Yunhua Fan

Urinary Levels of Tobacco-Specific Nitrosamine Metabolites in Relation to Lung Cancer Development in Two Prospective Cohorts of Cigarette Smokers

4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) and its glucuronides (sum of which is denoted as total NNAL) are metabolites of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). NNK and NNAL can induce lung cancer in laboratory animals but human data are limited. The association between prediagnostic levels of urinary total NNAL and risk of lung cancer development was evaluated in two prospective cohorts of Chinese cigarette smokers. We conducted a nested case-control study involving 246 cases of incident lung cancer and 245 cohort controls who were individually matched to the index cases by age, gender, neighborhood of residence at cohort enrollment, and date of urine collection. Urinary levels of total NNAL were significantly associated with risk of lung cancer in a dose-dependent manner. Relative to the lowest tertile, risks associated with the second and third tertiles of total NNAL were 1.43 [95% confidence interval (95% CI), 0.86-2.37] and 2.11 (95% CI, 1.25-3.54), respectively (P for trend=0.005) after adjustment for self-reported smoking history and urinary total cotinine. Smokers in the highest tertiles of urinary total NNAL and total cotinine exhibited a 8.5-fold (95% CI, 3.7-19.5) increased risk for lung cancer relative to smokers with comparable smoking history but possessing the lowest tertiles of urinary total NNAL and total cotinine. Findings of the present study directly link NNK exposure to lung cancer development in humans.

Alcohol, tobacco, and diet in relation to esophageal cancer: the Shanghai Cohort Study.

Prospective data on environmental exposures, especially with respect to alcohol, tobacco, and diet, in relation to the risk of esophageal cancer in high-risk populations are sparse. We analyzed data from a population-based cohort of 18,244 middle-aged and older men in Shanghai to identify risk factors for esophageal cancer in this high-risk population. The cohort was followed through 2006, and 101 incident esophageal cancer cases were identified. Cox proportional hazards models were used to estimate hazard ratios (HR) and their corresponding 95% confidence intervals (CI) for associations between exposures and esophageal cancer risk. With adjustment for tobacco use and other potential confounders, regular drinkers vs. nondrinkers of alcoholic beverages had a twofold risk of developing esophageal cancer (HR = 2.02, 95% CI = 1.31–3.12). With adjustment for alcohol and other potential confounders, long-term smokers (40+ yr) vs. nonsmokers of cigarettes showed a twofold risk of developing esophageal cancer (HR = 2.06, 95% CI = 1.11–3.82). Increased consumption of fruits (including oranges/tangerines), seafood, and milk were found to be protective against the development of esophageal cancer; HRs were decreased by 40–60% for high vs. low consumers after adjustment for cigarette smoking, alcohol drinking, and other confounders.

Prospective evaluation of hepatitis B 1762(T)/1764(A) mutations on hepatocellular carcinoma development in Shanghai, China.

Chronic infection with the hepatitis B virus (HBV) is the most important risk factor for hepatocellular carcinoma (HCC). However, determinants of HCC risk in infected individuals are not well understood. We prospectively evaluated the association between acquired HBV 1762T/1764A double mutations and HCC risk among 49 incident HCC cases and 97 controls with seropositive hepatitis B surface antigen at baseline from a cohort of 18,244 men in Shanghai, China, enrolled during 1986 to 1989. Compared with HBV carriers without the mutations, chronic HBV carriers with the HBV 1762T/1764A double mutations experienced an elevated risk of HCC (odds ratio, 2.47; 95% confidence interval, 1.04-5.85; P = 0.04). Risk increased with increasing copies of the double mutations; men with ≥500 copies/μL serum had an odds ratio of 14.57 (95% confidence interval, 2.41-87.98) relative to those without the double mutations (Ptrend = 0.004). Thus, the HBV 1762T/1764A double mutation is a codeterminant of HCC risk for people chronically infected with HBV. (Cancer Epidemiol Biomarkers Prev 2009;18(2):590–4)

Alcohol and tobacco use in relation to gastric cancer: a prospective study of men in Shanghai, China.

