Bladder Cancer Outcomes Research Articles

Comparative proteomics analysis in different stages of urothelial bladder cancer for identification of potential biomarkers: highlighted role for antioxidant activity

BackgroundNon-muscle-invasive bladder cancer (NMIBC) has a high recurrence rate and muscle-invasive bladder cancer (MIBC) has unfavorable outcomes in urothelial bladder cancer (UBC) patients. Complex UBC-related protein biomarkers for outcome prediction may provide a more efficient management approach with an improved clinical outcome. The aim of this study is to recognize tumor-associated proteins, which are differentially expressed in different stages of UBC patients compared non-cancerous tissues.MethodsThe proteome of tissue samples of 42 UBC patients (NMIBC n = 25 and MIBC n = 17) was subjected to two-dimensional electrophoresis (2-DE) combined with Liquid chromatography–mass spectrometry (LC–MS) system to identify differentially expressed proteins. The intensity of protein spots was quantified and compared with Prodigy SameSpots software. Functional, pathway, and interaction analyses of identified proteins were performed using geneontology (GO), PANTHER, Reactome, Gene MANIA, and STRING databases.ResultsTwelve proteins identified by LC-MS showed differential expression (over 1.5-fold, p < 0.05) by LC-MS, including 9 up-regulated in NMIBC and 3 up-regulated in MIBC patients. Proteins involved in the detoxification of reactive oxygen species and cellular responses to oxidative stress showed the most significant changes in UBC patients. Additionally, the most potential functions related to these detected proteins were associated with peroxidase, oxidoreductase, and antioxidant activity.ConclusionWe identified several alterations in protein expression involved in canonical pathways which were correlated with the clinical outcomes suggested might be useful as promising biomarkers for early detection, monitoring, and prognosis of UBC.

Racial and sex differences in tumor genomics in urothelial carcinoma

PurposeDifferences in bladder cancer outcomes have been demonstrated by sex and race/ethnicity, with studies showing a higher burden of adverse outcomes among women and racially minoritized populations. Despite these epidemiologic differences, populations with disproportionally adverse outcomes are often underrepresented in genomic cohorts. This exclusion impacts the accuracy and generalizability of genomic studies in bladder cancer and has the potential to widen disparities by sex and/or race/ethnicity. Basic ProceduresWe analyzed pooled somatic mutational data from publicly available cohorts in the cBioPortal open access platform. FindingsA total of 796 unique patients were identified. Average age for the cohort was 67 years (range: 25–98 years), 188 (24%) were female, and the majority were White (n = 423, 85% among those who report race). Median total mutation count was 91 (IQR: 20, 202) per patient. We used multivariable logistic regression to independently evaluate the association between race/sex and mutation status in each of 122 genes of interest, identified from TCGA, adjusting for age and bladder cancer invasive status. In adjusted analyses, male sex was associated with increased risk of mutation in ARID1A, CHD6, and NCOR1 compared with female sex. White race was associated with increased risk of mutation in ARID1A, EP300, PIK3CA, and TP53 and decreased risk of mutation in HRAS compared with non-White race. ConclusionsThese differences highlight the importance of enriching cohorts for female and non-White patients in genomic studies and clinical trials, especially as we test the use of molecular biomarkers to personalize care for patients with bladder cancer.

Immune inactivation by VISTA predicts clinical outcome and therapeutic benefit in muscle-invasive bladder cancer

BackgroundV domain Immunoglobulin suppressor of T cell activation (VISTA) has been proved to be a novel immune checkpoint molecule that positively regulates T cell infiltration in several malignancies. However, the clinical impact of VISTA on muscle-invasive bladder cancer (MIBC) patients remains relatively obscure.MethodsThis study enrolled 135 MIBC patients from Zhongshan Hospital (ZSHS) and 391 patients from The Cancer Genome Atlas (TCGA) to examine the VISTA expression and immune contexture based on immunohistochemistry (IHC) staining and CIBERSORT algorithm. Additionally, IMvigor210 Cohort included 195 bladder-derived urothelial carcinoma patients to evaluate the efficacy of immunotherapy. Kaplan-Meier curve and Cox regression analyses were conducted to assess clinical outcomes.ResultsMIBC patients with high VISTA+ immune cells (ICs) possessed poor overall survival and inferior therapeutic responsiveness to adjuvant chemotherapy (ACT), but superior responsiveness to PD-L1 inhibitor. VISTA+ ICs infiltration shaped an immunoevasive context featured by regulatory T cells (Tregs), M2 macrophages, mast cells and exhausted CD8+ T cells infiltration, with increased interleukin 10 (IL-10), transforming growth factor-β (TGF-β) and interferon-γ (IFN-γ), but also elevated T-cell immunoglobulin mucin-3 (TIM-3), lymphocyte activation gene 3 (LAG-3) and T-cell immunoglobulin and ITIM domain (TIGIT), which was also mainly presented in basal-squamous and luminal-infiltrated subtypes of MIBC.ConclusionVISTA+ ICs infiltration could be an independent predictor to identify poor prognosis and therapeutic responses (PD-L1 blockade and ACT) in MIBC patients, which was associated with immunoevasive contexture. The novel immune checkpoint VISTA might be utilized as a candidate treatment biomarker in MIBC patients.

