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Background: The contribution of measurable immunological and inflammatory parameters to lung cancer development remains unclear, particularly among never smokers. We investigated the relationship between total and differential white blood cell (WBC) counts and incident lung cancer risk overall and among subgroups defined by smoking status and sex in the United Kingdom (UK)., Methods: We evaluated 424 407 adults aged 37-73 years from the UK Biobank. Questionnaires, physical measurements, and blood were administered and collected at baseline in 2006-2010. Complete blood cell counts were measured using standard methods. Lung cancer diagnoses and histological classifications were obtained from cancer registries. Multivariable Cox regression models were used to estimate the hazard ratio (HR) and 95% confidence intervals of incident lung cancer in relation to quartiles (Q) of total WBC and subtype-specific counts, with Q1 as the reference., Results: There were 1493 incident cases diagnosed over an average 7-year follow-up. Overall, the highest quartile of total WBC count was statistically significantly associated with elevated lung cancer risk (HR Q4 = 1.67, 95% CI = 1.41 to 1.98). Among women, increased risks were found in current smokers ( n cases / n  = 244 / 19 464, HR Q4 = 2.15, 95% CI = 1.46 to 3.16), former smokers ( n cases / n  = 280 / 69 198, HR Q4 = 1.75, 95% CI = 1.24 to 2.47), and never smokers without environmental tobacco smoke exposure (n cases / n = 108 / 111 294, HR Q4 = 1.93, 95% CI = 1.11 to 3.35). Among men, stronger associations were identified in current smokers (n case s / n  = 329 / 22 934, HR Q4 = 2.95, 95% CI = 2.04 to 4.26) and former smokers ( n c ases / n  = 358/71 616, HR Q4 = 2.38, 95% CI = 1.74 to 3.27) but not in never smokers. Findings were similar for lung adenocarcinoma and squamous cell carcinoma and were driven primarily by elevated neutrophil fractions., Conclusions: Elevated WBCs could potentially be one of many important markers for increased lung cancer risk, especially among never-smoking women and ever-smoking men., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the US.)

Background: Tobacco and alcohol are well-established risk factors for numerous cancers, yet their relationship to biliary tract cancers remains unclear., Methods: We pooled data from 26 prospective studies to evaluate associations of cigarette smoking and alcohol consumption with biliary tract cancer risk. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) for associations with smoking and alcohol consumption were calculated. Random-effects meta-analysis produced summary estimates. All statistical tests were two-sided., Results: Over a period of 38 369 156 person-years of follow-up, 1391 gallbladder, 758 intrahepatic bile duct, 1208 extrahepatic bile duct, and 623 ampulla of Vater cancer cases were identified. Ever, former, and current smoking were associated with increased extrahepatic bile duct and ampulla of Vater cancers risk (eg, current vs never smokers HR = 1.69, 95% CI = 1.34 to 2.13 and 2.22, 95% CI = 1.69 to 2.92, respectively), with dose-response effects for smoking pack-years, duration, and intensity (all Ptrend < .01). Current smoking and smoking intensity were also associated with intrahepatic bile duct cancer (eg, >40 cigarettes per day vs never smokers HR = 2.15, 95 % CI = 1.15 to 4.00; Ptrend = .001). No convincing association was observed between smoking and gallbladder cancer. Alcohol consumption was only associated with intrahepatic bile duct cancer, with increased risk for individuals consuming five or more vs zero drinks per day (HR = 2.35, 95%CI = 1.46 to 3.78; Ptrend = .04). There was evidence of statistical heterogeneity among several cancer sites, particularly between gallbladder cancer and the other biliary tract cancers., Conclusions: Smoking appears to increase the risk of developing all biliary tract cancers except gallbladder cancer. Alcohol may increase the risk of intrahepatic bile duct cancer. Findings highlight etiologic heterogeneity across the biliary tract., (Published by Oxford University Press 2019. This work is written by US Government employees and is in the public domain in the United States.)

Importance: Cardiovascular disease (CVD) is a leading cause of morbidity and mortality in the United States. Despite substantial declines in CVD mortality rates during past decades, progress against cardiovascular deaths in midlife has stagnated, with rates increased in some US racial/ethnic groups., Objective: To examine the trends in premature (ages 25-64 years) mortality from CVD from 2000 to 2015 by demographics and county-level factors, including education, rurality, and the prevalence of smoking, obesity, and diabetes., Design, Setting, and Participants: This descriptive study used US national mortality data from the Surveillance, Epidemiology, and End Results data set and included all CVD deaths among individuals ages 25 to 64 years from January 2000 to December 2015. The data analysis began in February 2018., Exposures: Age, sex, race/ethnicity, and county-level factors., Main Outcomes and Measures: Age-standardized mortality rates and average annual percent change (AAPC) in rates by age, sex, race/ethnicity, and county-level factors (in quintiles) and relative risks of CVD mortality across quintiles of each county-level factor., Results: In 2000 to 2015, 2.3 million CVD deaths occurred among individuals age 25 to 64 years in the United States. There were significant declines in CVD mortality for black, Latinx, and Asian and Pacific Islander individuals (AAPC: range, -1.7 to -3.2%), although black people continued to have the highest CVD mortality rates. Mortality rates were second highest for American Indian/Alaskan Native individuals and increased significantly among those aged 25 to 49 years (AAPC: women, 2.1%; men, 1.3%). For white individuals, mortality rates plateaued among women age 25 to 49 years (AAPC, 0.05%). Declines in mortality rates were observed for most major CVD subtypes except for ischemic heart disease, which was stable in white women and increased in American Indian/Alaska Native women, hypertensive heart disease, for which significant increases in rates were observed in most racial/ethnic groups, and endocarditis, for which rates increased in white individuals and American Indian/Alaska Native men. Counties with the highest prevalence of diabetes (quintile 5 vs quintile 1: relative risk range 1.6-1.8 for white individuals and 1.4-1.6 for black individuals) had the most risk of CVD mortality., Conclusions and Relevance: There have been substantial declines in premature CVD mortality in much of the US population. However, increases in CVD mortality before age 50 years among American Indian/Alaska Native individuals, flattening rates in white people, and overall increases in deaths from hypertensive disease suggest that targeted public health interventions are needed to prevent these premature deaths.

Renal cell carcinoma (RCC) has an undisputed genetic component and a stable 2:1 male to female sex ratio in its incidence across populations, suggesting possible sexual dimorphism in its genetic susceptibility. We conducted the first sex-specific genome-wide association analysis of RCC for men (3227 cases, 4916 controls) and women (1992 cases, 3095 controls) of European ancestry from two RCC genome-wide scans and replicated the top findings using an additional series of men (2261 cases, 5852 controls) and women (1399 cases, 1575 controls) from two independent cohorts of European origin. Our study confirmed sex-specific associations for two known RCC risk loci at 14q24.2 (DPF3) and 2p21(EPAS1). We also identified two additional suggestive male-specific loci at 6q24.3 (SAMD5, male odds ratio (OR male ) = 0.83 [95% CI = 0.78-0.89], P male  = 1.71 × 10 -8 compared with female odds ratio (OR female ) = 0.98 [95% CI = 0.90-1.07], P female  = 0.68) and 12q23.3 (intergenic, OR male  = 0.75 [95% CI = 0.68-0.83], P male  = 1.59 × 10 -8 compared with OR female  = 0.93 [95% CI = 0.82-1.06], P female  = 0.21) that attained genome-wide significance in the joint meta-analysis. Herein, we provide evidence of sex-specific associations in RCC genetic susceptibility and advocate the necessity of larger genetic and genomic studies to unravel the endogenous causes of sex bias in sexually dimorphic traits and diseases like RCC.