Background: Epidemiologic findings of tobacco and alcohol use in relation to gastric cancer are inconsistent. Well-designed prospective studies examining their relationship are sparse. Methods: The association between cigarette smoking/alcohol intake and gastric cancer risk was examined in a population-based prospective cohort of 18,244 middle-aged and older men in Shanghai, China, who were enrolled in the study during 1986-1989. After up to 20 years of follow-up, 391 incident gastric cancer cases were identified. Cox proportional hazards regression models were used to estimate hazard ratios (HR) and corresponding 95% confidence intervals (95% CI). Results: Ever smokers experienced a statistically significant increased risk of gastric cancer (HR, 1.59; 95% CI, 1.27-1.99) compared with nonsmokers after adjustment for alcohol intake and other confounders. Among nondrinkers, smokers experienced 80% increased risk of gastric cancer (HR, 1.81; 95% CI,1.36, 2.41). Conversely, heavy drinkers experienced a statistically significant increase in risk of gastric cancer (HR, 1.46; 95% CI, 1.05-2.04) among all subjects and a statistically nonsignificant 80% increased risk among never smokers. Further adjustment for Helicobacter pylori serology, serum levels of β-carotene and vitamin C, and urinary level of total isothiocyanates in combination with glutathione S-transferase (GST) M1 and GSTT1 genotypes did not materially change the associations between smoking/alcohol consumption and gastric cancer risk. Conclusions: These results suggest that cigarette smoking and alcohol consumption may exert independent effects on the development of gastric cancer in this high-risk population. Impact: Modification of these lifestyle choices may reduce the incidence of gastric cancer. Cancer Epidemiol Biomarkers Prev; 19(9); 2287–97. ©2010 AACR.

Urinary 3,3′-Diindolylmethane: A Biomarker of Glucobrassicin Exposure and Indole-3-Carbinol Uptake in Humans

Background: Brassica vegetable consumption may confer a protective effect against cancer, possibly attributable to their glucosinolates. Glucobrassicin is a predominant glucosinolate and is the precursor of indole-3-carbinol (I3C), a compound with anticancer effects. However, objective assessments of I3C uptake from Brassica vegetables have not been successful. Methods: We conducted a randomized, crossover trial to test whether 3,3′-diindolylmethane (DIM, a metabolite of I3C) excreted in the urine after consumption of raw Brassica vegetables with divergent glucobrassicin concentrations is a marker of I3C uptake from such foods. Twenty-five subjects were fed 50 g of either raw “Jade Cross” Brussels sprouts (high glucobrassicin concentration) or “Blue Dynasty” cabbage (low glucobrassicin concentration) once daily for 3 days. All urine was collected for 24 hours after vegetable consumption each day. After a washout period, subjects crossed over to the alternate vegetable. Urinary DIM was measured using a novel liquid chromatography-electrospray ionization-tandem mass spectrometry–selected reaction monitoring (LC-ESI-MS/MS-SRM) method with [2H2]DIM as internal standard. Results: Urinary DIM was consistently and significantly higher after Brussels sprouts feeding than after cabbage feeding, as evidenced by an average difference of 8.73 pmol/mg creatinine (95% confidence interval, 5.36–12.10; P = 0.00002). Conclusion: We have successfully quantified urinary DIM after uptake of I3C from food, and demonstrated that differences in glucobrassicin exposure are reflected in urinary DIM levels. Impact: Our LC-ESI-MS/MS-SRM method and the results of our study indicate urinary DIM is a measure of I3C uptake from Brassica vegetables, a finding that can be utilized in prospective epidemiologic and chemoprevention studies. Cancer Epidemiol Biomarkers Prev; 23(2); 282–7. ©2013 AACR.

