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Grade is an important determinant of progression in non-muscle-invasive bladder cancer. Although the World Health Organization (WHO) 2004/2016 grading system is recommended, other systems such as WHO1973 and WHO1999 are still widely used. Recently, a hybrid (three-tier) system was proposed, separating WHO2004/2016 high grade (HG) into HG/grade 2 (G2) and HG/G3 while maintaining low grade. We assessed the prognostic performance of HG/G3 and HG/G2. Three independent cohorts with 9712 primary (first diagnosis) Ta-T1 bladder tumors were analyzed. Time to progression was analyzed with cumulative incidence functions and Cox regression models. Harrell's C-index was used to assess discrimination. Time to progression was significantly shorter for HG/G3 than for HG/G2 in multivariable analyses (cohort 1: hazard ratio [HR] = 1.92; cohort 2: HR = 2.51, and cohort 3: HR = 1.69). Corresponding progression risks at 5 yr were 18%, 20%, and 18% for HG/G3 versus 7.3%, 7.5%, and 9.3% for HG/G2, respectively. Cox models using hybrid grade performed better than models with WHO2004/2016 (all cohorts; p < 0.001). For the three cohorts, C-indices for WHO2004/2016 were 0.69, 0.62, and 0.75, while, for hybrid grade, C-indices were 0.74, 0.68, and 0.78, respectively. Subdividing the HG category into HG/G2 and HG/G3 stratifies time to progression and supports the recommendation to adopt the hybrid grading system for Ta/T1 bladder cancers., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Objective: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options., Methods: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions., Key Findings and Limitations: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials., Conclusions and Clinical Implications: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC., (Copyright © 2024 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background and Objective: This publication represents a summary of the updated 2024 European Association of Urology (EAU) guidelines for non-muscle-invasive bladder cancer (NMIBC), TaT1, and carcinoma in situ. The information presented herein is limited to urothelial carcinoma, unless specified otherwise. The aim is to provide practical recommendations on the clinical management of NMIBC with a focus on clinical presentation., Methods: For the 2024 guidelines on NMIBC, new and relevant evidence was identified, collated, and appraised via a structured assessment of the literature. Databases searched included Medline, EMBASE, and the Cochrane Libraries. Recommendations within the guidelines were developed by the panel to prioritise clinically important care decisions. The strength of each recommendation was determined according to a balance between desirable and undesirable consequences of alternative management strategies, the quality of the evidence (including the certainty of estimates), and the nature and variability of patient values and preferences., Key Findings and Limitations: Key recommendations emphasise the importance of thorough diagnosis, treatment, and follow-up for patients with NMIBC. The guidelines stress the importance of defining patients' risk stratification and treating them appropriately., Conclusions and Clinical Implications: This overview of the 2024 EAU guidelines offers valuable insights into risk factors, diagnosis, classification, prognostic factors, treatment, and follow-up of NMIBC. These guidelines are designed for effective integration into clinical practice., (Copyright © 2024 European Association of Urology. All rights reserved.)