Vitamin B supplementation can have side effects for human health, including cancer risk. We aimed to elucidate the role of vitamin B12 in lung cancer etiology via direct measurements of pre-diagnostic circulating vitamin B12 concentrations in a nested case-control study, complemented with a Mendelian randomization (MR) approach in an independent case-control sample. We used pre-diagnostic biomarker data from 5183 case-control pairs nested within 20 prospective cohorts, and genetic data from 29,266 cases and 56,450 controls. Exposures included directly measured circulating vitamin B12 in pre-diagnostic blood samples from the nested case-control study, and 8 single nucleotide polymorphisms associated with vitamin B12 concentrations in the MR study. Our main outcome of interest was increased risk for lung cancer, overall and by histological subtype, per increase in circulating vitamin B12 concentrations. We found circulating vitamin B12 to be positively associated with overall lung cancer risk in a dose response fashion (odds ratio for a doubling in B12 [OR log2B12 ] = 1.15, 95% confidence interval (95%CI) = 1.06-1.25). The MR analysis based on 8 genetic variants also indicated that genetically determined higher vitamin B12 concentrations were positively associated with overall lung cancer risk (OR per 150 pmol/L standard deviation increase in B12 [OR SD ] = 1.08, 95%CI = 1.00-1.16). Considering the consistency of these two independent and complementary analyses, these findings support the hypothesis that high vitamin B12 status increases the risk of lung cancer., (© 2018 International Agency for Research on Cancer (IARC/WHO); licensed by UICC.)

Background: A growing proportion of tobacco users in the United States use non-cigarette products including cigars, pipes, and smokeless tobacco. Studies examining the disease and mortality risks of these products are urgently needed., Methods: We harmonized tobacco use data from 165 335 adults in the 1991, 1992, 1998, 2000, 2005, and 2010 National Health Interview Surveys. Hazard ratios (HRs) and 95% confidence intervals (CIs) for overall and cause-specific mortality occurring through December 31, 2015, were estimated by exclusive use of cigarettes, cigars, pipes, or smokeless tobacco using Cox proportional hazards regression with age as the underlying time metric and never tobacco users as the referent group., Results: Current use of cigarettes (HR = 2.23, 95% CI = 2.13 to 2.33) and smokeless tobacco (HR = 1.36, 95% CI = 1.17 to 1.59) were each associated with overall mortality. Relative to never tobacco users, higher risks were observed both in daily (HR = 2.34, 95% CI = 2.24 to 2.44) and nondaily (HR = 1.69, 95% CI = 1.54 to 1.86) cigarette smokers, with associations also observed across major smoking-related causes of death. Daily use of smokeless tobacco was also associated with overall mortality (HR = 1.41, 95% CI = 1.20 to 1.66) as was daily use of cigars (HR = 1.52, 95% CI = 1.12 to 2.08). Current smokeless tobacco use was associated with a higher risk of mortality from heart disease and smoking-related cancer, with strong associations observed for cancers of the oral cavity and bladder., Conclusions: Exclusive daily use of cigarettes, cigars, and smokeless tobacco was associated with higher mortality risk. Tobacco control efforts should include cigars and smokeless tobacco.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m 2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases., (©2019 American Association for Cancer Research.)

Background: Human papillomavirus type 16 (HPV16)-E6 antibodies are detectable in peripheral blood before diagnosis in the majority of HPV16-driven oropharyngeal squamous cell carcinoma (OPSCC), but the timing of seroconversion is unknown., Patients and Methods: We formed the HPV Cancer Cohort Consortium which comprises nine population cohorts from Europe, North America and Australia. In total, 743 incident OPSCC cases and 5814 controls provided at least one pre-diagnostic blood sample, including 111 cases with multiple samples. Median time between first blood collection and OPSCC diagnosis was 11.4 years (IQR = 6-11 years, range = 0-40 years). Antibodies against HPV16-E6 were measured by multiplex serology (GST fusion protein based Luminex assay)., Results: HPV16-E6 seropositivity was present in 0.4% of controls (22/5814; 95% CI 0.2% to 0.6%) and 26.2% (195/743; 95% CI 23.1% to 29.6%) of OPSCC cases. HPV16-E6 seropositivity increased the odds of OPSCC 98.2-fold (95% CI 62.1-155.4) in whites and 17.2-fold (95% CI 1.7-170.5) in blacks. Seropositivity in cases was more frequent in recent calendar periods, ranging from 21.9% pre-1996 to 68.4% in 2005 onwards, in those with blood collection near diagnosis (lead time <5 years). HPV16-E6 seropositivity increased with lead time: 0.0%, 13.5%, 23.7%, and 38.9% with lead times of >30 years (N = 24), 20-30 years (N = 148), 10-20 years (N = 228), and <10 years (N = 301 cases) (p-trend < 0.001). Of the 47 HPV16-E6 seropositive cases with serially-collected blood samples, 17 cases seroconverted during follow-up, with timing ranging from 6 to 28 years before diagnosis. For the remaining 30 cases, robust seropositivity was observed up to 25 years before diagnosis., Conclusions: The immune response to HPV16-driven tumorigenesis is most often detectable several decades before OPSCC diagnosis. HPV16-E6 seropositive individuals face increased risk of OPSCC over several decades., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology.)

Disparities in cancer mortality by county-level income have increased. It is unclear whether these widening disparities have affected older and younger adults equally. National death certificate data were utilized to ascertain cancer deaths during 1999-2015. Average annual percent changes in mortality rates and mortality rate ratios (RRs) were estimated by county-level income quintile and age (25-64 vs ≥65 years). Among 25- to 64-year-olds, cancer mortality rates were 30% higher (RR = 1.30, 95% confidence interval [CI] = 1.29 to 1.31) in the lowest-vs the highest-income counties in 1999-2001 and 56% higher (RR = 1.56, 95% CI = 1.55 to 1.57) in 2013-2015; the disparities among those 65 years and older were smaller but also widened over time (RR1999-2001 = 1.04, 95% CI = 1.03 to 1.05; RR2013-2015 = 1.14, 95% CI = 1.13 to 1.14). Widening disparities occurred across cancer sites. If all counties had the mortality rates of the highest-income counties, 21.5% of cancer deaths among 25- to 64-year-olds and 7.3% of cancer deaths in those 65 years and older would have been avoided in 2015. These results highlight an ongoing need for equity-focused interventions, particularly among younger adults., (Published by Oxford University Press 2019.)

