Bladder Cancer Outcomes Research Articles

Oncological Outcomes in High-grade pTa Bladder Cancer

Amaç Primer Ta, high grade patolojili hastalarda onkolojik sonuçların değerlendirilmesi, nüks için olası risk faktörlerin belirlenmesi ve ikincil TUR (re-TUR) yapılmasının onkolojik sonuçlara olan etkisinin gösterilmesi amaçlandı. Materyal ve Metod Ocak 2000 ile Aralık 2020 tarihleri arasında kliniğimizde TUR-MT yapılan hastaların verileri retrospektif olarak incelendi. pTa, high grade veya G3 ürotelyal karsinom patolojisi olan hastalar çalışmamıza dahil edildi. Hastaların demografik verileri, yapılan TUR-MT operasyonlarına ait histopatolojik verileri, nüks ve progresyon gelişimi ve bunların süreleri tarandı. Hastalar öncelikle nüks saptanan ve saptanmayanlar olarak sonrasında ise re-TUR yapılanlar ve yapılmayanlar olarak iki gruba ayrıldı. Bulgular Toplam 72 hastadan 63’ü erkekti (%87,5). Ortanca 25 aylık takipte 21 hastada nüks, 4 hastada ise progresyon saptandı. On dört hastada (%66,7) nüks ilk bir yıl içerisinde gelişti. Nüks patolojilerinin büyük çoğunluğu pTa (%82) mesane tümörüydü. Kasa invaze olan 2 hastanın birine radikal sistektomi ve üriner diversiyon, diğer hastaya multimodal tedavi uygulandı. Nüks gelişen grupta mesleki kimyasal maruziyeti istatistiksel anlamlı daha fazlaydı (p=0,001). Re-TUR yapılan grupta 9 (%37,5) hastada nüks görülürken, yapılmayan grupta 12 (%25) hastada nüks görüldü (p=0,271). Re-TUR yapılan ve yapılmayan grup arasında nükssüz sağkalım açısından istatistiksel anlamlı farklılık saptanmadı (p=0,432). Sonuç Bu çalışma ile Ta, high grade mesane kanserlerinde mesleki kimyasal maruziyetlerinin nüks üzerine negatif etkisi gösterildi. 5 yıl sonrasında dahi nüks ve progresyon gözlenebilmektedir. Re-TUR yapılmasının nükssüz sağ kalım üzerine belirgin etkisi görülmese de bu konuda daha fazla hasta sayısına sahip çok merkezli çalışmalara ihtiyaç vardır.

Integrated molecular analyses of an interferon-γ based subtype with regard to outcome, immune characteristics, and immunotherapy in bladder cancer and experimental verification

This study attempted to explore the role of interferon-γ related genes (IRGs) in the prognosis and immunotherapy of bladder cancer (BC). Based on data downloaded from public databases, molecular subtypes with different IRG expression patterns were determined via nonnegative matrix factorization clustering. On the basis of IRGs, interferon-γ related gene signature (IRGS) was developed through Cox regression analyses. We identified that two molecular subgroups with different outcome and immune profiles. It was proved that IRGS possessed prediction efficiency for BC prognosis. Compared with low IRGS group, high IRGS group was related to less anti-cancer immune cells infiltration, less tumor mutation burden score, more cancer stem cell index, and less benefit from immunotherapy. Differential expression of six model genes (IRF5, LATS2, MTHFD2, VAMP8, HLA-G and PTPN6) was validated between paired tissues by RT-qPCR. This study presents a prognostic model, which could serve as an indicator for the benefit of BC immunotherapy.

