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BACKGROUND: Circular RNAs (circRNAs) have been uncovered to be implicated in the malignant development of bladder cancer (BC). OBJECTIVE: Herein, this work aimed to investigate the role and mechanism of circRNA ubiquitin-associated protein 2 (circUBAP2) in BC progression. DESIGN, SETTING, AND PARTICIPANTS: Quantitative real-time polymerase chain reaction and Western blotting were used for the detection of genes and proteins. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In vitro functional experiments were conducted using colony formation, 5-ethynyl-2′-deoxyuridine (EdU), Transwell, wound healing, and flow cytometry assays, respectively. A glycolysis analysis was conducted by assessing glucose uptake and lactate production. A murine xenograft model was established to perform in vivo experiments. The binding interaction between miR-496 and circUBAP2 or DNA topoisomerase 2-alpha (TOP2A) was verified using a dual-luciferase reporter assay. RESULTS AND LIMITATIONS: CircUBAP2 was highly expressed in BC patients, and high circUBAP2 expression showed a shorter survival rate. Functionally, knockdown of circUBAP2 could suppress BC cell growth, migration, invasion, and aerobic glycolysis in vitro, as well as impede BC growth in nude mice. Mechanistically, circUBAP2 acted as a sponge for miR-496, which targeted TOP2A. Moreover, circUBAP2 could indirectly regulate TOP2A expression through sequestering miR-496. Furthermore, a series of rescue experiments showed that miR-496 inhibition reversed the anticancer action of circUBAP2 knockdown on BC cells. Moreover, miR-496 could attenuate BC cell malignant phenotypes and aerobic glycolysis, which were abolished by TOP2A overexpression. CONCLUSIONS: Silencing of circUBAP2 could suppress BC growth, invasion, migration, and aerobic glycolysis by the miR-496/TOP2A axis, suggesting a promising target for the molecular targeted therapies of BC. PATIENT SUMMARY: Circular RNA ubiquitin-associated protein 2 (circUBAP2) was found to be associated with poor prognosis in bladder cancer (BC). Knockdown of circUBAP2 might suppress BC growth, invasion, migration, and aerobic glycolysis, indicating that it may be a new target for the development of molecular targeted therapy for BC.

Objective To assess the concordance of tumour grade in specimens obtained from diagnostic cystoscopic biopsy and transurethral resection of bladder tumour (TURBT) and explore the risk factors of upgrading. Methods The medical records of 205 outpatients who underwent diagnostic cystoscopic biopsy before initial TURBT were retrospectively reviewed. Comparative analysis of the tumour grade of biopsy and operation specimens was performed. Tumour grade changing from low-grade (LG) to high-grade (HG) with or without variant histology was defined as upgrading. Univariate and multivariate logistic regression analyses were performed to identify the risk factors of upgrading. Results For the 205 patients, the concordance of tumour grade between biopsy and operation was 0.639. The concordance for patients who were preoperatively diagnosed with LG and HG was 0.504 and 0.912, respectively. Univariate and multivariate logistic regression analyses showed that older age, tumour multifocality, high neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and low lymphocyte-to-monocyte ratio (LMR) were significantly associated with upgrading (odds ratio [OR] ranging from 0.412 to 4.364). The area under the curve of the different multivariate models was improved from 0.752 to 0.821, and decision curve analysis demonstrated a high net benefit when NLR, LMR, and PLR were added. Moreover, the nomogram was well calibrated. Conclusions Diagnostic cystoscopic biopsy may not accurately represent the true grade of new bladder cancer, especially for outpatients with LG. Moreover, older age, tumour multifocality, high NLR, PLR, and low LMR are risk factors of upgrading, and systemic inflammatory markers improve the predictive ability.

Bladder cancer is an aggressive and lethal disease. Even when presenting as localized muscle-invasive disease, the 5-year survival rate is about 70%, and the recurrence rate after radical cystectomy is approximately 50%. Neoadjuvant chemotherapy (NAC) has the potential to downstage the primary tumor and treat micrometastases, leading to a decrease in recurrence rates and an increase in cure rates. There is level 1 evidence in favor of neoadjuvant cisplatin-based chemotherapy prior to radical cystectomy. However, data from clinical trials evaluating NAC for patients undergoing bladder-sparing treatments are less robust, so this strategy remains controversial. The response to NAC is prognostic and patients with favorable pathological response have better overall survival. Strategies to select patients based on molecular biomarkers have the potential to guide treatment decisions and even de-intensify treatment, avoiding local treatment for those with complete responses to systemic therapy. This review outlines the current literature on the use of NAC in the context of bladder preservation for muscle-invasive bladder cancer, highlights neoadjuvant studies in patients ineligible for cisplatin-based NAC, and discusses novel bladder-preservation strategies, including multimodality combinations and biomarker-driven studies of definitive chemotherapy.

Non-muscle-invasive bladder cancer is one of the most common malignancies. Patients with intermediate-risk or high-risk disease can be treated with intravesical Bacillus Calmette-Guerin, a vaccine against tuberculosis. However, many of these patients will experience tumor recurrence, despite appropriate treatment. 1 The standard of care in these patients is radical cystectomy (RC) with urinary diversion. 2 Patients diagnosed with muscle-invasive bladder cancer (MIBC) have traditionally faced 2 main treatment options: RC and urinary diversion, as in Bacillus Calmette-Guerin-unresponsive Non-muscle-invasive bladder cancer, or alternatively, trimodal therapy comprising maximal transurethral resection of bladder tumor plus chemoradiation. 3 For patients with MIBC and clinical (c)T2-T4a, neoadjuvant chemotherapy (NAC) preceding RC is supported by Level 1 evidence with a modest 5-year overall survival benefit of 5% with cisplatin-based regimens. 4-9 A number of factors preclude MIBC patients from standard treatment options. For example, patients with serious comorbidities might be unable to tolerate general anesthesia, while others might be unwilling to adapt to the lifestyle changes after RC. 10-12 Likewise, patients with extensive carcinoma in situ or poor bladder function might not be optimal candidates for trimodal therapy or be prepared for the ongoing risk that salvage RC might be ultimately required. Reasons for the underuse of NAC range from the fear of delaying potentially curative surgery in nonresponders to patient ineligibility to cisplatin-based NAC. 13,14 Despite best efforts, in both surgical and bladder-sparing approaches, the 5-year overall survival in treated patients with MIBC is only 35% to 50%. 3,15 Strategies to improve overall prognosis as well as to reduce the indications of RC are desperately needed. Trial results have demonstrated the unprecedented ability of immune-checkpoint inhibitors to induce durable remissions in some patients with metastatic urothelial carcinoma. 16-20 Furthermore, immune-checkpoint inhibitors have shown to be better tolerated than traditional chemotherapy. 16 These successful results have spearheaded the research on these agents in earlier curative settings, with the shared goal of improving overall outcomes, and potentially avoid surgery in patients who show complete response (pT0). Strategies to enhance the immune response by combining immunotherapy with immune sensitizers such as chemotherapy, immunotherapy, targeted therapy or radiation are on the rise.

Background: Bladder cancer (BCa) is more common in men and presents differences in molecular subtypes based on sex. Fibroblast growth factor receptor 3 (FGFR3) mutations are enriched in the luminal papillary muscle-invasive BCa (MIBC) and non-MIBC subtypes. Objective: To determine whether FGFR3 mutations initiate BCa and impact BCa male sex bias. Design, setting, and participants: We developed a transgenic mouse model expressing the most frequent FGFR3 mutation, FGFR3-S249C, in urothelial cells. Bladder tumorigenesis was monitored in transgenic mice, with and without carcinogen exposure. Mouse and human BCa transcriptomic data were compared. Intervention: Mutant FGFR3 overexpression in mouse urothelium and siRNA knockdown in cell lines, and N-butyl-N(4-hydroxybutyl)-nitrosamine (BBN) exposure. Outcome measurements and statistical analysis: Impact of transgene dosage on tumor frequency, synergy with BBN treatment, and FGFR3 pathway activation were analyzed. The sex-specific incidence of FGFR3-mutated tumors was evaluated in mice and humans. FGFR3 expression in FGFR3-S249C mouse urothelium and in various human epithelia was measured. Mutant FGFR3 regulation of androgen (AR) and estrogen (ESR1) receptor activity was evaluated, through target gene expression (regulon) and reporter assays. Results and limitations: FGFR3-S249C expression in mice induced low-grade papillary BCa resembling human luminal counterpart at histological, genomic, and transcriptomic levels, and promoted BBN-induced basal BCa formation. Mutant FGFR3 expression levels impacted tumor incidence in mice, and mutant FGFR3–driven human tumors were restricted to epithelia presenting high normal FGFR3 expression levels. BCa male sex bias, also found in our model, was even higher in human FGFR3-mutated tumors compared with wild-type tumors and was associated with higher AR and lower ESR1 regulon activity. Mutant FGFR3 expression inhibited both ESR1 and AR activity in mouse tumors and human cell lines, demonstrating causation only between FGFR3 activation and low ESR1 activity in tumors. Conclusions: Mutant FGFR3 initiates luminal papillary BCa formation and favors BCa male sex bias, potentially through FGFR3-dependent ESR1 downregulation. Patients with premalignant lesions or early-stage BCa could thus potentially benefit from FGFR3 targeting. FGFR3 expression level in epithelia could account for FGFR3-driven carcinoma tissue specificity. Patient summary: By developing a transgenic mouse model, we showed that gain-of-function mutations of FGFR3 receptor, among the most frequent genetic alterations in bladder cancer (BCa), initiate BCa formation. Our results could support noninvasive detection of FGFR3 mutations and FGFR3 targeting in early-stage bladder lesions.

Radical cystectomy with bilateral pelvic lymphadenectomy and trimodality bladder-sparing therapy or TMT, are both curative options for patients with nonmetastatic muscle invasive bladder cancer. Patients should be afforded the opportunity for a multidisciplinary evaluation with equipoise in discussing these options for eligible patients. We discuss the barriers to broader acceptance and utilization of TMT and encourage support of clinical trials of TMT.

