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Purpose: The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years. Patients and Methods: The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan–Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes. Results: After a median (interquartile range, IQR) follow-up of 39 (30–47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8–81.7] and 83.8% (95% CI, 77.8–90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6–100) for patients achieving a ypT0N0, 96.1% (95% CI, 89–100) for ypT1/a/isN0, 74.9% (95% CI, 60.2–93) for ypT2–4N0, and 58.3% (95% CI, 36.2–94.1) for ypTanyN1–3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events. Conclusions: At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.

Purpose:The PURE-01 study (NCT02736266) pioneered the neoadjuvant immune-checkpoint inhibitor (ICI) therapy before radical cystectomy (RC) in patients with muscle-invasive urothelial bladder carcinoma (MIBC). We herein present the survival outcomes after a median follow-up of three years.Patients and Methods:The intention-to-treat (ITT) population included 155 patients. Event-free survival (EFS) was defined as the time from pembrolizumab initiation until radiographic disease progression precluding RC, initiation of neoadjuvant chemotherapy, recurrence after RC, or death. Further outcomes were recurrence-free survival (RFS) post-RC and overall survival (OS). Multivariable Cox regression analyses for EFS were performed. Kaplan–Meier analyses compared EFS outcomes according with baseline programmed cell-death-ligand-1 (PD-L1) combined positive score (CPS) and according to the molecular subtypes.Results:After a median (interquartile range, IQR) follow-up of 39 (30–47) months, 36-month EFS and OS were 74.4% [95% confidence interval (CI), 67.8–81.7] and 83.8% (95% CI, 77.8–90.2) in the ITT population, respectively. Overall, 143 (92.3%) patients underwent RC. Within the cohort of patients who did not receive additional chemotherapy (N = 125), 36-month RFS was 96.3% (95% CI, 91.6–100) for patients achieving a ypT0N0, 96.1% (95% CI, 89–100) for ypT1/a/isN0, 74.9% (95% CI, 60.2–93) for ypT2–4N0, and 58.3% (95% CI, 36.2–94.1) for ypTanyN1–3 response. EFS was significantly stratified among PD-L1 tertiles (lower tertile: 59.7% vs. medium tertile: 76.7% vs. higher tertile: 89.8%, P = 0.0013). The claudin-low and basal/squamous subtypes displayed the lowest rates of events.Conclusions:At a median follow-up of three years, PURE-01 results further confirm the sustained efficacy of neoadjuvant pembrolizumab before RC. PD-L1 expression was the strongest predictor of sustained response post-RC.

Surgical safety outcomes in PURE-01 trial

Supplementary Figure 1: Study flow-chart. Supplementary Figure 2: Kaplan-Meier curves of event-free survival according to tertile-split tumor mutational burden. Supplementary Figure 3. Kaplan-Meier curves of recurrence-free survival according to the molecular subtype. Supplementary Figure 4: PD-L1 staining values (CPS percentages) according to molecular subtypes, split by the three subtyping classifiers GSC/Decipher, Consensus classification, and TCGA.

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.

Despite bladder perforation (BP) is a frequent complication during transurethral resection of bladder (TURB) for bladder cancer (BCa), literature lacks systematic reviews focusing on this issue. We aimed to investigate incidence, diagnosis, therapy, and prognosis after BP during TURB for BCa; therapy was distinguished between conservative (without the need for bladder repair) and surgical management (requiring bladder wall closure).A systematic search was conducted up to April 2021 using PubMed, Scopus, Cochrane Database of Systematic Reviews, and Web of Science to identify articles focusing on incidence, detection, management, or survival outcomes after iatrogenic BP. The selection of articles followed the preferred reporting items for systematic review and meta-analyses process.We included 41 studies, involving 21,174 patients. Overall, 521 patients experienced BP during TURB for BCa, with a mean incidence of 2.4%, up to 58.3% when postoperative cystography is routinely performed after all TURB procedures. Risk factors were low body mass index (BMI) (P=0.01), resection depth (P=0.006 and P=0.03), and low surgical experience (P=0.006). Extraperitoneal BP (68.5%) were treated conservatively in 97.5% of patients; intraperitoneal BP were managed with surgical bladder closure in 56% of cases. Overall, three immediate BP-related deaths were recorded due to septic complications. Extravesical tumor seeding was observed after 6 intraperitoneal and 1 extraperitoneal BP (median time: 6.2 months). Intraperitoneal BP (P=0.0003) and bladder closure (P0.001) were found as independent predictors of extravesical tumor recurrence.BP is more frequent than expected when proper diagnosis is routinely performed after all TURB procedures. Risk factors include low BMI, resection depth, and unexperienced surgeon. The risk of sepsis after BP suggests empirical antibiotic prophylaxis after BP.

