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Strategies to identify tumors at highest risk for treatment failure are currently under investigation for patients with bladder cancer. We demonstrate that flow cytometric detection of poorly differentiated basal tumor cells (BTCs), as defined by the co-expression of CD90, CD44 and CD49f, directly from patients with early stage tumors (T1-T2 and N0) and patient-derived xenograft (PDX) engraftment in locally advanced tumors (T3-T4 or N+) predict poor prognosis in patients with bladder cancer. Comparative transcriptomic analysis of bladder tumor cells isolated from PDXs indicates unique patterns of gene expression during bladder tumor cell differentiation. We found cell division cycle 25C (CDC25C) overexpression in poorly differentiated BTCs and determined that CDC25C expression predicts adverse survival independent of standard clinical and pathologic features in bladder cancer patients. Taken together, our findings support the utility of BTCs and bladder cancer PDX models in the discovery of novel molecular targets and predictive biomarkers for personalizing oncology care for patients.

Cretostimogene grenadenorepvec is a serotype-5 oncolytic adenovirus designed to selectively replicate in cancer cells with retinoblastoma pathway alterations, previously tested as monotherapy in bacillus Calmette-Guérin (BCG)-experienced non-muscle-invasive bladder cancer. In this phase 2 study, we assessed the potential synergistic efficacy between intravesical cretostimogene and systemic pembrolizumab in patients with BCG-unresponsive non-muscle-invasive bladder cancer with carcinoma in situ (CIS). Thirty-five patients were treated with intravesical cretostimogene with systemic pembrolizumab. Induction cretostimogene was administered weekly for 6 weeks followed by three weekly maintenance infusions at months 3, 6, 9, 12 and 18 in patients maintaining complete response (CR). Patients with persistent CIS/high-grade Ta at the 3-month assessment were eligible for re-induction. Pembrolizumab was administered for up to 24 months. The primary endpoint was CR at 12 months as assessed by cystoscopy, urine cytology, cross-sectional imaging and mandatory bladder mapping biopsies. Secondary endpoints included CR at any time, duration of response, progression-free survival and safety. The CR rate in the intention-to-treat population at 12 months was 57.1% (20 out of 35, 95% confidence interval (CI) 40.7-73.5%), meeting the primary endpoint. A total of 29 out of 35 patients (82.9%, 95% CI 70.4-95.3%) derived a CR at 3 months. With a median follow-up of 26.5 months, the median duration of response has not been reached (95% CI 15.7 to not reached). The CR rate at 24 months was 51.4% (18 out of 35) (95% CI 34.9-68.0%). No patient progressed to muscle-invasive bladder cancer in this trial. Adverse events attributed to cretostimogene were low grade, self-limiting and predominantly limited to bladder-related symptoms. A total of 5 out of 35 patients (14.3%) developed grade 3 treatment-related adverse effects. There was no evidence of overlapping or synergistic toxicities. Combination intravesical cretostimogene and systemic pembrolizumab demonstrated enduring efficacy. With a toxicity profile similar to its monotherapy components, this combination may shift the benefit-to-risk ratio for patients with BCG-unresponsive CIS. ClinicalTrials.gov Identifier: NCT04387461 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Introduction: Urachal carcinoma (UrC) is a rare, nonurothelial malignancy, comprising less than 1% of all bladder cancers. It usually affects males in their fifth to sixth decade and is often diagnosed at an advanced stage with metastasis. This study examines UrC population characteristics and management., Methods: We identified UrC patients from bladder biopsies or TURB in the PearlDiver Mariner database (2010-2022). Descriptive statistics detailed patient characteristics. Student's T-Tests compared ages for partial vs. radical cystectomy, and Fisher's exact test compared SDOH presence. Significance was set at P < .05. Analyses used R version 3.6.0 within PearlDiver's software., Results: Among 2475 UrC patients (mean age 69.2 ± 9.2 years, 73.1% men), most were in the south (36.5%), outpatient settings (84.5%), and privately insured (65.3%). A total of 418 (16.2%) had at least 1 SDOH. Imaging before diagnosis was used in 65.74% of patients, primarily ultrasound. Smoking was present in 54.5%, diabetes in 42.9%, and obesity in 25.2%. After diagnosis, 1246 (50.34%) had localized disease; 407 underwent radical cystectomy and 330 partial cystectomy. Patients undergoing radical cystectomy were older (66.74 ± 8.13 years) compared to those undergoing partial cystectomy (60.55 ± 12.92 years) (P < .001), with SDOH factors more prevalent in the partial cystectomy group (P = .03)., Conclusion: UrC is a rare, often advanced-stage cancer predominantly affecting older men. Our study shows a trend towards partial cystectomy for localized UrC. Further research is needed to personalize surgery and integrate multidisciplinary approaches for better outcomes., Competing Interests: Disclosure All authors declare that there is no conflict of interest related to this manuscript. The authors have no financial, personal, or other relationships with other people or organizations that could inappropriately influence or bias the content of the paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Purpose: Nadofaragene firadenovec-vncg is a nonreplicating adenoviral vector-based gene therapy for bacillus Calmette-Guérin (BCG)-unresponsive carcinoma in situ (CIS) with/without high-grade Ta/T1. We report outcomes following 5 years of planned follow-up., Materials and Methods: This open-label phase 3 trial (NCT02773849) enrolled patients with BCG-unresponsive nonmuscle-invasive bladder cancer in 2 cohorts: CIS ± Ta/T1 (CIS; n = 107) and Ta/T1 without CIS (Ta/T1 cohort; n = 50). Patients received 75 mL (3 × 10 11 vp/mL) nadofaragene firadenovec intravesically once every 3 months with cystoscopy and cytology assessments, with continued treatment offered to those remaining high grade recurrence-free (HGRF)., Results: One hundred fifty-seven patients were enrolled from 33 US sites (n = 151 included in efficacy analyses). Median follow-up was 50.8 months (interquartile range 39.1-60.0), with 27% receiving ≥ 5 instillations and 7.6% receiving treatment for ≥ 57 months. Of patients with CIS 5.8% (95% CI 2.2-12.2) were HGRF at month 57, and 15% (95% CI 6.1-27.8) of patients with high-grade Ta/T1 were HGRF at month 57. Kaplan-Meier-estimated HGRF survival at 57 months was 13% (95% CI 6.9-21.5) and 33% (95% CI 19.5-46.6) in the CIS and Ta/T1 cohorts, respectively. Cystectomy-free survival at month 60 was 49% (95% CI 40.0-57.1): 43% (95% CI 32.2-53.7) in the CIS cohort and 59% (95% CI 43.1-71.4) in the Ta/T1 cohort. Overall survival at 60 months was 80% (71.0, 86.0): 76% (64.6-84.5) and 86% (70.9-93.5) in the CIS and Ta/T1 cohorts, respectively. Only 5 patients (4 with CIS and 1 with Ta/T1) experienced clinical progression to muscle-invasive disease., Conclusions: At 60 months, nadofaragene firadenovec-vncg allowed bladder preservation in nearly half of the patients and proved to be a safe option for BCG-unresponsive nonmuscle-invasive bladder cancer.

Bacillus Calmette-Guérin (BCG) is the standard of care for patients with high-risk non-muscle-invasive bladder cancer (NMIBC) after transurethral resection of bladder tumor (TURBT). BCG in combination with programmed cell death-1 (PD-1) inhibitors may yield greater anti-tumor activity compared with either agent alone. CREST is a phase III study evaluating the efficacy and safety of the subcutaneous PD-1 inhibitor sasanlimab in combination with BCG for patients with BCG-naive high-risk NMIBC. Eligible participants are randomized to receive sasanlimab plus BCG (induction ± maintenance) or BCG alone for up to 25 cycles within 12 weeks of TURBT. The primary outcome is event-free survival. Secondary outcomes include additional efficacy end points and safety. The target sample size is around 1000 participants.

Background: Academic and community urology centers participating in a pragmatic clinical trial in non-muscle-invasive bladder cancer completed monthly surveys assessing restrictions in aspects of bladder cancer care due to the COVID-19 Public Health Emergency. Our objective was to describe pandemic-related restrictions on bladder cancer care., Methods: We invited 32 sites participating in a multicenter pragmatic bladder cancer trial to complete monthly surveys distributed through REDCap beginning in May 2020. These surveys queried sites on whether they were experiencing restrictions in the use of elective surgery, transurethral resection of bladder tumors (TURBT), radical cystectomy, office cystoscopy, and intravesical bacillus Calmette-Guerin (BCG) availability. Responses were collated with descriptive statistics., Results: Of 32 eligible sites, 21 sites had at least a 50% monthly response rate over the study period and were included in the analysis. Elective surgery was paused at 76% of sites in May 2020, 48% of sites in January 2021, and 52% of sites in January 2022. Over those same periods, coinciding with COVID-19 incidence waves, TURBT was restricted at 10%, 14%, and 14% of sites, respectively, radical cystectomy was restricted at 10%, 14%, and 19% of sites, respectively, and cystoscopy was restricted at 33%, 0%, and 10% of sites, respectively., Conclusions: Bladder cancer care was minimally restricted compared with more pronounced restrictions seen in general elective surgeries during the COVID-19 pandemic., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

The use of blue light cystoscopy (BLC) has been shown to improve bladder tumor detection. However, data demonstrating the efficacy of BLC across different races are limited. Herein, we aim to evaluate heterogeneity in the characteristics of BLC for the detection of malignant lesions among various races. Clinicopathologic information was collected from patients enrolled in the multi-institutional Cysview ® registry (2014-2021) who underwent transurethral resection or biopsy of bladder tumors. Outcome variables included sensitivity and negative and positive predictive values of BLC and white light cystoscopy (WLC) for the detection of malignant lesions among various races. Overall, 2379 separate lesions/tumors were identified from 1292 patients, of whom 1095 (85%) were Caucasian, 96 (7%) were African American, 51 (4%) were Asian, and 50 (4%) were Hispanic. The sensitivity of BLC was higher than that of WLC in the total cohort, as well as in the Caucasian and Asian subgroups. The addition of BLC to WLC increased the detection rate by 10% for any malignant lesion in the total cohort, with the greatest increase in Asian patients (18%). Additionally, the positive predictive value of BLC was highest in Asian patients (94%), while Hispanic patients had the highest negative predictive value (86%). Our study showed that regardless of race, BLC increases the detection of bladder cancer when combined with WLC.

