Bladder Cancer Outcomes Research Articles

Mevalonate pathway inhibition reduces bladder cancer metastasis by modulating RhoB protein stability and integrin β1 localization

The progression and outcome of bladder cancer (BLCA) are critically affected by the propensity of tumor metastasis. Our previous study revealed that activation of the mevalonate (MVA) pathway promoted migration of BLCA cells; however, the exact mechanism is unclear. Here we show that elevated expression of MVA pathway enzymes in BLCA cells, correlating with poorer patient prognosis by analyzing single-cell and bulk-transcriptomic datasets. Inhibition of the MVA pathway, either through knockdown of farnesyl diphosphate synthase (FDPS) or using inhibitors such as zoledronic acid or simvastatin, led to a marked reduction in BLCA cell migration. Notably, this effect was reversed by administering geranylgeranyl pyrophosphate (GGPP), not farnesyl pyrophosphate (FPP) or cholesterol, indicating the specificity of geranylgeranylation for cell motility. Moreover, we found that RhoB, a Rho GTPase family member, was identified as a key effector of the impact of the MVA pathway on BLCA metastasis. The post-translational modification of RhoB by GGPP-mediated geranylgeranylation influenced its protein stability through the ubiquitin-proteasome pathway. Additionally, overexpression of RhoB was found to block the membrane translocation of integrin β1 in BLCA cells. In summary, our findings underscore the role of the MVA pathway in BLCA metastasis, providing insights into potential therapeutic targets of this malignancy.

Clinical and Pathological Characteristics of Bladder Cancer in Patients Aged 18–45 Undergoing Transurethral Resection of Bladder Tumor

Background and Objectives: Bladder cancer in patients under 45 is poorly characterized and rarely described, with variabilities in clinical outcomes and tumor properties. Our study aimed to elucidate the clinical and pathological features and outcomes of bladder cancer in this younger demographic to better inform management strategies. Materials and Methods: We conducted a retrospective analysis at the Urology Department of “Pius Brînzeu” County Emergency Clinical Hospital in Timișoara, Romania, on 60 patients aged 18–45 who underwent transurethral resection of bladder tumor (TURBT) during a 9-year period. Results: The cohort had a mean age of 38.5 ± 5.6 years with a male predominance (70%). Most tumors were non-muscle-invasive (NMIBC; 80%), with 16.7% being papillary urothelial neoplasms of low malignant potential (PUNLMP), 50% stage pTa, and 30% stage pT1. High-grade tumors were present in 43.3% of the patients. Recurrence occurred in 40% of the patients, while progression was observed in 16.7%. The 3-year overall survival rate was 93.3%, and the progression-free survival rate was 83.3%. Patients with high-grade tumors had a significantly higher recurrence rate (61.5% vs. 23.5%, p = 0.003) and lower survival rates compared to those with low-grade tumors. Conclusions: Young patients predominantly present with low-to-intermediate-stage tumors, yet a significant portion exhibit high-grade tumors associated with poorer outcomes. These findings suggest that while bladder cancer in younger patients tends to be less invasive, aggressive follow-up and treatment are crucial in those with high-grade tumors.

Understanding the long‐term impact of the COVID‐19 pandemic on non‐muscle‐invasive bladder cancer outcomes: 12‐Month follow‐up data from the international, prospective COVIDSurg Cancer study

