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Background: Follow-up after radical cystectomy (RC) for bladder cancer can be divided into oncological and functional surveillance. It remains unclear how follow-up after RC should ideally be scheduled. The aim of this report was to gain insight into the organization of follow-up after RC in Europe, for which we conducted a roundtable inventory within the EAU Young Academic Urologists Urothelial Cancer working group. Methods: An inventory semi-structured survey was performed among urologists of the EAU Young Academic Urologists Urothelial Cancer working group to describe the organization of follow-up. The surveys were analyzed using a deductive approach. Similarities and differences in follow-up after RC for bladder cancer were described. Results: The survey included 11 urologists from six different European countries. An institutional follow-up scheme was used by six (55%); three (27%) used a national or international guideline, and two (18%) indicated that there was no defined follow-up scheme. Major divergent aspects included the time points of follow-up, the frequency, and the end of follow-up. Six centers (55%) adopted a risk-adapted follow-up approach tailored to (varying) patient and tumor characteristics. Laboratory tests and CT scans were used in all cases; however, the intensity and frequency varied. Functional follow-up overlapped with oncological follow-up in terms of frequency and duration. Patient-reported outcome measures were only used by two (18%) urologists. Conclusions: Substantial variability exists across European centers regarding the follow-up after RC for bladder cancer. This highlights the need for an international analysis focusing on its organization and content as well as on opportunities to improve patients' needs during follow-up after RC. [ABSTRACT FROM AUTHOR]

In non-muscle invasive bladder cancer, Bacillus Calmette–Guérin (BCG) responders benefit from strong Th1-type inflammatory and T cell responses mediating tumor rejection. However, the corresponding lack of anti-inflammatory Th2-type immunity impairs tissue repair in the bladder wall and facilitates the development of cystitis, causing urinary pain, urgency, incontinence, and frequency. Mechanistically, the leakage of the glycosaminoglycan (GAG) layer enables an influx of potassium ions, bacteria, and urine solutes towards the underlying bladder tissue, promoting chronic inflammation. Treatments directed towards re-establishing this mucopolysaccharide-based protective barrier are urgently needed. We discuss the pathomechanisms, as well as the therapeutic rationale of how chondroitin and hyaluronic acid instillations can reduce or prevent BCG-induced irritative bladder symptoms. Moreover, we present a case series of five patients with refractory BCG-induced cystitis successfully treated with combined chondroitin and hyaluronic acid instillations. [ABSTRACT FROM AUTHOR]

BCG is the most efficient adjuvant therapy for high-risk, non-muscle-invasive bladder cancer (NMIBC). Both innate and adaptive immune responses have been implicated in BCG-mediated effects. BCG vaccination can boost innate immune responses via trained immunity (TI), resulting in an increased resistance to respiratory viral infections. Here we evaluated for the first time whether intravesical application of BCG triggers increased immunity against SARS-CoV-2 in patients with high-risk NMIBC. Serum and peripheral blood mononuclear cells (PBMCs) from heparinized whole blood samples of 11 unvaccinated SARSCoV-2-naïve high-risk NMIBC patients were collected at baseline and during BCG treatment in a pre-COVID-19 era. To examine B-cell or T cell-dependent adaptive immunity against SARS-CoV-2, sera were tested for the presence of SARS-CoV-2 neutralizing antibodies. Using a SARS-CoV-2 peptide pool, virusspecific T cells were quantified via IFNg ELISpot assays. To analyze innate immune responses, mRNA and protein expression levels of pro- and anti-inflammatory cytokines were measured after a 24-hour stimulation of PBMCs with either BCG or SARS-CoV-2 wildtype. ATAC-sequencing was performed to identify a potential epigenetic reprogramming in immune cells. We neither identified SARS-CoV-2 neutralizing antibodies nor SARS-CoV-2-reactive T cells, indicating that intravesical BCG did not induce adaptive immunity against SARS-CoV-2. However, a significant increase in mRNA as well as protein expression of IL-1β, IL-6 and TNFa, which are key cytokines of trained immunity, could be observed after at least four intravesical BCG instillations. Genomic regions in the proximity of TI genes (TLR2, IGF1R, AKT1, MTOR, MAPK14, HSP90AA1) were more accessible during BCG compared to baseline. Although intravesical BCG did not induce adaptive immune responses, repetitive intravesical instillations of BCG induced circulating innate immune cells that produce TI cytokines also in response to SARS-CoV-2. [ABSTRACT FROM AUTHOR]