Introduction: Clinical trials of personalized cancer vaccines have shown that on-demand therapies that are manufactured for each patient, result in activated T cell responses against individual tumor neoantigens. However, their use has been traditionally restricted to adjuvant settings and late-stage cancer therapy. There is growing support for the implementation of PCV earlier in the cancer therapy timeline, for reasons that will be discussed in this review., Areas Covered: The efficacy of cancer vaccines may be to some extent dependent on treatment(s) given prior to vaccine administration. Tumors can undergo radical immunoediting following treatment with immunotherapies, such as checkpoint inhibitors, which may affect the presence of the very mutations targeted by cancer vaccines. This review will cover the topics of neoantigen cancer vaccines, tumor immunoediting, and therapy timing., Expert Opinion: Therapy timing remains a critical topic to address in optimizing the efficacy of personalized cancer vaccines. Most personalized cancer vaccines are being evaluated in late-stage cancer patients and after treatment with checkpoint inhibitors, but they may offer a greater benefit to the patient if administered in earlier clinical settings, such as the neoadjuvant setting, where patients are not facing T cell exhaustion and/or a further compromised immune system.

Purpose: There is a significant unmet need for new and efficacious therapies in urothelial cancer (UC). To provide recommendations on appropriate clinical trial designs across disease settings in UC, the Society for Immunotherapy of Cancer (SITC) and the International Bladder Cancer Group (IBCG) convened a multidisciplinary, international consensus panel., Methods: Through open communication and scientific debate in small- and whole-group settings, surveying, and responses to clinical questionnaires, the consensus panel developed recommendations on optimal definitions of the disease state, end points, trial design, evaluations, sample size calculations, and pathology considerations for definitive studies in low- and intermediate-risk nonmuscle-invasive bladder cancer (NMIBC), high-risk NMIBC, muscle-invasive bladder cancer in the neoadjuvant and adjuvant settings, and metastatic UC. The expert panel also solicited input on the recommendations through presentations and public discussion during an open session at the 2021 Bladder Cancer Advocacy Network (BCAN) Think Tank (held virtually)., Results: The consensus panel developed a set of stage-specific bladder cancer clinical trial design recommendations, which are summarized in the table that accompanies this text., Conclusion: These recommendations developed by the SITC-IBCG Bladder Cancer Clinical Trial Design consensus panel will encourage uniformity among studies and facilitate drug development in this disease.

Background: Bladder cancer poses a significant public health burden, with high recurrence and progression rates in patients with non-muscle-invasive bladder cancer (NMIBC). Current treatment options include bladder-sparing therapies (BST) and radical cystectomy, both with associated risks and benefits. However, evidence supporting optimal management decisions for patients with recurrent high-grade NMIBC remains limited, leading to uncertainty for patients and clinicians. The CISTO (Comparison of Intravesical Therapy and Surgery as Treatment Options) Study aims to address this critical knowledge gap by comparing outcomes between patients undergoing BST and radical cystectomy., Methods: The CISTO Study is a pragmatic, prospective observational cohort trial across 36 academic and community urology practices in the US. The study will enroll 572 patients with a diagnosis of recurrent high-grade NMIBC who select management with either BST or radical cystectomy. The primary outcome is health-related quality of life (QOL) at 12 months as measured with the EORTC-QLQ-C30. Secondary outcomes include bladder cancer-specific QOL, progression-free survival, cancer-specific survival, and financial toxicity. The study will also assess patient preferences for treatment outcomes. Statistical analyses will employ targeted maximum likelihood estimation (TMLE) to address treatment selection bias and confounding by indication., Discussion: The CISTO Study is powered to detect clinically important differences in QOL and cancer-specific survival between the two treatment approaches. By including a diverse patient population, the study also aims to assess outcomes across the following patient characteristics: age, gender, race, burden of comorbid health conditions, cancer severity, caregiver status, social determinants of health, and rurality. Treatment outcomes may also vary by patient preferences, health literacy, and baseline QOL. The CISTO Study will fill a crucial evidence gap in the management of recurrent high-grade NMIBC, providing evidence-based guidance for patients and clinicians in choosing between BST and radical cystectomy. The CISTO study will provide an evidence-based approach to identifying the right treatment for the right patient at the right time in the challenging clinical setting of recurrent high-grade NMIBC., Trial Registration: ClinicalTrials.gov, NCT03933826. Registered on May 1, 2019., (© 2023. The Author(s).)

Context: Several recent phase 2 and 3 trials have evaluated the efficacy and toxicity of checkpoint inhibitor (CPI) therapy for urothelial carcinoma (UC) in the metastatic, localized muscle-invasive UC (MIUC), upper tract UC, and non-muscle-invasive bladder cancer (NMIBC) disease state., Objective: To assess the outcomes and toxicity of CPIs across the treatment landscape of UC and contextualize their application to current real-world treatment., Evidence Acquisition: We queried PubMed, Web of Science, and EMBASE databases and conference abstracts to identify prospective trials examining CPIs in UC. The primary endpoints included overall survival, recurrence-free survival, and toxicity (when available). A secondary analysis included biomarker evaluation of response., Evidence Synthesis: We identified 21 trials, 12 phase 2 and nine phase 3 trials, in which a CPI was used for metastatic UC (seven), MIUC (nine), and NMIBC (five). For first-line (1L) metastatic UC, concurrent chemotherapy with CPIs failed to show superiority. Improved overall and progression-free survival for switch maintenance avelumab (after achieving stable disease or response with induction systemic chemotherapy) has established the current standard of care for 1L metastatic UC. A single-agent CPI is a consideration for patients unable to tolerate chemotherapy. CPIs in the perioperative setting are limited to only the adjuvant treatment with nivolumab after radical surgery for MIUC in patients at a higher risk of recurrence based on pathologic stage. Only pembrolizumab is approved by the Food and Drug Administration for carcinoma in situ unresponsive to bacillus Calmette-Guérin (BCG) in patients who are not fit for or who refuse radical cystectomy. Trials investigating CPIs in combination with multiple immune regulators, antibody drug conjugates, targeted therapies, antiangiogenic agents, chemotherapy, and radiotherapy are enrolling patients and may shape the future treatment of patients with UC., Conclusions: CPIs have an established role across multiple states of UC, with broadened applications likely to occur in the future. Several combinations are being evaluated, while the development of predictive biomarkers and their validation may help identify patients who are most likely to respond., Patient Summary: Our findings highlight the broad activity of checkpoint inhibitors in urothelial carcinoma, noting the need for further investigation for the best application of combinations and patient selection to patient care., (Published by Elsevier B.V.)

