Risk Factor For Bladder Cancer Research Articles

A Prognostic Nomogram Based on Log Odds of Positive Lymph Nodes to Predict Overall Survival for Non-Metastatic Bladder Cancer Patients after Radical Cystectomy.

(1) Purpose: The purpose of this study was to evaluate the prognostic capacity of the pathological N status (pN), lymph node ratio (LNR), and the log odds of positive lymph nodes (LODDS), and to build a prognostic nomogram to predict overall survival (OS) for bladder cancer patients treated by radical cystectomy. (2) Methods: The clinical and pathological characteristics of 10,938 patients with bladder cancer were identified from the Surveillance, Epidemiology, and End Results (SEER) database from 2004 to 2017. The predictive capacity was assessed by univariate and multivariate Cox regression analyses, the area under the receiver operating characteristic curve (AUC), and C-index. Calibration curves, decision curve analysis (DCA), and risk-grouping were utilized to evaluate the predictive accuracy and discriminative ability of the nomogram. (3) Results: LODDS was an independent risk factor for bladder cancer (all p < 0.001) and demonstrated the highest values of C-index and AUC. The values of AUCs in the training cohort were 0.747, 0.743, and 0.735 for predicting 1-, 3-, and 5-year OS, respectively. Calibration curves and DCA curves suggested the excellent clinical application value of our nomogram. (4) Conclusions: LODDS is a better predictive indicator for bladder cancer patients compared to pN and LNR. The LODDS-incorporated nomogram has excellent accuracy and promising clinical application value for non-metastatic bladder cancer after radical cystectomy.

RISK FACTORS OF BLADDER CANCER PATIENTS IN ARIFIN ACHMAD REGIONAL GENERAL HOSPITAL, RIAU PROVINCE, INDONESIA

Objective: This study aims to describe the risk factors of bladder cancer patients in Arifin Achmad Regional General Hospital, Riau Province, Indonesia. Material &amp; Methods: We reviewed the medical records of bladder cancer patients managed in Arifin Achmad Regional General Hospital from January 2013 - December 2017. The data collected were sex, age, histopathology types, staging, smoking history, occupation, ethnic/tribes, and city/district origine. Statistical analysis of univariate was used. Approval on the study was obtained from the Ethical Review Board for Medicine and Health Research, Medical Faculty, University of Riau. Results: There were 101 bladder cancer patients consisting of 83.2% patients with transitional cell carcinoma and 65.3% with advanced stage. The result showed the most common (82.2%) patients were males and 35.6% of patients were in age 51-60 year old group, with the youngest was in 9 year old group and the oldest is 85 years. The most common risk factors of bladder cancer patient were farmers in 29.7% and the non-smoking patients were in 52.5%, Malay ethnic in 30.7% and Pekanbaru origin in 30.7% of patients. Conclusion: Bladder cancer risk factors in Arifin Achmad Regional General Hospital were males, farmers, Malay ethnic, and Pekanbaru origin.

Complete transurethral resection of bladder tumor before radical cystectomy is not a risk factor for organ-confined bladder cancer: A case-control study.

ObjectivesTo investigate the role of complete transurethral resection of bladder tumor (TURBT) before radical cystectomy (RC) for organ-confined bladder cancer.Materials and methodsData of patients who underwent RC in our center from January 2008 to December 2018 were retrospectively reviewed. Patients with >T2N0M0 disease and positive surgical margins and those who received neoadjuvant/adjuvant chemotherapy or radiotherapy were excluded. Complete TURBT was defined as no visible lesion under endoscopic examination after TURBT or in the bladder specimen after RC. Kaplan-Meier curves and log-rank tests assessed disease-free survival (DFS). Logistic and Cox regression analyses were performed to identify potential predictors.ResultsA total of 236 patients were included in this review, including 207 males, with a median age of 61 years. The median tumor size was 3 cm, and a total of 94 patients had identified pathological T2 stage disease. Complete TURBT was correlated with tumor size (p = 0.041), histological variants (p = 0.026), and down-staging (p < 0.001). Tumor size, grade, and histological variants were independent predictors of complete TURBT. During a median follow-up of 42.7 months, 30 patients developed disease recurrence. Age and histological variants were independent predictors of DFS (p = 0.022 and 0.032, respectively), whereas complete TURBT was not an independent predictor of DFS (p = 0.156). Down-staging was not associated with survival outcome.ConclusionsComplete TURBT was correlated with an increased rate of down-staging before RC. It was not associated with better oncologic outcomes for patients with organ-confined bladder cancer.

