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Objectives We examined the outcomes of eight weekly bacillus Calmette-Guerin induction therapy after second transurethral resection, and investigated risk factors for intravesical recurrence or disease progression in high-risk non-muscle-invasive bladder cancer patients. Methods This retrospective study included 146 high-risk non-muscle-invasive bladder cancer patients who received eight weekly bacillus Calmette-Guerin instillations without a maintenance schedule between 2000 and 2019. Intravesical recurrence-free and progression-free survival rates were evaluated using the Kaplan-Meier method. The Cox proportional hazards model was used to identify risk factors. Results Pathological T staging in the first transurethral resection was pTa in 56 patients (38.4%), pT1 in 75 (51.4%) and primary carcinoma in situ in 15 (10.2%). A total of 109 (83.2%) with pTa-1 disease underwent second transurethral resection before bacillus Calmette-Guerin induction therapy, and residual disease was detected in 54 (49.5%). The completion rate of eight instillations was 82.2%. The 2- and 5-year intravesical recurrence-free survival rates were 80.7% and 75.2%, whereas the 2- and 5-year progression-free survival rates were 85.7% and 82.0%. Recurrent tumors (hazard ratio 6.5830, P = 0.0007) and residual tumors at the second transurethral resection (hazard ratio 4.0337, P = 0.0021) were risk factors for intravesical recurrence. Multiple tumors (hazard ratio 5.8056, P = 0.0302), pT1 disease (hazard ratio 3.7351, P = 0.0447) and residual tumors at second transurethral resection (hazard ratio 3.2552, P = 0.0448) were associated with disease progression. Conclusions Accurate disease staging and disease elimination by second transurethral resection followed by eight weekly bacillus Calmette-Guerin instillations achieved good disease control. Our protocol (without a maintenance schedule) after thorough surgical resection has potential as a treatment option in the current bacillus Calmette-Guerin shortage.

We used real-world and large-scale data to assess the clinical efficacy and safety of pembrolizumab in older patients with advanced urothelial carcinoma (UC).A total of 608 patients who received pembrolizumab for the treatment of chemoresistant UC were retrospectively analyzed. All patients were histologically diagnosed with pure UC. Using propensity score matching (PSM) (ECOG performance status, site of metastasis, hemoglobin level and neutrophil-to-lymphocyte ratio, 1:1 matching), the overall survival (OS) and adverse events (AEs) of patients75 and ≥75 years old were compared.The median follow-up (IQR) period was 16.1 (9.9-20.5) months. After PSM, there were 215 patients each in the aged75 years and aged ≥75-year-old groups. The median OS of all patients was estimated to be 10.4 months (95% confidence interval [CI] = 8.8-12.1). After PSM, the median OS was 7.8 months (95% CI = 5.2-10.4) in the75-year-old group and 10.4 months (95% CI = 7.3-13.5) in the ≥75-year-old group (P = 0.186). Any-grade AEs were more frequently reported in the ≥75-year-old group in comparison to the age75-year-old group (55.3% vs. 41.9%, P = 0.007), whereas there was no significant difference between the two groups in the incidence of grade ≥3 AEs (10.2% vs. 12.6%, P = 0.544). The objective response rate, defined as complete remission or a partial response, was 22.8% in the75-year-old group and 25.1% in the ≥75-year-old group (P = 0.651).The present study demonstrates that age does not affect the efficacy and safety of pembrolizumab treatment for advanced chemoresistant UC. Pembrolizumab treatment should not be avoided based on chronological age; however, close monitoring for the development of treatment-related AE should be considered for older patients.

This study aimed to evaluate the pathological findings and oncological outcomes of deferred radical prostatectomy in patients who initially elected for active surveillance in a Japanese cohort. We retrospectively analyzed data collected from a multi-institutional prospective observational cohort of the Prostate Cancer Research International: Active Surveillance-JAPAN study between January 2010 and September 2020. Triggers for radical prostatectomy were disease progression based on pathological findings of repeat biopsy and patients’ request. The primary end point was evaluation of prostate-specific antigen recurrence-free survival. Secondary end points were overall survival and comparison of pathological and oncological outcomes between patients stratified into immediate or late radical prostatectomy group by time to radical prostatectomy. Overall, 162 patients (15.7%) with prostate cancer underwent initial active surveillance followed by radical prostatectomy. The median time to radical prostatectomy was 18 months (interquartile range 14–43.3), and the median postoperative follow-up was 32 months (interquartile range 14–57.5). Prostate-specific antigen recurrence was observed in eight patients (4.9%). The 3-year prostate-specific antigen recurrence-free survival rate was 96.9%. The 5-year overall survival rate was 100%; however, one patient died of another cause. There were no significant differences in pathological findings between immediate and late radical prostatectomy groups. No significant difference in prostate-specific antigen recurrence-free survival was found between the two groups (log-rank p = 0.34). Radical prostatectomy after active surveillance, as an initial treatment option, does not lead to loss of curative chances in Japanese patients with early-stage prostate cancer in the short follow-up period.