AbstractObjectiveThe objective of this study was to report the 12‐month oncological outcomes for patients with non‐muscle‐invasive bladder cancer (NMIBC) within the prospective, international COVIDSurg Cancer study.Patients and methodsEligible patients were aged ≥18 years and scheduled for elective surgical management of NMIBC with curative intent (transurethral resection of bladder tumour [TURBT] or bladder biopsy) from 21 January to 14 April 2020. The primary outcome was disease recurrence within 12 months of previous elective TURBT/bladder biopsy. Secondary outcomes included disease progression within 12 months of previous elective TURBT/bladder biopsy, site‐declared delay to surgery from diagnosis as a consequence of COVID‐19 and deviation in standard care due to COVID‐19. Comparisons were made to cohorts from the pre‐pandemic era.ResultsBladder cancer accounted for 2.2% (n = 446) of patients in the COVIDSurg Cancer study, with data contributed by 27 centres across 12 countries internationally. Within this included cohort, 229 patients had NMIBC and 12‐month follow‐up data available. On application of National Institute for Health and Care Excellence (NICE) criteria, 47.2% were classified as having high‐risk disease. Overall disease recurrence and progression rates were 29.3% and 9.7% at 12 months, respectively. In purely high‐risk pre‐pandemic cohorts, the International Bladder Cancer Group (IBCG) estimates a recurrence rate of 25% at 12 months, and the European Association of Urology (EAU) NMIBC 2021 scoring model estimates a 12‐month progression rate of 3.5%. As a consequence of the COVID‐19 pandemic, 10.9% of patients had site‐declared delay to TURBT/bladder biopsy; 7.4% did not undergo intravesical therapy or had early discontinuation of this; 9.2% did not undergo early repeat resection for high‐risk disease; and 18.3% had a delay to cystoscopic follow‐up surveillance.ConclusionsThis prospective study indicates that there were widespread deviations in usual care for NMIBC during the pandemic and that 12‐month oncological outcomes appear to be impaired compared to published pre‐pandemic outcomes.

Leveraging programmed cell death signature to predict clinical outcome and immunotherapy benefits in postoperative bladder cancer

Bladder cancer is the fourth most common malignancy in men with poor prognosis. Programmed cell death (PCD) exerts crucial functions in many biological processes and immunotherapy responses of cancers. Cell death signature (CDS) is novel gene signature comprehensively considering the characteristics of 15 patterns of programmed cell death, which could affect the prognosis and immunotherapy benefits of cancer patients. Integrative machine learning procedure including 10 algorithms was conducted to construct a prognostic CDS using TCGA, GSE13507, GSE31684, GSE32984 and GSE48276 datasets. Immunophenoscore, intratumor heterogeneity (ITH), tumor immune dysfunction and exclusion (TIDE) score and five immunotherapy cohorts were used to evaluate the predictive value of CDS in immunotherapy response. The prognostic CDS constructed by StepCox[backward] + Ridge algorithms was regarded as the optimal prognostic model. The CDS had a stable and powerful performance in predicting overall survival of bladder cancer patients with the AUCs at 3-year, 5-year, and 7-year ROC of 0.740, 0.763 and 0.820 in TCGA cohort. Moreover, CDS score acted as an independent risk factor for overall survival rate of bladder cancer patients. Low CDS score had a higher abundance of immuno-activated cells, higher PD1&CTLA4 immunophenoscore, higher TMB score, lower TIDE score, lower immune escape score, lower ITH score, lower cancer-related hallmarks score in bladder cancer. The CDS score was higher in non-responders in pan-cancer patients receiving immunotherapy. Our study constructed a novel prognostic CDS, which could serve as an indicator for predicting the prognosis in postoperative bladder cancer cases and immunotherapy benefits in pan-cancer. Low CDS score indicated a better prognosis and immunotherapy benefits.

Construction and Validation of a Prognostic Model Based on Pyroptosis-related Genes in Bladder Cancer.

Bladder cancer (BCa) is a highly prevalent disease with a poor prognosis. There is no better forecasting method for it yet. Current studies demonstrate that pyroptosis is involved in the development and progression of various cancers. This study employed bioinformatics techniques to analyze the data of BCa patients obtained from the TCGA and GEO databases in order to construct a prognostic risk model. The TCGA dataset was used for the training set, and the multiple external datasets (including GSE13507, GSE31684, GSE48075, IMvigor210, and GSE32894) were applied as the validation sets. Prognostic-associated pyroptosis genes screened by univariate Cox regression analysis were utilized to construct the lasso Cox regression model. GO and KEGG analysis results identified the selected genes that are primarily involved in the inflammation and cell death processes. The related patients were grouped into low- and high-risk groups. Kaplan-Meier survival analysis was performed to compare survival differences between the risk groups. The accuracy of this risk prediction model was assessed by ROC. We also applied the Human Protein Atlas (HPA) to detect the protein expression of these genes. Subsequently, qRT-PCR was performed to verify the expression of these model genes. There are 29 pyroptosis-related genes with significant expression differences between BCa and corresponding adjacent tissues, and 11 genes (SH2D2A, CHMP4C, MRFAP1L1, GBP2, EHBP1, RAD9A, ANXA1, TMEM109, HEYL, APOL2, ORMDL1) were picked by univariate and LASSO Cox regression analysis. Immunological cell infiltration and ssGSEA results further indicated that the low and high-risk groups were substantially correlated with the immune status of BCa patients. According to TCGA and multiple external datasets, Kaplan-Meier survival curves showed the overall survival rate of the high-risk group to be decreased. ROC curves showed the model established to be accurate and reliable. Moreover, the HPA database also demonstrated the verification of the modeled genes' expression in BCa and normal bladder tissue using the HPA database. qRT-PCR results also suggested the up-regulated EHBP1 and down-regulated RAD9A mRNA expression levels to be confirmed in 15 pairs of BCa and corresponding adjacent tissues. This study presents the development and validation of a novel gene signature associated with pyroptosis, which holds the potential for predicting patient outcomes in BCa and providing insights into the immune microenvironment of BCa.