Background: Available evidence on diet and glioma risk comes mainly from studies with retrospective collection of dietary data. To minimize possible differential dietary recall between those with and without glioma, we present findings from 3 large prospective studies., Methods: Participants included 692 176 from the UK Million Women Study, 470 780 from the US National Institutes of Health-AARP study, and 99 148 from the US Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cox regression yielded study-specific adjusted relative risks for glioma in relation to 15 food groups, 14 nutrients, and 3 dietary patterns, which were combined, weighted by inverse variances of the relative risks. Separate analyses by <5 and ≥5 years follow-up assessed potential biases related to changes of diet before glioma diagnosis., Results: The 1 262 104 participants (mean age, 60.6 y [SD 5.5] at baseline) were followed for 15.4 million person-years (mean 12.2 y/participant), during which 2313 incident gliomas occurred, at mean age 68.2 (SD 6.4). Overall, there was weak evidence for increased glioma risks associated with increasing intakes of total fruit, citrus fruit, and fiber and healthy dietary patterns, but these associations were generally null after excluding the first 5 years of follow-up. There was little evidence for heterogeneity of results by study or by sex., Conclusions: The largest prospective evidence to date suggests little, if any, association between major food groups, nutrients, or common healthy dietary patterns and glioma incidence. With the statistical power of this study and the comprehensive nature of the investigation here, it seems unlikely we have overlooked major effects of diet on risk of glioma that would be of public health concern., (© The Author(s) 2019. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Objective: Cross-sectional data indicate that systemic inflammation is important in oesophageal adenocarcinoma. We conducted a prospective study to assess whether prediagnostic circulating markers of inflammation were associated with oesophageal adenocarcinoma and to what extent they mediated associations of obesity and cigarette smoking with cancer risk., Design: This nested case-control study included 296 oesophageal adenocarcinoma cases and 296 incidence density matched controls from seven prospective cohort studies. We quantitated 69 circulating inflammation markers using Luminex-based multiplex assays. Conditional logistic regression models estimated associations between inflammation markers and oesophageal adenocarcinoma, as well as direct and indirect effects of obesity and smoking on risk of malignancy., Results: Soluble tumour necrosis factor receptor 2 (sTNFR2) (ORs quartile 4 vs 1 =2.67, 95% CI 1.52 to 4.68) was significantly associated with oesophageal adenocarcinoma. Additional markers close to the adjusted significance threshold included C reactive protein, serum amyloid A, lipocalin-2, resistin, interleukin (IL) 3, IL17A, soluble IL-6 receptor and soluble vascular endothelial growth factor receptor 3. Adjustment for body mass index, waist circumference or smoking status slightly attenuated biomarker-cancer associations. Mediation analysis indicated that sTNFR2 may account for 33% (p=0.005) of the effect of waist circumference on oesophageal adenocarcinoma risk. Resistin, plasminogen activator inhibitor 1, C reactive protein and serum amyloid A were also identified as potential mediators of obesity-oesophageal adenocarcinoma associations. For smoking status, only plasminogen activator inhibitor 1 was a nominally statistically significant (p<0.05) mediator of cancer risk., Conclusion: This prospective study provides evidence of a link between systemic inflammation and oesophageal adenocarcinoma risk. In addition, this study provides the first evidence that indirect effects of excess adiposity and cigarette smoking, via systemic inflammation, increase the risk of oesophageal adenocarcinoma., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Mosaic protein truncating variants (PTVs) in the phosphatase, Mg2+/Mn2+dependent 1D (PPM1D) gene in blood-derived DNA have been associated with increased risk of breast cancer. We analyzed PPM1D PTVs in blood from 3817 breast cancer cases and 3058 controls by deep sequencing of a previously defined region in exon 6 of PPM1D. We identified 50 of 6875 (0.73%) participants having a mosaic PPM1D PTV. We observed a higher frequency of mosaic PPM1D PTVs with increasing age (P trend  = 2.9 × 10 -6 ). We did not observe an overall association between PPM1D PTVs and increased breast cancer risk (OR = 1.51, 95% CI = 0.84-2.71). Evidence for an association was observed in a subset of cases with DNA collected 1-year or more before breast cancer diagnosis (OR = 3.44, 95% CI = 1.62-7.30, P-value = 0.001); however, no significant association was observed for the larger series of cases with DNA collected post diagnosis (OR = 1.01, 95% CI = 0.51-2.01, P-value = 0.98). Our study indicates that the PPM1D PTVs are present at higher rates than previously reported and the frequency of PPM1D PTVs increases with age. We observed limited evidence for an association between mosaic PPM1D PTVs and breast cancer risk, suggesting mosaic PPM1D PTVs in the blood likely do not influence risk of breast cancer.

Purpose: We evaluated the association of coffee and tea drinking with risk of the urinary tract cancer in Finnish men, with high coffee consumption, using data from the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study., Methods: The ATBC trial conducted from 1985 to 1993 enrolled 29,133 male smokers. We used Cox proportional hazards regression models to estimate hazard ratios (HRs) and confidence intervals (CIs), using men who drank more than 0 but less than 1 cup coffee/d and tea nondrinkers as our referent group for coffee and tea analyses, respectively., Results: During 472,402 person-years of follow-up, 835 incident cases of bladder cancer and 366 cases of renal cell carcinoma were ascertained. For bladder cancer, we observed no association for coffee consumption (HR ≥4 vs. >0 to <1 cups/d = 1.16, 95% CI = 0.86-1.56) and a borderline statistically significant inverse association for tea consumption (HR ≥1 vs. 0 cup/d = 0.77, 95% CI = 0.58-1.00). For renal cell carcinoma, we observed no association for coffee (HR ≥4 vs. >0 to <1 cups/d = 0.85, 95% CI = 0.55-1.32) or tea consumption (HR ≥1 vs. 0 cup/d = 1.00, 95% CI = 0.68-1.46). We found no impact of coffee preparation on coffee-cancer associations., Conclusions: Coffee drinking was not associated with urinary tract cancers risk. Further research on tea and bladder cancer is warranted., (Published by Elsevier Inc.)

Aflatoxin B 1 (AFB 1 ) is a known human hepatocarcinogen and a recent study reported elevated AFB 1 levels, measured by serum albumin biomarkers, among Guatemalan adults. While AFB 1 can contaminate a variety of foodstuffs, including maize, Guatemala's main dietary staple, the relationship of maize intake to serum AFB 1 -albumin adducts levels in Guatemala has not been previously examined. As a result, a cross-sectional study was conducted among 461 Guatemalan adults living in five geographically distinct departments of the country. Participants provided a serum sample and completed a semi-quantitative food frequency questionnaire and a sociodemographic questionnaire. Multiple linear regression analysis was used to estimate the least square means (LSQ) and 95% confidence intervals (95% CI) of log-transformed AFB 1 -albumin adducts by quintiles of maize consumption in crude and adjusted models. Additionally, analyses of tortilla consumption and levels of maize processing were conducted. The median maize intake was 344.3 g per day [Interquartile Range (IQR): 252.2, 500.8], and the median serum AFB 1 -albumin adduct level was 8.4 pg/mg albumin (IQR: 3.8, 22.3). In adjusted analyses, there was no association between overall maize consumption and serum AFB 1 -albumin levels. However, there was a statistically significant association between tortilla consumption and AFB 1 -albumin levels (p trend  = 0.01). The LSM of AFB 1 -albumin was higher in the highest quintile of tortilla consumption compared to the lowest quintile [LSM:9.03 95%CI: 7.03,11.70 vs 6.23, 95%CI: 4.95,8.17, respectively]. These findings indicate that tortilla may be an important source of AFB 1 exposure in the Guatemalan population. Therefore, efforts to control or mitigate AFB 1 levels in contaminated maize used for tortillas may reduce overall exposure in this population.

Background: Previously we showed that adulthood body mass index (BMI) trajectories that result in obesity were associated with elevated risks of fatal prostate cancer (PCA). To further explore this relationship, we conducted a study within the NIH-AARP Diet and Health Study., Methods: Among 153 730 eligible men enrolled in the NIH-AARP cohort from 1995 to 1996 (median follow-up = 15.1 years), we identified 630 fatal PCA cases and 16 896 incident cases. BMI was assessed for ages 18, 35 and 50 and at study entry, enabling examination of latent class-identified BMI trajectories. Hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using Cox proportional hazards regression., Results: BMI at study entry (mean age = 63, HR = 1.12; 95% CI = 1.01, 1.24, per 5-unit increase) and maximum BMI during adulthood (HR = 1.12; 95% CI = 1.02, 1.24, per 5-unit increase) shared modest associations with increased risk of fatal PCA. Smoking status likely modified the relationship between BMI trajectories and fatal PCA (Pinteraction = 0.035 via change-in-estimate variable section, P = 0.065 via full a priori model). Among never-smokers, BMI trajectory of normal weight to obesity was associated with increased risk of fatal disease (HR = 2.37; 95% CI = 1.38, 4.09), compared with the maintained normal weight trajectory, whereas there was no association among former or current-smokers. Total and non-aggressive PCA exhibited modest inverse associations with BMI at all ages, whereas no association was observed for aggressive PCA., Conclusions: Increased BMI was positively associated with fatal PCA, especially among never-smokers. Future studies that examine PCA survival will provide additional insight as to whether these associations are the result of biology or confounding., (Published by Oxford University Press on behalf of the International Epidemiological Association 2018. This work is written by US Government employees and is in the public domain in the US.)