Background: Despite recent drug development for non-muscle invasive bladder cancer (NMIBC), few therapies have been approved by the US Food and Drug Administration (FDA), and there remains an unmet clinical need. Bacillus Calmette-Guerin (BCG) supply issues underscore the importance of developing safe and effective drugs for NMIBC., Objective: On November 18-19, 2021, the FDA held a public virtual workshop to discuss NMIBC research needs and potential trial designs for future development of effective therapies., Methods: Representatives from various disciplines including urologists, oncologists, pathologists, statisticians, basic and translational scientists, and the patient advocacy community participated. The workshop format included invited lectures, panel discussions, and opportunity for audience discussion and comment., Results: In a pre-workshop survey, 92% of urologists surveyed considered the development of alternatives to BCG as a high drug development priority for BCG-naïve high-risk patients. Key topics discussed included definitions of disease states; trial design for BCG-naïve NMIBC, BCG-unresponsive carcinoma in situ, and BCG-unresponsive papillary carcinoma; strengths and limitations of single-arm trial designs; assessing patient-reported outcomes; and considerations for assessing avoidance of cystectomy as an efficacy measure., Conclusions: The workshop discussed several important opportunities for trial design refinement in NMIBC. FDA encourages sponsors to meet with the appropriate review division to discuss trial design proposals for NMIBC early in drug development., Competing Interests: E.C., J.F., S.A., V.B., A.A.J., P.B., K.S., J.R.B., E.B., R.O., K.B., Z.F., T.M.D., R.B., D.L.S., L.A.K., R.P., P.G.K., and C.W. have no conflicts of interest to report. N.M.H., S.P.L., A.M.K., R.S.S., M.A.O., M.J.R., M.D.G., P.C.B., K.P., C.P.D., R.B., and S.P.P. (Psutka) are Editorial Board members of this journal, but were not involved in the peer-review process nor had access to any information regarding its peer-review. N.M.H. receives consulting compensation from AstraZeneca, Merck, BioGears, Seattle Genetics, Mirati, Incyte, RemGen, Janssen, Pfizer, EMD Serono, Verity Pharmaceuticals, Huron Consulting, Guidepoint, Natera, Protara Therapeutics, Astellas Pharma; research support to the institution from HTG Molecular Diagnostics, AstraZeneca, Bristol Myers-Squibb, Genentech, Seattle Genetics, Pieris, Inovio, Principia Biopharm, Incyte, and Ikena Oncology; and speaking honorarium from Medscape. S.P.L. reports clinical trial involvement with Aura Bioscience, FKD, JBL (SWOG), Genentech (SWOG), Janssen (SWOG), Merck (Alliance), QED Therapeutics, UroGen, Vaxiion, Viventia; is on the advisory board or a consultant for Aura Bioscience, BMS, C2iGenomics, Ferring, Incyte, Pfizer/EMD Serono, Protara, Stimit, UroGen, Vaxiion, Verity; has a patent for a TCGA classifier; and receives honoraria from Grand Rounds Urology and UroToday. A.M.K. reports clinical trial involvement with FKD, Merck, Bristol Myers Squibb, Photocure, SWOG, Adolor, Heat Biologics, Janssen, Taris, Seattle Genetics; reports laboratory research with NIH, SPORE, AIBCCR, PCORI; is on the advisory board or a consultant for TMC Innovation, Arquer Diagnostics, Asieris, Astellas, Biological Dynamics, BMS, CG Oncology, Cystotech, Eisai, Engene, Ferring, InCyte, Imvax, Imagin Medical, Janssen, Medac, Merck, Nonagen, Photocure, ProTara, Pfizer, Roche, Seattle Genetics, Sessen Bio, Theralase, US Biotest, Urogen Inc; is on the editorial board of European Urology Oncology; Journal of Urology, UroToday; is president of International Bladder Cancer Network and International Bladder Cancer Group; and has a joint patent with UT MD Anderson Cancer Center for CyPRIT (Cytokine Predictors of Response to Intravesical Therapy). R.S.S. is a consultant for CG Oncology and Verity Pharma; and receives research support from Japanese BCG Laboratories and Merck. N.S. is a consultant for AbbVie, Accord, Alessa Therapeutics, Amgen, Antev, Arquer, Asieris, Astellas, Astra Zeneca, AuraBiosciences, Bayer, BMS, Bioprotect, Boston Scientific, Clarity, Dendreon, Exact Imaging, FizeMedical, CG Oncology, Genentech/Roche, Ferring, Foundation Medicine, ImmunityBio, Incyte, Invitae, Janssen, Lantheus, Lilly, MDX, Merck, Minomic, Myriad, Nonagen, Novartis, Nymox, Pacific Edge, Palette Life, Photocure, Pfizer, PlatformQ, Profound Medical, Promaxo, Propella, Protara, Sanofi, Specialty Networks, Telix, Tolmar, Urogen, and Vessi. M.K. receives grant funding from the American Cancer Society; is a consultant for Merck, Pfizer, Seagen/Astellas, Photocure, Aura, BMS, Nanology, and Janssen; and holds a patent for Nanoparticle Formulations for Enhanced Drug Delivery to the Bladder. M.A.O. receives grant/research/clinical trial support from Abbot Molecular, Photocure, Urogen; and is a consultant or on the advisory board for Fidia Pharmaceuticals, Sesen Bio, Merck, Theralase, and Urogen. G.D.S. is a member of the Clinical Trial Protocol Committee for Merck, BMS, Janssen, CG Oncology, Pfizer, PhotoCure, Fidia, Seagen, Protara; is or has been a scientific advisor /consultant with CG Oncology; PhotoCure; Merck; Taris Biomedical (Now Janssen); Fidia Farmaceuticals; Urogen, Ferring; Fergene, Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; Epivax Therapeutics; EnGene Bio; Astellas; SeaGen; Verity Pharmaceuticals, Protara, xCures, Nonagen, Nanology, Imvax, Asieris; and has equity stock/options with Epivax Therapeutics, Urogen, CG Oncology, Engene Bio. M.J.R. has intellectual property with Fina Biotech and is or has been a meeting participant or lecturer for Roche, AstraZeneca, and Bayer. M.D.G. receives research funding from Bristol Myers Squibb, Novartis, Dendreon, Astra Zeneca, Merck, Genentech; and is on the advisory board or a consultant for Bristol Myers Squibb, Merck, Genentech, AstraZeneca, Pfizer, EMD Serono, SeaGen, Janssen, Numab, Dragonfly, GlaxoSmithKline, Basilea, UroGen, Rappta Therapeutics, Alligator, Silverback, Fujifilm, Curis, Gilead, Bicycle, Asieris, Abbvie, Analog Devices. P.C.B is a member of the advisory board or equivalent with AbbVie, AstraZeneca, Astellas, Bayer, BMS, EMD-Serono, Ferring, Fergene, Janssen, Merck, miR Scientific, Nonagen, NanOlogy, Pfizer, Photocure, Prokarium, Protara Therapeutics, QED Bioscience, Roche, Sanofi, Sesen Bio, STIMIT, TerSera, Tolmar, Urogen, Verity; is a member of a Speaker’s bureau with Janssen, Minogue, Ferring, TerSera, Pfizer; has received a grant or honorarium from iProgen; and shares a patent with Veracyte. H.A. provides consultation to AstraZeneca, Flare Therapeutics and Paige.AI. K.P. receives consulting fees from Photocure. C.P.D. reports compensation for Scientific/Advisory Committee Member for AstraZeneca Pharmaceuticals, UroGen Pharma (formerly Theracoat Ltd.); consulting fees from STIMIT Corporation; consulting fees from General Atlantic; board member position for DF/HCC Kidney Cancer SPORE Advisory Board; research funding from Cancer Prevention Research Institute of Texas (CPRIT), Department of Defense (DoD), and NIH/NCI. S.P.P. (Porten) receives research support from Photocure, consulting compensation from Pacific Edge, grant funding from PCORI, BCAN, AHRQ, Genentech, Merck, and is on the advisory board for AstraZeneca. A.B.S. receives grant funding from PCORI, BCAN, AHRQ, Genentech, and Merck. S.P.P. (Psutka) reports being on Practice Guidelines Committee (Upper Tract Urothelial Carcinoma) of the American Urological Association (AUA), being AUA Core Curriculum Sr. Editor (2019-2023) and Senior Consultant (2023-); is or has been on Scientific Advisory Boards for Merck (Past), ImmunityBio (Past), Janssen (Current); has received travel funding/honoraria from Medtronic (Past), AstraZeneca (Past); receives research funding from PRIME Education, INC, Bladder Cancer Advocacy Network, National Institute on Aging, and is on the editorial boards for European Urology. N.A. receives research funding to institution from Arnivas, Astellas, Astra Zeneca, Bavarian Nordic, Bayer, Bristol Myers Squibb, Calithera, Celldex, Clovis, Crispr, Eisai, Eli Lilly, EMD Serono, Exelixis, Genentech, Gilead, Glaxo Smith Kline, Immunomedics, Janssen, Lava, Medivation, Merck, Nektar, Neoleukin, New Link Genetics, Novartis, Oric, Pfizer, Prometheus, Rexahn, Roche, Sanofi, Seattle Genetics, Takeda, and Tracon., (© 2023 – The authors. Published by IOS Press.)