Association between time to treatment and bladder cancer survival: a population-based analysis.

Cancer treatment delay is a global health system issue. However, data concerning the impact of treatment delays on survival in bladder cancer remain controversial. This study sought to evaluate the impact of time from diagnosis to treatment on survival outcomes of bladder cancer patients in the US Surveillance, Epidemiology, and End Results (SEER) database. The SEER was searched from 2000 to 2020 for bladder cancer patients. Logistical regression was used to explore potential factors related to treatment delay. Kaplan-Meier curves were generated to investigate the overall and cancer-specific survival. Multivariate Cox proportional hazards regression models were used to evaluate the effects of covariables on survival outcomes in bladder cancer with treatment delay. There were 12,686 eligible patients included in this study. A total of 2,379 patients experienced an initial treatment delay. Initial treatment delay was related to worse survival. Sex, age, pathological grade, clinical stage, and surgery were associated with increased odds of initial treatment delay. In the patients with initial treatment delay, age, advanced stage, lymph node involvement, high pathological grades and metastasis were independent predictors of poor overall survival and cancer-specific survival, while marital status at diagnosis, surgery, chemotherapy, and radiotherapy were found to improve both overall survival and cancer-specific survival. Significant disparities in pathological/clinical variables could contribute to treatment delay. Surgery, chemotherapy, and radiotherapy benefited the survival of patients with treatment delays.

APOL6 predicts immunotherapy efficacy of bladder cancer by ferroptosis

BackgroundImmune checkpoint inhibitors (ICIs) are rapidly evolving in the management of bladder cancer (BLCA). Nevertheless, effective biomarkers for predicting immunotherapeutic outcomes in BLCA are still insufficient. Ferroptosis, a form of immunogenic cell death, has been found to enhance patient sensitivity to ICIs. However, the underlying mechanisms of ferroptosis in promoting immunotherapy efficacy in BLCA remain obscure.MethodsOur analysis of The Cancer Genome Atlas (TCGA) mRNA data using single sample Gene Set Enrichment Analysis (ssGSEA) revealed two immunologically distinct subtypes. Based on these subtypes and various other public cohorts, we identified Apolipoprotein L6 (APOL6) as a biomarker predicting the efficacy of ICIs and explored its immunological correlation and predictive value for treatment. Furthermore, the role of APOL6 in promoting ferroptosis and its mechanism in regulating this process were experimentally validated.ResultsThe results indicate that APOL6 has significant immunological relevance and is indicative of immunologically hot tumors in BLCA and many other cancers. APOL6, interacting with acyl-coenzyme A synthetase long-chain family member 4 (ACSL4), mediates immunotherapy efficacy by ferroptosis. Additionally, APOL6 is regulated by signal transducer and activator of transcription 1 (STAT1).ConclusionsTo conclude, our findings indicate APOL6 has potential as a predictive biomarker for immunotherapy treatment success estimation and reveal the STAT1/APOL6/GPX4 axis as a critical regulatory mechanism in BLCA.

Perceptions and Expectations: A Study on Prognostic Perception and Quality of Life in Patients With Metastatic Renal and Bladder Cancer.

