Unlocking the Potential of Adequate Bacillus Calmette-Guérin Immunotherapy in Very-high-risk Non-muscle-invasive Bladder Carcinoma: A Multicenter Analysis of Oncological Outcomes and Risk Dynamics.

BACKGROUND: The European Association of Urology (EAU) recommends discussing upfront radical cystectomy for all patients with very high risk (VHR) non-muscle-invasive bladder carcinoma (NMIBC), but the role of bacillus Calmette-Guérin (BCG) treatment remains controversial. OBJECTIVE: To analyze oncological outcomes in VHR NMIBC patients (EAU risk groups) treated with adequate BCG. DESIGN, SETTING, AND PARTICIPANTS: A multi-institutional retrospective study involving patients with VHR NMIBC who received adequate BCG therapy from 2007 to 2020 was conducted. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: A survival analysis estimated recurrence-free survival (RFS), progression-free survival (PFS), and the cumulative incidence of cancer-specific mortality (CSM) after accounting for other causes of mortality as competing risk events and of the overall mortality (OM). Conditional survival probabilities for 0-4 yr without events were computed. Cox regression assessed the predictors of oncological outcomes. RESULTS AND LIMITATION: A total of 640 patients, with a median 47 (32-67) mo follow-up for event-free individuals, were analyzed. High-grade RFS and PFS at 5 yr were 53% (49-57%) and 78% (74-82%), respectively. The cumulative incidence of CSM and OM at 5 yr was 13% (10-16%) and 16% (13-19%), respectively. Conditional RFS, PFS, overall survival, and cancer-specific survival at 4 yr were 91%, 96%, 87%, and 94%, respectively. Cox regression identified tumor grade (hazard ratio [HR]: 1.54; 1.1-2) and size (HR: 1.3; 1.1-1.7) as RFS predictors. Tumor multiplicity predicted RFS (HR: 1.6; 1.3-2), PFS (HR: 2; 1.2-3.3), and CSM (HR: 2; 1.2-3.2), while age predicted OM (HR: 1.48; 1.1-2). CONCLUSIONS: Patients with VHR NMIBC who receive adequate BCG therapy have a more favorable prognosis than predicted by EAU risk groups, especially among those with a sustained response, in whom continuing maintenance therapy emerges as a viable alternative to radical cystectomy. PATIENT SUMMARY: Our research shows that a sustained response to bacillus Calmette-Guérin in patients can lead to favorable outcomes, serving as a viable alternative to cystectomy for select cases.

Natural history of renal angiomyolipoma in a high-volume center: our experience during more than 15 years of follow up.

OBJECTIVES: To describe the natural history of AML, the clinical results and the need for treatment during long-term follow-up of renal AML. METHODS: Retrospective study of patients diagnosed with AML by computed tomography or nuclear magnetic resonance between 2001 and 2019, with at least two follow-up images. Clinical and imaging variables, need for intervention, complications and follow-up time were recorded. Statistical analysis was performed using SPSS 22.0. RESULTS: 111 patients and 145 AML were included. The median follow-up was 6.17 years (range 0.7-18.1, IQR 11.8-12.2). The median tumor size at diagnosis was 13 mm (IQR 7.5-30), with 24 (16.4%) being ≥ 4 cm. Most presented as an incidental finding (85.5%); in 3 (2.1%) cases, the presentation was as a spontaneous retroperitoneal hematoma. The main indication for intervention was size ≥ 4 cm in 50%. Eighteen (12%) patients received a first intervention, being urgent in 3. Embolization was performed in 15 cases and partial nephrectomy in 3. The need for reintervention was recorded in five: two underwent partial nephrectomy and two total nephrectomy; one patient required a new urgent embolization. Of the non-operated patients, 43% decreased in size or did not change, while 57% increased, with the median annual growth being 0.13 mm (IQR - 0.11 to 0.73). There were no differences in the median growth in tumors measuring ≥ 4 cm (0.16 mm) at diagnosis vs. < 4 cm (0.13 mm) (p = 0.9). CONCLUSIONS: The findings of this study suggest that AML typically demonstrate a slow-progressing clinical course during long-term follow-up. Moreover, our observations, which cast doubt on tumor size as a reliable predictor of adverse clinical outcomes, advocate for a less intensive monitoring strategy in both monitoring frequency and choice of imaging modality.

The importance of second-look ureteroscopy implementation in the conservative management of upper tract urothelial carcinoma.