Background: Bacille Calmette-Guérin (BCG) is the standard therapy after transurethral resection of bladder tumour for high-risk non-muscle-invasive bladder cancer (NMIBC). However, post-BCG recurrence/progression occurs frequently, and noncystectomy options are limited., Objective: To evaluate the safety and clinical activity of atezolizumab ± BCG in high-risk BCG-unresponsive NMIBC., Design, Setting, and Participants: This phase 1b/2 GU-123 study (NCT02792192) treated patients with BCG-unresponsive NMIBC who had carcinoma in situ with atezolizumab ± BCG., Intervention: Patients in cohorts 1A and 1B received atezolizumab 1200 mg IV q3w for ≤96 wk. Those in cohort 1B also received standard BCG induction (six weekly doses) and maintenance courses (three doses weekly starting at month 3) with optional maintenance at 6, 12, 18, 24, and 30 mo., Outcome Measurements and Statistical Analysis: Coprimary endpoints were safety and 6-mo complete response (CR) rate. Secondary endpoints included 3-mo CR rate and duration of CR; 95% confidence intervals were calculated using the Clopper-Pearson method., Results and Limitations: At data cut-off (September 29, 2020), 24 patients were enrolled (cohort 1A, n = 12; cohort 1B, n = 12), and the recommended BCG dose was 50 mg in cohort 1B. Four patients (33%) had adverse events (AEs) leading to BCG dose modification/interruption. Three patients (25%) in cohort 1A reported atezolizumab-related grade 3 AEs; cohort 1B had no atezolizumab- or BCG-related grade ≥3 AEs. No grade 4/5 AEs were reported. The 6-mo CR rate was 33% in cohort 1A (median duration of CR, 6.8 mo) and 42% in cohort 1B (median duration of CR, not reached [≥12 mo]). These results are limited by the small sample size of GU-123., Conclusions: In this first report of the atezolizumab-BCG combination in NMIBC, atezolizumab ± BCG was well tolerated, with no new safety signals or treatment-related deaths. Preliminary results suggested clinically meaningful activity; the combination favoured a longer duration of response., Patient Summary: We studied atezolizumab with and without bacille Calmette-Guérin (BCG) to determine whether this combination was safe and had clinical activity in patients with high-risk noninvasive bladder cancer (high-grade bladder tumours that affect the outermost lining of the bladder wall) that has previously been treated with BCG and is still present or occurred again. Our results suggest that atezolizumab with or without BCG was generally safe and could be used to treat patients unresponsive to BCG., (Copyright © 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Objectives: To evaluate whether a restaging transurethral resection of bladder tumor (TURBT) is necessary in high-risk nonmuscle invasive bladder cancer (NMIBC) if the initial TURBT was performed using blue light (BL) technology., Methods and Materials: Using the multi-institutional Cysview registry between 2014 and 2021, all consecutive adult patients with known NMIBC (Ta and T1 disease) who underwent TURBT followed by a restaging TURBT within 8 weeks were reviewed. Patients were stratified according to their initial TURBT, BL vs. white light (WL), and compared to determine rates of residual disease and upstaging. Univariate analysis was performed using Mann-Whitney U and chi-square tests, with P < 0.05 considered significant., Results: Overall, 115 patients had TURBT for NMIBC followed by a restaging TURBT within 8 weeks and were included in the analysis. Patients who underwent BL compared to WL for their initial TURBT had higher rates of benign pathology on restaging TURBT, although this was not statistically significant (47% vs. 30%; P = 0.08). Of patients with residual tumors on restaging TURBT, there were no differences in rates of Ta (22% vs. 26.5%; P = 0.62), T1 (22% vs. 26.5%; P = 0.62), or CIS (5.5% vs. 13%; P = 0.49) when the initial TURBT was done using BL compared to WL. Rates of upstaging to muscle invasive disease were also not different when initial TURBT was performed using BL compared to WL (3% vs. 4%; P = 0.78)., Conclusions: TURBT using BL does not reduce rates of residual disease or risk of upstaging on restaging TURBT in Ta or T1 disease. Thus, a restaging TURBT is still necessary even if initial TURBT was performed using BL., Competing Interests: Conflict of interest Siamak Daneshmand is a paid consultant for Photocure. Yair Lotan is a paid consultant for Photocure and does research with Storz. Sima Porten is a paid consultant for Photocure. Brian Willard has research funding from and on speakers bureau for Photocure. Additional research funding with Jansseen, Myriad, and Coloplast. Gary D. Steinberg is a paid consultant for Photocure. Also, he is a member of Clinical Trial Protocol Committees for Photocure., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objectives: Neoadjuvant chemotherapy and radical cystectomy (RC) are underutilized standards of care for the treatment of muscle-invasive bladder cancer (MIBC) due to high patient burden from systemic toxicities and postoperative complications, respectively. TAR-200 is a novel intravesical drug delivery system developed to release gemcitabine into the bladder urine continuously, resulting in distribution of drug into stromal layers of the bladder. The primary aim of the TAR-200-101 study was to evaluate the safety of TAR-200 in patients with MIBC prior to RC (NCT02722538)., Methods and Materials: This phase I, open-label study was conducted across 6 US and European sites. Eligible patients were aged ≥18 years with histologically confirmed T2a-T3b N0-N1 M0 urothelial cancer and had refusal or were ineligible to receive cisplatin-based combination chemotherapy. Two arms were enrolled serially. Patients in Arm 1 had residual tumor >3 cm after transurethral resection of bladder tumor (TURBT); those in Arm 2 had undergone maximal TURBT (residual tumor <3 cm). Patients received two 7-day cycles of intravesical gemcitabine delivery via TAR-200 before undergoing RC. Primary outcome was safety; secondary outcomes were tolerability, pharmacokinetics, and preliminary efficacy., Results: Of 23 patients in the intention-to-treat population (11 in Arm 1, 12 in Arm 2), 20 completed both dosing cycles of TAR-200. No patients were classified as intolerant to TAR-200. Ten patients (4 in Arm 1, 6 in Arm 2) experienced ≥1 treatment-emergent adverse events (TEAEs). The most common TAR-200-related TEAEs were pollakiuria (n = 3) and urinary incontinence (n = 2). All TEAEs prior to RC were grade ≤2; 1 patient in Arm 2 experienced a grade 3 non-treatment-related TEAE. Plasma gemcitabine levels were undetectable. In Arm 1, those with residual tumor, 4 of 10 patients exhibited pathologic downstaging; 1 experienced a complete response (CR) and 3 a partial response (PR). In Arm 2, those undergoing maximal TURBT, 6 of 10 patients exhibited downstaging; 3 experienced a CR and 3 a PR., Conclusion: Controlled intravesical gemcitabine release via TAR-200 was safe and well tolerated in patients with MIBC., Competing Interests: Conflict of interests M Aron, ISG Brummelhuis, KS Pohar, and JA Witjes have no financial or other conflict of interest related to this study. CJ Cutie and JC Maffeo are former employees of TARIS Biomedical and are employees of Janssen Pharmaceuticals. KA Keegan and B Raybold are employees of Janssen Pharmaceuticals. A Chau and D Reynolds were paid consultants for TARIS Biomedical. A Chau, S Daneshmand and D Reynolds are paid consultants for Janssen Pharmaceuticals. S Daneshmand has equity interest in TARIS Biomedical. GD Steinberg is a member of Clinical Trial Committees for Janssen Pharmaceuticals and has been a scientific adviser for TARIS Biomedical and Janssen Pharmaceuticals., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: To evaluate the role of blue-light cystoscopy (BLC) in detecting invasive tumours that were not visible on white-light cystoscopy (WLC)., Patients and Methods: Using the multi-institutional Cysview registry database, patients who had at least one white-light negative (WL-)/blue-light positive (BL+) lesion with invasive pathology (≥T1) as highest stage tumour were identified. All WL-/BL+ lesions and all invasive tumours in the database were used as denominators. Relevant baseline and outcome data were collected., Results: Of the 3514 lesions (1257 unique patients), 818 (23.2%) lesions were WL-/BL+, of those, 55 (7%) lesions were invasive (48 T1, seven T2; 47 unique patients) including 28/55 (51%) de novo invasive lesions (26 unique patients). In all, 21/47 (45%) patients had WL-/BL+ concommitant carcinoma in situ and/or another T1 lesions. Of 22 patients with a WL-/BL+ lesion who underwent radical cystectomy (RC), high-risk pathological features leading to RC was only visible on BLC in 18 (82%) patients. At time of RC, 11/22 (50%) patients had pathological upstaging including four (18%) with node-positive disease., Conclusions: A considerable proportion of invasive lesions are only detectable by BLC and the rate of pathological upstaging is significant. Our present findings suggest an additional benefit of BLC in the detection of invasive bladder tumours that has implications for treatment approach., (© 2021 The Authors BJU International © 2021 BJU International.)

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., Competing Interests: Ashish M. Kamat, MD Consultant/Advisory Board Arquer Diagnostics, Asieris, Biological Dynamics, Bristol Myers Squibb, CG Oncology, H3 Biomedicine/Eisai, Engene, FerGene, Imagin Medical, Janssen, Medac, Merck, Photocure, ProTara, Seattle Genetics, Sessen Bio, Theralase, US Biotest, Urogen Inc, Roche, TMC Innovation Grants/Research Support Adolor, BMS, FKD Industries, FerGene, Heat Biologics, Merck, Photocure, SWOG, NIH/GU SPORE, AIBCCR, Janssen (+Taris), Seattle Genetics Patent CyPRIT (Cytokine Predictors of Response to Intravesical Therapy) Board Member International Bladder Cancer Group (IBCG) Dr. Kamat is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Colin P. Dinney, MD Consultant STIMIT Corp., UroGen Pharma Dr. Dinney is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Seth P. Lerner, MD Consultant/Advisory Board Aura Bioscience, BMS, C2iGenomics, FerGene, Genentech, Merck, Pfizer/EMD Serono, Stimit, UroGen, Vaxiion, Verity Honoraria Annenberg, Clinical Care Options, Grand Rounds Urology, Ology, UroToday Clinical trials Endo, FKD, JBL (SWOG), Genentech (SWOG), QED Therapeutics, UroGen, Vaxiion, Viventia Patent TCGA classifier Dr. Lerner is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Gary D. Steinberg, MD Clinical Trial Merck, BMS, Janssen, CG Oncology, Pfizer, PhotoCure, Fidia, Seagen, Protara Scientific advisor/consultant within the past 5 years for the following companies: Heat Biologics; CG Oncology; PhotoCure; Merck; Roche/Genentech; Ciclomed; Taris Biomedical (Now Janssen); MDxHealth; Fidia Farmaceuticals; Urogen, Ferring; Aduro; Boston Scientific; Bristol Myers Squibb; Astra Zeneca; Pfizer, Janssen; Epivax Therapeutics; Natera; FKD; EnGene Bio; SesenBio; BioCanCell (Now Archiano); Nucleix; Ipsen; Combat Medical; Astellas; Fergene; Dendreon; Abbvie; Seattle Genetics; Verity Pharmaceuticals, Regeneron, STIMIT, Vyriad Equity stock/options: Epivax Therapeutics, Urogen Dr. Steinberg is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Angela B. Smith, MD Funding: AHRQ, Genentech, PCORI, BCAN Consultant/Advisor: Merck, Urogen, Ambu, Fergene Dr. Smith is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Donald Lamm, MD Ongoing Research Trials: Nanology, CG Oncology Dr. Lamm is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Roger Li, MD Research support: Predicine; Decipher Biosciences. Clinical trial protocol committee: CG Oncology Scientific advisor/consultant: BMS, Ferring, Fergene, Arquer Diagnostics, Urogen Pharma. Morgan Roupret, MD Consultant/Advisory Board Arquer diagnostic, Ferring, Roche, BMS, Astellas Neal D. Shore, MD Consulting Abbvie, Amgen, Astellas, Astra Zeneca, Bayer, BMS, Boston Scientific, Clovis Oncology, Cold Genesys, Dendreon, Exact Imaging, Exact Sciences, FerGene, Foundation Medicine, Genesis Care, Invitae, Janssen, MDxhealth, Merck, Myovant, Myriad, Nymox, Pacific Edge, Pfizer, Phosphorous, Propella, Sanofi Genzyme, Sesen Bio, Tolmar, Urogen Speaker’s Bureau Astellas, AstraZeneca, Bayer, Clovis Oncology,Foundation Medicine, Janssen, Merck, Pfizer, Guardant Health Sam S. Chang, MD Consultant Pacific Edge Lantheus, Prokarium, KDx Diagnostics, CGOncology, Merck, Pfizer, UroGen, UroToday, Urovant, Virtuoso Surgical, Janssen Dr. Chang is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. J. Alfred Witjes, MD Advisor/Lecturer Sanofi, Ipsen, Astra Zeneca, Ferring,Beijene, Janssen, Nucleix, Merck, Astellas, BMS. Dr. Witjes is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Joan Palou, MD Clinical Trial Cepheid, Combat BRS, Arquer Diagnostics LTD, IDL Biotech AB. Consultant Pfizer, Astra Zeneca, Merck, Janssen, BMS Honoraria Combat BRS, Olympus, Sanofi Pasteur, Cepheid Dr. Palou is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Robert S. Svatek, MD, MSCI Consultant: Fergene, UroGen Research support: JBL, Merck, Pacific Edge, Decipher Dr. Svatek is an Editorial Board Member of this journal, but was not involved in the peer-review process nor had access to any information regarding its peer-review. Niyati Lobo and Justin T. Matulay declare no conflicts of interest., (© 2022 – The authors. Published by IOS Press.)