There is no useful predictive marker for reclassification on active surveillance. Thus, we aimed to investigate thresholds of [−2] proPSA (p2PSA)-related parameters to predict reclassification of the first-year protocol biopsy (1-year PBx) and evaluate the influence of clinical decision-making. This was an observational, prospective cohort study conducted at 19 Japanese institutes. The inclusion criteria included clinical stage T1c/T2, prostate-specific antigen (PSA) levels ≤10 ng/mL, PSA density

To investigate the association between the onset, severity, and type of immune-related adverse events (irAEs) and the efficacy of pembrolizumab in patients with platinum-pretreated advanced urothelial carcinoma (UC), we retrospectively collected clinical datasets of 755 patients and conducted landmark analysis. Patients who survived for fewer than 3 months were excluded from the evaluation to reduce the immortal time bias. In total, 620 patients were evaluated, of whom 220 patients (35.5%) experienced grade ≥2 irAEs, including 134 patients with grade 2 irAEs and 86 with grade ≥3 irAEs. Propensity score matching extracted 198 patients with and without grade ≥2 irAEs. The onset of grade ≥2 irAEs was associated with longer median progression-free survival (PFS) (8.3 months vs. 4.5 months, p = 0.003) and overall survival (OS) (20.4 months vs. 14.3 months, p = 0.031) and a higher objective response rate (ORR) (44.8% vs. 30.2%, p = 0.004). Patients with grade 2 irAEs had significantly better oncological outcomes (PFS, OS, and ORR) than grade ≤1 and ≥3 irAEs. Patients with grade ≥3 irAEs had worse outcomes than grade 2 irAEs. Endocrine and skin irAEs were related with better survival outcomes, and the rate of severities was lower in these categories. In conclusion, the occurrence of irAEs, particularly low-grade irAEs, was predictive of pembrolizumab efficacy in patients with platinum-pretreated advanced UC.

Objectives This study aimed to evaluate whether oncological outcomes of radical prostatectomy differ depending on adherence to the criteria in patients who opt for active surveillance. Materials and methods We retrospectively reviewed the data of 1035 patients enrolled in a prospective cohort of the PRIAS-JAPAN study. After applying the exclusion criteria, 136 of 162 patients were analyzed. Triggers for radical prostatectomy due to pathological reclassification on repeat biopsy were defined as on-criteria. Off-criteria triggers were defined as those other than on-criteria triggers. Unfavorable pathology on radical prostatectomy was defined as pathological ≥T3, ≥GS 4 + 3 and pathological N positivity. We compared the pathological findings on radical prostatectomy and prostate-specific antigen recurrence-free survival between the two groups. The off-criteria group included 35 patients (25.7%), half of whom received radical prostatectomy within 35 months. Results There were significant differences in median prostate-specific antigen before radical prostatectomy between the on-criteria and off-criteria groups (6.1 vs. 8.3 ng/ml, P = 0.007). The percentage of unfavorable pathologies on radical prostatectomy was lower in the off-criteria group than that in the on-criteria group (40.6 vs. 31.4%); however, the differences were not statistically significant (P = 0.421). No significant difference in prostate-specific antigen recurrence-free survival was observed between the groups during the postoperative follow-up period (median: 36 months) (log-rank P = 0.828). Conclusions Half of the off-criteria patients underwent radical prostatectomy within 3 years of beginning active surveillance, and their pathological findings were not worse than those of the on-criteria patients.

Objectives: With the emergence of several effective combination therapies, information on their effects at the primary site will be crucial for planning future cytoreductive nephrectomy (CN). The present study focused exclusively on changes in primary tumor sizes following treatment with nivolumab plus ipilimumab and investigated the clinical factors associated with a good response in primary tumors. Methods and materials: We retrospectively assessed 27 patients diagnosed with advanced renal cell carcinoma (RCC) who started treatment with nivolumab plus ipilimumab. Changes in tumor sizes at the primary site were described using waterfall and spider plots, respectively. We analyzed the correlation of tumor shrinkage between primary and metastatic site. The parameters analyzed between responders and non-responders according to primary tumor sizes were International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk scores, peripheral blood markers, and CRP. Results: The median age and follow-up period were 66 years and 9.3 months, respectively. The median IMDC risk score was 3 (range: 1-6). Nineteen patients were diagnosed with clear-cell RCC (ccRCC) and 8 patients with non-ccRCC. Among ccRCC patients, 9 (47.4%) achieved a significant response with a maximum reduction of 30% or more in the size of the primary tumor from baseline within 4 months, while 3 (37.5%) out of 8 patients with non-ccRCC achieved a significant response. Shrinkage of the primary tumor correlated with the metastatic tumors in both ccRCC and non-ccRCC cases. Of note, 6 patients underwent CN and no viable tumor cells were detected in the surgical specimens of 3 patients whose primary tumors shrank by approximately 50%-60% with a reduction to 4 cm or less. Among ccRCC patients, the neutrophil-to-lymphocyte ratio and monocyte-to-lymphocyte ratio were slightly lower in responders than in non-responders (P = 0.0944 and P = 0.0691). The platelet-to-lymphocyte ratio was significantly lower in responders than in non-responder (P = 0.0391). Conclusions: Significant responses in primary tumors to nivolumab plus ipilimumab were observed in 50% of ccRCC patients, while responses varied among non-ccRCC patients. Inflammation markers may be predictive factors of treatment responses in primary tumors. Although further studies are needed, the present results suggest the importance of considering CN from radiological and pathological viewpoints. (C) 2021 The Authors. Published by Elsevier Inc.