Chronic prednisone, metformin, and nonsteroidal anti-inflammatory drug use and clinical outcome in a cohort of bladder cancer patients undergoing radical cystectomy in Québec, Canada

BackgroundStudies have suggested a positive association between bladder cancer (BC) outcome and comedication use, including nonsteroidal anti-inflammatory drugs (NSAID), metformin, and prednisone use. To validate these associations, we evaluated whether these medications were associated with clinical outcome in a Canadian cohort of BC patients.MethodsThis is a retrospective cohort study on BC patients undergoing radical cystectomy (RC) in Québec province in 2000–2015, as registered in the provincial health administration databases. Medication use was considered chronic when prescribed for ≥ 1 year. Overall (OS), disease-specific (DSS) and recurrence-free (RFS) survival were compared using multivariable Cox proportional hazards models. Covariates included age, Charlson’s comorbidity index, region of residence, year of RC, distance to hospital, hospital type, hospital and surgeon annual RC volume, neoadjuvant chemotherapy use, and type of bladder diversion, as well as mutual adjustment for concomitant comedication use (statins, NSAIDs, metformin, and prednisone).ResultsOf 3742 patients included, 293, 420, and 1503 patients chronically used prednisone, metformin, and NSAIDs before surgery, respectively. In multivariable analyses, preoperative prednisone use was associated with improved OS (HR 0.67, 95%CI 0.55–0.82), DSS (HR 0.58, 95%CI 0.45–0.76), and RFS (HR 0.61, 95%CI 0.47–0.78). Patients who chronically used metformin preoperatively had a worse OS (HR 1.29, 95%CI 1.07–1.55), DSS (HR 1.38, 95%CI 1.10–1.72), and RFS (HR 1.41, 95%CI 1.13–1.74). Preoperative, chronic NSAID use was not significantly associated with all clinical outcomes, with adjusted HRs for OS, DSS, and RFS of 1.10 (95%CI 0.95–1.27), 1.24 (95%CI 1.03–1.48), and 1.22 (95%CI 1.03–1.45), respectively. Directionality of findings was similar when stratifying by comedication use in the year following surgery. Results were similar after propensity-score matching too.ConclusionsIn our Canadian cohort of BC undergoing RC, chronic prednisone use was associated with improved clinical outcomes, while metformin and NSAID were not.

Partial and radical cystectomy provides equivalent oncologic outcomes in bladder cancer when combined with adequate lymph node dissection: A population-based study.

To compare the oncologic outcomes of bladder cancer (BCa) patients after partial cystectomy (PC) or radical cystectomy (RC) combined with lymph node dissection (LND). Relevant data from BCa patients who had >3 lymph nodes (LNs) removed were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Different thresholds of LN count in LND were tested to eliminate potential selection bias, and the optimal threshold was applied to screen patients who underwent adequate LND. After propensity score matching, the oncologic outcomes after PC or RC were compared in patients who underwent adequate LND. After preliminary screening, 6,785 BCa cases diagnosed between 2004 and 2015 with removal of > 3 LNs were enrolled in the analysis, including 633 (9.3%) PC cases and 6,152 (90.7%) RC cases. The PC and RC groups presented entirely different profiles in clinical parameters such as sex, T stage, number of lymph nodes (LNs) removed, and adjuvant therapy. In particular, the LN-positive rate and count were higher in the RC group, even after adjusting for other confounding factors. After comparison using different thresholds, the LN positive rate and count were similar when the LN count in LND was restricted to > 12. In patients who had > 12 LNs removed, after propensity score matching, PC and RC presented similar oncologic outcomes. Further exploration found that the prognosis of patients was associated with age, T stage, and the number of positive LNs. PC and RC could provide equivalent oncologic outcomes in BCa when combined with adequate LND. The conclusion needs further validation in future studies.

