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Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer.

ABSTRACT: Glutathione (GSH) is an important molecule involved in cell detoxification and antioxidation and may affect cancer development or outcome. We hypothesized that genetic variation in the GSH pathway might influence the clinical outcome of patients who have non-muscle invasive bladder cancer (NMIBC).A total of 114 single nucleotide polymorphisms (SNPs) in 21 GSH pathway genes were genotyped in 414 NMIBC patients treated with transurethral resection alone (TUR) and both TUR and intravesical bacillus Calmette-Guérin instillation (BCG) therapy. The effect of each SNP on time to recurrence was estimated using the multivariate Cox proportional hazards model. Cumulative effect and survival tree analyses were performed to determine the joint effects of unfavorable genotypes and gene-gene interactions on bladder cancer prognosis.Seven SNPs showed significant associations with cancer recurrence in the TUR group and 15 SNPs showed significant associations with recurrence in the BCG group. The most significant SNP in the TUR group was rs3746162 in GPX4, whose variant genotype conferred a 5.4-fold increased risk of recurrence compared with wild-type (hazard ratio [HR] = 5.43, 95 % confidence interval [CI] = 2.19-13.46), whereas the most significant SNP in the BCG group was rs7265992 in GSS (HR 3.43, 95 % CI 1.56-7.56). The risk of recurrence increased with the number of unfavorable genotypes in both groups. Within treatment group, stratified analyses by tumor grade also indicated predictive variants.Genetic variants in GSH pathway may influence cancer recurrence in NMIBC patients receiving curative treatment.

SUBMITTER: Ke HL

PROVIDER: S-EPMC4598273 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer.

Ke Hung-Lung HL Lin Jie J Ye Yuanqing Y Wu Wen-Jeng WJ Lin Hui-Hui HH Wei Hua H Huang Maosheng M Chang David W DW Dinney Colin P CP Wu Xifeng X

Annals of surgical oncology 20150408 12

<h4>Background</h4>Glutathione (GSH) is an important molecule involved in cell detoxification and antioxidation and may affect cancer development or outcome. We hypothesized that genetic variation in the GSH pathway might influence the clinical outcome of patients who have non-muscle invasive bladder cancer (NMIBC).<h4>Methods</h4>A total of 114 single nucleotide polymorphisms (SNPs) in 21 GSH pathway genes were genotyped in 414 NMIBC patients treated with transurethral resection alone (TUR) and ...[more]

PMID: 25851338

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Project description:ObjectiveSeveral guidelines recommended that second transurethral resection should be performed in patients with diagnosis of high-risk non-muscle-invasive bladder cancer. However, therapeutic benefits of second transurethral resection before bacillus Calmette-Guérin intravesical instillation were conflicting amongst previous studies. We investigated the prognostic impact of second transurethral resection before bacillus Calmette-Guérin instillation in high-risk non-muscle-invasive bladder cancer patients.MethodsThis retrospective study included 3104 non-muscle-invasive bladder cancer patients who received bacillus Calmette-Guérin instillations between 2000 and 2019 at 31 collaborative institutions. Univariate and multivariate Cox proportional hazards models were used to assess the risk factors of intravesical recurrence, disease progression, cancer-specific mortality and overall mortality.ResultsIn the entire population, patients undergoing second transurethral resection (33%, 1026/3104) had a lower risk of intravesical recurrence on univariate analysis (hazard ratio 0.85, 95% confidence interval 0.73-0.98, P = 0.027), although it did not remain significant on multivariate analysis (hazard ratio 0.90, 95% confidence interval 0.76-1.07, P = 0.24). Subgroup analysis revealed that, in pT1 patients (n = 1487), second transurethral resection was significantly correlated with a lower risk of intravesical recurrence on multivariate analysis (hazard ratio 0.80, 95% confidence interval 0.64-1.00, P = 0.048), but lower risks of disease progression (hazard ratio 0.75, 95% confidence interval 0.56-1.00, P = 0.049), cancer-specific mortality (hazard ratio 0.54, 95% confidence interval 0.35-0.85, P = 0.007) and overall mortality (hazard ratio 0.73, 95% confidence interval 0.55-0.97, P = 0.027) on univariate analysis.ConclusionsSecond transurethral resection confers accurate pathological staging and could be used to safely select good candidates for intravesical bacillus Calmette-Guérin instillation. We further confirm that second transurethral resection could confer an oncological benefit in pT1 bladder cancer patients treated by bacillus Calmette-Guérin instillation, and so strongly recommend second transurethral resection in this patient population.