Simple Summary: Lymph node involvement is a prognostic determinant in the diagnostic work-up and management of muscle-invasive bladder cancer. Thus, it is crucial to provide an accurate staging of the bladder tumor to better identify the best therapeutic strategies to improve the chances of survival and the quality of life of patients affected by bladder cancer. Positron Emission Tomography/Computed Tomography (PET/CT) has been increasingly used in bladder cancer staging to improve the accuracy of lymph node detection and to overcome the lack of sensitivity and the understaging showed by conventional imaging. The aim of this narrative literature review is to provide an overview of the current evidence on the use of 18F-FDG PET/CT in the diagnosis, staging, and restaging of bladder cancer, with a particular focus on its sensitivity and specificity for the detection of LN metastasis. We aim to provide clinicians with a better understanding of 18F-FDG PET/CT's potential benefits and limitations in clinical practice. Despite the heterogeneity of the studies in the literature and the lack of a consensus, 18F-FDG PET/CT provides important incremental staging and restaging information that can potentially influence the clinical management of patients affected by muscle-invasive bladder cancer. Introduction: Lymph node (LN) involvement is a crucial determinant of prognosis for patients with bladder cancer, and an accurate staging is of utmost importance to better identify timely and appropriate therapeutic strategies. To improve the accuracy of LN detection, as an alternative to traditional methods such as CT or MRI, 18F-FDG PET/CT has been increasingly used. 18F-FDG PET/CT is also used in post-treatment restaging after neoadjuvant chemotherapy. The aim of this narrative literature review is to provide an overview of the current evidence on the use of 18F-FDG PET/CT in the diagnosis, staging, and restaging of bladder cancer, with a particular focus on its sensitivity and specificity for the detection of LN metastasis. We aim to provide clinicians with a better understanding of 18F-FDG PET/CT's potential benefits and limitations in clinical practice. Materials and Methods: We designed a narrative review starting from a wide search in the PubMed/MEDLINE and Embase databases, selecting full-text English articles that have examined the sensibility and specificity of PET/CT for nodal staging or restaging after neoadjuvant therapy in patients with bladder cancer. The extracted data were analyzed and synthesized using a narrative synthesis approach. The results are presented in a tabular format, with a summary of the main findings of each study. Results: Twenty-three studies met the inclusion criteria: fourteen studies evaluated 18F-FDG PET/CT for nodal staging, six studies examined its accuracy for restaging after neoadjuvant therapy, and three studies evaluated both applications. To date, the use of F-18 FDG PET/TC for detection of LN metastasis in bladder cancer is controversial and uncertain: some studies showed low accuracy rates, but over the years other studies have reported evidence of high sensitivity and specificity. Conclusions: 18F-FDG PET/CT provides important incremental staging and restaging information that can potentially influence clinical management in MIBC patients. Standardization and development of a scoring system are necessary for its wider adoption. Well-designed randomized controlled trials in larger populations are necessary to provide consistent recommendations and consolidate the role of 18F-FDG PET/CT in the management of bladder cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Bacillus of Calmette-Guérin (BCG) is the gold standard as per adjuvant intravesical treatment for intermediate and high-risk non-muscle invasive bladder cancer (NMIBC). Nevertheless, drug-related toxicity, compliance, and a shortage of BCG availability make the completion of the planned treatment schedule challenging in many patients, thus possibly impacting survival outcomes. No one specific BCG strain out of the several available ones worldwide has so far demonstrated its superiority profile in prolonging time to recurrence and progression. In our systematic review and network meta-analysis, we compared to most widely adopted BCG strains and demonstrated that BCG strain Tice, RIVM, and Tokyo 172 could display potential enhanced benefits, thus possibly supporting the use of such strains for future BCG trials in NMIBCs. Background: In an era of Bacillus of Calmette-Guérin (BCG) shortages, the comparative