Durable complete response rates for metastatic renal cell carcinoma (mRCC) and metastatic bladder cancer (mBC) are low despite new therapy. Palliative care focuses on life extension and quality of life (QoL), not cure. This study aims to investigate patients' perceptions of treatment outcomes in mRCC and mBC and to assess the influence of QoL and optimism levels on these perceptions. From March 15, 2023, to January 15, 2024, a multicenter, cross-sectional online survey was carried out, targeting patients diagnosed with mRCC and mBC. The survey comprised structured questions aimed at evaluating perceptions concerning disease cure, symptom improvement, daily activity performance, and life extension due to treatment. Additionally, to evaluate optimism and QoL, the European Organization for Research and Treatment of Cancer 30.3 QoL questionnaire and life orientation test were implemented. Study on patients' perceptions of treatment outcomes in metastatic kidney and bladder cancer shows high optimism, inaccurate cure beliefs. In total, 169 patients participated in the survey; the majority of the patients stated their general health status as good (72.2%) and excellent (13.6%). Patients who rated their overall health status as good-excellent had a higher median general QoL and optimism score compared with those who rated it as fair-poor. In all, 85.2% of patients considered the possibility of a cure very likely or likely. Most participants believed treatment could provide symptom relief (30.2% very likely, 49.1% likely), enhanced ability to perform daily activities (28.4% very likely, 55.6% likely), and life extension (32.5% very likely, 53.3% likely). Patients responding very likely and likely to these questions regarding treatment outcomes had higher QoL and optimism scores than those responding a little likely and not possible. The majority of patients with mRCC and mBC held inaccurate beliefs about treatment outcomes. Better QoL and optimism were associated with increased inaccuracy.

NAD+ metabolism enzyme NNMT in cancer-associated fibroblasts drives tumor progression and resistance to immunotherapy by modulating macrophages in urothelial bladder cancer

BackgroundThis study comprehensively investigates the association between the expression of nicotinamide N-methyltransferase (NNMT) and clinical outcomes of urothelial bladder cancer (UBC), as well as the molecular mechanisms by which NNMT...

The role of VI-RADS scoring criteria for predicting oncological outcomes in bladder cancer

PurposeOur purpose was to evaluate the prognostic value of Vesical Imaging Reporting and Data System (VI-RADS) in bladder cancer (BCa) staging and predicting recurrence or progression.MethodsWe retrospectively analyzed the prospectively collected data from 96 patients with bladder tumors who underwent VI-RADS-based multiparametric magnetic resonance imaging (mpMRI) before endourological treatment from April 2021 to December 2022. Diagnostic performance was evaluated by comparing mpMRI reports with final pathology, using logistic regression for muscle-invasive bladder cancer (MIBC) predictors. Follow-up until May 2023 included Kaplan-Meier and Cox regression analysis to assess VI-RADS predictive roles for recurrence-free survival (RFS) and progression-free survival (PFS).ResultsA total of 96 patients (19.8% women, 80.2% men; median age 68.0 years) were included, with 71% having primary tumors and 29% recurrent BCa. Multiparametric MRI exhibited high sensitivity (92%) and specificity (79%) in predicting MIBC, showing no significant differences between primary and recurrent cancers (AUC: 0.96 vs. 0.92, P = .565). VI-RADS emerged as a key predictor for MIBC in both univariate (OR: 40.3, P < .001) and multivariate (OR: 54.6, P < .001) analyses. Primary tumors with VI-RADS ≥ 3 demonstrated significantly shorter RFS (P = .02) and PFS (P = .04).ConclusionsIn conclusion, mpMRI with VI-RADS has a high diagnostic value in predicting MIBC in both primary and recurrent BCa. A VI-RADS threshold ≥ 3 is a strong predictor for MIBC, and in primary tumors predicts early recurrence and progression.

Unveiling Bladder Cancer Prognostic Insights by Integrating Patient-Matched Sample and CpG Methylation Analysis.