Background: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known., Materials and Methods: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models., Results: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23)., Conclusion: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Growing evidence suggests that people with autoimmune conditions may be at increased risk of hepatobiliary tumors. In the present study, we evaluated associations between autoimmune conditions and hepatobiliary cancers among adults aged ≥66 in the United States. We used Surveillance, Epidemiology, and End Results (SEER)-Medicare data (1992-2013) to conduct a population-based, case-control study. Cases (n = 32,443) had primary hepatobiliary cancer. Controls (n = 200,000) were randomly selected, cancer-free adults frequency-matched to cases by sex, age and year of selection. Using multivariable logistic regression, we calculated odds ratios (ORs) and 95% confidence intervals (CIs) for associations with 39 autoimmune conditions identified via Medicare claims. We also conducted separate analyses for diagnoses obtained via inpatient versus outpatient claims. Sixteen conditions were associated with at least one hepatobiliary cancer. The strongest risk estimates were for primary biliary cholangitis with hepatocellular carcinoma (OR: 31.33 [95% CI: 23.63-41.56]) and primary sclerosing cholangitis with intrahepatic cholangiocarcinoma (7.53 [5.73-10.57]), extrahepatic cholangiocarcinoma (5.59 [4.03-7.75]), gallbladder cancer (2.06 [1.27-3.33]) and ampulla of Vater cancer (6.29 [4.29-9.22]). Associations with hepatobiliary-related conditions as a group were observed across nearly all cancer sites (ORs ranging from 4.53 [95% CI: 3.30-6.21] for extrahepatic cholangiocarcinoma to 7.18 [5.94-8.67] for hepatocellular carcinoma). Restricting to autoimmune conditions diagnosed via inpatient claims, 6 conditions remained associated with at least one hepatobiliary cancer, and several risk estimates increased. In the outpatient restricted analysis, 12 conditions remained associated. Multiple autoimmune conditions are associated with hepatobiliary cancer risk in the US Medicare population, supporting a shared immuno-inflammatory etiology to these cancers., (© 2018 UICC.)

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., (Copyright © 2018 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. All rights reserved.)

Background: Increasing premature mortality among some groups of Americans has been largely driven by increases in drug poisoning deaths. However, to our knowledge, a formal descriptive study by race and ethnicity, socioeconomic status, rurality, and geography has not been done. In this study, we examined US trends in premature all-cause and drug poisoning mortality between 2000 and 2015 at the county level among white, black, and Latino people., Methods: We used US mortality data for the period Jan 1, 2000, to Dec 31, 2015, including underlying cause of death and demographic data, collected from death certificates by the Centers for Disease Control and Prevention National Center for Health Statistics, and ascertained county attributes from the 2011-15 Census American Community Survey. We categorised counties into quintiles on the basis of the percentage of people unemployed, the percentage of people with a bachelor's degree, median income, and rurality. We estimated premature (ie, deaths in those aged 25-64 years) age-standardised mortality for all causes (by race and ethnicity) and drug poisoning, by county, for the periods of 2000-03 and 2012-15. We estimated annual percentage changes in mortality (2000-15) by county-level characteristics., Findings: Premature mortality declined from 2000-03 to 2012-15 among black and Latino people, but increased among white people in many US counties. Drug poisoning mortality increased in counties throughout the country. Significant increases between 2000 and 2015 occurred across low and high socioeconomic status and urban and rural counties among white people aged 25-64 years (annual percentage change range 4·56% per year [95% CI 3·56-5·57] to 11·51% per year [9·41-13·65]), black people aged 50-64 years (2·27% per year [0·42-4·16] to 9·46% per year [7·02-11·96]), Latino women aged 25-49 years (2·43% per year [1·18-3·71] to 5·01% per year [3·80-6·23]), and Latino men aged 50-64 years (2·42% per year [0·53-4·34] to 5·96% per year [3·86-8·11]). Although drug poisoning mortality increased rapidly in counties with the lowest socioeconomic status and in rural counties, most deaths during 2012-15 occurred in the largest metropolitan counties (121 395 [76%] in metropolitan counties with ≥250 000 people vs 2175 [1%] in the most rural counties), reflecting population size., Interpretation: Premature mortality has declined among black and Latino people in the USA, and increased among white people, particularly in less affluent and rural counties. Increasing drug poisoning mortality was not limited to poor white people in rural areas. Rapid increases have occurred in communities throughout the USA regardless of race and ethnicity, socioeconomic status, or rurality. Widespread public health interventions are needed to addess this public health emergency., Funding: National Institutes of Health., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here, we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank, in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds [HR low = 1.18; 95% confidence interval (CI) low , 1.07-1.30; P low = 0.001; HR high = 1.36; 95% CI high , 1.09-1.71; P high = 0.007] and more specifically we observed an association with lung cancer (HR high = 2.25; 95% CI high , 1.36-3.71; P high = 0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking. SIGNIFICANCE: Evidence from the UK Biobank indicates mosaic chromosome Y loss in leukocytes is moderately associated with increased incidence of select solid tumors., (©2018 American Association for Cancer Research.)

Many smokers do not quit but instead reduce the number of cigarettes they smoke per day (CPD) over their lifetime. Yet the associations of such changes in CPD with health risks are unclear. We examined the association of changes in CPD with subsequent death in the period 2004-2011 among 253,947 participants of the National Institutes of Health-AARP Diet and Health Study. Using a questionnaire assessing responders' history of smoking cigarettes, we identified cigarette smokers who quit, decreased, maintained, or increased their CPD between ages 25-29 and 50-59 years. Hazard ratios and 95% confidence intervals were obtained from multivariable adjusted Cox proportional hazards regression models. Relative to never smokers, smokers who maintained a consistent CPD had 2.93 times (95% confidence interval (CI): 2.82, 3.05) higher all-cause mortality risk, and participants who increased their CPD had still higher risk (hazard ratio (HR) = 3.37, 95% CI: 3.23, 3.52). Death risk was lower among participants who decreased their CPD (HR = 2.38, 95% CI: 2.25, 2.52) or quit smoking (for quitting between ages 30 and 39 years, HR = 1.32, 95% CI: 1.25, 1.39). Similar patterns were observed for smoking-related causes of death, with particularly strong associations for lung cancer and respiratory disease. Reductions in CPD over the lifetime meaningfully decreased death risk; however, cessation provided a larger benefit than even large declines in CPD.

Background: Experimental and epidemiological studies suggest a protective role for vitamin D in colorectal carcinogenesis, but evidence is inconclusive. Circulating 25-hydroxyvitamin D (25(OH)D) concentrations that minimize risk are unknown. Current Institute of Medicine (IOM) vitamin D guidance is based solely on bone health., Methods: We pooled participant-level data from 17 cohorts, comprising 5706 colorectal cancer case participants and 7107 control participants with a wide range of circulating 25(OH)D concentrations. For 30.1% of participants, 25(OH)D was newly measured. Previously measured 25(OH)D was calibrated to the same assay to permit estimating risk by absolute concentrations. Study-specific relative risks (RRs) for prediagnostic season-standardized 25(OH)D concentrations were calculated using conditional logistic regression and pooled using random effects models., Results: Compared with the lower range of sufficiency for bone health (50-<62.5 nmol/L), deficient 25(OH)D (<30 nmol/L) was associated with 31% higher colorectal cancer risk (RR = 1.31, 95% confidence interval [CI] = 1.05 to 1.62); 25(OH)D above sufficiency (75-<87.5 and 87.5-<100 nmol/L) was associated with 19% (RR = 0.81, 95% CI = 0.67 to 0.99) and 27% (RR = 0.73, 95% CI = 0.59 to 0.91) lower risk, respectively. At 25(OH)D of 100 nmol/L or greater, risk did not continue to decline and was not statistically significantly reduced (RR = 0.91, 95% CI = 0.67 to 1.24, 3.5% of control participants). Associations were minimally affected when adjusting for body mass index, physical activity, or other risk factors. For each 25 nmol/L increment in circulating 25(OH)D, colorectal cancer risk was 19% lower in women (RR = 0.81, 95% CI = 0.75 to 0.87) and 7% lower in men (RR = 0.93, 95% CI = 0.86 to 1.00) (two-sided Pheterogeneity by sex = .008). Associations were inverse in all subgroups, including colorectal subsite, geographic region, and season of blood collection., Conclusions: Higher circulating 25(OH)D was related to a statistically significant, substantially lower colorectal cancer risk in women and non-statistically significant lower risk in men. Optimal 25(OH)D concentrations for colorectal cancer risk reduction, 75-100 nmol/L, appear higher than current IOM recommendations., (Published by Oxford University Press 2018.)