Context: The European Association of Urology (EAU) guidelines panel on upper urinary tract urothelial carcinoma (UTUC) has updated the guidelines to aid clinicians in evidence-based management of UTUC., Objective: To provide an overview of the EAU guidelines on UTUC as an aid to clinicians., Evidence Acquisition: The recommendations provided in these guidelines are based on a review of the literature via a systematic search of the PubMed, Ovid, EMBASE, and Cochrane databases. Data were searched using the following keywords: urinary tract cancer, urothelial carcinomas, renal pelvis, ureter, bladder cancer, chemotherapy, ureteroscopy, nephroureterectomy, neoplasm, (neo)adjuvant treatment, instillation, recurrence, risk factors, metastatic, immunotherapy, and survival. The results were assessed by a panel of experts., Evidence Synthesis: Even though data are accruing, for many areas there is still insufficient high-level evidence to provide strong recommendations. Patient stratification on the basis of histology and clinical examination (including imaging) and assessment of patients at risk of Lynch syndrome will aid management. Kidney-sparing management should be offered as a primary treatment option to patients with low-risk UTUC and two functional kidneys. In particular, for patients with high-risk or metastatic UTUC, new treatment options have become available. In high-risk UTUC, platinum-based chemotherapy after radical nephroureterectomy, and adjuvant nivolumab for unfit or patients who decline chemotherapy, are options. For metastatic disease, gemcitabine/carboplatin chemotherapy is recommended as first-line treatment for cisplatin-ineligible patients. Patients with PD-1/PD-L1-positive tumours should be offered a checkpoint inhibitor (pembrolizumab or atezolizumab)., Conclusions: These guidelines contain information on the management of individual patients according to the current best evidence. Urologists should take into account the specific clinical characteristics of each patient when determining the optimal treatment regimen according to the risk stratification of these tumours., Patient Summary: Cancer of the upper urinary tract is rare, but because 60% of these tumours are invasive at diagnosis, timely and appropriate diagnosis is most important. A number of known risk factors exist., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: Adjuvant intravesical chemotherapy following tumour resection is recommended for intermediate-risk non-muscle-invasive bladder cancer (NMIBC)., Objective: To assess the efficacy and safety of adjuvant intravesical chemohyperthermia (CHT) for intermediate-risk NMIBC., Design, Setting, and Participants: HIVEC-II is an open-label, phase 2 randomised controlled trial of CHT versus chemotherapy alone in patients with intermediate-risk NMIBC recruited at 15 centres between May 2014 and December 2017 (ISRCTN 23639415). Randomisation was stratified by treating hospital., Interventions: Patients were randomly assigned (1:1) to adjuvant CHT with mitomycin C at 43°C or to room-temperature mitomycin C (control). Both treatment arms received six weekly instillations of 40 mg of mitomycin C lasting for 60 min., Outcome Measurements and Statistical Analysis: The primary endpoint was 24-mo disease-free survival as determined via cystoscopy and urinary cytology. Analysis was by intention to treat., Results: A total of 259 patients (131 CHT vs 128 control) were randomised. At 24 mo, 42 patients (32%) in the CHT group and 49 (38%) in the control group had experienced recurrence. Disease-free survival at 24 mo was 61% (95% confidence interval [CI] 51-69%) in the CHT arm and 60% (95% CI 50-68%) in the control arm (hazard ratio [HR] 0.92, 95% CI 0.62-1.37; log-rank p = 0.8). Progression-free survival was higher in the control arm (HR 3.44, 95% CI 1.09-10.82; log-rank p = 0.02) on intention-to-treat analysis but was not significantly higher on per-protocol analysis (HR 2.87, 95% CI 0.83-9.98; log-rank p = 0.06). Overall survival was similar (HR 2.55, 95% CI 0.77-8.40; log-rank p = 0.09). Patients undergoing CHT were less likely to complete their treatment (n =75, 59% vs n = 111, 89%). Adverse events were reported by 164 patients (87 CHT vs 77 control). Major (grade III) adverse events were rare (13 CHT vs 7 control)., Conclusions: CHT cannot be recommended over chemotherapy alone for intermediate-risk NMIBC. Adverse events following CHT were of low grade and short-lived, although patients were less likely to complete their treatment., Patient Summary: The HIVEC-II trial investigated the role of heated chemotherapy instillations in the