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Background: Radical cystectomy with pelvic lymph node dissection is the recommended treatment in non-metastatic muscle-invasive bladder cancer (MIBC). In randomised trials, robot-assisted radical cystectomy (RARC) showed non-inferior short-term oncological outcomes compared with open radical cystectomy (ORC). Data on intermediate and long-term oncological outcomes of RARC are limited.Objective: To assess the intermediate-term overall survival (OS) and recurrence-free survival (RFS) of patients with MIBC and high-risk non-MIBC (NMIBC) who underwent ORC versus RARC in clinical practice.Methods and Materials: A nationwide retrospective study in 19 Dutch hospitals including patients with MIBC and high-risk NMIBC treated by ORC (n = 1086) or RARC (n = 386) between January 1, 2012 and December 31, 2015. Primary and secondary outcome measures were median OS and RFS, respectively. Survival outcomes were estimated using Kaplan-Meier curves. A multivariable Cox regression model was developed to adjust for possible confounders and to assess prognostic factors for survival including clinical variables, clinical and pathological disease stage, neoadjuvant therapy and surgical margin status.Results: The median follow-up was 5.1 years (95% confidence interval ([95%CI] 5.0-5.2). The median OS after ORC was 5.0 years (95%CI 4.3-5.6) versus 5.8 years after RARC (95%CI 5.1-6.5). The median RFS was 3.8 years (95%CI 3.1-4.5) after ORC versus 5.0 years after RARC (95%CI 3.9-6.0). After multivariable adjustment, the hazard ratio for OS was 1.00 (95%CI 0.84-1.20) and for RFS 1.08 (95%CI 0.91-1.27) of ORC versus RARC. Patients who underwent ORC were older, had higher preoperative serum creatinine levels and more advanced clinical and pathological disease stage.Conclusion: ORC and RARC resulted in similar intermediate-term OS and RFS in a cohort of almost 1500 MIBC and high-risk NMIBC. [ABSTRACT FROM AUTHOR]

Background: Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data., Objective: To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC., Design, Setting, and Participants: Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891)., Outcome Measurements and Statistical Analysis: The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided., Results and Limitations: The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias., Conclusions: CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC., Patient Summary: Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy., (Copyright © 2016 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: Data from single-center series suggest that a delay in time to radical cystectomy (RC) more than 3 months after diagnosis of muscle-invasive bladder cancer (MIBC) is associated with pathological upstaging and decreased survival. However, limited data is available from population-based studies. In this study, the effect of delayed RC was assessed in a nationwide cohort., Materials and Methods: Patients who underwent RC between 2006 and 2010 with primary clinical T2-T4N0M0 urothelial bladder cancer were selected using the Netherlands Cancer Registry database. Data from the Netherlands Cancer Registry was supplemented with data from the Nationwide Network and Registry of Histo- and Cytopathology database in case of incomplete information. The cohort was divided in patients who underwent RC ≤3 months (group I) vs. patients who underwent RC >3 months (group II). Median time from MIBC diagnosis to RC, variables associated with delayed RC >3 and the effect of delayed RC on staging and overall survival (OS) were evaluated in patients who underwent neoadjuvant therapy and patients who did not., Results: A total of 1,782 patients were included. Median follow-up time was 5.1 years for living patients and 1.3 years for deceased patients. Median time from MIBC diagnosis to RC was 50 days (interquartile range: 27 days) and 93% of patients underwent RC≤3 months. Patients older than 75 years (odds ratio [OR] = 0.50; 95% CI: 0.32-0.77), referred for RC (OR = 0.41; 95% CI: 0.26-0.69), and treated in a university hospital (OR = 0.34; 95% CI: 0.21-0.56) were less likely to undergo RC≤3 months. Pathologic upstaging rate (43.9% vs. 42.1%) and node-positive disease rate (20.2% vs. 21.7%) did not differ for group I and II. Delayed RC>3 months was not associated with decreased OS adjusting for confounding variables (hazard ratio = 1.16; 95% CI: 0.91-1.48; P = 0.25). Median time from MIBC diagnosis to RC in patients that received neoadjuvant therapy (n = 105) was 133 days (interquartile range: 62 days). Adjusting for confounding variables, delayed RC>3 months was not associated with OS (hazard ratio = 0.90; 95% CI: 0.45-1.82)., Conclusions: The vast majority of patient underwent RC within 3 months after diagnosis of MIBC, as recommended in the European Association of Urology MIBC guideline. Delayed RC for more than 3 months had no adverse effect on staging and survival., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: To explore whether urinary cytokine and chemokine (CK) levels differed between cold mitomycin-C (cold-MMC)-treated patients and chemohyperthermia (C-HT)-treated patients, to shed light on the possible molecular mechanisms that might explain the superior outcome of C-HT. Furthermore, CK-differences were explored between C-HT responders and C-HT non-responders., Methods: Twelve NMIBC patients were included. Nine received six-weekly C-HT, and three received four-weekly cold-MMC instillations. Urine was collected on 8-12 time points before and after every treatment. MDC, IL-2, IL-6, IL-8, IP-10, MCP-1 and RANTES were determined by Luminex(®)-analysis., Results: Elevated urinary CK levels were observed in both groups after treatment. In general, CK-peaks were lower in the cold-MMC group in comparison with levels in the C-HT group. Significant higher MCP-1 and IL-6 levels were observed in C-HT-treated patients. Additionally, significant cumulative effects were observed for IP-10 and IL-2. However, IP-10 and IL-2 levels did not significantly differ between treatments. MDC levels after the first week of treatment were significantly higher in the C-HT responders compared with the non-responders., Conclusion: MMC treatment leads to elevated urinary CK levels with significantly higher MCP-1 and IL-6 levels in C-HT-treated patients. Increased MDC levels after the first C-HT instillation appear to be related to good clinical outcome and might be of additional value to personalize treatment. Studies involving more patients and longer follow-up are needed to substantiate this observation.