efficacy from different adjuvant intravesical BCG strains in non-muscle invasive bladder cancer (NMIBC) has not been clearly elucidated. We aim to compare, through a systematic review and meta-analysis, the cumulative BC recurrence rates and the best efficacy profile of worldwide available BCG strains over the last forty years. Methods: PubMed, Scopus, Web of Science, Embase, and Cochrane databases were searched from 1982 up to 2022. A meta-analysis of pooled BC recurrence rates was stratified for studies with ≤3-y vs. >3-y recurrence-free survival (RFS) endpoints and the strain of BCG. Sensitivity analysis, sub-group analysis, and meta-regression were implemented to investigate the contribution of moderators to heterogeneity. A random-effect network meta-analysis was performed to compare BCG strains on a multi-treatment level. Results: In total, n = 62 series with n = 15,412 patients in n = 100 study arms and n = 10 different BCG strains were reviewed. BCG Tokyo 172 exhibited the lowest pooled BC recurrence rate among studies with ≤3-y RFS (0.22 (95%CI 0.16–0.28). No clinically relevant difference was noted among strains at >3-y RFS outcomes. Sub-group and meta-regression analyses highlighted the influence of NMIBC risk-group classification and previous intravesical treated categories. Out of the n = 11 studies with n = 7 BCG strains included in the network, BCG RIVM, Tice, and Tokyo 172 presented with the best-predicted probability for efficacy, yet no single strain was significantly superior to another in preventing BC recurrence risk. Conclusion: We did not identify a BCG stain providing a clinically significant lower BC recurrence rate. While these findings might discourage investment in future head-to-head randomized comparison, we were, however, able to highlight some potential enhanced benefits from the genetically different BCG RIVM, Tice, and Tokyo 172. This evidence would support the use of such strains for future BCG trials in NMIBCs. [ABSTRACT FROM AUTHOR]

Objective: To assess the prevalence of frailty, a status of vulnerability to stressors leading to adverse health events, in bladder cancer patients undergoing radical cystectomy (RC), and test the impact of frailty measurements on postoperative adverse outcomes. Methods: A systematic review of English-language articles published up to April 2020 was performed. Electronic databases were searched to quantify the frailty prevalence in RC patients and assess the predictive ability of frailty indexes on RC-related outcomes as postoperative complications, early mortality, hospitalization length (LOS), costs, discharge dispositions, readmission rate. Results: Eleven studies were selected. Patients' frailty was identified by Johns Hopkins indicator (JHI) in two studies, 11-item modified Frailty Index (mFI) in four, 5-item simplified FI (sFI) in three, 15-point mFI in one, Fried Frailty Criteria in one. Considering all the frailty measurements applied, 8% and 31% of patients were frail or pre-frail, respectively. Frail (43%) and pre-frail patients (35%) were more at risk of major complications compared to non-frail (27%) using sFI; with JHI the percentages of frail and non-frail were 53% versus 19%. According to JHI and mFI frailty was related to longer LOS and higher costs. JHI identified that 3% of frail patients experience in-hospital mortality versus 1.5% of non-frail. Finally, using sFI, frail (28%), and pre-frail (19%) were more likely to be discharged non-home compared to non-frail patients (8%) and had a higher risk of 30-day mortality (4% and 2% versus 1%). Conclusions: Almost half of RC patients were frail or pre-frail, conditions significantly related to an increased risk of postoperative adverse events with higher rates of major complications and early mortality. The most-used frailty index was mFI, while JHI and sFI resulted the most reliable to predict early postoperative RC-related adverse outcomes and should be routinely included in clinical practice after better standardization throughout prospective comparative studies. Abbreviations: ACG: Adjusted Clinical Groups; ACS: American College Surgeons; AUC: area under the curve; BCa: bladder cancer; CCI: Charlson Comorbidity Index; CSHA-FI: Canadian Study of Health and Aging Frailty Index; CCS: Clavien-Dindo Classification Score; ERAS: Enhanced Recovery After Surgery; FFC: Fried Frailty Criteria; (e)(m)(s)FI: (extended) (modified) (simplified) Frailty Index; ICU: intensive care unit; IQR: interquartile range; (p)LOS: (prolonged) length of hospital stay; NSQIP: National Surgical Quality Improvement Program; OR: odds ratio; (O)PN: (open) partial nephrectomy; PRISMA: Preferred Reporting Items for Systematic reviews and Meta-Analyses; (O)(RA)RC: (open)(robot-assisted) radical cystectomy; (O)RN: (open) radical nephrectomy; ROC: receiver operating characteristic; RNU: radical nephroureterectomy; (R)RP: (retropubic) radical prostatectomy; RR: relative risk; THCs: total hospital charges; nephrectomy; UD: urinary diversion [ABSTRACT FROM AUTHOR]

