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Lung cancer is a common cancer in people living with HIV, but the risk of cancer in this group has not been investigated for over a decade. We investigated trends in relative and absolute risk of lung cancer among people living with HIV of various age groups in the USA.In this population-based registry linkage study, we used 2001-16 data from the HIV/AIDS Cancer Match study, which links data from HIV and cancer registries from 13 regions in the USA. We included non-Hispanic White, non-Hispanic Black, and Hispanic individuals living with HIV aged 20-89 years in our study population. Average annual percentage changes in lung cancer rates were estimated with multivariable Poisson regression, and standardised incidence ratios (SIRs) and excess absolute risks were estimated comparing people living with HIV with the general US population. We used non-parametric cumulative incidence curves to estimate the 5-year cumulative incidence of lung cancer and two AIDS-defining cancers (non-Hodgkin lymphoma and Kaposi sarcoma).There were 3426 lung cancers in 4 310 304 person-years of follow-up in our study population. Age-standardised lung cancer incidence rates in people living with HIV declined by 6% per year (95% CI -7 to -5) during 2001-16, with greater declines in the 20-29 age group (-11%, -16 to 6) than in the older age groups (eg, -3% [-6 to 1] in those aged 70-89 years). During 2013-16, the SIR of lung cancer in people living with HIV was 2·01 (95% CI 1·52 to 2·61) in those aged 40-49 years, and 1·31 (1·12 to 1·52) in those aged 60-69 years, whereas the excess absolute risk among people living with HIV was 11·87 (3·95 to 21·89) per 100 000 person-years for those aged 40-49 years and 48·23 (6·88 to 95·47) per 100 000 person-years for those aged 60-69 years. Beginning in 2011, the 5-year cumulative incidence for lung cancer (1·36%, 95% CI 1·17 to 1·53) surpassed that of Kaposi sarcoma (0·12%, 0·06 to 0·17) and non-Hodgkin lymphoma (0·45%, 0·35 to 0·56) for people living with HIV aged 60-69 years.Between 2001 and 2016, the risk of lung cancer decreased for people living with HIV aged 20-69 years, but remained substantially elevated compared with the general population, probably due to a combination of smoking and immunosuppression. For people living with HIV aged 60 years and older, the risk of lung cancer exceeds that of two of the most common AIDS-defining cancers, highlighting the importance of lung cancer among the growing older population of people living with HIV.Intramural Research Program of the US National Cancer Institute.

BACKGROUND: A growing body of literature suggests chronically higher bile acid (BA) concentrations may be associated with multiple health conditions. Diet may affect BA metabolism and signaling; however, evidence from human populations is lacking. OBJECTIVES: We systematically investigated cross-sectional associations of a priori–selected dietary components (fiber, alcohol, coffee, fat) with circulating BA concentrations. METHODS: We used targeted, quantitative LC-MS/MS panels to measure 15 circulating BAs in a subset of the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC; n = 2224) and Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO; n = 986) comprising Finnish male smokers and United States men and women, respectively. We used multivariable linear regression to estimate associations of each dietary component with log-transformed BAs; exponentiated coefficients estimate proportional differences. We included the median of the dietary component quartile in linear regression models to test for trend. RESULTS: In ATBC, fiber was inversely associated with multiple circulating BAs. The proportional difference was –10.09% (95% CI: −19.29 to 0.16; P-trend = 0.04) when comparing total BAs among those in the highest relative to the lowest fiber quartile. Alcohol, trans fat, and polyunsaturated fat were positively associated with BAs in ATBC. The proportional difference comparing total BAs among those in the highest relative to the lowest alcohol quartile was 8.76% (95% CI: –3.10 to 22.06; P-trend = 0.03). Coffee and monounsaturated fat were inversely associated with BAs. The proportional difference comparing total BAs among those in the highest relative to the lowest coffee quartile was –24.03% (95% CI: –31.57 to –15.66; P-trend

Background Metabolomics has proven useful for detecting objective biomarkers of diet that may help to improve dietary measurement. Studies to date, however, have focused on a relatively narrow set of lipid classes. Objective The aim of this study was to uncover candidate dietary biomarkers by identifying serum metabolites correlated with self-reported diet, particularly metabolites in underinvestigated lipid classes, e.g. triglycerides and plasmalogens. Methods We assessed dietary questionnaire data and serum metabolite correlations from 491 male and female participants aged 55-75 y in an exploratory cross-sectional study within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Self-reported intake was categorized into 50 foods, food groups, beverages, and supplements. We examined 522 identified metabolites using 2 metabolomics platforms (Broad Institute and Massachusetts General Hospital). Correlations were identified using partial Pearson's correlations adjusted for age, sex, BMI, smoking status, study site, and total energy intake [Bonferroni-corrected level of 0.05/(50 × 522) = 1.9 × 10-6]. We assessed prediction of dietary intake by multiple-metabolite linear models with the use of 10-fold crossvalidation least absolute shrinkage and selection operator (LASSO) regression. Results Eighteen foods, beverages, and supplements were correlated with ≥1 serum metabolite at the Bonferroni-corrected significance threshold, for a total of 102 correlations. Of these, only 5 have been reported previously, to our knowledge. Our strongest correlations were between citrus and proline betaine (r = 0.55), supplements and pantothenic acid (r = 0.46), and fish and C40:9 phosphatidylcholine (PC) (r = 0.35). The multivariate analysis similarly found reasonably large correlations between metabolite profiles and citrus (r = 0.59), supplements (r = 0.57), and fish (r = 0.44). Conclusions Our study of PLCO participants identified many novel food-metabolite associations and replicated 5 previous associations. These candidate biomarkers of diet may help to complement measures of self-reported diet in nutritional epidemiology studies, though further validation work is still needed.

Environmental tobacco smoke (ETS) increases the risk of mortality among nonsmokers. Yet, few studies have examined this association among racial/ethnic minorities or among people with less education or income. We assessed self-reported ETS exposure at home among never smoking participants (n = 110,945) of the 1991-2010 National Health Interview Surveys. Deaths through 2015 were identified by the National Death Index. Hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality were estimated using Cox proportional hazards regression models with age as the underlying time metric and adjusted for sex, race/ethnicity, education, household income, body mass index, region of residence, and survey year. We further stratified all-cause mortality analyses by race/ethnicity, household income, and education. Relative to no ETS at home, every day exposure was associated with higher risk of all-cause mortality (HR = 1.33, 95%CI: 1.23, 1.45), with similar HRs observed across strata of education and income. HRs were similar among non-Hispanic Black (HR = 1.28, 95%CI: 1.08, 1.53) and non-Hispanic White adults (HR = 1.34, 95%CI: 1.21, 1.48) although somewhat higher among Hispanic adults (HR = 1.65, 95%CI: 1.29, 2.10; P for pairwise comparison = 0.04). ETS exposure at home is an important contributor to mortality across strata of race/ethnicity, education, and income in the US.

