Association of Age with Non-muscle-invasive Bladder Cancer: Unearthing a Biological Basis for Epidemiological Disparities?

BACKGROUND: Age disparity in patients with non-muscle-invasive bladder cancer (NMIBC) exists. Whether this is due to differences in adequate cancer care or tumour biology is unclear. OBJECTIVE: To investigate age disparities in NMIBC using the Surveillance, Epidemiology, and End Results (SEER)-Medicare and UROMOL datasets. DESIGN, SETTING, AND PARTICIPANTS: The SEER-Medicare data were used to identify patients with clinical stage Ta, Tis, and T1 NMIBC between 2005 and 2017 (n = 32 225). Using the UROMOL cohort (n = 834), age disparities across transcriptomic, genomic, and spatial proteomic domains were assessed. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: For the SEER-Medicare data, multivariable competing-risk regression was used to examine the association between age and recurrence, progression, and bladder cancer-specific mortality (BCSM). For the UROMOL cohort, multivariable general linear model and multinomial logistic regression were performed to evaluate the association between age and tumour biology. RESULTS AND LIMITATIONS: An analysis of the SEER-Medicare cohort revealed 5-yr recurrence rates of 55.2%, 57.4%, and 58.9%; 5-yr progression rates of 25.6%, 29.2%, and 36.9%; and 5-yr BCSM rates of 3.9%, 5.8%, and 11.8% in patients aged 66-70, 71-80, and ≥81 yr, respectively. After multivariable adjustment, age ≥81 yr was associated with a higher risk of recurrence (hazard ratio [HR] 1.07, 95% confidence interval [CI] 1.03-1.12; p = 0.001), progression (HR 1.32, p < 0.001), and BCSM (HR 2.58, p < 0.001). UROMOL2021 transcriptomic class 2a was most frequently observed in patients with advanced age (34.0% in ≥76 yr vs 21.6% in ≤65 yr; p = 0.004), a finding confirmed on multivariable analysis (risk ratio [RR] 3.86, p = 0.002). UROMOL2021 genomic class 3 was observed more frequently in patients aged ≥76 yr (4.9% vs 24.2%; p = 0.001). Limitations include the definitions used for recurrence and progression, which may lead to under- or overestimation of true rates. CONCLUSIONS: Among SEER-Medicare patients with NMIBC, advanced age is associated with inferior oncological outcomes. These results reflect age-related molecular biological differences observed across transcriptomic and genomic domains, providing further evidence that innate tumour biology contributes to observed disparities in NMIBC outcomes. PATIENT SUMMARY: Older patients with non-muscle-invasive bladder cancer have worse oncological outcomes than younger patients. Some of this age disparity may be due to differences in tumour biology.

Ileal conduit obstruction secondary to tethering of the small bowel anastomosis to the pubic bone.

We present the case of a late 60s male who presented to hospital 3 years postradical cystectomy and ileal conduit diversion with polyuria and acute kidney injury. CT of the kidneys, ureters and bladder (KUB) revealed mild hydronephrosis of a solitary left kidney and a 3-cm calculus in the ileal conduit. The patient subsequently underwent a laparotomy which revealed the cause of obstruction to be tethering of the small bowel anastomosis to the pubic bone. The conduit was excised with the calculus in situ and a new conduit was fashioned. The patient recovered from surgery without complication, and his kidney function improved.

Impact of age >70 years on oncological outcomes in patients with non-muscle-invasive bladder cancer treated with Bacillus Calmette-Guérin.

OBJECTIVE: To evaluate the impact of age on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate Bacillus Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved retrospective study analysing patients with NMIBC treated with adequate BCG at our institution from 2000 to 2020. Adequate BCG was defined as per United States Food and Drug Administration (FDA) guidelines as being receipt of at least five of six induction BCG instillations with a minimum of two additional doses (of planned maintenance or of re-induction) of BCG instillations within a span of 6 months. The study's primary outcome was to determine if age >70 years was associated with progression to MIBC cancer or distant metastasis. The cumulative incidence method and the competing-risk regression analyses were used to investigate the association of advanced age (>70 years) with progression, high-grade (HG) recurrence and cancer-specific mortality (CSM). RESULTS: Overall, data from 632 patients were analysed: 355 patients (56.2%) were aged ≤70 years and 277 (43.8%) were >70 years. Age >70 years did not adversely affect either cumulative incidence of progression or HG recurrence (P = 0.067 and P = 0.644, respectively). On competing-risk regression analyses, age >70 years did not emerge as an independent predictor of progression or HG recurrence (sub-standardised hazard ratio [SHR] 1.57, 95% confidence interval [CI] 0.87-2.81, P = 0.134; and SHR 1.05, 95% CI 0.77-1.44, P = 0.749). Not unexpectedly, patients in the older group did have higher overall mortality (P < 0.001) but not CSM (P = 0.057). CONCLUSION: Age >70 years was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. BCG should not be withheld from older patients seeking for bladder sparing options.