Introduction/background: Non-muscle-invasive bladder cancer (NMIBC) has a strong tendency to recur despite adjuvant instillations. TMX-101 is a new liquid form of imiquimod for intravesical instillation and has activity in vitro against urothelial carcinoma. The purpose was to analyze the activity of TMX-101 in low-grade NMIBC. Furthermore, pharmacokinetic and pharmacodynamic characteristics and adverse events were evaluated., Patients and Methods: A multicenter, prospective phase 1 trial in 7 patients with low-grade NMIBC was conducted. All patients underwent a marker lesion transurethral resection of the bladder tumor and 6 weekly instillations with TMX-101 0.2% or 0.4%. Cystoscopy 2 to 4 weeks after the last instillation evaluated the effect of TMX-101., Results: The effective biologic dose (EBD = complete response [CR] in > 2 patients) could not be defined because none of the patients experienced CR. Maximum plasma concentration was 75.1 ng/mL in the 0.4% dose group. No drug accumulation was observed. In the pharmacodynamic analysis, urinary interleukin 1 receptor agonist (IL-1ra) represents the most sensitive and uniform response after TMX-101 instillation. A total of 87.0% reported at least 1 adverse event. All events were of grade 2 severity or less (Common Terminology Criteria of Adverse Events version 4.02). No clinically significant changes in laboratory parameters or vital signs were observed during or after treatment., Conclusion: Toll-like receptor 7 (TLR-7) agonists are effective in urothelial carcinoma in preclinical research. The EBD in this phase 1 study could not be determined because no patient experienced CR. IL-1ra could be valuable as a urinary biomarker in future developments. The safety of TMX-101 has been reconfirmed. New doses, other schedules, and NMIBC subgroups should be tested to define the EBD. A pilot study in carcinoma-in-situ patients is currently ongoing and results are expected shortly., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Non-muscle-invasive bladder cancer is a highly recurrent disease. The health care costs for non-muscle-invasive bladder cancer are a major burden for society. Bladder cancer treatment starts with a presumed complete transurethral resection of a bladder tumor. Despite international guidelines for perioperative and/or adjuvant intravesical instillation therapy in non-muscle-invasive bladder cancer, adequate worldwide application is lacking. In patients who do get adjuvant intravesical instillations, recurrences are still frequent. New therapies in non-muscle-invasive bladder cancer are unsatisfactory and still experimental., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Purpose: Nonmuscle invasive bladder cancer is characterized by a high recurrence rate. New adjuvant treatments are needed to decrease this high number of recurrences. We present the results of more than 10 years of experience with chemohyperthermia in patients with nonmuscle invasive bladder cancer., Materials and Methods: Using standardized medical record forms we prospectively collected patient and tumor characteristics of patients treated with chemohyperthermia between 2002 and 2013. Median followup was 75.6 months. Recurrence-free survival was the primary objective. The secondary objective was to observe recurrence-free survival differences in 1) the epirubicin group vs the mitomycin group and 2) the highly recurrent (greater than 2 recurrences in 24 months) nonmuscle invasive bladder cancer group vs the other groups., Results: A total of 160 patients with nonmuscle invasive bladder cancer were included in study, including 20 (13%) treated with epirubicin and 129 (81%) previously treated with bacillus Calmette-Guérin. One and 2-year recurrence-free survival was 60% and 47%, respectively. Muscle invasive progression was seen in 4% of cases. Two-year recurrence-free survival in the epirubicin and mitomycin groups was 55% and 46%, respectively (p = 0.30). The highly recurrent nonmuscle invasive bladder cancer group had significant decreased recurrence-free survival compared to other groups (p <0.01). Patients treated with 2 or fewer vs greater than 2 transurethral bladder tumor resections before chemohyperthermia had higher recurrence-free survival (p = 0.01). On multivariable analysis the highly recurrent cancer criteria remained independently associated with decreased recurrence-free survival (HR 2.40, 95% CI 1.30-4.43, p = 0.01)., Conclusions: Chemohyperthermia is an effective approach to nonmuscle invasive bladder cancer for which standard intravesical treatments fail. Patients with highly recurrent disease before chemohyperthermia have lower recurrence-free survival. Furthermore, recurrence-free survival appears to improve with earlier chemohyperthermia. No significant differences were observed between the 2 chemotherapy agents., (Copyright © 2014 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.)