Exposure to Agent Orange and Risk of Bladder Cancer Among US Veterans

To date, limited data exist regarding the association between Agent Orange and bladder cancer, and the Institute of Medicine concluded that the association between exposure to Agent Orange and bladder cancer outcomes is an area of needed research. To examine the association between bladder cancer risk and exposure to Agent Orange among male Vietnam veterans. This nationwide Veterans Affairs (VA) retrospective cohort study assesses the association between exposure to Agent Orange and bladder cancer risk among 2 517 926 male Vietnam veterans treated in the VA Health System nationwide from January 1, 2001, to December 31, 2019. Statistical analysis was performed from December 14, 2021, to May 3, 2023. Agent Orange. Veterans exposed to Agent Orange were matched in a 1:3 ratio to unexposed veterans on age, race and ethnicity, military branch, and year of service entry. Risk of bladder cancer was measured by incidence. Aggressiveness of bladder cancer was measured by muscle-invasion status using natural language processing. Among the 2 517 926 male veterans (median age at VA entry, 60.0 years [IQR, 56.0-64.0 years]) who met inclusion criteria, there were 629 907 veterans (25.0%) with Agent Orange exposure and 1 888 019 matched veterans (75.0%) without Agent Orange exposure. Agent Orange exposure was associated with a significantly increased risk of bladder cancer, although the association was very slight (hazard ratio [HR], 1.04; 95% CI, 1.02-1.06). When stratified by median age at VA entry, Agent Orange was not associated with bladder cancer risk among veterans older than the median age but was associated with increased bladder cancer risk among veterans younger than the median age (HR, 1.07; 95% CI, 1.04-1.10). Among veterans with a diagnosis of bladder cancer, Agent Orange was associated with lower odds of muscle-invasive bladder cancer (odds ratio [OR], 0.91; 95% CI, 0.85-0.98). In this cohort study among male Vietnam veterans, there was a modestly increased risk of bladder cancer-but not aggressiveness of bladder cancer-among those exposed to Agent Orange. These findings suggest an association between Agent Orange exposure and bladder cancer, although the clinical relevance of this was unclear.

Physicianreported treatment patterns and outcomes in metastatic bladder cancer in the USA: the CancerMPact® Survey 2020.

Aim: This study assessed physician-reported treatment patterns for metastatic bladder cancer. Materials & methods: A total of106 USA-based physicians were surveyed in 2020 using the CancerMPact® online survey. Results: Among cisplatin-eligible patients, 86.1% received first-line (1L) platinum-containing chemotherapy, most commonly cisplatin plus gemcitabine, and 9.8% received immune checkpoint inhibitor monotherapy. Among cisplatin-ineligible patients, 46.5% received 1L platinum-containing chemotherapy, most commonly carboplatin plus gemcitabine and 46.2% received 1L immune checkpoint inhibitor therapy. Approximately 44% of patients who received 1L treatment received second-line (2L) therapy after progression. Conclusion: Platinum-containing chemotherapy was the most widely reported 1L treatment approach. A high proportion of patients received no 2L therapy. Validation in an updated dataset is warranted following the practice-changing approvals of avelumab 1L maintenance and additional 2L options.

ACSM6 overexpression indicates a non-inflammatory tumor microenvironment and predicts treatment response in bladder cancer: results from multiple real-world cohorts.

Background: ACSMs play critical roles in lipid metabolism; however, their immunological function within the tumor microenvironment (TME) remains unclear, especially that of ACSM6. In this study, we investigate the latent effect of ACSM6 on bladder cancer (BLCA). Methods: Several real-world cohorts, including the Xiangya (in-house), The Cancer Genome Atlas (TCGA-BLCA), and IMvigor210 cohorts, with TCGA-BLCA cohort serving as the discovery cohort were compared. We investigated the potential immunological effects of ACSM6 in regulating the BLCA tumor microenvironment by analyzing its correlation with immunomodulators, anti-cancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, we assessed the precision of ACSM6 in predicting BLCA molecular subtypes and responses to several treatments using ROC analysis. To ensure the robustness of our findings, all results were confirmed in two independent external cohorts: the IMvigor210 and Xiangya cohorts. Results: ACSM6 expression was markedly upregulated in BLCA. Our analysis suggests that ACSM6 might have significant impact to promote the formation of a non-inflamed tumor microenvironment because of its negative correlation with immunomodulators, anticancer immune cycles, immune checkpoints, tumor-infiltrating immune cells, and the T-cell inflamed score (TIS). Additionally, high ACSM6 expression levels in BLCA may predict the luminal subtype, which is typically associated with resistance to chemotherapy, neoadjuvant chemotherapy, and radiotherapy. These findings were consistent across both the IMvigor210 and Xiangya cohorts. Conclusion: ACSM6 has the potential to serve as a valuable predictor of the tumor microenvironment phenotypes and treatment outcomes in BLCA, thereby contributing to more precise treatment.

Medicaid Expansion and Racial Disparity in Timely Multidisciplinary Treatment in Muscle Invasive Bladder Cancer.