Although prostate cancer control using radiotherapy is dose‐dependent, dose–volume effects on late toxicities in organs at risk, such as the rectum and bladder, have been observed. Both protons and carbon ions offer advantageous physical properties for radiotherapy, and create favorable dose distributions using fewer portals compared with photon‐based radiotherapy. Thus, particle beam therapy using protons and carbon ions theoretically seems suitable for dose escalation and reduced risk of toxicity. However, it is difficult to evaluate the superiority of particle beam radiotherapy over photon beam radiotherapy for prostate cancer, as no clinical trials have directly compared the outcomes between the two types of therapy due to the limited number of facilities using particle beam therapy. The Japanese Society for Radiation Oncology organized a joint effort among research groups to establish standardized treatment policies and indications for particle beam therapy according to disease, and multicenter prospective studies have been planned for several common cancers. Clinical trials of proton beam therapy for intermediate‐risk prostate cancer and carbon‐ion therapy for high‐risk prostate cancer have already begun. As particle beam therapy for prostate cancer is covered by the Japanese national health insurance system as of April 2018, and the number of facilities practicing particle beam therapy has increased recently, the number of prostate cancer patients treated with particle beam therapy in Japan is expected to increase drastically. Here, we review the results from studies of particle beam therapy for prostate cancer and discuss future developments in this field.

In selected patients, long-term systemic chemotherapy could be performed with a 1–3-month drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the options for long-term disease control., Objective Aiming to achieve long-term disease control, maintenance systemic chemotherapy (MSC) with a 1–3-month drug-free interval is continued in selected patients. We report our experience of MSC for metastatic urothelial carcinoma (UC). Methods Of 228 metastatic UC patients treated with systemic chemotherapy, 40 (17.5%, 40/228) had continuously undergone MSC. Data on the regimen, cycle number, and reason for the discontinuation of MSC were also collected. We analyzed OS from the initiation of MSC until death or the last follow-up, using the log-rank test to assess the significance of differences. Results The median number of cycles of chemotherapy was 6, and the responses were CR in 6, PR in 20, SD in 13, and PD in 1 before MSC. Gemcitabine plus CDDP or carboplatin was mainly performed as MSC (70%, 28/40). MSC was repeated quarterly in 30 (75%, 30/40), every two months in 8 (20%, 8/40), and with other intervals in 2 (5%, 2/40). Overall, a median of 3.5 cycles (range: 1–29) of MSC was performed. The reason for the discontinuation of MSC was PD in 24 (60%, 24/40), favorable disease control in 9 (22.5%, 9/40), and myelosuppression in 3 (7.5%, 3/40), and for other reasons in 2 (5%, 2/40). MSC was ongoing in 2 (5%, 2/40). The median OS was 27 months from the initiation of MSC. PS0 (P = 0.0169), the absence of lung metastasis (P = 0.0387), and resection of the primary site (P = 0.0495) were associated with long-term survival after MSC. Conclusions In selected patients, long-term systemic chemotherapy could be performed with a drug-free interval. Our maintenance strategy with cytotoxic drugs may become one of the treatment options for long-term disease control.

Neutrophil-to-lymphocyte ratio (NLR) was reported to be associated with prognosis of urothelial cancer (UC) patients receiving systemic chemotherapy or immunotherapy. However, it has not been elucidated how preceding first-line chemotherapy affects NLR and subsequent second-line pembrolizumab treatment. This multicenter study analyzed 458 patients with metastatic UC who received first-line chemotherapy and second-line pembrolizumab with regard to pre-chemotherapy and pre-pembrolizumab NLR in association with the efficacy of chemotherapy and pembrolizumab treatment. NLR was increased in 47% while decreased in 53% of patients before and after first-line chemotherapy. High pre-chemotherapy NLR (≥ 3) was significantly associated with unfavorable overall (OS, P = 0.0001) and progression-free (P