Background: How carcinogen exposure varies across users of different, particularly noncigarette, tobacco products remains poorly understood., Methods: We randomly selected 165 participants of the Golestan Cohort Study from northeastern Iran: 60 never users of any tobacco, 35 exclusive cigarette, 40 exclusive (78% daily) waterpipe, and 30 exclusive smokeless tobacco (nass) users. We measured concentrations of 39 biomarkers of exposure in 4 chemical classes in baseline urine samples: tobacco alkaloids, tobacco-specific nitrosamines (TSNA), polycyclic aromatic hydrocarbons (PAH), and volatile organic compounds (VOC). We also quantified the same biomarkers in a second urine sample, obtained 5 years later, among continuing cigarette smokers and never tobacco users., Results: Nass users had the highest concentrations of tobacco alkaloids. All tobacco users had elevated TSNA concentrations, which correlated with nicotine dose. In both cigarette and waterpipe smokers, PAH and VOC biomarkers were higher than never tobacco users and nass users, and highly correlated with nicotine dose. PAH biomarkers of phenanthrene and pyrene and two VOC metabolites (phenylmercapturic acid and phenylglyoxylic acid) were higher in waterpipe smokers than in all other groups. PAH biomarkers among Golestan never tobacco users were comparable to those in U.S. cigarette smokers. All biomarkers had moderate to good correlations over 5 years, particularly in continuing cigarette smokers., Conclusions: We observed two patterns of exposure biomarkers that differentiated the use of the combustible products (cigarettes and waterpipe) from the smokeless product. Environmental exposure from nontobacco sources appeared to contribute to the presence of high levels of PAH metabolites in the Golestan Cohort., Impact: Most of these biomarkers would be useful for exposure assessment in a longitudinal study., (©2019 American Association for Cancer Research.)

Background: Several obesity-related factors have been associated with renal cell carcinoma (RCC), but it is unclear which individual factors directly influence risk. We addressed this question using genetic markers as proxies for putative risk factors and evaluated their relation to RCC risk in a mendelian randomization (MR) framework. This methodology limits bias due to confounding and is not affected by reverse causation., Methods and Findings: Genetic markers associated with obesity measures, blood pressure, lipids, type 2 diabetes, insulin, and glucose were initially identified as instrumental variables, and their association with RCC risk was subsequently evaluated in a genome-wide association study (GWAS) of 10,784 RCC patients and 20,406 control participants in a 2-sample MR framework. The effect on RCC risk was estimated by calculating odds ratios (ORSD) for a standard deviation (SD) increment in each risk factor. The MR analysis indicated that higher body mass index increases the risk of RCC (ORSD: 1.56, 95% confidence interval [CI] 1.44-1.70), with comparable results for waist-to-hip ratio (ORSD: 1.63, 95% CI 1.40-1.90) and body fat percentage (ORSD: 1.66, 95% CI 1.44-1.90). This analysis further indicated that higher fasting insulin (ORSD: 1.82, 95% CI 1.30-2.55) and diastolic blood pressure (DBP; ORSD: 1.28, 95% CI 1.11-1.47), but not systolic blood pressure (ORSD: 0.98, 95% CI 0.84-1.14), increase the risk for RCC. No association with RCC risk was seen for lipids, overall type 2 diabetes, or fasting glucose., Conclusions: This study provides novel evidence for an etiological role of insulin in RCC, as well as confirmatory evidence that obesity and DBP influence RCC risk., Competing Interests: I have read the journal's policy and the authors of this manuscript have the following competing interests: TE declared employment, research support, and stock in AstraZeneca and research support from Bayer and Pfizer. PCH is a population health fellow of Cancer Research UK. GDS is a member of the Editorial Board of PLOS Medicine.

Background: Esophageal adenocarcinoma (EA) and gastric cardia adenocarcinoma (GCA) are characterized by a strong male predominance. Concentrations of sex steroid hormones have been hypothesized to explain this sex disparity. However, no prospective population-based study has examined sex steroid hormones in relation to EA/GCA risk. Thus, we investigated whether prediagnostic circulating sex steroid hormone concentrations were associated with EA/GCA in a nested case-control study drawn from participants in three prospective cohort studies., Methods: Using gas chromatography-mass spectrometry (GC-MS) and electrochemiluminescence immunoassay, we quantitated sex steroid hormones and sex hormone binding globulin, respectively, in serum from 259 EA/GCA male case participants and 259 matched male control participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, and Cancer Prevention Study II Nutrition Cohort. Multivariable conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for associations between circulating hormones and EA/GCA risk. All statistical tests were two-sided., Results: Higher concentrations of dehydroepiandrosterone (DHEA) were associated with a 38% decreased risk of EA/GCA (OR per unit increase in log2 DHEA = 0.62, 95% CI = 0.47 to 0.82, Ptrend = .001). Higher estradiol concentrations were associated with a 34% reduced risk of EA/GCA (OR = 0.66, 95% CI = 0.45 to 0.98, Ptrend = .05), and the association with free estradiol was similar. No other associations between baseline hormone concentrations and future EA/GCA risk were observed., Conclusions: This study provides the first evidence that higher concentrations of circulating DHEA, estradiol, and free estradiol may be associated with lower risks of EA/GCA in men.

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., (Published by Elsevier Inc.)

Background: Prior research has established that the prevalence of pathogenic/likely pathogenic (P/LP) variants across all of the American College of Medical Genetics (ACMG) Secondary Findings (SF) genes is approximately 0.8-5%. We investigated the prevalence of P/LP variants in the 24 ACMG SF v2.0 cancer genes in a family-based cancer research cohort (n = 1173) and in cancer-free ethnicity-matched controls (n = 982)., Methods: We used InterVar to classify variants and subsequently conducted a manual review to further examine variants of unknown significance (VUS)., Results: In the 24 genes on the ACMG SF v2.0 list associated with a cancer phenotype, we observed 8 P/LP unique variants (8 individuals; 0.8%) in controls and 11 P/LP unique variants (14 individuals; 1.2%) in cases, a non-significant difference. We reviewed 115 VUS. The median estimated per-variant review time required was 30 min; the first variant within a gene took significantly (p = 0.0009) longer to review (median = 60 min) compared with subsequent variants (median = 30 min). The concordance rate was 83.3% for the variants examined by two reviewers., Conclusion: The 115 VUS required database and literature review, a time- and labor-intensive process hampered by the difficulty in interpreting conflicting P/LP determinations. By rigorously investigating the 24 ACMG SF v2.0 cancer genes, our work establishes a benchmark P/LP variant prevalence rate in a familial cancer cohort and controls.