Immunoinformatics design of multi-epitope peptide for the diagnosis of Schistosoma haematobium infection

Schistosoma haematobium has been identified as a significant cause of urogenital disease, as well as a risk factor for bladder cancer and HIV/AIDS. The parasites are obtained trans-dermally by swimming or wading in contaminated freshwater, and they are also transmitted to humans by freshwater snails. The organisms infect the vasculature of the gastrointestinal or genitourinary tracts. Worms live in blood vessels and lay eggs that become embedded in the bladder wall, causing chronic immune-mediated disease and squamous cell carcinoma growth. The primary goal of this research is to predict and design a novel synthetic protein containing multiple immunodominant B cell epitopes using three schistosome proteins: XP-012801068.2, XP-012801892.2, and XP-012793835.2 softwares were used to analyze the proteins’ primary, secondary, and tertiary structures (BepiPred, BcPred).The B cell construct was then evaluated using I-TASSER server, and physicochemical properties, as well as homology modeling of the 3 D structure of the protein, was obtained. In silico analyses revealed regions with high immunogenicity. For XP-012801068.2, three epitopes are found between residues 292–334, 3–22, and 314–333; for XP-012801892.2, three epitopes are found in the residues 184–236, 81–100, and 329–348 for XP-012793835.2, four epitopes are found in the residues 185–222, 469–512, 649–713, and 338–357. The construct’s has an average length of 308 bp, instability index of 49.96, theoretical PI of 4.2 and a C score −1.59. Furthermore, these parameters analyzed reveals that the constructed multi-epitope peptide has the potential to provide a theoretical basis for the development of a Schistosoma haematobium diagnostic kit. Communicated by Ramaswamy H. Sarma

DNA Damage and Oxidative Stress of Tobacco Smoke Condensate in Human Bladder Epithelial Cells.

Smoking is a major risk factor for bladder cancer (BC), with up to 50% of BC cases being attributed to smoking. There are 70 known carcinogens in tobacco smoke; however, the principal chemicals responsible for BC remain uncertain. The aromatic amines 4-aminobiphenyl (4-ABP) and 2-naphthylamine (2-NA) are implicated in BC pathogenesis of smokers on the basis of the elevated BC risk in factory workers exposed to these chemicals. However, 4-ABP and 2-NA only occur at several nanograms per cigarette and may be insufficient to induce BC. In contrast, other genotoxicants, including acrolein, occur at 1000-fold or higher levels in tobacco smoke. There is limited data on the toxicological effects of tobacco smoke in human bladder cells. We have assessed the cytotoxicity, oxidative stress, and DNA damage of tobacco smoke condensate (TSC) in human RT4 bladder cells. TSC was fractionated by liquid-liquid extraction into an acid-neutral fraction (NF), containing polycyclic aromatic hydrocarbons (PAHs), nitro-PAHs, phenols, and aldehydes, and a basic fraction (BF) containing aromatic amines, heterocyclic aromatic amines, and N-nitroso compounds. The TSC and NF induced a time- and concentration-dependent cytotoxicity associated with oxidative stress, lipid peroxide formation, glutathione (GSH) depletion, and apurinic/apyrimidinic (AP) site formation, while the BF showed weak effects. LC/MS-based metabolomic approaches showed that TSC and NF altered GSH biosynthesis pathways and induced more than 40 GSH conjugates. GSH conjugates of several hydroquinones were among the most abundant conjugates. RT4 cell treatment with synthetic hydroquinones and cresol mixtures at levels present in tobacco smoke accounted for most of the TSC-induced cytotoxicity and the AP sites formed. GSH conjugates of acrolein, methyl vinyl ketone, and crotonaldehyde levels also increased owing to TSC-induced oxidative stress. Thus, TSC is a potent toxicant and DNA-damaging agent, inducing deleterious effects in human bladder cells at concentrations of <1% of a cigarette in cell culture media.