Bladder cancer prognosis remains a pressing clinical challenge, necessitating the identification of novel biomarkers for precise survival prediction and improved quality of life outcomes. This study proposes a comprehensive strategy to uncover key prognostic biomarkers in bladder cancer using DNA methylation analysis and extreme survival pattern observations in matched pairs of cancer and adjacent normal cells. Unlike traditional approaches that overlook cancer heterogeneity by analyzing entire samples, our methodology leverages patient-matched samples to account for this variability. Specifically, DNA methylation profiles from adjacent normal bladder tissue and bladder cancer tissue collected from the same individuals were analyzed to pinpoint critical methylation changes specific to cancer cells while mitigating confounding effects from individual genetic differences. Utilizing differential threshold settings for methylation levels within cancer-associated pathways enabled the identification of biomarkers that significantly impact patient survival. Our analysis identified distinct survival patterns associated with specific CpG sites, underscoring these sites' pivotal roles in bladder cancer outcomes. By hypothesizing and testing the influence of methylation levels on survival, we pinpointed CpG biomarkers that profoundly affect the prognosis. Notably, CpG markers, such as cg16269144 (PRKCZ), cg16624272 (PTK2), cg11304234, and cg26534425 (IL18), exhibited critical methylation thresholds that correlate with patient mortality. This study emphasizes the importance of tailored approaches to enhancing prognostic accuracy and refining therapeutic strategies for bladder cancer patients. The identified biomarkers pave the way for personalized prognostication and targeted interventions, promising advancements in bladder cancer management and patient care.

Machine learning-based CT radiomics enhances bladder cancer staging predictions: A comparative study of clinical, radiomics, and combined models.

Predicting the accurate preoperative staging of bladder cancer (BLCA), which markedly affects treatment decisions and patient outcomes, using traditional clinical parameters is challenging. Nevertheless, emerging studies in radiomics, especially machine learning-based computed tomography (CT) image-based radiomics, hold promise in improving stage prediction accuracy in various tumors. However, the comparative performance and clinical utility of models for BLCA are under investigation. We aimed to investigate the application value of machine learning-based CT radiomics in preoperative staging prediction by comparing the performance of clinical, radiomics, and clinical-radiomics combined models. A retrospective cohort of 105 patients with initial BLCA was randomized into training (70%) and testing (30%) cohorts. Radiomics features were extracted from CT images using the optimal feature filter, followed by the application of the least absolute shrinkage and selection operator algorithm for optimum feature selection. Furthermore, machine learning algorithms were used to establish a radiomics model within the training cohort. Independent risk factors for muscle-invasive BLCA (MIBC) obtained by multivariate logistic regression (LR) analysis were separately used to construct a clinical model. For a clinical-radiomics fusion model, radiomics features were combined with clinical parameters. Performance was evaluated based on receiver operating characteristic curves, calibration curves, decision curve analysis (DCA), and standard performance metrics. Patients exhibited a significantly higher age (p=0.029), larger tumor size (p=0.01), and an increased neutrophil-to-lymphocyte ratio (NLR; p=0.045) in the MIBC group than in the NMIBC group. LR analysis revealed age (p=0.026), tumor size (p=0.007), and NLR (p=0.019) as significant predictors for constructing the clinical model. In the testing cohort, the radiomics model, which used an Support Vector Machine classifier, achieved the highest area under the curve (AUC) value of 0.857. The clinical-radiomics model outperformed the remaining two models, with AUC values of 0.958 and 0.893 in the training and testing cohorts, respectively. DeLong's test indicated significant differences between the three models. Calibration curves showed good agreement, and DCA confirmed the superior clinical utility of the clinical-radiomics model. Machine learning-based CT radiomics combined with clinical parameters was a promising approach in staging BLCA accurately, which outperformed the individual models. Integrating radiomics features with clinical information holds the potential to improve personalized treatment planning and patient outcomes in BLCA.

Machine learning developed an intratumor heterogeneity signature for predicting clinical outcome and immunotherapy benefit in bladder cancer.

