AhRR methylation contributes to disease progression in urothelial bladder cancer.

BACKGROUND: Bladder Cancer (BCa) is the tenth most incident malignancy worldwide. BCa is mostly attributed to environmental exposure and lifestyle, particularly tobacco smoking. The Aryl Hydrocarbon Receptor Repressor (AhRR) participates in the induction of many enzymes involved in metabolizing carcinogens, including tobacco smoke components. Additionally, studies have shown that smoking demethylates the (AhRR) gene in blood, suggesting AhRR demethylation as a specific serum smoking biomarker. OBJECTIVE: This study aimed to validate AhRR demethylation as a smoking biomarker in the target tissue and investigate its contribution to bladder carcinogenesis. METHODS: AhRR percent methylation was tested for its association with patient smoking status and oncogenic outcome indicators, particularly p53, RB1, and FGFR3 activating mutations, muscle-invasiveness, and tumor grade, in 180 BCa tissue-based DNA. RESULTS: Results showed significantly higher AhRR percent methylation in muscle-invasive compared to non-muscle invasive tumors (42.86% vs. 33.98%; p= 0.011), while lower AhRR methylation was significantly associated with FGFR3 Codon 248 mutant genotype compared to wild-type (28.11% ± 9.44 vs. 37.87% ± 22.53; p= 0.036). All other tested associations were non-statistically significant. CONCLUSIONS: Although AhRR methylation did not predict smoking status in BCa tumors, it may be a contributor to carcinogenesis and disease progression. Our findings constitute the basis for further research.

Slow N-acetylation as a possible contributor to bladder carcinogenesis.

Bladder cancer (BCa) is an exophytic tumor that presents as either noninvasive confined to the mucosa (NMIBC) or invading the detrusor muscle (MIBC), and was recently further subgrouped into molecular subtypes. Arylamines, major BCa environmental and occupational risk factors, are mainly metabolized by the genetically polymorphic N-acetyltransferases 1, NAT1 and NAT2. In this study, we investigated the association between N-acetyltransferases genetic polymorphism and key MIBC and NMIBC tumor biomarkers and subtypes. A cohort of 250 males with histologically confirmed urothelial BCa was identified. Tumors were genotyped for NAT1 and NAT2 using real-time polymerase chain reaction (PCR), and characterized for mutations in TP53, RB1, and FGFR3 by PCR-restriction fragment length polymorphism. Pathology data and patients' smoking status were obtained from medical records. Pearson χ2 and Fisher exact tests were used to check for associations and interactions. Results show that NAT1 G560 A polymorphism is significantly associated with higher muscle-invasiveness (MIBC vs NMIBC; P = .001), higher tumor grade (high grade vs low grade; P = .011), and higher FGFR3 mutation frequency within the MIBC subgroup (P = .042; .027). NAT2 G857 A polymorphism is also found to be significantly associated with higher muscle-invasiveness (MIBC vs NMIBC; P = .041). Our results indicate that slow N-acetylation is a contributor to bladder carcinogenesis and muscle-invasiveness. These findings highlight NAT1 as a biomarker candidate in BCa and a potential target for drug development.

Non-Angled Intercostal Percutaneous Access Under Full Expiration: Safety Is Not an Issue Anymore.