Genetic variants of antioxidant enzymes and environmental exposures as molecular biomarkers associated with the risk and aggressiveness of bladder cancer

Bladder cancer (BC) is one of the top 10 most common tumours worldwide; however, no molecular markers are currently available for tumour management and follow-up. BC could benefit from molecular biomarkers in environmental disease, which provide mechanistic understanding of individual susceptibility to exposure-related cancers and allow characterizing genetic alterations in the molecular pathway for malignancy. This case-control study performed a molecular analysis in 99 BC and 125 controls. Buccal swabs were collected to assess SNPs in eleven genes coding for xenobiotic detoxification enzymes, cellular antioxidant defences, and hormone synthesis and signalling (NAT2 (rs1801280), GPX1 (rs1050450 and rs17650792), TXNRD1 (rs7310505), PRDX3 (rs3740562), PON1 (rs662), SOD1 (rs10432782), SOD2 (rs4880), CAT (rs1001179), CYP17A1 (rs743572) and ESR1 (rs746432)). A structured questionnaire was administered to study participants to assess environmental and dietary chemical exposures. Several miRNAs associated with BC and detoxification/antioxidant pathways were analysed in a subsample of the study population, including miR-93-5p, miR-221-3p, miR-126, miR-27a-3p, miR-193b, and miR-193a-5p. Levels of selected environmental pollutants (polycyclic aromatic hydrocarbons and endocrine disrupting chemicals) were determined in urine from a subsample of BC cases and controls. We found that CYP17A1, CAT, SOD1, ESR1, PON1, and GPX1 (rs17650792) were associated with BC risk. Furthermore, exposure to smoke and/or dust, and alcohol intake were identified as risk factors for BC. Increased urinary levels of benzo[a]pyrene and bisphenol A were observed in BC patients relative to controls, along with an increased expression of miR-193b, miR-27a and miR-93-5p in BC. Nevertheless, further studies with a larger sample size are warranted to confirm these exploratory results. This study also shows that the combination of genetic markers (PON1 and CYP17A1) and miRNA (miR-221-3p and miR-93-5p) open a new scenario in the use of non-invasive biomarkers in the stratification of BC to guide personalized medicine, which is extremely urged in the current clinical setting.

Abstract 3060: Changes in mouse gut microbiome upon exposure to N-butyl-N-(4-hydroxybutyl) nitrosamine

Abstract Background: BBN (N-butyl-N-(4-hydroxybuytl) nitrosamine), a closely related compound to the carcinogens found in tobacco smoke is an attractive and most commonly used agent to model bladder cancer in mice. BBN closely recapitulates the morphological characteristics of human bladder cancer and conceptually simulates tobacco exposure as the leading risk factor for bladder cancer. We employ the BBN model in mice to decipher the microbial changes that occur in the gut of the mice during the chemical carcinogenesis induced by BBN exposure. Methods: Starting at 8-12 weeks of age, male (N=30) and female (N=21) C57BL/6 mice were administered 0.05% BBN in drinking water for 12 weeks then switched to regular water. Control mice drank regular water. Stool was collected pre-exposure, after 6 and 12 weeks of exposure, and at the time of tumor identification (tumors typically detectable between 14-22 weeks from start of treatment using this model). DNA extracted from stool was subjected to PCR amplification using primers for the V3-V4 regions of the bacterial 16S rRNA. Results: Gender-based differences in the microbial composition were noted in response to BBN treatment. While gut microbial diversity in the female mice was markedly reduced (Shannon, Simpson, Inverse Simpson, and Richness) upon BBN treatment, that of male mice remained unchanged from baseline. Additionally, there was a distinct clustering of microbes based on sex (p=0.024) but not BBN exposure (p=0.86) as evidenced by principal coordinate analysis. Differences in the microbial composition were seen upon BBN exposure, with BBN mice showing an increase in Bacteroidales (53%), Lactobacillales (17.5%), Coriobacteriales (19.87%) in females and male mice exhibited an increase in Erysipelotrichales (14.76%) at the order level. On the other hand while male mice showed no significant decreases, female mice exhibited reduction in abundance of Clostridiales (log change -7.79, padj &amp;lt;0.004), Veeruccomicrobiales (log change -2.21, padj&amp;lt;0.005), and Bacillales (log -17.60, padj =0.005). Conclusions: Pronounced gut microbial changes are induced by BBN in the murine model, with microbiome of the female mice exhibiting more significant variations compared to baseline, suggesting gender-based disparities in the effect of BBN exposure. Citation Format: Rashida Ginwala, Laura Bukavina, Jodie Franklin, Mohit Sindhani, Philip Abbosh. Changes in mouse gut microbiome upon exposure to N-butyl-N-(4-hydroxybutyl) nitrosamine [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 3060.