Gynaecological organ involvement in females undergoing radical cystectomy: a multicentre study.

OBJECTIVE: To report the incidence of malignancy in gynaecological organs removed during radical cystectomy (RC). PATIENTS AND METHODS: A retrospective multicentre study of 1600 RCs at three high-volume institutions between January 2009 and March 2022 was performed. Pathological findings in gynaecological organs in female RC specimens were reviewed. Multivariable logistic regression analyses were used to identify predictors of malignant gynaecological organ involvement (GOI) at time of RC. RESULTS: Overall, 302 females with a median (interquartile range) age of 68 (61-75) years underwent RC for clinical (c)Ta-T4 bladder cancer. In all, 56 patients (18.5%) received neoadjuvant chemotherapy. Malignant GOI was seen in 20 patients (6.6%); the most common single sites of GOI were the uterus (five patients) and vaginal wall (four), followed by cervix (one), and ovaries (one). Nine patients had involvement of more than one gynaecological organ. No females had a primary gynaecological malignancy detected incidentally at RC. Patients with GOI were more likely to have cT3/T4 stage (P < 0.001), preoperative hydronephrosis (P = 0.004), lymphovascular invasion (P = 0.002), and squamous cell carcinoma (P = 0.005) than those without GOI. On multivariable analysis, cT4 stage was an independent predictor of malignant GOI (odds ratio 88.3, 95% confidence interval 10.1-1214; P < 0.001). CONCLUSION: To our knowledge, we present the largest multi-institutional study examining malignant GOI in females with bladder cancer undergoing RC. The rate of GOI at the time of RC is low and associated with higher clinical stage. In the absence of clinical or radiological evidence of sexual organ involvement, our results do not support their routine removal at the time of RC.

Competing mortality risk from second primary malignancy in bladder cancer patients following radical cystectomy: Implications for survivorship.

INTRODUCTION: Muscle-invasive bladder cancer (BC) often occurs in patients with competing mortality risks, while also being associated with the highest rate of second primary nonurothelial cancers (SNUC) of all solid malignancies. We investigated the incidence, risk factors, and timing of SNUC as a competing mortality risk factor in patients with BC who were treated with curative intent radical cystectomy (RC). METHODS: We performed a retrospective cohort study assessing patients who underwent RC for cT2-4 N0M0 BC from January 1, 2005 to December 31, 2018 at a single, high volume tertiary care referral center. The Fine-Gray multivariable regression model was used to evaluate predictive factors for SNUC. Cumulative incidence of mortality (CIM) was estimated with modified Kaplan-Meier analysis. RESULTS: The median follow-up time for the 693 patients who underwent RC was 3.7 years (interquartile range [IQR] 1.9-5.9 years). SNUC developed in 85 (12.3%) patients at a median 3.0 years post-RC (IQR 1.2-5.5 years). On multivariable analysis, the only significant predictor for developing SNUC was freedom from BC recurrence or metastasis (HR 1.54, 95% CI 1.12-1.76, P = 0.019). The most common SNUCs were primary lung cancer (24, 3.2% of cohort) and colon cancer (9, 1.3% of cohort). BC surveillance imaging diagnosed SNUC in 35/52 (67.3%) patients with solid-organ visceral primaries. The overall mortality rate for any SNUC was 38.8%, with the 3 most lethal cancer types being pancreatic, lung, and colon (62.5%, 54.2%, and 44.4% mortality, respectively). The incidence of SNUC uniformly increased postoperatively, with a cumulative incidence of 22.1% (95% CI, 16.8-27.9%) at 12-years post-RC. 163 patients (23.5%) died from BC, 33 patients (4.8%) died from SNUC, and 94 patients (13.6%) died from other causes. While the CIM for BC plateaued around 5-years post-RC at 24%, the incidence of other-cause mortality uniformly rose throughout the postoperative period. By post-RC year 9 there was no significant difference in CIM between BC (CIM 27.2%, 95% CI, 23.5-31.1%) and other-causes (CIM 20.0%, 95% CI, 15.8-24.6%). CONCLUSIONS: The cumulative incidence of SNUC at 12-years post-RC was 22%, with the majority identified on BC surveillance imaging. While BC mortality plateaued around 5-years post-RC, mortality related to SNUC or other causes rose steadily in the postoperative period. These data have clinical significance with regards to patient counseling, survivorship and oncologic surveillance in the highly comorbid muscle-invasive BC population.