Objectives This study aimed to evaluate how health-related quality of life (HRQOL) is related to repeat protocol biopsy compliance. Materials and methods We conducted a retrospective analysis using data from a prospective cohort in the Prostate Cancer Research International: Active Surveillance (PRIAS)-JAPAN study between January 2010 and August 2019. We used the Short Form 8 Health Survey (SF-8), as patient-reported outcomes, to assess HRQOL at AS enrollment and the first year of the protocol. The physical component summary (PCS) and mental component summary (MCS) were calculated from SF-8 questionnaires. The primary outcome was the evaluation of the association of HRQOL at enrollment on the first repeat biopsy compliance. The secondary outcome was the comparison of SF-8 scores during AS, stratified by repeat protocol biopsy compliance. Results Of 805 patients who proceeded to the first year of the protocol, the non-compliance rate was 15% (121 patients). In the adjusted model, lower MCS at enrollment was significantly associated with the first repeat protocol biopsy non-compliance (odds ratio [OR], 2.134; 95% confidence interval [CI], 1.031-4.42; P = 0.041) but not in lower PCS (OR, 0.667; 95% CI, 0.294-1.514; P = 0.333). All subscales of SF-8 were lower in the non-compliance group than in the compliance group at any point. MCS in the non-compliance group improved over time from the time of AS enrollment (2.34 increased, P = 0.152). Conclusion Our data suggest that lower MCS at AS enrollment using patient-reported outcomes was negatively associated with the first repeat protocol biopsy compliance. Our study may support the availability of a simple questionnaire to extract non-compliance.

Radical cystectomy (RC) is the gold standard for managing muscle-invasive and high-risknon-muscleinvasive bladder cancer, but is accompanied by non-negligible operative risk. The aim of this study is to identify preoperative variables to predict major perioperative complications after RC and to develop a nomogram using the cohort from multiple institutions in Japan. We retrospectively reviewed 668 patients who underwent open RC with ileal conduit or neobladder at Hokkaido University hospital and 20 affiliated institutions between 1997 and 2010. Complications occurring within 90 days of surgery were graded using modified Clavien classification system. We defined modified Clavien grade 3 or more as major complications and performed univariate and multivariate logistic regression analyses. Predictive accuracy of the nomogram was evaluated with the area under the receiver operating characteristics curve (AUC). A total of 528 men and 140 women were included in this study. There were a total of 160/668 patients (24%) with major perioperative complications. A multivariate model identified gender (OR : 1. 63, p=0. 04), cardiovascular comorbidity (OR : 1.48, p=0.03) and simultaneous nephroureterectomy (OR : 2.81, p=0. 01) as independent predictors. Using these 3 variables, a nomogram was developed with the AUC of 0.58. Predictive performance of our nomogram showed only fair performance ; but at least, we identified male, cardiovascular comorbidity and simultaneous nephroureterectomy as independent predictors of perioperative major complications.

Recently, Programmable Microfluidic Device (PMD) has got an attention of the design automation communities as a new type of microfluidic biochips. For the design of PMD chips, one of the important tasks is to minimize the number of flows for loading the reactant fluids into specific cells (by creating some flows of the fluids) before the bio-protocol is executed. Nevertheless of the importance of the problem, there has been almost no work to study this problem. Thus, in this paper, we intensively study this fluid loading problem in PMD chips. First, we successfully formulate the problem as a constraint satisfaction problem (CSP) to solve the problem optimally for the first time. Then, we also propose an efficient heuristic called Determining Flows from the Last (DFL) method for larger problem instances. DFL is based on a novel idea that it is better to determine the flows from the last flow unlike the state-of-the-art method Fluid Loading Algorithm for PMD (FLAP) [Gupta et al., TODAES, 2019]. Simulation results confirm that the exact method can find the optimal solutions for practical test cases, whereas our heuristic can find near-optimal solutions, which are better than those obtained by FLAP.

Tumor endothelial cells (TEC) lining tumor blood vessels actively contribute to tumor progression and metastasis. In addition to tumor cells, TEC may develop drug resistance during cancer treatment, allowing the tumor cells to survive chemotherapy and metastasize. We previously reported that TECs resist paclitaxel treatment via upregulation of ABCB1. However, whether TEC phenotypes are altered by anticancer drugs remains to be clarified. Here, we show that ABCB1 expression increases after chemotherapy in urothelial carcinoma cases. The ratio of ABCB1-positive TEC before and after first-line chemotherapy in urothelial carcinoma tissues (n = 66) was analyzed by ABCB1 and CD31 immunostaining. In 42 cases (64%), this ratio increased after first-line chemotherapy. Chemotherapy elevated ABCB1 expression in endothelial cells by increasing tumor IL8 secretion. In clinical cases, ABCB1 expression in TEC correlated with IL8 expression in tumor cells after first-line chemotherapy, leading to poor prognosis. In vivo, the ABCB1 inhibitor combined with paclitaxel reduced tumor growth and metastasis compared with paclitaxel alone. Chemotherapy is suggested to cause inflammatory changes in tumors, inducing ABCB1 expression in TEC and conferring drug resistance. Overall, these findings indicate that TEC can survive during chemotherapy and provide a gateway for cancer metastasis. Targeting ABCB1 in TEC represents a novel strategy to overcome cancer drug resistance. Significance: These findings show that inhibition of ABCB1 in tumor endothelial cells may improve clinical outcome, where ABCB1 expression contributes to drug resistance and metastasis following first-line chemotherapy.