A novel approach to assessing the effects of smoking on treatment response rate in muscle-invasive bladder cancer.

e16554 Background: Cigarette smoking is the strongest modifiable risk factor for bladder cancer and has been implicated in mechanisms of chemotherapy resistance. Prior studies examining tobacco exposure on chemotherapy response were limited by use of retrospective design and self-report assessment of smoking status, potentially under-estimating the association and risking bias towards the null. Cotinine is the central metabolite of nicotine and can be detected in saliva for up to 4 days after tobacco use. In this prospective cohort study, we tested the association between salivary cotinine level and pathologic response to neoadjuvant chemotherapy, assessed post-chemotherapy at the time of cystectomy, among patients with muscle-invasive bladder cancer (MIBC). Methods: Thirty-one patients with MIBC were prospectively recruited and surveyed on their smoking habits. Salivary cotinine was measured during chemotherapy using NicAlert test strips with cotinine concentration &gt; 10ng/mL indicating active smoking (cotinine = 1) and cotinine concentration &lt; 10ng/mL indicating no evidence of active tobacco use (cotinine = 0). Primary outcome was pathologic response at cystectomy, defined as complete response (pT0) or residual disease (pT1-4 or node+). For patients with prior history of tobacco use, the association between pre-chemotherapy cotinine level and post-chemotherapy response at cystectomy was assessed using a chi-squared test and an odds ratio with a 95% confidence interval (CI) using the Baptista-Pike method. Results: Thirty-one patients had cotinine levels measured during chemotherapy and 25 reported prior history of smoking. Of these 25 patients, 17 patients denied active smoking, 2 of whom had cotinine levels = 1 during chemotherapy. Response to chemotherapy by cotinine level among patients with prior history of tobacco use are shown in table 1. One patient declined cystectomy and was excluded from the analysis. The odds ratio of a complete response at cystectomy for patients with cotinine = 0 vs. cotinine = 1 was 3.86 (95% CI: 0.54-22.05) (p = 0.148). The odds ratio of residual disease with cotinine = 0 vs. cotinine = 1 was 0.26 (95% CI: 0.045-1.86) (p = 0.148). Conclusions: Prior smokers with no evidence of active tobacco use during curative chemotherapy were more than three-times as likely to demonstrate a complete response at the time of cystectomy compared to those with evidence of current tobacco use based on salivary cotinine levels. While this study was limited by a small sample size, it highlights a novel approach to tobacco use monitoring and the importance of continued smoking cessation counseling in patients with bladder cancer even after the diagnosis of cancer is made.[Table: see text]

Secondary bladder cancer during long-term follow-up after iodine-125 permanent seed implantation for localized prostate cancer

IntroductionBrachytherapy for prostate cancer treatment may induce secondary bladder cancer during long-term follow-ups. This study reviews the risk and tumor characteristics of secondary bladder cancer after brachytherapy. MethodsThis single-institution retrospective study included 1162 patients treated with low-dose-rate permanent seed implantation brachytherapy with iodine-125, with or without external beam radiation therapy, for localized prostate cancer. We calculated and compared the rates of secondary bladder cancer among patients treated with brachytherapy and radical prostatectomy (n = 218) before and after a propensity score-matching analysis. Possible risk factors for secondary bladder cancer, such as patient age and external beam radiation therapy administration, were analyzed. ResultsOf 1162 patients with a median follow-up period of 11.4 (range: 0.7–15.5) years, 26 presented with urothelial carcinomas and 1 with adenocarcinoma at a median of 8.9 (range: 2.9–14.0) years after brachytherapy, although the incidence rates of secondary bladder cancer after brachytherapy were not significantly different from those after radical prostatectomy. No significant risk factors for secondary bladder cancer were identified. The initial symptoms of secondary bladder cancer were gross hematuria (74%) and microscopic hematuria with positive urine cytology (15%). Among 26 cases of secondary urothelial carcinoma, 54% were high-grade and 46% were invasive. After brachytherapy, invasive urothelial carcinoma occurred later than noninvasive urothelial carcinoma (p = 0.01). ConclusionsConsidering the aggressive malignancy of secondary bladder cancer, cystoscopy and urine cytology should be performed for further investigation of the causes of gross or microscopic hematuria and rule out secondary bladder cancer in cases followed longer than 3 years after brachytherapy.

In Silico Establishment and Validation of Novel Lipid Metabolism-Related Gene Signature in Bladder Cancer.