552 Background: The possibility to predict the pathologic complete response (pT0) or downstaging (pT≤1) after neoadjuvant therapy may have profound impact on the management of MIBC and orient next-generation bladder-sparing trials. The VIRADS is a standardized reporting system that uses mpMRI parameters to predict the probability of MIBC. No studies have analyzed the ability of VIRADS to predict the pT0 or pT≤1 response post-immunotherapy (IO). Methods: In PURE-01 patients (pts) were staged with bladder multiparametric magnetic resonance imaging (mpMRI: T2-weighted imaging, diffusion-weighted imaging, dynamic contrast enhancement) before and after treatment (3 cycles of pembro) prior to radical cystectomy (RC). All mpMRI scans were centrally reviewed. Logistic regression models analyzed pre- and post-pembro VIRADS against pT≤1 (primary endpoint) and pT0 (secondary endpoint). VIRADS scores were dichotomized between 0-3 and 4-5. Covariates included cT-stage, age, gender, PD-L1 combined positive score (CPS) and tumor mutational burden (TMB). Results: In total, 58 pts were had centrally-reviewed MRI scans (N=116 mpMRI), treated between 02/17 and 08/18. Demographic characteristics and outcomes were generally similar between the all-treated and VIRADS-evaluable populations of PURE-01. Median age was 65 years, 52 (89%) had pure/predominant urothelial carcinoma (UC) histology, 25 (43.1%) had cT3-4N0 MIBC. Pre-pembro: 8 pts (13.8%) had no measurable disease (VIRADS=0), 20 (34.5%) a VIRADS 1-3 score, and 30 (51.7%) had a VIRADS 4-5 score. Six pts (10.3%) had a downstage from VIRADS 4-5 to VIRADS 0-3 post-pembro. Both pre-pembro and post-pembro VIRADS 0-3 scores were significantly associated with pT≤1 endpoint on multivariable analyses (MVA): the strongest effect was seen with post-pembro VIRADS 0-3 against pT≤1 response (OR: 30.2, 95%CI: 6.2-223.2, p

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.

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: 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/Aim: Covid-19 pandemic has led to profound changes in healthcare system in Italy as well as in other countries showing a rapid spread of the disease (1). Italian hospitals modified their usual practice to ensure adequate number of beds for COVID-19 patients. The common management of admitted patients changed to reduce the risk of transmission and parent's visits were strongly limited. Moreover, fear and anxiety caused patients to delay appropriate treatment, resulting in poor outcomes. Urinary tract infection (UTI) is one of the major nosocomial infections. In more than 80% of cases it is related to urological diseases, especially linked to infective stone disease and use of urinary drainages. Pre-operative and post-operative infections are a main challenge in everyday urologic activity. The aim of the present study was to compare the incidence of nosocomial urinary infection during the pandemic period of 2020 with the non-pandemic period of 2019 to investigate the prophylactic role of the strict antiseptic rules adopted during pandemic. Materials and Methods: According with the aims of the study the files of the patients submitted to urological interventions in a 3-month period (March-May) 2019 and (March-May) 2020 were reviewed. A dedicated database was generated. Patients' clinical pre-operative characteristics, including smoking status and BMI were recorded. Charlson comorbidity index and main comorbidities with particular attention to cardiovascular, pulmonary and neurological diseases, diabetes and hypertension were included. Symptoms, fever, laboratory data and urine culture were recorded pre-intra- and postoperatively when available. Urological surgery was classified in five categories: i) major abdominal surgery, (both open and laparoscopic), ii) endoscopic intervention upper urinary tract, iii). endoscopic intervention lower urinary tract, iv) minor open surgery, v) nephrostomy and ureteral stenting. Post-operative complications were classified according to Clavien-Dindo score. The data obtained were submitted to statistical analysis to compare the two different 3-month periods, pre-pandemic in 2019 and pandemic in 2020. The association of the treatment period with categorical variables was assessed using χ2 test. All p-values were two-sided and statistical significance was defined as p