Multidisciplinary cancer care (neoadjuvant chemotherapy+radical cystectomy (NAC+RC) or trimodality treatment (TMT)) is crucial for outcome of muscle invasive bladder cancer (MIBC), a potentially curable illness. Medicaid expansion through Affordable Care Act (ACA) increased insurance coverage especially among patients of racial minorities. This study aims to investigate the association between Medicaid expansion and racial disparity in timely treatment in MIBC. This quasi-experimental study analyzed 18-64-year-old Black and White people with stage II&III bladder cancer treated with NAC+RC or TMT from National Cancer Database 2008-2018. Primary outcome was timely treatment started within 45 days following cancer diagnosis. Racial disparity is the percentage-point difference between Black and White patients. Patients in expansion and nonexpansion states were compared using difference-in-differences (DID) and difference-in-difference-in-differences (DDD) analyses, controlling for age, sex, area level income, clinical stage, comorbidity, metropolitan status, treatment type, and year of diagnosis. The study included 4991 patients (92.3% White, N = 4605; 7.7% Black, N = 386). Percent of Black patients received timely care increased following the ACA in Medicaid expansion states (54.5% pre-ACA vs 57.4% post-ACA) whereas decreased in non-expansion states (69.9% pre-ACA vs 53.7% post-ACA). After adjusting covariates, Medicaid expansion was associated with a net 13.7 percentage-point reduction of Black-White disparity in timely receipt of MIBC treatment (95%CI: 0.5%-26.8%; p < .01). Medicaid expansion was associated with statically significant reduction in racial disparity between Black and White patients in timely multidisciplinary treatment for MIBC.

P-48 Outcomes of early gall bladder cancer (GBCA): A retrospective analysis from a tertiary care centre in India

P-48 Outcomes of early gall bladder cancer (GBCA): A retrospective analysis from a tertiary care centre in India

Association of tumor-informed minimal residual disease (MRD) with clinical outcomes for muscle invasive bladder cancer (MIBC): A multicenter retrospective real-world analysis.

3050 Background: Muscle invasive bladder cancer is associated with a significant elevated risk of mortality and morbidity due to micro metastatic spread at the time of diagnosis. Accurate biomarkers to guide treatment determination and evaluate response are needed. Previous studies using tumor informed ct-DNA have shown that MRD assessment may be informative in these scenarios. Methods: We conducted a retrospective multicenter analysis of real-world data obtained from commercial testing (Signatera; Natera, Inc.). This cohort of MIBC patients included those who underwent radical cystectomy with a minimum follow up of 90 days. Data were collected on patient demographics, clinical and pathological staging, histologic type, and treatments. Correlation of ct-DNA status with clinical outcomes was analyzed using Cox-regression analysis to evaluate utility of the assay for detecting residual disease post-surgery and radiological recurrence. Results: A total of 109 patients with 545 plasma samples were identified that fit the inclusion criteria. The majority of the patients [79, 72.5%] were male, with a median age of 70 (range: 32-88) years. Most patients had pure urothelial carcinoma [73.4%, 80/109]. Median follow-up was 13.63 (range: 3-89.04) months. On analyzing the first time point post-surgery (median 54 days), 91.55% (65/71) of ct-DNA negative patients at the first post-surgical test remained recurrence free while 65.79% (25/38) of positive patients had recurred at data cut-off. Therefore, ct-DNA positivity at the first post-surgical timepoint was associated with shorter disease-free survival (DFS) (HR=9.9, 95%CI: 4.1-24%, p&lt;0.001). ct-DNA detected imaging recurrence with a median lead time of 61 days (range: 12-381). Similarly, on analyzing ct-DNA positivity at any time post-surgery, of those who remained ct-DNA negative (N=63), 96.83% (61/63) showed no evidence of recurrent disease. On the other hand, 63.04% (29/46) of pts with ct-DNA positivity at any time after cystectomy recurred and experienced reduced DFS (HR=25, 95%CI: 5.9-103%, p&lt;0.001). The assay’s sensitivity for predicting radiological recurrence at any time post-surgery was 93.55%. Notably, in the multivariate analysis, anytime ct-DNA positivity after cystectomy was found to be the only significant risk factor associated with shorter DFS (HR=23.07, 95%CI: 5.1-104.4, p&lt;0.001). Conclusions: In this initial analysis of real-world data, MRD detection via tumor-informed ct-DNA testing was highly prognostic of patient outcomes post-surgery and may guide adjuvant treatment decisions. Future studies in this setting will explore the utility of ct-DNA testing as a predictive biomarker in response to systemic therapy.

Association of CD47 Expression with Clinicopathologic Characteristics and Survival Outcomes in Muscle Invasive Bladder Cancer.

