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Background: Prospective data collection for perioperative outcomes might increase awareness of surgical results obtained for patients with prostate cancer (PCa) undergoing robot-assisted radical prostatectomy (RARP). This would prompt the implementation of measures aimed at reducing the risk of adverse outcomes. Objective: To assess the efficacy of an audit and feedback process aimed at identifying the most common complications after RARP and at implementing measures to improve outcomes. Design, setting, and participants: Overall, 415 patients treated with RARP by a high-volume surgeon were included. Perioperative outcomes for 187 patients treated between September 2016 and December 2017 were prospectively collected at 30 d according to the European Association of Urology guideline recommendations (group 1). An audit and feedback process was implemented in January 2018 whereby the most common complication (anastomotic leak) was identified and measures aimed at improving outcomes (changes in the anastomotic technique) were implemented. The outcomes for group 1 were then compared to 228 patients treated after implementation of the modified surgical technique (group 2). Surgical procedure: A novel technique for posterior reconstruction and urethrovesical anastomosis was introduced. Measurements: Perioperative outcomes included blood loss, operative time, length of stay, and 30-d postoperative complications. Logistic regression models tested the effect of the novel surgical technique on anastomotic leaks. Results and limitations: Overall, 97 patients (23%) experienced postoperative complications at 30 d. The rate of anastomotic leaks was significantly lower in group 2 compared to group 1 (3.1% vs 9.6%; p < 0.01). Similarly, overall and Clavien-Dindo grade ≥2 complication rates were lower in group 2 versus group 1 (17% vs 31%, and 6% vs 20%; both p ≤ 0.001). In multivariable analyses, treatment after implementation of changes in the anastomotic technique independently predicted a lower risk of complications (odds ratio [OR] 0.58, 95% confidence interval [CI] 0.38–0.89) and of anastomotic leaks (OR 0.43, 95% CI 0.17–0.97). The lack of randomization represents the main limitation. Conclusions: Implementation of changes in the urethrovesical anastomosis technique arising from increased awareness of surgical outcomes reduced the risk of anastomotic leaks. These findings highlight the importance of audit and feedback processes using a standardized method for reporting surgical morbidity. Patient summary: Increased awareness of surgical outcomes prompted us to change our technique for connecting the bladder to the urethra during robot-assisted surgery to remove the prostate in patients with prostate cancer. These changes resulted in significant improvements in surgical outcomes.

In the PURE-01 study, patients with muscle-invasive bladder cancer (MIBC) who achieved a pathological complete response (CR; ypT0N0) had tumor features suggesting that pre-existing immunity may promote response. We focused on fibroblast growth factor receptor-3 (FGFR3) genomic alterations (GAs) as potential tumor resistance features. The primary endpoint of our study was CR. FGFR3 GAs were assessed via comprehensive genomic profiling of sequenced DNA (N = 112), a transcriptome-based FGFR3 activity signature, an FGFR3 subtyping model based on long noncoding RNA (lncRNA), and gene expression profiling (N = 84 for all three). We used Wilcoxon rank-sum tests, Fisher's exact test, and logistic regression analyses to analyze the associations between the various FGFR3 alterations and CR. High FGFR3 activity was defined as a signature score that was higher than the median value. Cases that were positive for lncRNA-FGFR3 subtype (lncRNA-FGFR3 active, N = 11) had consistent biology with published data: low epithelial-mesenchymal transition and immune-signature scores, high p53 activity, FGFR3 activity, and sonic hedgehog activity. In total, 17 (15.2%), 42 (50%), and 11 patients (13%) showed FGFR3 GAs or high FGFR3 signature scores, or had lncRNA-FGFR3–active tumors. Despite an association of high FGFR3 gene expression with a lower CR rate (p = 0.01), we did not find a correlation between FGFR3 activity or mutation/fusion and CR (p = 0.2 and p = 0.8). We conclude that the association of FGFR3 expression with pathological response is balanced by multiple factors. Overall, FGFR3-altered tumors should not be excluded from neoadjuvant immunotherapy studies at this time. Patient summary In patients with muscle-invasive bladder cancer treated within the PURE-01 trial, we analyzed the role of fibroblast growth factor receptor-3 (FGFR3) alterations, at the DNA and RNA levels, in association with the pathological response. We did not find any robust association, mainly when analyzing the landscape of alterations defining tumors with higher biological FGFR activity. Overall, FGFR3 activity and gene alterations did not provide sufficiently robust data to exclude patients whose tumors harbor these alterations from neoadjuvant immunotherapy trials.

Presently, major guidelines do not provide specific recommendations on oncologic surveillance for patients who harbor variant histology (VH) bladder cancer (BCa) at radical cystectomy. We aimed to create a personalized followup scheme that dynamically weighs other cause mortality (OCM) vs the risk of recurrence for VH BCa, and to compare it with a similar one for pure urothelial carcinoma (pUC).Within a multi-institutional registry, 528 and 1,894 patients with VH BCa and pUC, respectively, were identified. The Weibull regression was used to detect the time points after which the risk of OCM exceeded the risk of recurrence during followup. The risk of OCM over time was stratified based on age and comorbidities, and the risk of recurrence on pathological stage and recurrence site.Individuals with VH had a higher risk of recurrence (recurrence-free survival 30% vs 51% at 10 years, p0.001) and shorter median time to recurrence (88 vs 123 months, p0.01) relative to pUC. Among VH, micropapillary variant conferred the greatest risk of recurrence on the abdomen and lungs, and mixed variants carried the greatest risk of metastasizing to bones and other sites compared to pUC. Overall, surveillance should be continued for a longer time for individuals with VH BCa. Notably, patients younger than 60 years with VH and pT0/Ta/T1/N0 at radical cystectomy should continue oncologic surveillance after 10 years vs 6.5 years for pUC individuals.VH BCa is associated with greater recurrence risk than pUC. A followup scheme that is valid for pUC should not be applied to individuals with VH. Herein, we present a personalized approach for surveillance that may allow an improved shared decision.

Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by 18[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes. Background: Data regarding the incidence and prognostic impact of immune-related imaging changes, assessed by 18[F] fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) scan, in patients receiving immune-checkpoint inhibitors (ICIs) are lacking. We relied on the population of patients enrolled in the PURE-01 study to evaluate such changes. Objective: To evaluate the role of PET/CT to visualize the immune-related adverse events (irAEs) following pembrolizumab. Design, setting, and participants: From February 2017 to August 2019, in 103 patients with nonmetastatic, clinical T2–4aN0M0 bladder cancer, PET/CT scan was performed before and after neoadjuvant pembrolizumab (N = 206 scans), before radical cystectomy. Intervention: PET/CT before and after neoadjuvant pembrolizumab, before radical cystectomy. Outcome measurements and statistical analysis: We analyzed the occurrence of irAEs, evaluated according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, against the development of inflammatory FDG uptake described at PET/CT (irAEs + PET/CT). Logistic regression analyses evaluated the association between irAEs + PET/CT and the pathological response to pembrolizumab. Kaplan-Meier curves tested their association with progression-free survival (PFS) after pembrolizumab and radical cystectomy. Results and limitations: Forty patients (39%) developed irAEs + PET/CT in several target organs. The most frequent target organs were the thyroid (N = 18), stomach (N = 14), mediastinal lymph nodes (N = 9), and lung (N = 5). These changes were clinically evident in 18 (45%) and were not associated with the pathological response, neither in terms of complete response (ypT0N0, p = 0.07) nor as downstaging to ypT≤1N0 disease (p = 0.1), although ypT0N0 responses were numerically more frequent in patients with irAEs+ PET/CT (47.5% vs 32%). Furthermore, irAE+ PET/CT events were associated with longer, not statistically significant, 24-mo PFS: 88.3% versus 76.5% (p = 0.5). Our results warrant further validation in larger datasets. Conclusions: We presented unique surrogate data of PET/CT that could help improve our understanding of nonclinically evident effects of ICI administration, especially in patients at the early disease stage. Patient summary: We evaluated the utility of PET/CT to visualize the occurrence of inflammatory changes after pembrolizumab in patients with localized bladder cancer without metastases. After immunotherapy, 39% of the patients developed 18[F] fluorodeoxyglucose uptake consistent of inflammatory changes. Overall, our data improve our knowledge on the effects induced by immunotherapy, which may have a clinical impact at longer follow-up. Take Home Message ● In the PURE-01 study, T2–4N0M0 muscle-invasive bladder cancer patients were staged with fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) before and after pembrolizumab. ● PET/CT after pembrolizumab revealed inflammatory FDG uptake in 39% of patients, but only 45% of these cases of uptake corresponded to clinically evident adverse events. ● The development of inflammatory uptake was associated with a higher pathological complete response rate and longer progression-free survival, although these differences were not statistically significant.

Objectives Lymph node invasion (LNI) is related to long-term survival in patients with muscle-invasive bladder cancer. However, in the case of variant histology (VH), data on pelvic lymph node dissection (PLND) and LNI are sparse. We described the pattern of care of PLND in patients with VHs of bladder cancer, exploring predictors of LNI. Methods Using the 2001–2016 SEER registry, 20 767 bladder cancer patients who underwent PLND were identified. Included histological variants were pure urothelial carcinoma (UC), micropapillary UC, sarcomatoid UC, lymphoepithelioma-like UC, adenocarcinoma, sarcoma, giant and spindle cell carcinoma, squamous cell carcinoma (SCC), and neuroendocrine tumor. Uni- and multivariable logistic regression analyses tested for LNI predictors. Cox regression was used to test for predictors of overall mortality (OM) among both LNI positive and LNI negative patients. Results Overall, 2464 (11.9%) harbored a VH. On multivariate analysis, only micropapillary UC was associated with higher risk (OR = 3.39) of LNI. This association was maintained when only the subset of patients treated without perioperative chemotherapy were analyzed (OR = 3.30). Similarly, higher T stage (T2 stage OR = 2.24; T3–4 stage OR = 9.44) and the use of chemotherapy (OR = 2.29) were associated with a higher risk of LNI. Among patients with LNI (5299, 25.5%), SCC (HR = 1.87), T3–4 stage (HR = 1.94), age at diagnosis (HR = 1.01) and geographic region (south) (HR = 1.22) were predictors of higher risk of OM. Conversely, chemotherapy (HR = 0.69) and number of removed LN (HR = −0.99) were associated with lower risk of OM. Finally, in a subgroup of patients without LNI, sarcomatoid UC (HR = 1.58) and giant and spindle cell carcinoma (HR = 1.83) were the only VH predictors of OM. Conclusions We described different patterns of care in patients with VHs of bladder cancer. Micropapillary UC was an independent risk factor for LNI. Among patients harboring LNI, those with SCC VH had higher OM compared to pure UC. Conversely, sarcomatoid UC and giant and spindle cell carcinoma were predictors of OM in patients without nodal involvement.

BackgroundIn the PURE-01 study (NCT02736266), we aimed to evaluate the ability to predict the pathologic complete response (pT0N0) after pembrolizumab by using clinical and tumor biomarkers.MethodsIn an open-label, single-arm, phase 2 study, 3 courses of 200 mg pembrolizumab preceding radical cystectomy were administered in patients with T2-4aN0M0 muscle-invasive bladder cancer. The analyses included a comprehensive genomic profiling and programmed cell-death-ligand-1 (PD-L1)–combined positive score assessment (CPS; Dako 22C3 antibody) of pre- and posttherapy samples. Multivariable logistic regression analyses evaluated baseline clinical T stage and tumor biomarkers in association with pT0N0 response. Corresponding coefficients were used to develop a calculator of pT0N0 response based on the tumor mutational burden (TMB), CPS, and the clinical T stage. Decision-curve analysis was also performed. All statistical tests were 2-sided.ResultsFrom February 2017 to June 2019, 112 patients with biomarker data were enrolled (105 with complete TMB and CPS data). Increasing TMB and CPS values featured a linear association with logistic pT0N0 probabilities (P = .02 and P = .004, respectively). For low TMB values (≤11 mut/Mb, median value, n = 53), pT0N0 probability was not associated with increasing CPS. Conversely, for high TMB values (>11 mut/Mb, n = 52), pT0N0 was statistically significantly associated with higher CPS (P = .004). The C index of the pT0N0 probability calculator was 0.77. On decision-curve analysis, the net benefit of the model was higher than the “treat-all” option within the clinically meaningful threshold probabilities of 40%-50%.ConclusionsThe study presents a composite biomarker-based pT0N0 probability calculator that reveals the complex interplay between TMB and CPS, added to the clinical T stage.