Purpose: The utility of blue light cystoscopy (BLC) in patients receiving bacillus Calmette-Guérin (BCG) during post-treatment cystoscopy is not well understood. Our objective was to determine if BLC improves recurrence detection in patients with non-muscle invasive bladder cancer (NMIBC) undergoing BCG., Materials and Methods: Using the prospective multi-institutional Cysview® Registry (2014-2019), patients with NMIBC who received BCG within 1 year prior to BLC were identified. Primary outcomes were recurrences and whether lesions were detected on white light cystoscopy (WLC), BLC or both. We calculated the percentage of cystoscopies with recurrences that were missed with WLC alone. The cystoscopy-level BLC false-positive rate was the proportion of cystoscopies with biopsies only due to BLC suspicious lesions without recurrence., Results: Of 1,703 BLCs, 282 cystoscopies were in the analytic cohort. The overall recurrence rate was 45.0% (127). With only WLC, 13% (16/127) of recurrences would have been missed as 5.7% (16/282) of cystoscopies performed had recurrence only identified with BLC. Among 16 patients with recurrence missed with WLC, 88% (14) had carcinoma in situ. The cystoscopy-level BLC false-positive rate was 5% (15)., Conclusions: BLC helped detect recurrences after recent BCG that would have been missed with WLC alone. Providers should consider BLC for high-risk patients undergoing BCG and should discuss the risk of false-positives with these patients. As clinical trials of novel therapies for BCG-unresponsive disease increase and there are no clear guidelines on BLC use for post-treatment cystoscopies, it is important to consider how variable BLC use could affect enrollment in and comparisons of these studies.

A recent phase 3 trial of intravesical nadofaragene firadenovec reported a promising complete response rate for patients with bacillus Calmette-Guérin-unresponsive non-muscle-invasive bladder cancer. This study examined the ability of antiadenovirus antibody levels to predict the durability of therapeutic response to nadofaragene firadenovec. A standardized and validated quantitative assay was used to prospectively assess baseline and post-treatment serum antibody levels among 91 patients from the phase 3 trial, of whom 47 (52%) were high-grade recurrence free at 12 mo (responders). While baseline titers did not predict treatment response, 3-mo titer >800 was associated with a higher likelihood of durable response (p = 0.026). Peak post-treatment titers >800 were noted in 42 (89%) responders versus 26 (59%) nonresponders (p = 0.001; assay sensitivity, 89%; negative predictive value, 78%). Moreover, 22 (47%) responders compared with eight (18%) nonresponders had a combination of peak post-treatment titers >800 and peak antibody fold change >8 (p = 0.004; assay specificity, 82%; positive predictive value, 73%). A majority of responders continued to have post-treatment antibody titers >800 after the first 6 mo of therapy. In conclusion, serum antiadenovirus antibody quantification may serve as a novel predictive marker for nadofaragene firadenovec response durability. Future studies will focus on large-scale validation and clinical utility of the assay. PATIENT SUMMARY: This study reports on a planned secondary analysis of a phase 3 multicenter clinical trial that established the benefit of nadofaragene firadenovec, a novel intravesical gene therapeutic, for the treatment of patients with bacillus Calmette-Guérin (BCG)-unresponsive high-risk non-muscle-invasive bladder cancer. Prospective assessment of serum anti-human adenovirus type-5 antibody levels of patients in this trial indicated that a combination of post-treatment titers and fold change from baseline can predict treatment efficacy. While this merits additional validation, our findings suggest that serum antiadenovirus antibody levels can serve as an important predictive marker for the durability of therapeutic response to nadofaragene firadenovec., (Copyright © 2021 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Introduction: The field of cancer therapy has undergone a major transformation in less than a decade due to the introduction of checkpoint inhibitors, the advent of next generation sequencing and the discovery of neoantigens. The key observation that the breadth of each patient's immune response to the unique mutations or neoantigens present in their tumor is directly related to their survival has led oncologists to focus on driving immune responses to neoantigens through vaccination. Oncology has entered the era of precision immunotherapy, and cancer vaccine development is undergoing a paradigm shift., Areas Covered: Neoantigens are short peptide sequences found in tumors, but not noncancerous tissues, the vast majority of which are unique to each patient. In addition to providing a description of the distinguishing features of neoantigen discovery platforms, this review will address cross-cutting personalized cancer vaccine design themes and developmental stumbling blocks., Expert Opinion: Immunoinformatic pipelines that can rapidly scan cancer genomes and identify 'the best' neoantigens are in high demand. Despite the need for such tools, immunoinformatic methods for identifying neoepitopes in cancer genomes are diverse and have not been well-validated. Validation of 'personalized vaccine design pipelines' will bring about a revolution in neoantigen-based vaccine design and delivery.

Purpose: Smoking has a strong causal association with bladder cancer but the relationship with recurrence is not well established. We sought to assess the association of smoking status on recurrence of non-muscle invasive bladder cancer (NMIBC) in a contemporary cohort of patients with predominantly high-risk, recurrent NMIBC managed with photodynamic enhanced cystoscopy., Materials and Methods: We performed a retrospective study of patients with NMIBC included in a multi-institutional registry. Our primary exposure of interest was smoking status. Our primary outcome was first recurrence of NMIBC. Kaplan-Meier analysis was used to calculate recurrence free probabilities and Cox proportional hazards regression was used to evaluate the impact of smoking status on recurrence free survival., Results: Our analytic cohort included 723 adults with bladder cancer, 11.5% with primary NMIBC and 88.5% with recurrent NMIBC. The majority of patients were white, male, and had high-risk NMIBC (72.6%). 52.6% of included patients were former smokers and 12.7% were current smokers. During the three-year study period, there was a NMIBC recurrence in 259 of the 723 patients (35.8%). The 1- and 3-year probability of recurrence was 19% and 44%, respectively. The grade and stage of recurrences were 28.9% LG Ta, 34.4% HG Ta, 15.8% pure CIS, 0.3% LG T1, 15.4% HG T1, and 5.4% unknown. After adjustment for a priori clinical and demographic factors, smoking status had no significant association with recurrence., Conclusion: Smoking status was not significantly association with recurrence in a study of patients with predominantly high-risk recurrent NMIBC managed with photodynamic enhanced cystoscopy., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Aim: This review article summarizes the current clinical practice guidelines around disease definitions and risk stratifications, and the treatment of non-muscle-invasive bladder cancer (NMIBC). Recently completed and ongoing clinical trials of novel and investigational therapies in Bacillus Calmette-Guérin (BCG)-naïve, BCG-recurrent, and BCG-unresponsive patient populations are also described, e.g., those involving immune checkpoint inhibitors, targeted therapies, other chemotherapy regimens, vaccines, and viral- or bacterial-based treatments. Finally, a brief overview of enhanced cystoscopy and drug delivery systems for the diagnosis and treatment of NMIBC is provided., Background: A global shortage of access to BCG is affecting the management of BCG-naïve and BCG-recurrent/unresponsive NMIBC; hence, there is an urgent need to assist patients and urologists to enhance the treatment of this disease., Methods: Searches of ClinicalTrials.gov, PubMed, and Google Scholar were conducted. Published guidance and conference proceedings from major congresses were reviewed., Conclusion: Treatment strategies for NMIBC are generally consistent across guidelines. Several novel therapies have demonstrated promising antitumor activity in clinical trials, including in high-risk or BCG-unresponsive disease. The detection, diagnosis, surveillance, and treatment of NMIBC have also been improved through enhanced disease detection., (Copyright © 2021 Pfizer Inc., the Author(s). Published by Elsevier Inc. All rights reserved.)

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., (© 2021. Springer Nature Limited.)

Background: The work-up and diagnosis of indeterminate lung nodules at time of bladder cancer diagnosis may delay or change treatment., Objective: To quantify the incidence of synchronous and metachronous lung cancers in adults with bladder cancer and compare these rates to the incidence of bladder cancer metastases in the lung., Methods: We retrospectively analyzed all adults diagnosed with bladder cancer in the Surveillance, Epidemiology and End Results (SEER) registry (2010- 2015) and identified second primary lung cancers defined as being either synchronous (diagnosed within 6 months of bladder cancer diagnosis) or metachronous (more than 6 months following index bladder cancer diagnosis). The risk of second primary lung cancers were reported as a standardized incidence ratio (SIR) reflecting observed and expected case ratios., Results: A total of 88,335 patients diagnosed with bladder cancer were included. Among adults with NMIBC ( n  = 66,071) and MIBC ( n  = 18,879), 0.3% and 3.9% had bladder cancer metastatic to the lungs at diagnosis. Synchronous second primary lung cancers were diagnosed in 0.4% and 0.7% of patients with NMIBC and MIBC, respectively. Compared to the general population, the SIR for synchronous lung cancers among adults with NMIBC was 2.5 (95% CI 2.3- 2.9) and was 4.7 (95% CI 4.0- 5.6) for adults with MIBC., Conclusions: Bladder cancer metastatic to the lung is more common in adults with MIBC compared to NMIBC. There are similar frequencies of synchronous second primary lung cancers regardless of initial bladder cancer stage., Competing Interests: Disclosures for Gary D Steinberg:Is a member of Clinical Trial Protocol Committees for the following companies: Merck, BMS, Janssen, Cold Genesys, Pfizer, PhotoCure, Fidia He has or has been a scientific advisor/consultant within the past 5 years for the following companies: Heat Biologics, Cold Genesys, PhotoCure, Merck, Roche/Genentech, Ciclomed, Taris Biomedical, MDxHealth, Fidia Farmaceuticals, Urogen, Ferring, Aduro, Boston Scientific, Bristol Myers Squibb, Astra Zeneca, Pfizer, Janssen, Epivax Oncology, Natera, FKD, Ferring, EnGene Bio, SesenBio, BioCanCell, Nucleix, Ipsen, Combat Medical, Astellas, Fergene, Dendreon, Abbvie, Seattle Genetics. He has equity stock/options: Epivax Oncology, UrogenDisclosures for Arjun BalarGenentech: Fees for Contracted Research (institution), Consultant/Advisory Role, Speaking Engagements. Incyte: Fees for Consultant/Advisory Role. Janssen: Fees for Consultant/Advisory Role. Merck: Fees for Contracted Research (institution), Consultant/Advisory Role, Speaking Engagements, Steering/Scientific Advisory Committee. Pfizer: Fees for Consultant/Advisory Role. AstraZeneca/Medimmune: Fees for Consultant/Advisory Role, Contracted Research (institution), Speaking Engagements. Nektar: Fees for Consultant Advisory Role, Contracted Research, Steering Committee Membership. Seattle Genetics: Fees for Consultant/Advisory Role, Contracted Research (institution). Immunomedics: Fees for contracted research (Institution), Fees for Consultant/Advisory Role. EpiVax Oncology: Equity, Scientific Advisory Board Member. Jacob Taylor, Adam Weiner, Binhuan Wang and Richard S Matulewicz have nothing to disclose., (© 2021 – The authors. Published by IOS Press.)