Objective Guidelines for muscle-invasive bladder cancer (MIBC) recommends that patients receive neoadjuvant chemotherapy with radical cystectomy as treatment over radical cystectomy alone. Though trends and practice patterns of MIBC have been defined using the National Cancer Database, data using the Surveillance, Epidemiology, and End Results (SEER) program have been poorly described. Methods Using the SEER database, we collected data of MIBC according to the American Joint Commission on Cancer (AJCC). We considered differences in patient demographics and tumor characteristics based on three treatment groups: Chemotherapy (both adjuvant and neoadjuvant) with radical cystectomy, radical cystectomy, and chemoradiotherapy. Multinomial logistic regression was performed to compare likelihood ratios. Temporal trends were included for each treatment group. Kaplan–Meier curves were performed to compare cause-specific survival. A Cox proportional-hazards model was utilized to describe predictors of survival. Results Of 16 728 patients, 10 468 patients received radical cystectomy alone, 3236 received chemotherapy with radical cystectomy, and 3024 received chemoradiotherapy. Patients who received chemoradiotherapy over radical cystectomy were older and more likely to be African American; stage III patients tended to be divorced. Patients who received chemotherapy with radical cystectomy tended to be males; stage II patients were less likely to be Asian than White. Stage III patients were less likely to receive chemoradiotherapy as a treatment option than stage II. Chemotherapy with radical cystectomy and chemoradiotherapy are both underutilized treatment options, though increasingly utilized. Kaplan–Meier survival curves showed significant differences between stage II and III tumors at each interval. A Cox proportional-hazards model showed differences in gender, tumor stage, treatment modality, age, and marital status. Conclusions Radical cystectomy alone is still the most commonly used treatment for muscle-invasive bladder cancer based on temporal trends. Significant disparities exist in those who receive radical cystectomy over chemoradiotherapy for treatment.

BACKGROUND: The functional status of immune cells in the tumor microenvironment and tumor characteristics may explain bacillus Calmette-Guérin (BCG) failure in high-risk non-muscle-invasive bladder cancer (NMIBC).OBJECTIVE: To characterize molecular correlates of post-BCG high-grade (HG) recurrence using multiomics analysis.DESIGN, SETTING, AND PARTICIPANTS: Patients with BCG-treated NMIBC (n = 156) were included in the study. Metachronous tumors were analyzed using RNA sequencing (n = 170) and whole-exome sequencing (n = 195). Urine samples were analyzed for immuno-oncology-related proteins (n = 190) and tumor-derived DNA (tdDNA; n = 187).OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary endpoint was post-BCG HG recurrence. Cox regression and Wilcoxon rank-sum, t, and Fisher's exact tests were used for analyses.RESULTS AND LIMITATIONS: BCG induced activation of the immune system regardless of clinical response; however, immunoinhibitory proteins were observed in the urine of patients with post-BCG HG recurrence (CD70, PD1, CD5). Post-BCG HG recurrence was associated with post-BCG T-cell exhaustion (p = 0.002). Pre-BCG tumors from patients with post-BCG T-cell exhaustion had high expression of genes related to cell division and immune function. A high predicted post-BCG exhaustion score for pre-BCG tumors was associated with worse post-BCG HG recurrence-free survival (HGRFS; p = 0.002). This was validated in independent cohorts. Pre-BCG class 2a and 2b tumors (UROMOL2021 scheme) were associated with worse post-BCG HGRFS (p = 0.015). Post-BCG exhaustion was observed in patients with high pre-BCG neoantigen load (p = 0.017) and MUC4 mutations (p = 0.002). Finally, the absence of post-BCG tdDNA clearance identified patients at high risk of recurrence (p = 0.018). The retrospective design and partial overlap for analyses are study limitations.CONCLUSIONS: Post-BCG HG recurrence may be caused by T-cell exhaustion. Tumor subtype and pre-BCG tumor characteristics may identify patients at high risk of post-BCG HG recurrence. Urinary measurements have potential for real-time assessment of treatment response.PATIENT SUMMARY: A dysfunctional immune response to bacillus Calmette-Guérin (BCG) therapy may explain high-grade recurrences of bladder cancer.

Consumer technology in the form of personal computers, mobile devices, and wearable technology, despite current underutilization, has the potential to greatly enhance the practice of urologic oncology and the surgical care of bladder cancer patients, particularly through the dissemination of educational videos, telemedicine, and the use of wearable technology for patient monitoring. A comprehensive healthcare application can unite all of these features, providing curated educational videos at different timepoints in surgical care, facilitating communication between the patient and the care team, and interfacing with wearable technology and other peripherals to allow for nonintrusive patient monitoring to help facilitate early identification of complications and to follow post-operative patient progress. Here we seek to review the available literature on this topic, discuss our institutional experience, and provide future perspectives in the perioperative management of bladder cancer patients.

Immune checkpoint inhibitors are a well-established treatment option for advanced urothelial carcinoma, and biomarkers of response are needed for better patient selection. We show that metastatic disease confined to lymph nodes is associated with better outcomes, while metastases to liver, bone or both are associated with poor outcomes with immune checkpoint inhibitor therapy. Results are hypothesis-generating but relevant to practice. BACKGROUND: Sites of metastasis have prognostic significance in advanced urothelial carcinoma (aUC), but more information is needed regarding outcomes based on metastatic sites in patients treated with immune checkpoint inhibitors (ICI). We hypothesized that presence of liver/bone metastases would be associated with worse outcomes with ICI. METHODS: We identified a retrospective cohort of patients with aUC across 26 institutions, collecting demographics, clinicopathological, treatment, and outcomes information. Outcomes were compared with logistic (observed response rate; ORR) and Cox (progression-free survival; PFS, overall survival; OS) regression between patients with/without metastasis beyond lymph nodes (LN) and those with/without bone/liver/lung metastasis. Analysis was stratified by 1st or 2nd(+) line. RESULTS: We identified 917 ICI-treated patients: in the 1st line, bone/liver metastases were associated with shorter PFS (Hazard ratio; HR: 1.65 and 2.54), OS (HR: 1.60 and 2.35, respectively) and lower ORR (OR: 0.48 and 0.31). In the 2nd(+) line, bone/liver metastases were associated with shorter PFS (HR: 1.71 and 1.62), OS (HR: 1.76 and 1.56) and, for bone-only metastases, lower ORR (OR: 0.29). In the 1st line, LN-confined metastasis was associated with longer PFS (HR: 0.53), OS (HR:0.49) and higher ORR (OR: 2.97). In the 2nd(+) line, LN-confined metastasis was associated with longer PFS (HR: 0.47), OS (HR: 0.54), and higher ORR (OR: 2.79); all associations were significant. CONCLUSION: Bone and/or liver metastases were associated with worse, while LN-confined metastases were associated with better outcomes in patients with aUC receiving ICI. These findings in a large population treated outside clinical trials corroborate data from trial subset analyses.

Objective Vesical Imaging Reporting and Data System (VIRADS) score was developed to standardize the reporting and staging of bladder tumors on pre-operative multiparametric magnetic resonance imaging (mpMRI). It helps in avoiding unnecessary repeat transurethral resection of bladder tumor (Re-TURBT) in high-risk non-muscle-invasive bladder cancer (NMIBC) patients. This study was done to determine the validity of VIRADS score prospectively for the diagnosis of muscle-invasive bladder cancer. Methods This study was conducted from March 2019 to March 2020 at Sawai Mansingh Medical College and Hospital, Jaipur, Rajasthan, India. Patients admitted with the provisional diagnosis of bladder tumor were included as participants. All these patients underwent a 3 T mpMRI to obtain a VIRADS score before they underwent a TURBT and these data were analysed to evaluate the correlation of pre-operative VIRADS score with muscle invasiveness of the tumor in final biopsy report. Results A cut off of VIRADS ≥4 for prediction of detrusor muscle invasion yielded a sensitivity of 79.4%, specificity of 94.2%, positive predictive value (PPV) of 90%, negative predictive value (NPV) of 87.5%, and diagnostic accuracy of 86.37%. A cut off of VIRADS ≥3 for prediction of detrusor muscle invasion yielded a sensitivity of 91.2%, specificity of 78.8%, PPV of 73.8%, NPV of 93.2%, and accuracy of 83.7%. The receiver operating curve (ROC) showed the area under the curve (AUC) to be 0.922 (95% confidence interval: 0.862–0.983). Conclusions VIRADS score appears to be an excellent and effective preoperative radiological tool for the prediction of detrusor muscle invasion in bladder cancer.

BACKGROUND Chronic urinary retention (CUR) is a frequent complication after orthotopic neobladder (ONB) reconstruction in women. To decrease CUR, several open surgical modifications to provide back support to the ONB have been established on the basis of pelvic anatomical differences between females and males. OBJECTIVE To illustrate our technique for robotic intracorporeal reconfiguration of ONB as integrated into our open surgical approach to provide back support to the ONB with round ligaments in women. DESIGN, SETTING, AND PARTICIPANTS From November 2017 to April 2021, 28 patients underwent robotic intracorporeal ONB with a minimum of 6 mo of follow-up at a single centre. SURGICAL PROCEDURE We performed robotic radical cystectomy, pelvic lymphadenectomy, and a complete intracorporeal ONB suspended with round ligaments (rONB). Our surgical procedure is demonstrated in the accompanying video. MEASUREMENTS Demographics and clinical and pathological data were collected. Perioperative and 90-d complications and 6-mo functional outcomes were compared for the rONB group (n = 12) and the patients receiving a traditional ONB (tONB; n = 16). RESULTS AND LIMITATIONS The median total operative time was 305 min (interquartile range [IQR] 270-370) for tONB and 303 min (IQR 287-330) for rONB. The median estimated blood loss was 325 ml (IQR 200-700) for tONB and 350 ml (IQR 262-600) for rONB. Some 50% of the tONB group and 41.7% of the rONB group experienced low-grade complications. A total of 12.5% tONB and 8.3% rONB patients experienced high-grade complications with neobladder-vaginal fistula. The cumulative risk of CUR was 37.5% in the tONB group and 16.7% in the rONB group. This study is limited by the small sample size and the short follow-up period. CONCLUSIONS We established a feasible surgical technique for a robotic intracorporeal ONB configuration suspended with round ligaments. This may prevent the occurrence of emptying dysfunction in women. PATIENT SUMMARY We describe our stepwise technique for creating a new bladder within the body that is suspended with round ligaments. Patients undergoing removal of the bladder for bladder cancer may benefit from this technique in terms of better urinary function and the advantages of a robotic surgical approach.