To compare cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and Bacillus Calmette-Guérin (BCG) immunotherapy for T1 squamous bladder cancer (BCa).We retrospectively analysed 188 T1 high-grade squamous BCa patients treated between 1998 and 2019 at fifteen tertiary referral centres. Median follow-up time was 36 months (interquartile range: 19-76). The cumulative incidence and Kaplan-Meier curves were applied for CSM and OM, respectively, and compared with the Pepe-Mori and log-rank tests. Multivariable Cox models, adjusted for pathological findings at initial transurethral resection of bladder (TURB) specimen, were adopted to predict tumour recurrence and tumour progression after BCG immunotherapy.Immediate RC and conservative management were performed in 20% and 80% of patients, respectively. 5-year CSM and OM did not significantly differ between the two therapeutic strategies (Pepe-Mori test p = 0.052 and log-rank test p = 0.2, respectively). At multivariable Cox analyses, pure squamous cell carcinoma (SqCC) was an independent predictor of tumour progression (p = 0.04), while concomitant lympho-vascular invasion (LVI) was an independent predictor of both tumour recurrence and progression (p = 0.04) after BCG. Patients with neither pure SqCC nor LVI showed a significant benefit in 3-year recurrence-free survival and progression-free survival compared to individuals with pure SqCC or LVI (60% vs. 44%, p = 0.04 and 80% vs. 68%, p = 0.004, respectively).BCG could represent an effective treatment for T1 squamous BCa patients with neither pure SqCC nor LVI, while immediate RC should be preferred among T1 squamous BCa patients with pure SqCC or LVI at initial TURB specimen.

Context: Upper tract urothelial carcinoma (UTUC) represents the third most frequent malignancy in Lynch syndrome (LS). Objective: To systematically review the available literature focused on incidence, diagnosis, clinicopathological features, oncological outcomes, and screening protocols for UTUC among LS patients. Evidence acquisition: Medline, Scopus, Google Scholar, and Cochrane Database of Systematic Reviews were searched up to May 2021. Risk of bias was determined using the modified Cochrane tool. A narrative synthesis was undertaken. Evidence synthesis: Overall, 43 studies between 1996 and 2020 were included. LS patients exhibited a 14-fold increased risk of UTUC compared with the general population, which further increased to 75-fold among hMSH2 mutation carriers. Patients younger than 65 yr and patients with personal or family history of LS-related cancers should be referred to molecular testing on tumour specimen and subsequent genetic testing to confirm LS. Newly diagnosed LS patients may benefit from a multidisciplinary management team including gastroenterologist and gynaecologist specialists, while genetic counselling should be recommended to first-degree relatives (FDRs). Compared with sporadic UTUC individuals, LS patients were significantly younger (p = 0.005) and exhibited a prevalent ureteral location (p = 0.01). Radical nephroureterectomy was performed in 75% of patients (5-yr cancer-specific survival: 91%). No consensus on screening protocols for UTUC was achieved: starting age varied between 25-35 and 50 yr, while urinary cytology showed sensitivity of 29% and was not recommended for screening. Conclusions: Urologists should recognise patients at high risk for LS and address them to a comprehensive diagnostic pathway, including molecular and genetic testing. Newly diagnosed LS patients should be referred to a multidisciplinary team, while genetic counselling should be recommended to FDRs. Patient summary: In this systematic review, we analysed the existing literature focused on upper tract urothelial carcinoma (UTUC) among patients with Lynch syndrome (LS). Our purpose is to provide a comprehensive overview of LS-related UTUC to reduce misdiagnosis and improve patient prognosis.

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.

The prognostic role of prior history of bladder cancer (BCa) among patients treated with radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC) is poorly addressed. We aimed to investigate the role of prior BCa on any recurrence, distant metastases, and bladder recurrence following RNU among low-grade (LG) and high-grade (HG) UTUC patients.We retrospectively analyzed 1,580 UTUC patients treated with RNU at 8 tertiary referral centers between 1992 and 2016. Any recurrence was defined as recurrence in the urinary tract, in the resection bed, or distant metastases (defined as disease outside the urinary tract and regional lymph nodes). Time to recurrence was computed from RNU. Multivariable Cox models were generated to predict risk of any recurrence, distant metastases, and bladder recurrence according to prior BCa history, coded as no prior BCa, non-muscle-invasive (NMIBC), and muscle-invasive BCa (MIBC).Median follow-up for survivors was 4 years. Overall, 71%, 25%, and 4% of patients had no prior BCa, NMIBC and MIBC. 5-year any recurrence-free survival was 61%, 41%, and 19% in LG (P.001) and 42%, 34%, and 30% in HG patients (P = .1) with no prior BCa, NMIBC, and MIBC. On multivariable models, LG patients with NMIBC and MIBC showed a significantly higher risk of any recurrence compared to no prior BCa (both p≤0.005); previous NMIBC was associated with any recurrence among HG patients (P = 0.04). 5-year distant metastases-free survival was 92%, 90%, and 87% in LG (P.05) and 68%, 75%, and 45% in HG patients (P = .01) with no prior BCa, NMIBC, and MIBC. Previous NMIBC increased the risk of bladder recurrence among LG (P.001) and HG (P = .003) patients.UTUC patients with prior history of BCa exhibit a higher risk of any recurrence after RNU. Our study provides important information which could address patient's counseling and decision-making process.