bladder for treatment of intermediate-risk non-muscle-invasive bladder cancer. We found no cancer control benefit from heated chemotherapy instillations over room-temperature chemotherapy. Adverse events following heated chemotherapy were low grade and short-lived, although these patients were less likely to complete their treatment., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Clinical outcomes from non-muscle-invasive bladder cancer (NMIBC) are partly determined by the quality of initial interventions. To improve and standardise treatment for cancer, Scotland implemented a national Quality Performance Indicator (QPI) programme for bladder cancer (BC)., Objective: To evaluate compliance with specific quality indicators (QIs) related to transurethral resection of bladder tumour (TURBT) and to understand clinical outcomes from NMIBC following the introduction of the QPI programme., Design, Setting, and Participants: Within a robust governance framework, 12 mandatory evidence-based QPIs were implemented nationally in April 2014. We report prospectively collected data for all new BC patients (between April 2014 and March 2017). We include follow-up data for 2689 patients., Intervention: The TURBT-related QPIs were (1) using a bladder diagram, (2) single post-TURBT instillation of mitomycin C (SPI-MMC), (3) detrusor muscle (DM) in the specimen, and (4) early re-TURBT in high-risk NMIBC., Outcome Measurements and Statistical Analysis: We measured compliance with these QPIs and (1) recurrence rate at first follow-up cystoscopy (RRFFC), (2) rates of residual cancer, and (3) pT2 cancer at re-TURBT. Associations between QPI compliance, tumour features, and outcomes were assessed with multivariable logistic regression models., Results and Limitations: Among 4246 new BC patients, SPI-MMC was used in 67% (2029/3023) NMIBC patients. In 1860 NMIBC patients undergoing TURBT, RRFFC, rate of residual cancer, and rate of pT2 at re-TURBT were 13% (116/888), 33% (212/653), and 2.9% (19/653), respectively. SPI-MMC was associated with lower RRFFC, independent of all variables including hospital volume and surgeon. Presence of DM in the specimen halved the likelihood of residual disease in pT1 cancers. The main limitation is the lack of a pre-QPI introduction cohort for comparison., Conclusions: The implementation of a QI programme in Scotland appears to facilitate high-quality TURBT, which in a real-world setting is associated with low early recurrence/residual cancer and accurate pathological staging., Patient Summary: Following the first 3 yr of implementing a novel Quality Performance Indicator (QPI) programme in Scotland, we assessed compliance and outcomes in non-muscle-invasive bladder cancer. Evaluating over 4000 new bladder cancer patients, we found that the QPI programme was associated with low recurrence and accurate staging following the initial transurethral resection of bladder tumour., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: To assess urologists' ability to predict the grade and stage of new bladder cancers from the cystoscopic features alone., Patients and Methods: We conducted a prospective clinical study on consecutive patients who underwent transurethral resection of bladder tumor (TURBT) for new bladder cancers. Using only cystoscopic tumor morphology at the time of initial TURBT, 3 urology consultants predicted the grade and stage, recording these on a proforma along with tumor features. Predictions were compared with assessments by uropathologists, blinded to the clinical prediction. We analyzed the accuracy in (1) predicting the exact grade and stage of the cancer; (2) differentiating between low- and high-grade cancers; and (3) discerning between Ta, T1, and T2 cancers., Results: Of 248 patients, 224 were suitable for analysis. The positive predictive values for low- and high-grade cancers were 85.8% and 71.3%, respectively. The overall likelihood of a consultant predicting high-grade cancers as being low grade was 16/83 (19.3%). When tumors were large (>30 mm), this likelihood dropped significantly to 7.3% (4/55) (odds ratio = 3.1, 95% confidence interval = 1.0-9.7, P = .04). Non-muscle-invasive and muscle-invasive cancers were predicted accurately in 93.4% and 85.2% patients, respectively. Six of 161 (3.7%) tumors predicted to be non-muscle-invasive bladder cancer were actually muscle invasive on histology., Conclusion: For clinical purposes, in newly presenting patients with bladder cancer, urologists appear to reliably predict lower grade and muscle-invasive disease, confirming widely held belief. This allows for appropriate and