Diffusion-weighted MRI to determine response and long-term clinical outcomes in muscle-invasive bladder cancer following neoadjuvant chemotherapy

This study aims to determine local treatment response and long-term survival outcomes in patients with localised muscle-invasive bladder cancer (MIBC) patients receiving neoadjuvant chemotherapy (NAC) using diffusion-weighted MRI (DWI) and apparent diffusion coefficient (ADC) analysis. Patients with T2-T4aN0-3M0 bladder cancer suitable for NAC were recruited prospectively. DWI was performed prior to NAC and was repeated following NAC completion. Conventional response assessment was performed with cystoscopy and tumour site biopsy. Response was dichotomised into response (<T2) or poor response (≥T2). Patients proceeded to either radical cystectomy or chemo-radiotherapy as standard of care. Tumour ADC values were calculated for all b-values (ADCall) and high b-values (ADCb100). Mean ADC, percentiles, skew, kurtosis, and their change (ΔADC and %ΔADC) were determined. Threshold predictive of response with highest specificity was ascertained using receiver operating characteristic (ROC) analysis. Median overall survival (OS), bladder-cancer-specific survival (bCSS), progression-free survival (PFS), and time to cystectomy were estimated using Kaplan-Meier method. Significant area under the curve (AUC) cut points were used to determine relationship with long-term endpoints and were compared using log-rank test. Forty-eight patients (96 DWI) were evaluated. NAC response was associated with significant increase in mean ΔADC and %ΔADC compared to poor response (ΔADCall 0.32×10-3 versus 0.11×10-3 mm2/s; p=0.009, and %ΔADCall 21.70% versus 8.23%; p=0.013). Highest specificity predicting response was seen at 75th percentile ADC (AUC, 0.8; p=0.01). Sensitivity, specificity, positive predictive power, and negative predictive power of %ΔADCb100 75th percentile was 73.7%, 90.0%, 96.6%, and 52.9%, respectively. %ΔADCb100 75th percentile >15.5% was associated with significant improvement in OS (HR, 0.40; 95% CI, 0.19-0.86; p=0.0179), bCSS (HR, 0.26; 95% CI, 0.08-0.82; p=0.0214), PFS (HR, 0.16; 95% CI, 0.05-0.48; p=0.0012), and time to cystectomy (HR, 0.19; 95% CI, 0.07-0.47; p=0.0004). Quantitative ADC analysis can successfully identify NAC response and improved long-term clinical outcomes. Multi-centre validation to assess reproducibility and repeatability is required before testing within clinical trials to inform MIBC treatment decision making. We successfully demonstrated that measured change in DWI can successfully identify NAC response and improved long-term survival outcomes.

Centralization and prospective audit of cystectomy are necessary: a commentary on the case for centralization, supported by a contemporary series utilizing the ANZUP cystectomy database.

Bladder cancer (BC) outcomes are unacceptably poor. In Australia, BC survival is actually deteriorating. There is an urgent need to improve outcomes in BC patients, which requires a multipronged approach. One area deserving closer scrutiny is radical cystectomy. Audit is necessary to identify areas for improvement and without it, outcomes remain unknown. Evidence convincingly shows high-volume surgeons and centers improve cystectomy outcomes including overall survival, yet centralization has still not occurred. The Australia and New Zealand Urogenital and Prostate (ANZUP) Cancer Trials Group cystectomy database has been established to facilitate cystectomy audit in Australia and New Zealand. We present initial data from the ANZUP cystectomy database from a single high-volume center, discuss the benefits of centralization and its challenges in the Asia-Pacific context.

Neutrophil-related genes predict prognosis and response to immune checkpoint inhibitors in bladder cancer.