Background Survivors of prostate, bladder, and colorectal cancer endure many sexual side-effects of treatment that negatively impact their relationships and diminish their quality of life. Multiple barriers exist in addressing men's sexual concerns in oncological care. Objective To describe barriers of sexual recovery in men with prostate, bladder, and colorectal cancer. Methods We searched PubMed for peer-reviewed, English-language articles published from 1999 to 2019 using the following search terms: “prostate cancer,” or “bladder cancer,” or “colorectal cancer,” and “male,” and “sexual function,” or “sexual barrier” or “sexual dysfunction.” Criteria for inclusion consisted of peer-reviewed articles (review, cross-sectional, longitudinal, interventional, or pilot studies) addressing sexual issues in men with a history of prostate, bladder, or colorectal cancer. Results Barriers to sexual recovery in men with prostate, bladder, and colorectal cancer include psychosocial barriers such as the feeling of loss, grief, depression and anxiety, the poor utilization, and excessive cost of pro-erectile aids, a diminished sense of masculinity and reluctance to seek help for sexual problems, as well as poor couple coping. Barriers in healthcare also exist, as healthcare providers often do not effectively address sexual issues due to poor communication, lack of comfort in discussing sexual issues, time constraints, and patients’ hesitation to initiate discussions on sexual dysfunction. Patients with stomas and gay, bisexual, and queer men face additional challenges in their recovery of sexual intimacy. Barriers to sexual recovery are present in men during all stages of cancer and all modalities of treatment including surgery, radiation, or androgen deprivation therapy. Conclusion There are multiple overlapping psychosocial and healthcare system barriers to sexual recovery after prostate, bladder, and colorectal cancer treatment. Oncological providers must be cognizant of these complex barriers so they can facilitate patients’ access to resources needed for successful sexual recovery after genitourinary cancer treatment. Evidence based interventions, such as couple psychosexual counseling and peer support should be implemented via multidisciplinary care.

Background Delay in treatment is a prognostic factor in muscle-invasive bladder cancer. Objective To evaluate clinical outcomes associated with delays in diagnosis and treatment for patients with non–muscle invasive bladder cancer (NMIBC). Design, setting, and participants In this retrospective study we analyzed data for patients treated at our center between November 2008 and December 2016 for intermediate risk (IR) or high risk (HR) NMIBC with an additional intravesical treatment. Outcome measurements and statistical analysis Time delays from diagnosis to first transurethral resection (TT-TUR), from resection to restaging resection (TT-reTUR), and from the last resection to first instillation (TT-INST) of bacillus Calmette-Guerin (BCG) or mitomycin C (MMC) were documented. To identify the interval of time from which recurrence rates significantly increased, we used nonparametric series regression. Recurrence-free survival (RFS) and progression-free survival for patients in each time delay category were compared using the Kaplan-Meier method. Factors associated with tumor recurrence were analyzed in a multivariable model. Results and limitations A total of 434 patients were included, of whom 168 (38.7%) had IR and 266 (61.3%) had HR NMIBC. Among the patients, 34.6% had reTUR, 63.6% received BCG, and 36.4% received MMC. The median TT-TUR, TT-reTUR, and TT-INST was 4.0 wk, 6.5 wk, and 7.0 wk, respectively. At 40 mo the rate of recurrence was 28.4% and the rate of progression was 7.3%. Nonparametric analysis revealed that each week in delay increased the risk of recurrence, starting from week 6 for TT-TUR for IR and HR cases, and starting from week 7 for TT-INST for IR cases. RFS was significantly lower with TT-TUR > 6 wk among patients in the IR (p 7 wk for patients in the IR group (p = 0.001). TT-reTUR >7 wk had a significant negative impact on progression (p 6 wk (p = 0.001 and p = 0.03) were independent predictors of recurrence, while TT-INST >7 wk predicted recurrence (p = 0.04) for IR NMIBC. Conclusions Our results suggest that delays of >6 wk to first TUR in IR and HR NMIBC, and >7 wk to first instillation in IR cases are associated with increases in the risk of recurrence. TT-reTUR of >7 wk is also associated with higher risk of progression. Patient summary We evaluated the impact of treatment delays on outcomes for patients with intermediate- and high-risk bladder cancer not invading the bladder wall muscle. We found that delays from diagnosis to first bladder resection, from first resection to repeat resection, and from last resection to bladder instillation treatment increase the rates of cancer recurrence and progression. The medical team should avoid delays in treatment, even for low-grade bladder cancer.

Background Chemotherapy is a first-line treatment for advanced and metastatic bladder cancer, but the unsatisfactory objective response rate to this treatment yields poor 5-year patient survival. Only PD-1/PD-L1-based immune checkpoint inhibitors, FGFR3 inhibitors and antibody-drug conjugates are approved by the FDA to be used in bladder cancer, mainly for platinum-refractory or platinum-ineligible locally advanced or metastatic urothelial carcinoma. Emerging studies indicate that the combination of targeted therapy and chemotherapy shows better efficacy than targeted therapy or chemotherapy alone. Newly identified targets in cancer cells and various functions of the tumour microenvironment have spawned novel agents and regimens, which give impetus to sensitizing chemotherapy in the bladder cancer setting. Aim of Review: This review aims to present the current evidence for potentiating the efficacy of chemotherapy in bladder cancer. We focus on combining chemotherapy with other treatments as follows: targeted therapy, including immunotherapy and antibody-drug conjugates in clinic; novel targeted drugs and nanoparticles in preclinical models and potential targets that may contribute to chemosensitivity in future clinical practice. The prospect of precision therapy is also discussed in bladder cancer. Key Scientific Concepts of Review: Combining chemotherapy drugs with immune checkpoint inhibitors, antibody-drug conjugates and VEGF inhibitors potentially elevates the response rate and survival. Novel targets, including cancer stem cells, DNA damage repair, antiapoptosis, drug metabolism and the tumour microenvironment, contribute to chemosensitization. Gene alteration-based drug selection and patient-derived xenograft- and organoid-based drug validation are the future for precision therapy.

Background Despite years of slow progress, muscle invasive bladder cancer (MIBC) is finally entering the era of molecularly guided targeted therapy. However, tumor heterogeneity is high in MIBC and may impact treatment response and resistance. The objective of this review is to dissect recent insights into inter- and intratumor heterogeneity (ITH) in MIBC, with emphasis on the clinical implications of this heterogeneity for biomarker-driven strategies and the development of new therapies. Methods A nonsystematic review was performed in PubMed and EMBASE using the terms “tumor heterogeneity” and “bladder cancer.” Results Intertumor heterogeneity, as reflected by different clinical phenotypes in different patients, has been partially explained with next generation sequencing and other molecular profiling technologies. RNA-based molecular subtyping, for example, provides a classification of MIBC into distinct categories that can be used for further molecular analysis, biomarker discovery, risk stratification, and treatment selection. Molecular subtyping and specific genomic alterations, especially in DNA damage repair genes, may help explain why some patients respond better to systemic chemotherapy and immunotherapy. Conversely, spatial and temporal ITH threaten to confound attempts to target specific molecular lesions since not all tumor cells within a patient may carry the relevant lesion. Improved understanding and management of ITH is required for the most effective use of biomarker-driven targeted therapies. Conclusion Strategies to assess and overcome intertumor and ITH in MIBC will be critical steps toward realizing the objectives of precision oncology. Novel techniques such as analysis of circulating tumor DNA and single cell sequencing are likely to revolutionize our understanding of tumor heterogeneity.

Blue light cystoscopy (BLC) during transurethral resection of bladder tumor (TURBT) is guideline-recommended as it improves cancer detection and decreases recurrence of the disease. However, the extent to which BLC is used has not been established. We studied BLC use in the Premier Healthcare Database, a large, national sample that captured 158 870 index TURBT procedures between January 2011 and March 2020. Billing data were queried for the administration of hexaminolevulinate at TURBT as a proxy for BLC, and logistic regression models were constructed to identify variables associated with BLC use. BLC was used in 1.2% of index TURBT procedures over the study period. Its use increased following the American Urological Association non-muscle-invasive bladder cancer guideline publication in October 2016 but plateaued in late 2018. After adjusting for patient characteristics, higher odds for BLC use were found for academic hospitals and hospitals with higher TURBT volumes and higher radical cystectomy volumes. Within hospitals with BLC capability, predictors of a surgeon never using BLC included low surgeon TURBT volumes, low surgeon radical cystectomy volumes, and lack of mitomycin C use. Our findings highlight a concerning underutilization and stagnation in the adoption of evidence and guideline-supported intervention. PATIENT SUMMARY: Use of blue light visualization of the bladder improves the detection of cancer during removal of bladder tumors via the urethra. We reviewed records in a large US database for use of this technique and found that it is being underutilized. Since this technique improves detection of cancer in the bladder so that it can be removed to reduce recurrence, blue light visualization should be more widely used.

The Cancer Genome Atlas (TCGA) for bladder cancer was published in 2014 with updated annotation of over 400 patients with muscle-invasive bladder cancer (MIBC) in 2017. This tremendous work established the foundation of the genomic landscape of MIBC. The next steps to utilize information from The Cancer Genome Atlas is to (1) identify the causes of mutation, (2) determine the significant differences and sources of heterogeneity, and (3) apply these tools toward patient care. In this review, we discuss the full spectrum of the genomic landscape of MIBC toward the goal of therapeutic application.

