the associations of soy and isoflavone intakes with bladder cancer incidence in a population-based prospective study in Japan. Subjects were 14,233 men and 16,584 women age 35 years or older in September 1992. Soy and isoflavone intakes were assessed via a validated food-frequency questionnaire, while controlling for total energy intake. Cancer incidence was mainly confirmed through regional population-based cancer registries. Bladder cancer was defined as code C67 according to the International Classification of Diseases and Health Related Problems, 10th Revision. Results: During mean follow-up of 13.6 years, 120 men and 41 women had developed bladder cancer. After adjustments for multiple confounders, compared with the lowest quartile of soy food intake, the estimated hazard ratios for the second, third, and highest quartiles of soy food intake were 0.74, 0.52, and 0.55, respectively, in men ( P -trend: 0.023). The corresponding values were 0.60, 0.75, and 0.64, respectively, in women ( P -trend: 0.43). Similar inverse associations were observed between isoflavone intake and bladder cancer risk. Conclusions: A significant decreased risk of bladder cancer was observed among men who had higher intakes of total soy and isoflavones. Impact: Our finding on the potential benefit of consuming soy foods against bladder cancer is promising and warrants further studies. Cancer Epidemiol Biomarkers Prev; 27(11); 1371-5. ©2018 AACR., (©2018 American Association for Cancer Research.)

Objective: To confirm the reproducibility of the effectiveness and safety in photodynamic diagnosis of non-muscle-invasive bladder cancer using 5-aminolevulinic acid in a prospective multicenter non-randomized phase III trial., Methods: A total of 61 patients with primary or recurrent non-muscle-invasive bladder cancer were prospectively enrolled from five hospitals between May 2015 and March 2016. 5-Aminolevulinic acid (20 mg/kg) was orally administered 3 h before transurethral resection of bladder tumors using white light or fluorescent light. Of 60 evaluable patients, 511 specimens were obtained from tumor-suspicious lesions and normal-looking mucosa. The primary end-point was sensitivity. The secondary end-points were specificity, positive and negative predictive values, and safety., Results: The sensitivity of the fluorescent light source (79.6%) was significantly higher (P < 0.001) than that of the white light source (54.1%). In total, 25.4% (46/181) of tumor specimens were diagnosed as positive with only the fluorescent light source. In nine (15%) of 60 patients, the risk classification and recommended treatment after transurethral resection of bladder tumors were changed depending on the additional types of tumor diagnosed by the fluorescent light source. The specificity of the fluorescent light versus white light source was 80.6% versus 95.5%. No grade 4-5 adverse event was noted. Hypotension and urticaria were severe adverse events whose relationship to oral 5-aminolevulinic acid could not be excluded., Conclusions: These findings confirm the diagnostic efficacy and safety of photodynamic diagnosis with 20 mg/kg of oral 5-aminolevulinic acid, and show that transurethral resection of bladder tumors with a fluorescent light source using oral 5-aminolevulinic acid is well tolerated., (© 2018 The Japanese Urological Association.)

Purpose: Single immediate intravesical instillation of chemotherapy after transurethral resection of bladder tumor (TURBT) has been the gold standard treatment for patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC). Herein, we conducted a multicenter prospective randomized controlled trial in Japan, comparing recurrence-free survival between single and two-time instillation of pirarubicin (THP) for solitary NMIBC., Methods: Between 2005 and 2009, 257 patients with solitary NMIBC were enrolled and randomized to single instillation of THP (30 mg/50 mL) immediately after TURBT (Group A) or two-time instillation of THP immediately after and 1 day after TURBT (Group B). The primary endpoint was recurrence-free survival. Secondary endpoints included rates of recurrence and adverse effects, including hematuria, micturition pain, difficult urination, pollakiuria, systemic symptoms, and other complications. This study was registered as UMIN C000000266., Results: Of 257 patients, 99 in Group A and 102 in Group B could be evaluated for recurrence. Median follow-up was 71 months. The overall recurrence rate was 39 and 31%, respectively (p = 0.2704). Although the 5-year recurrence-free survival rates were 55.9% and 67.7% in groups A and B, respectively, the difference between groups was not significant (p = 0.2031). No significant differences in adverse effects were observed between groups, except for pollakiuria (7 vs 22%, p = 0.0031). Multivariate analyses did not show that the treatment group was a significant risk factor for bladder cancer recurrence., Conclusions: Postoperative two-time intravesical instillation of THP was not superior to single immediate instillation for preventing recurrence after complete resection of a solitary NMIBC.