PURPOSE: The purpose of the study was to evaluate the effect of second-look ureteroscopy (SU) in the endoscopic operative work-up of patients with upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: Patients with UTUC who underwent SU between 2016 and 2021 were included. Cancer detection rate (CDR) at SU was defined as endoscopic visualization of tumor. The effect of SU on recurrence-free survival (RFS), radical nephroureterectomy-free survival (RNU-FS), bladder cancer-free survival (BC-FS), and cancer-specific survival (CSS) was estimated using the Kaplan-Meier method. Multivariate logistic regression analysis (MLR) assessed predictors of negative SU. Finally, we evaluated the effect of SU timing on oncological outcomes, classifying SUs as "early" (≤ 8 weeks) and "late" (> 8 weeks). RESULTS: Overall, 85 patients underwent SU. The CDR at SU was 44.7%. After a median follow-up was 35 (IQR: 15-56) months, patients with positive SU had a higher rate of UTUC recurrence (47.4% vs 19.1%, p = 0.01) and were more frequently radically treated (34.2% vs 8.5%, p = 0.007). Patients with high-grade disease (hazard ratio [HR]: 3.14, 95% CI 1.18-8.31; p = 0.02) had a higher risk of UTUC recurrence, while high-grade tumor (HR: 3.87, 95%CI 1.08-13.77; p = 0.04) and positive SU (HR: 4.56, 95%CI 1.05-22.81; p = 0.04) were both predictors of RNU. Low-grade tumors [odds ratio (OR): 5.26, 95%CI 1.81-17.07, p = 0.003] and tumor dimension < 20 mm (OR: 5.69, 95%CI 1.48-28.31, p = 0.01) were predictors of negative SU. Finally, no significant difference emerged regarding UTUC recurrence, RNU, BC-FS, and CSM between early vs. late SUs (all p > 0.05). CONCLUSIONS: SU may help in identifying patients with UTUC experiencing an early recurrence after conservative treatment. Patients with low-grade and small tumors are those in which SU could be safely postponed after 8 weeks.

Long-Term Oncologic Outcomes of Endoscopic Management of High-Risk Upper Tract Urothelial Carcinoma: The Fundació Puigvert's Experience.

Objectives: Many patients with upper tract urothelial carcinoma (UTUC) outside of the low-risk criteria may possess low absolute risks of distant progression. Herein, we hypothesized that careful selection of high-risk patients undergoing an endoscopic approach could result in acceptable oncologic outcomes. Materials and Methods: Patients with high-risk UTUC managed endoscopically between 2015 and 2021 were retrospectively identified from a prospectively maintained single academic institution database. Elective and imperative indications for endoscopic treatment were considered. Regarding elective indications, the decision to perform endoscopic treatment was systematically proposed to high-risk patients in whom macroscopically complete ablation was deemed feasible, excluding invasive appearance on CT scan, and without histologic variant. Results: A total of 60 patients with high-risk UTUC met our inclusion criteria (29 imperative and 31 elective indications). The median follow-up in patients without any event was 36 months. At 5 years, the estimated overall survival, cancer-specific survival, metastasis-free survival, UTUC recurrence-free survival, radical nephroureterectomy-free survival, and bladder recurrence-free survival were 57% (41-79), 75% (57-99), 86% (71-100), 56% (40-76), 81% (70-93), and 69% (54-88), respectively. All oncologic outcomes were similar between patients with elective and imperative indications (all log-rank p > 0.05). Conclusions: In conclusion, we report the first large series of endoscopic treatment in patients with high-risk UTUC, arguing that promising oncologic outcomes can be achieved in properly selected candidates. We encourage multi-institutional collaborative work as a large cohort of high-risk patients treated endoscopically may allow subgroup analyses to define the best candidates.

Use of Moses 2.0 with extended frequency and optimized Moses vs. high-power laser in MiniPCNL: a randomized controlled trial.