Background Literature lacks clear evidence regarding the optimal treatment for non–muscle-invasive micropapillary bladder cancer (MPBC) due to its rarity and the presence of only small sample size and single-centre studies. Objective To assess cancer-specific mortality (CSM) and overall mortality (OM) between immediate radical cystectomy (RC) and conservative management among T1 high-grade (HG) MPBC. Design, setting, and participants We retrospectively analysed a multicentre dataset including 119 T1 HG MPBC patients treated between 2005 and 2019 at 15 tertiary referral centres. The median follow-up time was 35 mo (interquartile range: 19–64). Intervention Patients underwent immediate RC versus conservative management with bacillus Calmette-Guerin. Outcomes measurements and statistical analysis Cumulative incidence functions and Kaplan-Meier methods were applied to estimate survival outcomes. Multivariable Cox analyses were performed to assess independent predictors of disease recurrence and disease progression after conservative management; covariates consisted of pure MPBC, concomitant lymphovascular invasion (LVI), and carcinoma in situ at initial diagnosis. Results and limitations Immediate RC and conservative management were performed in 27% and 73% of patients, respectively. CSM and OM did not differ significantly among patient treated with immediate RC versus conservative management (Pepe-Mori test p = 0.5 and log-rank test p = 0.9, respectively). Overall, 66.7% and 34.5% of patients experienced disease recurrence and disease progression after conservative management, respectively. At multivariable Cox analyses, concomitant LVI was an independent predictor of disease recurrence (p = 0.01) and progression (p = 0.03), while pure MPBC was independently associated with disease progression (p = 0.03). The absence of a centralised re-review and the retrospective design represent the main limitations of our study. Conclusions Conservative management could achieve satisfactory results among T1 HG MPBC patients with neither pure MPBC nor LVI at initial diagnosis. Patient summary Bacillus Calmette-Guerin seems to be an effective therapy for T1 micropapillary bladder cancer patients with neither pure micropapillary disease nor lymphovascular invasion at initial diagnosis.

The MAGNOLIA study, investigating the concept of perioperative immunotherapy in muscle- invasive bladder cancer, was prematurely terminated. The lessons learned that should be considered before initiating and conducting future clinical trials in this field are highlighted.

The preoperative lymph node (LN) staging of bladder cancer (BCa) addresses the subsequent therapeutic strategy and influences patient's prognosis. However, sparce evidence exists regarding the accuracy of conventional cross-sectional imaging, such as computed tomography or magnetic resonance imaging, in correctly detect LN status. We aimed to assess the diagnostic accuracy of conventional cross-sectional imaging in detecting preoperative LN involvement among BCa patients treated with radical cystectomy and pelvic lymph node dissection.We retrospectively analyzed data of 1,104 patients who underwent preoperative LN staging with computed tomography or magnetic resonance imaging and subsequent radical cystectomy with pelvic lymph node dissection for BCa between 1997 and 2017 at three tertiary referral centers. Patients receiving neoadjuvant chemotherapy were excluded. We assessed the concordance between clinical (cN) and pathological LN (pN) status, defined as the accuracy of imaging in detecting LN involvement using pathological specimen as reference; concordance was expressed according to Cohen's kappa coefficient. Location-based sub-analyses were performed, distinguishing among external iliac, intern iliac, obturator, common iliac, presacral and paraaortic LNs.Among 870 cN0 patients, 68.9% were confirmed pN0 at pathological report; while among 234 cN+ patients, 50.5% were found with LN metastases at pathological specimen. Overall, conventional imaging showed slight concordance (64.9%) between cN and pN stages (sensitivity: 30%; specificity: 84%). At sub-analysis, no agreement between cN and pN status was found in each LN location, with the only exception of common iliac LNs with slight concordance (37.5%). Common iliac LNs achieved the highest sensitivity and positive likelihood ratio (15% and 2.4, respectively) compared to other LN locations.Overall, preoperative cross-sectional imaging exhibited a slight concordance between cN and pN status. Our location-based sub-analyses showed unsatisfactory results in each LN location- Thus, nomograms combining morphological patterns with serological and clinicopathological features are urgently required.