Project description:PurposePrior reports suggest that renin-angiotensin system inhibition may decrease nonmuscle invasive bladder cancer recurrence. We evaluated whether angiotensin converting enzyme inhibitor or angiotensin receptor blocker treatment at initial surgery was associated with decreased recurrence or progression in patients with nonmuscle invasive bladder cancer.Materials and methodsUsing an institutional bladder cancer database we identified 340 patients with data available on initial transurethral resection of bladder tumor. Progression was defined as an increase to stage T2. Cox proportional hazards models were used to evaluate associations with recurrence-free and progression-free survival.ResultsMedian patient age was 69.6 years. During a median followup of 3 years (IQR 1.3-6.1) 200 patients (59%) had recurrence and 14 (4.1%) had stage progression. Of those patients 143 were receiving angiotensin converting enzyme inhibitor/angiotensin receptor blockers at the time of the first transurethral resection. On univariate analysis factors associated with improved recurrence-free survival included carcinoma in situ (p = 0.040), bacillus Calmette-Guérin therapy (p = 0.003) and angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (p = 0.009). Multivariate analysis demonstrated that patients treated with bacillus Calmette-Guérin therapy (HR 0.68, 95% CI 0.47-0.87, p = 0.002) or angiotensin converting enzyme inhibitor/angiotensin receptor blocker therapy (HR 0.61, 95% CI 0.45-0.84, p = 0.005) were less likely to experience tumor recurrence. The 5-year recurrence-free survival rate was 45.6% for patients treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers and 28.1% in those not treated with angiotensin converting enzyme inhibitor/angiotensin receptor blockers (p = 0.009). Subgroup analysis was performed to evaluate nonmuscle invasive bladder cancer pathology (Ta, T1 and carcinoma in situ) in 85 patients on bacillus Calmette-Guérin therapy alone and in 52 in whom it was combined with angiotensin converting enzyme inhibitor/angiotensin receptor blocker. Multivariate analysis revealed that patients treated with bacillus Calmette-Guérin alone (HR 2.19, 95% CI 1.01-4.77, p = 0.04) showed worse recurrence-free survival compared to patients treated with bacillus Calmette-Guérin and angiotensin converting enzyme inhibitor/angiotensin receptor blocker (stage Ta HR 0.45, 95% CI 0.21-0.98, p = 0.04).ConclusionsPharmacological inhibition of the renin-angiotensin system is associated with improved outcomes in patients with bladder cancer. Renin-angiotensin system inhibitor administration in nonmuscle invasive bladder cancer cases should be studied in a prospective randomized trial.

Project description:BackgroundThe high recurrence rate of non-muscle-invasive bladder cancer (NMIBC) after tumor resection brings huge physical and financial burdens for patients. Several predictive models that predict the recurrence of patients with NMIBC have drawbacks in clinical practice. With the rapid development of therapeutic methods, more factors should be taken into consideration when constructing predictive model.MethodsWe retrospectively enrolled 90 patients who were diagnosed as intermediate- or high-risk NMIBC and received a Thulium laser resection of bladder tumor (TmLRBT) or transurethral resection of bladder tumor (TURBT) followed by BCG instillation. Univariate Cox regression analysis and multivariate Cox regression analysis were performed to screen out the independent prognostic factors of recurrence free survival (RFS). A nomogram and risk index were constructed using these prognostic factors.ResultsIn this study, 22 patients suffered recurrence; 37 patients (41%) received TmLRBT, and over 90% patients completed intravesical BCG instillation for one year. The univariate Cox regression showed that surgery (TURBT vs TmLRBT), previous bladder tumor, tumor number, pathological stage, post-operative catheterization and number of BCG therapy were associated with RFS. The multivariate Cox regression revealed that surgery (TURBT vs TmLRBT) (HR = 3.16, 95%CI [1.02 - 9.83]); previous bladder tumor (HR = 4.03, 95%CI [1.41 - 11.54]); number of BCG therapy (HR = 0.89, 95%CI [0.84 - 0.95]) were independent prognostic factors. A nomogram was constructed and exhibited excellent capability in predicting the RFS with an AUC of 0.789, 0.848, 0.806 at 6-, 12- and 24-months respectively and a c-index of 0.822. Also, the calibration curve and decision curve analysis were performed to verify the predictive efficacy. The risk index was derived from the nomogram and also exhibited favorable capability in predicting the progression free survival (PFS) of patients.ConclusionsPatients who received TmLRBT, without previous bladder tumor history and had more intravesical BCG instillations are likely to have better RFS. The nomogram and the risk index which were constructed to predict the RFS and PFS of patients may help urologists to make clinical decisions and aid in precision medicine.

Dataset Information

Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer.

Publications

Genetic Variations in Glutathione Pathway Genes Predict Cancer Recurrence in Patients Treated with Transurethral Resection and Bacillus Calmette-Guerin Instillation for Non-muscle Invasive Bladder Cancer.

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