Survival analysis in association with GST gene polymorphism and Treatment outcomes of Gemcitabine and Cisplatin/Carboplatin-based chemotherapy among patients with Gallbladder Carcinoma.

PURPOSE: Majority of the gallbladder cancer (GBC) cases are diagnosed at an advanced stage where chemotherapy alone (or in combination with other treatment methods) is mainly opted as therapeutic approach. However, success or failure of this approach largely depends on the interindividual genetic differences. Careful consideration on the genetic association could assist in the evaluation of patient's treatment response and survival rate. Hence, the present study aims to investigate the survival of patients with GBC and their treatment response to gemcitabine and cisplatin/carboplatin-based chemotherapy in association with Glutathione S-transferase (GSTs) gene polymorphism. MATERIAL AND METHODS: A total of 216 histologically confirmed cases of gallbladder cancer were recruited. A total of 180 patients were treated with gemcitabine and cisplatin/carboplatin-based chemotherapy. GSTM1, GSTT1, and GSTP1 genotypes were determined by multiplex PCR and by PCR restriction fragment length polymorphism (PCR-RFLP), respectively. The influence of genetic polymorphism on overall survival was analyzed by Kaplan-Meier method, survival rate difference was analyzed by log-rank test, and hazard ratio for mortality outcomes was estimated using Cox regression method. RESULTS: GBC patients having genotype GSTP1 (AG + GG) showed poor 3-year survival rate of 0.8% compared to 10.9% of GSTP1 (AA) genotype (χ2 = 6.456, P = 0.011). The multivariate Cox regression results showed that the death risk was significantly higher in GSTP1 (AG + GG) genotype (HR = 3.858, P = 0.050). We found no association of GSTM1 and GSTT1 gene polymorphism with the survival; however, the combined genotypes of GSM1/GSTP1, GSTT1/GSTP1, and GSTM1/GSTT1/GSTP1 were associated with survival (P = 0.053, 0.006, and 0.058, respectively). Increased death hazard was noted by the genotype combinations of GSTM1+/GSTP1AG + GG (HR = 3.484, P = 0.024), GSTM1-/GSTP1AG + GG (HR = 2.721, P = 0.014), GSTT1+/GSTP1AG + GG (HR = 20.690, P = 0.001), and GSTT1-/GSTP1AA (HR = 26.111, P < 0.0001). Our findings indicate that chemotherapy treatment response of GSTP1 (AG + GG) has 1.62-fold increased risk for progression compared to GSTP1 (AA) genotype (p = 0.018); however, none of the genotypes showed association with overall survival and death risk after chemotherapeutic treatment. CONCLUSION: We found that the presence of GSTP1 (AG + GG) genotype showed survival disadvantage and poor treatment outcomes in response to gemcitabine and cisplatin/carboplatin-based chemotherapy. This could serve as biomarker, and future research in pharmacogenomics will definitely pave the way for the development of better treatment approach for GBC.

GSTs genetic polymorphism, gene-environment interaction and association with gallbladder cancer risk in North Indian population: A case-controlled study.

AIM: In the present case-controlled study, we explored the role of genetic polymorphism in three xenobiotic metabolizing genes, GSTM1, GSTT1 and GSTP1, and their association to gallbladder cancer (GBC) risk in a North Indian population. Its etiology is influenced by genetic, food habits, lifestyle, and environmental factors. GBC incidence is significantly higher in the Gangetic belt, India. Therefore, we explored the prognostic factors in the susceptibility of GBC through gene-gene and gene-environment interaction in this region. MATERIAL AND METHODS: Genetic polymorphism was analyzed in 108 GBC patients from Kamala Nehru Memorial Cancer Hospital, Prayagraj and 142 matched controls. GSTM1 and GSTT1 genotypes were analyzed by multiplex PCR method, while restriction fragment length polymorphism (RFLP) was performed to analyze GSTP1 genotypes. Logistic regression analysis calculating the odds ratio (OR) and 95% confidence interval (CI) was performed to analyze the GBC risk. RESULTS: GSTT1 (null) genotype was at a significantly higher risk and susceptible to GBC (OR = 2.044, CI = 1.225-3.411, P = 0.006), while GSTM1 and GSTP1 genotypes did not show any association to GBC risk. After sex stratification, females diagnosed with GBC had higher GSTT1 (null) genotype (OR = 2.754, CI = 1.428-5.310, P = 0.003) compared to males. GBC patients dwelling in rural areas show higher GSTT1 (null) genotype with two-fold GBC risk (OR = 2.031, CI = 1.200-3.439, P = 0.008). Further, GBC patients with histopathology of adenocarcinoma also showed higher GSTT1 (null) genotype (OR = 2.113, CI = 1.248-3.578, P = 0.005). Gene-gene interaction between GSTT1 (non-null)/GSTP1 (Ile/Val + Val/Val), enhance the GBC risk (OR = 1.840, CI = 1.135-2.982, P = 0.013). CONCLUSIONS: The present study suggests that GSTT1 (null) genotype has higher susceptibility and risk towards GBC in North Indian population. Female patients, patients with histopathology of adenocarcinoma and rural dwelling GBC patients have higher GSTT1 (null) genotypes and may be at risk of developing GBC. The genotype combination GSTT1 (non-null)/GSTP1 (Ile/Val + Val/Val) has increased GBC susceptibility and may be considered as 'at risk' genotypes for GBC in North Indians.

Survival analysis and prognostic factors of the carcinoma of gallbladder.