efficient use of surgical expertise, available technology, and selection of participants for clinical trials on the basis of prehistology risk categories., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: To compare early recurrence between good-quality white-light transurethral resection of bladder tumor (GQ-WLTURBT) and photodynamic diagnosis-assisted (PDD) transurethral resection of bladder tumor (TURBT) in a real-life controlled setting., Methods: A prospective controlled study was conducted commencing with a planned prospective cohort of patients with new tumors undergoing white-light TURBT in 2007-2008. Previously defined principles of GQ-WLTURBT for standardization and comparison of TURBT techniques, which are (1) cystoscopic mapping using a bladder diagram, (2) documented complete resection of the tumor, (3) resection performed or supervised by an experienced surgeon, (4) presence of detrusor muscle in the specimen, and (5) patient receiving mitomycin C within 24 hours of the resection, were applied. This was followed by a prospective cohort of new patients undergoing PDD-TURBT in 2009-2011. Only patients with new non-muscle-invasive bladder cancer (NMIBC) deemed to have had complete first TURBT were included for analysis. Tumor features and findings at first check cystoscopy and early re-TURBT (in high-risk NMIBC) were evaluated. Early recurrence (for calculating recurrence rate at first follow-up cystoscopy) was defined as pathologically confirmed tumor on early re-TURBT or recurrence at the first check cystoscopy. Comparison was analyzed between GQ-WLTURBT and good-quality PDD-TURBT (GQ-PDDTURBT)., Results: A total of 808 patients were evaluated. The overall RRFFCs for GQ-WLTURBT and GQ-PDDTURBT were 30.9% and 13.6%, respectively (odds ratio = 2.9; 95% CI = 1.6-5.0; P <.001), with statistically significant lower recurrence rates in low- and intermediate-risk NMIBC after GQ-PDDTURBT., Conclusion: Hexvix PDD-assisted TURBT is associated with a significantly lower risk of early recurrence compared with GQ-WLTURBT in a real-life clinical setting., (Crown Copyright © 2015. Published by Elsevier Inc. All rights reserved.)

Context: Non-muscle-invasive bladder cancer (NMIBC) is associated with a high recurrence risk, partly because of the persistence of lesions following transurethral resection of bladder tumour (TURBT) due to the presence of multiple lesions and the difficulty in identifying the exact extent and location of tumours using standard white-light cystoscopy (WLC). Hexaminolevulinate (HAL) is an optical-imaging agent used with blue-light cystoscopy (BLC) in NMIBC diagnosis. Increasing evidence from long-term follow-up confirms the benefits of BLC over WLC in terms of increased detection and reduced recurrence rates., Objective: To provide updated expert guidance on the optimal use of HAL-guided cystoscopy in clinical practice to improve management of patients with NMIBC, based on a review of the most recent data on clinical and cost effectiveness and expert input., Evidence Acquisition: PubMed and conference searches, supplemented by personal experience., Evidence Synthesis: Based on published data, it is recommended that BLC be used for all patients at initial TURBT to increase lesion detection and improve resection quality, thereby reducing recurrence and improving outcomes for patients. BLC is particularly useful in patients with abnormal urine cytology but no evidence of lesions on WLC, as it can detect carcinoma in situ that is difficult to visualise on WLC. In addition, personal experience of the authors indicates that HAL-guided BLC can be used as part of routine inpatient cystoscopic assessment following initial TURBT to confirm the efficacy of treatment and to identify any previously missed or recurrent tumours. Health economic modelling indicates that the use of HAL to assist primary TURBT is no more expensive than WLC alone and will result in improved quality-adjusted life-years and reduced costs over time., Conclusions: HAL-guided BLC is a clinically effective and cost-effective tool for improving NMIBC detection and management, thereby reducing the burden of disease for patients and the health care system., Patient Summary: Blue-light cystoscopy (BLC) helps the urologist identify bladder tumours that may be difficult to see using standard white-light cystoscopy (WLC). As a result, the amount of tumour that is surgically removed is increased, and the risk of tumour recurrence is reduced. Although use of BLC means that the initial operation costs more than it would if only WLC were used, over time the total costs of managing