(Objective) To evaluate the utility of laparoscopic radical cystectomy (LRC), we retrospectively compared the background factors and perioperative parameters of LRC with those of open radical cystectomy (ORC). (Patients and methods) The study cohort consisted of 116 consecutive patients who underwent radical cystectomy by LRC (n=59) or ORC (n=57). The background factors and perioperative parameters were compared between LRC and ORC. (Results) The patients consisted of 103 men and 13 women with a median age of 69 years and median BMI of 23.0. Their clinical stage was as follows, ≤T1: 19 cases, T2: 69 cases, T3: 25 cases and T4: 3 cases, respectively.While the patients' age at the time of LRC was significantly higher than that of ORC (71.3 yrs vs. 66.2 yrs, P<0.001) and the ASA physical status of LRC was significantly higher than that of ORC (P=0.028), the other background factors were not different between the two groups.Although there was no difference in the total operating time between LRC and ORC, the estimated blood loss for LRC was significantly less than that for ORC (372.3 ml vs. 2,134.5 ml, P<0.001) and the duration of the postoperative hospital stay for LRC was significantly shorter than that for ORC (23.5 days vs. 36.9 days, P<0.001).There were no significant differences in the pathological findings, of the postoperative recurrence-free rate or cancer-specific survival rate between the LRC and ORC groups. In multivariate analysis, only pN+was an independent predictive factor of postoperative recurrence. (Conclusion) This study showed that LRC is less invasive and can lead to similar oncological outcomes compared with ORC.

Purpose: We determined whether intravesical recurrence is affected by inhibition of androgen signaling among men with nonmuscle invasive bladder cancer., Materials and Methods: We examined the intravesical recurrence rate among men treated with or without androgen suppression therapy by androgen deprivation therapy for prostate cancer or 5α-reductase inhibitor dutasteride for benign prostatic hyperplasia., Results: We studied 228 men, including 32 with and 196 without androgen suppression therapy. During a median followup of 3.6 and 3.0 years intravesical recurrence developed in 4 (12.5%) and 59 men (30.1%) with and without androgen suppression therapy, respectively. On multivariate analysis multiple tumors (HR 1.82, p = 0.027), a large tumor (HR 2.13, p = 0.043) and ever smoking (HR 2.45, p = 0.020) as well as the presence of androgen suppression therapy (HR 0.36, p = 0.024) were independent risk factors for intravesical recurrence. Notably, tumor progressed to muscle invasive bladder cancer in 6 men (3.1%) without androgen suppression therapy. No man with androgen suppression therapy progressed to muscle invasive bladder cancer., Conclusions: Our study suggests the possibility of androgen suppression therapy as prophylaxis for intravesical recurrence of bladder cancer. Further explorations are warranted of the prophylactic effect of androgen suppression therapy on bladder cancer pathogenesis., (Copyright © 2017 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Japanese patients who undergo radical cystectomy have a unique feature, i.e., the ratio of octogenarians is higher than in Western patients because of the aging Japanese population. The purpose of this study was to compare perioperative outcomes, complications, and oncologic outcomes between robot-assisted radical cystectomy and open radical cystectomy., Methods: From 2010-2015, 20 (of which 8 were octogenarians) and 40 (of which 11 were octogenarians) patients underwent robot-assisted radical cystectomy and open radical cystectomy, respectively., Results: There was no significant difference in terms of patient demographics between the two surgical cohorts, regardless of patient age. In the octogenarian patient cohort, the rates of previous abdominal surgery and the median age-adjusted Charlson comorbidity index were higher. The median estimated blood loss, transfusion rate and the days to resumption of a regular diet were significantly lower in the robot-assisted radical cystectomy cohort, regardless of patient age. Robot-assisted radical cystectomy significantly decreased grade II or higher complications, but there were no significant differences in terms of decreasing grade III or higher complications, regardless of patient age. Positive surgical margin and the mean number of lymph nodes removed were similar between the two surgical cohorts, regardless of patient age., Conclusion: Although robot-assisted radical cystectomy has a short history in Japan, the outcomes were generally comparable to those of previous studies. In a country that is aging rapidly like Japan, robot-assisted radical cystectomy could be a valid option for the management of muscle-invasive and high-risk superficial bladder cancer.