Bladder cancer is a common malignancy with high invasion and poor clinical outcome. Intratumor heterogeneity (ITH) is linked to cancer progression and metastasis and high ITH can accelerate tumor evolution. Our objective is to develop an ITH-related signature (IRS) for predicting clinical outcome and immunotherapy benefit in bladder cancer. Integrative procedure containing ten machine learning methods was applied to develop an IRS with The Cancer Genome Atlas (TCGA), gene series expression (GSE)13507, GSE31684, GSE32984 and GSE48276 datasets. To evaluate the performance of IRS in predicting the immunotherapy benefit, we also used several predicting scores and three immunotherapy datasets, including GSE91061, GSE78220 and IMvigor210. The predicting model constructed with Enet (alpha =0.2) algorithm had a highest average C-index of 0.69, which was suggested as the optimal IRS. As an independent risk factor for bladder cancer, IRS had a powerful performance in predicting the overall survival (OS) rate of patients, with an area under curve of 1-, 3- and 5-year receiver operating characteristic (ROC) curve being 0.744, 0.791 and 0.816 in TCGA dataset. Bladder cancer patients with low IRS score presented with a higher level of immune-activated cells, cytolytic function and T cell co-stimulation. We also found a lower tumor immune dysfunction and exclusion (TIDE) score, lower immune escape score, higher programmed cell death protein 1 (PD-1) & cytotoxic T-lymphocyte associated protein 4 immunophenoscore, higher tumor mutation burden (TMB) score, higher response rate and better prognosis in bladder cancer with low IRS score. Bladder cancer cases with high IRS score had a higher half maximal inhibitory concentration value of common chemotherapy and targeted therapy regimens. The current study developed an optimal IRS for bladder cancer patients, which acted as an indicator for predicting prognosis, stratifying risk and guiding treatment for bladder cancer patients. Further analysis should be focused on the exploration the differentially expressed genes (DEGs) and related underlying mechanism mediating the development of bladder cancer in different IRS score group.

Evaluation of miRNA 130a-3P and miRNA 301a-3P in Egyptian patients with urinary bladder carcinoma

ObjectivesTo study the role of microRNA 130a-3p and microRNA 301a-3p in urinary bladder carcinoma. BackgroundDespite the discovery of several clinical and molecular indicators for predicting outcomes in bladder cancer, it is unclear how to use these indicators in clinical practice. A recent study revealed that the miR-130 family may play a vital role in the occurrence and development of BC by regulating signal pathways through various target genes. We intend to apply them as novel, nonintrusive, and easily detectable bladder cancer indicators. Subjects and methodsThe current study involved one hundred subjects. Fifty subjects had bladder cancer diagnosed by cystoscope biopsy and histopathological examination, and the other fifty were age- and gender-matched healthy adults serving as a control group. All participants were subjected to complete history taking through medical examination and estimation of expression levels of plasma miRNA 130a-3p by reverse transcriptase – polymerase chain reaction (RT-PCR) through quantitative real-time technique. ResultsmiRNA 130a-3p and miRNA 301a-3p were expressed at higher levels in the plasma of bladder cancer patients than in the controls. The points for the diagnostic capacities of miR 130a-3p and miR 301a-3p for bladder cancer were > 0.921 and > 1.32, respectively, indicating that they are potential clinical diagnostic biomarkers for bladder cancer with good sensitivity and specificity. Moreover, stage IIIA versus stage IIIB can be discriminated as >0.96 (miR 130a-3p) and > 2.48 (miR 301a-3p), which can be utilized for estimating the clinical prognosis of bladder cancer. ConclusionmiRNA 130a-3p and miRNA 301a-3p expression levels in plasma can differentiate bladder cancer patients from healthy controls and discriminate between stage IIIA and stage IIIB. This finding may facilitate the clinical diagnosis of bladder cancer.

A Multinational, Multi-Institutional Study Assessing the Impact of Diabetes Mellitus on the Prognosis of Patients with Non-Muscle Invasive Bladder Cancer Treated with Bacillus Calmette-Guérin

The study aimed to examine the impact of diabetes mellitus type 2 (DMII) on the oncological outcomes of non-muscle invasive bladder cancer (NMIBC) treated with Bacillus Calmette-Guérin (BCG) using comprehensive real-world data. We performed an analysis of data on NMIBC patients treated with BCG from the United States (US) National Phase II BCG/Interferon (IFN) trial database (125 centers) and pooled databases from three tertiary care institutions: France (FR), Lebanon (LB) (2000–2021), and the US (University of Iowa) (2011–2021). There were 867 patients from the Phase II trial, 1232 from the FR/LB cohort, and 233 from the US (Iowa) cohort (n = 2332). DM II was reported in 13% of the Phase II trial cohort, 14.4% of the FR/LB cohort, and 33.5% of the US (Iowa) cohort. The median follow-up was 24 months in the Phase II trial cohort, 25 months in the FR/LB cohort, and 48 months in the US (Iowa) cohort. In multivariable Cox regression analyses, DMII was not significantly associated with recurrence or progression of the tumor in any of the cohorts included in this study. DMII may not be a clinical prognostic factor for NMIBC patients treated with BCG. Prospective evaluation is needed.