bladder cancer are reduced because patients do not need as many additional operations for recurrent tumours., (Copyright © 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background: An European Organisation for Research and Treatment of Cancer analysis of multicentre trials found significant interinstitutional variability in recurrence rates at first follow-up cystoscopy (RR-FFC) and attributed this to variable transurethral resection of bladder tumour (TURBT) quality., Objective: To determine whether resection of detrusor muscle (DM) in the first, apparently complete TURBT is a surrogate marker of quality and whether the presence of DM is dependent on a surgeon's experience., Design, Setting, and Participants: Over a 2-yr period, patients with new bladder tumours that were judged to have been completely resected were recruited from our prospectively maintained bladder tumour database. Strict exclusion criteria were applied., Measurements: Prospectively recorded tumour size, tumour multiplicity, surgeon category, DM status, grade and stage of tumour, and findings at first follow-up cystoscopy (at 3 mo) and at early re-TURBT were evaluated. Surgeons were stratified into seniors (consultants and year 5 or year 6 trainees) and juniors (trainees lower than year 5). Early recurrence (for calculating RR-FFC) was defined as pathologically confirmed tumour on early re-TURBT or recurrence at the first follow-up cystoscopy. Logistic regression multivariate analyses were carried out to determine associations between variables., Results and Limitations: In a total of 356 patients, DM was present in 241 patients (67.7%). Multivariate analyses revealed that large tumours, high-grade tumours, and surgery by senior surgeons was independently associated with the presence of DM in the resected specimens. The RR-FFCs when DM was absent and present were 44.4% and 21.7%, respectively (odds ratio: 2.9; 95% confidence interval: 1.6-5.4; p=0.0002). The absence of DM and resection by less experienced surgeons independently predicted a higher RR-FFC. This association was also seen in small and low-grade tumours. The number of patients in this study appears modest, and further validation may be required., Conclusions: DM absence or presence in the first, apparently complete TURBT specimen appears to be a surrogate marker of resection quality by independently predicting the RR-FFC, which is also dependent on surgeon experience., (Copyright © 2009 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objective: Surgery and pelvic floor muscle training are established methods for treating stress urinary incontinence (SUI). A new serotonin and noradrenaline reuptake inhibitor, duloxetine, has been studied in multiple phase 3 trials as a form of medical management of this condition. This systematic review determined the effectiveness and acceptability of duloxetine in managing SUI., Methods: We reviewed all randomised controlled trials comparing duloxetine with placebo or no treatment. The search included the Cochrane Incontinence Group specialised register, CENTRAL, MEDLINE, PREMEDLINE, dissertation abstracts, and the reference lists of relevant articles. The primary outcome was the number of participants whose symptoms were "cured" while on treatment. Secondary outcomes included subjective improvement, incontinent episodes, quality of life, adverse events, and discontinuation rates., Results: Nine trials were included, totalling 3063 women with predominantly SUI, all randomised to receive duloxetine or placebo. Treatment duration was 3-36 wk. Subjective cure favoured duloxetine (from three trials, 10.8% vs. 7.7%; RR=1.42; 95%CI, 1.02-1.98, p=0.04). The limited data available to assess objective cure rates were consistent with this. Individual studies showed a significant reduction in the Incontinence Episode Frequency (IEF) by approximately 50% during treatment. Duloxetine groups had significantly better quality-of-life scores (weighted mean difference for Incontinence Quality of Life Index for participants on 80 mg daily: 4.5; 95%CI, 2.83-6.18; p<0.00001) and rates of symptom improvement. Adverse effects were common (71% vs. 59%) but are reported as not serious and were equivalent to about one in eight participants reporting adverse effects (most commonly nausea) directly related to duloxetine treatment. About one in eight stopped treatment as a consequence of taking duloxetine (17% vs. 4%)., Conclusions: Duloxetine can significantly improve the quality of life of patients with SUI, but it is unclear whether or not benefits are sustainable. Side-effects such as nausea are common.