The epidemiological evidence regarding the carcinogenicity of nitrate and sodium in drinking water is limited, partly because measuring the exposure at the individual level is complex. Most studies have used nitrate in water supplies as a proxy for individual exposure, but dietary intakes and other factors may contribute to the exposure. The present study investigates the factors associated with urinary nitrate and sodium in a high-risk area for esophageal and gastric cancers.For this cross-sectional study, we used data and samples collected in 2004-2008 during the enrollment phase of the Golestan Cohort Study from a random sample of 349 participants (300 individuals from 24 rural villages and 49 from the city of Gonbad), stratified by average water nitrate in their district, the source of drinking water, and the usual dietary intake of nitrate and sodium. Nitrate, sodium, and creatinine were measured in a spot urine sample collected at the time of interview. We used the provincial cancer registry data to calculate the cumulative incidence rates of esophageal and gastric cancers for each location through June 1, 2020, and used weighted partial Pearson correlation to compare the incidence rates with median urinary nitrate and sodium in each village or the city.Among 349 participants (mean age±SD: 50.7 ± 8.6 years), about half (n = 170) used groundwater for drinking, and the use of groundwater was significantly more common in high-elevation locations (75.8%). The geometric mean of the creatinine-corrected urinary nitrate concentration was 68.3 mg/g cr (95%CI: 64.6,72.3), and the corresponding geometric mean for urinary sodium was 150.0 mmoL/g cr (95%CI: 139.6,161.1). After adjusting for confounders, urinary nitrate was associated with being a woman, drinking groundwater, and living in high-elevation locations, but not with estimated dietary intake. Urinary sodium concentration was significantly associated with monthly precipitation at the time of sampling but not with elevation or drinking water source. There were significant positive correlations between both median urinary nitrate and sodium in each location and esophageal cancer incidence rates adjusted for sex and age (r = 0.65 and r = 0.58, respectively, p 0.01), but not with gastric cancer incidence.In a rural population at high risk for esophageal and gastric cancers, nitrate excretion was associated with living at a higher elevation and using groundwater for drinking. The associations between nitrate and sodium excretion with esophageal cancer incidence warrant future investigation.

Background There are no data on the prevalence of non-alcoholic fatty liver disease (NAFLD) in general population samples in Guatemala or in other Central American countries. The prevalence and distribution of NAFLD and its associated risk factors were evaluated in a population-based sample of adults in Guatemala. Methods Cross-sectional study of 411 men and women 40 years of age or older residing in urban and rural areas of Guatemala. Metabolic outcomes included obesity, central obesity, hypercholesterolemia, diabetes, and metabolic syndrome (MetS). Liver disease outcomes included elevated liver enzymes, elevated Fatty Liver Index (FLI), and elevated FIB-4 score. Results The overall prevalence of obesity, central obesity, diabetes, and MetS were 30.9, 74.3, 21.6, and 64.2%, respectively. The fully-adjusted prevalence ratios (95% CI) for obesity, central obesity, diabetes, and MetS comparing women to men were 2.83 (1.86–4.30), 1.72 (1.46–2.02), 1.18 (1.03–1.34), and 1.87 (1.53–2.29), respectively. The overall prevalence of elevated liver enzymes (ALT or AST), elevated FLI, and elevated FIB-4 scores were 38.4, 60.1, and 4.1%, respectively. The fully-adjusted prevalence ratios (95% CI) for elevated liver enzymes (either ALT or AST) and elevated FLI score comparing women to men were 2.99 (1.84–4.86) and 1.47 (1.18–1.84), respectively. Conclusions The prevalence of metabolic abnormalities and liver outcomes in this general population study was very high. The prevalence of metabolic and liver abnormalities was particularly high among women, an observation that could explain the atypical 1:1 male to female ratio of liver cancer in Guatemala.

Introduction Worldwide, an estimated 189 million adults smoke tobacco “occasionally” but not every day. Yet few studies have examined the health risks of non-daily smoking. Methods Data from the 1991, 1992, and 1995 U.S. National Health Interview Surveys, a nationally representative sample of 70,913 U.S. adults (aged 18–95 years) were pooled. Hazard ratios and 95% CIs for death through 2011 were estimated from Cox proportional hazards regression using age as the underlying time metric and stratified by 5-year birth cohorts in 2017. Results Non-daily smokers reported smoking a median of 15 days and 50 cigarettes per month in contrast to daily smokers who smoked a median of 600 cigarettes per month. Compared with never smokers, lifelong nondaily smokers who had never smoked daily had a 72% higher mortality risk (95% CI=1.36, 2.18): higher risks were observed for cancer, heart disease, and respiratory disease mortalities. Higher mortality risks were observed among lifelong non-daily smokers who reported 11–30 (hazard ratio=1.34, 95% CI=0.81, 2.20); 31–60 (hazard ratio=2.02, 95% CI=1.17, 3.29); and >60 cigarettes per month (hazard ratio=1.74, 95% CI=1.12, 2.72) than never smokers. Median life-expectancy was about 5 years shorter for lifelong non-daily smokers than never smokers. As expected, daily smokers had even higher mortality risks (hazard ratio=2.50, 95% CI=2.35, 2.66) and shorter survival (10 years less). Conclusions Although the mortality risks of non-daily smokers are lower than daily smokers, they are still substantial. Policies should be specifically directed at this growing group of smokers.