The aim of the study was to compare standard high-power laser (with < 80 Hz) to extended frequency (> 100 Hz) lithotripsy during miniPCNL. 40 patients were randomized in to two groups undergoing MiniPCNL. For both groups, the Holmium Pulse laser Moses 2.0 (Lumenis) was used. For group A, standard high-power laser with < 80 Hz, with Moses distance was set using up to 3 J. For Group B, extended frequency (100-120 Hz) was used allowing up to 0.6 J. All patients underwent MiniPCNL using an 18 Fr balloon access. Demographics were comparable between groups. Mean stone diameter was 19 mm (14-23) with no differences between groups (p = 0.14). Mean operative time was 91 and 87 min for group A and B (p = 0.71), mean laser time was similar in both groups, 6.5 min and 7.5 min, respectively (p = 0.52) as well as the number of laser activations during the surgery (p = 0.43). Mean Watts used was 18 and 16 respectively being similar in both groups (p = 0.54) as well as the total KJoules (p = 0.29). Endoscopic vision was good in all surgeries. The endoscopic and radiologic stone free rate was achieved in all patients expect for two in both groups (p = 0.72). Two Clavien I complications were seen, a small bleeding for group A and a small pelvic perforation in group B. The use of high-power holmium laser with extended frequency and optimized Moses was effective and safe being comparable to standard high-power laser for MiniPCNL allowing more versatility with the setting range.

Initial experience of robot-assisted partial nephrectomy with Hugo™ RAS system: implications for surgical setting.

PURPOSE: Hugo™ RAS system is one of the most promising new robotic platforms introduced in the field of urology. To date, no data have been provided on robot-assisted partial nephrectomy (RAPN) performed with Hugo™ RAS system. The aim of the study is to describe the setting and report the performance of the first series of RAPN performed with Hugo™ RAS system. METHODS: Ten consecutive patients who underwent RAPN at our Institution between February and December 2022 were prospectively enrolled. All RAPN were performed transperitoneally with a modular four-arm configuration. The main outcome was to describe the operative room setting, trocar placement and the performance of this novel robotic platform. Pre, intra and post-operative, variables were recorded. A descriptive analysis was performed. RESULTS: Seven patients underwent RAPN for right-side and three for left-side masses. Median tumor size and PADUA score were 3 (2.2-3.7) cm and 9 (8-9), respectively. Median docking and console time were 9.5 (9-14) and 138 (124-162) minutes, respectively. Median warm ischemia time was 13 (10-14) minutes, and one case was performed clamp-less. Median estimated blood loss was 90 (75-100) mL. One major complication (Clavien-Dindo 3a) occurred. No case of positive surgical margin was recorded. CONCLUSION: This is the first series to prove the feasibility of Hugo™ RAS system in the setting of RAPN. These preliminary results may help new adopters of this surgical platform to identify critical steps of robotic surgery with this platform and explore solutions before in-vivo surgery.

The DEpth of Endoscopic Perforation scale to assess intraoperative perforations during transurethral resection of bladder tumor: subgroup analysis of a randomized controlled trial.

PURPOSE: Bladder perforation (BP) is the most important intraoperative adverse event of transurethral resection of bladder tumor (TURBT). It is frequently underreported despite its impact on the postoperative course. There is no standardized classification of BP. The study aims to develop a classification of the depth of endoscopic bladder perforation during TURBT. METHODS: This is a sub-analysis of a prospective randomized trial enrolling 248 patients submitted to en-bloc vs conventional TURBT from 03/2018 to 06/2021. The DEpth of Endoscopic Perforation (DEEP) scale is as follows: "0" visible muscular layer with no perivesical fat; "1" visible muscle fibers with spotted perivesical fat; "2" exposition of perivesical fat; "3" intraperitoneal perforation. Logistic and linear regression models were used to investigate predictors of high-grade perforations (DEEP 2-3) and to assess whether the DEEP scale independently predicted patients' postoperative outcomes. RESULTS: A total of 146/248 (58.9%), 56/248 (22.6%), 41/248 (16.5%), 5/248 (2.0%) patients presented DEEP grade 0, 1, 2, and 3, respectively. Female gender [B coeff. 0.255 (95% CI 0.001-0.513); p = 0.05], tumor location [B coeff. 0.188 (0.026-0.339); p = 0.015], and obturator-nerve reflex [B coeff. 0.503 (0.148-0.857); p = 0.006] were independent predictors of DEEP. The scale predicted independently major complications [Odd Ratio (OR) 2.221 (1.098-4.495); p = 0.026], no post-operative chemotherapy intravesical instillation [OR 9.387 (2.434-36.200); p = 0.001], longer irrigation time [B coeff. 0.299 (0.166-0.441); p < 0.001] and hospital stay [B coeff. 0.315 (0.111-0.519); p = 0.003]. CONCLUSION: The DEEP scale provides a visual tool for grading bladder perforation during TURBT, which can help physicians standardize complication reporting and plan postoperative management accordingly.