We revealed prognostic factors in metastatic urothelial carcinoma patients treated with second-line systemic chemotherapy in real-world clinical practice. Performance status, C-reactive protein level and response to prior chemotherapy were prognostic indicators., Objectives The objective of the present study was to investigate the survival outcome and prognostic factors of metastatic urothelial carcinoma patients treated with second-line systemic chemotherapy in real-world clinical practice. Methods Overall, 114 patients with metastatic urothelial carcinoma undergoing second-line systemic chemotherapy were included in this retrospective analysis. The dominant second-line chemotherapy was a paclitaxel-based combination regimen (60%, 68/114). We assessed the progression-free survival and overall survival times using the Kaplan–Meier method. The Cox proportional hazards model was applied to identify the factors affecting overall survival. Results The median progression-free survival and overall survival times were 4 and 9 months, respectively. In the multivariate analysis, an Eastern Cooperative Oncology Group performance status score greater than 0 at presentation, C-reactive protein level ≧1 mg/dl and poor response to prior chemotherapy were adverse prognostic indicators. Patients with 0, 1, 2 and 3 of those risk factors had a median overall survival of 17, 12, 7 and 3 months, respectively. Conclusions The Eastern Cooperative Oncology Group performance status at presentation, C-reactive protein level and response to prior chemotherapy were prognostic factors for metastatic urothelial carcinoma patients undergoing second-line chemotherapy. In the future, this information might help guide the choice of salvage treatment, such as second-line chemotherapy or immune checkpoint inhibitors, after the failure of first-line chemotherapy.

Axitinib was approved for use in Japan as a salvage therapy for patients with metastatic renal cell carcinoma (RCC) in 2012. We retrospectively evaluated the cases of 32 RCC patients that were treated with Axitinib as a 2nd- or further-line therapy between November 2012 and March 2017. Overall survival (OS), progression-free survival (PFS), and adverse events were assessed. The median OS and PFS from the initiation of Axitinib were 29 and 11 months, respectively. Nineteen patients received Axitinib as a 2nd-line treatment, in whom the median OS and median PFS were 22 and 10 months, respectively, while the median OS and PFS were 29 and 15.5 months, respectively, amongthe 13 patients who received Axitinib as a 3rd- or further-line treatment, which suggested that Axitinib is effective in the 3rd-line and further-line settings. A Cox multivariate model revealed that bone metastasis was a significant adverse factor for OS. Common grade 3 or higher adverse events included hypertension (28%), diarrhea (7%), and proteinuria (7%). Although the present study demonstrated the efficacy and safety of salvage Axitinib treatment in patients who had recurrent disease after the initial systemic therapy, further large-scale studies should be warranted to make clear its clinical effectiveness in these patients.

Objectives: This study investigated the relapse pattern and oncologic outcomes after laparoscopic nephroureterectomy with template-based lymph node dissection (LND) in patients with clinically node-negative (cN0) upper urinary tract urothelial carcinoma. The frequency of lymph node metastasis, including micrometastases, was also evaluated. Methods and materials: A total of 105 patients with cTa-3N0M0 upper urinary tract urothelial carcinoma were analyzed, all of whom underwent regional LND during laparoscopic nephroureterectomy. Of those patients, 96 (91%) underwent complete LND in accordance with an anatomical template-based rule. We collected patient characteristics, pathological data, and follow-up data from medical charts. Micrometastases were assessed by pan-cytokeratin immunohistochemistry. Nonurothelial recurrence-free survival and cancer-specific survival were estimated using the Kaplan-Meier method. Results: The median number of lymph nodes removed was 12 (range, 1-59). Lymph node metastasis was identified by routine pathological examination in 7 (7/105, 6.7%) patients. Pan-cytokeratin immunohistochemistry revealed micrometastases in 5 additional patients (pNmicro +: 5/105, 4.8%). Nonurothelial disease recurrence was observed in 21 (20%) patients at a median of 10 months (range: 1- 33) after surgery. Distant metastasis was dominant (15/105, 14.3%), followed by locoregional recurrence (5/105, 4.8%) and both (1/105, 0.95%). The 5-year nonurothelial recurrence-free survival rates were 84.8% for pN0, 53.3% for pNmicro+, and 19.1% for pN+ (3-sample log-rank test, P < 0.0001). The 5-year cancer-specific survival rates were 95.0% for pN0, 53.3% for pNmicro+, and 23.8% for pN+ (P < 0.0001). Conclusions: Our observation showed that template-based LND could contribute to precise disease staging and better local disease control probably by eliminating nodal disease, compared with previous studies. The survival impact and ideal management of pNmicro+ disease should be evaluated in a larger cohort. (C) 2020 The Authors. Published by Elsevier Inc.