Summary Background Although life expectancy has been projected to increase across high-income countries, gains for the USA are anticipated to be among the smallest, and overall US death rates actually increased from 2014 to 2015, with divergence for specific US populations. Therefore, projecting future premature mortality is essential for clinical and public health service planning, curbing rapidly increasing causes of death, and sustaining progress in declining causes of death. We aimed to project premature mortality (here defined as deaths of individuals aged 25–64 years) trends through 2030, and to estimate the total number of projected deaths, the projected number of potential years of life lost due to premature mortality, and the effect of reducing projected accidental death rates by 2% per year. Methods We obtained death certificate data for the US population aged 25–64 years for 1990–2015 from the US Centers for Disease Control and Prevention (CDC) National Center for Health Statistics. We obtained US mortality data for 2016 for non-American Indian or Alaska native groups from CDC WONDER; data for 2016 were not available for American Indians or Alaska natives. Our analysis focused on all-cause premature mortality and the commonest causes of premature death (cancer, heart disease, accidents, suicide, and chronic liver disease or cirrhosis) among white, black, Hispanic, Asian or Pacific islanders, and American Indian or Alaska native men and women. We estimated age-standardised premature mortality and corresponding annual percentage changes for 2017–30 by sex and race or ethnic origin by use of age–period–cohort forecasting models. We also did a sensitivity analysis projecting future mortality from cross-sectional mortality and a JoinPoint of the (log) period rate ratio curve. We calculated absolute death counts by use of corresponding age-specific and year-specific US census population projections, and estimated years of potential life lost. Findings During 2017–30, all-cause deaths are projected to increase among white women and American Indians or Alaska natives, resulting in 239 700 excess premature deaths relative to 2017 rates (a 10% increase). Mortality declines in white men and black, Hispanic, and Asian or Pacific islander men and women will result in 945 900 fewer deaths (a 14% reduction). Cancer mortality rates are projected to decline among white, black, Hispanic, and Asian or Pacific islander women and men, with the largest declines among black women (age-standardised premature mortality rate 2016: 104·5 deaths per 100 000 woman-years; 2030: 77·1 per 100 000 woman-years) and men (2016: 116·8 per 100 000 man-years; 2030: 81·6 per 100 000 man-years). Heart disease death rates are projected to increase in American Indian or Alaska native men (2015: 150·9 per 100 000 man-years; 2030: 175·9 per 100 000 man-years) and decline in other groups, albeit only slightly in white (2016: 35·6 per 100 000 woman-years; 2030: 31·1 per 100 000 woman-years) and American Indian or Alaska native women (2015: 64·4 per 100 000 woman-years; 2030: 62·8 per 100 000 woman-years). Accidental death rates are projected to increase in all US populations except Asian or Pacific islander women, and will increase most rapidly among white women (2030: 60·5 per 100 000 woman-years) and men (2030: 101·9 per 100 000 man-years) and American Indian or Alaska native women (2030: 97·5 per 100 000 woman-years) and men (2030: 298·7 per 100 000 man-years). Suicide rates are projected to increase for all groups, and chronic liver disease and cirrhosis deaths are projected to increase for all groups except black men. A 2% per year reduction in projected accidental deaths would eliminate an estimated 178 700 deaths during 2017–30. Interpretation To reduce future premature mortality, effective interventions are needed to address rapidly rising mortality rates due to accidents, suicides, and chronic liver disease and cirrhosis. Funding National Cancer Institute Intramural Research Program.

Introduction Tobacco use remains a leading modifiable cause of cancer incidence and premature mortality in the U.S. and globally. Despite increasing life expectancy worldwide, less is known about the effects of cigarette smoking on older populations. This study sought to determine the effects of smoking on mortality in older age. Methods Associations of mortality with self-reported age at smoking cessation, age at smoking initiation, and amount smoked after age 70 years were examined in 160,113 participants of the NIH-AARP Diet and Health Study aged >70 years. Participants completed a questionnaire detailing their smoking use in 2004–2005, and were followed for mortality through December 31, 2011. Analyses were conducted between 2014 and 2016. Results Relative to never smokers, current smokers were more likely to die during follow-up (hazard ratio, 3.18; 95% CI=3.04, 3.31). Furthermore, former smokers had lower risks than current smokers (hazard ratios for quitting between ages 30–39, 40–49, 50–59, and 60–69 years were 0.41 [95% CI=0.39, 0.43], 0.51 [95% CI=0.49, 0.54], 0.64 [95% CI=0.61, 0.67], and 0.77 [95% CI=0.73, 0.81], respectively). Among current smokers, mortality was inversely associated with age at initiation, but directly associated with the number of cigarettes smoked per day at age >70 years. Conclusions As among younger people, lifetime cigarette smoking history is a key determinant of mortality after age 70 years.

Mounting evidence suggests that copy number variations (CNVs) can contribute to cancer susceptibility. The main goal of this study was to evaluate the role of germline CNVs in melanoma predisposition in high-risk melanoma families. We used genome-wide tiling comparative genomic hybridization and single nucleotide polymorphism arrays to characterize CNVs in 335 individuals (240 melanoma cases) from American melanoma-prone families (22 with germline CDKN2A or CDK4 mutations). We found that the global burden of overall CNVs (or deletions or duplications separately) was not significantly associated with case-control or CDKN2A/CDK4 mutation status after accounting for the familial dependence. However, we identified several rare CNVs that either involved known melanoma genes (e.g., PARP1, CDKN2A) or cosegregated with melanoma (duplication on 10q23.23, 3p12.2 and deletions on 8q424.3, 2q22.1) in families without mutations in known melanoma high-risk genes. Some of these CNVs were correlated with expression changes in disrupted genes based on RNASeq data from a subset of melanoma cases included in the CNV study. These results suggest that rare cosegregating CNVs may influence melanoma susceptibility in some melanoma-prone families and genes found in our study warrant further evaluation in future genetic analyses of melanoma.

Background The nonessential amino acid cysteine is known to be involved in many antioxidant and anticarcinogenic pathways. Cysteinylglycine is a pro-oxidant metabolite of glutathione and a precursor of cysteine. Objective To examine the relation between serum cysteine and cysteinylglycine and risk of gastric adenocarcinomas, esophageal squamous cell carcinomas, and head and neck squamous cell carcinomas, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention study of male Finnish smokers aged 50-69 y at baseline. Design In total, 170 gastric adenocarcinomas, 68 esophageal squamous cell carcinomas, and 270 head and neck squamous cell carcinomas (identified from the Finnish Cancer Registry) were matched one-to-one with cancer-free control subjects on age and the date of serum collection. We calculated ORs and 95% CIs with the use of a multivariate-adjusted conditional logistic regression. Results Cysteine had a U-shaped association with gastric adenocarcinomas; a model that included a linear and a squared term had a significant global P-test (P = 0.036). Serum cysteinylglycine was inversely associated with adenocarcinomas of the gastric cardia (OR for above the median compared with below the median: 0.07; 95% CI: 0.01, 0.70; n = 38 cases) but not for other sites. Both cysteine and cysteinylglycine were not associated with esophageal squamous cell carcinoma or head and neck squamous cell carcinoma. Conclusions We observed associations between serum cysteine and cysteinylglycine with upper gastrointestinal cancer risk. Future studies are needed to replicate these findings. This trial was registered at clininicaltrials.gov as NCT00342992.