Epidemiology, Screening, and Prevention of Bladder Cancer.

CONTEXT: Bladder cancer (BC) represents a significant health problem due to the potential morbidity and mortality associated with disease burden, which has remained largely unaltered over time. OBJECTIVE: To provide an expert collaborative review and describe the incidence, prevalence, and mortality of BC and to evaluate current evidence for BC screening and prevention. EVIDENCE ACQUISITION: Data on the estimated incidence and mortality of BC for 2020 in 185 countries were derived from the International Agency for Research on Cancer GLOBOCAN database. A review of English-language articles published over the past 5 yr was conducted using PubMed/MEDLINE to identify risk factors in addition to contemporary evidence on BC screening and prevention. EVIDENCE SYNTHESIS: BC is the tenth most common cancer worldwide, with 573 278 cases in 2020. BC incidence is approximately fourfold higher in men than women. Tobacco smoking remains the principal risk factor, accounting for approximately 50% of cases. There is insufficient evidence to recommend routine BC screening. However, targeted screening of high-risk individuals (defined according to smoking history or occupational exposure) may reduce BC mortality and should be the focus of prospective randomized trials. In terms of disease prevention, smoking cessation represents the most important intervention, followed by a reduction in exposure to occupational and environmental carcinogens. CONCLUSIONS: BC confers a significant disease burden. An understanding of BC epidemiology and risk factors provides an optimal foundation for disease prevention and the care of affected patients. PATIENT SUMMARY: Bladder cancer is the tenth most common cancer worldwide and is approximately four times more common among men than among women. The main risk factors are tobacco smoking, followed by exposure to carcinogens in the workplace or the environment. Routine screening is not currently recommended, but may be beneficial in individuals at high risk, such as heavy smokers. Primary prevention is extremely important, and smoking cessation represents the most important action for reducing bladder cancer cases and deaths.

All High-Grade Ta Tumors Should Be Classified as High Risk: Bacillus Calmette-Guérin Response in High-Grade Ta Tumors.

PURPOSE: There is variation amongst guidelines with respect to risk stratification of Ta tumors, specifically high-grade (HG) Ta tumors. We sought to investigate the response of all Ta tumors to bacillus Calmette-Guérin (BCG) and compare response rates based on European Association of Urology (EAU) classification as intermediate- (IR) or high-risk (HR). MATERIALS AND METHODS: An institutional review of all patients who received adequate BCG from 2000-2018 was conducted. EAU 2021 prognostic risk groups were used to stratify patients including by the newly proposed adverse risk factors. RESULTS: When patient with Ta tumors were stratified into IR and HR, 37 (16%) had IR low-grade (LG) Ta, 92 (40%) had IR HG Ta and 101 (44%) had HR HG Ta tumors. BCG unresponsiveness developed in 13% of HR HG Ta tumors and 14% of IR HG Ta tumors compared to 0.0% of IR LG Ta tumors (p=0.003). While no patients with IR LG Ta tumors progressed, progression rates were similar in HR HG Ta and IR HG Ta tumors (≥T2: 5.9% and 6.5%; [Formula: see text]T1: 13% and 13%, respectively). Rates of recurrence, BCG unresponsiveness and progression were similar, irrespective of number of EAU risk factors present (p=0.9, p=0.8 and p=0.9, respectively). CONCLUSIONS: All HG Ta tumors, regardless of EAU risk stratification, have inferior response to BCG and increased rates of progression compared to IR LG Ta tumors. EAU clinical risk factors did not improve prediction of oncologic outcomes among HG Ta patients who received adequate BCG. These data support consideration of all HG tumors as high risk.

Management, Surveillance Patterns, and Costs Associated With Low-Grade Papillary Stage Ta Non-Muscle-Invasive Bladder Cancer Among Older Adults, 2004-2013.