Importance: The United States has higher infant and youth mortality rates than other high-income countries, with striking disparities by racial/ethnic group. Understanding changing trends by age and race/ethnicity for leading causes of death is imperative for focused intervention., Objective: To estimate trends in US infant and youth mortality rates from 1999 to 2015 by age group and race/ethnicity, identify leading causes of death, and compare mortality rates with Canada and England/Wales., Design, Setting, and Participants: This descriptive study analyzed death certificate data from the US National Center for Health Statistics, Statistics Canada, and the UK Office of National Statistics for all deaths among individuals younger than 25 years. The study took place from January 1, 1999, to December 31, 2015, and analyses started in September 2017., Exposures: Race/ethnicity., Main Outcomes and Measures: Average annual percent changes in mortality rates from 1999 to 2015 and absolute rate change between 1999 to 2002 and 2012 to 2015 for each age group, race/ethnicity, and cause of death., Results: Among individuals from birth to age 24 years, 1 169 537 deaths occurred in the United States, 80 540 in Canada, and 121 183 in England/Wales from 1999 to 2015. In the United States, 64% of deaths occurred in male individuals and 52.6% occurred in white individuals (25.1% deaths occurred in black individuals and 17.9% in Latino individuals). All-cause mortality declined for all age groups (infants younger than 1 year [38.5% of deaths], children aged 1-9 years [10.6%], early adolescents aged 10-14 years [5%], late adolescents aged 15-19 years [17.7%], and young adults aged 20-24 years [28.1%]) in the United States, Canada, and England/Wales from 1999 to 2015. However, rates were highest in the United States. Within the United States, annual declines in all-cause mortality rates occurred among all age groups of black, Latino, and white individuals, except for white individuals aged 20 to 24 years, whose rates remained stable. Mortality rates declined across most major causes of death from 1999 to 2002 and 2012 to 2015, with notable declines observed for sudden infant death syndrome, unintentional injury death, and homicides. Among infants, unintentional suffocation and strangulation in bed increased (difference between 2012-2015 and 1999-2002 range, 6.11-29.03 per 100 000). Further, suicide rates among Latino and white individuals aged 10 to 24 years (range, 0.21-2.63 per 100 000) and black individuals aged 10 to 19 years (range, 0.10-0.45 per 100 000) increased, as did unintentional injury deaths in white young adults (0.79 per 100 000). The rise in unintentional injury deaths is attributed to increases in drug poisonings and was also observed in black and Latino young adults., Conclusions and Relevance: Mortality rates in the United States have generally declined for infants and youths from 1999 to 2015 owing to reductions in sudden infant death syndrome, unintentional injury death, and homicides. However, US mortality rates remain higher than Canada and England/Wales, with particularly elevated rates among black and American Indian/Alaskan Native youth. Further, there is a concerning increase in suicide and drug poisoning death rates among US adolescents and young adults.

The role of alcoholic beverages in the etiology of gastric cancer is unclear. Recent summaries showed a positive association between higher alcohol intake and gastric cancer risk, but the magnitude of association is small, there is moderate heterogeneity among studies, and most cases were from Asian populations. We prospectively investigated the associations of alcohol consumption with gastric cardia adenocarcinoma (GCA) and gastric noncardia adenocarcinoma (GNCA) in 490,605 adults, aged 50-71 years at baseline who participated in the NIH-AARP diet and health study. Alcohol consumption in the past year was assessed at baseline by questionnaire and defined as total grams of ethanol intake per day or as a categorical variable: nondrinker, up to or including one drink per day, one to three drinks per day and greater than three drinks per day. We used multivariable-adjusted Cox proportional hazards regression to calculate the hazard ratios (HR) and 95% confidence intervals (CI) for associations between alcohol intake and risk of gastric adenocarcinomas. Through 2011, 662 incident cases of GCA and 713 of GNCA occurred. We found no association between higher alcohol consumption and GCA or GNCA, when examined as total alcoholic beverage intake or individual beverage types of beer, wine and liquor. Furthermore, we observed no association by stratum of sex, ethnic group, educational level or smoking status. We did, however, observe lower risk of GNCA among participants who drank up to one drink per day (HR = 0.81, 95% CI: 0.67-0.97) compared to nondrinkers. In conclusion, alcohol consumption was not associated with increased risk of GCA or GNCA in this large U.S. cohort., (© 2018 UICC.)

Background: Self-reported smoking is the principal measure used to assess lung cancer risk in epidemiological studies. We evaluated if circulating cotinine-a nicotine metabolite and biomarker of recent tobacco exposure-provides additional information on lung cancer risk., Methods: The study was conducted in the Lung Cancer Cohort Consortium (LC3) involving 20 prospective cohort studies. Pre-diagnostic serum cotinine concentrations were measured in one laboratory on 5364 lung cancer cases and 5364 individually matched controls. We used conditional logistic regression to evaluate the association between circulating cotinine and lung cancer, and assessed if cotinine provided additional risk-discriminative information compared with self-reported smoking (smoking status, smoking intensity, smoking duration), using receiver-operating characteristic (ROC) curve analysis., Results: We observed a strong positive association between cotinine and lung cancer risk for current smokers [odds ratio (OR ) per 500 nmol/L increase in cotinine (OR500): 1.39, 95% confidence interval (CI): 1.32-1.47]. Cotinine concentrations consistent with active smoking (≥115 nmol/L) were common in former smokers (cases: 14.6%; controls: 9.2%) and rare in never smokers (cases: 2.7%; controls: 0.8%). Former and never smokers with cotinine concentrations indicative of active smoking (≥115 nmol/L) also showed increased lung cancer risk. For current smokers, the risk-discriminative performance of cotinine combined with self-reported smoking (AUCintegrated: 0.69, 95% CI: 0.68-0.71) yielded a small improvement over self-reported smoking alone (AUCsmoke: 0.66, 95% CI: 0.64-0.68) (P = 1.5x10-9)., Conclusions: Circulating cotinine concentrations are consistently associated with lung cancer risk for current smokers and provide additional risk-discriminative information compared with self-report smoking alone.

Distal and proximal colon tumors have distinct incidence trends and embryonic origins; whether these sub-sites have distinct susceptibilities to known risk factors is unclear. We used pooled data from 407,270 participants in three US-based studies, with overall median follow-up of 13.8 years. We used adjusted Cox models to analyze the association between dietary intakes (from diet history questionnaire) of total, processed and unprocessed red meat; total white meat, poultry and fish and meat-related compounds: heme iron, nitrate, nitrite, the heterocyclic amines (HCAs) and benzo(a)pyrene (B(a)P) and incidence of colorectal cancer subsites. The risk of colorectal cancer (n = 6,640) increased by 35% for each 50 g/1,000 kcal higher daily intake of total red meat, with a significant right-to-left trend from proximal colon (HR: 1.24; 95% CI: 1.09-1.39) to distal colon (HR: 1.34; 95% CI: 1.13-1.55) and rectum (HR: 1.53; 95% CI: 1.28-1.79). Only unprocessed red meat showed a significant right-to-left trend. Each 50 g/1,000 kcal increase in white meat intake was associated with a 26% reduction in total colorectal cancer risk (HR: 0.74; 95% CI: 0.68-0.80), with a significant inverse right-to-left trend. The highest quintile of heme iron was associated with increased cancer risk only in the distal colon (HR: 1.20; 95% CI: 1.02-1.42) and rectum (HR: 1.27; 95% CI: 1.07-1.52). The highest quintile of HCAs, and nitrate/nitrite were associated with increased risk of total colorectal cancer, but these associations did not vary across anatomical subsites. In summary, right and left subsites of the colon may have distinct susceptibilities to meat and possibly other dietary risk factors, suggesting that the causes of colorectal cancer may vary across anatomical subsites., (© 2018 UICC.)

While vitamin D has been associated with improved overall cancer survival in some investigations, few have prospectively evaluated organ-specific survival. We examined the accepted biomarker of vitamin D status, serum 25-hydroxyvitamin D [25(OH)D], and cancer survival in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. Of 4616 cancer cases with measured serum 25(OH)D, 2884 died of their cancer during 28 years of follow-up and 1732 survived or died of other causes. Proportional hazards regression estimated hazard ratios (HR) and 95% confidence intervals (CI) for the association between pre-diagnostic 25(OH)D and overall and site-specific survival. Serum 25(OH)D was significantly lower among cases who subsequently died from their malignancy compared with those who did not (medians 34.7 vs. 36.5 nmol/L, respectively; p = 0.01). Higher 25(OH)D was associated with lower overall cancer mortality (HR = 0.76, 95% CI 0.67-0.85 for highest vs. lowest quintile, p-trend < 0.0001). Higher 25(OH)D was related to lower mortality from the following site-specific malignancies: prostate (HR = 0.74, 95% CI 0.55-1.01, p-trend = 0.005), kidney (HR = 0.59, 95% CI 0.35-0.98, p-trend = 0.28), and melanoma (HR = 0.39, 95% CI 0.20-0.78, p-trend = 0.01), but increased mortality from lung cancer (HR = 1.28, 95% CI 1.02-1.61, p-trend = 0.19). Improved survival was also suggested for head and neck, gastric, pancreatic, and liver cancers, though not statistically significantly, and case numbers for the latter two organ sites were small. Higher 25(OH)D status years prior to diagnosis was related to improved survival for overall and some site-specific cancers, associations that should be examined in other prospective populations that include women and other racial-ethnic groups.