Simple Summary: Intravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer. Different BCG strains are currently available and the superiority of any BCG strain over another could not be demonstrated yet. We compared the efficacy of two BCG strains: RIVM and TICE, respectively. In this propensity-score matched cohort study, we showed no particular survival benefit of TICE vs RIVM in the case of high-risk disease. Nevertheless, stratifying our data for re-staging procedures and for those who received BCG maintenance, we identified BCG TICE to improve RFS independently. Herein, we corroborated the importance of performing a routine secondary resection followed by an adequate maintenance course of BCG. Future larger prospective randomized head-to-head trials are needed to further elucidate this important topic, especially in this era of BCG shortage. Background: Intravesical immunotherapy with bacillus Calmette–Guerin (BCG) is the standard therapy for high-risk non-muscle invasive bladder cancer (NMIBC). The superiority of any BCG strain over another could not be demonstrated yet. Methods: Patients with NMIBCs underwent adjuvant induction ± maintenance schedule of intravesical immunotherapy with either BCG TICE or RIVM at two high-volume tertiary institutions. Only BCG-naïve patients and those treated with the same strain over the course of follow-up were included. One-to-one (1:1) propensity score matching (PSM) between the two cohorts was utilized to adjust for baseline demographic and tumor characteristics imbalances. Kaplan–Meier estimates and multivariable Cox regression models according to high-risk NMIBC prognostic factors were implemented to address survival differences between the strains. Sub-group analysis modeling of the influence of routine secondary resection (re-TUR) in the setting of the sole maintenance adjuvant schedule for the two strains was further performed. Results: 852 Ta-T1 NMIBCs (n = 719, 84.4% on TICE; n = 133, 15.6% on RIVM) with a median of 53 (24–77) months of follow-up were reviewed. After PSM, no differences at 5-years RFS, PFS, and CSS at both Kaplan–Meier and Cox regression analyses were detected for the whole cohort. In the sub-group setting of full adherence to European/American Urology Guidelines (EAU/NCCN), BCG TICE demonstrated longer 5-years RFS compared to RIVM (68% vs. 43%, p = 0.008; HR: 0.45 95% CI 0.25–0.81). Conclusion: When routinely performing re-TUR followed by a maintenance BCG schedule, TICE was superior to RIVM for RFS outcomes. However, no significant differences were detected for PFS and CSS, respectively. [ABSTRACT FROM AUTHOR]

Background and Purpose: The European Association of Urology guidelines recommend restaging transurethral resection of bladder tumours (reTURB) 2–6 weeks after primary TURB. However, in clinical practice some patients undergo a second TURB procedure after Bacillus Calmette-Guérin immunotherapy (BCG)induction. To date, there are no studies comparing post-BCG reTURB with the classic pre-BCG approach. The aim of this study was to assess whether the performance of reTURB after BCG induction in T1HG bladder cancer is related to potential oncological benefits. Materials and Methods: Data from 645 patients with primary T1HG bladder cancer treated between 2001 and 2019 in 12 tertiary care centres were retrospectively reviewed. The study included patients who underwent reTURB before BCG induction (Pre-BCG group: 397 patients; 61.6%) and those who had reTURB performed after BCG induction (Post-BCG group: 248 patients, 38.4%). The decision to perform reTURB before or after BCG induction was according to the surgeon's discretion, as well as a consideration of local proceedings and protocols. Due to variation in patients' characteristics, both propensity-score-matched analysis (PSM) and inverse-probability weighting (IPW) were implemented. Results: The five-year recurrence-free survival (RFS) was 64.7% and 69.1% for the Pre- and Post-BCG groups, respectively, and progression-free survival (PFS) was 82.7% and 83.3% for the Pre- and Post-BCG groups, respectively (both: p > 0.05). Similarly, neither RFS nor PFS differed significantly for a five-year period or in the whole time of observation after the PSM and IPW matching methods were used. Conclusions: Our results suggest that there might be no difference in recurrence-free survival and progression-free survival rates, regardless of whether patients have reTURB performed before or after BCG induction. [ABSTRACT FROM AUTHOR]