Background: In the PURE-01 study, pembrolizumab was given preoperatively before radical cystectomy in clinical T2-4aN0M0 patients. An accurate clinical response assessment may be useful for developing new perioperative strategies in these patients. Objective: To evaluate the association between bladder multiparametric magnetic resonance imaging (mpMRI) findings after pembrolizumab and the pathological complete response (CR; pT0). Design, setting, and participants: Patients were staged using bladder mpMRI whereby radiologists were asked to characterize the following parameters: residual disease at T1- and T2-weighted images (step 1: yes/no), presence of hyperintense spots within the bladder wall on diffusion-weighted imaging (step 2: yes/no), and presence of pathological contrast enhancement (step 3: yes/no), before and after three cycles of pembrolizumab. Examinations were internally assessed by two senior radiologists and externally evaluated by a third senior radiologist. Intervention: To evaluate bladder tumor response after neoadjuvant pembrolizumab, mpMRI was used. Outcome measurements and statistical analysis: The primary objective was to predict the pT0 after neoadjuvant pembrolizumab by relying on the mpMRI findings. Cohen's kappa statistics was used to assess interobserver variability. Univariable analyses for pT0 were performed including internal and external post-therapy mpMRI steps. Results and limitations: From February 2017 to October 2018, 82 patients (164 total mpMRI assessments) were analyzed. The agreement between the internal and external mpMRI assessments after therapy was acceptable (κ values ranging from 0.5 to 0.76). Each mpMRI step was significantly associated with pT0 in both internal and external assessments. In patients with CR/no evidence of residual disease (NED) in all internally evaluated mpMRI steps (N = 37), the pT0 was seen in 23 (62%), compared with 19 of 26 externally evaluated NED patients (73%). Conclusions: In post-pembrolizumab muscle-invasive bladder cancer, mpMRI sequence assessment had acceptable interobserver variability and represented the basis for the proposal of a radiological CR/NED status definition predicting the pT0 response to pembrolizumab. After validation of these findings with external datasets, we propose this tool for developing bladder-sparing immunotherapy maintenance therapies. Patient summary: Assessment of the extent of disease in patients with muscle-invasive bladder cancer using conventional imaging yields serious limitations. In the PURE-01 study, we evaluated the potential of bladder multiparametric magnetic resonance imaging (MRI) to predict the pathological complete response to neoadjuvant pembrolizumab. After validation with larger datasets, the proposed stepwise assessment incorporating multiparametric MRI sequences will be used at our center to develop bladder-sparing approaches in future studies. • In the PURE-01 study, multiparametric magnetic resonance imaging (mpMRI) of the bladder was used to stage and evaluate the response to pembrolizumab, before radical cystectomy. • Assessments of mpMRI sequence were externally reviewed, showing preliminary but promising reproducibility. • We proposed an mpMRI-based definition of complete response predicting the pathological complete response to pembrolizumab that was externally replicated.

Purpose: To assess the impact of perioperative chemotherapy on survival in cN+ BCa patients and analyze it according to the pN status. Methods: A retrospective analysis was conducted on639 BCa patients with cTanyN1-3M0 BCa treated with radical cystectomy (RC) and bilateral lymph node dissection (LND) with or without perioperative chemotherapy in ten tertiary referral centers from 1990 to 2017. Selected cN+ patients received induction chemotherapy (IC), whereas adjuvant chemotherapy (ACT) was delivered to selected pN+ patients. Univariable and multivariable Cox regression analyses were used to predict overall mortality (OM) after surgery, adjusting for clinicopathological confounders. Kaplan–Meier analyses assessed OM according to the treatment modality. Results: Overall, 356 (56%) patients were treated with surgery alone, 155 (24%) with IC followed by surgery, and 128 (20%) with ACT following surgery. Over a median follow-up of 25months, 316 deaths were recorded. At univariable analysis, patients treated with IC and surgery had lower OM both considering cN+ [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49–0.87, p = 0.004] and cN+pN− patients (HR 0.61, 95% CI 0.37–0.99, p = 0.05) compared to those treated with surgery alone. cN+pN+ patients treated with ACT experienced lower OM compared to those treated with IC or surgery alone at multivariable analysis (HR 0.40, 95% CI 0.22–0.74, p = 0.003). Conclusion: Patients with cTany cN+ cM0 BCa benefit more in terms of OS when treated with IC followed by RC + LND compared to RC + LND alone, regardless of LNMs at final histopathology examination. More data are needed to assess the role of ACT in the management of cN+ patients.