Genetic polymorphisms of epidermal growth factor in relation to risk of hepatocellular carcinoma: two case-control studies

BackgroundEarlier, we reported a highly statistically significant association between T-helper 1 (Th1) and Th2 cytokine genotypes and hepatocellular carcinoma (HCC) risk among natives of southern Guangxi, China, a hyperendemic region for HCC. Epidermal growth factor (EGF) plays a critical role in malignant transformation of hepatocytes and tumor progression. A polymorphism in the EGF gene (61A > G) results in elevation of EGF in liver tissues and blood. Epidemiological data are sparse on the possible association between EGF genetic polymorphism and HCC risk.MethodsThe EGF 61A > G polymorphism, multiple Th1 and Th2 genotypes, and environmental risk factors for HCC were determined on 117 HCC cases and 225 healthy control subjects among non-Asians of Los Angeles County, California, a low-risk population for HCC, and 250 HCC cases and 245 controls of southern Guangxi, China.ResultsFollowing adjustment for all known or suspected HCC risk factors, non-Asians in Los Angeles who possessed at least one copy of the high activity 61*G allele of the EGF gene showed a statistically non-significant, 78% increased risk of HCC compared with those possessing the EGF A/A genotype. This EGF-HCC risk association significantly strengthened among heavy users of alcohol [odds ratio (OR) = 3.44, 95% confidence interval (CI) = 0.93–12.76, P = 0.065)], and among individuals carrying the high-risk Th1/Th2 genotypes for HCC (OR = 3.34, 95% CI = 1.24-9.03, P = 0.017). No association between EGF genotype and HCC risk was observed among Chinese in southern Guangxi, China.ConclusionGenetic polymorphism in the EGF gene resulting in elevated level of EGF, may contribute to HCC risk among low-risk non-Asians in Los Angeles.

Finasteride does not prevent bladder cancer: A secondary analysis of the Medical Therapy for Prostatic Symptoms Study

BACKGROUND Preclinical models have demonstrated that androgen receptor modulation can influence bladder carcinogenesis with an inverse association observed between serum androgen levels and bladder cancer (BC) incidence. It is still unclear whether 5α-reductase inhibitors, by preventing the conversion of testosterone to dihydrotestosterone, have a similar effect. This study aims to evaluate whether dihydrotestosterone-mediated androgen activity has an impact on BC incidence in a cohort of men included in a clinical trial of finasteride vs. placebo with rigorous compliance monitoring. METHODS A secondary analysis was performed on all patients enrolled in the Medical Therapy for Prostatic Symptoms (MTOPS) Study and included in the biopsy substudy. Men were stratified into groups based on receiving finasteride and the incidence of BC compared between the groups. RESULTS After exclusions for poor finasteride compliance (n = 338) and missing serum hormone results (n = 9), 2,700 men were eligible for analysis. In total, 0.8% (n = 18) of the cohort was diagnosed with BC during the trial period. There was no difference in the incidence of BC between men who received finasteride and those who did not (0.74% [n = 9] vs. 0.61% [n = 9], P = 0.67). Neither serum testosterone levels, prostate cancer diagnosis nor urinary bother (measured by International Prostate Symptom Score) demonstrated an association with BC diagnosis. These relationships were consistent in the subgroup of men in the biopsy substudy. CONCLUSION There was no observable relationship between decreased dihydrotestosterone levels and BC diagnosis.

Extended outpatient chemoprophylaxis reduces venous thromboembolism after radical cystectomy

PURPOSE Venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism, is a common cause of morbidity and mortality after radical cystectomy. The purpose of our study was to evaluate the utility of extended outpatient chemoprophylaxis against VTE after radical cystectomy-with a focus on any reduction in the incidence of VTE, including DVT and pulmonary embolism. MATERIALS AND METHODS Beginning in April 2013, we prospectively instituted a policy of extending inpatient VTE prophylaxis with subcutaneous heparin/enoxaparin for 30 days postoperatively. For this study, we reviewed the electronic medical records of all patients who underwent radical cystectomy at our institution from January 2012 through December 2015. The experimental group (n = 79) received extended outpatient chemoprophylaxis against VTE; the control group (n = 51) received no chemoprophylaxis after discharge. The primary outcome was the 90-day incidence of VTE. The secondary outcomes included the overall complication rate, the hemorrhagic complication rate, as well as the rate of readmission within 30 days of hospital discharge. RESULTS The experimental group experienced a significantly lower rate of DVT (5.06%), assessed as of 90 days postoperatively, than the control group (17.6%): a relative risk reduction of 71.3% (P = 0.021). We found no significant differences in secondary outcomes between the 2 groups, including the overall complication rate (54.4% vs. 68.6%), the hemorrhagic complication rate (3.7% vs. 2.0%), and the readmission rate (21.5% vs. 29.4%). CONCLUSION Extended outpatient chemoprophylaxis significantly reduced the incidence of VTE.