BACKGROUND Despite widespread popularity and possible health effects, the prevalence and distribution of coffee consumption in US adults are poorly characterized. OBJECTIVE We sought to estimate usual daily coffee intakes from all coffee-containing beverages, including decaffeinated and regular coffee, among US adults according to demographic, socioeconomic, and health-related factors. METHODS Dietary intake data from ≤2 nonconsecutive 24-h dietary recalls and a food-frequency questionnaire administered during the NHANES 2003-2006 were used to estimate the person-specific probability of consuming coffee on a particular day and the usual amount consumed on consumption days. Trends in population mean coffee consumption over time were evaluated by using multiple linear regression and 1-d 24-h recall data from NHANES 2003-2012. Analyses were weighted to be representative of the US adult population aged ≥20 y. RESULTS An estimated 154 million adults, or 75% of the US population, aged ≥20 y reported drinking coffee; 49% reported drinking coffee daily. Prevalence did not vary by sex, education, income, or self-reported general health (all P ≥ 0.05) but did vary by age, race/ethnicity, smoking status, and alcohol drinking (all P < 0.05). Among coffee drinkers, the mean ± SE usual intake was 14.1 ± 0.5 fluid ounces/d (417 ± 15 mL/d). Mean usual intakes were higher in men than women, in older age groups than in those aged 20 to

BACKGROUND: Relative telomere length in peripheral blood leukocytes has been evaluated as a potential biomarker for renal cell carcinoma (RCC) risk in several studies, with conflicting findings. OBJECTIVE: We performed an analysis of genetic variants associated with leukocyte telomere length to assess the relationship between telomere length and RCC risk using Mendelian randomization, an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations. DESIGN, SETTING, AND PARTICIPANTS: Genotypes from nine telomere length-associated variants for 10 784 cases and 20 406 cancer-free controls from six genome-wide association studies (GWAS) of RCC were aggregated into a weighted genetic risk score (GRS) predictive of leukocyte telomere length. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Odds ratios (ORs) relating the GRS and RCC risk were computed in individual GWAS datasets and combined by meta-analysis. RESULTS AND LIMITATIONS: Longer genetically inferred telomere length was associated with an increased risk of RCC (OR=2.07 per predicted kilobase increase, 95% confidence interval [CI]:=1.70-2.53, p0.5) with GWAS-identified RCC risk variants (rs10936599 and rs9420907) from the telomere length GRS; despite this exclusion, a statistically significant association between the GRS and RCC risk persisted (OR=1.73, 95% CI=1.36-2.21, p

INTRODUCTION: Smoking is known to be a major cause of death among middle-aged adults, but evidence on its impact and the benefits of smoking cessation among older adults has remained limited. There ...

Background: Coffee intake may be inversely associated with colorectal cancer; however, previous studies have been inconsistent. Serum coffee metabolites are integrated exposure measures that may clarify associations with cancer and elucidate underlying mechanisms. Objectives: Our aims were 2-fold as follows: 1) to identify serum metabolites associated with coffee intake and 2) to examine these metabolites in relation to colorectal cancer. Design: In a nested case-control study of 251 colorectal cancer cases and 247 matched control subjects from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, we conducted untargeted metabolomics analyses of baseline serum by using ultrahigh-performance liquid-phase chromatography–tandem mass spectrometry and gas chromatography–mass spectrometry. Usual coffee intake was self-reported in a food-frequency questionnaire. We used partial Pearson correlations and linear regression to identify serum metabolites associated with coffee intake and conditional logistic regression to evaluate associations between coffee metabolites and colorectal cancer. Results: After Bonferroni correction for multiple comparisons (P = 0.05 ÷ 657 metabolites), 29 serum metabolites were positively correlated with coffee intake (partial correlation coefficients: 0.18–0.61; P 0.40) included trigonelline (N′-methylnicotinate), quinate, and 7 unknown metabolites. Of 29 serum metabolites, 8 metabolites were directly related to caffeine metabolism, and 3 of these metabolites, theophylline (OR for 90th compared with 10th percentiles: 0.44; 95% CI: 0.25, 0.79; P-linear trend = 0.006), caffeine (OR for 90th compared with 10th percentiles: 0.56; 95% CI: 0.35, 0.89; P-linear trend = 0.015), and paraxanthine (OR for 90th compared with 10th percentiles: 0.58; 95% CI: 0.36, 0.94; P-linear trend = 0.027), were inversely associated with colorectal cancer. Conclusions: Serum metabolites can distinguish coffee drinkers from nondrinkers; some caffeine-related metabolites were inversely associated with colorectal cancer and should be studied further to clarify the role of coffee in the cause of colorectal cancer. The Prostate, Lung, Colorectal, and Ovarian trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00002540","term_id":"NCT00002540"}}NCT00002540.

Mechanisms involved in wound healing play some role in carcinogenesis in multiple organs, likely by creating a chronic inflammatory milieu. This study sought to assess the role of genetic markers in selected inflammation-related genes involved in wound healing (interleukin (IL)-1a, IL-1b, IL-1 Receptor type I (IL-1Ra), IL-1 Receptor type II (IL-1Rb), tumour necrosis factor (TNF)-α, tumour necrosis factor receptor superfamily member (TNFRSF)1A, nuclear factor kappa beta (NF-kB)1, NF-kB2, inducible nitric oxide synthase (iNOS), cyclooxygenase (COX)-2, hypoxia induced factor (HIF)-1α, vascular endothelial growth factor (VEGF)A and P-53) in risk to oesophageal squamous cell carcinoma (OSCC).We genotyped 125 tag single nucleotide polymorphism (SNP)s in 410 cases and 377 age and sex matched disease-free individuals from Nutritional Intervention Trial (NIT) cohort, and 546 cases and 556 controls individually matched for age, sex and neighbourhood from Shanxi case-control study, both conducted in high-risk areas of north-central China (1985-2007). Cox proportional-hazard models and conditional logistic regression models were used for SNPs analyses for NIT and Shanxi, respectively. Fisher's inverse test statistics were used to obtain gene-level significance.Multiple SNPs were significantly associated with OSCC in both studies, however, none retained their significance after a conservative Bonferroni adjustment. Empiric p-values for tag SNPs in VEGFA in NIT were highly concentrated in the lower tail of the distribution, suggesting this gene may be influencing risk. Permutation tests confirmed the significance of this pattern. At the gene level, VEGFA yielded an empiric significance (P=0.027) in NIT. We also observed some evidence for interaction between environmental factors and some VEGFA tag SNPs.Our finding adds further evidence for a potential role for markers in the VEGFA gene in the development and progression of early precancerous lesions of oesophagus.

