Wild-type p53 controls cell motility and invasion by dual regulation of MET expression.

Recent observations suggest that p53 mutations are responsible not only for growth of primary tumors but also for their dissemination. However, mechanisms involved in p53-mediated control of cell motility and invasion remain poorly understood. By using the primary ovarian surface epithelium cell culture, we show that conditional inactivation of p53 or expression of its mutant forms results in overexpression of MET receptor tyrosine kinase, a crucial regulator of invasive growth. At the same time, cells acquire increased MET-dependent motility and invasion. Wild-type p53 negatively regulates MET expression by two mechanisms: (i) transactivation of MET-targeting miR-34, and (ii) inhibition of SP1 binding to MET promoter. Both mechanisms are not functional in p53 absence, but mutant p53 proteins retain partial MET promoter suppression. Accordingly, MET overexpression, cell motility, and invasion are particularly high in p53-null cells. These results identify MET as a critical effector of p53 and suggest that inhibition of MET may be an effective antimetastatic approach to treat cancers with p53 mutations. These results also show that the extent of advanced cancer traits, such as invasion, may be determined by alterations in individual components of p53/MET regulatory network.

[15O]H2O PET/MRI for Assessment of Complete Response to Neoadjuvant or Induction Chemotherapy in Patients with Muscle-Invasive Bladder Cancer: A Pilot Study.

Background: Accurate assessment of therapy response to chemotherapy could possibly offer a bladder-sparing approach in selected patients with localized muscle-invasive bladder cancer (MIBC). The aim of this study was to evaluate whether [15O]H2O PET/MRI can be used for assessment of complete local pathological response to preoperative chemotherapy in patients with MIBC. Methods: This prospective pilot study included 13 patients with MIBC treated with neoadjuvant or induction chemotherapy and subsequent radical cystectomy. Patients underwent a [15O]H2O PET/MRI scan before chemotherapy and another scan after chemotherapy before radical cystectomy. Volumes of interest were delineated on T2-weighted MRI and transferred to parametric images for dynamic analysis. Tumor blood flow (TBF) was estimated by [15O]H2O PET. Changes in TBF were compared with histopathology. The Wilcoxon matched-pairs signed-ranks test was used for comparing pre- and post-chemotherapy measurements. Results: Mean TBF decreased by 49%. Mean TBF in complete responders (ypT0N0/ypTis) was not significantly different from non-complete responders (≥ypT1) (p = 0.52). Conclusions: Despite a measurable decrease in TBF after chemotherapy treatment, we were not able to estimate a TBF threshold for identifying complete responders to chemotherapy for MIBC patients. Further studies are needed to elucidate the potential of [15O]H2O PET/MRI in assessing therapy response in MIBC.

DaBlaCa-16: Retrosigmoid Versus Conventional Ileal Conduit in Robot-assisted Radical Cystectomy, the MOSAIC Randomized Controlled Trial-Feasibility and 90-day Postoperative Complications.

Background: Approximately 15% of patients undergoing radical cystectomy (RC) develop benign ureteroenteric strictures. Of these strictures, the majority are located in the left ureter. To lower the rate of strictures, a retrosigmoid ileal conduit has been suggested. Objective: To investigate the feasibility and safety of a retrosigmoid ileal conduit during robot-assisted RC in bladder cancer patients. Design setting and participants: This randomized controlled trial included 303 patients from all five cystectomy centers in Denmark from May 2020 to August 2022. Participants were diagnosed with bladder cancer and scheduled for robot-assisted RC with an ileal conduit. Intervention: Intervention group: a retrosigmoid ileal conduit was constructed using approximately 25 cm of the terminal ileum and tunneled behind the sigmoid where the left ureter was anastomosed from end to side. Control group: the conventional ileal conduit ad modum Bricker with individual end-to-side anastomoses. Outcome measurements and statistical analysis: Patients were analyzed by the intention-to-treat approach. Complications within 90 d were categorized using the Clavien-Dindo grading system and compared using Fisher's exact test. Wilcoxon's test was used for pre- and postoperative renal function. Results and limitations: Of the 149 patients randomized for the retrosigmoid ileal conduit (MOSAIC), a total of 137 (92%) patients received the allocated conduit. Postoperative complications were distributed equally between the two groups. The relative risk of Clavien-Dindo complications of grade ≥III was 1.12 (95% confidence interval: 0.96-1.31) in the intervention group compared with the control group. Conclusions: The retrosigmoid ileal conduit with robot-assisted RC was technically feasible. Early postoperative complications were not significantly different when comparing the two groups. Further investigation of long-term complications, including strictures, is needed. Patient summary: We compared a conventional urinary diversion with a longer conduit to prevent constriction from developing in the ureters. The new conduit is feasible and safe within the first 90 d, with no differences in postoperative complications from those of the conventional diversion.

DaBlaCa-17: nationwide observational study in Denmark on survival before and after implementation of neoadjuvant chemotherapy prior to cystectomy for muscle-invasive bladder cancer.