Oncological and Renal Function Outcomes in Patients Who Underwent Simultaneous Radical Cystectomy and Nephroureterectomy for Synchronous or Metachronous Panurothelial Carcinoma.

OBJECTIVE: To assess clinical outcomes of patients who underwent simultaneous radical cystectomy (RC) and radical nephroureterectomy (RNU) for panurothelial carcinoma (PanUC). MATERIALS AND METHODS: A retrospective analysis of 67 patients who underwent simultaneous RC and unilateral RNU for PanUC, from 1996 to 2017. Kaplan-Meier estimates for remnant urothelium recurrence-free survival, metastasis-free survival, overall survival (OS), and cancer-specific survival (CSS) were performed. Cox multivariate models were constructed. RESULTS: The median follow-up was 38 months, 29.8% of patients had a recurrence, 34.3% had metastasis, 67.2% of patients died from any cause, and 37.3% died from urothelial carcinoma. Overall survival and CSS rates at 5 years were 44% and 61%, respectively. In multivariate analysis, progression to muscle-invasive bladder cancer before surgery, presence of muscle-invasive stages at RC and/or RNU, and prostatic urethra involvement were predictors for worse metastasis-free survival and CSS. Forty-one patients (61.2%) had an estimated glomerular filtration rate (eGFR) <60 mL/min before surgery and the number rose to 56 (83.5%) after surgery; 29.8% patients needed renal function replacement therapy after surgery (16 haemodialysis and 4 renal transplant). CONCLUSION: Patients with PanUC who undergo simultaneous surgery have adverse oncological (only 4 out of every 10 remain alive at 5 years) and functional outcomes (1 out of 3 will need renal function replacement therapy after surgery). Up to a third of the patients had a recurrence (urethra or contralateral kidney) within 18 months, justifying close surveillance or considering prophylactic urethrectomy. These data should help in counsel on morbidity and life expectancy.

Long-term Recurrence and Progression Patterns in a Contemporary Series of Patients with Carcinoma In Situ of the Bladder With or Without Associated Ta/T1 Disease Treated with Bacillus Calmette-Guérin: Implications for Risk-adapted Follow-up.

BACKGROUND: Limited data are available on patients with carcinoma in situ (CIS) of the bladder managed according to current clinical practice guidelines. OBJECTIVE: To assess the patterns of recurrence, progression to muscle-invasive bladder cancer (MIBC), and upper tract urothelial carcinoma (UTUC) in patients with CIS, and to compare the effectiveness of adequate versus inadequate bacillus Calmette-Guérin (BCG) immunotherapy. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 386 patients with CIS of the bladder with or without associated pTa/pT1 disease treated with BCG between 2008 and 2015. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Kaplan-Meier estimations and an inverse probability of treatment weighting (IPTW)-Cox regression were performed to compare recurrence-free survival (RFS) and progression-free survival (PFS) and UTUC incidence over time for patients who received adequate versus inadequate BCG treatment. RESULTS AND LIMITATIONS: The median follow-up was 70.5 mo. At 5 and 10 yr, RFS was 82% and 52%, PFS was 93.6% and 75.8%, and UTUC incidence was 1.7% and 2.9%, respectively. Most recurrence (73.6%) and progression (69.1%) events occurred in the first 3 yr of follow-up, while 38.7% of UTUC incident events were recorded after 5 yr of follow-up. IPTW-Cox regression revealed that patients who received BCG treatment had a lower risk of recurrence (hazard ratio [HR] 0.21, 95% confidence interval [CI] 0.13-0.34), progression (HR 0.46, 95% CI 0.25-0.87), and UTUC incidence (HR 0.24, 95% CI 0.09-0.64). Limitations include the retrospective design and potential selection bias. CONCLUSIONS: Patients with CIS of the bladder show a high risk of recurrence, progression, and UTUC incidence. Most of these outcomes occur during the first 3 yr of follow-up, but a significant proportion of the events occur at long-term follow-up. Although receipt of adequate BCG treatment improves outcomes, intensive and long-term surveillance may be warranted. PATIENT SUMMARY: We investigated the long-term cancer control outcomes for patients with carcinoma in situ (CIS; cancerous cells that have not spread from where they first formed) of the bladder. Patients with CIS have a high risk of cancer recurrence and progression. Treatment with bacillus Calmette-Guérin (BCG) improves outcomes.