BACKGROUND Elevated preoperative plasma levels of the angiogenesis-related marker VEGF have been associated with worse oncological outcomes in various malignancies. OBJECTIVE To investigate the predictive/prognostic role of VEGF in patients with urothelial carcinoma of the bladder (UCB) treated with radical cystectomy (RC). DESIGN, SETTING, AND PARTICIPANTS VEGF plasma levels were measured preoperatively in 1036 patients with UCB who underwent RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The correlation between plasma VEGF levels and pathological and survival outcomes was assessed using logistic regression and Cox regression analyses. Discrimination was assessed using the concordance index (C index). The clinical net benefit was evaluated using decision curve analysis (DCA). RESULTS AND LIMITATIONS Patients with higher pretreatment plasma VEGF levels had poorer recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS) according to log-rank tests (all p 0.05). Preoperative plasma VEGF levels were independently associated with RFS, CSS, and OS in preoperative and postoperative multivariable models. However, in all cases the C index increased by

Docetaxel and gemcitabine have different mechanisms of action, are well tolerated as monotherapies, and are affordable. This combination represents a good option for the second-line, bladder-preserving standard of care for non-muscle-invasive bladder cancer unresponsive to bacillus Calmette-Guérin.

Novel immune checkpoint inhibitors hold promise for non-muscle-invasive bladder cancer. Cooperation between urologists and other multidisciplinary bladder cancer specialists can surmount the challenges involved in using these agents in bladder-sparing approaches. This strategy could deliver a new era of comprehensive evaluation and multimodal treatment for this patient population.

Background Guideline indications for restaging transurethral resection (reTUR) for high-grade (HG) Ta bladder tumors vary due to a paucity of data. Objective To investigate guideline-based, risk-adapted approaches to reTUR for HG Ta lesions. Design, setting, and participants An institutional review of HG Ta patients who received adequate bacillus Calmette-Guerin (BCG) from 2000 to 2019 was conducted. Outcome measurements and statistical analysis Guideline criteria for reTUR were used to stratify patients. Kaplan-Meier product limits estimated survival. Cox regression and log-rank tests identified association of variables with survival. Results and limitations Of the 209 patients with HG Ta bladder cancer, 104 (50%) underwent reTUR, which identified residual disease in 39 patients (38%). Only one patient (1%) was upstaged to pT1 on reTUR. In all unstratified HG Ta patients, reTUR was associated with improved progression-free survival (p = 0.050) and recurrence-free survival (RFS; p = 0.003). The 5-yr RFS for patients who underwent versus those who did not undergo reTUR based on AUA guidelines was 73% (95% confidence interval 63–81%) versus 52% (40–62%), and for those who underwent versus those who did not undergo reTUR based on EAU guidelines was 76% (61–86%) versus 22% (4–49%). In 45 patients meeting both AUA high-risk criteria (large, multifocal tumors) and EAU criteria (lack of detrusor muscle) for reTUR, lack of restaging was associated with over a two-fold increase in recurrence (67% vs 15%, p = 0.002) and progression (25% vs 6%, p = 0.109). Data were limited by selection bias unaccounted for in selecting candidates for reTUR. Conclusions Restaging TUR in all HG Ta patients, regardless of risk stratification, was associated with improved outcomes. The benefit of reTUR was most notable in high-risk patients without muscle in the index specimen, consistent with components of both AUA and EAU guidelines. These data support a non–risk-adapted approach to reTUR for all HG Ta lesions. Patient summary Restaging bladder tumor resection improves outcomes in patients with high-grade Ta tumors treated with bacillus Calmette-Guerin (BCG).

Background Receptor activator of NF kappa B (RANK) and its ligand have an essential role in T-cell regulation and the development of bone metastases. The role of RANK expression in muscle-invasive bladder cancer (MIBC) is unknown. Objective To assess the relevance of RANK expression in patients with MIBC. Design, setting, and participants Expression of RANK was assessed via immunohistochemistry of benign urothelium, MIBC tissue, and lymph node metastases from 153 patients undergoing radical cystectomy. Expression data from The Cancer Genome Atlas (TCGA) cohort were analyzed for potential associations with molecular subtypes and outcome. Outcome measurements and statistical analysis RANK expression was correlated with clinical and pathological parameters and to individual data for the clinical course of MIBC. Results and limitations Expression of RANK was significantly higher in both primary tumors (p = 0.02) and lymph node metastases (p = 0.01) compared to normal urothelium. In tumor tissue, RANK expression was significantly lower in patients with locally advanced disease and lymph node involvement compared to those with organ-confined disease (p = 0.0009) and node-negative MIBC (p = 0.0002). In univariable and multivariable analyses, high expression of RANK was associated with a longer time to recurrence (p = 0.0005 and 0.01) and better cancer-specific (p = 0.0004 and 0.007) and overall survival (p = 0.002 and 0.04). High expression of RANK was associated with better outcome for patients with luminal infiltrated tumors in the TCGA cohort. Conclusions RANK expression is increased in bladder cancer tissue compared to benign urothelium, with higher expression in organ-defined compared to locally advanced disease. High RANK expression indicates a favorable prognosis in MIBC. The prognostic role differs in tumors of different molecular subtypes. Patient summary Expression of a protein involved in bone turnover regulation (RANK) is higher in bladder cancer tissue than in benign bladder tissue. However, high levels of RANK on tumor cells indicate favorable prognosis for patients with bladder cancer that invades the muscle layer of the bladder.

INTRODUCTION To evaluate the functional outcomes and quality of life beyond 1 year, in patients treated with radical cystectomy and orthotopic diversion for invasive bladder cancer. To investigate various potential contributing factors on patient's quality of life after radical cystectomy and urinary diversion via orthotopic neobladder. MATERIALS AND METHODS This retrospective study was conducted at the National Cancer Institute (NCI), Cairo; including a total of 97 patients who underwent radical cystectomy and orthotopic diversion. Functional and sexual outcome and patient QoL were assessed by ICIQ-SF, IIEF-5 and QLQ-C30 questionnaires. Potential association of patient QoL with pre-and intraoperative variables was studied. RESULTS Our results show that preoperative ECOG performance status 0 (P=0.0001), and nerve sparing surgery (P=0.001), were associated with high QoL and functional outcomes. On the contrary, ECOG performance status 2, preoperative comorbidities as ischemic heart diseases (P=0.01), recurrence (0.041), adjuvant chemotherapy (P=0.017) and radiotherapy (P=0.001) were associated with low QoL on univariate analysis. However, only ECOG performance status 2 (P

Among the growing family of inhibitory receptors regulating immunity, sialic acid-binding immunoglobulin domain-containing lectins (Siglecs) have recently emerged as immunoregulatory receptors recognizing sialylated ligands on tumor cell surface. However, their role in the immunoregulation of bladder cancer (BCa) remains unknown. Here, we determined the presence of eight Siglec ligands (SLs) on bladder nontumor and tumor cell lines. S2L, S3L, and S6L were not expressed, and few bladder tumor cell lines expressed S5L and S14L. In contrast, S7L and S10L were upregulated on all bladder tumor cell lines. We found a discrepency in S9L expression by nontumor cell lines, which is however highly expressed by bladder tumor cell lines. Notably, expression of S5L, S6L, and S14L was increased upon bacillus Calmette-Guerin (BCG) infection. Furthermore, we analyzed the expression of Siglecs on T cells from healthy donors and BCa patients. Circulating T cells only expressed Siglec-6, which is upregulated in non-muscle-invasive BCa patients. In addition, BCG therapy induced the overexpression of Siglec-6 by urinary CD8+ T cells. In vitro functional assays suggested that Siglecs may decrease cytotoxic functions of effector CD8+ T cells. Finally, analyses from two BCa datasets (The Cancer Genome Atlas and UROMOL cohorts) showed that Siglec-6 is associated with tumor progression and poor survival. Our findings indicate that Siglec-6 might be a new target for BCa treatments. PATIENT SUMMARY: We investigated the expression of Siglecs, a family of immunoregulatory receptors, in bladder cancer patients. We observed that the expression of Siglec-6 is increased on circulating and urinary T cells of non-muscle-invasive bladder cancer patients. We also showed that Siglec-6 is associated with lower survival in bladder cancer patients and might contribute to bladder cancer recurrence.

Context Radiomics is a field of science that aims to develop improved methods of medical image analysis by extracting a large number of quantitative features. New data have emerged on the successful application of radiomics and machine-learning techniques to the prediction of muscle-invasive bladder cancer (MIBC). Objective To systematically review the diagnostic performance of radiomic techniques in predicting MIBC. Evidence acquisition The literature search for relevant studies up to July 2020 was performed in the PubMed and EMBASE databases by two independent reviewers. The meta-analysis was inducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Inclusion criteria comprised studies that evaluated the diagnostic accuracy of radiomic models in predicting MIBC and used pathological examination as the reference standard. For bias assessment, Quality Assessment of Diagnostic Accuracy Studies-2 and Radiomic Quality Score were used. Weighted summary proportions were used to calculate pooled sensitivity and specificity. A linear mixed model was implemented to calculate the hierarchical summary receiver-operating characteristic (HSROC). Meta-regression analyses were performed to explore heterogeneity. Evidence synthesis Eight studies with a total of 860 patients were included. The summary estimates for sensitivity and specificity in predicting MIBC were 82% (95% confidence interval [CI]: 77–86%) and 81% (95% CI: 76–85%), respectively. The area under HSROC was 0.88. There were no relevant heterogeneity in diagnostic accuracy measures (I2 = 33% and 41% for sensitivity and specificity, respectively), which was confirmed by a subsequent meta-regression analysis. Conclusions Radiomics shows high diagnostic performance in predicting MIBC. Despite differences in approaches, radiomic models were relatively homogeneous in their diagnostic accuracy. With further improvements, radiomics has the potential to become a useful adjunct in clinical management of bladder cancer. Patient summary Rapidly evolving imaging analysis methods using artificial intelligence algorithms, called radiomics, show high diagnostic performance in predicting muscle-invasive bladder cancer.