CD47 is an antiphagocytic molecule that plays a critical role in immune surveillance. A variety of malignancies have been shown to evade the immune system by increasing the expression of CD47 on the cell surface. As a result, anti-CD47 therapy is under clinical investigation for a subset of these tumors. Interestingly, CD47 overexpression is associated with negative clinical outcomes in lung and gastric cancers; however, the expression and functional significance of CD47 in bladder cancer is not fully understood. We retrospectively studied patients with muscle invasion bladder cancer (MIBC) who underwent a transurethral resection of bladder tumor (TURBT) and subsequently underwent radical cystectomy (RC) with or without neoadjuvant chemotherapy (NAC). CD47 expression was examined by IHC in both TURBT and matched RC specimens. The difference in CD47 expression levels between TURBT and RC was also compared. The association of CD47 levels (TURBT) with clinicopathological parameters and survival outcomes was evaluated by Pearson's chi-squared tests and the Kaplan-Meier method, respectively. A total of 87 MIBC patients were included. The median age was 66 (39-84) years. Most patients were Caucasian (95%), male (79%), and aged >60 (63%) and most often (75%) underwent NAC prior to RC. Of those who received NAC, 35.6% were responders and 64.4% were non-responders. The final reported stages as per AJCC for all patients were as follows: stage 0 (32%), stage 1 (1%), stage 2 (20%), stage 3 (43%), and stage 4a (5%). A total of 60% of patients were alive; of those, 30% had disease recurrence and 40% died from bladder cancer at a median follow-up of 3.1 (0.2-14.2) years. CD47 levels were detectable in 38 (44%) TURBT samples. There was no association between CD47 levels and clinicopathological parameters such as age, gender, race, NAC, final stage, disease recurrence, and overall survival (OS). Patients aged >60 (p = 0.006), non-responders (p = 0.002), and at stage ≥ 3 (p < 0.001) were associated with worse OS by a univariate analysis and stage ≥ 3 remained significant even after a multivariate analysis. In patients managed with NAC, there were decreased CD47 levels in RC specimens compared to the TURBT specimens, but this did not reach statistical significance. CD47 expression was not a predictive nor prognostic marker for MIBC patients. However, expression of CD47 was detected in nearly half of MIBCs, and future studies are needed to explore the potential role of anti-CD47 therapy in these patients. Furthermore, there was a slight positive trend in decreased CD47 levels (from TURBT to RC) in patients receiving NAC. As a result, more research is needed to understand how NAC may modify immune surveillance mechanisms in MIBC.

The potential crosstalk between tumor and plasma cells and its association with clinical outcome and immunotherapy response in bladder cancer

BackgroundAlthough immunotherapy is effective in improving the clinical outcomes of patients with bladder cancer (BC), it is only effective in a small percentage of patients. Intercellular crosstalk in the tumor microenvironment strongly influences patient response to immunotherapy, while the crosstalk patterns of plasma cells (PCs) as endogenous antibody-producing cells remain unknown. Here, we aimed to explore the heterogeneity of PCs and their potential crosstalk patterns with BC tumor cells.MethodsCrosstalk patterns between PCs and tumor cells were revealed by performing integrated bulk and single-cell RNA sequencing (RNA-seq) and spatial transcriptome data analysis. A risk model was constructed based on ligand/receptor to quantify crosstalk patterns by stepwise regression Cox analysis.ResultsBased on cell infiltration scores inferred from bulk RNA-seq data (n = 728), we found that high infiltration of PCs was associated with better overall survival (OS) and response to immunotherapy in BC. Further single-cell transcriptome analysis (n = 8; 41,894 filtered cells) identified two dominant types of PCs, IgG1 and IgA1 PCs. Signal transduction from tumor cells of specific states (stress-like and hypoxia-like tumor cells) to PCs, for example, via the LAMB3/CD44 and ANGPTL4/SDC1 ligand/receptor pairs, was validated by spatial transcriptome analysis and associated with poorer OS as well as nonresponse to immunotherapy. More importantly, a ligand/receptor pair-based risk model was constructed and showed excellent performance in predicting patient survival and immunotherapy response.ConclusionsPCs are an important component of the tumor microenvironment, and their crosstalk with tumor cells influences clinical outcomes and response to immunotherapies in BC patients.Graphical

OC-0432 Patterns of Recurrence & Outcomes in Bladder Cancer Treated with Radiotherapy & Radiosensitisation

OC-0432 Patterns of Recurrence & Outcomes in Bladder Cancer Treated with Radiotherapy & Radiosensitisation

Abstract 6675: Integration of associations of immune profiles in peripheral blood and tumor microenvironment with bladder cancer outcomes