Purpose: A second transurethral resection (TUR) has been recommended by guidelines for high-grade non-muscle-invasive bladder cancer (NMIBC). However, the impact of surgical quality and post-TUR intra-vesical instillation therapy on oncologic outcome still remains unclear for newly diagnosed NMIBC. We conducted a retrospective cohort study for the patients who underwent extensive TUR followed by appropriate intra-vesical therapy for newly diagnosed NMIBC to assess their oncological outcomes., Methods: We treated a cohort of 150 patients with NMIBC by our single but extensive TUR protocol at Hirosaki University Hospital between January 2005 and May 2012. The extensive TUR procedure comprised complete resection of all visible tumors including the muscle layer with a separate cold cup-biopsy of the marginal bottom. After visible tumors resection, additional resection for 5 mm wider area around the first surgical margin was performed. TUR was conducted by three expert urologists who had common agreement with the extensive TUR. All patients received 50 mg of epirubicin instillation immediately after TUR. Out of 150 patients, 74 patients who had multiple tumors or high-grade T1 disease received 40 mg of bacillus Calmette-Guérin Tokyo 172 strain once a week for six consecutive weeks. Patients who received second TUR were not included. The endpoints in this study were the recurrence-, progression-free, cancer-specific, and overall survivals., Results: The 5-year recurrence- and progression-free survival rates were 77.2 and 98.0 %, respectively. The 5-year cancer-specific and overall survival rates were 98.0 and 92.6 %, respectively. The 5-year recurrence- and progression-free survival rates in high-grade T1 disease were 77.1 and 97.6 %, respectively, which were not significantly different from those in the cohort with Ta or low-grade BC. Cystoscopy revealed that 93 % of the patients were tumor-free, at the first cystoscopy, and four patients (3 %) showed progression to stage T2 or higher disease during the first year., Conclusion: While the present study has several limitations, including single-arm and retrospective nature, a single but extensive TUR combined with adjuvant intravesical treatment may have acceptable oncological outcomes in NMIBC patients.

Objective: To determine the prognostic factors of primary T1 high-grade bladder cancer and to validate the Spanish Urological Club for Oncological Treatment model in Japanese patients with T1 high-grade bladder cancer treated at a single institution., Methods: Records of 106 patients with T1 high-grade bladder cancer treated from 1998 to 2013 were retrospectively reviewed. Variables included various clinicopathological parameters, including lymphovascular invasion and tumor growth pattern at the invasion front. Recurrence-free survival and progression-free survival were analyzed. Multivariate Cox proportional regression analysis was used to verify the prognostic significance of the variables. Scores for recurrence and progression were calculated using the Spanish Urological Club for Oncological Treatment model., Results: Of 106 patients, 44 (42%) had recurrence and 16 (15%) developed progression after a median (interquartile range) follow-up period of 54 months (range 32-81 months). Non-papillary shape was the only independent predictor for recurrence, while broad-based tumor stalk and infiltrative tumor growth pattern at the invasion front were determined to be independent predictors for progression. Stratification of patients according to the number of progression risk factors yielded hazard ratios of 10.1 and 13.1 in patients having one and two risks, respectively, compared with those without any risks. The Spanish Urological Club for Oncological Treatment model successfully stratified our patients with a trend toward different probabilities of recurrence and progression., Conclusions: The results of the present study might be helpful for counseling certain patients towards intensive treatment, such as radical cystectomy and/or platinum-based systemic chemotherapy. In addition, the Spanish Urological Club for Oncological Treatment model might be applicable to Japanese patients with T1 high-grade bladder cancer., (© 2015 The Japanese Urological Association.)

Sex differences in bladder cancer pathology and epidemiology have been the focus of recent research. We investigated the epidemiological characteristics and compared bladder cancer pathology and survival between men and women in Japan. A total of 13,184 patients with primary bladder cancer diagnosed from 1954 to 2010 were identified in a large-scale cancer registry database in Kanagawa Prefecture. Using this database, we compared the odds ratios (ORs) for nonurothelial carcinoma (non-UC) using a multiple logistic regression model adjusted for age and diagnosis periods. We also compared hazard ratios (HRs) for overall death and cancer-specific death using a Cox proportional hazards model adjusted for non-UC, age, and diagnosis period. The proportion of non-UC was significantly higher in female compared with male patients (OR = 2.14, 95% confidence interval [CI]: 1.81-2.52). Furthermore, survival was significantly poorer in female patients than in male patients after adjusting for UC or non-UC (HR for overall death = 1.15, 95% CI: 1.06-1.23; HR for cancer-specific death = 1.39, 95% CI: 1.28-1.52). Sex differences exist in the epidemiological characteristics of bladder cancer in Japan, with female patients having less favorable pathology and poorer survival compared with male patients., (© 2014 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