OBJECTIVE: To investigate the impact of neoadjuvant chemotherapy implementation with gemcitabine-cisplatin on survival outcomes for patients with muscle-invasive bladder cancer in Denmark. MATERIALS AND METHODS: Data were collected on all patients in Denmark undergoing radical cystectomy who were potential candidates for neoadjuvant chemotherapy from 2010 to 2015 (n = 851). A cohort before the implementation of neoadjuvant chemotherapy (Cohort 2010-12) was compared with a cohort after implementation (Cohort 2013-15). Patients in Cohort 2013-15 receiving neoadjuvant chemotherapy (+NAC, n = 213) were compared with patients in Cohort 2013-15 not receiving neoadjuvant chemotherapy (-NAC, n = 139). Pathological results after radical cystectomy and oncological outcomes were compared between the study cohorts. Overall survival, disease-free survival, and disease-specific survival were compared with Kaplan-Meier plots and with univariable and multivariable Cox regression. Kaplan-Meier estimates of overall survival were also performed separately for treating hospital and for pathological stage. RESULTS: Pathological T0 (pT0) was more frequent in patients who received neoadjuvant chemotherapy: 34% versus 18% when comparing Cohort 2013-15 with Cohort 2010-12 (p < 0.001), and 46% versus 16% in +NAC compared with -NAC (p < 0.001). Overall survival, disease-free survival, and disease-specific survival at 5 years after cystectomy were not improved in Cohort 2013-15 compared with Cohort 2010-12 with adjusted hazard ratios of 1.11 (95% confidence interval [CI]: 0.87-1.43), 1.02 (95% CI: 0.81-1.29), and 1.06 (95% CI: 0.80-1.41), respectively. CONCLUSIONS: This observational study found no improved survival in a national cohort of patients with muscle-invasive bladder cancer undergoing radical cystectomy after implementation of NAC. However, reservations should be made regarding the study design and the true effect of NAC on survival outcomes.

A population-based retrospective analysis on variation in use of neoadjuvant chemotherapy depending on comorbidity in patients with muscle-invasive bladder cancer undergoing cystectomy in Denmark in the period 2013-2019.

INTRODUCTION: The recommended treatment of localized muscle-invasive bladder cancer (MIBC) is cystectomy and neoadjuvant chemotherapy (NAC) for eligible patients. However, the percentage who receive NAC is varying. OBJECTIVE: The aim was to evaluate the variation in percentage of patients receiving NAC in Denmark since implementation in 2013, the potential influence of comorbidity on NAC administration, and the pathological outcome at time of cystectomy with and without NAC. METHODS: Patients were identified by cystectomy procedure codes and date of diagnosis in the period 2013-2019 in The Danish Bladder Cancer Database. Chi square test and Fisher's exact test were used to evaluate demographics and tumor-specific characteristics. Wilcoxon rank-sum test was used to compare Charlson Comorbidity Index (CCI) and compare age-adjusted CCI subgroups. RESULTS: Overall, 1032 patients age ≤75 years and tumor stage ≥T2 were included in the study; 594 patients (58%) received NAC. The percentage of NAC administration varied from 27% to 92%. Patients who received NAC had significantly less comorbidity estimated by CCI when compared to patients not receiving NAC. Of patients with MIBC who received NAC, 57% had complete response (CR) at cystectomy, whereas 29% of patients who did not receive NAC had CR at cystectomy (p < 0.01). CONCLUSIONS: Patients with comorbidity estimated by high CCI score had a lower probability of receiving NAC. The probability of CR was twice as high in patients with MIBC treated with NAC compared to patients undergoing cystectomy alone. However, almost one third of patients with MIBC were tumor free at cystectomy despite no NAC administration.

Which data are available in central registries on bladder cancer patients in the five Nordic countries.

OBJECTIVE: The aim of this study was to give a collective overview on all available data sources on bladder cancer patients in the Nordic countries including the amount of detail and coverage. METHODS: National representatives from five Nordic countries were asked to fill out a questionnaire on available information regarding bladder cancer patients from databases in their respective countries. Additional information was retrieved from descriptions of the relevant registries. RESULTS: Non-muscle invasive bladder cancer: from all countries, information on stage and grade at transurethral resection of the bladder (TURB) could be retrieved. Details on procedures (TURB, instillation therapy, photodynamic diagnosis, and perioperative instillation) were varying within different databases. Muscle invasive bladder cancer: in all Nordic countries, detailed information on cystectomy patients could be retrieved but with variable registration of complications. Completeness of available information on oncological treatment (radiation, chemotherapy, and immunotherapy) were varying. Oncological outcome: Information on overall survival was available in all countries whereas recurrence-free survival and cancer-specific survival were available for some but not all patients depending on treatment modality. CONCLUSIONS: Despite limitations, we found that it was possible to retrieve detailed information on diagnostics, treatment, and outcome for most aspects of bladder cancer in the Nordic countries on a population based, non-selected patient cohort.

Robot-assisted vesicovaginal fistula repair - initial experience.

Purpose: To report our initial experience of robot-assisted vesicovaginal fistula (VVF) repair.Materials and methods: Data from all patients who underwent robot-assisted VVF repair from August 2015 to October 2018 were analyzed. Preoperative data included age, BMI, smoking status, alcohol consumption, etiology of fistula and location and size of fistula. Operative data was operation time and the use of tissue interposition. Postoperative data included time to follow up, complications and reoperations.Results: A total of 13 patients underwent robot-assisted VVF repair and 15 operations were performed as 2 patients required a repeated procedure. The mean age was 45.0 ± 14.5 years (±SD) and operative time was 138.3 ± 58.9 min (±SD). The mean time to follow up was 18.3 ± 16.1 weeks (±SD). Postoperative complications were reported by one patient and was Clavien-Dindo I. Relapse of fistula was found in two patients who had a successful reoperation with repeated robotic-assisted surgery. An interposition flap was used in a single patient. The overall success rate was 84.6% after primary surgery (11 out of 13) and 100% after repeated procedure (2 out of 2).Conclusions: In this initial small series, we found that robot-assisted VVF repair is a safe procedure with results comparable to transvaginal repair. This procedure has a high success rate and few complications without using interposed tissue.