Abstract Immune cell profiles in peripheral blood have been associated with bladder cancer outcomes, however, their association with response to immunotherapy and the tumor microenvironment is a major unresolved issue. Although tumor growth can be attenuated via the activation of tumor-infiltrating effector T cells, the relationship between tumor infiltration and immune activation remains unclear. This study explored the interaction between bladder cancer outcomes and immune profiles within peripheral blood and a tumor microenvironment (TME) based on DNA methylation profiles. Peripheral blood and the matched tumor FFPE DNA methylation profiles of 60 non-muscle-invasive bladder cancer (NMIBC) and 12 muscle-invasive bladder cancer (MIBC) patients. Cell-type deconvolution approaches were applied to estimate 12 peripheral immune cell-type proportions and 17 cell-type proportions within TME. We found a positive correlation between dendritic cell proportions in the TME with peripheral CD8T memory cell proportions (r = 0.35, P = 0.003) and a negative correlation between dendritic cell proportions in the TME with peripheral regulatory T cell proportions (r = -0.28, P = 0.021). In addition, monocyte cell proportions in TME had a positive correlation with peripheral B memory (r = 0.37, P = 0.002) and CD8T memory cell proportions (r = 0.43, P = 0.0002). To investigate associations of bladder cancer outcomes with immune cell profiles, using Cox proportional hazard models, we observed an association between the fraction of dendritic cells and the hazard of death (HR = 1.27, 95% CI = 1.06-1.53). Further, a high endothelial cell proportion was significantly associated with an increased hazard of death and tumor recurrence (HR = 1.06, 95% CI = 1.01-1.13) in TME. In addition, the peripheral neutrophil-to-lymphocyte ratio (HR = 1.49, 95% CI = 1.01-2.22), monocyte (HR = 1.17, 95% CI = 1.05-1.31), neutrophil (HR = 1.04, 95% CI = 1.01-1.07), and basophil (HR = 1.35, 95% CI = 1.01-1.81) cell proportions were associated with an increased hazard of death and tumor recurrence. Our results integrated the information on bladder cancer outcomes and cell profiles in TME and peripheral blood, providing biomarkers for estimating bladder cancer prognosis using genome-scale DNA methylation measures. Citation Format: Ji-Qing Chen, Lucas A. Salas, John K. Wiencke, Devin C. Koestler, Annette M. Molinaro, Angeline S. Andrew, John D. Seigne, Margaret R. Karagas, Karl T. Kelsey, Brock C. Christensen. Integration of associations of immune profiles in peripheral blood and tumor microenvironment with bladder cancer outcomes. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6675.

Prolonged Opioid Use Following Bladder Tumor Resection for Opioid-Naïve Patients.

Bladder cancer patients represent a high-risk group for opioid dependence due to the frequency of surgical procedures. Using MarketScan insurance commercial claims (CC) and Medicare-eligible (ME) databases, we sought to identify whether filling an opioid prescription following initial TURBT resulted in increased odds of prolonged opioid use. We analyzed 43,741 CC and 45,828 ME opioid-naïve patients with a new diagnosis of bladder cancer from 2009 to 2019. Multivariable analyses were completed to assess the odds of prolonged opioid use at 3-6 months based on initial exposure to opioids and initial opioid dose quartile. We performed subgroup analyses by sex and eventual treatment modality. Those who filled an opioid prescription following initial TURBT had greater odds of persistent opioid use (CC: 27% vs 12%, OR 2.14, 95% CI (1.84-2.45), ME: 24% vs 12%, OR 1.95, 95% CI (1.70-2.22). Increasing dosage quartile of opioids was associated with increased odds of prolonged opioid use. Those going on to radical therapy had the highest rates of an initial opioid prescription (31% (CC) and 23% (ME)). Men and women had similar rates of initial prescriptions, but female sex was associated with higher odds of persistent opioid use at 3-6 months in the ME group: OR 1.08, 95% CI (1.01-1.16). Opioids following initial TURBT increase the odds of continued use at 3-6 months, with the greatest odds in those prescribed the highest initial doses. These data suggest that short-term prescriptions have long-term effects, and additional research on opioid use and bladder cancer outcomes is merited.

Abstract 6145: Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis

Abstract Killer lymphocyte-mediated tumor cell killing is a vital and final step of anti-tumor protective immunity. Killer cells, including cytotoxic CD8 T cells and Natural Killer (NK) cells, deliver granzymes (Gzm) into target cells, which normally activates noninflammatory cell death, but becomes inflammatory when target cells express the gasdermin (GSDM) proteins responsible for pyroptosis. GzmA and GzmB cleave and activate GSDMB and GSDME, respectively. However, the role of GSDMB in anti-tumor immunity is unclear - GSDMB pore formation is controversial and GSDMB expression has been linked to both anti- and pro-tumor functions. Here we found that GSDMB splicing variants are functionally distinct. Cleaved N-terminal (NT) fragments of isoforms 3 and 4 caused pyroptosis, but isoforms 1, 2 and 5, which deleted or modified exon 6, did not. Structural analysis based on AlphaFold predictions and the cryoEM structures of GSDMA3 and GSDMD showed that pore formation required the formation of a functional stabilizing belt structural element near the C-terminus of the cleaved N-terminal fragment, which was disrupted in the non-cytotoxic alternatively spliced isoforms. NK attack of GSDMB3-expressing cells caused pyroptosis, but GSDMB4 cells died mostly by apoptosis, and GSDMB1/2 cells died only by apoptosis. GSDMB4 partially resisted NK cell-triggered cleavage, suggesting that only GSDMB3 is fully functional. GSDMB1-3 were the most abundant isoforms in tested cells and were similarly induced by IFNγ and a chemotherapy drug methotrexate. Expression of cytotoxic GSDMB3/4, but not GSDMB1/2, was associated with better outcome in bladder and cervical cancer, suggesting GSDMB-mediated pyroptosis was protective in those tumors. Our study uncovers a novel role of alternative splicing in modulating caner-associated pyroptosis, and suggests that tumors may manipulate GSDMB splicing to avoid pyroptosis. Thus, modulating GSDMB splicing to increase cytotoxic GSDMB variants but suppress non-cytotoxic GSDMB isoforms could improve anti-tumor immunity and have therapeutic utility. Citation Format: Qing Kong, Shiyu Xia, Xingxin Pan, Kaixiong Ye, Zhouyihan Li, Haoyan Li, Nidhi Sahni, S. Stephen Yi, Xing Liu, Hao Wu, Judy Lieberman, Zhibin Zhang. Alternative splicing of GSDMB modulates killer lymphocyte-triggered pyroptosis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6145.