A number of immunotherapies have been developed and adopted for the treatment of urothelial cancer (encompassing cancers arising from the bladder, urethra, or renal pelvis). For these immunotherapies to positively impact patient outcomes, optimal selection of agents and treatment scheduling, especially in conjunction with existing treatment paradigms, is paramount. Immunotherapies also warrant specific and unique considerations regarding patient management, emphasizing both the prompt identification and treatment of potential toxicities. In order to address these issues, the Society for Immunotherapy of Cancer (SITC) convened a panel of experts in the field of immunotherapy for urothelial cancer. The expert panel developed this clinical practice guideline (CPG) to inform healthcare professionals on important aspects of immunotherapeutic treatment for urothelial cancer, including diagnostic testing, treatment planning, immune-related adverse events (irAEs), and patient quality of life (QOL) considerations. The evidence- and consensus-based recommendations in this CPG are intended to give guidance to cancer care providers treating patients with urothelial cancer., Competing Interests: Competing interests: AVB─Consulting fees: Genentech, Incyte, Janssen, Merck, Pfizer, AstraZeneca, Nektar, Seattle Genetics, DragonFly Therapeutics; Non-CME services: Genentech, AstraZeneca, Merck, Seattle Genetics; Contracted research: Genentech, Merck, AstraZeneca, Nektar, Seattle Genetics, Immunomedics. PCB─Consulting fees: AbbVie, Asieris Pharmaceuticals, Astellas, AstraZeneca, Bayer, Biosyent, Bristol-Myers Squibb, EMD Serono, Ferring, Fergene, H3 Biomedicine, Janssen, Merck, Roche, Sanofi, TerSera, Urogen; Contracted research: iProgen. MTC─Consulting fees: Pfizer, EMD Serono, AstraZeneca, Exelixis, Eisai, Seattle Genetics, Astellas; Contracted research: Exelixis, Pfizer/EMD Serono, Janssen, Apricity Health. GSD─Participant/unpaid volunteer: HealthVibe focus group 2020. MDG─Consulting fees: Inovio, NuMab, Janssen, Merck, GlaxoSmithKline, Genentech, Bristol-Myers Squibb, Seattle Genetics, Dracen, Dragonfly, Astellas, Novartis, Pfizer, AstraZeneca, Incyte, Dendreon, Eli Lilly, EMD Serono, Aileron Therapeutics; Ownership interest: Rappta Therapeutics; NPI: 1639140668. PG─Consulting fees: AstraZeneca, Dyania Health, EMD Serono, Immunomedics, Janssen, Merck, Mirati Therapeutics, Genentech, Pfizer, Seattle Genetics; Contracted Research: Bavarian Nordic, Bristol-Myers Squibb, Clovis Oncology, Debiopharm, Immunomedics, Pfizer, Merck, QED Therapeutics, GlaxoSmithKline, Kure It Cancer Research, Mirati Therapeutics. SG─Consulting fees: Merck, Bristol-Myers Squibb, Janssen, Seattle Genetics, AstraZeneca; Contracted research: Bristol-Myers Squibb, Pfizer; Non-CME services: Exelixis. CJH─Consulting fees: Astellas, Bristol-Myers Squibb, Genentech, Merck, Eisai, Seattle Genetics, 2bPrecise; Non-CME services: Astellas, Bristol-Myers Squibb, Genentech, Eisai, Seattle Genetics. AMK─Consulting fees: Abbott Molecular, Arquer, ArTara, Asieris, AstraZeneca, BioClin Therapeutics, Bristol-Myers Squibb, Cepheid, Cold Genesys, Eisai, Engene, Inc., Ferring, FerGene, Imagin, Janssen, MDxHealth, Medac, Merck, Pfizer, Photocure, ProTara, Roviant, Seattle Genetics, Sessen Bio, Theralase, TMC Innovation, US Biotest; Contracted research: Adolor, Bristol-Myers Squibb, FKD Industries, Heat Biologics, Merck, Photocure, SWOG/NIH, SPORE, AIBCCR; Clinical trials: FKD, Merck, Bristol-Myers Squibb, Photocure, SWOG, Adolor, Heat Biologics; Laboratory research: NIH, SPORE, AIBCCR; Educational grant: CEC Oncology; Editorial board: European Urology Oncology; Journal of Urology, UroToday; President of organization: International Bladder Cancer Network (IBCN), International Bladder Cancer Group (IBCG); IP Rights: CyPRIT (Cytokine Predictors of Response to Intravesical Therapy) Joint with UT MD Anderson Cancer Center. LPL─Consulting fees: Pfizer Advisory Nursing board, 2018; Lecture/Speaker/Expert Panel: ASCO Bladder Program 2019, Pfizer learning day 2019, ASCO Bladder Program Panel Member and Faculty 2019, Pfizer Learning Day Speaker 2019, BCAN Webinar Faculty 11/2020. JJM─Consulting fees: AstraZeneca, Ferring, Janssen, Nucleix, Foundation Medicine; Contracted research: Epizyme, Tesaro, Abbvie; Teaching an endoscopy course: Olympus. ERP─Consulting fees: AstraZeneca, Infinity Pharma, Pfizer, Flatiron, Genentech, Merck, Seattle Genetics; Contracted research: Astellas, Bristol-Myers Squibb, Genentech, Merck. JER─Consulting fees: Merck, Bristol-Myers Squibb, AstraZeneca, Astellas, Seattle Genetics, Boehringer Ingelheim, Bayer, Pfizer, Roche/Genentech, Mirati, QED Therapeutics, Janssen, Pharmacyclics, GlaxoSmithKline; Contracted research/Clinical trial funding: Seattle Genetics, Astellas, Roche/Genentech, Bayer, AstraZeneca, QED Therapeutics. NS─Consulting fees: Amgen, Astellas, AstraZeneca, Bayer, Bristol-Myers Squibb, Dendreon, Fergene, Ferring, Janssen, Merck, Myovant, Nymox, Pfizer, Sanofi/Genzyme, Sesen Bio, Sun Pharma, Tolmar. GDS─Consulting fees: Merck, Janssen, Ferring, Bristol-Myers Squibb, Pfizer, Genentech, Epivax Oncology, AstraZeneca, Fidia, Cold Genesys, EnGene Bio, Aduro Biotech, Dendreon, FKD Therapies, CiClomed, Seattle Genetics, Urogen, PhotoCure. SITC staff: SMW—Shares owned: Pacific Biosciences, Editas Medicine; EG, AK, BL, LL─Nothing to disclose., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: While numerous current clinical trials are testing novel salvage therapies (ST) for patients with recurrent nonmuscle invasive bladder cancer (NMIBC) after bacillus Calmette-Guérin (BCG), the natural history of this disease state has been poorly defined to date. Herein, we evaluated oncologic outcomes in patients previously treated with BCG and ST who subsequently underwent radical cystectomy (RC)., Methods: We identified 378 patients with high-grade NMIBC who received at least one complete induction course of BCG (n = 378) with (n = 62) or without (n = 316) additional ST and who then underwent RC between 2000 and 2018. Oncologic outcomes were compared using the Kaplan-Meier method and Cox proportional hazards models. Sensitivity analyses were conducted stratifying by presenting tumor stage, matched 1:3 for receipt vs. no receipt of ST., Results: Patients receiving ST were more likely to initially present with CIS (26% vs. 17%) and less likely with T1 disease (34% vs. 50%, P = 0.06) compared to patients not treated with ST. Receipt of ST was not associated with increased risk of adverse pathology (≥pT2 or pN+) at RC (31% vs. 41%, P = 0.14). Likewise, 5-year cancer-specific survival did not significantly differ between groups on univariable Kaplan-Meier analysis (73% for ST and 74% for no ST, P = 0.7). Moreover, on multivariable analysis, receipt of ST was not significantly associated the risk of death from bladder cancer (HR 1.12; 95% CI 0.60-2.09, P = 0.7). Results were unchanged on sensitivity analysis., Conclusions: These data suggest that, in carefully selected patients, ST following BCG for high grade NMIBC does not compromise oncologic outcomes for patients who ultimately undergo RC., Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Improvement of risk stratification through prognostic biomarkers may enhance the personalization of cancer patient monitoring and treatment. We used Ancer, an immunoinformatic CD8, CD4, and regulatory T cell neoepitope screening system, to perform an advanced neoantigen analysis of genomic data derived from the urothelial cancer cohort of The Cancer Genome Atlas. Ancer demonstrated improved prognostic stratification and five-year survival prediction compared to standard analyses using tumor mutational burden or neoepitope identification using NetMHCpan and NetMHCIIpan. The superiority of Ancer, shown in both univariate and multivariate survival analyses, is attributed to the removal of neoepitopes that do not contribute to tumor immunogenicity based on their homology with self-epitopes. This analysis suggests that the presence of a higher number of unique, non-self CD8- and CD4-neoepitopes contributes to cancer survival, and that prospectively defining these neoepitopes using Ancer is a novel prognostic or predictive biomarker.