Importance: Low-risk non-muscle-invasive bladder cancer (NMIBC) is associated with extremely low rates of progression and cancer-specific mortality; however, patients with low-risk NMIBC may often receive non-guideline-recommended and potentially costly surveillance testing and treatment. Objective: To describe current surveillance and treatment practices, cancer outcomes, and costs of care for low-grade papillary stage Ta (low-grade Ta) NMIBC and identify factors associated with increased cost of care. Design, Setting, and Participants: This population-based cohort study identified 13 054 older adults (aged 66-90 years) diagnosed with low-grade Ta tumors in the Surveillance, Epidemiology and End Results-linked Medicare database from January 1, 2004, through December 31, 2013. Medicare claims data through December 31, 2014, were also reviewed. Data were analyzed from April 1 to October 6, 2021. Exposures: Surveillance testing and treatment among patients with low-grade Ta NMIBC. Main Outcomes and Measures: The primary outcome was patterns in population-level surveillance and treatment practice over time among patients with low-grade Ta NMIBC. Secondary outcomes were recurrence (defined as receipt of subsequent transurethral resection of bladder tumor >3 months after index diagnosis of NMIBC and initial transurethral resection of bladder tumor), progression (defined as receipt of definitive treatment for bladder cancer), and costs of care. Results: Among 13 054 patients who met inclusion criteria, 9596 (73.5%) were male and 3458 (26.5%) were female, with a median age of 76 years (IQR, 71-81 years). A total of 403 patients (3.1%) were Black, 120 (0.9%) were Hispanic, 12 123 (92.9%) were White, and 408 (3.1%) were of other races and/or ethnicities. Rates of surveillance cystoscopy increased over the study period (from 79.3% in 2004 to 81.5% in 2013; P = .007), with patients receiving a median of 3.0 cystoscopies per year (IQR, 2.0-4.0 per year). Rates of upper tract imaging (particularly computed tomography or magnetic resonance imaging) also increased over the study period (from 30.4% in 2004 to 47.0% in 2013; P < .001), with most patients receiving a median of 2.0 imaging tests per year (IQR, 1.0-2.0 per year). The use of urine cytologic testing or other urine biomarker assessment also increased (from 44.8% in 2004 to 54.9% in 2013; P < .001). Rates of adherence to current guidelines were similar over time (eg, a median of 4398 patients [55.2%] received ≤2 cystoscopies per year in 2004-2008 vs a median of 2736 patients [53.8%] in 2009-2013; P = .11), suggesting overuse of all surveillance testing modalities. With regard to treatment, 2250 patients (17.2%) received intravesical bacillus Calmette-Guérin, and 792 patients (6.1%) received intravesical chemotherapy (excluding receipt of a single perioperative dose). Among all patients with low-grade Ta NMIBC, 217 (1.7%) experienced disease recurrence and 52 (0.4%) experienced disease progression. The total annual median costs of low-grade Ta surveillance testing and treatment increased by 60% (from $34 792 in 2004 to $53 986 in 2013), with higher 1-year median expenditures noted among those with disease recurrence ($76 669) vs no disease recurrence ($53 909) at the end of the study period. Conclusions and Relevance: In this cohort study, despite low rates of disease recurrence and progression, rates of surveillance testing increased during the study period. The annual cost of care also increased over time, particularly among patients with recurrent disease. Efforts to improve adherence to current practice guidelines, with the focus on limiting overuse of surveillance testing and treatment, may mitigate associated increasing costs of care.

Evolution of immunotherapy in the treatment of non-muscle-invasive bladder cancer.

INTRODUCTION: Immunotherapy with intravesical bacillus Calmette-Guérin (BCG) has been the gold standard treatment for intermediate- and high-risk non-muscle-invasive bladder cancer (NMIBC) for nearly half a century. Yet, many patients with high-risk disease will experience recurrence, including those who progress and eventually become unresponsive to BCG. For decades, apart from radical cystectomy, few therapeutic options existed for this at-risk population. However, the advent of novel immunotherapeutic agents has transformed treatment in a range of tumor types, including urothelial carcinoma. These immunotherapies have yielded promising results in the treatment of metastatic urothelial carcinoma and, as such, are also being investigated for use in NIMIBC. AREAS COVERED: This article provides an overview of the evolution of immunotherapy for NMIBC, beginning from the original immunotherapy-BCG - to current agents including checkpoint inhibitors, IL-15 agonists, viral gene therapies and therapeutic cancer vaccines. EXPERT OPINION: Emerging insights over the last decade have led to the development of novel immunotherapiesfor the treatment of NMIBC whilst providing new opportunities to enhance the anti-tumour activity of BCG. In particular, the KEYNOTE-057 trial represents a pivotal moment for immunotherapy in NMIBC, leading to approval of pembrolizumab by the US Food & Drug Administration for patients with BCG-unresponsive disease. However, patient selection and the development of biomarkers to guide the identification of patients who will benefit most from a particular immunotherapy remains critical. As research efforts come to fruition, these novel immunotherapies may become integrated into the standard treatment paradigm for intermediate- and high-risk NMBIC.