Background and Objectives: To investigate other-cause mortality (OCM) rates over time according to several baseline characteristics in bladder cancer (BCa) patients treated with radical cystectomy (RC). Methods: Within the Surveillance, Epidemiology, and End Results database (1988-2011), we identified 7702 T1-2N0M0 urothelial BCa patients treated with RC. Temporal trends and multivariable Cox regression (MCR) analyses assessed 5-year OCM. Data were stratified according to the year of diagnosis (1988-1995 vs 1996-2000 vs 2001-2004 vs 2005-2008 vs 2009-2011), age group (75 years), sex, race, marital status, and socioeconomic status. Results: Overall, OCM rates decreased from 13.9% in 1988-1995 to 8.6% in 2009-2011. The greatest decrease was recorded in elderly (>75) patients (32%-16%, slope: −0.55% per year; P =.01), followed by patients aged 60 to 75 (21%-5%, slope: −0.35% per year; P =.01), unmarried patients (16%-10%, slope: −0.26% per year; P

Background Patients with predominant variant histology (VH) of bladder tumors, defined as involving >50 % of the tumor specimens, are typically excluded from clinical trials, and for these patients, the efficacy of standard chemotherapy is limited. Objective To evaluate the activity of preoperative pembrolizumab in patients with muscle-invasive bladder carcinoma (MIBC) and VH, enrolled in PURE-01 study (NCT02736266). Design, setting, and participants In the open-label, single-arm, phase 2 PURE-01 study, three courses of 200 mg pembrolizumab preceding radical cystectomy (RC) were administered in T2-4aN0M0 MIBC patients. The amended study design included patients with predominant VH. Intervention Neoadjuvant pembrolizumab and RC. Outcome measurements and statistical analysis Pathological complete response (pT0) in intention-to-treat population was the primary endpoint. Biomarker analyses included programmed cell-death ligand-1 (PD-L1) expression using the combined positive score (CPS; Dako 22C3 antibody) and comprehensive genomic profiling (FoundationOne assay). Multivariable logistic regression analyses (MVAs) evaluated the histological category (predominant VH vs nonpredominant VH vs pure urothelial carcinoma), tumor mutational burden (TMB) and CPS in association with the pathological response. Results and limitations From February 2017 to June 2019, 114 patients were enrolled; 34 (30%) of them presented with VH, including 19 (17%) with predominant VH. In total, the pT0 rate was 37% (95% confidence interval [CI]: 28–46) and the pT ≤ 1 rate was 55% (95% CI: 46–65). The majority of predominant VH patients presented with squamous-cell carcinoma (SCC; N = 7), and six of seven (86%) had downstaging to pT ≤ 1, with one pT0; two of three lymphoepithelioma-like (LEL) variants had a pT0 response. None of the remaining nine predominant VHs had a response. On MVA, TMB and CPS were associated with both the pT0 and the pT ≤ 1 response, regardless of tumor histology. Conclusions The updated PURE-01 results confirm the activity of neoadjuvant pembrolizumab in MIBC. Patients with SCC and LEL features may be suitable for neoadjuvant immunotherapy trials. CPS and TMB are the key response predictors irrespective of the histological subtypes. Patient summary In the PURE-01 study, we have preliminarily evaluated the activity of neoadjuvant pembrolizumab in patients with predominant variant histology (VH). Of these patients, those harboring squamous-cell carcinoma or a lymphoepithelioma-like variant feature had major, although preliminary, pathological responses compared with those with other predominant VHs. Expression of programmed cell-death ligand-1 and tumor mutational burden may predict the pathological response to pembrolizumab, and provide a rationale for selecting patients according to these features instead of the histological bladder cancer subtypes.

Background and objectives To examine the effect of conditional survival on 5-year cancer-specific survival (CSS) probability after radical nephroureterectomy (RNU) in a contemporary cohort of patients with non-metastatic urothelial carcinoma of the upper urinary tract (UTUC). Methods Within the Surveillance, Epidemiology and End Results database (2004-2015), 6826 patients were identified. Conditional 5-year CSS estimates were assessed after event-free follow-up duration. Multivariable Cox regression (MCR) models predicted cancer-specific mortality (CSM) according to event-free follow-up length. Results Overall, 956 (14.0%) were T1 low grade(LG)N0 , 1305 (19.1%) T1 high grade(HG)N0 , 1215 (17.8%) T2 N0 , 2249 (32.9%) T3 N0 and 1101 (16.1%) T4 N0 /Tany N1-3 . From baseline, 93.4% to 94.2% in T1 LGN0 provided 5-year CSS and, respectively, 86.2% to 95.3% in T1 HGN0 , 77.5% to 87.8% in T2 N0 , 63.0% to 91.1% in T3 N0 , and 38.8% to 88.2% in T4 N0 /Tany N1-3 . In MCR models, relative to T1 LGN0 , T1 HGN0 (Hazard ratio [HR] 1.7), T2 N0 (HR 3.0), T3 N0 (HR: 5.2), and T4 N0 /Tany N1-3 (HR 11.9) were independent predictors of higher CSM. Conditional HRs decreased to levels equivalent to T1 LGN0 at 3 years vs 5 years of event-free survival for T1 HGN0 and all other groups, respectively. Conclusions A direct relationship exists between event-free follow-up and survival probability after RNU. From a clinical perspective, such survival estimates may have particular importance during preoperative counseling.