Purpose To investigate the association of patients’ sex with recurrence and disease progression in patients treated with intravesical bacillus Calmette–Guérin (BCG) for T1G3/HG urinary bladder cancer (UBC). Materials and methods We analyzed the data of 2635 patients treated with adjuvant intravesical BCG for T1 UBC between 1984 and 2019. We accounted for missing data using multiple imputations and adjusted for covariate imbalance between males and females using inverse probability weighting (IPW). Crude and IPW-adjusted Cox regression analyses were used to estimate the hazard ratios (HR) with their 95% confidence intervals (CI) for the association of patients’ sex with HG-recurrence and disease progression. Results A total of 2170 (82%) males and 465 (18%) females were available for analysis. Overall, 1090 (50%) males and 244 (52%) females experienced recurrence, and 391 (18%) males and 104 (22%) females experienced disease progression. On IPW-adjusted Cox regression analyses, female sex was associated with disease progression (HR 1.25, 95%CI 1.01–1.56, p = 0.04) but not with recurrence (HR 1.06, 95%CI 0.92–1.22, p = 0.41). A total of 1056 patients were treated with adequate BCG. In these patients, on IPW-adjusted Cox regression analyses, patients’ sex was not associated with recurrence (HR 0.99, 95%CI 0.80–1.24, p = 0.96), HG-recurrence (HR 1.00, 95%CI 0.78–1.29, p = 0.99) or disease progression (HR 1.12, 95%CI 0.78–1.60, p = 0.55). Conclusion Our analysis generates the hypothesis of a differential response to BCG between males and females if not adequately treated. Further studies should focus on sex-based differences in innate and adaptive immune system and their association with BCG response.

Item does not contain fulltext Introduction and objectives: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis in order to adequately stage the patient. It is well known that the presence of detrusor muscle in the specimen is a prerequisite to minimize the risk of under staging. Persistent disease after resection of bladder tumors is not uncommon and is the reason why the European Guidelines recommended a re-TUR for all T1 tumors. It was recently published that when there is muscle in the specimen, re-TUR does not influence progression or cancer specific survival. We present here the patient and tumor factors that may influence the presence of residual disease at re-TUR. Material and methods: In our retrospective cohort of 2451 primary T1G3 patients initially treated with BCG, pathology results for 934 patients (38.1%) who underwent re-TUR are available. 74% had multifocal tumors, 20% of tumors were more than 3 cm in diameter and 26% had concomitant CIS. In this subgroup of patients who underwent re-TUR, there was no residual disease in 267 patients (29%) and residual disease in 667 patients (71%): Ta in 378 (40%) and T1 in 289 (31%) patients. Age, gender, tumor status (primary/recurrent), previous intravesical therapy, tumor size, tumor multi-focality, presence of concomitant CIS, and muscle in the specimen were analyzed in order to evaluate risk factors of residual disease at re-TUR, both in univariate analyses and multivariate logistic regressions. Results: The following were not risk factors for residual disease: age, gender, tumor status and previous intravesical chemotherapy. The following were univariate risk factors for presence of residual disease: no muscle in TUR, multiple tumors, tumors >= 3 cm, and presence of concomitant CIS. Due to the correlation between tumor multi-focality and tumor size, the multivariate model retained either the number of tumors or the tumor diameter (but not both), p < 0.001. The presence of muscle in the specimen was no longer significant, while the presence of CIS only remained significant in the model with tumor size, p < 0.001. Conclusions: The most significant factors for a higher risk of residual disease at re-TUR in T1G3 patients are multifocal tumors and tumors more than 3 cm. Patients with concomitant CIS and those without muscle in the specimen also have a higher risk of residual disease. (C) 2021 AEU. Published by Elsevier Espana, S.L.U. All rights reserved.

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 Scarce data are available regarding the technique and outcomes for patients with RCC and Mayo III caval thrombi. To report surgical and oncological outcomes of RCC patients with Mayo III thrombi treated with radical nephrectomy and thrombectomy after liver mobilization (LM) and Pringle Manoeuvre (PM). Methods Retrospective analysis of surgical technique, outcomes and cancer control in 19 patients undergoing LM and PM in a single tertiary care institution. Results Overall, 78% of the patients had performance status ECOG 1 and 58% had a comorbidity index >2. Median surgical time was 305 minutes (IQR 264-440). Intraoperative complications were reported for 39% of patients and postoperative ones for 58% (only Grade 1 and 2). Intensive Care Unit support was necessary in 16% of the cases. Median length of hospital stay was 9 days (IQR 7-11). Thirty- and 90-day mortality were 5% and 15%. Twoyear overall survival and cancer-specific survival were 60% and 62%, respectively. Conclusions We reported surgical techniques, intra and perioperative complications and follow-up in the largest cohort of RCC patients requiring LM and PM.