Neutrophils play a key role in the occurrence and development of cancer. However, the relationship between neutrophils and cancer prognosis remains unclear due to their great plasticity and diversity. To explore the effects of neutrophils on the clinical outcome of bladder cancer, we acquired and analyzed gene expression data and clinical information of bladder cancer patients from IMvigor210 cohort and The Cancer Genome Atlas dataset (TCGA) database. We established a neutrophil-based prognostic model incorporating five neutrophil-related genes (EMR3, VNN1, FCGRT, HIST1H2BC, and MX1) and the predictive value of the model was validated in both an internal and an external validation cohort. Multivariate Cox regression analysis further proved that the model remained an independent prognostic factor for overall survival and a nomogram was constructed for clinical practice. Additionally, FCGRT was identified as the key neutrophil-related gene linked to an adverse prognosis of bladder cancer. Up-regulation of FCGRT indicated activated cancer metabolism, immunosuppressive tumor environment, and dysregulated functional status of immune cells. FCGRT overexpression was also correlated with decreased expression of PD-L1 and low levels of tumor mutation burden (TMB). FCGRT predicted a poor response to immunotherapy and had a close correlation with chemotherapy sensitivity. Taken together, a novel prognostic model was developed based on the expression level of neutrophil-related genes. FCGRT served as a promising candidate biomarker for anti-cancer drug response, which may contribute to individualized prognostic prediction and may contribute to clinical decision-making.

A review of the biology and therapeutic implications of cancer-associated fibroblasts (CAFs) in muscle-invasive bladder cancer.

Cancer-associated fibroblasts (CAFs) play a fundamental role in the development of cancers and their response to therapy. In recent years, CAFs have returned to the spotlight as researchers work to unpick the mechanisms by which they impact tumour evolution and therapy responses. However, study of CAFs has largely been restricted to a select number of common cancers, whereas research into CAF biology in bladder cancer has been relatively neglected. In this review, we explore the basics of CAF biology including the numerous potential cellular origins of CAFs, alongside mechanisms of CAF activation and their diverse functionality. We find CAFs play an important role in the progression of bladder cancer with significant implications on tumour cell signaling, epithelial to mesenchymal transition and the capacity to modify components of the immune system. In addition, we highlight some of the landmark papers describing CAF heterogeneity and find trends in the literature to suggest that the iCAF and myCAF subtypes defined in bladder cancer share common characteristics with CAF subtypes described in other settings such as breast and pancreatic cancer. Moreover, based on findings in other common cancers we identify key therapeutic challenges associated with CAFs, such as the lack of specific CAF markers, the paucity of research into bladder-specific CAFs and their relationship with therapies such as radiotherapy. Of relevance, we describe a variety of strategies used to target CAFs in several common cancers, paying particular attention to TGFβ signaling as a prominent regulator of CAF activation. In doing so, we find parallels with bladder cancer that suggest CAF targeting may advance therapeutic options in this setting and improve the current poor survival outcomes in bladder cancer which sadly remain largely unchanged over recent decades.

Artificial intelligence-driven consensus gene signatures for improving bladder cancer clinical outcomes identified by multi-center integration analysis.

To accurately predict the prognosis and further improve the clinical outcomes of bladder cancer (BLCA), we leveraged large-scale data to develop and validate a robust signature consisting of small gene sets. Ten machine-learning algorithms were enrolled and subsequently transformed into 76 combinations, which were further performed on eight independent cohorts (n = 1218). We ultimately determined a consensus artificial intelligence-derived gene signature (AIGS) with the best performance among 76 model types. In this model, patients with high AIGS showed a higher risk of mortality, recurrence, and disease progression. AIGS is not only independent of traditional clinical traits [(e.g., American Joint Committee on Cancer (AJCC) stage)] and molecular features (e.g., TP53 mutation) but also demonstrated superior performance to these variables. Comparisons with 58 published signatures also indicated that AIGS possessed the best performance. Additionally, the combination of AIGS and AJCC stage could achieve better performance. Patients with low AIGS scores were sensitive to immunotherapy, whereas patients with high AIGS scores might benefit from seven potential therapeutics: BRD-K45681478, 1S,3R-RSL-3, RITA, U-0126, temsirolimus, MRS-1220, and LY2784544. Additionally, some mutations (TP53 and RB1), copy number variations (7p11.2), and a methylation-driven target were characterized by AIGS-related multi-omics alterations. Overall, AIGS provides an attractive platform to optimize decision-making and surveillance protocol for individual BLCA patients.