Background Aberrant lipid metabolism is an alteration common to many types of cancer. Dysregulation of lipid metabolism is considered a major risk factor for bladder cancer. Accordingly, we focused on genes related to lipid metabolism and screened novel markers for predicting the prognosis of bladder cancer. Methods RNA-seq data for bladder cancer were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. The nonnegative matrix factorization (NMF) algorithm was used to classify the molecular subtypes. Weighted correlation network analysis (WGCNA) was applied to identify coexpressed genes, and least absolute shrinkage and selection operator (LASSO) multivariate Cox analysis was used to construct a prognostic risk model. External validation data and in vitro experiments were used to verify the results from in silico analysis. Results Bladder cancer samples were grouped into two clusters based on the NMF algorithm. A total of 1467 genes involved in coexpression modules were identified in WGCNA. We finally established a 5-gene signature (TM4SF1, KCNK5, FASN, IMPDH1, and KCNJ15) that exhibited good stability across different datasets and was also an independent risk factor for prognosis. Furthermore, the predictive efficacy of our model was generally higher than the predictive efficacy of other published models. Distinct risk groups of patients also showed significantly different immune infiltration cell patterns and associations with clinical variables. Moreover, the 5 signature genes were verified in clinical samples by quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry, which were in agreement with the in silico analysis. For in vitro experiments, knockdown of IMPDH1 markedly inhibited cell proliferation in bladder cancer. Conclusion We established a 5-gene prognosis signature based on lipid metabolism in bladder cancer, which could be an effective prognostic indicator.

Risk Factors for Unfavorable Pathological Types of Intravesical Recurrence in Patients With Upper Urinary Tract Urothelial Carcinoma Following Radical Nephroureterectomy.

BackgroundNumerous studies have investigated the risk factors of intravesical recurrence (IVR) after radical nephroureterectomy (RNU) in patients with upper urinary tract urothelial carcinoma (UTUC). However, few studies explore the predictors for unfavorable pathological types of IVR following RNU.MethodsWe retrospectively reviewed 155 patients diagnosed with bladder cancer (BC) following RNU. Binary logistic regression was used for the univariable and multivariable analyses. Nomograms were developed based on the multivariable analysis. The concordance index (C-index) was used to assess the performance of the nomograms. We performed internal validation by generating calibration plots.ResultsMuscle-invasive BC (MIBC) was significantly correlated with operation interval (p = 0.004) and UTUC T-stage (p = 0.016). Operation interval (p = 0.002) and UTUC T-stage (p = 0.028) were also risk factors for BC > 3 cm. UTUC grade (p = 0.015), operation interval (p = 0.003), and hydronephrosis (p = 0.049) were independent predictors for high-grade BC (HGBC). MIBC (p = 0.018) and surgical approach (p = 0.003) were associated with multifocal IVR. Besides, MIBC and HGBC were associated with UTUC grade (p = 0.009), operation interval (p = 0.001), and hydronephrosis (p = 0.023). Moreover, only operation interval (p = 0.036) was a predictor for BC with at least one unfavorable pathological type. We developed nomograms for MIBC, HGBC, BC > 3 cm, and MIBC and/or HGBC. The calibration curves of the nomograms showed good agreement between the observation and prediction cases. The C-indexes of the nomograms were 0.820 (95% CI, 0.747–0.894), 0.728 (95% CI, 0.649–0.809), 0.770 (95% CI, 0.679–0.861), and 0.749 (95% CI, 0.671–0.827), respectively.ConclusionsThe current study found that operation interval, UTUC T-stage, UTUC grade, surgical approach, and hydronephrosis are independent predictors for unfavorable pathological types of IVR following RNU. Nomograms based on these predictors were developed and internally validated to assess the risk of developing unfavorable pathological types of IVR. Furthermore, patients at high risk of developing unfavorable pathological types BC may benefit from more active follow-up 1 year after RNU by early detection of IVR.

Cigarette smoking and risk of bladder cancer: a dose-response meta-analysis.