Background: Head and neck cancer (HNC) is the seventh most common cancer worldwide. Although diet has been proposed to play an important role in HNC, few associations with diet have been convincing other than alcohol intake. Studies of dietary patterns that examine overall diets may provide broader insight than studies of individual foods. Little is known about the association between dietary patterns and risk of HNC. Objective: We prospectively evaluated the association between 2 index-based dietary patterns [ie, the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet Score (aMED)] and risk of head and neck squamous cell carcinoma. Design: We included 494,967 participants from the NIH-AARP Diet and Health study (1995-2006). HRs (95% CIs) were estimated by using Cox regression. Scores for the HEI-2005 and aMED were calculated on the basis of diet assessed by using a baseline food-frequency questionnaire. Higher scores reflected adherence to dietary recommendations for healthy eating. Our main outcome was the incidence of HNC, including cancer of the larynx, oral cavity, and orohypopharynx. Results: A total of 1868 HNC cases were identified during follow-up. Higher HEI-2005 scores were associated with reduced risk of HNC in men [HR: 0.74 (95% CI: 0.61, 0.89) for highest compared with lowest quintiles; P-trend = 0.0008] and women [HR: 0.48; 95% CI: 0.33, 0.70; P-trend < 0.0001]. High aMED scores were also associated with lower HNC risk in men (HR: 0.80; 95% CI: 0.64, 1.01; P-trend = 0.002) and women (HR: 0.42; 95% CI: 0.24, 0.74; P-trend < 0.0001). Associations were similar among subsites. We did not find significant interactions between smoking and alcohol intake and each index on HNC risk. Conclusions: HEI-2005 and aMED scores were associated inversely with risk of HNC. Large interventional studies are required to assess the causality before conveying definite public health messages. This trial was registered at clinicaltrials.gov as {"type":"clinical-trial","attrs":{"text":"NCT00340015","term_id":"NCT00340015"}}NCT00340015.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of abnormal telomere biology on survival after unrelated donor hematopoietic cell transplant (HCT) for acquired severe aplastic anemia (SAA). Patient pre-transplant blood samples, and clinical and outcome data were available at the Center for International Blood and Marrow Transplant Research. We used qPCR to measure relative telomere length (RTL) and whole exome sequencing to identify patients with pathogenic (P) or likely pathogenic (LP) variants in telomere biology disorder (TBD) related genes. Cox proportional hazard models were used for survival analysis. The study included 490 SAA patients who received HCT between 1990 and 2013 at a median age of 20 years. Eighty patients (16.3%) had pre-HCT RTL 0.10 for all other categories). A similar high mortality risk was found in patients with P/LP TBD-related variants (HR=2.0, 95% CI=1.28-3.15, p=0.003). A time-dependent effect for post-HCT mortality was only observed in relation to RTL (HR for RTL

Background Few studies have examined the association of common genetic variants related to vitamin D metabolism and signaling to esophageal squamous cell carcinoma (ESCC). Methods We evaluated the association between 12 single nucleotide polymorphisms (SNPs) in four genes related to vitamin D levels and ESCC risk using data from a genome-wide association study. Participants were recruited from the Shanxi Upper Gastrointestinal Cancer Genetics Project and the Linxian Nutrition Intervention Trials, and included 1942 ESCC cases and 2111 controls. We used logistic models to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for the SNP associations, after controlling for age and gender. Results None of the 12 evaluated SNPs in the four vitamin D-related genes were significantly associated with risk of ESCC. The strongest associations were for rs3794060 ( P =0.07) and rs12800438 ( P =0.08) in the DHCR7 / NADSYN1 gene. No association between vitamin D-related SNPs and risk of ESCC was observed in a genotype score analysis that included all 12 SNPs. ORs for quartiles 2, 3 and 4 of the genotype scores were 0.83 (95% CI: 0.68, 1.01), 1.02 (0.85, 1.21), and 1.08 (0.89, 1.30), respectively, with no evidence for a significant monotonic trend ( P =0.120). Conclusions Our results suggested that common genetic variants related to vitamin D levels are not associated with risk of ESCC in this Chinese population.

Background: China has some of the highest incidence rates for gastric adenocarcinoma (GA) and esophageal squamous cell carcinoma (ESCC) in the world. Prospective studies suggested that vitamin C may reduce risks; however, associations are unclear because of limited sample size. Objective: The objective was to examine the relation between prediagnostic plasma vitamin C and the risk of GA and ESCC. Design: A case-cohort study was used to assess the association between prediagnostic plasma vitamin C and incidence of GA (n = 467) and ESCC (n = 618) in the General Population Nutrition Intervention Trial. With the use of multivariate Cox proportional hazards models, we estimated the HRs and 95% CIs. We also conducted a meta-analysis of the literature up to 1 October 2012 on the relation between circulating vitamin C and gastric cancer incidence. Two cohort studies and the current study were included to assess the body of evidence. Results: For GA, each 20-μmol/L increase in plasma vitamin C was associated with a 14% decrease in risk (HR: 0.86; 95% CI: 0.76, 0.96). Compared with individuals with low plasma vitamin C concentrations (≤28 μmol/L), those with normal concentrations (>28 μmol/L) had a 27% reduced risk of GA (HR: 0.73; 95% CI: 0.56, 0.94). No association between vitamin C concentrations and ESCC was seen. Meta-analysis showed that the risk of incident GA among those with the highest concentration of plasma vitamin C was 31% lower (random-effects-pooled-odds ratio 0.69; 95% CI: 0.54, 0.89) than those in the lowest category. Conclusion: Our data provide evidence that higher circulating vitamin C was associated with a reduced risk of incident GA, but no association was seen for ESCC.