OBJECTIVE: Percutaneous nephrolithotomy (PCNL) is a well-established procedure for the management of urinary calculi and can be performed intercostally or subcostally. Favoring one approach vs the other is still debatable, and literature has been inconclusive regarding the efficacy and safety of both approaches. Hence, this study aims to assess the safety and efficacy of direct non-angled intercostal technique performed under full expiration and to compare it to the subcostal approach. METHODS: PCNL was conducted among 361 patients during 2010-2015 at Saint George Hospital University Medical Center in Beirut, Lebanon. PCNL was done by one operator and by following a standard technique. After reviewing the medical records, 304 patients were included. Data analysis was conducted using Stata/IC 10.0. Bivariate analysis was conducted using Pearson's Chi-square, and logistic regression model was run. Alpha level was set at 0.05. RESULTS: Of the total patients, 54.6% and 45.4% underwent intercostal (Group I) and subcostal (Group II) access, respectively. Mean drop in hemoglobin in Group II was 1.9 g/dL vs 1.48 g/dL in Group I (p-value = 0.0040). The mean difference in operation time between group I (88.61 minutes) and group II (102.58 minutes) was statistically significant (p-value = 0.0064). Patients were stone free in 88.05% of the intercostal cases and 78.52% of the subcostal cases. Group II patients were twice more likely to have residual stones compared to Group I (p-value = 0.029). No statistical significance was observed in postoperative complications among both groups. In addition, no cases of pneumothorax were reported. CONCLUSION: Compared to subcostal access, intercostal approach under full expiration is a safe technique that provides optimal approach to the intrarenal collecting system and allows less angulation, less bleeding, and yields higher stone clearance with minimal complications. When performed by a well-trained urologist, intercostal access should be advocated in PCNL to obtain a direct non-angled access to the tip of the desired posterior calix.

CYP2E1 and NQO1 genotypes and bladder cancer risk in a Lebanese population.

Urinary bladder cancer incidence in Lebanon ranks among the highest in the world. Cytochrome P450 2E1 (CYP2E1), NAD(P)H quinone oxidoreductase1 (NQO1), and N-Acetyltransferase1 (NAT1), are drug-metabolizing enzymes (DMEs) involved in the metabolism of carcinogens, such as arylamines and heterocyclic amines, implicated in bladder cancer. The present study attempts to investigate the role of these DMEs genetic polymorphism in bladder cancer risk among Lebanese men. 54 cases and 106 controls were recruited from two hospitals in Beirut. An interview-based questionnaire was administered to assess suspected environmental and occupational risk factors. PCR-RFLP was performed on blood-based DNA samples to determine DMEs genotypes. Associations between bladder cancer and putative risk factors were measured using adjusted odds ratios (ORs) and their 95% confidence intervals (CIs). Results showed CYP2E1 c1/c1, NAT1*14A, and smoking, to be risk factors for bladder cancer. No significant differences in frequency distribution of the NQO1 genotypes were found in cases versus controls. The odds of carrying the CYP2E1 c1/c1 genotype were 4 times higher in cases compared to controls (OR=3.97, 95% CI: 0.48-32.7). The odds of carrying at least one NAT1*14A allele were 14 times higher in cases versus controls (OR=14.4, 95% CI: 1.016-204.9). Our study suggests CYP2E1 c1/c1, NAT1*14A, and smoking, as potential risk factors for bladder cancer in Lebanese. Further studies with larger samples must be conducted to confirm these findings.

N-Acetyltransferase 1 (NAT1) Genotype: A Risk Factor for Urinary Bladder Cancer in a Lebanese Population.

In Lebanon, bladder cancer is the second most incident cancer among men. This study investigates a possible association between N-acetyltransferase 1 (NAT1) genotype, a drug-metabolizing enzyme coding gene, and bladder cancer in Lebanese men. A case-control study (54 cases and 105 hospital-based controls) was conducted in two major hospitals in Beirut. Cases were randomly selected from patients diagnosed in the period of 2002-2008. Controls were conveniently identified and selected from the same settings. Data was collected using interview questionnaire and blood analysis. NAT1 genotypes were determined by PCR-RFLP. Statistical analysis revolved around univariate, bivariate, and multivariate logistic regression models, along with checks for effect modification. Results showed NAT1(∗)14A allele, smoking, occupational exposure to combustion fumes, and prostate-related symptoms, to be risk factors for bladder cancer. The odds of carrying at least one NAT1(∗)14A allele are 7 times higher in cases compared to controls (OR = 7.86, 95% CI: 1.53-40.39). A gene-environment interaction was identified for NAT1(∗)14A allele with occupational exposure to combustion fumes. Among carriers of NAT1(∗)14A allele, the odds of bladder cancer dropped to 2.03 from 3.72. Our study suggests NAT1(∗)14A allele as a possible biomarker for bladder cancer. Further research is recommended to confirm this association.