Reduced-dose bacillus Calmette-Guérin (BCG) in an era of BCG shortage: real-world experience from a tertiary cancer centre.

OBJECTIVE: To evaluate the impact of one-third-dose (1/3D) bacillus Calmette-Guérin (BCG) on oncological outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate BCG (as defined by the US Food & Drug Administration (FDA)) in a real-world setting. PATIENTS AND METHODS: We performed an institutional review board-approved review of patients with NMIBC treated with adequate BCG at our institution between 2000 and 2020. Patients were stratified according to whether they had received 1/3D BCG or full-dose (FD) BCG. Time to recurrence, time to progression and cancer-specific survival were estimated using Kaplan-Meier methods. RESULTS: Of 563 patients with NMIBC treated with adequate BCG, 150 (26.6%) received 1/3D and 413 (73.4%) received FD. The use of 1/3D BCG did not adversely affect time to recurrence (P = 0.449) or time to progression (P = 0.716), and this remained consistent when patients were stratified by individual 2021 European Association of Urology (EAU) prognostic factor risk groups. Cancer-specific survival was similar in patients receiving 1/3D and those receiving FD BCG (P = 0.320). CONCLUSION: The use of 1/3D BCG was not associated with adverse oncological outcomes in a large cohort of patients receiving adequate BCG for intermediate- and high-risk NMIBC. Based on this real-world experience, risk-stratified split-vial dosing may represent a valuable approach for other institutions facing BCG shortages whilst also providing reassurance to patients who may be concerned about suboptimal outcomes.

Should patients with non-muscle-invasive bladder cancer discontinue fibrin clot inhibitors during bacille Calmette-Guérin?

OBJECTIVE: To determine the impact of fibrin clot inhibitor (FCI) use on oncological outcomes in a large contemporary cohort of patients with non-muscle-invasive bladder cancer (NMIBC) treated with adequate bacille Calmette-Guérin (BCG). PATIENTS AND METHODS: We performed an Institutional Review Board-approved review of patients with NMIBC treated with adequate intravesical BCG, at our institution between 2000 and 2018. FCI use at the time of BCG therapy was recorded for each patient. Patients were stratified according to use of FCI medication. Recurrence- and progression-free survival were analysed using Kaplan-Meier methods and Cox proportional hazard models. RESULTS: Overall, 226 of 526 patients (43.0%) used a FCI: aspirin (205), clopidogrel (38), warfarin (18) and novel oral anticoagulant (NOAC; seven). The use of FCIs did not adversely affect either recurrence- or progression-free survival (P = 0.385 and P = 0.131, respectively). These results did not change when the impact of aspirin, clopidogrel or warfarin/NOAC use on recurrence and progression was evaluated separately. On multivariate analysis, FCI use was neither associated with tumour recurrence nor progression. CONCLUSION: The use of FCIs was not associated with adverse oncological outcomes in a large contemporary cohort of patients receiving adequate intravesical BCG for NMIBC. Based on these results, FCIs may be safely continued during BCG immunotherapy.

Clinicopathological analysis and outcomes of inflammatory myofibroblastic tumours of the urinary bladder.

OBJECTIVES: To describe clinical, imaging, and histopathological characteristics of inflammatory myofibroblastic tumour (IMT) of the urinary bladder and provide initial management and surveillance recommendations. PATIENTS AND METHODS: We identified patients with IMT of the bladder treated at our facility from 1998 to 2020. Categorical variables were analysed with chi-square and Fisher's exact tests and continuous variables with the Mann-Whitney U-test. Kaplan-Meier analysis was performed for recurrence-free survival. RESULTS: IMT was diagnosed in 35 patients with median (interquartile range [IQR]) follow-up of 20 (11.5-68.5) months. At initial diagnosis 86% were clinically organ-confined, 9% locally advanced, and 5% metastatic. Majority of patients (92%) had residual disease on re-staging transurethral resection (TUR). Of the 15 patients with organ-confined disease managed initially with TUR alone, five (33%) recurred at a median (IQR) of 5 (3.0-5.5) months from initial diagnosis. Presentation with visible haematuria was associated with recurrence (100% in recurrence vs 40% in non-recurrence groups, P = 0.044). There were no patients who developed a recurrence beyond 6 months after diagnosis. Partial or radical cystectomy was required in 23% and 9% of patients, respectively. One patient presented with metastatic disease associated with anaplastic lymphoma kinase (ALK) translocation and achieved a durable complete remission with 7 months of crizotinib therapy. CONCLUSIONS: No patient with IMT treated with aggressive endoscopic management developed recurrences beyond 6 months. There were additionally no recurrences noted after definitive radical or partial cystectomy. These data support organ sparing therapy with aggressive endoscopic management and short-term surveillance in patients with localised IMT, with extirpative surgery reserved for refractory cases.