High-level coffee consumption has been associated with reduced progression of pre-existing liver diseases and lower risk of hepatocellular carcinoma. However, its relationship with therapy for hepatitis C virus infection has not been evaluated.Patients (n=885) from the lead-in phase of the Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis Trial recorded coffee intake before retreatment with peginterferon α-2a (180 μg/wk) and ribavirin (1000-1200 mg/day). We assessed patients for early virologic response (2 log10 reduction in level of hepatitis C virus RNA at week 12; n=466), and undetectable hepatitis C virus RNA at weeks 20 (n=320), 48 (end of treatment, n=284), and 72 (sustained virologic response; n=157).Median log10 drop from baseline to week 20 was 2.0 (interquartile range [IQR], 0.6-3.9) among nondrinkers and 4.0 (IQR, 2.1-4.7) among patients that drank 3 or more cups/day of coffee (P trend.0001). After adjustment for age, race/ethnicity, sex, alcohol, cirrhosis, ratio of aspartate aminotransferase to alanine aminotransferase, the IL28B polymorphism rs12979860, dose reduction of peginterferon, and other covariates, odds ratios for drinking 3 or more cups/day vs nondrinking were 2.0 (95% confidence interval [CI]: 1.1-3.6; P trend=.004) for early virologic response, 2.1 (95% CI: 1.1-3.9; P trend=.005) for week 20 virologic response, 2.4 (95% CI: 1.3-4.6; P trend=.001) for end of treatment, and 1.8 (95% CI: 0.8-3.9; P trend=.034) for sustained virologic response.High-level consumption of coffee (more than 3 cups per day) is an independent predictor of improved virologic response to peginterferon plus ribavirin in patients with hepatitis C.

Background Adenocarcinomas of the upper gastrointestinal tract (UGI) show remarkable male predominance. As smoking is a well-established risk factor, we investigated the role of tobacco smoking in the male predominance of UGI adenocarcinomas in the United States NIH-AARP Diet and Health Study. Method A questionnaire was completed by 281,422 men and 186,133 women in 1995–1996 who were followed until 31st December 2003. Incident UGI adenocarcinomas were identified by linkage to state cancer registries. We present age-standardised cancer incidence rates per 100,000-person years and male/female ratios (M/F) calculated from age-adjusted Cox proportional hazards models, both with 95% confidence intervals (CI). Results After 2013,142-person years follow-up, 338 adenocarcinomas of the oesophagus, 261 of gastric cardia and 222 of gastric non-cardia occurred in men. In women, 23 tumours of oesophagus, 36 of gastric cardia and 88 of gastric non-cardia occurred in 1351,958-person years follow-up. The age-standardised incidence rate of all adenocarcinoma sites was 40.5 (37.8–43.3) and 11.0 (9.2–12.8) in men and women, respectively. Among smokers, the M/F of all UGI adenocarcinomas was 3.4 (2.7–4.1), with a M/F of 7.3 (4.6–11.7) for tumours in oesophagus, 3.7 (2.5–5.4) for gastric cardia and 1.7 (1.2–2.3) for gastric non-cardia. In non-smokers, M/F ratios were 14.2 (5.1–39.5) for oesophagus, 6.1 (2.6–14.7) for gastric cardia and 1.3 (0.8–2.0) for gastric non-cardia. The overall M/F ratio was 3.0 (2.2–4.3). Conclusion The male predominance was similar in smokers and non-smokers for these cancer sites. These results suggest that the male predominance of upper GI adenocarcinomas cannot be explained by differences in smoking histories.

Background Few studies have investigated the relationship of physical activity to esophageal and gastric carcinoma according to histology and anatomic site. Methods This study prospectively investigated the association between physical activity and esophageal and gastric carcinoma in a cohort of 487,732 U.S. men and women, followed from 1995–1996 to December 31, 2003. All analyses were performed in 2007–2008. Results During 8 years of follow-up study, 523 cases of esophageal carcinoma (149 squamous cell and 374 adenocarcinoma) and 642 cases of gastric carcinoma (313 cardia and 329 noncardia) were documented. Physical activity was associated with reduced risk of esophageal and gastric adenocarcinomas but was unrelated to esophageal squamous cell carcinoma. The inverse association with physical activity was strongest for gastric noncardia adenocarcinoma (multivariate relative risk [RR] for highest versus lowest physical activity level=0.62, 95% CI=0.44, 0.87). Relationships were weaker but evident for gastric cardia adenocarcinoma (RR=0.83; 95% CI=0.58, 1.19) and esophageal adenocarcinoma (RR=0.75; 95% CI=0.53, 1.06). No significant relationship with physical activity was observed for esophageal squamous cell carcinoma (RR=1.05; 95% CI=0.64, 1.74). Exclusion of cases diagnosed during the first 2 follow-up years did not change those estimates, indicating that the findings are not due to decreased activity levels among participants with undiagnosed cancer at entry. Conclusions Physical activity may play a role in the prevention of upper gastrointestinal tract adenocarcinomas. No association was seen between physical activity and esophageal squamous cell carcinoma.

Summary Background Whether women are more susceptible than men to lung cancer caused by cigarette smoking has been controversial. To address this question, we aimed to compare incidence rates of lung cancer by stratum of smoking use in men and women of the National Institutes of Health (NIH)-AARP cohort. Methods Participants in the NIH-AARP Diet and Health study responded to a postal questionnaire between Oct 13, 1995, and May 6, 1996, and were followed up until Dec 31, 2003. The questionnaire asked participants about their past and current smoking status, demographics, alcohol intake, tobacco smoking, physical activity, and included a food-frequency questionnaire of 124 items. Incident lung cancers were identified by linkage to individual state cancer registries. We present age-standardised incidence rates for cancer and multivariate hazard ratios (HRs) adjusted for potential confounders, with 95% CIs. This study conforms to the STROBE guidelines. Findings 279 214 men and 184 623 women from eight states in the USA aged 50–71 years at study baseline were included in this analysis. During follow-up, lung cancers occurred in 4097 men and 2237 women. Incidence rates were 20·3 (95% CI 16·3–24·3) per 100 000 person-years in men who had never smoked (99 cancers) and 25·3 (21·3–29·3) in women who had never smoked (152 cancers); for this group, the adjusted HR for lung cancer was 1·3 (1·0–1·8) for women compared with men. Smoking was associated with increased risk of lung cancer in men and women. The incidence rate of current smokers who smoked more than two packs per day was 1259·2 (1035·0–1483·3) in men and 1308·9 (924·2–1693·6) in women. In current smokers, in a model adjusted for typical smoking dose, the HR was 0·9 (0·8–0·9) for women compared with men. For former smokers, in a model adjusted for years of cessation and typical smoking dose, the HR was 0·9 (0·9–1·0) for women compared with men. Incidence rates of adenocarcinoma, small-cell carcinoma, and undifferentiated tumours were similar in men and women; incidence rates of squamous tumours in men were about twice that in women. Interpretation Our findings suggest that women are not more susceptible than men to the carcinogenic effects of cigarette smoking in the lung. In smokers, incidence rates tended to be higher in men than women with comparable smoking histories, but differences were modest; smoking was strongly associated with lung cancer risk in both men and women. Future studies should confirm whether incidence rates are indeed higher in women who have never smoked than in men who have never smoked. Funding Intramural Research Program of the National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Bethesda, MD, USA.