Accuracy of the CUETO, EORTC 2016 and EAU 2021 scoring models and risk stratification tables to predict outcomes in high-grade non-muscle-invasive urothelial bladder cancer.

PURPOSE: Non-muscle-invasive bladder cancers (NMIBC) constitute 3-quarters of all primary diagnosed bladder tumors. For risk-adapted management of patients with NMIBC, different risk group systems and predictive models have been developed. This study aimed to externally validate EORTC2016, CUETO and novel EAU2021 risk scoring models in a multi-institutional retrospective cohort of patients with high-grade NMIBC who were treated with an adequate BCG immunotherapy. METHODS: The Kaplan-Meier estimates for recurrence-free survival and progression-free survival were performed, predictive abilities were assessed using the concordance index (C-index) and area under the curve (AUC). RESULTS: A total of 1690 patients were included and the median follow-up was 51 months. For the overall cohort, the estimates recurrence-free survival and progression-free survival rates at 5-years were 57.1% and 82.3%, respectively. The CUETO scoring model had poor discrimination for disease recurrence (C-index/AUC for G2 and G3 grade tumors: 0.570/0.493 and 0.559/0.492) and both CUETO (C-index/AUC for G2 and G3 grade tumors: 0.634/0.521 and 0.622/0.525) EAU2021 (c-index/AUC: 0.644/0.522) had poor discrimination for disease progression. CONCLUSION: Both the CUETO and EAU2021 scoring systems were able to successfully stratify risks in our population, but presented poor discriminative value in predicting clinical events. Due to the lack of data, model validation was not possible for EORTC2016. The CUETO and EAU2021 systems overestimated the risk, especially in highest-risk patients. The risk of progression according to EORTC2016 was slightly lower when compared with our population analysis.

En Bloc Versus Conventional Transurethral Resection of Bladder Tumors: A Single-center Prospective Randomized Noninferiority Trial.

BACKGROUND: It has been proposed that en bloc resection of bladder tumor (ERBT) improves the quality of tumor resection. A recent international collaborative consensus statement on ERBT underlined the lack of high-quality prospective studies precluding the achievement of solid conclusion on ERBT. OBJECTIVE: To compare conventional transurethral resection of bladder tumor (cTURBT) and ERBT. DESIGN, SETTING, AND PARTICIPANTS: This study (NCT04712201) was a prospective, randomized, noninferiority trial enrolling patients diagnosed with bladder cancer (BC) undergoing endoscopic intervention. Inclusion criteria were: tumor size ≤3 cm, three or fewer lesions, and no sign of muscle invasion and/or ureteral involvement. For a noninferiority rate in BC staging of 5% (α risk 2.5%; ß risk 20%), a total of 300 subjects were randomized to ERBT treatment at a 1:1.5 allocation ratio. INTERVENTION: TURBT and ERBT. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was the presence of detrusor muscle at final histology. Secondary outcomes include BC staging, T1 substaging, artifacts, complications, the rate of adjuvant treatment, and oncological outcomes. RESULTS AND LIMITATIONS: From April 2018 to June 2021, 300 patients met the inclusion criteria. Of these, 248 (83%) underwent the assigned intervention: 108 patients (44%) underwent cTURBT and 140 (57%) underwent ERBT. The rate of detrusor muscle presence for ERBT was noninferior to that for TURBT (94% vs 95%; p = 0.8). T1 substaging was feasible in 80% of cTURBT cases versus 100% of ERBT cases (p = 0.02). Complication rates, rates of postoperative adjuvant treatment, catheterization time, and hospital stay were comparable between the two groups (p > 0.05). The recurrence rate at median follow-up of 15 mo (interquartile range 7-28) was 18% for cTURBT versus 13% for ERBT (p = 0.16). Limitations include the single high-volume institution and the short-term follow-up. CONCLUSIONS: Our study has the highest level of evidence for comparison of ERBT versus TURBT. ERBT was noninferior to TURBT for BC staging. The rate of T1 substaging feasibility was significantly higher with ERBT. PATIENT SUMMARY: We compared two techniques for removing tumors from the bladder. The en bloc technique removes the tumor in one piece and is not inferior to the conventional method in terms of the quality of the surgical resection and cancer staging assessment.

Mitomycin C allergy after passive and device-assisted hyperthermia for non-muscle invasive bladder cancer treatment: A retrospective cohort from a high-volume center.