Background: The aim of this study was to present survival outcomes and identify prognostic factors in patients undergoing radical cystectomy (RC) for urothelial bladder cancer (UBC) in a homogeneous surgery-only series., Patients and Methods: Patients who underwent RC for UBC with intent-to-cure between January 1998 and December 2010 without neoadjuvant or adjuvant treatment were included in this retrospective study. Clinical and histopathologic data were collected and institutional review board approval was obtained. Outcomes of interest were 30-day mortality (30dM), RFS, and OS. Univariable and multivariable analysis were performed. Median follow-up was 9.1 years., Results: Two hundred forty-five patients were included with a median age of 65 years (range, 34-92 years). 30dM rate was in 5 out of 245 patients (2.0%) and 5-year RFS and OS rates were 67% and 58%, respectively. A total of 223 patients (91%) underwent lymph node (LN) dissection. Median number of removed and positive LNs were 9 and 1.5, respectively. Variables independently associated with decreased OS and RFS were tumor stage and LN status. In addition, positive soft tissue surgical margin (STSM) status was independently associated with decreased OS. In LN-positive patients, presence of extranodal extension (ENE) was associated with decreased RFS (39.7% vs. 7.3%; P = .005)., Conclusion: Radical cystectomy for UBC was associated with low perioperative mortality rate and provided 5-year disease control in approximately two-thirds of patients. Independent prognostic factors included tumor stage, LN status (RFS and OS), and STSM status (OS). Presence of ENE in LN-positive patients was univariably associated with decreased RFS and OS., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Non-muscle-invasive bladder cancer is a highly prevalent disease and recurrences, after initial therapy, are common. Consequently, the healthcare costs for non-muscle-invasive bladder cancer are high. Despite a primary adequate response to adjuvant intravesical treatment, many patients suffer from recurrences, and some even from progression. To date, cystectomy remains the only option for those non-responding patients with high risk of recurrence and progression. Mainly because outcome after progression, in this group, is poor. Therefore, new intravesical therapies are needed. Moreover, new accurate and individual parameters, to distinguish responder from non-responders, will provide additional benefit in clinical decision-making. In this review, current diagnostics and therapies will be discussed. In addition, we will elucidate developing therapies in non-muscle-invasive bladder cancer.

Regulated exocytosis of Weibel-Palade bodies (WPBs) is a pivotal mechanism via which vascular endothelial cells initiate repair in response to injury and inflammation. Several pathways have been proposed to enable differential release of bioactive molecules from WPBs under different pathophysiologic conditions. Due to the complexity, many aspects of WPB biogenesis and exocytosis are still poorly understood. Herein, we have investigated the regulated exocytosis of the major WPB constituent, von Willebrand Factor (VWF), which upon its release forms strings of up to several millimeters long that capture circulating platelets and thereby initiate the formation of a haemostatic plug. Using correlative, fluorescence, and electron microscopic imaging techniques, we provide evidence that multigranular exocytosis is an important pathway for VWF release in secretagogue-challenged human umbilical vein endothelial cells. A novel membrane-delimited structure (secretory pod) was identified as the site of WPB coalescence and VWF exocytosis. Clathrin-coated profiles present on the secretory pods suggested remodeling via compensatory membrane retrieval. Small, 30- to 40-nm cytoplasmic vesicles (nanovesicles) mediated the fusion of WPBs with secretory pods. Multigranular exocytosis may facilitate VWF string formation by pooling the content of multiple WPBs. In addition, it may provide a novel mechanism for the differential release of WPB cargo.