Background: The PURE-01 study (NCT02736266) evaluated the use of pembrolizumab before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). Objective: To evaluate the ability of molecular signatures to predict the pathological complete response (CR: ypT0N0) and progression-free survival (PFS) after pembrolizumab and RC. Design, setting, and participants: We analyzed the expression data from patients with T2–4aN0M0 MIBC enrolled in the PURE-01 study (N = 84) and from patients of a retrospective multicenter cohort treated with cisplatin-based neoadjuvant chemotherapy (NAC; N = 140). Intervention: Neoadjuvant pembrolizumab or NAC and RC. Outcome measurements and statistical analysis: Immune signatures and molecular subtyping (The Cancer Genome Atlas, consensus model, and genomic subtyping classifier [GSC]) were evaluated in relation to CR and PFS. Multivariable logistic regression analyses for CR were used, adjusting for gender and clinical T stage. Results and limitations: The Immune190 signature was significant for CR on multivariable logistic regression analyses (p = 0.02) in PURE-01, but not in the NAC cohort (p = 0.7). Hallmark signatures for interferon gamma (IFNγ; p = 0.004) and IFNα response (p = 0.006) were also associated with CR for PURE-01, but not for NAC (IFNγ: p = 0.9 and IFNα: p = 0.8). In PURE-01, 93% of patients with the highest Immune190 scores (>1st quartile) had 2-yr PFS versus 79% of those with lower scores; no difference was observed in NAC patients, as well as for the other hallmarks in both groups. The neuroendocrine-like subtype had the worst 2-yr PFS in all three subtyping models (33%) and the GSC claudin-low subtype had the best, with no recurrences in 2 yr. Basal subtypes (across classifications) with higher Immune190 scores showed 100% 2-yr PFS after pembrolizumab therapy (p = 0.04, compared with basal-Immune190 low). Statistical analyses are limited by the small number of events and short follow-up. Conclusions: Higher RNA-based immune signature scores were significantly associated with CR and numerically improved PFS outcomes after pembrolizumab, but not after NAC. These data emphasize that RNA profiling is a potential tool for personalizing neoadjuvant therapy selection. Patient summary: We used gene expression profiling to evaluate the association between immune gene expression and response to neoadjuvant immunotherapy, compared with standard chemotherapy, in patients with muscle-invasive bladder cancer (MIBC). We found a significant association between immune gene expression and response to pembrolizumab, but not chemotherapy. We conclude that gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC. By using gene expression profiling of transurethral bladder tumor resection samples from patients with muscle-invasive bladder cancer (MIBC), we reported a significant association between pre-existing immune gene expression and response to neoadjuvant pembrolizumab, but not to neoadjuvant chemotherapy. Different outcomes were also obtained according to the molecular subtype. Gene expression profiling has the potential to guide personalized neoadjuvant therapy in MIBC.

Background: Use of inpatient palliative care (IPC) in the treatment of advanced cancer represents a well-established guideline recommendation. A recent analysis showed that patients with genitourinary cancer benefit from IPC at the second lowest rate among 4 examined primary cancers, namely lung, breast, colorectal, and genitourinary. Based on this observation, temporal trends and predictors of IPC use were examined in patients with metastatic urothelial carcinoma of the bladder (mUCB) receiving critical care therapies (CCTs). Patients and Methods: Patients with mUCB receiving CCTs were identified within the Nationwide Inpatient Sample database (2004–2015). IPC use rates were evaluated in estimated annual percentage change (EAPC) analyses. Multivariable logistic regression models with adjustment for clustering at the hospital level were used. Results: Of 1,944 patients with mUCB receiving CCTs, 191 (9.8%) received IPC. From 2004 through 2015, IPC use increased from 0.7% to 25.0%, respectively (EAPC, +23.9%; PPPP=.02) were associated with higher IPC rates. Conversely, Hispanic race (OR, 0.42; P=.03) and being hospitalized in the Northeast (OR, 0.36; P=.01) were associated with lower rate of IPC adoption. Finally, patients with a primary admission diagnosis that consisted of infection (OR, 2.05; P=.002), cardiovascular disorders (OR, 2.10; P=.03), or pulmonary disorders (OR, 2.81; P=.005) were more likely to receive IPC. Conclusions: The rate of IPC use in patients with mUCB receiving CCTs sharply increased between 2004 and 2015. The presence of liver metastases, infections, or cardiopulmonary disorders as admission diagnoses represented independent predictors of higher IPC use. Conversely, Hispanic race, nonteaching hospital status, and hospitalization in the Midwest were identified as independent predictors of lower IPC use and represent targets for efforts to improve IPC delivery in patients with mUCB receiving CCT.

INTRODUCTION AND OBJECTIVE:Immunotherapy (IO) by immune checkpoint inhibitors (ICIs) is effective in metastatic urothelial carcinoma (UC) and showed promising activity in muscle-invasive and non-mu...

INTRODUCTION AND OBJECTIVE:The ligation of the dorsal venous complex (DVC) and the approach to the prostatic apex represent crucial steps of robot-assisted radical prostatectomy (RARP) which may af...

INTRODUCTION AND OBJECTIVE:Cytoreductive radical prostatectomy (cRP) might be an option in oligometastatic prostate cancer (PCa). However, no preoperative risk tool is available to select candidate...

Objectives: Adjuvant chemotherapy (ACT) is recommended for non-organ-confined bladder cancer (BCa) after radical cystectomy (RC) and pelvic lymph node dissection (PLND), but there are sparse data regarding its specific efficacy in patients with histological variants. The aim of our study was to evaluate the role of ACT on survival outcomes in patients with variant histology in a large multicenter cohort. Materials and methods: We retrospectively evaluated data of 3963 patients with BCa treated with RC and bilateral PLND with curative intent at several institutions between 1999 and 2018. The histological type was classified into six groups: pure urothelial carcinoma (PUC) or squamous, sarcomatoid, micropapillary, glandular and neuroendocrine differentiation. Multivariable competing risk analysis was applied to assess the role of ACT on recurrence and cancer-specific mortality (CSM) in each histological subtype. Results: Of the 3963 patients included in the study, 23% had variant histology at RC specimen and 723 (18%) patients received ACT. ACT was found to be significantly associated with reduced risk of recurrence (sub-hazard ratio [SHR]: 0.55, confidence interval [CI] 0.42–0.71, p < 0.001) and CSM (SHR: 0.58, CI 0.44–0.78, p < 0.001) in the PUC only, while no histological subtype received a significant benefit on survival outcomes (all p > 0.05) from administration of ACT. The limitation of the study includes the retrospective design, the lack of a central pathology review and the number of ACT cycles. Conclusion: In our study, the administration of ACT was associated with improved survival outcomes in PUC only. No histological subtype found a benefit in overall recurrence and CSM from ACT.