MP22-02 THE IMPACT OF RURAL RESIDENCY ON THE TREATMENT AND OUTCOMES OF LOCALLY INVASIVE/ADVANCED BLADDER CANCER IN LOUISIANA

You have accessJournal of UrologyCME1 Apr 2023MP22-02 THE IMPACT OF RURAL RESIDENCY ON THE TREATMENT AND OUTCOMES OF LOCALLY INVASIVE/ADVANCED BLADDER CANCER IN LOUISIANA Megan Escott, Tingting Li, Mei-Chin Hsieh, Scott Delacroix, Jessie Gills, Xiao-Cheng Wu, and Mary Westerman Megan EscottMegan Escott More articles by this author , Tingting LiTingting Li More articles by this author , Mei-Chin HsiehMei-Chin Hsieh More articles by this author , Scott DelacroixScott Delacroix More articles by this author , Jessie GillsJessie Gills More articles by this author , Xiao-Cheng WuXiao-Cheng Wu More articles by this author , and Mary WestermanMary Westerman More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003247.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: A later stage at diagnosis, gender, and race are independent predictors of bladder cancer-specific survival. There remains a need, however, to investigate additional contributors. We investigated the effect of urban and rural residency on a patient’s likelihood to receive standard of care in Louisiana and its impact on cancer-specific and overall survival. METHODS: Using the Louisiana Tumor Registry, we identified microscopically confirmed AJCC stage II – III bladder cancer diagnoses between 2014 and 2018. Multivariable logistic regression, Kaplan-Meier method, and Multivariate Cox proportional hazard analysis was performed. RESULTS: We identified 704 patients, with 75% having AJCC stage two disease. 598 (85%) patients lived in urban settings and 106 (15%) patients lived in rural settings. After controlling for race, socioeconomic status, and insurance coverage, there was no significant difference in the probability of urban and rural residents receiving the standard of care for definitive management. However, rural residency was independently associated with an increased risk of cancer-specific mortality (Figure 1). The median overall survival for residents of urban areas was 27 months (95% CI [23, 33]) compared to 13 months (95% CI [10, 20]) for residents of rural areas (Figure 2). CONCLUSIONS: A recent study using national census data called for further epidemiologic investigations after finding that patients with bladder cancer who lived in rural areas had significantly higher overall mortality and marginally increased cancer-specific mortality. Despite all Louisiana residents receiving the standard of care for definitive management of locally invasive bladder cancer, rural patients still had increased risks of cancer-specific and overall mortality after controlling for several demographic factors, only highlighting the need for continued investigation into disparities in bladder cancer outcomes. Source of Funding: NCI’s Surveillance, Epidemiology, End Result (SEER): HHSN261201800007I/HHSN26100002. CDC’s National Program Cancer Registries (NPCR): NU58DP006332 © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e295 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Megan Escott More articles by this author Tingting Li More articles by this author Mei-Chin Hsieh More articles by this author Scott Delacroix More articles by this author Jessie Gills More articles by this author Xiao-Cheng Wu More articles by this author Mary Westerman More articles by this author Expand All Advertisement PDF downloadLoading ...