Treatment and outcomes of bladder cancer in Armenia.

Treatment and outcomes of bladder cancer in Armenia.

Analyzing disparities in socioeconomic factors, clinical characteristics, and outcomes in bladder cancer: Insights from the National Cancer Database (NCDB).

4572 Background: Social determinants of health can influence mortality in bladder cancer. We sought to understand the trends and survival differences for urothelial cancer (UC) and non-urothelial cancer (nUC) based on demographic, socioeconomic, clinical, and treatment from the NCDB. Methods: Using the NCDB database with patient-level data extraction from 2004 to 2020, we sought to identify the socioeconomic differences, clinical characteristics and examine survival trends for both UC and nUC bladder cancer. Results: Majority of UC patients (pts) were M (555107, 75.6%) and 178733 were F; nUC pts had 14296 M and 8835 F, median age was 72 years. 669,669 (or 91.3%) of UC pts were White (W), 5.4% (39444) were Black (B) and nUC pts had 19771 (85.5%) W and 2492 (10.8%) B. 41.2% of UC pts were treated at a Comprehensive Community Cancer Program (CCCP) followed by 28.3% at an academic/research program (ARP) with 20.7% at an integrated network cancer program (INCP) compared to nUC pts at 37.5%, 34.3% and 19.2%, respectively. Most UC pts (65.6%) had Medicare followed by 26.9% with private insurance and 3.2% with Medicaid. Distribution of stage at diagnosis for UC pts were: Stage 0 at 36.9%, Stage I at 16.3%, Stage II &amp; III at 11.8% and Stage IV at 3.6%. While most (51.74%) of F UC pts had stage I, only 12.81% of F nUC had stage I. Majority had Charlson-Deyo Score (CDS) of 0 at 512237 (69.8%). Median Overall survival (mOS) in UC for M was 89.26 months (mos) (CI 88.8-89.76) and for F it was 94.88 mos (CI 93.83-95.93), Log-rank p=0.0011; worse for B = 73.03 mos (CI 71.03 – 74.84) vs W = 90.38 mos (CI 89.95-90.81), Log-rank p&lt;0.0001; mOS was highest for ARP at 96.46 mos (CI 95.54-97.45); CDS of 0 at 108.29 mos (CI 107.66-108.85); private insurance at 185.79 mos (CI 183.98-188.16); mOS for nUC was better for M at 15.64 (CI, 15.05 -16.28) vs F at 12.68 (CI, 12.02, 13.31), Log-rank p&lt;0.001. mOS for metastatic involvement for bone: UC: 5.03 (CI, 4.8, 5.39) vs nUC: 5.42 (4.4, 6.34), Log-rank p=0.2007; brain: U: 3.61 (CI 2.99, 4.3) vs nUC: 5.06 (2.5, 7.13); Log-rank p=0.5765; lung: U: 5.09 (CI, 4.76, 5.39) vs nUC: 4.8 (3.68, 5.78); Log-rank p=0.2163; liver: U: 3.32 (CI,3.06, 3.61) vs nUC: 5.42 (CI, 4.11, 6.44); Log-rank p=0.0009; LN: U: 7.1 (CI, 6.6, 7.56) vs nUC: 6.34 (5.36, 6.9); Logrank p=0.0007; Treatment using surgery, radiation, chemotherapy and immunotherapy all showed improvement in U vs nUC (all Log-rank p&lt;0.0001). Conclusions: Women had better survival than men in UC but not in nUC. Factors including lower stages, Whites, private insurance, better CDS scores, treatment at academic/research facility, and lymph node metastases all showed improved survival. These data highlight the importance of bridging the gap between socioeconomic differences to improve outcomes for UC and nUC pts.

Survival outcomes of small cell variant bladder cancer: Analysis from nationwide study.

Survival outcomes of small cell variant bladder cancer: Analysis from nationwide study.

Effectiveness of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin as compared to gemcitabine-based regimens as neoadjuvant chemotherapy for oncologic outcomes in muscle-invasive bladder cancer cases-Single-center study in Japan.