Background: BCG is the most effective therapy for high-risk non-muscle-invasive bladder cancer. Nadofaragene firadenovec (also known as rAd-IFNa/Syn3) is a replication-deficient recombinant adenovirus that delivers human interferon alfa-2b cDNA into the bladder epithelium, and a novel intravesical therapy for BCG-unresponsive non-muscle-invasive bladder cancer. We aimed to evaluate its efficacy in patients with BCG-unresponsive non-muscle-invasive bladder cancer., Methods: In this phase 3, multicentre, open-label, repeat-dose study done in 33 centres (hospitals and clinics) in the USA, we recruited patients aged 18 years or older, with BCG-unresponsive non-muscle-invasive bladder cancer and an Eastern Cooperative Oncology Group status of 2 or less. Patients were excluded if they had upper urinary tract disease, urothelial carcinoma within the prostatic urethra, lymphovascular invasion, micropapillary disease, or hydronephrosis. Eligible patients received a single intravesical 75 mL dose of nadofaragene firadenovec (3 × 10 11 viral particles per mL). Repeat dosing at months 3, 6, and 9 was done in the absence of high-grade recurrence. The primary endpoint was complete response at any time in patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour). The null hypothesis specified a complete response rate of less than 27% in this cohort. Efficacy analyses were done on the per-protocol population, to include only patients strictly meeting the BCG-unresponsive definition. Safety analyses were done in all patients who received at least one dose of treatment. The study is ongoing, with a planned 4-year treatment and monitoring phase. This study is registered with ClinicalTrials.gov, NCT02773849., Findings: Between Sept 19, 2016, and May 24, 2019, 198 patients were assessed for eligibility. 41 patients were excluded, and 157 were enrolled and received at least one dose of the study drug. Six patients did not meet the definition of BCG-unresponsive non-muscle-invasive bladder cancer and were therefore excluded from efficacy analyses; the remaining 151 patients were included in the per-protocol efficacy analyses. 55 (53·4%) of 103 patients with carcinoma in situ (with or without a high-grade Ta or T1 tumour) had a complete response within 3 months of the first dose and this response was maintained in 25 (45·5%) of 55 patients at 12 months. Micturition urgency was the most common grade 3-4 study drug-related adverse event (two [1%] of 157 patients, both grade 3), and there were no treatment-related deaths., Interpretation: Intravesical nadofaragene firadenovec was efficacious, with a favourable benefit:risk ratio, in patients with BCG-unresponsive non-muscle-invasive bladder cancer. This represents a novel treatment option in a therapeutically challenging disease state., Funding: FKD Therapies Oy., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Dissemination of misinformation through social media is a major societal issue. Bladder cancer is the second most common urological cancer in the world, but there are limited data on the quality of bladder cancer information on social networks. Our objective was to characterize the quality of information and presence of misinformation about bladder cancer on YouTube, the most commonly used social media platform. We reviewed the first 150 YouTube videos about "bladder cancer" using two validated instruments for consumer health information and assessed the videos for the presence of misinformation. The videos had a median of 2288 views (range, 14-511 342), but the overall quality of information was moderate to poor in 67%, based on scores of 1-3 out of 5 on the validated DISCERN instrument. A moderate to high amount of misinformation was present in 21% of videos and reached 1 289 314 viewers. Commercial bias was apparent in 17% of videos, which reached 324 287 viewers. From a networking perspective, comments sections in the videos were sometimes used to request medical advice (20%), provide medical advice to others (9%), or give support (19%). In conclusion, YouTube is a widely used source of information and advice about bladder cancer, but much of the content is of poor quality. PATIENT SUMMARY: A large quantity of content about bladder cancer is available on YouTube. Unfortunately, much of the content is of moderate to poor quality and presents a risk of exposure to misinformation., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Several molecular subtypes of bladder cancer were identified with differing clinical behavior and responses to platinum-based chemotherapy. But so far, their urothelial histomorphologic features, besides association with some variant histologies, have remained fully undefined. We sought to characterize the histological features of genomically classified bladder cancers more extensively to tumor in radical cystectomy (RC) specimens. Forty-eight bladder cancers submitted to The Cancer Genome Atlas (TCGA) were classified using the BASE47 genomic classifier into luminal subtype (LS) (14 cases), basal subtype (BS) (18 cases), and claudin-low subtype (CLS) (16 cases), and TCGA samples and the corresponding RC specimens were histologically assessed. Marked pleomorphism was more extensive in CLS tumors (87.5% had >15% extent) than in LS tumors (21.4%) (p = 0.0006), whereas the extent in BS tumors was in between LS and CLS tumors. Pleomorphism in distant carcinoma in situ appeared to correlate with that in the main tumor. Ki-67 proliferation was higher in CLS tumors (mean = 61%) than in LS tumors (mean = 29%) or BS (mean = 30%) (p < 0.001). Squamous differentiation was more extensive in BS and CLS tumors (38.2% of BS and CLS tumors versus 7.1% of LS tumors had >30% squamous, p = 0.040). Sarcomatoid change was present in BS and CLS tumors only. The micropapillary variant was identified in LS (3/14) and BS (4/18) tumors only. Histologic features associated with aggressiveness (eg, marked pleomorphism, high proliferation, and sarcomatoid change) are enriched in CLS tumors, correlating with its known poorer outcome that may provide hints in their microscopic distinction. Features more associated with BS than with LS tumors (eg, squamous, marked pleomorphism, and sarcomatoid change) are also identified or enhanced in CLS tumors, supporting the genomic findings suggesting CLS tumor as a hyperbasal form of BS tumor., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To characterize Bacillus Calmette-Guérin (BCG) treatment patterns and associated outcomes in a large cohort of patients with non-muscle-invasive bladder cancer (NMIBC)., Methods: Our retrospective analysis of patients aged ≥66 years with stage 0-1 urothelial bladder carcinoma diagnosed between 2000 and 2012 in the United States Surveillance, Epidemiology, and End Results-Medicare database estimated proxies for recurrence and secondary events and both all-cause and bladder cancer-specific mortality. Proportional hazards models were used in conditional landmark analyses to compare adequate (≥5 induction instillations and ≥2 maintenance instillations) and inadequate BCG, stratified by National Comprehensive Cancer Network risk group., Results: Of 39,532 patients who met the selection criteria, 16,225 (41.0%) received BCG; of them, 4602 (28.4%; 11.6% overall) received adequate treatment. Adequately treated patients were slightly younger and healthier than inadequately treated patients. Half of patients with intermediate- and high-risk NMIBC did not receive BCG; few received adequate treatment. At the 12-month landmark, adequate BCG treatment was associated with decreased risks of recurrence and of cancer-specific and all-cause mortality in patients with intermediate- and high-risk disease., Conclusion: We observed lower than expected use of adequate BCG treatment in patients with intermediate- to high-risk NMIBC despite evidence of improved outcomes, which suggested that practice patterns may not be in line with management recommendations in this population., (Published by Elsevier Inc.)

Context: Enhanced Recovery After Surgery (ERAS) is a perioperative approach to managing surgical patients. The impact of ERAS on radical cystectomy (RC) outcomes remains understudied., Objective: To review the literature regarding ERAS protocols and RC outcomes. The primary outcome was hospital length of stay (LOS)., Evidence Acquisition: A systematic review of the articles published from 1970 through 2018 was conducted. Individual patient data (IPD) were requested and a meta-analysis was performed., Evidence Synthesis: A total of 4197 articles were retrieved and 22 (reporting 4048 patients) were selected for the review. LOS followed by 30-d and that followed by 90-d complications were the most common endpoints. ERAS use was associated with reduced morbidity, quicker bowel recovery, and shorter LOS, without affecting mortality. IPD were obtained for 2077 patients from 11 studies. In multivariable models, LOS was associated with ERAS use (regression coefficient: -4.54 [95% confidence interval {CI}: -5.79 to -3.28] d with ERAS p <  0.001) and Charlson Comorbidity Index (+1.64 [1.38-1.90] d for each point increase, p <  0.001), and varied between hospitals (from -1.59 [-3.03 to -0.14] to +4.55 [1.89-7.21] d, p <  0.03). Individual ERAS components associated with shorter LOS included no nasogastric (NG) tube (-8.70 [-11.9 to -5.53] d, p <  0.001) and local anesthesia blocks compared with regional anesthesia (-3.29 [-6.31 to -0.27] d, p =  0.03)., Conclusions: ERAS protocols were associated with reduced LOS and postoperative complication rate. Avoidance of NG tubes and use of local anesthesia blocks were significantly associated with reduced LOS. These findings reflect different components of recovery, which ERAS can optimize and further support documentation of the use of ERAS components when reporting RC outcomes., Patient Summary: Use of enhanced recovery in patients undergoing surgery to remove the bladder is associated with fewer surgical complications and a shorter hospital stay. Avoidance of nasogastric tubes and use of local anesthesia after the operation were associated with a shorter length of stay., (Copyright © 2020 European Association of Urology. All rights reserved.)