The impact of non-modifiable sociodemographic factors on bladder cancer survival outcomes after radical cystectomy: A systematic review and cumulative analysis of population cohort studies

IntroductionSociodemographic factors have been shown to have significant impacts on bladder cancer (BC) outcomes, but there are conflicting data in the literature regarding certain non-modifiable factors. We sought to determine the effect of sociodemographic factors on survival outcomes after radical cystectomy (RC) for BC.Materials and methodsA systematic review of population-based cohort studies published before March 2020 from Surveillance, Epidemiology, and End Results (SEER) and National Cancer Database (NCDB) was performed per Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines by searching PubMed®, Scopus®, and Web of Science®. All full-text English-language articles assessing the impact of sociodemographic factors on BC survival after RC were obtained. Two investigators (WY and AC) independently screened all articles. Discrepancies were resolved by consensus. All studies reporting survival outcomes after RC based on any of the sociodemographic factors were included, except for systematic reviews, which were excluded. Primary end points were overall survival (OS) and disease-specific survival (DSS) after RC. Cohort studies reporting Cox proportional hazards or logistic regression analysis were independently screened. Available multivariable hazard ratios (HRs) were included in the quantitative analysis.ResultsOur search returned 147 studies, of which 14 studies (11 SEER and 3 NCDB) were included for cumulative analysis. Only race and gender were evaluable due to heterogeneity of other factors. Compared to White patients, Black patients have worse OS [HR 0.83; 95% confidence intervals (CIs) 0.75, 0.92; p &amp;lt; 0.01; I2 = 79%] and DSS (HR 0.83; 95% CI 0.69, 1.00; p = 0.05; I2 = 69%), Asian patients have worse OS (HR 0.84; 95% CI 0.77, 0.92; p &amp;lt; 0.01; I2 = 15%) but not DSS (HR 0.81; 95% CI 0.31, 2.10; p = 0.66), Hispanic patients have no difference in OS (HR 1.03; 95% CI 0.79, 1.34; p = 0.66; I2 = 72%) or DSS (HR 2.63; 95% CI 0.34, 20.34; p = 0.35), and Native American patients have no difference in OS (HR 2.16; 95% CI 0.80, 5.83; p = 0.13). Compared to men, women have no difference in OS (HR 1.03; 95% CI 0.93, 1.15; p = 0.53; I2 = 92%) nor DSS (HR 0.99; 95% CI 0.90, 1.08; p = 0.78; I2 = 1%).ConclusionsDisparate BC survival outcomes after RC are present, with Black patients having poorer OS and DSS as compared to White patients. Asian patients have lower OS but not DSS. Survival outcomes do not appear to differentiate by gender. Significant heterogeneity in variable and outcome definitions limited our ability to perform meta-analyses involving other potentially important drivers and sources of disparate outcomes.

1556MO The iBLAD study: Patient-reported outcomes in bladder cancer during oncological treatment: A multicenter national randomized controlled trial

Patient-reported outcomes (PROs) are widely used, but little is known of the impact of applying PROs in specific cancer diagnoses. We report the results of a randomized controlled trial (RCT) of PROs in patients with muscle-invasive or metastatic bladder cancer (BC) undergoing medical oncological treatment (MOT) with focus of determining the effects of using PROs during chemo- or immunotherapy.

1771P Genomic characteristics and clinical outcomes of HRAS-mutated urothelial bladder cancer