Context Decision aids (DAs) aim to support patients in the process of shared decision-making for complex treatment decisions. To improve patient-centered care in uro-oncology, it is essential to evaluate the availability and quality of existing DAs. Objective To assess the quality of existing DAs for patients across the most prevalent uro-oncological entities. Evidence acquisition This study was conducted in accordance with the Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) guidelines. A systematic literature search (MedLine, Cochrane Library, Web of Science Core Collection, and CCMed) was conducted to identify DAs for treatment decisions for patients with prostate, renal, or bladder cancer. All studies reporting on the development or evaluation of DAs were included. The DAs were examined based on the International Patient Decision Aid Standards (IPDAS) and the evaluation studies were compared in accordance with Standards for Universal reporting of a patient Decision Aid Evaluations (SUNDAE). Evidence synthesis The literature search identified 1995 potentially relevant publications. Thirty-two studies reporting on 25 DAs met the inclusion criteria. Twenty-two DAs address prostate cancer, two renal tumor, and one bladder cancer. In the majority of DAs (n = 20), patients can enter individual data. A few (n = 6) DAs allow for personalization using a risk-adapted presentation of treatment options. The percentage of IPDAS criteria met in DAs ranged between 50% and 100% (median 87.5%), and the studies’ adherence to the SUNDAE checklist was between 62% and 96% (median 86.6%). Evaluation studies suggest that interventions are likely efficacious. However, a preliminary meta-analysis revealed no significant difference between "DA" and "usual care" for decisional conflict or decisional regret. Conclusions This review highlights that a number of well-developed DAs exist in urology. However, there is a need for specific instruments targeting kidney and bladder cancer. Personalization of tools and adherence to international standards of DAs should be further improved. Patient summary The majority of uro-oncological decision aids target prostate cancer, whereas fewer address kidney or bladder cancer. The quality of the existing instruments is high, but can be increased further to better address specific needs of individual patients.

Background: Transurethral resection of bladder tumours (TURBT) is the initial diagnostic treatment for patients with bladder cancer. TURBT is not an easy procedure to master and simulator training may play a role in improving the learning curve. Objective: To implement a national training programme for simulation-based mastery learning in TURBT and explore operating theatre performance after training. Design, setting, and participants: From June 2019 to March 2021, 31 doctors at urology departments in Denmark performed two pretraining TURBT procedures on patients, followed by proficiency-based mastery learning on a virtual reality simulator and then two post-training TURBTs on patients. Outcome measurements and statistical analyses: Operating theatre performances were video-recorded and assessed by two independent, blinded raters using the Objective Structured Assessment for Transurethral Resection of Bladder Tumours Skills (OSATURBS) assessment tool. Paired-sample t tests were used to compare pretraining and post-training analyses and independent t tests for between-group comparisons. This trial is registered at ClinicalTrials.gov as NCT03864302. Results and limitations: Before training, novices had significantly lower performance scores in comparison to those with intermediate experience (p = 0.017) and experienced doctors (p < 0.001). After training, novices significantly improved their clinical performance score (from 11.4 to 17.1; p = 0.049, n = 10). Those with intermediate experience and experienced doctors did not benefit significantly from simulator training (p = 0.9 and p = 0.8, respectively). Conclusions: Novices improved their TURBT performance in the operating theatre after completing a proficiency-based training programme on a virtual reality simulator. Patient summary: We trained surgeons in an operation to remove bladder tumours using a virtual reality simulator. Novice doctors improved their performance significantly after the training, but the training effects for more experienced doctors were minimal. Therefore, we suggest the introduction of mandatory simulator training in the residency programme for urologists.

Background For muscle-invasive bladder cancer (MIBC), no tissue biomarkers are available for clinical use to predict response to neoadjuvant chemotherapy. Objective To investigate how molecular subtypes impact pathological response and survival in patients receiving preoperative cisplatin-based chemotherapy. Design, setting, and participants Classification of a retrospective cohort of 149 patients was performed by tumor transcriptomic profiling and immunostaining. A cohort treated with radical cystectomy alone and public data sets were used for comparison and external validation. Outcome measurements and statistical analysis Complete pathological response in the cystectomy specimen (ypT0N0) and survival were compared in predefined molecular subtypes. Differential gene expression and chemotherapy response were explored beyond molecular subtypes. Results and limitations Patients with genomically unstable (GU) and urothelial-like (Uro) tumors had higher proportions of complete pathological response (16/31 [52%] and 17/54 [31%]), versus five out of 24 (21%) with the basal/squamous (Ba/Sq) subtype following neoadjuvant chemotherapy and radical cystectomy. Molecular subtype was independently associated with improved survival for patients with GU tumors (hazard ratio [HR] 0.29, 95% confidence interval [CI]: 0.11–0.79) and UroC tumors (HR 0.37, 95% CI: 0.14–0.94) compared with Ba/Sq tumors, adjusting for clinical stage. In addition, expression of the gene coding for osteopontin (SPP1) showed a subtype-dependent effect on chemotherapy response. Conclusions Urothelial cancer of the luminal-like (GU and Uro) subtypes is more responsive to cisplatin-based neoadjuvant chemotherapy. A second-generation of subtype-specific biomarkers, for example, SPP1, may be a way forward to develop a more precision-based treatment approach for neoadjuvant chemotherapy in MIBC. Patient summary This study shows that tumor classification by gene expression profiling and molecular subtyping can identify patients who are more likely to benefit from chemotherapy before radical cystectomy for muscle-invasive bladder cancer. Together with other markers for response, molecular subtypes could have a role in selective administration of such chemotherapy.

Background: The utilisation of robot-assisted radical cystectomy with intracorporeal reconstruction (iRARC) has increased in recent years. Little is known about the length of the learning curve (LC) for this procedure. Objective: To study the length of the LC for iRARC in terms of 90-d major complications (MC90; Clavien-Dindo grade >= 3), 90-d overall complications (OC90, Clavien-Dindo grades 1-5), operating time (OT), estimated blood loss (EBL), and length of hospital stay (LOS). Design, setting, and participants: This was a retrospective analysis of all consecutive iRARC cases from nine European high-volume hospitals with >= 100 cases. All patients had bladder cancer for which iRARC was performed, with an ileal conduit or neobladder as the urinary diversion. Outcome measurements and statistical analysis: Outcome parameters used as a proxy for LC length were the number of consecutive cases needed to reach a plateau level in two-piece mixed-effects models for MC90, OC90, OT, EBL, and LOS. Results and limitations: A total of 2186 patients undergoing iRARC between 2003 and 2018were included. The plateau levels for MC90 and OC90 were reached after 137 cases (95% confidence interval [CI] 80-193) and 97 cases (95% CI 41-154), respectively. The mean MC90 rate at the plateau was 14% (95% CI 7-21%). The plateau level was reached after 75 cases (95% CI 65-86) for OT, 88 cases (95% CI 70-106) for EBL, and 198 cases (95% CI 130-266) for LOS. A major limitation of the study is the difference in the balance of urinary diversion types between centres. Conclusions: This multicentre retrospective analysis for the iRARC LC among nine European centres showed that 137 consecutive cases were needed to reach a stable MC90 rate. Patient summary: We carried out a multicentre analysis of the surgical learning curve for robot-assisted removal of the bladder and bladder reconstruction in patients with bladder cancer. We found that 137 consecutive cases were needed to reach a stable rate of serious complications.

Background Recent advances in genomic and genetic technologies have facilitated better health outcomes for urologic cancer patients. Genomic and genetic heterogeneity may contribute to differences in tumor biology and urologic cancer burden across various populations. Objective To examine how emerging genomic and genetic biomarkers, self-reported race, and ancestry-informative markers are associated with kidney, prostate, and bladder cancer outcomes. Results Genomic and genetic alterations found in African American kidney cancer patients included distinct somatic mutations, somatic copy number alterations, chromosomal instability, germ-line risk alleles, and germ-line genetic variants. These changes correlated with improved risk prediction, prognosis, and survival; and a predicted decrease in response to targeted therapies. SNP risk alleles and ancestry-informative markers were associated with improved risk prediction in prostate cancer patients of both African and European descent. AKT activation suggest differential response to AKT-targeted therapies in African American, Asian American, and Tunisian bladder cancer patients. Both self-reported race and genetic ancestry predicted urologic cancer risk prediction. Conclusion Precision medicine approaches that integrate population-specific genomic and genetic information with other known urologic cancer-specific characteristics can improve outcomes and be leveraged to reduce cancer health disparities. Further investigations are necessary to identify novel genomic biomarkers with clinical utility.

Non-muscle invasive bladder cancer (NMIBC) generally has a good prognosis; however, recurrence after transurethral resection (TUR), the standard primary treatment, is a major problem. Clinical management after TUR has been based on risk classification using clinicopathological factors, but these classifications are not complete. In this study, we attempted to predict early recurrence of NMIBC based on machine learning of quantitative morphological features. In general, structural, cellular, and nuclear atypia are evaluated to determine cancer atypia. However, since it is difficult to accurately quantify structural atypia from TUR specimens, in this study, we used only nuclear atypia and analyzed it using feature extraction followed by classification using Support Vector Machine and Random Forest machine learning algorithms. For the analysis, 125 patients diagnosed with NMIBC were used; data from 95 patients were randomly selected for the training set, and data from 30 patients were randomly selected for the test set. The results showed that the support vector machine-based model predicted recurrence within 2 years after TUR with a probability of 90% and the random forest-based model with probability of 86.7%. In the future, the system can be used to objectively predict NMIBC recurrence after TUR.