The high incidence of tumor recurrence following transurethral resection (TUR) represents a major problem encountered in the management of bladder cancer. This study examined the efficacy of intravesical chemotherapy in superficial bladder cancer. We retrospectively analyzed 90 Japanese cases with low-grade superficial transitional cell carcinoma (stage T1, grades 1 and 2) who were rendered tumor-free by TURBT (TUR of bladder tumor) and who thereafter were treated with or without intravesical chemotherapy. Among them, instillation was terminated in 2 patients due to adverse effects (severe but reversible chemical cystitis). Remaining 88 patients were divided into 2 groups according to therapy: the TURBT-only group (n = 46), defined as patients treated with TURBT alone, and the Instillation group (n = 42), defined as patients treated with weekly intravesical instillation therapies using epirubicin plus Ara-C. Recurrence-free rate was significantly higher in the Instillation group than in the TURBT-only group (p = 0.02, HR = 0.457). The 5-year recurrence-free rate was 58.5% for the Instillation group and 38.6% for the TURBT-only group. Our instillation schedule represents the most intensive regimen among previously reported therapies and resulted in a 54.3% decrease in incidence of tumor recurrence. We believe that the results of this study could provide useful information on management of bladder cancer.

Background: We aimed to identify patients with a chief complaint of hematuria who could safely avoid unnecessary radiation and instrumentation in the diagnosis of bladder cancer (BC), using automated urine flow cytometry to detect isomorphic red blood cells (RBCs) in urine., Methods: We acquired urine samples from 134 patients over the age of 35 years with a chief complaint of hematuria and a positive urine occult blood test or microhematuria. The data were analyzed using the UF-1000i (®) (Sysmex Co., Ltd., Kobe, Japan) automated urine flow cytometer to determine RBC morphology, which was classified as isomorphic or dysmorphic. The patients were divided into two groups (BC versus non-BC) for statistical analysis. Multivariate logistic regression analysis was used to determine the predictive value of flow cytometry versus urine cytology, the bladder tumor antigen test, occult blood in urine test, and microhematuria test., Results: BC was confirmed in 26 of 134 patients (19.4 %). The area under the curve for RBC count using the automated urine flow cytometer was 0.94, representing the highest reference value obtained in this study. Isomorphic RBCs were detected in all patients in the BC group. On multivariate logistic regression analysis, only isomorphic RBC morphology was significantly predictive for BC (p < 0.001). Analytical parameters such as sensitivity, specificity, positive predictive value, and negative predictive value of isomorphic RBCs in urine were 100.0, 91.7, 74.3, and 100.0 %, respectively., Conclusion: Detection of urinary isomorphic RBCs using automated urine flow cytometry is a reliable method in the diagnosis of BC with hematuria.

Background: Few studies have described the clinical courses and outcomes in the bladder after treatment of intravesical recurrence after radical nephroureterectomy (RNU) in patients with primary upper tract urothelial carcinoma (UTUC). We investigated the indicators for predicting subsequent bladder outcomes after treatment of intravesical recurrence after RNU., Methods: A total of 241 patients with primary UTUC (pTa-4N0M0) who experienced intravesical recurrence after RNU were included. Of these patients, 101 (41.9 %) underwent Bacillus Calmette-Guérin treatments, whereas 49 (20.3 %) underwent intravesical chemotherapy. The median follow-up period after initial transurethral resection of the bladder tumor was 33 months. Relationships with bladder outcomes were analyzed by using multivariable analysis., Results: Ninety-six patients experienced intravesical recurrence, and bladder progression was observed in 13. Cumulative incidence rates of intravesical recurrence at 1 and 5 years after treatment of the first intravesical recurrence were 31.0 and 48.4 %, whereas those of bladder progression at 1 and 5 years thereafter were 2.4 and 8.0 %. Multivariate analysis showed that the number of recurrent tumors and pT1 tumors at the time of the first intravesical relapse were independent risk factors for subsequent intravesical recurrence. With respect to bladder progression, multivariate analysis showed that pT1 tumors, the appearance of concomitant carcinoma-in situ at the time of the first intravesical relapse, and the absence of the Bacillus Calmette-Guérin treatment were independent risk factors., Conclusions: This retrospective study presents a detailed picture of further bladder outcomes after intravesical recurrence after RNU in primary UTUC patients. The results may assist physicians to develop a more rational protocol in bladder surveillance.