Objective To evaluate the association between the RENAL nephrometry score (RNS) and tumor proliferative activity assessed by immunohistochemistry in patients with localized renal cell carcinoma. Methods The current study included 145 pathological T1 (pT1) clear cell renal cell carcinomas (ccRCC). Tumor proliferative activity was assessed with the Ki67 index and microvessel density (MVD). RNS was retrospectively assessed in the present study. We divided patients into 3 groups according to RNS (RNS 4–6: low-complexity, 7–9: moderate complexity, and 10–12: high-complexity tumors) and compared the Ki67 index as well as MVD among the 3 groups. The association between the Ki67index/MVD and each component (R, E, N, A, L, h) was also evaluated. Results There were 56 low, 84 moderate, and 5 high-complexity tumors. The median Ki67 index of all tumors was 5.34% (interquartile range: 3.28–8.57). The median Ki67 index of low, moderate, and high-complexity tumors was 3.97%, 6.39%, and 11.27%, respectively, with a significant difference among the 3 groups (Kruskal–Wallis test, P = 0.0004). On the other hand, the median MVD of low, moderate, and high-complexity tumors was 14.11%, 14.42%, and 21.22%, respectively, and there were no significant differences among the 3 groups. In terms of each RNS component, there were significant differences in the Ki67 index among the 3 groups in N (P = 0.0101) and L (P = 0.0280) components, respectively. Conclusions The revealed association between RNS and the Ki67 index in pT1 clear cell renal cell carcinomas further supports the previous findings that the anatomy of renal cell carcinoma is associated with the malignant potential of localized clear cell renal cell carcinoma, which may provide additional information for treatment decision.

We revealed the feasibility of lymph node dissection (LND) with a laparoscopic approach and the equivalent oncological outcome of laparoscopic nephroureterectomy compared with open nephroureterectomy when regional LND is performed., Objective To assess the number of lymph nodes removed as a surrogate marker of the extent of lymph node dissection, and compare survival outcomes between laparoscopic radical nephroureterectomy (LRNU) and open radical nephroureterectomy (ORNU) in patients undergoing standardized lymph node dissection. Methods We retrospectively analyzed the data of 214 cTanyN0M0 patients undergoing radical NU with regional lymph node dissection according to the tumor location. The Kaplan–Meier method and Cox hazards model were utilized for survival analyses, including recurrence-free survival (RFS), cancer-specific survival (CSS) and overall survival (OS). Results A total of 114 patients underwent LRNU and 100 underwent ORNU. There was no significant difference in the pT stage, pN stage, or tumor grade, but distal ureteral tumors were more frequent in the LRNU group. The number of lymph nodes removed did not differ between the two groups [LRNU: 12 (median), ORNU: 11.5, P = 0.3852]. Lymph node metastasis was pathologically identified in 19 patients (8.9%). The 5-year RFS (ORNU: 71.7%, LRNU: 74%, P = 0.7829), CSS (77.8 and, 80%, P = 0.8441) and OS (72.8, and 75.9%, P = 0.3456) did not differ between the two groups. In the sub-analysis of pT3/4 patients (n = 83), there were no significant differences in RFS, CSS, or OS between the two groups, although Kaplan–Meier survival curves were slightly better for those receiving ORNU. In the multivariate model, LRNU was not significantly correlated with a poorer RFS, CSS or OS. Conclusion Our data support the feasibility of lymph node dissection with a laparoscopic approach and the equivalent oncological outcome of LRNU compared with ORNU when regional lymph node dissection is performed. However, LRNU should be performed after careful patient selection for advanced disease.

To determine the appropriate template of regional lymph node dissection (LND) at the time of laparoscopic nephroureterectomy (LNU) for patients with clinically node- negative urothelial carcinoma of the upper urinary tract.This prospective study included 45 patients undergoing LND with LNU in accordance with our prospective rules regarding the area of LND. Perioperative, pathologic, and follow-up data were collected. Micrometastasis in lymph nodes (LNs) was later evaluated by immunohistochemistry (IHC). Recurrence-free survival (RFS) was calculated with the Kaplan-Meier method.The median number of LNs removed was 14 (range 1-33). One patient with pT3 disease had node metastasis based on routine pathologic examination, and IHC revealed micrometastases in two additional patients (pT2 in one and pT3 in one). Therefore, 15% (3/20) of patients with ≥pT2 disease had node disease. After surgery, six patients experienced minor complications (Grade 1 or 2), and Grade 5 gastrointestinal bleeding after aspiration pneumonia developed in one elderly male patient on the 45th postoperative day, which was not considered to be associated with LND. At the last follow-up, lung metastasis developed in four patients (pT1 in one, pT2 in one, and pT3 in two), and presacral lymph node metastasis developed in one patient with a lower ureteral tumor (pT2), which was not included in our prospective template for a lower ureteral tumor. LN recurrence within/ near the LND area was not observed in patients with pelvic/upper ureteral carcinoma. The 2-year nonurothelial RFS rate was 84%.We consider that the present template represents regional LNs for patients with clinically node-negative pelvic/upper ureteral carcinoma, while presacral LNs may be incorporated into the regional LND template for patients with clinically node-negative lower ureteral carcinoma.