Objective To compare the differences in adverse effects and efficacy profile between bacillus Calmette-Guerin (BCG) Danish 1331 and BCG Moscow-I strain in management of non-muscle invasive bladder cancer (NMIBC). Methods Clinical data of 188 cases of NMIBC treated with BCG between 2008 and 2018 in our institute were collected prospectively and analysed retrospectively, and 114 patients who completed a minimum of 12 months of follow-up were analysed. Patient and tumor characters, strain of BCG, adverse effects and tumor progression were included for analysis. Intravesical BCG was instilled in intermediate and high-risk patients. Six weeks of induction BCG, followed by three weekly maintenance BCG at 3,6,12, 18 and 24 months was advised in high-risk patients. Results Overall 68 patients received BCG Danish 1331 strain and 46 patients received Moscow-I strain. Patient and tumor characteristics were well balanced between the two groups. The median follow-up period was 42.5 months and 34.5 months in Danish-1331 and Moscow groups, respectively. Adverse events like dropout rate, anti-tubercular treatment requirement and need of cystectomy were higher in Moscow group (n = 31, 67.4%) when compared to Danish 1331 strain (n = 33, 48.5%) (p = 0.046). On direct comparison between Danish-1331 and Moscow strain, there was similar 3-year recurrence-free survival (RFS) (80% vs. 72.9%) and 3-year progression-free survival (PFS) (96.5% vs. 97.8%). Conclusion Study results suggest no significant differences between Danish 1331 and Moscow strain in RFS and PFS, but a significantly higher incidence of moderate to severe adverse events in BCG Moscow strain.

Introduction : Use of hypofractionated radiation (HFRT) and intensity-modulated radiation (IMRT) for organ preservation in bladder cancer is controversial and highly variable. We investigated practice patterns, trends, and predictors of HFRT and IMRT. Patients and Methods : The National Cancer Database was queried for patients with muscle-invasive, non-metastatic urothelial bladder cancer, treated with definitive (chemo)radiotherapy between 2004-2017. HFRT was defined as 50-60 Gy at >2 Gy/fraction. Multivariable logistic regression was used to identify predictors of receiving HFRT or IMRT. Multivariable Cox regression was used to model overall survival (OS), adjusting for potential confounders such as age, comorbidity, and chemotherapy. Results : Of 5132 patients identified, 490 (9.5%) received HFRT, and only 334 (6.5%) received ≥ 2.5 Gy/fraction. HFRT patients were significantly older, less fit, and less likely to receive chemotherapy relative to CFRT, even after controlling for age and comorbidity (adjusted odds ratio 0.36, 95% confidence interval [CI] 0.29-0.45, P Conclusion : HFRT is largely underutilized, being primarily reserved for older, frailer patients. Chemotherapy is significantly underused with HFRT relative to CFRT. IMRT is used frequently and was associated with equivalent or modestly increased overall survival. MICROABSTRACT : This National Cancer Database study of bladder cancer patients treated with definitive (chemo) radiotherapy uncovered significant under-utilization of hypofractionated RT (HFRT). Furthermore, chemotherapy was significantly underused with HFRT compared to patients receiving conventional fractionation. Use of both intensity-modulated RT (IMRT) and HFRT increased over time. IMRT was associated with similar or modestly increased survival, particularly in patients receiving HFRT.

BACKGROUND: An improved risk assessment of patients with bladder cancer (BC) is important to optimize clinical management. OBJECTIVE: To identify whether immune cell subpopulations and cancer cell-intrinsic features are associated with outcome and response to first-line chemotherapy in BC. DESIGN, SETTING, AND PARTICIPANTS: Primary tumor tissue from 785 patients with BC (stage Ta-T4b) were stained using multiplex immunofluorescence (CD3, CD8, FOXP3, CD20, CD68, CD163, and MHC-I) and immunohistochemistry (pancytokeratin, CK5/6, GATA3, programmed death 1 [PD-1], and programmed death ligand 1 [PD-L1]). A digital image analysis quantified staining results within the carcinoma cell and stromal part of the tumor. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Primary endpoints were progression-free survival, recurrence-free survival, and response to first-line chemotherapy. Optimal cutoff values for investigated markers were estimated using maximally selected rank statistics and receiver operating characteristic for each primary endpoint. Time-to-event analyses were performed using Cox regression analyses. RESULTS AND LIMITATIONS: Several immune subpopulations were independently associated with clinical outcomes. Especially, high PD-1 and PD-L1 expression was independently associated with an increased risk of recurrence and progression in non-muscle-invasive tumors, but with a lower risk of recurrence in muscle-invasive tumors. Furthermore, we observed a lower likelihood of response to first-line chemotherapy in patients with basal differentiation features. Finally, a model combining clinical risk factors with our most evident prognosticator improved prediction accuracy compared with clinical risk factors alone for progression in non-muscle-invasive BC and recurrence in muscle-invasive BC. The use of tissue microarrays and a long inclusion period are limitations to this study. CONCLUSIONS: Immune cell subpopulations and cancer cell-intrinsic features are associated with different clinical outcomes in BC. PATIENT SUMMARY: Immune cells play an important role in cancer development and treatment outcomes. Infiltration with specific immune cells and the presence of markers associated with immune evasion in the tumor predict clinical outcomes in bladder cancer.

Fibroblast growth factor receptor (FGFR) inhibitor treatment has become the first clinically approved targeted therapy in bladder cancer. However, it requires previous molecular testing of each patient, which is costly and not ubiquitously available.To determine whether an artificial intelligence system is able to predict mutations of the FGFR3 gene directly from routine histology slides of bladder cancer.We trained a deep learning network to detect FGFR3 mutations on digitized slides of muscle-invasive bladder cancers stained with hematoxylin and eosin from the Cancer Genome Atlas (TCGA) cohort (n = 327) and validated the algorithm on the "Aachen" cohort (n = 182; n = 121 pT2-4, n = 34 stroma-invasive pT1, and n = 27 noninvasive pTa tumors).The primary endpoint was the area under the receiver operating curve (AUROC) for mutation detection. Performance of the deep learning system was compared with visual scoring by an uropathologist.In the TCGA cohort, FGFR3 mutations were detected with an AUROC of 0.701 (p0.0001). In the Aachen cohort, FGFR3 mutants were found with an AUROC of 0.725 (p0.0001). When trained on TCGA, the network generalized to the Aachen cohort, and detected FGFR3 mutants with an AUROC of 0.625 (p = 0.0112). A subgroup analysis and histological evaluation found highest accuracy in papillary growth, luminal gene expression subtypes, females, and American Joint Committee on Cancer (AJCC) stage II tumors. In a head-to-head comparison, the deep learning system outperformed the uropathologist in detecting FGFR3 mutants.Our computer-based artificial intelligence system was able to detect genetic alterations of the FGFR3 gene of bladder cancer patients directly from histological slides. In the future, this system could be used to preselect patients for further molecular testing. However, analyses of larger, multicenter, muscle-invasive bladder cancer cohorts are now needed in order to validate and extend our findings.In this report, a computer-based artificial intelligence (AI) system was applied to histological slides to predict genetic alterations of the FGFR3 gene in bladder cancer. We found that the AI system was able to find the alteration with high accuracy. In the future, this system could be used to preselect patients for further molecular testing.

Background Open radical cystectomy (ORC) is still considered the reference approach for RC, although robot-assisted RC (RARC) has recently gained in popularity. There are literature reports on perioperative and oncologic outcomes of RARC, but functional outcomes and aspects related to health-related quality of life (HRQoL) remain unexplored. Objective To report an interim analysis of 1-yr HRQoL outcomes from an ongoing randomised controlled trial comparing ORC and RARC with totally intracorporeal urinary diversion (iUD) (ClinicalTrials.gov NCT03434132). Design, setting, and participants Patients with cT2–4N0M0 non–muscle-invasive bladder cancer or bacillus Calmette-Guerin failure who were candidates for cystectomy with curative intent without absolute contraindications to robotic surgery were included. A covariate adaptive randomisation based on the following variables was used: body mass index, American Society of Anesthesiologists score, preoperative haemoglobin level, cT stage, type of UD, and neoadjuvant chemotherapy. Intervention ORC or RARC with iUD. Outcome measurements and statistical analysis Data from patient-reported European Organization for Research and Treatment of Cancer QoL questionnaires (QLQ-C30 and QLQ-BLM30) were collected at baseline and 1 yr. Continuous variables were compared using the Student t test. Results and limitations At interim analysis, 51 patients (24 RARC, 27 ORC) were analysed. Overall, both groups reported significant worsening of body image and physical and sexual functions (all p ≤ 0.012). Patients receiving ORC were more likely to report significant 1-yr impairment of role functioning, symptoms scales and bowel symptoms (all p ≤ 0.048). Patients receiving RARC reported significant impairment of urinary symptoms and problems (p = 0.018). Conclusions This study suggests equivalence between RARC-iUD and ORC for most HRQoL domains. Notwithstanding, after 1 yr patients receiving ORC were more likely to experience a decline in role functioning and higher symptoms scale, while RARC-iUD patients were more likely to report significant increases in urinary symptoms and problems. Patient summary We analysed 1-year data for health-related quality of life from an ongoing trial comparing open and robotic surgery for removal of the bladder in patients with bladder cancer. Robotic surgery seems to provide benefits for most quality-of-life items on patient-reported questionnaires. This trial is registered at ClinicalTrial.gov as NCT03434132.

Context Grading is the mainstay for treatment decisions for patients with non–muscle-invasive bladder cancer (NMIBC). Objective To determine the requirements for an optimal grading system for NMIBC via expert opinion. Evidence acquisition A multidisciplinary working group established by the International Society of Urological Pathology reviewed available clinical, histopathological, and molecular evidence for an optimal grading system for bladder cancer. Evidence synthesis Bladder cancer grading is a continuum and five different grading systems based on historical grounds could be envisaged. Splitting of the World Health Organization (WHO) 2004 low-grade class for NMIBC lacks diagnostic reproducibility and molecular-genetic support, while showing little difference in progression rate. Subdividing the clinically heterogeneous WHO 2004 high-grade class for NMIBC into intermediate and high risk categories using the WHO 1973 grading is supported by both clinical and molecular-genetic findings. Grading criteria for the WHO 1973 scheme were detailed on the basis of literature findings and expert opinion. Conclusions Splitting of the WHO 2004 high-grade category into WHO 1973 grade 2 and 3 subsets is recommended. Provision of more detailed histological criteria for the WHO 1973 grading might facilitate the general acceptance of a hybrid four-tiered grading system or—as a preferred option—a more reproducible three-tiered system distinguishing low-, intermediate (high)-, and high-grade NMIBC. Patient summary Improvement of the current systems for grading bladder cancer may result in better informed treatment decisions for patients with bladder cancer.