Unlabelled: What's known on the subject? and What does the study add? So far, few previous reports have analysed the risk factors for tumour recurrence and stage progression with a special focus on BCG-relapsing disease, defined as the recurrence after achieving a disease-free status by initial BCG instillations for 6 months. There are no guidelines outlining a specific treatment strategy for BCG-relapsing disease, although many BCG failure cases are attributable to BCG-relapsing disease. In this study, additional BCG instillation was shown to decrease the subsequent tumour recurrence rate against BCG-relapsing tumours with intermediate pathological risk features; however, a BCG-relapsing tumour with a pathologically high risk was a significant risk factor for both subsequent tumour recurrence and stage progression. This information might identify a therapeutic strategy for BCG-relapsing tumours., Objective: • To investigate the risk of subsequent tumour recurrence and stage progression in bacillus Calmette-Guérin (BCG)-relapsing non-muscle-invasive bladder cancer, defined as recurrence after achieving a disease-free status for 6 months., Patients and Methods: • A total of 183 patients with BCG-relapsing tumours were treated with conservative therapy between 1985 and 2008 at our three institutions. • We analysed the association between their clinicopathological parameters and subsequent tumour recurrence or stage progression., Results: • Additional induction courses of BCG or anticancer drug (mitomycin C or epirubicin) instillations were performed in 119 patients and 24 patients, respectively. The remaining 40 patients did not undergo any adjuvant therapy. • Multivariate analysis showed that a relapsing tumour with a pathologically high risk (defined as tumours with G3 and/or pT1 and/or concomitant carcinoma in situ) was a significant risk factor for subsequent tumour recurrence (P= 0.002; hazard ratio [HR] 2.15). Additional BCG instillation significantly decreased the subsequent tumour recurrence rate (P<0.001; HR 0.41). • Multivariate analysis also showed that a relapsing tumour with a pathologically high risk was also significantly associated with stage progression (P < 0.001; HR 8.05)., Conclusions: • An additional course of BCG instillation might be effective in patients with BCG-relapsing tumours with pathologically intermediate risk. • Nevertheless, some patients with high-risk pathological features developed subsequent stage progression. Such patients should be followed up closely and counselled on the need for aggressive therapeutic options, such as radical cystectomy., (© 2012 THE AUTHORS. BJU INTERNATIONAL © 2012 BJU INTERNATIONAL.)

Objective: In Japan, no study has compared the perioperative outcomes observed between robot-assisted radical cystectomy (RARC) and open radical cystectomy (ORC). This study aimed at a prospective comparison of the perioperative outcomes between RARC and ORC performed by a single surgeon., Methods: Between 2008 and 2011, 26 bladder cancer patients underwent radical cystectomy by one surgeon, 11 robotically and 15 by open procedure. We prospectively collected perioperative and pathological data for these 26 patients, and retrospectively compared these two different surgical procedures., Results: The RARC cohort had a significant decrease in both estimated blood loss (656.9 vs. 1788.7 ml, P=0.0015) and allogeneic transfusion requirement (0 vs. 40%, P=0.0237). The total operative time was almost the same (P=0.2306) but increased duration of bladder removal and lymphadenectomy was observed in the RARC cohort (P=0.0049). Surgery-related complication rates within 30 days were not significantly different (P=0.4185). Positive surgical margin was observed in three patients in the ORC cohort and in one patient in the RARC cohort (P=0.4664). The RARC cohort had a larger number of removed lymph nodes than the ORC cohort, and the difference was statistically significant (20.7 vs. 13.8, P=0.0421)., Conclusions: We confirmed that RARC is safe and yields acceptable outcomes in comparison with ORC for the treatment of bladder cancer if it is performed by a surgeon who has experience of over 60 cases of robot-assisted radical prostatectomy. It is hoped that RARC will gain acceptance in Japan as a minimally invasive surgery for muscle-invasive bladder cancer.