The disease burden of bladder cancer is increasing worldwide; therefore, to deal with this situation, many studies on bladder cancer have been carried out extensively. Among these studies, the risk factors studies may provide a possible way to reduce the incidence of bladder cancer. Meta-analyses and original researches have confirmed that smoking is a risk factor of bladder cancer. However, the specific dose-response relationship between smoking and bladder cancer risk was still unclear. This meta-analysis addresses this research gap by summarizing the accumulated evidences, quantitatively. Relevant studies were obtained by searching PubMed, Embase and Web of Science database since inception until August 10, 2021, without restrictions. To obtain more comprehensive data, reference lists of identified articles were also browsed. Studies that reported risk estimates (relative risks (RR) or odds ratio (OR)) with 95% confidence intervals (CIs) focusing on the association between cigarette smoking and risk of bladder cancer were included in a dose-response meta-analysis. A non-linear dose-response relationship was confirmed between cigarette smoking and risk of bladder cancer on the basis of 8 cohorts and 44 case-control studies. The summary relative risk of developing bladder cancer for 1 more cigarettes/day (7 cohorts and 24 case-control studies) was 1.039 (95% CI 1.038-1.040, I2 = 0%), for 1 more pack-year (3 cohorts and 21 case-control studies) was 1.017(95% CI 1.016-1.019, I2 = 0%) and for 1 more year of exposure (16 case-control studies) was 1.021 (95% CI 1.020-1.023, I2 = 0%). A positive non-linear dose-response relationship is confirmed between all smoking intensity, pack-years of smoking, smoking duration(years) and the risk of bladder cancer, but the plateau only occurred when smoking intensity reached 20 cigarettes/day. Further studies should report more detailed results, including those for subtypes of gender, age, region and be stratified by other risk factors to rule out residual confounding.

Cigarette Smoke Containing Acrolein Contributes to Cisplatin Resistance in Human Bladder Cancers through the Regulation of HER2 Pathway or FGFR3 Pathway.

Cisplatin-based chemotherapy is the first-line therapy for bladder cancer. However, cisplatin resistance has been associated with the recurrence of bladder cancer. Previous studies have shown that activation of FGFR and HER2 signaling are involved in bladder cancer cell proliferation and drug resistance. Smoking is the most common etiologic risk factor for bladder cancer, and there is emerging evidence that smoking is associated with cisplatin resistance. However, the underlying mechanism remains elusive. Acrolein, a highly reactive aldehyde, is abundant in tobacco smoke, cooking fumes, and automobile exhaust fumes. Our previous studies have shown that acrolein contributes to bladder carcinogenesis through the induction of DNA damage and inhibition of DNA repair. In this study, we found that acrolein induced cisplatin resistance and tumor progression in both non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC) cell lines RT4 and T24, respectively. Activation of HER2 and FGFR3 signaling contributes to acrolein-induced cisplatin resistance in RT4 and T24 cells, respectively. Furthermore, trastuzumab, an anti-HER2 antibody, and PD173074, an FGFR inhibitor, reversed cisplatin resistance in RT4 and T24 cells, respectively. Using a xenograft mouse model with acrolein-induced cisplatin-resistant T24 clones, we found that cisplatin combined with PD173074 significantly reduced tumor size compared with cisplatin alone. These results indicate that differential molecular alterations behind cisplatin resistance in NMIBC and MIBC significantly alter the effectiveness of targeted therapy combined with chemotherapy. This study provides valuable insights into therapeutic strategies for cisplatin-resistant bladder cancer.

An Oxidative Stress-Related Genes Signature for Predicting Survival in Bladder Cancer: Based on TCGA Database and Bioinformatics.

BackgroundOxidative stress (OS) responses have been linked to oncogenesis and tumor progression and have recently been regarded as a potential strategy for tumor therapy. However, OS-related therapeutic targets have not been identified to date in the bladder cancer (BC).MethodsThe mRNA expression and clinical data of BC were downloaded from the public database. Prognostic risk score signature was constructed using LASSO Cox regression analysis. External validation was performed in GSE15307 cohort. ESTIMATE, CIBERSORT, and ssGSEA algorithm were used to analyze immune cell infiltration and immune microenvironment. Next, functional enrichment analysis was performed to elucidate the mechanism underlying the signature. Additionally, we performed a nomogram to forecast the survival rate of individual BC patients.ResultsAn OS-related genes (OSRGs) signature was constructed. Overall survival was lower in the high-risk group than in the low-risk group, according to survival analyses. The area under the curve (AUC) of ROC curves further validated the prognostic signature’s strong prediction performance in these two cohorts. The risk score was verified as an independent risk factor for BC by independent prognostic analysis. Moreover, as compared to TNM stage alone, a nomogram that integrated the risk score with TNM stage showed a much superior predictive value. Immune infiltration and tumor microenvironment studies indicated that immune cells and functions may play a significant role in carcinogenesis and development. The levels of expression of prognostic genes were shown to be substantially linked with drug sensitivity.ConclusionWe developed a novel OSRGs signature for predicting overall survival and impacting the immune status in patients with BC. New nomogram can help clinicians predict the survival rate of BC patients. These findings shed new light on the potential usage of OSRGs signature in BC patients.