HRAS gene encodes the GTPase HRAS protein, a member of the RAS superfamily, which is enriched in high-grade urothelial bladder carcinoma (UBC). We aimed to characterize genomic and clinical outcomes of patients with HRAS mutations (HRASmt) as a possible prognostic and therapeutic biomarker. A total of 3,426 UBC tissue samples underwent molecular profiling at Caris Life Sciences utilizing NGS of DNA. MAP kinase pathway activation and the likelihood of a tumor’s response to anti-PD(L)1 therapy were measured via MPAS and IFN signature, respectively. Wilcoxon, Fisher’s exact were used for statistical significance. Overall survival (OS) was calculated from the date of tissue collection or the start of treatment until the last contact from insurance claims. All comparisons were conducted between HRAS mutated tumors and the entire UBC general cohort (GC). HRASmt were detected in 107 patients with metastatic UBC (3.12%). Of those, 70% were detected in primary and 30% from metastatic sites. HRASmt were associated with lower TMB (5 vs 8 mut/Mb, q<0.01) and higher PD-L1 expression (55.3% vs 39.1%, q<0.01). HRASmt tumors harbored less TP53 (25.5% vs 60.1%, q<0.05), RB1 (5.3% vs 22.1%, q<0.05), FGFR3 (1.9% vs 13.9%, q<0.05), and KMT2D (14.0% vs 25.4%, q<0.05), but more BRAF mutations (14.0% vs 2.1%, q<0.05). The most frequent HRAS point mutation involved Q61 (47.6%). HRAS-Q61 mutant tumors showed higher MPAS scores (2.21 vs 0.6, q<0.001), enrichment in pathways (all q<0.05) such as EMT (0.86 vs 0.83), TGFb (0.91 vs 0.89), angiogenesis (0.78 vs 0.75) and notch signaling (0.82 vs 0.81). Patients with HRAS-Q61 point mutations experienced worse OS and prognosis compared to HRASwt tumors when treated with checkpoint inhibitors (HR 1.45, 95% 1.01-2.10; p <0.05). HRAS-Q61 point mutations represent a clinically relevant mutation in UBC, as evidenced by its association with worse clinical outcomes compared to HRASwt tumors. Our transcriptomic analysis suggests HRAS-Q61 mutations were associated with lower response to immunotherapy and leads to MAPK activation, as well as modulation of important TME pathways, possibly indicating a distinct biological and clinical phenotype. Our study provides rationale for therapeutic HRAS targeting in UBC.

1755P The impact of upfront transurethral resection of bladder tumor (TURBT) and intravesical BCG versus radical cystectomy on survival outcomes of high-risk non-muscle invasive bladder cancer: A meta-analysis of comparative studies

High-risk non-muscle invasive bladder cancers (HRNMIBC), including TaG3, T1G2, T1G3, and/or Tis, carry an increased risk of progression, recurrence, and even death. The commonly used therapeutic approaches are TURBT+BCG or radical cystectomy (RC). So far, there have been no randomized clinical trials comparing the efficacy of these two different modalities. However, there continue to be some concerns regarding the long-term outcomes of the bladder preserving approach. Therefore, we conducted this meta-analysis to compare the relative risk (RR) of cancer-specific and all-cause death rates between TURBT+BCG and RC in HRNMIBC.

A retrospective cohort study of bladder cancer following the COVID-19 pandemic: Are patients presenting with more aggressive disease?

BackgroundThe COVID-19 pandemic has resulted in delays in the treatment of patients with urological malignancies. The management of bladder cancer (BC) in particular poses a significant challenge given the recurrent nature of the disease and the intense follow-up regime required for many cases. The aim of this study was to evaluate potential changes in the presentation and operative management of BC in our hospital following the pandemic. Materials and methodsThis is a retrospective cohort study. Potential BC cases were identified through the histopathology database between March 2019 and February 2021. Details were obtained on patient demographics, procedure type such as biopsy, resection or excision, grade and stage of BC. Cases were divided into two groups: period one (pre-COVID between March 2019 and February 2020) and period two (post-COVID between March 2020 and February 2021). ResultsA total of 207 procedures for confirmed BC were performed during the study period, 126 in period one and 81 in period two. New cases accounted for 52.4% (n = 66) and 53.1% (n = 43) of cases during periods one and two respectively. There was a higher rate of invasive disease (43.2% vs 26.2%) as well as high grade disease (47.4% vs 35.8%) in period two than in period one. ConclusionFewer BC procedures were performed in the COVID period. The higher rate of more advanced stage and grade of disease seen in period two suggests patients are presenting later. This should be considered when allocating resources in the management of non-COVID related diseases. Further studies are needed to assess the long-term impact of COVID-19 on bladder cancer outcome.