To define clinical and pathological factors predicting reclassification at the time of 1-year repeat biopsy (re-Bx) based on a Japanese cohort forming part of the Prostate Research International: Active Surveillance (PRIAS) study. The inclusion criteria for the PRIAS study are as follows: clinical stage T1c/T2, PSA ≤ 10 ng/ml, PSA density (PSAD)

The pituitary production of human chorionic gonadotropin (hCG) can cause false-positive results during or after germ cell tumor (GCT) treatment. Because hypogonadism leads to pituitary hCG production, testosterone administration test (TAT) has been recommended for pituitary hCG diagnosis. However, little is known about its efficacy for the discrimination of pituitary hCG as detected by currently used hCG assays in treatment of GCT. We conducted a retrospective multicenter study to determine the usefulness of TAT. The study included 60 patients who underwent TAT for the discrimination of pituitary hCG. In principle, serum hCG levels were measured 1 week after testosterone enanthate administration (250 mg). When the serum hCG levels decreased below the normal upper range, the results of TAT were determined positive. In this case, the elevated hCG was considered to be derived from pituitary and not from GCT. Serum hCG levels were normalized after TAT in 36 of 60 patients (60%). Before TAT, the hCG levels were below 1.0 IU/L in 13 patients (36%), 1.0–1.9 IU/L in 11 (31%), 2.0–2.9 IU/L in 7 (19%), and >3.0 IU/L in 5 (14%) of TAT-positive patients. Of them, 28 (78%) patients were successfully managed without further treatment with chemotherapy after TAT. Pituitary hCG was associated with higher levels of LH and not necessarily associated with low levels of testosterone. Determining the TAT status of patients was effective in discriminating pituitary hCG production.

Background: Current adaptive and dose escalating radiotherapy for muscle invasive bladder cancer requires knowledge of both inter-fractional and intra-fractional motion of the bladder wall involved. The purpose of this study is to characterize inter- and intra-fractional movement of the partial bladder wall using implanted fiducial markers and a real-time tumor-tracking radiotherapy system. Methods: Two hundred fifty one sessions with 29 patients were analysed. After maximal transurethral bladder tumor resection and 40 Gy of whole bladder irradiation, up to six gold markers were implanted transurethrally into the bladder wall around the tumor bed and used for positional registration. We compared the systematic and random uncertainty of positions between cranial vs. caudal, left vs. right, and anterior vs. posterior tumor groups. The variance in intrafractional movement and the percentage of sessions where 3 mm and 5 mm or more of intrafractional wall movement occurring at 2, 4, 6, 8, 10, and at more than 10 min until the end of a session were determined. Results: The cranial and anterior tumor group showed larger interfractional uncertainties in the position than the opposite side tumor group in the CC and AP directions respectively, but these differences did not reach significance. Among the intrafractional uncertainty of position, the cranial and anterior tumor group showed significantly larger systematic uncertainty of position than the groups on the opposite side in the CC direction. The variance of intrafractional movement increased over time; the percentage of sessions where intrafractional wall movement was larger than 3 mm within 2 min of the start of a radiation session or larger than 5 mm within 10 min was less than 5%, but this percentage was increasing further during the session, especially in the cranial and anterior tumor group. Conclusions: More attention for intrafractional uncertainty of position is required in the treatment of cranial and anterior bladder tumors especially in the CC direction. The optimal internal margins in each direction should be chosen or a precise intrafractional target localization system is required depending on the tumor location and treatment delivery time in the setting of partial bladder radiotherapy.

Japanese octogenarians developed similar perioperative comorbidities after radical cystectomy. Old age as a single criterion should not be used to abandon RC; careful preoperative assessment is mandatory., Objective To determine the characteristics of 90-day morbidity and mortality after radical cystectomy in Japanese octogenarians. Methods A retrospective multi-institutional study. We reviewed the records of 834 patients treated by open radical cystectomy between 1997 and 2010. All complications within 90 days after surgery were sorted into the 11 categories proposed by the Memorial Sloan-Kettering Cancer Center and graded according to the modified Clavien-Dindo system. We compared the characteristics of complications between ≥80-year (n = 86) and

Objective To evaluate the association between the RENAL nephrometry score and annual growth rates of renal masses presumed to be renal cell carcinoma. Methods The current study included 47 renal tumors followed up for at least 12 months, of which 26 tumors were found to be pathologically proven renal cell carcinomas. Annual tumor growth rates were calculated from changes in the maximal diameter on computed tomography, and RENAL nephrometry scores were recorded on initial imaging by two senior urologists. The associations between clinical characteristics including the RENAL nephrometry score and annual growth rates were analyzed using a linear regression model. Results The median tumor size at diagnosis was 1.7 cm (range 0.6–5.8). The median nephrometry score at diagnosis was 7 (range 4–10). Overall, the median tumor growth rate was 0.34 cm per year (range −0.19–2.0). Linear regression analysis showed that the annual tumor growth rate was associated with the RENAL nephrometry score (P