Updated European Association of Urology (EAU) Prognostic Factor Risk Groups Overestimate the Risk of Progression in Patients with Non-muscle-invasive Bladder Cancer Treated with Bacillus Calmette-Guérin.

BACKGROUND: The 2021 European Association of Urology (EAU) guidelines contain updated prognostic factor risk groups for non-muscle-invasive bladder cancer (NMIBC). These groups are based on the following predictors of progression: tumour stage, grade, number, and size; concomitant carcinoma in situ; and age. However, the groups were derived from datasets excluding patients treated with bacillus Calmette-Guérin (BCG). OBJECTIVE: To determine the validity of the updated EAU prognostic factor risk groups in patients with NMIBC treated with BCG. DESIGN, SETTING, AND PARTICIPANTS: We reviewed patients treated with BCG at our institution between 2000 and 2018. Patients were analysed according to the receipt of "at least induction" and "adequate" BCG (as defined by the US Food and Drug Administration). Risk groups were assigned according to the 2021 EAU NMIBC risk calculator (https://nmibc.net/). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The Kaplan-Meier method was used to estimate the risks of progression at 1 and 5 yr. Probabilities of progression obtained with the updated prognostic factor risk groups in our series were compared with those reported by the EAU. Discrimination was assessed using the concordance index (c-index). RESULTS AND LIMITATIONS: A total of 529 patients received at least induction BCG with a median follow-up of 47.3 mo (interquartile range 25.3-86.9). Of these patients, 494 received adequate BCG. We found lower progression rates at 1 yr in the very-high-risk group patients receiving at least induction (6.9%) and adequate BCG (4.0%) versus 16.0% for the EAU predicted rates. Additionally, progression rates were also lower at 5 yr in the high-risk group-7.4% for at least induction and 5.3% for adequate BCG versus 9.6% for EAU predicted rates; the rates in the very-high-risk group were as follows: 16.7% for at least induction and 14.9% for adequate BCG versus 40.0% for EAU predicted rates. The c-index in our series was lower than that reported by the EAU (0.63 vs 0.80). Of interest, our multivariable analysis identified grade, stage, and age (p < 0.02) to be the predictors of progression after BCG therapy. CONCLUSIONS: While the 2021 EAU prognostic factor risk groups successfully stratified progression risks in our cohort, treatment with BCG reduced their discriminative ability. Furthermore, the groups overestimate progression risks in BCG-treated patients. These findings should be used in conjunction with the updated risk groups to counsel patients with higher-risk NMIBC about their risk of progression with and without BCG. PATIENT SUMMARY: Although the updated European Association of Urology prognostic factor risk groups are able to stratify patients with non-muscle-invasive bladder cancer according to their risk of progression to muscle-invasive bladder cancer, this risk is overestimated in patients treated with bacillus Calmette-Guérin (BCG).

Reduced Dose Intravesical Bacillus Calmette-Guérin: Why It Might Not Matter.

When it comes to the treatment of patients with non-muscle-invasive bladder cancer (NMIBC) with intravesical bacillus Calmette-Guérin (BCG), two questions must be considered: 1) what dose to give, and 2) for how long? The issue of optimal dose and duration has been the subject of several randomized trials and is especially pertinent in the context of a global BCG shortage. Despite this, there appears to be uncertainty as to whether BCG dose or duration may be compromised in the event of shortage. As such, we wish to summarize the available evidence as an aid to the practicing urologist.

100 years of Bacillus Calmette-Guérin immunotherapy: from cattle to COVID-19.