Prognostic values of distal ureter involvement and survival outcomes in bladder cancer at T1 and T2 stages: a propensity score matching study.

To study prognostic values of distal ureter involvement (DUI) and survival outcomes in bladder cancer at T1 and T2 stages. The national Surveillance, Epidemiology, and End Results database (2004-2015) was applied to obtain bladder cancer patients. We used the Kaplan-Meier method with the log-rank test, subgroup analyses, the multivariable Cox proportional hazard model and propensity score matching (PSM). A total of 490 patients with DUI and 28,498 patients with non-DUI (non-involvement) were enrolled in our study. After 1:1 PSM, 490 matched pairs were picked out. The multivariable Cox regression before and after PSM revealed that the DUI group had a high risk of overall mortality (HR = 1.374, P < 0.001 before PSM; HR = 1.513, P < 0.001 after PSM) and cancer-specific mortality (HR = 1.632, P < 0.001 before PSM; HR = 1.699, P < 0.001 after PSM). The results of survival analyses showed that patients in the DUI group had lower survival probability in OS (P = 0.0011) and CSS (P < 0.0001) analyses. Nevertheless, in the subgroup analysis, significant differences were only observed in the T1 stage in terms of CSS and T2a stage in terms of OS and CSS (all P < 0.05). The prognosis of DUI was poorer than that of non-DUI. DUI was an independent risk factor for OM and CSM in bladder cancer at T1 and T2 stages especially for those at T1 and T2a stages.

Cuproptosis scoring system to predict the clinical outcome and immune response in bladder cancer.

Cuproptosis is a novel copper ion-dependent cell death type being regulated in cells, and this is quite different from the common cell death patterns such as apoptosis, pyroptosis, necroptosis, and ferroptosis. Interestingly, like with death patterns, cuproptosis-related genes have recently been reported to regulate the occurrence and progression of various tumors. However, in bladder cancer, the link between cuproptosis and clinical outcome, tumor microenvironment (TME) modification, and immunotherapy is unknown. To determine the role of cuprotosis in the tumor microenvironment, we systematically examined the characteristic patterns of 10 cuproptosis-related genes in bladder cancer (BLCA). By analyzing principal component data, we established a cuproptosis score to determine the degree of cuproptosis among patients. Finally, we evaluated the potential of these values in predicting BLCA prognosis and treatment responses. A comprehensive study of the mutations of cuproptosis-related genes in BLCA specimens was conducted at the genetic level, and their expression and survival patterns were evaluated using The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO). Two cuproptosis patterns were constructed based on the transcription level of 10 cuproptosis-related genes, featuring differences in the prognosis and the infiltrating landscape of immune cells (especially T and dendritic cells) with interactions between cuproptosis and the TME. Our study further demonstrated that cuproptosis score may predict prognosis, immunophenotype sensitivity to chemotherapy, and immunotherapy response among bladder cancer patients. The development and progression of bladder cancer are likely to be influenced by cuproptosis, which may involve a diverse and complex TME. The cuproptosis pattern evaluated in our study may enhance understanding of immune infiltrations and guide more potent immunotherapy interventions.

A Systematic Review of Plant-Based Diets and Bladder Cancer: A Call for Further Research

The relationship between plant-based dietary patterns and bladder cancer has not been extensively studied. Our objective was to perform a systematic review of the relationship between plant-based diets and bladder cancer risk and/or outcomes. We searched the literature for all relevant papers published before October 2020 was conducted. Of 74 identified records, only 2 references were included in the final qualitative analysis. These publications found that vegetarian diets are associated with a lower risk of bladder cancer diagnosis. We did not identify any studies investigating the impact of plant-based dietary patterns on outcomes for individuals diagnosed with bladder cancer, which represents an important area for further study.