INTRODUCTION: Mitomycin C (MMC) is one of the most frequently utilized intravesical chemotherapy drugs for the management of non-muscle-invasive bladder cancer (NMIBC). Allergic reactions (Type 4 delayed hypersensitivity) are seldomly reported in the literature but not so infrequent in daily practice, its incidence has been increasing with the use of device-assisted hyperthermia. This study aims to identify the incidence, risk factors, and clinical characteristics of patients with allergic reactions to MMC. PATIENTS AND METHODS: Single-center retrospective cohort from June 2014 to August 2018. Patients with intermediate or high-risk NMIBC were included. Patients received passive MMC (4 weekly and eleven monthly instillations of 40mg of MMC) or Chemohyperthermia (CHT) with MMC (6 weekly and 6-monthly instillations, heated at 43°C [+/- 0.5°C] using Combat BRS). RESULTS: We included 258 patients (MMC = 157, CHT = 101) and found 7 (4.4%) suspected and 4 confirmed (2.4%) allergies in the passive MMC group and 11 suspected (10.9%) and 7 confirmed (6.9%) in the CHT group. The mean number of instillations received before developing the allergy was 6 in the passive MMC and 5 in the CHT group. Seven out of 18 suspected allergy cases were pseudo-allergic reactions with negative allergy tests. Early postoperative MMC instillation was associated with an increased risk of allergy (OR 2.47 [CI 1.39-4.36], P = 0.001), while neither history of atopy nor history of other medications allergy was found to increase the risk. CONCLUSION: MMC allergy risk is increased with the use of device-assisted hyperthermia with an incidence of 2.4% for passive MMC and 6.9% for CHT. History of prior allergies does not seem to increase the risk of developing MMC allergy. In this series 38% of suspected cases were found to be pseudo-allergic reactions, highlighting the need to confirm the diagnosis before definitively stopping the treatment.

Contemporary outcomes of bladder carcinoma in situ treated with an adequate bacille Calmette-Guérin immunotherapy.

OBJECTIVE: To assess whether bacillus Calmette-Guérin (BCG) responsiveness after initiation of an adequate BCG treatment (at least five of six instillations of induction and at least two of three instillations of maintenance) impacts oncological outcomes in patients with carcinoma in situ (CIS) of the bladder treated with BCG immunotherapy. PATIENTS AND METHODS: Data were available for 193 patients with bladder CIS with or without associated cTa/cT1 disease who received an adequate BCG treatment between 2008 and 2015. Bladder biopsies were taken at 6 months and patients were then stratified as either BCG responsive (negative biopsies) or BCG unresponsive (positive biopsies). Inverse probability weighting (IPW)-adjusted Kaplan-Meier and IPW-adjusted Cox regression were performed to compare progression-free survival (PFS), radical cystectomy-free survival (RCFS), overall survival OS, and cancer-specific survival (CSS) in the two groups. RESULTS AND LIMITATIONS: Comparing the BCG-responsive and BCG-unresponsive groups, IPW-adjusted Kaplan-Meier analysis revealed, respectively, a median (interquartile range) of PFS of 9 (5-15) vs 48.5 (28-77) months (P = 0.001), a RCFS of 11 (9-15) vs 49 (24-76) months (P < 0.001), and a CSS of 25 (13-60) vs 109 (78-307) months (P = 0.004). On IPW-adjusted Cox regression analysis, BCG-unresponsive patients had a worse PFS (hazard ratio [HR] 3.40, 95% confidence interval [CI] 1.59-7.27), RCFS (HR 3.52, 95% CI 1.77-7), and CSS (HR 4.42, 95% CI 1.95-10.01). We found no significant differences for OS. CONCLUSION: Using an IPW method we found that lack of response after initiation of an adequate BCG treatment has prognostic implications beyond identification of complete response in patients with CIS. BCG-unresponsive patients, satisfying the novel definition of BCG unresponsive, showed a poor PFS, RCFS, and CSS. In this setting, the patients should be counselled regarding RC as a first option or enrolled in a clinical trial if they refuse RC or are unfit for surgery.

Impact of clinical and pathological subtypes of carcinoma in situ (CIS) of the bladder: Lessons learned from long-term follow-up of a series of CIS patients treated with BCG.