Background and Aims The use of Pembrolizumab, a selective humanized IgG4 kappa monoclonal antibody that inhibits the programmed death-1 receptor, has been largely accepted, especially in a series of trials in patients with advanced melanoma and in other cancers such as renal cell carcinoma (RCC), lymphoma and others. However, few recent studies demonstrated that Pembrolizumab promotes several renal dysfuncion such as acute tubular injury, acute interstitial nephritis and minimal change disease. To better elucidate this topic, we analyzed the renal function’s aspects from the PURE-01 protocol’s data, a phase 2, open label study of neoadjuvant Pembrolizumab before radical cystectomy (RC) for muscle invasive urothelial bladder cancer (MIUB). Method PURE-01 study (NCT02736266) enrolled preliminary 143 patients (pts). Eligibility criteria included: T2-T4N0 stage and residual disease after transurethral reduction of bladder. Pts received 3 cycles of Pembrolizumab 200 mg 3 weekly before RC. Computed tomography scan, FDG-PET/CT scan, and bladder multipara metric magnetic resonance imaging were performed during screening and before RC. Radiologically non-responders to pembro (per investigator decision) are given 3 additional courses of dose-dense MVAC chemotherapy. The collected data consisted in: the serum creatinine at baseline, after the first, second and last cycle in order to obtain the renal function by using eGFR formula (CKD-EPI-2009) for each time step; urine test analysis data after each cycle; the T stage from cTNM (AJCC TNM system-2019) before the treatment; clinical data such as presence of Diabetes, Hypertension, Hydronephrosis, BMI. The main outcome of the study was to correlate the renal function variation (from the pre-treatment to each treatment cycle) with the other clinical variables. Data analysis were performed using linear model, Kruskal-Wallis test and Wilcoxon test with holm’s correction. Results The median age of the patients was 68 years (62-73), with the 13% of the pts as female. We observed the presence of Hypertension, Hydronephrosis, Diabetes, Overweight (BMI≥25 and BMI Conclusion We observed that the treatment with neoadjuvant pembrolizumab, in patients with bladder cancer, does not correlate with a decay of eGFR, but on the contrary, from our data, is associated with a small improvement of renal function, especially for those patients who presented higher stage of T and hydronephrosis before the treatment suggesting the Permbrolizumab’s safety in neoadjuvant therapy before RC for MIUBC from the nephrological point of view. This results needs more in-depths studies to be confirmed.

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.

Comprehensive characterization of the urinary and urothelium-bound microbiomes in bladder cancer (BCa) and healthy state is essential to understand how these local microbiomes may play a role in BCa tumorigenesis and response to therapy, as well as to explain sex-based differences in BCa pathobiology. Performing 16 s rDNA microbiome analysis on 166 samples (urine and paired bladder tissues) from therapy-naive BCa patients undergoing radical cystectomy and healthy controls, we defined (1) sex-specific microbiome differences in the urine and bladder tissue, and (2) representativeness of the tissue microenvironment by the voided urinary microbiome. The genus Klebsiella was more common in the urine of female BCa patients versus healthy controls, while no clinically relevant bacteria were found differently enriched in men. In tissues, the genus Burkholderia was more abundant in the neoplastic versus the non-neoplastic tissue in both sexes, suggesting a potential role in BCa pathobiology. Lastly, we found that the urinary microbiome shares >80% of the bacterial families present in the paired bladder tissue, making the urinary microbiome a fair proxy of the tissue bacterial environment. Patient summary We identified specific bacteria present in the urine and tissues of male and female bladder cancer patients. These novel data represent a first step toward understanding the influence of the bladder microbiome on the development of bladder cancer and on the response to intravesical and systemic therapies.

The COVID-19 pandemic influenced the normal course of clinical practice leading to significant delays in the delivery of healthcare services for patients non affected by COVID-19. In the near future, it will be crucial to identify facilities capable of providing health care in compliance with the safety of healthcare professionals, administrative staff and patients. All the staff involved in the project of a Covid-free hospital should be subjected to a diagnostic swab for COVID-19 before the beginning of healthcare activity and then periodically in order to avoid the risk of contamination of patients during the process of care. The modifications of various activities involved in the process of care are described: outpatient care, reception of inpatients, inpatient ward and operating room. For outpatient care, modality of appointment procedure, characteristics of waiting room and personal protective equipment (PPE) for healthcare professionals and administrative staff are presented. Reception of inpatients shall be conditional on a negative swab for COVID-19 obtained with a drive-in procedure. The management of the operating room represents the most crucial step of the patient's care process. The surgical team should be restricted and monitored with periodic swabs; surgical procedures should be performed by experienced surgeons according to standard procedures; surgical training experimental treatments and research protocols should be suspended. Adequate personal protective equipment and measures to reduce aerosolization in the operating room (closed circuits, continuous cycle insufflators, fume extraction) should be adopted. Prevention of possible transmission of the virus during procedures in open, laparoscopic and endoscopic surgery is to use a multi-tactic approach, which includes correct filtration and ventilation of the operating room, the use of appropriate PPE (FFP3 plus surgical mask and protective visor for all the staff working in the operating room) and smoke evacuation devices with a suction and filter system. on behalf of the UrOP Executive CommitteeGiuseppe Ludovico, Angelo Cafarelli, Ottavio De Cobelli, Ferdinando De Marco, Giovanni Ferrari, Stefano Pecoraro, Angelo Porreca, Domenico Tuzzolo