Introduction: the Italian Radical Cystectomy Registry (RIC) is an observational prospective study aiming to understand clinical variables and patient characteristics associated with short- and long-term outcomes among bladder cancer (BC) patients undergoing radical cystectomy (RC). Moreover, it compares the effectiveness of three RC techniques - open, robotic, and laparoscopic.Methods: from 2017 to 2020, 1400 patients were enrolled at one of the 28 centers across Italy. Patient characteristics, as well as preoperative, postoperative, and follow-up (3, 6, 12, and 24 months) clinical variables and outcomes were collected. Results: preoperatively, it was found that patients undergoing robotic procedures were younger (pConclusion: the present study summarizes the characteristic of patients included in the RIC. Future results will provide invaluable information about outcomes among BC patients undergoing RC. This will inform physicians about the best techniques and course of care based on patient clinical factors and characteristics.

Background Analyzing the relationship between perioperative outcomes and age in urothelial carcinoma of the bladder (UCB) patients treated with radical cystectomy (RC) in a continuous fashion may provide detailed information on the increased risk of complications in older patients, even after accounting for different comorbidity profiles. Given the limited data available in the literature, we tested these relationships within a large scale, population-based database. Materials and Methods Within the NIS database (2003–2015), we identified patients who underwent RC for UCB. Multivariable logistic regression (MLoR) and Poisson regression (MPR) models were used after adjustment for clustering and stratification for comorbidity profiles. Results Overall, 20,144 patients underwent RC with a median age of 70 years (interquartile range: 62–77). In MLoR models, continuously coded age represented an independent predictor of overall (odds ratio [OR]: 1.008, 95%-confidence interval [CI]: 1.005–1.012), cardiac (OR: 1.042, 95%-CI: 1.035–1.049), vascular (OR: 1.024, 95%-CI: 1.014–1.034), respiratory (OR: 1.016, 95%-CI 1.009–1.022), miscellaneous medical (OR: 1.013, 95%-CI: 1.009–1.017), infectious (OR: 1.012, 95%-CI 1.004–1.019), transfusions (OR: 1.011, 95%-CI 1.007–1.015) and bowel obstruction (OR: 1.009, 95%-CI 1.004–1.013) complications, and in-hospital mortality (OR: 1.057, 95%-CI 1.039–1.075). Conversely, patients age did not predict intraoperative (p = 0.7), genitourinary (p = 0.9), operative wound (p = 0.2) and miscellaneous surgical complications (p = 0.1). In MPR models, patients age predicted longer LOS (relative risk [RR]: 1.002, 95%-CI 1.001–1.003). Finally, a decreasing effect of age was observed in patients low vs high comorbidity burden for cardiac, respiratory and overall complications. Conclusions Most of early postoperative RC complications are related to patients age, but its impact varies according to comorbidity profile. Further studies are needed to validate our findings that may be then considered for individual counselling and informed consent, as well as for health expenditure planning.

OBJECTIVE To examine the incidence and time trends of secondary bladder cancer (BCa) and rectal cancer (RCa) after brachytherapy (BT) relative to radical prostatectomy (RP). MATERIALS AND METHODS Within the Surveillance, Epidemiology and End Results (SEER) database (1988-2015), we identified patients with localized PCa as an only or first primary cancer, who underwent BT or RP. Cumulative incidence plots and multivariable competing-risks regression (CRR) models were used. Sensitivity analyses focused on patients' age and year of diagnosis intervals and tested the effect of an unmeasured confounder. RESULTS Of 318 058 patients with localized prostate cancer (PCa), 55 566 (18.4%) underwent BT. After propensity score-matching, 20-year secondary BCa incidence was 6.0% in patients who had undergone BT vs 2.4% in those who had undergone RP (P CONCLUSIONS: Brachytherapy predominantly increases the risk of secondary BCa and, to a lesser extent, that of RCa. Follow-up of such patients is therefore required. It is encouraging that both secondary BCa, and RCa rates, in particular, have recently decreased, RCa.

Background: Patients with organ confined muscle-invasive bladder cancer (MIBC) who are candidates for radical cystectomy (RC) should receive neoadjuvant chemotherapy (CHT). However, the most contemporary CHT use rates indicate low adherence to these guidelines. We tested contemporary neoadjuvant CHT rates and associated cancer-specific mortality (CSM) and overall mortality (OM) in pT2N0 MIBC patients treated with RC. Materials and methods: Within the SEER database (2004–2015), we identified patients with pT2N0 MIBC patients who underwent RC. CHT administration rates were evaluated using estimated annual percentage changes (EAPCs) analyses. After inverse probability of treatment weighting (IPTW), Kaplan–Meier (KM) analyses and Cox regression models (CRMs) were used to test the effect of CHT vs no CHT on survival. Landmark analyses tested for immortal time bias. Results: Of 3978 RC patients, 38.2% of patients received CHT. Between 2004 and 2015, CHT rates increased from 15.9% to 66.2% (EAPC: +14.2%; p < 0.001). IPTW-adjusted KM showed 10-year CSM-free survival rates of 78.9% for CHT vs 76.7% for no CHT patients (p = 0.6). Similarly, IPTW-adjusted KM showed 10-year OM-free survival rates of 54.6% for CHT vs 57.9% for no CHT patients (p = 0.8). In IPTW-adjusted MCRMs, CHT was not significantly associated with lower CSM (HR 0.97, CI 0.82–1.14; p = 0.7) or OM (HR 1.02, CI 0.90–1.16; p = 0.7). Virtually the same CSM and OM rates were recorded after landmark analyses. Conclusions: CHT use in pT2N0 MIBC RC patients sharply increased over the study span. However, neoadjuvant CHT was not associated with better survival in this patient group.