Bacillus Calmette-Guérin (BCG) is the most widely used vaccine worldwide and has been used to prevent tuberculosis for a century. BCG also stimulates an anti-tumour immune response, which urologists have harnessed for the treatment of non-muscle-invasive bladder cancer. A growing body of evidence indicates that BCG offers protection against various non-mycobacterial and viral infections. The non-specific effects of BCG occur via the induction of trained immunity and form the basis for the hypothesis that BCG vaccination could be used to protect against the severity of coronavirus disease 2019 (COVID-19). This Perspective article highlights key milestones in the 100-year history of BCG and projects its potential role in the COVID-19 pandemic.

Gender differences in acute stone admissions - should we have a lower threshold for treatment in female patients?

OBJECTIVES: To examine the gender-related differences in the presentation, management and outcomes of patients admitted with acute renal colic at our institution. PATIENTS AND METHODS: A retrospective analysis of 231 consecutive patients requiring inpatient admission for acute renal colic between October 2015 and March 2018. For each admission, data on demographics, admission blood results, stone characteristics, management and outcomes were collected. Differences between genders were compared using the chi-squared and Student's t-test. RESULTS: Gender distribution was 35% female: 65% male. There was no significant difference in age, American Society of Anesthesiologists Physical Status Classification grade or history of diabetes. Women had a higher admission C-reactive protein level (89.3 vs 32.9 mg/L, P < 0.001) and neutrophil count (10.0 vs 8.8 × 109 /L, P = 0.04) than men. They also had more positive cultures (34.1% vs 6.0%, P < 0.001) and were more likely to require percutaneous nephrostomy insertion (9.8% vs 0.7%, P = 0.005). Women had more intensive therapy unit (ITU) admissions (12.2% vs 0.6%, P < 0.001) and longer lengths of stay (4.4 vs 1.8 days, P < 0.001) than men. There was no mortality in our series. CONCLUSION: In the present study, women admitted with acute renal colic were more likely to have an associated infection than men and require rapid decompression. Although there was no difference in mortality, women experienced greater morbidity as evidenced by the higher rate of ITU admissions and longer length of stay. These differences are important to consider when assessing the suitability of conservative management for female patients.

The "Is mpMRI Enough" or IMRIE Study: A Multicentre Evaluation of Prebiopsy Multiparametric Magnetic Resonance Imaging Compared with Biopsy.

BACKGROUND: Multiparametric magnetic resonance imaging (mpMRI) is now recommended prebiopsy in numerous healthcare regions based on the findings of high-quality studies from expert centres. Concern remains about reproducibility of mpMRI to rule out clinically significant prostate cancer (csPCa) in real-world settings. OBJECTIVE: To assess the diagnostic performance of mpMRI for csPCa in a real-world setting. DESIGN, SETTING, AND PARTICIPANTS: A multicentre, retrospective cohort study, including men referred with raised prostate-specific antigen (PSA) or an abnormal digital rectal examination who had undergone mpMRI followed by transrectal or transperineal biopsy, was conducted. Patients could be biopsy naïve or have had previous negative biopsies. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary definition for csPCa was International Society of Urological Pathology (ISUP) grade group (GG) ≥2 (any Gleason ≥7); the accuracy for other definitions was also evaluated. RESULTS AND LIMITATIONS: Across ten sites, 2642 men were included (January 2011-November 2018). Mean age and PSA were 65.3yr (standard deviation [SD] 7.8yr) and 7.5ng/ml (SD 3.3ng/ml), respectively. Of the patients, 35.9% had "negative MRI" (scores 1-2); 51.9% underwent transrectal biopsy and 48.1% had transperineal biopsy, with 43.4% diagnosed with csPCa overall. The sensitivity and negative predictive value (NPV) for ISUP GG≥2 were 87.3% and 87.5%, respectively. The NPVs were 87.4% and 88.1% for men undergoing transrectal and transperineal biopsy, respectively. Specificity and positive predictive value of MRI were 49.8% and 49.2%, respectively. The sensitivity and NPV increased to 96.6% and 90.6%, respectively, when a PSA density threshold of 0.15ng/ml/ml was used in MRI scores 1-2; these metrics increased to 97.5% and 91.2%, respectively, for PSA density 0.12ng/ml/ml. ISUP GG≥3 (Gleason ≥4+3) was found in 2.4% (15/617) of men with MRI scores 1-2. They key limitations of this study are the heterogeneity and retrospective nature of the data. CONCLUSIONS: Multiparametric MRI when used in real-world settings is able to rule out csPCa accurately, suggesting that about one-third of men might avoid an immediate biopsy. Men should be counselled about the risk of missing some significant cancers. PATIENT SUMMARY: Multiparametric magnetic resonance imaging (MRI) is a useful tool for ruling out prostate cancer, especially when combined with prostate-specific antigen density (PSAD). Previous results published from specialist centres can be reproduced at smaller institutions. However, patients and their clinicians must be aware that an early diagnosis of clinically significant prostate cancer could be missed in nearly 10% of patients by relying on MRI and PSAD alone.