OBJECTIVE: Some attempts have previously been made to stratify patients with CIS for the purpose of risk-adapted clinical management and clinical trial design. In particular, two classification systems have been proposed: clinical classification, comprising primary (P-CIS), concomitant (C-CIS), and secondary (S-CIS) disease, and pathological classification, comprising P-CIS, cTa-CIS, and cT1-CIS. The aim of the present study was to assess the impact of both classifications on BCG response, recurrence-free survival (RFS), progression-free survival (PFS), overall survival (OS), and cancer-specific survival (CSS). PATIENTS AND METHODS: We performed a retrospective analysis of 386 patients with bladder CIS, with or without associated cTa/cT1 disease, treated with BCG instillations between 2008 and 2015. Patients were stratified according to the two classification systems. Cox multivariate regression models were used to assess the impact of these subtypes on BCG response, RFS, PFS, OS, and CSS. We also performed a cumulative meta-analysis according to PRISMA guidelines. RESULTS: The median follow-up was 70.5 months. According to the clinical classification, 34 (8.8%) patients had P-CIS, 81 (21%) S-CIS, and 271 (70.2%) C-CIS. The pathological classification showed 34 (8.8%) patients to have P-CIS, 190 (49.2%) cTa-CIS, and 162 (42%) cT1-CIS. In the overall cohort, BCG response was reported in 296 (76.7%); 159 (41.2%) had recurrence, 55 (14.2%) had progression, and 67 (17.4%) underwent radical cystectomy. Death from any cause was recorded in 135 (35%) and death from urothelial carcinoma in 38 (9.9%). Cox multivariate regression analysis showed that neither clinical classification nor pathological classification is an independent predictive factor for BCG response, RFS, PFS, OS, or CSS after adjusting for confounders. In the pooled meta-analysis, two studies and the present series were included for evidence synthesis, recruiting a total of 941 patients. We found no statistically significant difference across the groups for both classifications with respect to BCG response, RFS, PFS, and CSS. CONCLUSIONS: Currently, the supporting evidence for an impact of clinical classification and pathological classification on oncological outcomes of CIS of the bladder is insufficient to justify their use to guide clinical management or follow-up.

Predicting Recurrence and Progression in Patients with Non-Muscle-Invasive Bladder Cancer: Systematic Review on the Performance of Risk Stratification Models.

BACKGROUND: Several classifications have been reported to stratify non-muscle-invasive bladder cancer (NMIBC) in risk groups according to the probability of recurrence and progression. OBJECTIVE: To systematically review the current evidence regarding risk stratification of NMIBC. METHODS: The systematic review was performed in accordance with the PRISMA statement. Studies providing data on development and/or external validation cohorts of models and risk stratification tables for recurrence and/or progression for patients with NMIBC, reporting at least one discrimination measure (AUC or C-Index) were included. RESULTS: Twenty-five studies involving 22,737 patients were included. Six classifications were identified, three of them were predictive models (EORTC, CUETO, EAU 2021) and three were based on expert opinion (EAU 2020, AUA, NCCN). A high risk of bias was present in the majority of the studies. Certain heterogenicity was found among the studies regarding adjuvant therapy, postoperative instillation or second resection. The definition of oncological outcomes was not standardized in the included studies. CUETO and EORTC scoring systems are the most validated. In general, validations showed a poor discrimination capability to predict recurrence, slightly better for progression. The EAU 2021 model overestimates the risk of progression in patients treated with BCG. Carcinoma in situ is underrepresented in all the studies analyzed. CONCLUSIONS: The existing classifications show poor discrimination capability for recurrence and possibly helpful discrimination capability for progression in NMIBC patients. These results highlight the unmet need to develop novel accurate risk models for patients with NMIBC, which could be improved with the combination of clinicopathological and molecular information.

Endoscopic exploration directly impacts clinical decision making in the management of patients with suspected upper tract urothelial carcinoma following radical cystectomy.