See corresponding article on page 809. Excessive alcohol consumption is the third leading contributor to preventable death worldwide, contributing to 2.5 million deaths per year (1–3). Casual drinking is an aspect of the typical diet in many parts of the world. Yet, excessive alcohol consumption has a devastating effect on public health. Excessive drinking, which is correlated with alcoholism (4), is a serious concern and levies a profound economic and social burden (2). That alcohol consumption is heritable is well recognized (5, 6). Nearly 50% of the variation in excessive alcohol consumption and problem drinking is attributable to genetic influences (7). As reported in this issue of the Journal, in an effort to delineate the genetic variants that comprise this genetic variance Baik et al (8) embarked on an exploration of the human genome. In a sample of 1721 Korean adult male drinkers, they identify and replicate several loci that are associated with more frequent alcohol consumption. The most promising results, which easily surpass thresholds for genome-wide significance, were observed on chromosome 12 for rs2074356 and rs11066280, which are highly correlated with a functional polymorphism in the aldehyde dehydrogenase (ALDH2) gene, rs671. These results are consistent with past studies that have linked specific functional polymorphisms in ALDH2, particularly rs671, with both alcohol intake and the flushing response. The less common and protective form of this variant induces a change from the amino acid glutamic acid to lysine in the 12th exon of the gene, leading to reduced alcohol tolerance (9, 10). Associations between single nucleotide polymorphisms (SNPs) in ALDH2 with alcohol intake reconcile well with the known biology of alcohol metabolism (11). After intake, alcohol is metabolized into acetaldehyde by alcohol dehydrogenase enzymes (ADH); the ALDH2 enzyme metabolizes acetaldehyde into acetic acid, which is nontoxic. In addition to being an International Agency for Research on Cancer class 1 carcinogen, accumulating acetaldehyde causes flushing and the unpleasant symptoms associated with a hangover (12). Intriguingly, genome-wide association studies (GWAS) have shown that these same SNPs are associated with increased risk of esophageal squamous cell carcinoma—a cancer partly caused by alcohol intake (13). The genetic etiology of alcohol consumption holds considerable intrigue for a number of fields, including nutrition, psychiatry, and chronic diseases such as cancer. Thus, the study by Baik et al (8) bears promise. However, the functional rs671 ALDH2 SNP is not polymorphic in non-Asian populations, and in fact the genetic architecture underlying polymorphisms in the alcohol and aldedehyde dehydrogenase family of genes is complex and shows considerable variation across ethnic groups (14). This begs the critical question of why existing and ongoing GWAS of alcohol involvement in non-Asian populations have failed to identify polymorphisms in additional regions besides 12q24. The lowest P value reported by Baik et al (8) exceeds 10 × 10−50, and the study identified variants with a substantial effect on alcohol intake. For example, the mean intake of participants with the common homozygote of rs2074356 was 32.4 g, whereas those homozygous for the protective allele had a mean daily intake of only 4.9 g. The authors also report dramatic associations with the flushing response—for instance, carriers of the less common/protective allele of rs11066280 were >13 times as likely to experience alcohol-related flushing than those homozygous for the common allele. In addition, there was evidence for association with alcohol problems consistent with alcoholism. Although the same protective effects were noted, the effect sizes were smaller and did not reach similar levels of genome-wide significance, which was likely due to the reduced sample size available for those analyses. Due to the infrequent presence of the protective form of rs671 and correlated variants (eg, rs2074356 and rs11066280) in other populations (eg, European Americans), it is likely that other genetic variants exert an influence on alcohol intake in these populations. This might reflect genetic heterogeneity in the etiology of alcohol intake (6). A related possibility is that the long history of alcohol consumption in certain populations produced nutritional adaptation via preferential selection of the more common variant of these genes. This natural selection may allow individuals in these populations to efficiently metabolize and tolerate alcohol (15–17). Conversely, an intriguing theory suggests that the presence of the protective forms of alcohol and aldehyde dehydrogenase variants in Asian populations may reflect adaptation to diet, food toxins, and infectious agents previously indigenous to this population (15). Regardless of the evolutionary basis of ALDH2 variants, polymorphisms in other genes are likely to gain prominence in studies in non-Asian populations. Currently, there are 3 published GWAS of alcoholism (18–20), with others forthcoming. Across these efforts, not surprisingly, few loci have reached statistical significance, and there has been a near absence of replication, despite sample sizes in those studies well exceeding the pooled sample (n = 2834) used by Baik et al (8). Several consortia have also embarked on meta-analytic GWAS of alcohol consumption. Energized by the recent successes of smoking-related phenotypes, these consortia have amassed enviable sample sizes; however, these meta-analyses are challenged by differences in the assessment of alcohol intake across the different studies (21). It is likely that those genes that robustly correlate with a general vulnerability to alcohol use and misuse will skim to the top. Understanding the biological pathways that underlie these “top hits” will provide new insights into its etiology. Where can investigators look to maximize the most genomic bang for their (millions of) bucks? Collaboration across multiple samples is the immediate and obvious requirement. However, within their own samples, investigators may wish to consider the role of gene-environment interplay. For instance, a wealth of epidemiologic literature suggests that those who begin drinking at an early age may be at greater risk for a maladaptive and more genetically pronounced form of alcohol consumption (22, 23). Other well-documented interactions with socioregional characteristics (eg, living in an urban environment) (24), low religious affiliations (25), and marital status (26) indicate that, in certain environmental milieus, the heritability of alcohol consumption is higher (27). Much like Baik et al who reported on a subpopulation of middle-aged male drinkers, analyses that either focus on subgroups of individuals (eg, older men) or capture the interactions between genotype and sex, birth cohort, age, and environmental covariates may identify alleles with a larger effect size. Alcohol intake has often been considered to be the environmental background against which other physiologic processes occur. As environmental factors modify genetic vulnerability to alcohol intake, alcohol itself modifies the action of genetic influences on cardiovascular (28) and other disease outcomes (29). For instance, those with the less common allele of rs671 who also drank were at a nearly 9-fold increased risk of esophageal squamous cell carcinoma when compared with those with the risk genotype alone. This partly reflects a genotype-environment correlation, whereby rs671 modifies risk of esophageal cancer and for likelihood of exposure to alcohol (13). It also represents a gene-environment interaction, whereby exposure to alcohol exacerbates the genetic risk of esophageal cancer. Hence, as supported by an extensive literature and shown by Baik et al (8) in this issue, alcohol is an important environmental factor with a strong genetic basis and studying it in both of these contexts will be vital to understanding its role in public health.