Comprehensive analysis of autophagy related long non-coding RNAs in prognosis, immunity, and treatment of muscular invasive bladder cancer

To predict disease outcome in muscle-invasive bladder cancer (MIBC), we constructed a prognostic autophagy-related (PAR) lncRNA signature. Comprehensive bioinformatics analyses were performed using data from TCGA and GTEx databases. Univariate Cox, and least absolute shrinkage and selection operator regression analyses were also performed, based on differentially expressed genes, to identify PAR-related lncRNAs to establish the signature. Furthermore, the Kaplan–Meier OS curve and receiver operating characteristic curve analyses were performed and a nomogram was constructed, all of which together confirmed the strong predictive ability of the constructed signature. Patients with MIBC were then divided into high- and low-risk groups. Gene enrichment and immune infiltration analyses revealed the potential mechanisms in MIBC. We also further evaluated the signature of molecules related to immune checkpoints and the sensitivity toward chemotherapeutic agents and antitumor-targeted drugs to find better treatment prescriptions. We identified a number of PAR-related lncRNA signatures, including HCP5, AC024060.1, NEAT1, AC105942.1, XIST, MAFG-DT, and NR2F1-AS1, which could be valuable prognostic tools to develop more efficient, individualized drug therapies for MIBC patients.

Age of menarche and primary bladder cancer risk: A meta-analysis and systematic review.

The incidence and outcomes of bladder cancer (BCa) have apparent sex differences. Various observational studies have demonstrated that the age of menarche might be associated with female BCa. To explore this relationship, a meta-analysis and systematic review were performed based on available studies. A systematic search was performed in PubMed, Embase, and Web of Science for studies published up to October 1, 2021. Two reviewers independently extracted related data between age of menarche and BCa risk from the included studies. The Newcastle-Ottawa quality assessment scale was applied to evaluate the quality of the studies. The relative risk (RR) ratio and its 95% confidence interval (CI) were then calculated. A total of 12 studies containing 3,719 BCa cases and 1,350,207 women, were included in this meta-analysis. The pooled data showed that the age of menarche was not significantly associated with BCa risk (RR = 0.96, 95% CI: 0.85-1.08), although the evidence was of moderate quality. Similar results were observed in case-control (RR = 1.33, 95% CI = 0.77-2.21) and cohort studies (RR = 0.95, 95% CI = 0.84-1.07). Moreover, subgroup analyses based on study quality, population, exposure assessment, and several potential important confounders and risk factors revealed similar results. No evidence of publication bias and significant heterogeneity was found among these studies. Furthermore, a random-effects dose-response meta-regression model was established, which revealed negative results. Our findings suggested that the age of menarche was not associated with BCa risk in women. However, these findings needed to be further confirmed given the limitations and potential biases.

Correlation of Metabolic Syndrome with Clinicopathological Characteristics and Treatment Outcome in Bladder Cancer: A Retrospective Observational Study

The relationship between metabolic syndrome (MetS) with the clinicopathological characteristics, chemotherapy responsiveness and survival outcome in bladder cancer is under-investigated and often conflicting. We retrospectively analysed data of 45 patients who were diagnosed with non-muscle invasive bladder cancer (NMIBC) or muscle-invasive bladder cancer (MIBC) and received chemotherapy at the University of Malaya Medical Centre (UMMC) between 2010 and 2020. Overall, 24 patients (53.3%) were presented with MetS criteria at the time of diagnosis. Across MetS and its components, no significant association was found with tumour pathological stage, histological grade, and chemotherapy response in our patient population. Interestingly, there was a significant difference in overall survival between patients with and without diabetes (62.47 + 8.32 months and 84.93 + 3.96 months respectively, p=0.045). Although no significant association between MetS with bladder cancer clinicopathological characteristics and treatment outcome was found, intensive care and lifestyle modification should be considered for bladder cancer patients with metabolic disorders.