Interim data from the PURE-01 study, using pembrolizumab before radical cystectomy in muscle-invasive bladder cancer (MIBC), suggested that multiparametric magnetic resonance imaging (mpMRI) was able to predict the pathologic response. Owing to the availability of novel effective therapies in MIBC, the possibility to assess tumor response easily has become exceedingly important. The primary objective of the present study was to evaluate the association between individual and combined MRI sequences, and the pathologic response in the final PURE-01 population. Images were internally evaluated and the diagnostic performance was analyzed for separate sequences, along with their combination. From February 2017 to December 2019, 143 patients were enrolled in PURE-01, and 123 with suitable paired imaging assessments before and after pembrolizumab tests (N = 246 mpMRI in total) were analyzed in relation to the pathologic response. The area under the curve (AUC) of the combination of all sequences to predict ypT0ypN0 response was 0.74. By excluding dynamic contrast enhancement (DCE) assessment, the AUC was 0.74. When looking at ypT1/a/is ypN0 response, the AUC was 0.87 in both cases. Without DCE, 95% of patients with no evidence of disease resulted in ypT1/a/is ypN0 and 65% ypT0ypN0 responders. In conclusion, the final results confirmed the reliability of mpMRI and suggested the opportunity to avoid intravenous gadolinium contrast to personalize bladder-sparing strategies in radiologically complete responders. Patient summary We evaluated the reliability of multiparametric bladder magnetic resonance imaging to predict the pathologic response to pembrolizumab administered before radical cystectomy in muscle-invasive bladder cancer. We observed that this radiologic examination is promising in the attempt to identify opportunities to spare the bladder in selected, radiologically defined complete responders. We also observed that the use of intravenous gadolinium contrast can be avoided in future studies. ClinicalTrials.gov, number NCT02736266.

Purpose To evaluate the predictive factors of pT0 at repeated transurethral resection of the bladder (re-TURB) in pT1 high-grade (HG) nonmuscle invasive bladder cancer in order to explore the possibility to avoid it in well-selected patients. Methods This multicenter retrospective study included patients with pT1HG nonmuscle invasive bladder cancer from 4 different centers who underwent a complete TURB. Re-TURB was defined as a second resection which involved the site of the first TURB performed within 2-6 weeks from the previous resection. A multivariable logistic-regression model was performed to evaluate the predictors of pT0 at re-TURB. A nomogram was built to calculate the probability of obtaining a negative histology at re-TURB. The performance of the nomogram and its net benefit were tested with the decision curve analysis. Results Overall, 321 patients were included in the study. On multivariable logistic regression, detrusor muscle in the specimen (HR 1.99, P = 0.02), concomitant carcinoma in situ (HR 0.29, P = 0.005) and resection performed with en-bloc technique (HR 7.71, P = 0.01) were independent predictors of pT0 at re-TURB. Decision curve analysis showed a net benefit for the nomogram for each probability over 0.35 compared to the strategy to perform a re-TURB in all pT1HG tumors. Conclusions The presence of detrusor muscle in TURB specimen, the absence of concomitant carcinoma in situ and the en-bloc resection were able to predict a negative histology at re-TURB, opening the door to the possibility to avoid it in an extremely well-selected cohort of patients. External validations and prospective studies are urgently needed.