Introduction The standard of care for intermediate- and high-risk non-muscle invasive bladder cancer (NMIBC) patients is transurethral resection of bladder tumor followed by intravesical adjuvant immunotherapy with Bacillus Calmette-Guerin (BCG). However, a non-negligible portion of patients is doomed to fail BCG-therapy and, consequently, undergo radical cystectomy as only treatment option available. In this context, effective options to improve tumor response, thus delaying or even avoiding radical cystectomy, are urgently needed. A narrative review of the literature was performed to summarize the rationale and the clinical outcomes regarding the use of immunotherapy and novel therapeutic perspectives both for BCG-treated and BCG-naive NMIBC patients. Results Several clinical trials are currently investigating immune checkpoint inhibitors and novel targeted approaches, including cancer vaccines, for NMIBC patients with BCG-naive and BCG-unresponsive disease. Despite the lack of long-term safety data, novel therapeutic options, both by systemic and intravesical delivery, demonstrated a good tolerability, antitumor efficacy, and low rates of recurrence and/or progression to muscle-invasive disease. Conclusions Although clinical data available are mostly limited to phase I/II trials, novel targeted therapies have raised as an effective and reliable approach for patients failing BCG and for those who are therapy naive. Phase III trials will be crucial in order to change the current clinical practice, after many years in which BCG was the only therapy available for intermediate- and high-risk NMIBC patients.

OBJECTIVES To evaluate outcomes of patients achieving a post-treatment pathological stage of

Background: The increased awareness regarding the sex gap in bladder cancer (BCa) care over the last decade may have resulted in more timely-wise referral patterns and treatment of female patients with BCa. Thus, we tested the association of sex with disease stage at presentation, as well as with cancer-specific mortality (CSM) after radical cystectomy (RC) in a contemporary cohort of patients with nonmetastatic urothelial bladder cancer (UCUB). Methods: Within the Surveillance, Epidemiology, and End Results database (2004–2016), we identified 14,086 patients (10,879 men and 3,207 women) treated with RC for non-metastatic UCUB. Temporal trend, interaction analyses, logistic regression, cumulative incidence, and competing-risks regression analyses were used. Results: Overall, 10,879 (77.2%) men and 3,207 (22.8%) women underwent RC between 2004 and 2016. Female gender was an independent predictor of non-organ-confined (NOC) UCUB at RC in multivariable analyses (odds ratio: 1.23; 95% confidence intervals [CI] 1.10–1.38; P < 0.001). While NOC rates in men decreased over time (from 54.8% to 45.7%; P < 0.01), NOC rates in women remained stationary (from 60.6% to 57.3%; P = 0.15) and the excess NOC rate between men and women increased from + 5.8% in 2004 to +11.6% in 2016. Moreover, in multivariable analyses adjusted for other covariates, female gender was an independent predictor of higher CSM after RC in NOC UCUB (HR: 1.14; 95%CI 1.04–1.24; P < 0.01), but not in localized UCUB (P = 0.06). Conclusion: It is worrisome that, while in men the rate of NOC is decreasing, NOC rates in females have not improved over time. Moreover, it is also worrisome that, despite adjustment for both pathological tumor and patient characteristics, female sex remains an adverse prognostic factor for CSM. Reassessment of referral, diagnostic, and treatment patterns aimed at eliminating these sex discrepancies appears warranted.

In locally advanced and metastatic malignancies, antibiotic (ATB) therapy has a negative effect on immunotherapy efficacy. Therefore, we aimed to evaluate whether ATB therapy and use of specific ATB classes with concomitant neoadjuvant pembrolizumab affected pathologic complete response (ypT0N0) and relapse-free survival (RFS) for patients with clinical T2–4N0M0 bladder cancer enrolled in the PURE-01 study. Of the 149 patients evaluated, 48 (32%) received any concomitant ATB therapy. The ATB class most commonly administered was fluoroquinolones (16 patients; 33%). In the ATB cohort, seven patients (15%) achieved ypT0N0 status, compared to 50 (50%; p < 0.001) in the untreated group. Moreover, ATB use was negatively associated with ypT0N0 status (odds ratio 0.18, 95% confidence interval [CI] 0.05–0.48; p = 0.001). The 24-mo RFS rate was 63% (95% CI 48-83%) in the ATB group versus 90% (95% CI 83–97) in the untreated group. We found that ATB use was associated with a higher recurrence rate (hazard ratio [HR] 2.64, 95% CI 1.08–6.50; p = 0.03). Exploratory analyses showed that fluoroquinolone use was associated with a higher recurrence rate (HR 3.28, 95% CI 1.12–9.60; p = 0.03). Our study revealed an association between ATB use and neoadjuvant immunotherapy efficacy in an intention-to-cure population, highlighting the need for future studies to better investigate this relationship. Patient summary: The efficacy of immunotherapy for cancer is influenced by several patient and tumor factors, including the use of antibiotics. We found that antibiotics taken at the same time as immunotherapy drugs were associated with lower rates of complete response and of recurrence-free survival among patients with muscle-invasive bladder cancer. These findings need to be confirmed in future studies.

Background In patients with muscle-invasive urothelial bladder cancer (MIBC), molecular alterations in immunotherapy-resistant tumors found at radical cystectomy (RC) remain largely unstudied. Objective To investigate the biology of pembrolizumab-resistant tumors in comparison to an RC cohort treated without any systemic therapy and a cohort of neoadjuvant chemotherapy (NAC)-treated tumors. Design, setting, and participants Transcriptome-wide expression profiling was performed on 26 RC samples from patients with ypT2–4 disease after pembrolizumab treatment, of which 22 had matched pretherapy samples. Unsupervised consensus clustering (CC) was performed to compare 26 post-pembrolizumab samples with 94 RC samples without neoadjuvant treatment and 21 samples collected from the former tumor bed of NAC-treated patients (scar tissue). Clusters were investigated for their biological and clinical characteristics and were compared to a cohort of post-NAC tumors (n = 133). Outcome measurements and statistical analysis Patient and tumor characteristics were compared between subgroups using χ2 tests and two-sided Wilcoxon rank-sum tests. The primary endpoint was recurrence-free survival. Results and limitations Molecular subtyping of pre- and post-pembrolizumab samples revealed significant differences: only 36% of samples had a concordant subtype according to the consensus classifier. Unsupervised CC revealed three distinct post-pembrolizumab clusters (basal, luminal, and scar-like). A scar-like subtype was present in 50% of the post-pembrolizumab cases (n = 13) and expressed genes associated with wound healing/scarring. This subtype had higher luminal marker expression in the post-pembrolizumab setting compared to CC scar-like tumors from the other cohorts. Patients with the scar-like subtype showed favorable prognosis after systemic therapy, but not in the RC-only setting. The small numbers in each subgroup represents the major study limitation. Conclusions This study expands our understanding of the biology of pembrolizumab-resistant MIBC and provides a framework for defining molecular subtypes after treatment. The results further support the hypothesis that luminal-type tumors may be resistant to immunotherapy or that this treatment may select for, or induce, a luminal phenotype. Patient summary We carried out genetic analysis for bladder cancer tumors from patients who had received an immunotherapy agent called pembrolizumab and compared them to tumors treated with standard chemotherapy or just bladder removal. We found differences in gene expression between the treatment types and between tumor tissue from the same patient before and after treatment. These results may be helpful in personalizing therapy strategies for patients with bladder cancer.