Purpose: The American Urological Association (AUA) introduced evidence-based guidelines for the management of nonmuscle invasive bladder cancer (NMIBC) in 2016. We sought to assess the implementation of these guidelines among members of the Society of Urologic Oncology (SUO) with an aim to identifying addressable gaps., Methods and Materials: An SUO approved survey was distributed to 747 members from December 28, 2018 to February 2, 2019. This 14-question online survey (Qualtrics, SAP SE, Germany) consisted of 38 individual items addressing specific statements from the AUA NMIBC guidelines within 3 broad categories - initial diagnosis, surveillance, and imaging/biomarkers. Adherence to guidelines was assessed by dichotomizing responses to each item that was related to recommended action statement within the guidelines. Statistical analysis was applied using Pearson's chi-squared test, where a P-value of <0.05 was considered statistically significant., Results: A total of 121 (16.2%) members completed the survey. Members reported a mean of 71% guidelines adherence; adherence was higher for the intermediate- and high-risk subgroups (82% and 76%, respectively) compared to low-risk (58%). Specifically, adherence to guideline recommended cystoscopic surveillance intervals for low-risk disease differed based on clinical experience (60.9% [<10 years] vs. 36.8% [≥10 years], P = 0.01) and type of fellowship training (55.2% [urologic oncology] vs. 28.0% [none/other], P = 0.02)., Conclusion: Adherence to guidelines across risk-categories was higher for intermediate- and high-risk patients. Decreased adherence observed for low-risk patients resulted in higher than recommended use of cytology, imaging, and surveillance cystoscopy. These results identify addressable gaps and provide impetus for targeted interventions to support high-value care, especially for low-risk patients., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Context: There is a critical need for effective bladder-sparing therapies for bacillus Calmette-Guérin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC). Owing to the current lack of effective agents that can be used as a control, the US Food and Drug Administration began to accept single-arm trials for patients with carcinoma in situ (CIS), using complete response rate (CRR) and duration of response as the primary endpoints to support marketing applications. Despite the ensuing growth of clinical trials in this space, no consensus exists on a clinically relevant benchmark for CRR., Objective: To elucidate the CRR and recurrence-free rate (RFR) using bladder-sparing agents after BCG failure in order to provide a frame of reference for future clinical trial results., Evidence Acquisition: We performed a systematic review of clinical trials utilizing bladder-sparing therapeutics for NMIBC recurring after intravesical BCG (PROSPERO CRD42019130553). The search was performed in MEDLINE, EMBASE, and Cochrane Library. Relevant studies identified from bibliography search and conference abstracts were searched to complement the systematic review. A total of 42 studies utilizing 24 treatment options and consisting of 2254 patients were included for final analysis., Evidence Synthesis: Median CRRs in the treatment of CIS-containing tumors were 26% at 6 mo, 17% at 12 mo, and 8% at 24 mo after treatment. In comparison, median RFRs in the papillary-only studies were 67% at 6 mo, 44% at 12 mo, and 10% at 24 mo. Specifically in the BCG-unresponsive population, 6- and 12-mo CRRs in CIS-containing patients treated with Mycobacterium phlei cell wall-nucleic acid complex were 45% and 27%, respectively, and the median 6-, 12-, and 24-mo disease-free rates in the other studies were 43%, 35%, and 18%, respectively. The median progression-free rate was 91%: 95% in the CIS-containing studies and 89% in studies restricted to papillary-only recurrences. Toxicities of intravesical agents were generally mild, with very few dose limiting toxicities., Conclusions: We demonstrate that, to date, bladder-sparing therapies achieved modest efficacy in patients with NMIBC after BCG. Results from the current study will serve as a frame of reference for emerging trial results in the BCG-unresponsive space., Patient Summary: In this study, we found that bladder-sparing therapies achieved modest efficacy in patients with non-muscle-invasive bladder cancer after bacillus Calmette-Guérin (BCG). These results will serve to inform future clinical trial results for salvage agents used to treat BCG-unresponsive bladder cancer., (Copyright © 2020 European Association of Urology. Published by Elsevier B.V. All rights reserved.)

Background, Context and Purpose: In spite of the mixed evidence for their impact, survivorship Care Plans (SCPs) are recommended to enhance quality of care for cancer survivors. Data on the feasibility of SCPs in bladder cancer (BC) is sparse. Using a mixed-methods approach, this study describes the iterative development, acceptability and feasibility of BC specific SCP (BC-SCP) in clinical settings., Methods: In Phase I, we developed the BC-SCP. In Phase II, we conducted four focus groups with 19 patients and 15 providers to examine its acceptability and usability challenges. Data analyses using the Atlas.ti program, informed refinement of the BC-SCP. In Phase III, we conducted feasibility testing of the refined BC-SCP with 18 providers from 12 health-centers. An encounter survey was completed after each assessment to examine the feasibility of the BC-SCP. Chi-square and Fisher Exact tests were used for comparative analyses., Results: During phase I, we observed high patient and provider acceptability of the BC-SCP and substantial engagement in improving its content, design, and structure. In Phase II, providers completed 59 BC-SCPs. Mean time for BC-SCP completion was 12.3 min. Providers reported that BC-SCP content was clear, did not hamper clinic flow and was readily completed with easy-to-access information. Comparative analyses to examine differences in SCP completion time by patient clinico-demographic characteristics and provider type revealed no significant differences., Conclusions: Our BC-SCP has clinical relevance, and can be used in an active practice setting. However, considerable progress will be necessary to achieve implementation of and sharing the BC-SCP with patients and care providers, particularly within the electronic medical record. In summary, BC-SCPs are essential to improve the follow up care of BC survivors. Clinical resources are required to ensure appropriate implementation of BC-SCPs., Trial Registration: Study HUM00056082.

Background: Lymphovascular invasion (LVI) in muscle-invasive bladder cancer is associated with a poor prognosis when identified from radical cystectomy (RC) specimens. However, LVI is not clearly emphasized in any risk models to guide clinical decision-making. The impact of LVI on the risk of lymph node (LN) metastasis after a transurethral resection of bladder tumor (TURBT) specimen is less understood., Objective: The goal was to describe the impact of LVI and the risk of LN metastasis at each clinical stage of urothelial carcinoma of the bladder (UC)., Design, Setting, and Participants: The National Cancer Database was queried for patients with bladder cancer who underwent RC with LN dissection from 2004 to 2014. Patients with non-bladder primary, non-UC histology, clinical metastatic disease, and having received chemotherapy/radiation were excluded. Pathologic LN positive rates at RC were determined., Outcome Measurements and Statistical Analysis: The primary outcome was pathologic upstaging at RC and pathologic node positivity. Secondary outcomes included determining overall survival (OS). All hypotheses testing were two-sided and a p value of <0.05 was considered statistically significant. All statistical analyses were performed using Stata version 13.1., Results and Limitations: A total of 3007 patients with UC underwent RC with pelvic LN dissection. In patients with LVI, the risk of LN metastasis was significantly higher at each clinical stage as was the rate of pathologic upstaging. Patients with LVI on TURBT had worse OS stage for stage in pure UC (p<0.001). Limitations include that there was no central pathologic review and the number of TURBTs per patient was not known., Conclusions: Patients with UC with LVI had worse OS and are at higher risk for LN-positive disease and pathologic upstaging at surgery than patients without LVI., Patient Summary: In this report we examined the impact of lymphovascular invasion (LVI) at transurethral resection of bladder tumor on pathologic upstaging and lymph node metastasis at radical cystectomy using the National Cancer Database. We identified LVI as being prognostic at each stage of urothelial carcinoma., (Published by Elsevier B.V.)

Non-muscle-invasive bladder cancer (NMIBC) is the most common form of bladder cancer, with frequent recurrences and risk of progression. Risk-stratified treatment and surveillance protocols are often used to guide management. In 2017, BJUI reviewed guidelines on NMIBC from four major organizations: the American Urological Association/Society of Urological Oncology, the European Association of Urology, the National Comprehensive Cancer Network, and the National Institute for Health and Care Excellence. The present update will review major changes in the guidelines and broadly summarize new recommendations for treatment of NMIBC in an era of bacillus Calmette-Guérin shortage and immense novel therapy development., (© 2019 The Authors BJU International © 2019 BJU International Published by John Wiley & Sons Ltd.)

Immune checkpoint inhibitors have revolutionized the treatment of patients with metastatic urothelial carcinoma. In cisplatin-eligible muscle-invasive bladder cancer (MIBC), cisplatin-based neoadjuvant chemotherapy (NAC) before radical cystectomy improves overall survival. Tumor PD-L1 expression increases in MIBC after NAC, suggesting potential synergy in combining PD1/PD-L1 inhibitors with NAC. IDO1 is overexpressed in bladder cancer and is associated with poor outcomes. Linrodostat mesylate (BMS-986205) - a selective, potent, oral IDO1 inhibitor - combined with nivolumab has demonstrated safety and preliminary evidence of clinical activity in metastatic urothelial carcinoma. Here, we discuss the rationale and trial design of the ENERGIZE, a Phase III trial investigating the efficacy of NAC in combination with nivolumab with or without linrodostat followed by postsurgery nivolumab or nivolumab with linrodostat in cisplatin-eligible patients with MIBC. Clinical trial registration number: NCT03661320.

Non-muscle-invasive bladder cancer (NMIBC) is a heterogeneous subclassification of urothelial carcinoma with significant variation in individual risk of recurrence and progression to muscle-invasive disease. Risk stratification by American Urological Association (AUA) and European Association of Urology (EAU) guidelines or by using nomograms/risk calculators developed from clinical trial data can help inform patient treatment decisions but may not accurately classify all patients. Risk-adapted adjuvant (post-transurethral resection of bladder tumor [TURBT]) treatment strategies using intravesical therapies are an important means of balancing disease control with potential adverse effects. Adjuvant intravesical instillation with various chemotherapy agents and bacillus Calmette-Guérin (BCG) is well studied and associated with excellent outcomes for most patients. However, upwards of 40% of patients recur within 2 years and roughly 10% progress to muscle-invasive bladder cancer. Novel approaches and agents that aim to reduce the treatment burden associated with NMIBC are increasingly needed. We review the current landscape of NMIBC as it pertains to the use of and rationale for emerging neoadjuvant chemoablative therapies., (© 2020 MedReviews®, LLC.)