Background: Experimental and clinical evidence implicates testosterone in the aetiology of prostate cancer. Variation across the normal range of circulating free testosterone concentrations may not lead to changes in prostate biology, unless circulating concentrations are low. This may also apply to prostate cancer risk, but this has not been investigated in an epidemiological setting., Objective: To examine whether men with low concentrations of circulating free testosterone have a reduced risk of prostate cancer., Design, Setting, and Participants: Analysis of individual participant data from 20 prospective studies including 6933 prostate cancer cases, diagnosed on average 6.8 yr after blood collection, and 12 088 controls in the Endogenous Hormones, Nutritional Biomarkers and Prostate Cancer Collaborative Group., Outcome Measurements and Statistical Analysis: Odds ratios (ORs) of incident overall prostate cancer and subtypes by stage and grade, using conditional logistic regression, based on study-specific tenths of calculated free testosterone concentration., Results and Limitations: Men in the lowest tenth of free testosterone concentration had a lower risk of overall prostate cancer (OR=0.77, 95% confidence interval [CI] 0.69-0.86; p<0.001) compared with men with higher concentrations (2nd-10th tenths of the distribution). Heterogeneity was present by tumour grade (p het =0.01), with a lower risk of low-grade disease (OR=0.76, 95% CI 0.67-0.88) and a nonsignificantly higher risk of high-grade disease (OR=1.56, 95% CI 0.95-2.57). There was no evidence of heterogeneity by tumour stage. The observational design is a limitation., Conclusions: Men with low circulating free testosterone may have a lower risk of overall prostate cancer; this may be due to a direct biological effect, or detection bias. Further research is needed to explore the apparent differential association by tumour grade., Patient Summary: In this study, we looked at circulating testosterone levels and risk of developing prostate cancer, finding that men with low testosterone had a lower risk of prostate cancer., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Prevailing dietary guidelines recommend regular fish consumption. However, the associations of fish and long-chain omega-3 polyunsaturated fatty acids (LCn-3 PUFAs) intakes with mortality remain unclear., Objectives: To examine the associations of fish and LCn-3 PUFAs intakes with total and cause-specific mortality., Methods: A total of 240 729 men and 180 580 women from NIH-AARP Diet and Health Study were prospectively followed-up for 16 years. Dietary intakes were assessed using a validated NIH Diet History Questionnaire., Results: A total of 54 230 men and 30 882 women died during 6.07 million person-years of follow-up. Higher fish and LCn-3 PUFAs intakes were significantly associated with lower total mortality (P < 0.0001). Comparing the highest with lowest quintiles of fish intake, men had 9% (95% confidence interval, 6-11%) lower total mortality, 10% (6-15%) lower cardiovascular disease (CVD) mortality, 6% (1-10%) lower cancer mortality, 20% (11-28%) lower respiratory disease mortality and 37% (17-53%) lower chronic liver disease mortality, while women had 8% (5-12%) lower total mortality, 10% (3-17%) lower CVD mortality and 38% (20-52%) lower Alzheimer's disease mortality. Fried fish consumption was not related to mortality in men whereas positively associated with mortality from all causes (P = 0.011), CVD and respiratory disease in women. LCn-3 PUFAs intake was associated with 15% and 18% lower CVD mortality in men and women across extreme quintiles, respectively., Conclusion: Consumption of fish and LCn-3 PUFAs was robustly associated with lower mortality from major causes. Our findings support current guidelines for fish consumption while advice on non-frying preparation methods is needed., (© 2018 The Association for the Publication of the Journal of Internal Medicine.)

Background: Several studies have examined association between human papillomaviruses (HPV) and esophageal cancer, but results have been inconsistent. This is the first prospective study to investigate associations between α, β and γ HPV detection in the oral cavity and risk of esophageal cancer. Methods: We conducted a nested case-control study among 96,650 cancer-free participants in the American Cancer Society Cancer Prevention Cohort and the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident esophageal cancer cases ( n = 125) were identified during an average 3.9 years of follow-up. Three controls per case ( n = 372) were selected and matched on age, sex, race/ethnicity, and time since mouthwash collection. α, β, and γ HPV DNA in oral samples were detected using a next-generation sequencing assay. Conditional logistic regression models were used to estimate OR and 95% confidence intervals (CIs), adjusting for smoking and alcohol consumption. Statistical significance was evaluated using permutation test. Results: Prevalence of oral α, β, and γ HPV was 18.4%, 64.8%, and 42.4% in cases and 14.3%, 55.1%, and 33.6% in controls, respectively. Oral HPV16 detection was not associated with esophageal cancer (OR = 0.54, 95% CI, 0.1-4.84) and none of the esophageal squamous cell carcinoma cases ( n = 28) were HPV16 positive. Some oral HPV types were more common in cases than controls; however, none of the associations were statistically significant. Conclusions: Although HPVs in the oral cavity are very common, this study showed no evidence of association between oral HPVs and esophageal cancer. Impact: Oral HPVs may not contribute to risk of esophageal cancer. Cancer Epidemiol Biomarkers Prev; 27(10); 1168-75. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Objective: Obesity and diabetes are associated with an increased liver cancer risk. However, most studies have examined all primary liver cancers or hepatocellular carcinoma, with few studies evaluating intrahepatic cholangiocarcinoma (ICC), the second most common type of liver cancer. Thus, we examined the association between obesity and diabetes and ICC risk in a pooled analysis and conducted a systematic review/meta-analysis of the literature., Design: For the pooled analysis, we utilized the Liver Cancer Pooling Project, a consortium of 13 US-based, prospective cohort studies with data from 1,541,143 individuals (ICC cases n = 414). In our systematic review, we identified 14 additional studies. We then conducted a meta-analysis, combining the results from LCPP with results from the 5 prospective studies identified through September 2017., Results: In the LCPP, obesity and diabetes were associated with a 62% [Hazard Ratio (HR) = 1.62, 95% Confidence Interval (CI): 1.24-2.12] and an 81% (HR = 1.81, 95% CI: 1.33-2.46) increased ICC risk, respectively. In the meta-analysis of prospectively ascertained cohorts and nested case-control studies, obesity was associated with a 49% increased ICC risk [Relative Risk (RR) = 1.49, 95% CI: 1.32-1.70; n = 4 studies; I 2  = 0%]. Diabetes was associated with a 53% increased ICC risk (RR = 1.53, 95% CI: 1.31-1.78; n = 6 studies). While we noted heterogeneity between studies (I 2  = 67%) for diabetes, results were consistent in subgroup analyses. Results from hospital-based case-control studies (n = 9) were mostly consistent, but these studies are potentially subject to reverse causation., Conclusions: These findings suggest that obesity and diabetes are associated with increased ICC risk, highlighting similar etiologies of hepatocellular carcinoma and intrahepatic cholangiocarcinoma. However, additional prospective studies are needed to verify these associations.