Propensity-Weighted Comparison of Long-Term Risk of Urinary Adverse Events in Elderly Women Treated For Cervical Cancer.

PURPOSE Cervical cancer treatment is associated with a risk of urinary adverse events (UAEs) such as ureteral stricture and vesicovaginal fistula. We sought to measure the long-term UAE risk after surgery and radiation therapy (RT), with confounding controlled through propensity-weighted models. METHODS AND MATERIALS From the Surveillance, Epidemiology, and End Results (SEER)-Medicare database, we identified women ≥66 years old with nonmetastatic cervical cancer treated with simple surgery (SS), radical hysterectomy (RH), external beam RT plus brachytherapy (EBRT+BT), or RT+surgery. We matched them to noncancer controls 1:3. Differences in demographic and cancer characteristics were balanced by propensity weighting. Grade 3 to 4 UAEs were identified by diagnosis codes plus treatment codes. Cumulative incidence was measured using Kaplan-Meier methods. The hazard associated with different cancer treatments was compared using Cox models. RESULTS UAEs occurred in 272 of 1808 cases (17%) and 222 of 5424 (4%) controls; most (62%) were ureteral strictures. The raw cumulative incidence of UAEs was highest in advanced cancers. UAEs occurred in 31% of patients after EBRT+BT, 25% of patients after RT+surgery, and 15% of patients after RH; however, after propensity weighting, the incidence was similar. In adjusted Cox models (reference = controls), the UAE risk was highest after RT+surgery (hazard ratio [HR], 5.07; 95% confidence interval [CI], 2.32-11.07), followed by EBRT+BT (HR, 3.33; 95% CI, 1.45-7.65), RH (HR, 3.65; 95% CI, 1.41-9.46) and SS (HR, 0.99; 95% CI, 0.32-3.01). The higher risk after RT+surgery versus EBRT+BT was statistically significant, whereas, EBRT+BT and RH were not significantly different from each other. CONCLUSIONS UAEs are common after cervical cancer treatment, particularly in patients with advanced cancers. UAEs are more common after RT, but these women tend to have the advanced cancers. After propensity weighting, the risk after RT was similar to that after surgery.

The Impact of Age on Urethroplasty Success

OBJECTIVE To determine if age is an independent predictor of surgical success in patients undergoing urethroplasty. Urethroplasty performed by excision and primary anastomosis depends on vascular collateralization. Successful augmented urethroplasty depends on graft neovascularization. Older patients have more comorbid conditions including peripheral vascular disease associated with reduced penile blood flow. METHODS This is a retrospective review of urethroplasties from 11 institutions. Primary outcome was functional success at 1 year from surgery, defined as freedom from post-urethroplasty procedures. Secondary outcome was freedom from cystoscopic evidence of stricture recurrence at 3 months. Study outcomes were compared between 2 age cohorts (<60 years old and ≥60 years old). Multivariable logistic regression analysis evaluated the influence of patient factors on our primary and secondary outcomes, using age as a continuous variable. RESULTS Of 322 urethroplasties, 258 were performed in patients <60 years and 64 in patients ≥60 years. Median follow-up was 1.8 years. The following were not significantly different between groups: stricture length or location, smoking status, number of previous urethrotomies or dilations, and urethroplasty type. The following were more common in patients ≥60 years: diabetes, hypertension, hyperlipidemia, coronary artery and peripheral vascular disease, chronic obstructive pulmonary disease, and cancer. There was no difference in need for repeat procedures or anatomic recurrence between age groups or with increasing age. Stricture length was the only statistically significant clinical factor. CONCLUSION Urethroplasty success may be affected by comorbidities but not age. Age alone should not be used as an absolute exclusion criterion for men needing urethral reconstruction.