The similar clinical behavior, overlapping therapeutic patterns, and several clinical trials addressing the neoadjuvant and first-line therapy settings for bladder cancer support the call for a more uniform definition of "locally advanced" disease. We highlight the diverse therapeutic opportunities that patients with locally advanced bladder cancer may receive at present. Multimodal management, and post-therapy surgery in particular, may still have a role in selected patients.

A 41-yr-old, otherwise healthy, premenopausal woman presented at our uro-oncology clinic with a diagnosis of muscle-invasive bladder cancer following a transurethral resection of the bladder performed at another center. After a thorough discussion with the patient, she was enrolled in the phase II PURE-01 trial (NCT02736266), testing three cycles of neoadjuvant pembrolizumab (200mg) every 3 wk before radical cystectomy. Before treatment, imaging studies were obtained as per the protocol using computed tomography (CT), [18F]fluorodeoxyglucose positron emission tomography/CT, and multiparametric magnetic resonance imaging of the bladder, defining a clinically localized T2N0M0 stage. As per the protocol, potential biomarkers were assessed, including PD-L1 expression (84% combined positive score), tumor mutational burden (16.67 mut/Mb), and genomic profiling (FoundationONE assay; somatic mutation in TP53, EZH2, APC, TERT, CDKN1A, CDKN1B, and ARID1A genes, and truncation in BRCA2 gene). After immunotherapy, the patient underwent a robot-assisted radical cystectomy with extended pelvic lymph node dissection. The final pathology report revealed absence of residual disease (ie, pathological complete response, ypT0ypN0). During follow-up, the only relevant and permanent immune-mediated adverse event was hypothyroidism secondary to an autoimmune thyroiditis. It appeared 2 mo after radical cystectomy and it was managed successfully with hormonal replacement therapy. Two years after treatment, the patient is asymptomatic and free from disease recurrence. PATIENT SUMMARY: Increasing evidence suggests that frontline neoadjuvant immunotherapy may be beneficial for patients diagnosed with non-locally advanced, muscle-invasive bladder cancer (cT2N0), with fewer drawbacks than traditional chemotherapy. Although further studies are needed in support, this vision opens the opportunity for future clinical trials testing the potential incremental benefits of immunotherapy and the utility of novel biomarker- and imaging-based strategies to assess response to therapy.

Background Initial studies of preoperative checkpoint inhibition before radical cystectomy (RC) have shown promising pathologic complete responses. We aimed to analyze the survival outcomes of patients enrolled in the PURE-01 study ( NCT02736266 ). Patients and methods We report the results of the secondary end points of PURE-01 in the final population of 143 patients. In particular, we report the event-free survival (EFS) outcomes, defined as the time from the first cycle of pembrolizumab to radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy (NAC), recurrence after RC, or death from any cause. Other end points were recurrence-free survival (RFS) and overall survival (OS). Subgroup analyses were carried out, including pathological response category, clinical complete responses (CR) assessed via multiparametric magnetic resonance imaging (mpMRI), and molecular subtyping. Cox regression analyses for EFS were also carried out. Results After a median [interquartile range (IQR)] follow-up of 23 (15-29) months, 12- and 24-month EFS were 84.5% [95% confidence interval (CI): 78.5-90.9] and 71.7% (62.7-82). The prognosis was favorable across all the different pathological response subgroups, with the exception of ypN+ (N = 21), showing a 24-month RFS (95% CI) of 39.3% (19.2% to 80.5%). A statistically significant EFS benefit was observed in patients with a clinical CR (P = 0.002). Programmed cell-death-ligand-1 combined positive score was significantly associated with longer EFS in multivariable analyses. Four patients refused RC after clinical evidence of CR, and none of them have recurred after a median follow-up of 10 months (IQR: 11-15). The claudin-low subtype displayed a numerically longer EFS after pembrolizumab and RC compared with the other subtypes. Conclusions The EFS results from PURE-01 revealed that the immunotherapy effect was maintained post-RC in most patients. Pembrolizumab compared favorably with neoadjuvant chemotherapy, irrespective of the biomarker status. Molecular subtyping may be a useful tool to select the patients who are predicted to benefit the most from neoadjuvant pembrolizumab.

INTRODUCTION AND OBJECTIVE:The ligation of the dorsal venous complex (DVC) is a key step during robot-assisted radical prostatectomy (RARP) and it may affect urinary continence (UC) recovery. We hy...

INTRODUCTION AND OBJECTIVE:Neoadjuvant immunotherapy with three cycles of Pembrolizumab was associated with a complete response (pT0N0) of 41% and a partial (pT1N0 or less) of 54%. While biomarkers...

INTRODUCTION AND OBJECTIVE:PSMA PET/CT scan recently emerged as a promising tool in the re-staging of prostate cancer (PCa) patients who experienced biochemical recurrence (BCR) after radical prost...

INTRODUCTION AND OBJECTIVE:Cytoreductive radical prostatectomy (cRP) represents an option in oligo-metastatic prostate cancer (mPCa). However, the optimal multi-modal strategy of these men is unkno...