Background: Although circulating 25-hydroxyvitamin D [25(OH)D] concentrations were linked to liver cancer and chronic liver disease (CLD) in laboratory studies, few epidemiologic studies have addressed the associations. Methods: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we measured 25(OH)D in baseline serum of 202 incident liver cancer cases and 225 CLD deaths that occurred during nearly 25 years of follow-up, and 427 controls. ORs and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. We examined predetermined clinically defined cut-points, and season-specific and season-standardized quartiles. Results: Low serum 25(OH)D concentrations were associated with higher risk of liver cancer (<25 nmol/L vs. ≥50 nmol/L: 1.98; 95% CI, 1.22-3.20; P trend across categories = 0.003) and CLD mortality (1.93; 95% CI, 1.23-3.03; P trend = 0.006) in models adjusted for age and date of blood draw. After additional adjustment for body mass index, diabetes, smoking, and other potential confounders, the association remained statistically significant for liver cancer (1.91; 95% CI, 1.16-3.15; P trend = 0.008), but was somewhat attenuated for CLD mortality (1.67; 95% CI, 1.02-2.75; P trend = 0.05). Associations were similar for analyses using season-specific and season-standardized quartiles, and after excluding participants with diabetes, or hepatitis B or C. Conclusions: Our results suggest a possible preventive role for vitamin D against liver cancer and CLD, although the importance of the liver for vitamin D metabolism and the lack of information about underlying liver disease makes reverse causality a concern. Impact: Future studies are needed to evaluate associations of vitamin D with liver cancer and liver disease in other populations, particularly those with a different constellation of risk factors. Cancer Epidemiol Biomarkers Prev; 27(9); 1075-82. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: Colorectal cancers are the third most common cancers in women and men in the USA. While dietary and lifestyle factors such as Western diet, physical inactivity and obesity have been linked to an increased risk of this malignancy, the mechanisms for these associations are unclear. GI hormones, including ghrelin, are involved in energy balance by mediating appetite and metabolism; however, the association between ghrelin and colorectal cancer has not been studied., Methods: We conducted a case-control study nested within the all-male Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study of Finnish smokers (aged 50-69 years) to examine serum ghrelin concentration and colorectal cancer risk. Data from 284 colon and 239 rectal cancers and 523 controls (matched on age, date of blood draw and serum availability) were analysed. ORs and 95% CIs were calculated using multivariable (conditional) logistic regression., Results: Overall, low-serum ghrelin was significantly associated with increased risk of colorectal cancer (Q1 vs Q4: OR:1.57, 95% CI 1.05 to 2.34). For individuals developing tumours within 10 years of blood draw, those in the lowest quartile of serum ghrelin concentrations were statistically significantly more likely to develop colorectal cancers than those with higher serum ghrelin concentrations (OR: 10.86, 95% CI 5.01 to 23.55). However, for individuals with tumours developing more than 20 years after blood draw, low-serum ghrelin concentrations were associated with a decreased risk of colorectal cancer relative to those with the highest serum ghrelin concentrations (OR: 0.26, 95% CI 0.11 to 0.64)., Conclusion: Low-serum ghrelin was associated with an increased colorectal cancer risk within 10 years of blood draw with a decreased risk for developing colorectal cancer more than 20 years after blood draw. These results suggest that ghrelin concentrations may vary across the carcinogenic process., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Mosaic loss of the Y chromosome (mLOY) is the most commonly reported large structural somatic event. Previous studies have indicated age and cigarette smoking increase the risk of mLOY, but the relationship of other exposures with mLOY and mLOY with disease has not been adequately investigated. We characterized mLOY in a large cohort of 223,338 men from the UK Biobank by scanning for deviations in genotyping array median log 2 intensity ratios (mLRR) of the Y chromosome using a standard algorithm. A total of 3,789 (1.7%) men showed evidence for mLOY (mLRR < -0.15). In multivariable-adjusted logistic regression models, we found that mLOY increases exponentially with age (overall P-value < 4.9 × 10 -324 ; p-value for the quadratic term = 2.1 × 10 -7 ), and observed a strong association with current smoking (P-value = 7.8 × 10 -184 ). We observed less mLOY in men of African ancestry (0.4%) compared to men of European ancestry (1.8%, P-value = 0.003). Although mLOY was not associated with prevalent cancer (P-value = 0.61), associations were observed for diabetes (P-value = 0.003) and cardiovascular disease (P-value = 0.01). Using Cox proportional hazards regression models, mLOY was associated with all-cause mortality among men with a high proportion of cells affected (mLRR < -0.40; HR = 1.35, 95% CI = 1.08-1.70, P-value = 0.009). In conclusion, mLOY was associated with several health-related factors as well as with all-cause mortality. Further functional studies are warranted to understand how and in what way mLOY could influence adult male health.

Ewing sarcoma (EWS) is a pediatric cancer characterized by the EWSR1-FLI1 fusion. We performed a genome-wide association study of 733 EWS cases and 1346 unaffected individuals of European ancestry. Our study replicates previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1, and identifies new loci at 6p25.1, 20p11.22 and 20p11.23. Effect estimates exhibit odds ratios in excess of 1.7, which is high for cancer GWAS, and striking in light of the rarity of EWS cases in familial cancer syndromes. Expression quantitative trait locus (eQTL) analyses identify candidate genes at 6p25.1 (RREB1) and 20p11.23 (KIZ). The 20p11.22 locus is near NKX2-2, a highly overexpressed gene in EWS. Interestingly, most loci reside near GGAA repeat sequences and may disrupt binding of the EWSR1-FLI1 fusion protein. The high locus to case discovery ratio from 733 EWS cases suggests a genetic architecture in which moderate risk SNPs constitute a significant fraction of risk.

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., (Copyright © 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: Coffee intake has been associated with risk of various cancers, but the findings, mostly from studies in white populations, are inconsistent. We examined the association of coffee consumption with overall cancer incidence and specific cancer sites in a large prospective study of African Americans, Native Hawaiians, Japanese Americans, Latinos, and whites. Methods: 167,720 participants of the Multiethnic Cohort Study in Hawaii and Los Angeles were included. Baseline coffee intake was assessed by a validated food-frequency questionnaire. HRs and 95% confidence intervals (CIs) for sixteen cancers associated with coffee intake were calculated using Cox regressions. Results: During a mean follow-up of 15.3 years, 34,031 incident cancer cases were identified among study participants. Coffee intake was associated inversely with liver (≥4 cups/day vs. none: HR = 0.57; 95% CI, 0.38-0.87; P trend < 0.001), ovarian (HR = 0.33; 95% CI, 0.17-0.65; P trend = 0.007), and thyroid (HR = 0.44; 95% CI, 0.23-0.87; P trend = 0.007) cancers and melanoma (HR = 0.72; 95% CI, 0.52-0.99; P trend = 0.002). Coffee intake was also inversely associated with endometrial cancer among women with a body mass index >30 kg/m 2 (HR = 0.31; 95% CI, 0.14-0.72; P trend = 0.04). The associations were similar across five ethnic groups ( P heterogeneity > 0.06) and were mainly observed among those who drank caffeinated coffee. Conclusions: On the basis of our prospective data in diverse populations, we found a decreased risk of liver, ovarian, thyroid, and endometrial cancers and melanoma associated with higher coffee intake. Impact: These results suggest that coffee drinking may protect against liver, ovarian, thyroid, and endometrial cancers, and melanoma. Cancer Epidemiol Biomarkers Prev; 27(8); 928-35. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study. Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake. Results: Higher tea intake was associated with greater oral microbiota richness ( P = 0.05) and diversity ( P = 0.006), and shifts in overall community composition ( P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella , Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes. Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers. Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814-21. ©2018 AACR ., (©2018 American Association for Cancer Research.)

Circulating vitamin B6 levels have been found to be inversely associated with lung cancer. Most studies have focused on the B6 form pyridoxal 5'-phosphate (PLP), a direct biomarker influenced by inflammation and other factors. Using a functional B6 marker allows further investigation of the potential role of vitamin B6 status in the pathogenesis of lung cancer. We prospectively evaluated the association of the functional marker of vitamin B6 status, the 3-hydroxykynurenine:xanthurenic acid (HK:XA) ratio, with risk of lung cancer in a nested case-control study consisting of 5,364 matched case-control pairs from the Lung Cancer Cohort Consortium (LC3). We used conditional logistic regression to evaluate the association between HK:XA and lung cancer, and random effect models to combine results from different cohorts and regions. High levels of HK:XA, indicating impaired functional B6 status, were associated with an increased risk of lung cancer, the odds ratio comparing the fourth and the first quartiles (OR 4th vs. 1st ) was 1.25 (95% confidence interval, 1.10-1.41). Stratified analyses indicated that this association was primarily driven by cases diagnosed with squamous cell carcinoma. Notably, the risk associated with HK:XA was approximately 50% higher in groups with a high relative frequency of squamous cell carcinoma, i.e., men, former and current smokers. This risk of squamous cell carcinoma was present in both men and women regardless of smoking status., (© 2017 UICC.)