BACKGROUND: The present study aims to evaluate the survival status of patients with gallbladder cancer (GBC) and explore the prognostic factors for the improvement and preventions. METHODS: The study consists of 176 patients with clinically diagnosed gallbladder cancer; the study was conducted between 2019 and 2021 registered at Kamala Nehru Memorial Cancer Hospital, Prayagraj, India. The survival rates were analyzed by the Kaplan-Meier method; survival rate difference was analyzed by log-rank test, prognosis factors; and hazard ratio for mortality outcomes was estimated using Cox regression method. RESULTS: The overall median survival time of patients was 5 months with the 1-year, 2-year, and 3-year survival rates of 24.4%, 8.5%, and 4.5%, respectively. The 3-year survival for patients with jaundice was 2.9%, liver infiltration (4.2%), gallstones (0.8%), and with advanced tumor grade (1.4%). Elderly GBC patients had lower survival rates (3.8%), while the 3-year overall survival for patients residing in urban areas dropped to zero. No patients in the tumor stage (T3/T4) and with distance metastasis stage survived in 3 years, while only 1.1% of patients with advanced nodal stage survived. On receiving surgery and radiation therapy, the 3-year survival rate increased to 19.5% and 35%, respectively. The results of multivariate analysis showed that urban region (HR = 1.568, p = 0.040), gallstone or not (1.571, p = 0.049), N stage (HR = 1.468, p = 0.029), and M stage (HR = 2.289, p < 0.0001) were independent risk factors for prognosis, while surgery or not (HR = 0.573, p = 0.030) was the protective factor for the prognosis of GBC. CONCLUSION: The overall survival of GBC in the Gangetic belt is poor. The geographical region of patients, gallstones, and N and M stage was the risk factors for prognosis, while surgery or not was the protective factor for the prognosis of GBC.

Metabolic Pathways, Enzymes, and Metabolites: Opportunities in Cancer Therapy.

Metabolic reprogramming enables cancer cells to proliferate and produce tumor biomass under a nutrient-deficient microenvironment and the stress of metabolic waste. A cancer cell adeptly undergoes a variety of adaptations in metabolic pathways and differential expression of metabolic enzyme genes. Metabolic adaptation is mainly determined by the physiological demands of the cancer cell of origin and the host tissue. Numerous metabolic regulators that assist cancer cell proliferation include uncontrolled anabolism/catabolism of glucose metabolism, fatty acids, amino acids metabolism, nucleotide metabolism, tumor suppressor genes, microRNAs, and many regulatory enzymes and genes. Using this paradigm, we review the current understanding of metabolic reprogramming in tumors and discuss the new strategies of cancer metabolomics that can be tapped into for cancer therapeutics.

Investigating the Role of Glutathione S- Transferase Genes, Histopathological and Molecular Subtypes, Gene-Gene Interaction and Its Susceptibility to Breast Carcinoma in Ethnic North- Indian Population.

BACKGROUND: Breast Cancer (BC) is a genetically and clinically heterogeneous disease including complex interactions between gene-gene and gene-environment components. This study aimed, to explore whether the Glutathione S- transferase (GSTs) gene polymorphism has role in BC susceptibility. We further evaluated the frequency of four subtypes of BC based on molecular classification followed by microscopic histological analysis to study the grades of invasive ductal carcinoma (IDC). MATERIALS AND METHOD: Polymorphism in GST genes in North-Indian BC patients was assessed by multiplex-PCR and PCR-RFLP methods. 105 BC patients and 145 healthy controls were enrolled for this study. Data was analyzed by calculating the odds ratio (OR) and 95% CI from logistic regression analyses. RESULTS: Our findings revealed that GSTM1 null genotype (OR = 2.231; 95% CI = 1.332-3.737; p-value= 0.002) is significantly associated to BC risk in ethnic North- Indian population. However, the risk for BC susceptibility in North-Indians does not appear to be associated with GSTT1 null genotype. The GSTP1 (Val/Val) genotype (OR=1.545; CI=0.663-3.605; p-value= 0.314) was also found to be susceptible for BC risk. Combination of three high risk GST genotypes association exhibiting gene-gene interaction further confirmed the increased risk to BC in this region. CONCLUSIONS: The results of present study indicated that polymorphism in GSTM1 and rs1695 of GSTP1 genes may influence BC development among North-Indian women. Thus, the screening of GSTM1 and GSTP1 gene should be recommended for the earlier investigation for BC as a precautionary measure.

Predictors of postpartum family planning uptake in Sindh and Punjab provinces of Pakistan.

OBJECTIVE: Combination of beneficiary and supply side factors for determining what influences Postpartum family planning use in Sindh and Punjab provinces of Pakistan. METHODS: A facility-based survey was conducted among 1690 married women of reproductive age (MWRA - i.e. married women between the ages of 15 and 49 years) visiting public facilities in six districts across Sindh and Punjab provinces of Pakistan. RESULTS: Half (53%) of the interviewed women used postpartum contraceptives. Participants who used PPFP were: 55% more likely to be from Punjab than Sindh, 39% more likely to be between 25 to 34 year of age than under 25 years. After adjusting for all variables in the model, women who delivered in the private sector remained to have lower odds of PPFP use compared to those who delivered in public facilities. Women who had four or more sons were nearly 20 time more likely to use PPFP compared to women with no sons, and the PPFP use increases with the number of sons. On the contrary, women who had four or more daughters were 16 times less likely to use PPFP compared with women with no daughters. CONCLUSIONS: Postpartum women are among those with the greatest unmet need as a result of a combination of beneficiary and supplier side factors. The health system's response to meet the contraceptive needs of postpartum women should work along the continuum of care from pregnancy to postpartum, with expanded method choice and alternative service delivery outlets.