B7-H4 correlates with clinical outcome and immunotherapeutic benefit in muscle-invasive bladder cancer

AimB7-H4, a sibling to PD-L1 in B7 family, has been reported to be a novel immune checkpoint that is prevalent among non-inflamed tumors. Herein, we attempt to explore the potential of B7-H4 in survival prediction and therapeutic guidance in muscle-invasive bladder cancer (MIBC) patients. MethodsThis study included 391 patients from The Cancer Genome Atlas (TCGA) database and 122 patients from Zhongshan (ZS) Hospital. The evaluation of response to PD-L1 inhibitors was based on 270 patients in IMvigor210 cohort. Kaplan–Meier survival and multivariate analyses were performed to assess clinical outcomes in three cohorts. The correlation of B7-H4 expression with immune contexture and genomic alterations was analyzed based on immunohistochemistry, Microenvironment Cell Populations-counter (MCP-counter) tool, and whole-exome sequencing. ResultsMIBC patients with the high level of B7-H4 expression (B7-H4high) were found to possess an inferior overall and recurrence-free survival. Nonetheless, substantial clinical benefits of cisplatin-based chemotherapy and anti-PD-L1 immunotherapy were observed in these patients. After identifying a positive correlation between B7-H4 and tumor mutation burden (TMB), clinical benefits in B7-H4high TMBhigh subgroup were found to be the most upon PD-L1 blockade. Further studies revealed that B7-H4high subgroup was featured by non-inflamed immune contexture and cell cycle-related gene alterations. ConclusionsDespite adverse clinical outcomes, B7-H4high patients possessed superior responsiveness to chemotherapy and immunotherapy. B7-H4 stratification could also synergize with TMB to pinpoint the patients who benefited most from immunotherapy. The clinical exploration of B7-H4 as a companion predictor could allow clinicians to direct proper therapeutic agents to patients.

Abstract 2417: Elucidating the role of SMARCB1 in bladder cancer progression and metastasis

Abstract Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Bladder cancer (BLCA) is the second most common urological malignancy in the US and is usually not curable at an advanced stage. The transcriptomic profiling data of bladder cancer revealed that 64% of BLCA patients have frequent dysregulation of the components of the SWI/SNF, a chromatin remodeling complex. Alterations in chromatin remodeling genes have been previously implicated in human oncogenesis. SMARCB1/INI1 is one of the critical core components of the SWI/SNF complex. In this study, we demonstrate that primary BLCA patients harboring SMARCB1 loss strongly associate with worse survival. Specifically, the biallelic inactivation of the SMARCB1 (SMARCB1 knockout (KO)) in BLCA cell lines resulted in the emergence of aggressive tumor growth leading to soft tissue metastasis to lungs, liver, kidney, and intestine in vivo. Mechanistic studies revealed that IL-6- STAT3 axis is upregulated in SMARCB1 KO BLCA cells. Our data suggest that the STAT3 specific inhibitor, inhibits invasive potential of SMARCB1 KO cells suggesting potential therapeutic efficacy for STAT3 inhibitor to treat subsets of BLCA harboring SMARCB1 loss. In addition, we identified a unique transcriptional signature activated upon SMARCB1 loss, which is predictive of poor patient outcome in BLCA, and hence may be clinically valuable. Citation Format: Chandra Sekhar Amara, Karthik Reddy Reddy, Yuntao Yang, Badrajee Waduge Danthasinghe, Allison Bellman, Andrea B. Apollo, David J. Shih, Leomar Ballester, Pavlos Msaouel, Wenjin J. Zheng, Matthew J. Ellis, Seth P. Lerner, Arun Sreekumar, Shyam M. Kavuri, Nagireddy Putluri. Elucidating the role of SMARCB1 in bladder cancer progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2417.