Induction of APOBEC3-mediated genomic damage in urothelium implicates BK polyomavirus (BKPyV) as a hit-and-run driver for bladder cancer

Limited understanding of bladder cancer aetiopathology hampers progress in reducing incidence. Mutational signatures show the anti-viral apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) enzymes are responsible for the preponderance of mutations in bladder tumour genomes, but no causative viral agent has been identified. BK polyomavirus (BKPyV) is a common childhood infection that remains latent in the adult kidney, where reactivation leads to viruria. This study provides missing mechanistic evidence linking reactivated BKPyV-infection to bladder cancer risk. We used a mitotically-quiescent, functionally-differentiated model of normal human urothelium to examine BKPyV-infection. BKPyV-infection led to significantly elevated APOBEC3A and APOBEC3B protein, increased deaminase activity and greater numbers of apurinic/apyrimidinic sites in the host urothelial genome. BKPyV Large T antigen (LT-Ag) stimulated re-entry from G0 into the cell cycle through inhibition of retinoblastoma protein and activation of EZH2, E2F1 and FOXM1, with cells arresting in G2. The single-stranded DNA displacement loops formed in urothelial cells during BKPyV-infection interacted with LT-Ag to provide a substrate for APOBEC3-activity. Addition of interferon gamma (IFNγ) to infected urothelium suppressed expression of the viral genome. These results support reactivated BKPyV infections in adults as a risk factor for bladder cancer in immune-insufficient populations.

Tumor genomic landscape in smokers compared to non-smoker patients with locally advanced or metastatic urothelial carcinoma.

554 Background: Cigarette smoking is a known risk factor for bladder cancer. Smokers have been reported to have greater ERCC2-Signature mutations and APOBEC-Signature 13 mutations when compared to non-smokers in a TCGA based study (PMID: 33849962). Our objective was to assess the frequency of targetable genomic alterations in smokers (current or past) vs never smokers patients (pts) with locally advanced or metastatic urothelial carcinoma (mUC). Methods: In this IRB approved retrospective study, smokers vs non-smokers pts with mUC undergoing tumor comprehensive genomic profiling (CGP) from CLIA-certified laboratory were included. Genes with alterations (GA) in &lt; 5% pts and variants of unknown significance were excluded from the analysis. A chi square test was used to compare gene frequency aberration and the analysis was adjusted for false discovery using Benjamini-Hochberg (BH) correction. The median number of genomic aberrations per pt was compared using Wilcoxon rank-sum test. Results: 137 pts were eligible and included. Smokers (n=70) and non-smokers (n=67): median age, 67 vs 68 years; male vs female: 55/15 vs 42/25. The genomic aberrations enriched in smokers and non-smokers are shown in the table. The most common GA observed in smokers were TERT, TP53, CDKN2B, RB1 and KDM6A; and non-smokers were TERT, TP53, CDKN2B, PIK3CA and RB1 (Table). Tumor mutation burden and the frequency of genomic aberrations per pt were similar in both groups. Conclusions: Herein, we independently validate the findings by Walasek, Almassi et. al. (abstract B20, AACR 2020) of no significant difference in the tumor GA between smokers vs non-smokers pts with advanced urothelial carcinoma, despite high prevalence of targetable genomic aberrations in both cohorts. Future directions should include the investigation of epigenomic changes and transcriptomic profiling to further elucidate the effect of smoking on bladder cancer.[Table: see text]

Awareness of Smoking as a Risk Factor in Bladder Cancer: Results from the Prospective FinnBladder 9 Trial