364 Background: Bladder-preserving therapy with a real-time tumor-tracking radiotherapy system (RTRT system) has been used for muscle-invasive bladder cancer (MIBC) since 1998 in our institution. We evaluate long term outcomes of this therapy. Methods: From 1998 to 2016, 38 patients with a T2-T4N0M0 bladder cancer who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection (TUR) and 40 Gy irradiation to the whole bladder was followed by TUR of the tumor bed (1st Evaluation) and endoscopic implantation of fiducial markers in the bladder wall around the primary tumor. Then, a boost of 25 Gy was made to the primary tumor using RTRT system. Protocol TUR of the tumor bed was performed 6 months later (2nd Evaluation). Patients with adequate renal function (CCR>45ml/min) received concurrent chemoradiotherapy with nedaplatin (cisplatin analog made in Japan, 70mg/m2 intravenously, day1, day22, day50). Results: Median follow-up for surviving patients was 6 yr. 5- and 10-yr OS were 55%, 40%, and 5- and 10-yr PFS were 55% and 39%, respectively. The CR rate at 1st evaluation was 66%, in those patients 5- and 10-yr OS rates were 70% and 61%. Among the patients with non-CR at 1st evaluation, CR rate at 2nd evaluation was 31%. Local recurrence occurred in 13 patients. One of them was performed cystectomy and 9 were performed TUR and/or bladder injection therapy. 11 patients experienced distant recurrence, 2 of those was performed chemotherapy. In univariate analysis, male (OS; HR: 0.33, 95% CI: 0.12-0.92, PFS; HR:0.25, 95% CI: 0.09-0.69) and PS0-1 (OS; HR: 0.26, 95% CI: 0.09-0.79, PFS; HR: 0.29, 95% CI: 0.10-0.85) were significantly associated with good OS and PFS (shown in Table). In multivariate analysis, the both of these covariates were also significantly associated with good OS and PFS (male; OS; HR: 0.31, 95% CI: 0.11-0.88, PFS; HR: 0.21, 95% CI: 0.07-0.62, PS0-1; OS; HR: 0.25, 95% CI: 0.08-0.76, PFS; HR: 0.24, 95%CI: 0.09-0.75). Conclusions: Bladder-preserving therapy is a considerable option in patients medically unfit for or not desiring cystectomy.

Objective To determine the differences in the type, incidence, and severity of 90-day morbidity after radical cystectomy between two different methods of urinary diversion, ileal conduit and neobladder. Methods We carried out a retrospective multi-institutional study by reviewing the records of 668 patients treated with open radical cystectomy, and ileal conduit (n = 493) or neobladder substitution (n = 175) between 1997 and 2010. All complications within 90 days after surgery were divided into 11 specific categories as reported by the Memorial-Sloan Kettering Cancer Center, and graded according to the modified Clavien system. Type, incidence and severity of the 90-day morbidity between the two different types of urinary diversions were compared. Results There was no significant difference in the overall complication rates between the two groups (ileal conduit: 72% [353/493], neobladder: 74% [129/175], P = 0.5909), whereas the neobladder group had fewer major (grade 3 or more) complications (13 vs 20%, respectively, P = 0.0271). The neobladder group had more infectious complications (43 vs 31%, respectively, P = 0.0037), mainly as a result of urinary tract infection, whereas the ileal conduit group had more wound-related complications (24 vs 14%, respectively, P = 0.0068), mainly as a result of surgical site infection. The 90-day mortality rates were 1.1% (2/175) in the neobladder group and 1.6% (8/493) in the ileal conduit group (P = 0.6441). Conclusions There was no significant difference in the overall complication rates between the two methods, and patients with neobladder had fewer major complications. The neobladder group had more infectious complications, whereas the ileal conduit group had more wound-related complications.

Objective: The real-time tumor-tracking radiotherapy system with fiducial markers has the advantage that it can be used to verify the localization of the markers during radiation delivery in real-time. We conducted a prospective Phase II study of image-guided local-boost radiotherapy for locally advanced bladder cancer using a real-time tumor-tracking radiotherapy system for positioning, and here we report the results regarding the safety and efficacy of the technique. Methods: Twenty patients with a T2-T4N0M0 urothelial carcinoma of the bladder who were clinically inoperable or refused surgery were enrolled. Transurethral tumor resection and 40 Gy irradiation to the whole bladder was followed by the transurethral endoscopic implantation of gold markers in the bladder wall around the primary tumor. A boost of 25 Gy in 10 fractions was made to the primary tumor while maintaining the displacement from the planned position at less than +2 mm during radiation delivery using a real-time tumor-tracking radiotherapy system. The toxicity, local control and survival were evaluated. Results: Among the 20 patients, 14 were treated with concurrent chemoradiotherapy. The median follow-up period was 55.5 months. Urethral and bowel late toxicity (Grade 3) were each observed in one patient. The local-control rate, overall survival and cause-specific survival with the native bladder after 5 years were 64, 61 and 65%. Conclusions: Image-guided local-boost radiotherapy using a real-time tumor-tracking radiotherapy system can be safely accomplished, and the clinical outcome is encouraging. A larger prospective multi-institutional study is warranted for more precise evaluations of the technological efficacy and patients’ quality of life.