Background: Data regarding clinical node metastases (cN+) in patients undergoing radical cystectomy (RC) are scarce. Objective: To evaluate the performance of conventional imaging in detecting cN+ and analyze the impact of cN+ on survival among patients treated with RC without neoadjuvant chemotherapy (NAC). Design, setting, and participants: Data from three independent centers of consecutive patients with bladder cancer treated with RC without NAC were analyzed. Outcome measurements and statistical analysis: cN+ was defined as pelvic nodes >8. mm or abdominal nodes >10. mm in maximum short-axis diameter as detected via preoperative computed tomography or magnetic resonance imaging. Performance characteristics were evaluated considering pN+ disease as the reference standard. Multivariable Cox regression analyses were performed for prediction of survival. Results and limitations: Overall, 196 patients (7.1%) had cN+ disease before RC and pN+ status was confirmed for 122 of them (62.2%). cN+ status in the overall population had sensitivity of 18% and specificity of 96% with a calculated area under the curve of 57%. The median follow-up was 108 mo. On multivariable analyses, cN+pN+ (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.26-2.68) and cN-pN+ (HR 2.36, 95% CI 1.90-2.92) were predictors of CSM (both . p . 0.2). Conclusions: Our study confirms the poor accuracy of conventional preoperative imaging in assessing nodal disease status. cN status had no independent impact on survival when all confounders were evaluated, and potentially curative treatments should not be withheld on the basis of clinical nodal status alone. Patient summary: The accuracy of conventional imaging techniques for detection of pathologic lymph node-positive disease before radical cystectomy for bladder cancer is suboptimal. The presence of clinical lymph node positivity on preoperative imaging is not an independent predictor of oncologic outcomes, and if the node invasion is not confirmed at radical cystectomy, these patients may have good long-term outcomes. Conventional imaging techniques are suboptimal in detecting preoperative node metastases. The presence of node metastases on preoperative imaging is not a predictor of poor oncologic outcomes if the node invasion is not confirmed pathologically after surgery.

Objective: Growing literature supports good survival expectancies in bladder cancer (BCa) patients affected by clinical node metastases (cN+) treated with multimodal therapy. We evaluated the role of adjuvant chemotherapy in cN+BCa patients treated with radical cystectomy (RC) and pelvic lymph node dissection (PLND) without neoadjuvant chemotherapy (NAC). Methods: We evaluated a total of 192 patients with BCa and cN+. All patients were treated with RC and PLND without NAC between 2001 and 2013. Kaplan–Meier analyses and Cox regression analyses were used to assess the impact of adjuvant chemotherapy (ACT) on recurrence, cancer-specific mortality (CSM) and overall mortality (OM) after surgery. Results: Overall, 99 patients (51.6%) were found without node metastases at RC, while 18 (9.4%), 58 (30.2%) and 17 (8.9%) patients were found pN1, pN2 and pN3, respectively. With a median follow-up of 48 months, in cN+ patients we recorded 5-year recurrence, CSM and OM of 55, 53 and 51%, respectively. Overall, 36 (18.8%) patients were treated with adjuvant chemotherapy. At univariable analyses, ACT was associated with improved overall survival [Hazard ratio (HR): 0.42, confidence interval (CI) 0.20–0.86, p = 0.02) in pN+ subgroup only. These results were confirmed at multivariable analyses, where ACT was associated with improved CSS (HR: 0.45, CI 0.21–0.89, p = 0.03) and OS (HR: 0.37, CI 0.17–0.81, p = 0.01). Conclusions: We report good survival outcomes in cN+ patients treated with RC. The use of ACT after surgery increases survival expectancies, especially in those patients with pathological node disease. Our data need to be further evaluated in prospective setting.

Introduction We sought to describe incidence of histological variants after radical cystectomy (RC) due to bladder cancer (BCa). Moreover, we investigated survival outcomes accounting for this parameter. Methods We retrospectively evaluated data from 1,067 patients with BCa treated with RC between 1990 and 2013 at a single tertiary care referral center. All specimen were evaluated by dedicated uropathologists. Univariable and multivariable Cox regression analyses tested the effect of different histopathological variant on recurrence, cancer-specific mortality (CSM), and overall mortality (OM) after accounting for all available confounders. Results Of 1,067 patients, 729 (68.3%) harbored pure urothelial BCa while 338 (31.7%) were found to have a variant. Considering uncommon variants, 21 (2.0%) were sarcomatoid, 10 (0.9%) lymphoepitelial, 19 (1.8%) small cell, 109 (10.2%) squamous, 89 (8.3%) micropapillary, 23 (2.2%) glandular, 34 (3.2%) mixed variants, and 33 (3.1%) were found with other types of variants. With a median follow-up of 6.2 years, 343 recurrence, 365 CSM, and 451 OM were recorded, respectively. At multivariable Cox regression analyses, the presence of small cell variant was associated with higher recurrence (hazard ratio [HR] = 3.47, P 0.1). Conclusion Our study confirms that histological variant is not an infrequent event at RC specimen. However, in our single-center series, only patients found with small cell variant were associated with a negative effect on survival after RC.