BackgroundData regarding patient education and smoking habits among bladder cancer patients are scarce. ObjectiveTo investigate awareness of smoking as a risk factor for bladder cancer among bladder cancer patients. Design, setting, and participantsThis is a substudy of a prospective, randomized, multicenter phase 3 trial (FinnBladder 9, NCT01675219). The data were collected at baseline and after 12 mo of follow-up between 2012 and 2020. InterventionPatients completed a comprehensive nonvalidated questionnaire on smoking in relation to bladder cancer. Outcome measurements and statistical analysisThe outcomes measured were patient-reported awareness of smoking as a risk factor for bladder cancer, and the effect of smoking on bladder cancer–related recurrence, progression, and death. Parametric data were compared using Student’s t test and proportions using Fischer’s exact test. Factors affecting baseline awareness of the effect of smoking cessation on bladder cancer were studied using logistic regression. Results and limitationsOf the 411 patients randomized, 370 completed the baseline questionnaire and were included in the analysis. At baseline, 44% of patients were uncertain if smoking was a risk factor for bladder cancer. Patient awareness of the fact that smoking cessation reduces the risk of bladder cancer recurrence increased from 86% to 92% after 12 mo of follow-up (p = 0.038). Older patients and patients with recurrent bladder cancer had significantly less knowledge about the effect of smoking on bladder cancer recurrence, progression, and mortality. A major limitation is that the response rate was lower at the 12-mo follow-up visit than at baseline. ConclusionsAwareness of smoking as a bladder cancer risk factor is low. Older patients and patients with recurrent bladder cancer may need special attention regarding education. Patient summaryWe looked at outcomes for smoking-related patient education on bladder cancer in a Finnish population. We conclude that older patients and patients with recurrent bladder cancer may need to be educated on this subject.

Can Routine Blood and Urine Parameters Reveal Clues to Detect Bladder Cancer? A Case-Control Study.

ObjectiveLimited attention has been paid to abnormal blood and urine test results for patients with bladder cancer. The present study aimed to identify whether blood and urine parameters are associated with bladder cancer.MethodsWe used a case–control design and matched each patient with bladder cancer with three healthy controls of the same age and sex. Univariate conditional logistic regression was used to calculate the crude and adjusted odds ratio (OR) and its 95% CI. Multivariate conditional logistic regression was performed for confounders adjustment, and Spearman’s correlation coefficient was used to assess the correlation between tumor T stages and urine parameters.ResultsPatients with bladder cancer (n = 360) and controls (n = 1050) were recruited. In the univariate conditional logistic analysis, higher urine pH was associated with a decreased risk of bladder cancer (OR = 0.67, 95% CI = 0.57–0.78), while higher values of urine protein (OR = 4.55, 95% CI = 3.36–6.15), urine glucose (OR = 1.56, 95% CI = 1.18–2.05), and urine occult blood (OR = 4.27, 95% CI = 3.44–5.29) were associated with an increased risk of bladder cancer. After adjustment for body mass index, fasting blood glucose, hypertension, red blood cells, white blood cells, lymphocytes, neutrophils, and platelets, significance still remained for urine pH (OR = 0.68, 95% CI = 0.53–0.88), urine protein (OR = 1.97, 95% CI = 1.21–3.19), urine glucose (OR = 2.61, 95% CI = 1.39–4.89), and urine occult blood (OR = 3.54, 95% CI = 2.73–4.58).ConclusionThis study indicated that lower urine pH and higher values of urine protein, urine glucose, and urine occult blood might be risk factors for bladder cancer.

Explore the unexplored: Potential anti-tumor properties of Rhododendron against bladder cancer.

Explore the unexplored: Potential anti-tumor properties of Rhododendron against bladder cancer.

Increased risk of bladder cancer in young adult men with hyperlipidemia: A population-based cohort study.

A high-cholesterol diet increases the risk of bladder cancer. The purpose of this nationwide longitudinal population-based retrospective cohort study is to investigate whether hyperlipidemia is a risk factor for bladder cancer.Data from Taiwan National Health Insurance Database were analyzed. The primary study end point was the occurrence of newly diagnosed bladder cancer. The relative risk of bladder cancer in a hyperlipidemia cohort was compared with that in an age- and gender-matched non-hyperlipidemia cohort by using the Cox proportional hazards regression model. Cox regression analyses were further adjusted by the propensity score.Our data revealed that the hyperlipidemia cohort (n = 33,555) had a significantly higher subsequent risk of bladder cancer than did the non-hyperlipidemia cohort (n = 33,555) (adjusted hazard ratio [HR] = 1.37, P = .005) after propensity score adjustment. Subgroup analyses revealed that men in the hyperlipidemia cohort had a significantly higher subsequent risk of bladder cancer than did those in the non-hyperlipidemia cohort (adjusted HR = 1.36, P = .040). However, the risk of bladder cancer was not significantly different between women in the hyperlipidemia cohort and those in the non-hyperlipidemia cohort. Subgroup analyses further revealed that the risk of bladder cancer was significantly higher in men aged 20 to 39 years in the hyperlipidemia cohort than in those in the non-hyperlipidemia cohort (adjusted HR = 5.45, P = .029).In conclusion, hyperlipidemia is a risk factor for bladder cancer in young adult men.