To compare the efficacy and safety of dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (dd-MVAC) with gemcitabine-based regimens for neoadjuvant chemotherapy (NAC) in muscle-invasive bladder cancer (MIBC) patients treated in Japan. Data for MIBC patients who received NAC-dd-MVAC followed by a radical cystectomy from June 2019 to May 2023 performed at our hospital were analyzed. For comparisons, data for MIBC patients who received NAC gemcitabine and cisplatin (GC) or gemcitabine and carboplatin (GCarbo) therapy between January 2010 and March 2019 were also obtained. Rates of ypT1N0 or less, progression-free survival (PFS), overall survival (OS), and NAC adverse effects were compared between the GC/GCarbo and dd-MVAC regimens. Results for 32 patients who received dd-MVAC and 30 who received GC/GCarbo NAC therapy were analyzed. ypT1N0 or less was noted in 40.7% of the dd-MVAC and 40.0% of the GC/GCarbo groups, while ypT0N0 rates were 25% and 10%, respectively, with no statistical differences noted. However, Kaplan-Meier analysis of the total cohort demonstrated that dd-MVAC was associated with significantly better PFS and OS rates than GG/GCarbo (hazard ratios: 0.33, p = 0.0237, and 0.23, p = 0.0127, respectively). Propensity-matched models also showed similar results for both PFS and OS. Adverse effects of dd-MVAC were acceptable and the incidence of hematologic toxicity was lower as compared with GC/GCarbo therapy. The present study is the first to show that dd-MVAC as NAC can provide better survival as compared with a gemcitabine-based regimen for patients with MIBC treated in Japan.

Abstract A021: The role of MGAT5 in sex-dependent regulation of CD8+ T cells in muscle-invasive bladder cancer

Abstract Biological sex significantly affects bladder cancer incidence and outcome. Although men have much greater incidence of bladder cancer than women, females tend to be diagnosed with more advanced tumors and have worse outcomes. The mechanisms driving these differences are likely multifactorial, with biological factors playing an important role, however, much of the biology underlying these differences is unknown. The immune system is a critical regulator of cancer biology, and immune features have been associated with bladder cancer grade, stage, progression, and response to therapies. Sex dramatically affects the immune system including anti-tumor immunity. However, how sex and immunity intersect to affect clinical outcomes in bladder cancer patients remains unclear. CD8+ T cells are a key part of anti-tumor immune responses and the importance of inhibitory receptors such as programmed cell death-1 (PD-1), is now well established as a mechanism restricting T cell responses in MIBC. However, there are a variety of other regulatory pathways that restrict their anti-tumor function, which have yet to be investigated. One such pathway involves alterations in protein glycosylation, which can affect T cell function at many levels. The activity of the glycosyltransferase N-acetylglucosaminyltransferase V (MGAT5), responsible for complex N-glycan branching, has been shown to regulate T cell function in autoimmunity and chronic viral infections, however, its role in regulating anti-tumor CD8+ T cell responses has yet to be explored. We assessed the activity of MGAT5 in circulating and tumor-infiltrating CD8+ T cells in mice using a panel of cell lines in a syngeneic orthotopic model of muscle-invasive bladder cancer (MIBC). We found that in all tumor models, MGAT5 activity was upregulated in tumor infiltrating CD8+ T cells compared with circulating cells. Furthermore, using high parameter flow cytometry, we assessed the activity of MGAT5 in CD8+ T cells from mice with bladder cancer induced by the carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN), and in patients with MIBC. In both mice and humans, we found that sex affects MGAT5 activity in memory CD8+ T cells, with females exhibiting decreased MGAT5 activity in these cells compared to males. The functional significance of altering MGAT5 activity in T cells was also assessed in vivo. To do this, chimeric mice were generated by mixed bone-marrow transplant resulting in mice with loss of Mgat5 in T cells. Bladder cancer was then induced using BBN, and morbidity (defined as either 10% weight loss in one week, 10% weight loss post-BBN, or humane endpoint), as a proxy for mortality, was assessed over time. In this model, male mice were protected from BBN-induced morbidity compared to female mice, and this protection was abrogated by homozygous or heterozygous loss of Mgat5 in T cells. Overall, our data suggest that sex-dependent regulation of MGAT5 activity in CD8+ T cells may be an important underlying factor affecting outcomes in bladder cancer. Citation Format: Morgan E. Roberts, Igor Moskalev, Peter C. Black. The role of MGAT5 in sex-dependent regulation of CD8+ T cells in muscle-invasive bladder cancer [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr A021.