BACKGROUND: Radical cystectomy (RC) has the potential for profound changes to health-related quality of life (HRQOL). OBJECTIVE: To evaluate a broad range of HRQOL outcomes in a large RC cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-center prospective study enrolled RC patients from 2008 to 2014. We collected 14 separate patient-reported outcome measures at the presurgical visit and at 3, 6, 12, 18, and 24 mo after RC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: To visualize the patterns of recovery over time across domains, we used generalized estimating equations (GEEs) with nonlinear terms. Given substantial differences in patient selection for the type of urinary diversion, we separately modeled longitudinal HRQOL within conduit and continent diversion groups. The mean pre-RC scores were compared to illustrate the baseline HRQOL differences between diversion groups. RESULTS AND LIMITATIONS: The analyzed cohort included 411 patients (n = 205 ileal conduit, n = 206 continent diversion). At baseline, patients receiving continent diversion reported better mean physical (p < 0.001), urinary (p = 0.006), and sexual function (p < 0.001), but lower social function (p = 0.015). After RC, GEE modeling showed physical function scores decreasing 5/100 points by 6 mo, and subsequently stabilizing or returning to baseline. By 12 mo, social function improved by 10/100 points among continent diversions, while remaining stable among ileal conduits. Global quality of life exceeded baseline scores by 6 mo. Sexual function scores were low before RC, with limited recovery. Psychosocial domains were stable or improved, except for 10/100-point worsening of body image among ileal conduits. CONCLUSIONS: RC patients reported favorable HRQOL recovery within 24 mo in most areas other than body image (ileal conduits) and sexual function (both). Importantly, large measurable decreases in scores were not reported by 3 mo after RC. These contemporary outcomes and the excellent locoregional control provided by RC further support it as the gold standard therapy for high-risk bladder cancer. PATIENT SUMMARY: We review quality of life in the 24 mo following radical cystectomy. Large decreases in health-related quality of life were not reported, with most areas returning to, or exceeding, baseline, except for sexual function and body image.

Background "Trousseau's Sign" was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is 5-6 times more likely to occur in cancer patients, while there is a greater risk of cancer diagnoses following thromboses. In considering novel players, factor VIII (FVIII), an essential coagulation co-factor with emerging extra-coagulative functions, has been identified as an independent VTE risk factor in cancer, however, the basis of this increase is unknown. Objective To investigate the possible direct expression and secretion of FVIII by cancer cells. Methods Bladder cancer, with a high VTE-risk, and normal bladder tissue and epithelium, were used to investigate FVIII. Factor VIII protein and secretion were examined in bladder cancer cell lines. Expanding to other cancers, the Cancer Cell line Encyclopedia (CCLE) database was used to analyze FVIII, Tissue Factor (TF), FV, FVII, FIX, FX and von Willebrand factor (vWF) mRNA in 811 cell lines subdivided according to origin. Factor VIII protein synthesis, secretion and bioactivity were investigated in a profile of cancer cell lines of differing origins. Results and conclusions While expressed in the normal bladder epithelium, FVIII mRNA and protein were higher in matched bladder neoplasms, with synthesis and secretion of bioactive FVIII evident in bladder cancer cells. This can be extended to other cancer cell lines, with a pattern reflecting the tumor origin, and which is independent of vWF and other relevant players in the coagulation cascade. Herein, evidence is provided of a possible independent role for FVIII in cancer-related pathophysiology.

Transurethral resection of bladder tumor (TURBT) followed by intravesical therapy remains the most effective strategy for the management of non-muscle-invasive bladder cancer worldwide. TURBT has two purposes: to remove all visible tumors and to obtain tumor specimens for histopathological analysis. However, the detection of flat and small malignant lesions under white-light cystoscopy is extremely challenging, and residual lesions are still the main reason for the high recurrence rate of bladder cancer. We hypothesized that visual enhancement of malignant lesions using targeted optical molecular imaging could potentially highlight residual tumors in the bladder during surgery, and near-infrared photoimmunotherapy (NIR-PIT) could kill exfoliated cancer cells and residual tumors. A mouse model of complete or partial bladder tumor resection was established under the guidance of optical molecular imaging mediated by indocyanine green and anti-CD47-Alexa Fluor 790, respectively. Once the tumor recurred, mouse model received repeated CD47-targeted NIR-PIT. After complete resection, there was no tumor recurrence. Furthermore, the growth rate of recurrent tumor decreased significantly after repeated NIR-PIT. Therefore, CD47-targeted optical molecular imaging can potentially assist urologists to detect and remove all tumors, and repeated NIR-PIT shows the potential to reduce tumor recurrence rates and inhibit the growth of recurrent tumor., Graphical abstract, This study aimed at researching the role of CD47-targeted optical molecular imaging and near-infrared photoimmunotherapy (NIR-PIT) in the management of bladder cancer. The authors showed that CD47-targeted optical molecular imaging can potentially help urologists detect and remove all tumors, and NIR-PIT shows the potential to inhibit tumor growth.

Purpose Muscle invasive bladder cancer surgical management has been historically a radical cystoprostatectomy in males and an anterior exenteration in females. Uterine, ovarian, and vaginal preservation are utilized, but raise concerns regarding risk to oncologic control, especially in variant histopathology or advanced stage. Materials and Methods A retrospective single institutional analysis identified radical cystectomies performed in women, including those with variant histology, which were defined as reproductive organ sparing (uterine, vaginal, and ovary sparing) or non-organ sparing. The Kaplan-Meier method was used for recurrence-free (RFS) cancer specific survival (CSS) and overall (OS) survival in patients with advanced disease. Results From 2000 to 2020, 289 women were identified, 188 underwent reproductive organ-sparing cystectomy. No statistical differences were noted for clinical parameters or presence of variant histology for organ-sparing (ROS) and non-organ sparing (non-ROS). Positive margin rates did not differ for ROS and non-ROS; 4.3% vs 7.9%, p=0.19, respectively. Median RFS was not statistically significantly different for ROS vs non-ROS (26.1 vs 15.3 months) p=0.937 HR 1.024. CSS was not statistically different for ROS vs non-ROS (36.3 vs 28.6 months), p=0.755 HR 0.9. OS was not statistically different for ROS vs non-ROS (25.8 v 23.8 months), p=0.5 HR=1.178. Variant histology did not change survival (HR 1.1, p=0.643). Conclusions In this analysis, ROS in women with advanced disease did not increase positive margin rates or decrease RFS, CSS, or OS compared to non-ROS. Variant histology did not decrease survival odds. Based on preoperative assessment and intraoperative findings, ROS in patients with variant histology and advanced disease should be considered.

Bladder cancer is the most common malignant tumours with high morbidity, mortality and recurrence. However, currently developed detection methods for bladder cancer-associated urine biomarkers are hindered by their extremely low abundance. Hence, the exploration of a highly sensitive and selective approach for the detection of trace bladder cancer-associated biomarkers in human urine is of vital importance for the diagnosis of bladder cancer. Herein, we developed a highly reliable indium gallium zinc oxide field effect transistor (IGZO FET) biosensor for the detection of bladder cancer-related biomarker microRNA. The single-stranded DNA-functionalized IGZO FET biosensors exhibit high sensing reproducibility and stability with an ultralow detection limit of 19.8 amol/L. The device could also be used for quantitative detection of trace microRNA in human urine samples and can effectively distinguish bladder cancer patients from healthy donors. The development of high performance IGZO FET biosensors presents new opportunities for the achievement of early-stage diagnosis of bladder cancer.

Despite being standard tools for decision-making, the European Organisation for Research and Treatment of Cancer (EORTC), European Association of Urology (EAU), and Club Urologico Espanol de Tratamiento Oncologico (CUETO) risk groups provide moderate performance in predicting recurrence-free survival (RFS) and progression-free survival (PFS) in non-muscle-invasive bladder cancer (NMIBC). In this retrospective combined-cohort data-mining study, the training group consisted of 3570 patients with de novo diagnosed NMIBC. Predictors included gender, age, T stage, histopathological grading, tumor burden and diameter, EORTC and CUETO scores, and type of intravesical treatment. The models developed were externally validated using an independent cohort of 322 patients. Models were trained using Cox proportional-hazards deep neural networks (deep learning; DeepSurv) with a proprietary grid search of hyperparameters. For patients treated with surgery and bacillus Calmette-Guérin-treated patients, the models achieved a c index of 0.650 (95% confidence interval [CI] 0.649-0.650) for RFS and 0.878 (95% CI 0.873-0.874) for PFS in the training group. In the validation group, the c index was 0.651 (95% CI 0.648-0.654) for RFS and 0.881 (95% CI 0.878-0.885) for PFS. After inclusion of patients treated with mitomycin C, the c index for RFS models was 0.6415 (95% CI 0.6412-0.6417) for the training group and 0.660 (95% CI 0.657-0.664) for the validation group. Models for PFS achieved a c index of 0.885 (95% CI 0.885-0.885) for the training set and 0.876 (95% CI 0.873-0.880) for the validation set. Our tool outperformed standard-of-care risk stratification tools and showed no evidence of overfitting. The application is open source and available at https://biostat.umed.pl/deepNMIBC/. PATIENT SUMMARY: We created and validated a new tool to predict recurrence and progression of early-stage bladder cancer. The application uses advanced artificial intelligence to combine state-of-the-art scales, outperforms these scales for prediction, and is freely available online.