Although previous results indicate that alpha-subunit residues Trp(187), Val(188), Phe(189), Tyr(190), and Pro(194) of the mouse nicotinic acetylcholine receptor are solvent-accessible and are in a position to contribute to the alpha-bungarotoxin (alpha-Bgtx) binding site (Spura, A., Russin, T. S., Freedman, N. D., Grant, M., McLaughlin, J. T., and Hawrot, E. (1999) Biochemistry 38, 4912-4921), little is known about the accessibility of other residues within this region. By determining second-order rate constants for the reaction of cysteine mutants at alpha184-alpha197 with the thiol-specific biotin derivative (+)-biotinyl-3-maleimidopropionamidyl-3,6-dioxaoctanediamine , we now show that only very subtle differences in reactivity (approximately 10-fold) are detectable, arguing that the entire region is solvent-exposed. Importantly, biotinylation in the presence of saturating concentrations of the long neurotoxin alpha-Bgtx is significantly retarded for positions alphaW187C, alphaF189C, and reduced wild-type receptors (alphaCys(192) and alphaCys(193)), further emphasizing their major contribution to the alpha-Bgtx binding site. Interestingly, although biotinylation of position alphaV188C is not affected by the presence of alpha-Bgtx, erabutoxin a, which is a member of the short neurotoxin family, inhibits biotinylation at position alphaV188C, but not at alphaW187C or alphaF189C. Taken together, these results indicate that short and long neurotoxins establish interactions with distinct amino acids on the nicotinic acetylcholine receptor.

Background & Aims Pernicious anemia, a result of autoimmune gastritis, is the most common cause of vitamin B 12 deficiency, affecting 2% to 5% of the elderly population. Treatment with vitamin B 12 cures the anemia, but not the gastritis. Findings from small studies have indicated that patients with pernicious anemia could have an increased risk of cancer. Methods We performed a population-based, case–control study of individuals in the Surveillance, Epidemiology, and End Results–Medicare database, comparing 1,138,390 cancer cases (age, 66–99 y) with 100,000 matched individuals without cancer (controls). Individuals with pernicious anemia were identified based on their medical claims within the year before selection for the study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated using unconditional logistic regression, and models were adjusted for sex, age, and calendar year of diagnosis and selection. Results Compared with controls, we found individuals with pernicious anemia to be at increased risk for noncardia gastric adenocarcinoma (OR, 2.18; 95% CI, 1.94–2.45) and gastric carcinoid tumors (OR, 11.43; 95% CI, 8.90–14.69). In addition, people with pernicious anemia have an increased risk of developing tonsilar cancer (OR, 2.00; 95% CI, 1.40–2.85), hypopharyngeal cancer (OR, 1.92; 95% CI, 1.35–2.73), esophageal squamous cell carcinoma (OR, 2.12; 95% CI, 1.76–2.55), small intestinal cancer (OR, 1.63; 95% CI, 1.32–2.02), liver cancer (OR, 1.49; 95% CI, 1.28– 1.73), myeloma (OR, 1.55; 95% CI, 1.37–1.75), acute myeloid leukemia (OR, 1.68; 95% CI, 1.46–1.93), and myelodysplastic syndrome (OR, 2.87; 95% CI, 2.53–3.26). People with pernicious anemia have a lower risk of rectal cancer than the general population (OR, 0.82; 95% CI, 0.74– 0.92). Conclusions In a population-based, case–control study of individuals in the Surveillance, Epidemiology, and End Results–Medicare database, we found individuals with pernicious anemia to have significantly increased risks of gastric carcinoid tumors, adenocarcinomas, and other cancers located throughout the body.

Purpose The proportion of cancer deaths in the contemporary United States caused by cigarette smoking (the population attributable fraction [PAF]) is not well documented. Methods The PAF of all cancer deaths due to active cigarette smoking among adults 35 years and older in the United States in 2010 was calculated using age- and sex-specific smoking prevalence from the National Health Interview Survey (NHIS) and age- and sex-specific relative risks from the Cancer Prevention Study-II (for ages 35–54 years) and from the Pooled Contemporary Cohort data set (for ages 55 years and older). Results The PAF for active cigarette smoking was 28.7% when estimated conservatively, including only deaths from the 12 cancers currently formally established as caused by smoking by the US Surgeon General. The PAF was 31.7% when estimated more comprehensively, including excess deaths from all cancers. These estimates do not include additional potential cancer deaths from environmental tobacco smoke or other type of tobacco use such as cigars, pipes, or smokeless tobacco. Conclusions Cigarette smoking causes a large proportion of cancer deaths in the contemporary United States. Reducing smoking prevalence as rapidly as possible should be a top priority for the US public health efforts to prevent cancer deaths.

BACKGROUND & AIMS: Diet could affect risk for esophageal and gastric cancers, but associations have been inconsistent. The diet is complex, so studies of dietary patterns, rather than studies of individual foods, might be more likely to identify cancer risk factors. There is limited research on index-based dietary patterns and esophageal and gastric cancers. We prospectively evaluated associations between the Healthy Eating Index-2005 (HEI-2005) and alternate Mediterranean Diet (aMED) scores and risk of esophageal and gastric cancers. METHODS: We analyzed data from 494,968 participants in the National Institutes of Health–AARP Diet and Health study, in which AARP members (age, 51–70 y) completed a self-administered baseline food frequency questionnaire between 1995 and 1996. Their answers were used to estimate scores for each index. RESULTS: During the follow-up period (1995–2006), participants developed 215 esophageal squamous cell carcinomas (ESCCs), 633 esophageal adenocarcinomas (EACs), 453 gastric cardia adenocarcinomas, and 501 gastric noncardia adenocarcinomas. Higher scores from the HEI-2005 were associated with a reduced risk of ESCC (comparing the highest quintile with the lowest quintile: hazard ratio, 0.51; 95% confidence interval, 0.31– 0.86; Ptrend .001) and EAC (hazard ratio, 0.75; 95% confidence interval, 0.57– 0.98; Ptrend .01). We observed an inverse association between ESCC, but not EAC, and a higher aMED score (meaning a higher-quality diet). HEI-2005 and aMED scores were not associated significantly with gastric cardia or noncardia adenocarcinomas. CONCLUSIONS: By using data collected from 1995 through 2006 from the National Institutes of Health– AARP Diet and Health Study, HEI-2005 and aMED scores were associated inversely with risk for esophageal cancers, particularly ESCC. Adherence to dietary recommendations might help prevent esophageal cancers.