OBJECTIVES: To assess whether the use of endoscopic exploration (EE) as a routine diagnostic tool in patients with clinical suspicion of upper tract urothelial carcinoma (UTUC) following radical cystectomy (RC) significantly impacts management decision-making and to describe the oncological outcomes of patients with UTUC after RC. MATERIALS AND METHODS: We performed a retrospective review of medical records of patients with suspicion of UTUC after RC between 2000 and 2019. Patient demographics, clinicopathological features, treatments, and outcomes were analyzed. RESULTS: We identified 60 patients with suspicion of UTUC. After diagnostic work-up, 16 were submitted to radical nephroureterectomy (RNU) and 44 underwent diagnostic EE. After EE, a further 18/44 (40.9%) were submitted to RNU, while no evidence of tumor was found in 12 (27.3%) and the remaining 12 (27.3%) underwent endoscopic treatment (ET). Thus, in 24/44 (54.5%) patients the primary treatment strategy, i.e., RNU, was altered. Twenty-nine (85.3%) of the 34 patients who underwent RNU had high-grade tumors and 16 (47%) had the muscle-invasive disease. In the ET group, 6 (50%) had high-grade tumors and 10 (83.4%) had tumors less than 2 cm. The 5-year estimated recurrence-free survival and cancer-specific survival were, respectively, 58.4% and 45.6% in the RNU group and 25% and 80.8% in the ET group. CONCLUSION: EE significantly impacts clinical decision-making in patients with suspicion of UTUC after RC, resulting in a change in treatment strategy in approximately half of the patients. UTUC following RC has a poor prognosis and although RNU is the gold standard, ET could be considered in a selected group of patients.

Diagnostic accuracy of ureteroscopic biopsy in predicting stage and grade at final pathology in upper tract urothelial carcinoma: Systematic review and meta-analysis.

OBJECTIVE: To assess the accuracy of ureteroscopic (URS) biopsies in predicting stage and grade at final pathology in upper tract urothelial carcinoma (UTUC). MATERIALS AND METHODS: The meta-analysis was performed in accordance with the PRISMA statement. Studies providing data on tumor stage and grade at URS biopsy and surgical specimens were included. The negative predictive value (NPV) implies concordance between the absence of subepithelial connective tissue invasion or the presence of low-grade tumors at URS biopsy and the absence of a muscle-invasive disease in the final pathology. RESULTS: A total of 23 studies were included (3547 patients). The stage-to-stage match between URS biopsy/final pathology showed a positive predictive value (PPV) for cT1+/muscle-invasive disease of 94% (95% CI: 84%-100%) and a NPV for cTa-Tis/non-muscle-invasive disease of 60% (95% CI: 52%-68%). The grade-to-grade match between URS biopsy/final pathology was 66% (95% CI: 55%-77%) for low-grade (cLG/pLG) tumors and 97% (95% CI: 94%-98%) for high-grade (cHG/pHG) tumors. The PPV for cHG/muscle-invasive disease was 60% (95% CI: 54%-66%) and the NPV for cLG/non-muscle-invasive disease was 77% (95% CI: 73%-82%). The undergrading and understaging rates were 32% (95%CI: 25%-38%) and 46% (95% CI: 38%-54%), respectively. CONCLUSIONS: There is a substantial correlation between tumor grade at URS biopsy and the final pathology. The identification of cHG tumors and subepithelial connective tissue invasion (cT1+) in URS biopsy showed a moderate and a strong correlation with invasive UTUC, respectively. Nevertheless, a certain risk of undergrading and understaging should be assumed.

Carcinoma in situ of the bladder: why is it underdetected?

PURPOSE OF REVIEW: The standard diagnosis of carcinoma in situ (CIS) of the bladder, based on white light cystoscopy and urine cytology, is limited because CIS can vary from normal-appearing mucosa to a lesion indistinguishable from an inflammatory process. Intravesical instillation of Bacillus Calmette-Guerin (BCG) remains first-line therapy; however, a significant proportion of cases persist or recur after BCG treatment. This review summarizes recent improvements in the detection and treatment of CIS. RECENT FINDINGS: The new optical technologies improve CIS detection, with a potential positive impact on oncological outcomes. The usefulness of MRI-photodynamic diagnosis fusion transurethral resection in CIS detection is unclear and further studies are needed. BCG instillation remains the first-line therapy in CIS patients and seems to improve recurrence and progression rates, especially with the use of maintenance. Intravesical device-assisted therapies could be effective in both BCG-naïve and BCG-unresponsive CIS patients, but further studies are ongoing to clarify their clinical benefit. A phase II clinical trial with pembrolizumab has shown the potential effectiveness of immune checkpoint inhibitors in BCG-unresponsive CIS patients and further trials are ongoing. SUMMARY: New optical techniques increase the CIS detection rate. BCG instillation remains the first-line treatment. Immune checkpoint inhibitors could be a future alternative in BCG-naïve and BCG-unresponsive CIS patients.