The treatment landscape for advanced urothelial cancer has changed dramatically owing to the US Food and Drug Administration approval and introduction of antibody-drug conjugates (ADCs), including enfortumab vedotin and sacituzumab govitecan. Efforts have begun to use these therapies in earlier disease states, specifically bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). We assessed gene expression associated with these newly approved therapies in a novel cohort of treatment-naïve NMIBC tumors before and after BCG therapy. Multiple genes, including Nectin-4, Trop-2, and Her-2, exhibited increased expression after BCG therapy compared to baseline. However, few of the tumors with increased expression of ADC targets also exhibited increased PD-L1/PD-1 expression. Taken together, these data demonstrate the heterogeneous genomic landscape of BCG-exposed NMIBC, and provide evidence supporting the evaluation of ADCs in NMIBC. PATIENT SUMMARY: We evaluated the potential role of targeted therapies that have been approved in the USA for advanced non-muscle-invasive bladder cancer (NMIBC) that has recurred after treatment with bacillus Calmette-Guérin (BCG). By assessing levels of specific genes and proteins linked to the targeted therapies, we demonstrate that there is rationale for further evaluation of these therapies in NMIBC.

Introduction To describe the efficacy of infigratinib, a potent, selective fibroblast growth factor receptor (FGFR) 1-3 tyrosine kinase inhibitor, across lines of therapy (LOT) in patients with metastatic urothelial cancer (mUC). Patients and Methods Eligible patients had mUC and prior platinum-based chemotherapy, unless contraindicated, and activating FGFR3 mutation/fusion. Patients received infigratinib 125 mg orally daily (3 weeks on/1 week off) in a single-arm, open-label study. Primary endpoint: investigator-assessed confirmed objective response rate (ORR). Disease control rate (DCR), progression-free survival (PFS), best overall response (BOR) that included unconfirmed responses, and overall survival (OS) were also assessed. Subgroup analysis of efficacy and safety outcomes by LOT was performed. Results Sixty-seven patients were enrolled; 13 (19.4%) received infigratinib as early-line therapy for mUC due to ineligibility to receive platinum-based chemotherapy. Overall, ORR was 25.4% (95% CI 15.5-37.5) and DCR was 64.2% (95% CI 51.5-75.5). ORR was 30.8% (95% CI 9.1-61.4) with early-line infigratinib and 24.1% (95% CI 13.5-37.6) for ≥2 LOT. DCR was 46.2% (95% CI 19.2-74.9) for early-line and 68.5% (95% CI 54.4-80.5) for ≥2 LOT. PFS and OS appeared similar in both groups. Thirteen of 59 patients with a bladder primary tumor received early-line treatment with an ORR of 30.5% (95% CI 9.1-61.4), and 46 received ≥2 LOT with an ORR of 20.3% (95% CI 9.4-33.9); BOR was 38.5% (95% CI: 13.9-68.4%) and 42.6% (95% CI: 29.2-56.8%) in the early-line and salvage settings, respectively. Eight patients with upper tract urothelial carcinoma received salvage therapy (ORR, 50.0%; DCR, 100.0%). No significant differences in toxicities between LOT were observed. Conclusion Infigratinib has notable activity in patients with mUC regardless of LOT. The findings support the evaluation of infigratinib across different settings in mUC.

Objective Intractable hematuria is a leading critical problem occurring in patients with advanced stage bladder cancer (BCa) that are not suitable for radical cystectomy. The present study, for the first time in the literature, aimed to compare the effectiveness of intravesical formalin (IF) and superselective vesical artery embolization (SVAE) in the management of intractable and life-threatening hematuria in BCa patients. Methods The retrospective study included 40 BCa patients who underwent SVAE or IF treatment due to intractable hematuria after failure of other methods. Patients were divided into two groups based on the procedures administered: SVEA Group (n = 24) and IF Group (n = 16). Results The success rate at first-line therapy was 50% (12/24) in SVAE Group and 82% (13/16) in IF Group (p = 0.046). Based on the success rates at first- and second-line therapies, the overall success rate in SVAE Group was 75% and this rate was similar to that of IF Group (p = 0.439). Complication rate was significantly higher in IF patients than in SVAE patients (37.5% vs. 8.3; p = 0.024), whereas duration of postoperative hospital stay was significantly longer in SVAE Group (15.8 vs. 6 days; p = 0.041). Conclusion The advantages of IF appear to include shorter postoperative hospital stays and higher success rates at a single session, while the advantages of SVAE seem to include non-requirement of spinal/general anesthesia, easy repeatability, and low complication rates. In the management of patients with intractable hematuria, patients’ general condition, comorbidities, and anesthesia-related risks should be taken into consideration.

Contains fulltext : 248305.pdf (Publisher’s version ) (Closed access) CONTEXT: Treatment of metastatic urothelial carcinoma is currently undergoing a rapid evolution. OBJECTIVE: This overview presents the updated European Association of Urology (EAU) guidelines for metastatic urothelial carcinoma. EVIDENCE ACQUISITION: A comprehensive scoping exercise covering the topic of metastatic urothelial carcinoma is performed annually by the Guidelines Panel. Databases covered by the search included Medline, EMBASE, and the Cochrane Libraries, resulting in yearly guideline updates. EVIDENCE SYNTHESIS: Platinum-based chemotherapy is the recommended first-line standard therapy for all patients fit to receive either cisplatin or carboplatin. Patients positive for programmed death ligand 1 (PD-L1) and ineligible for cisplatin may receive immunotherapy (atezolizumab or pembrolizumab). In case of nonprogressive disease on platinum-based chemotherapy, subsequent maintenance immunotherapy (avelumab) is recommended. For patients without maintenance therapy, the recommended second-line regimen is immunotherapy (pembrolizumab). Later-line treatment has undergone recent advances: the antibody-drug conjugate enfortumab vedotin demonstrated improved overall survival and the fibroblast growth factor receptor (FGFR) inhibitor erdafitinib appears active in case of FGFR3 alterations. CONCLUSIONS: This 2021 update of the EAU guideline provides detailed and contemporary information on the treatment of metastatic urothelial carcinoma for incorporation into clinical practice. PATIENT SUMMARY: In recent years, several new treatment options have been introduced for patients with metastatic urothelial cancer (including bladder cancer and cancer of the upper urinary tract and urethra). These include immunotherapy and targeted treatments. This updated guideline informs clinicians and patients about optimal tailoring of treatment of affected patients.

Background: Non–muscle-invasive bladder cancer (NMIBC) is characterized by frequent recurrence of the disease, which is difficult to predict. Objective: To combine digital histopathology slides with clinical data to predict 1- and 5-yr recurrence-free survival of NMIBC patients using deep learning. Design, setting, and participants: Data of patients undergoing a transurethral resection of a bladder tumor between 2000 and 2018 at a Dutch academic medical center were selected. Corresponding histological slides were digitized. A three-step approach was used to predict 1- and 5-yr recurrence-free survival. First, a segmentation network was used to detect the urothelium on the digital histopathology slides. Second, a selection network was trained for the selection of patches associated with recurrence. Third, a classification network, combining the information of the selection network with clinical data, was trained to give the probability of 1- and 5-yr recurrence-free survival. Outcome measurements and statistical analysis: The accuracy of the deep learning–based model was compared with a multivariable logistic regression model using clinical data only. Results and limitations: In the 1- and 5-yr follow-up cohorts, 359 and 281 patients were included with recurrence rates of 27% and 63%, respectively. The areas under the curve (AUCs) of the model combining digital histopathology slide data with clinical data were 0.62 and 0.76 for 1- and 5-yr recurrence predictions, respectively, which were higher than those of the model using digital histopathology slide data only (AUCs of 0.56 and 0.72, respectively) and the multivariable logistic regression (AUCs of 0.58 and 0.57, respectively). Conclusions: In our population, the deep learning–based model combining digital histopathology slides and clinical data enhances the prediction of recurrence (within 5 yr) compared with models using clinical data or image data only. Patient summary: By combining histopathology images and patient record data using deep learning, the prediction of recurrence in bladder cancer patients is enhanced. The proposed deep learning method showed promising results for the 5-yr prediction of recurrence when combining clinical data and digital histopathology images. Although not yet validated for clinical practice, this deep learning approach has the potential to improve recurrence prediction.

Take Home Message This systematic review and meta-analysis, based on updated individual participant data, demonstrates that cisplatin-based adjuvant chemotherapy is a valid option for improving outcomes for muscle-invasive bladder cancer., Context Our prior systematic review and meta-analysis of individual participant data (IPD) suggesting a benefit of adjuvant chemotherapy for muscle-invasive bladder cancer was limited by the number and size of included randomised trials. We have updated results to include additional trials, providing the most up-to-date and reliable evidence of the effects of this treatment. Objective To investigate the role of adjuvant cisplatin-based chemotherapy in the treatment of muscle-invasive bladder cancer. Evidence acquisition Published and unpublished trials were sought via searches of bibliographic databases, trials registers, conference proceedings, and hand searching. Updated IPD were centrally collected, checked, and analysed. Results from individual randomised controlled trials (RCTs) were combined using a two-stage fixed-effect model. Prespecified analyses explored any variation in effect by trial and participant characteristics. Evidence synthesis Analyses of ten RCTs (1183 participants) demonstrated a benefit of cisplatin-based adjuvant chemotherapy on overall survival (hazard ratio [HR] = 0.82, 95% confidence interval [CI] = 0.70–0.96, p = 0.02). This represents an absolute improvement in survival of 6% at 5 yr, from 50% to 56%, and a 9% absolute benefit when adjusted for age, sex, pT stage, and pN category (HR = 0.77, 95% CI = 0.65–0.92, p = 0.004). There was no clear evidence that the effect varied by trial or participant characteristics. Adjuvant chemotherapy was also shown to improve recurrence-free survival (HR = 0.71, 95% CI = 0.60–0.83, p