The Impact of Blue Light Cystoscopy Use Among Nonmuscle Invasive Bladder Cancer Patients in an Equal Access Setting: Implications on Recurrence and Time to Recurrence

IntroductionPrior studies suggest that white light cystoscopy (WLC) alone can fail to detect cases of non-muscle invasive bladder cancer (NMIBC) vs. blue light cystoscopy (BLC). We describe bladder cancer outcomes and the impact of BLC among NMIBC patients in an equal access setting. Materials and MethodsWe assessed 378 NMIBC patients within the Veterans Affairs system that had a CPT code for BLC from December 1, 2014 to December 31, 2020. We determined recurrence rates and time to recurrence prior to BLC (ie, after previous WLC if available) and following BLC. We used the Kaplan-Meier method to estimate event-free survival and Cox regression to determine association between BLC and recurrence, progression, and overall survival; and further, whether these outcomes differed by race. ResultsOf 378 patients with complete data, 43 (11%) were Black and 300 (79%) White. Median follow-up was 40.7 months from bladder cancer diagnosis. Median time to first recurrence following BLC was longer vs. WLC alone (40 [33-NE] vs. 26 [17-39] months). Recurrence risk was significantly lower following BLC (Hazard Ratio [HR] 0.70; 95% Confidence Interval [CI], 0.54-0.90). There was no significant difference in recurrence (HR 0.69; 95% CI, 0.39-1.20), progression (HR 1.13; 95% CI, 0.32-3.96), and overall survival (HR 0.74; 95% CI, 0.31-1.77) following BLC by Black vs. White race. ConclusionIn this study from an equal access setting in the VA, we observed significantly decreased recurrence risk and prolonged time interval to recurrence following BLC vs. WLC alone. There was no difference in bladder cancer outcomes by race.

PD36-09 TIME TRENDS IN SYSTEMIC TREATMENTS AND SURVIVAL IN PATIENTS WITH METASTATIC UROTHELIAL BLADDER CANCER: OUTCOMES IN THE ERA OF IMMUNOTHERAPY

You have accessJournal of UrologyCME1 Apr 2023PD36-09 TIME TRENDS IN SYSTEMIC TREATMENTS AND SURVIVAL IN PATIENTS WITH METASTATIC UROTHELIAL BLADDER CANCER: OUTCOMES IN THE ERA OF IMMUNOTHERAPY Harshit Garg, Mukund Bhandari, Monica Sridhar, Onika Noel, Furkan Dursun, Michael Liss, Dharam Kaushik, Robert Svatek, Chethan Ramamurthy, and Ahmed Mansour Harshit GargHarshit Garg More articles by this author , Mukund BhandariMukund Bhandari More articles by this author , Monica SridharMonica Sridhar More articles by this author , Onika NoelOnika Noel More articles by this author , Furkan DursunFurkan Dursun More articles by this author , Michael LissMichael Liss More articles by this author , Dharam KaushikDharam Kaushik More articles by this author , Robert SvatekRobert Svatek More articles by this author , Chethan RamamurthyChethan Ramamurthy More articles by this author , and Ahmed MansourAhmed Mansour More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003334.09AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: The management of metastatic urothelial carcinoma of the urinary bladder has been revolutionized with the advent of immune-checkpoint inhibitors (ICI). However, the survival outcomes in metastatic bladder cancer over the past decade with improvements in systemic therapies have not been studied. The aim of the study is to investigate the time trends in treatment strategies and overall survival (OS) in patients with metastatic urothelial cancer of the bladder. METHODS: Using the recently updated National Cancer Database, patients with newly diagnosed metastatic urothelial cancer of the urinary bladder between 2014-2019 were included. We analyzed changes in the first-line systemic treatment and the changes in the 1-year OS using cox multivariable regression and Kaplan Meier analysis. The OS analysis was censored at 1-year to account for possible bias due to shorter follow-up in most recent years. RESULTS: Overall, 10,965 patients met the inclusion criteria with 9,229 receiving systemic chemotherapy and 1,666 patients receiving systemic immunotherapy. The use of immunotherapy increased from 2.3% (9/391) in 2007 to 36.5% (484/1325) to 2019 (p<0.001) and the use of systemic chemotherapy decreased from 98.2% (270/275) in 2004 to 63.5% (841/1325) in 2019 (p<0.001). (Figure 1a). The median and 1-year OS of the entire cohort increased from 9.9 months and 38.6% in 2004 to 12.5 months and 50.8% in 2018 respectively (p<0.001) (Figure 1b). From 2009 to 2018, the 1-y OS improved gradually from 38.3% to 53.6% in systemic chemotherapy and 44.4% to 46.3% in the systemic immunotherapy group. (Figure 1c) The improvement in systemic chemotherapy arm could be potentially attributed to increased use of second line immunotherapy in this cohort. CONCLUSIONS: The use of immunotherapy as first-line therapy has substantially increased over the past years. The median OS in metastatic bladder cancer has also improved over the past 15 years, possibly because of the advent of immune-checkpoint therapy. Source of Funding: None © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e983 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Harshit Garg More articles by this author Mukund Bhandari More articles by this author Monica Sridhar More articles by this author Onika Noel More articles by this author Furkan Dursun More articles by this author Michael Liss More articles by this author Dharam Kaushik More articles by this author Robert Svatek More articles by this author Chethan Ramamurthy More articles by this author Ahmed Mansour More articles by this author Expand All Advertisement PDF downloadLoading ...