What Is the Significance of Variant Histology in Urothelial Carcinoma?

CONTEXT: Urothelial carcinoma can exhibit a wide range of variant morphologies. Many variants present diagnostic challenges and carry clinical implications that inform prognosis and treatment decisions. OBJECTIVE: To provide an overview of the diagnostic, therapeutic, and prognostic significance of histological variants of urothelial carcinoma. EVIDENCE ACQUISITION: A PubMed/MEDLINE-based literature search was conducted using the key terms "urothelial carcinoma", "variant histology", "nested", "micropapillary", "microcystic", "sarcomatoid", "squamous differentiation", "glandular differentiation", "clear cell", "plasmacytoid", "lymphoepithelioma-like carcinoma", "squamous cell carcinoma", "small cell carcinoma", "adenocarcinoma", "radiotherapy", "neoadjuvant chemotherapy", and "adjuvant chemotherapy". EVIDENCE SYNTHESIS: The incidence of variant histology is increasing due to improved recognition. Nonetheless, diagnosis can pose challenges due to sampling limitations and interobserver variability. Although associated with advanced disease at presentation, survival outcomes for most variants do not differ significantly compared with pure urothelial carcinoma of the same stage. Controversy exists regarding optimal management due to the low quality of available evidence. For most cases, radical cystectomy with pelvic lymph node dissection (with neoadjuvant chemotherapy when appropriate) represents the standard of care. Small cell carcinoma and lymphoepithelioma-like carcinoma appear to be particularly chemosensitive. CONCLUSIONS: Accurate identification of variant histological subtypes is an important part of risk stratification, as these variants exhibit aggressive biological behaviour. Variant histology tumours are associated with advanced disease at presentation, which must be considered when counselling patients regarding survival outcomes. Optimal management remains to be defined but in most cases; neoadjuvant chemotherapy and radical cystectomy with pelvic lymph node dissection remains the mainstay of treatment. PATIENT SUMMARY: It is important to recognise histological variants of urothelial carcinoma as they indicate aggressive disease. When compared with patients with pure urothelial carcinoma of the same disease stage, survival does not appear to be significantly worse. In most cases, patients with invasive variant histology should be treated with neoadjuvant chemotherapy and radical cystectomy. Take Home Messages Accurate identification of variant histology is important as it exhibits aggressive biological behaviour and affects treatment. Although associated with advanced disease at presentation, with appropriate treatment, survival outcomes are not significantly different compared with pure urothelial carcinoma of the same stage.

Robot-assisted radical cystectomy with intracorporeal urinary diversion - The new 'gold standard'? Evidence from a systematic review.

OBJECTIVE: To investigate whether a totally intracorporeally radical cystectomy (RC) can be considered the new 'gold standard' in bladder cancer, as open RC (ORC) is the current 'gold standard' for surgical treatment of muscle-invasive and high-grade non-muscle-invasive bladder cancer. However, robot-assisted radical cystectomy (RARC) is becoming the preferred surgical approach in many centres as it seems to maintain the oncological control of open surgery whilst offering improved perioperative benefits. MATERIALS AND METHODS: A review of the literature was conducted using the Pubmed/MEDLINE, ISI Web of Knowledge and Cochrane Databases to identify studies that included both ORC and RARC with intracorporeal and extracorporeal urinary diversion (UD) published up to July 2017. RESULTS: Evidence from four single-centre randomised controlled trials and now the multicentre Randomized Trial of Open versus Robotic Cystectomy (RAZOR) trial demonstrate the oncological equivalence of RARC to ORC. The only convincing evidence for the superiority of RARC is in the area of blood loss and transfusion rates. However, the UD procedure in these trials was performed extracorporeally and, to realise the full benefits of RARC, a totally intracorporeal approach is needed. Intracorporeal UDs (ICUDs) have been shown to be technically feasible by a few expert centres and have demonstrated some improved short-term perioperative outcomes compared to extracorporeal UDs. CONCLUSIONS: Although initial outcomes appear promising, RARC with ICUD is far from gaining 'gold standard' status. Further studies are needed to confirm that outcomes are reproducible widely. Furthermore, the benefits of a totally intracorporeal approach must be confirmed in randomised controlled trials.