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Background: Accumulating evidence suggests that positive and negative emotions, as well as emotion regulation, play key roles in human health and disease. Recent work has shown the gut microbiome is important in modulating mental and physical health through the gut–brain axis. Yet, its association with emotions and emotion regulation are understudied. Here we examined whether positive and negative emotions, as well as two emotion regulation strategies (i.e. cognitive reappraisal and suppression), were associated with the gut microbiome composition and functional pathways in healthy women. Methods: Participants were from the Mind-Body Study (N = 206, mean age = 61), a sub-study of the Nurses' Health Study II cohort. In 2013, participants completed measures of emotion-related factors. Two pairs of stool samples were collected, 6 months apart, 3 months after emotion-related factors measures were completed. Analyses examined associations of emotion-related factors with gut microbial diversity, overall microbiome structure, and specific species/pathways and adjusted for relevant covariates. Results: Alpha diversity was negatively associated with suppression. In multivariate analysis, positive emotions were inversely associated with the relative abundance of Firmicutes bacterium CAG 94 and Ruminococcaceae bacterium D16 , while negative emotions were directly correlated with the relative abundance of these same species. At the metabolic pathway level, negative emotions were inversely related to the biosynthesis of pantothenate, coenzyme A, and adenosine. Conclusions: These findings offer human evidence supporting linkages of emotions and related regulatory processes with the gut microbiome and highlight the importance of incorporating the gut microbiome in our understanding of emotion-related factors and their associations with physical health. [ABSTRACT FROM AUTHOR]

Background: Hypertension and the use of antihypertensive medications have been intensively investigated in relation to colorectal cancer (CRC). Prior epidemiologic studies have not been able to examine this topic with adequate confounding control and follow-up time, or disentangle the effects of antihypertensive agents and hypertension.Methods: Eligible participants in the Nurses' Health Study and Health Professionals Follow-up Study were followed for up to 28 years, with repeat assessments of exposures. Cox proportional hazards models were used to estimate hazard ratios and 95% confidence intervals.Results: In fully adjusted analyses based on both new-user and prevalent-user designs, there was no association between the use of beta-blockers, calcium-channel blockers, thiazide diuretics, angiotensin-converting enzyme inhibitors, furosemide, other antihypertensive drugs and CRC risk and mortality reached the statistically significant threshold after Bonferroni correction. The results remained similar in sensitivity analyses among participants with hypertension. Before Bonferroni correction, suggestive associations between beta-blocker use and CRC risk and between furosemide use and CRC-specific mortality were observed specifically in analyses using a new-user design. Hypertension was not associated with CRC risk in analyses based on both new-user and prevalent-user designs.Conclusions: Hypertension and long-term use of major classes of antihypertensive medications are unlikely to be associated with CRC risk and mortality. [ABSTRACT FROM AUTHOR]

Background: Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the liver, biliary tract and pancreas in the U.S. were relatively limited.Methods: We followed 115,036 women from the Nurses' Health Study (1982-2012) and 49,729 men from the Health Professionals Follow-up Study (1986-2012). History of gallstones, including with or without performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard ratios (HRs) and 95% confidence intervals (95% CIs).Results: During up to 30-year follow-up, we identified 204 incidents of liver cancer, 225 biliary tract cancer and 1147 pancreatic cancer cases. Compared to those without gallstones diagnosis, the multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14-2.26), 4.79 for biliary tract cancer (95% CI: 3.02-7.58), and 1.13 for pancreatic cancer (95% CI: 0.96-1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90-1.95) and 1.15 for pancreatic cancer (95% CI: 0.98-1.36).Conclusions: Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas. [ABSTRACT FROM AUTHOR]

Background: The link between oral diseases and mortality remains under-explored. We aimed to evaluate the associations between tooth count, untreated caries and risk of all-cause and cause-specific mortality.Methods: Data on 24 029 adults from the National Health and Nutrition Examination Survey 1988-94/1999-2010, with mortality linkage to the National Death Index to 31 December 2015, were analysed. Baseline total number of permanent teeth and any untreated caries were assessed by trained dental professionals.Results: During up to 27 years of follow-up, 5270 deaths occurred. Fewer permanent teeth were associated with higher all-cause mortality, including heart disease and cancer mortality (all P <0.05 for trend) but not cerebrovascular disease mortality. For every 10 teeth missing, the multivariable-adjusted hazard ratios (HRs) were 1.13 (95% CI: 1.08 to 1.18) for all-cause, 1.16 (95% CI: 1.05, 1.29) for heart disease and 1.19 (95% CI: 1.09, 1.29) for cancer mortality. Untreated caries was associated with increased all-cause (HR: 1.26, 95% CI: 1.15, 1.39) and heart disease mortality (HR: 1.48, 95% CI: 1.17, 1.88) but not cerebrovascular disease/cancer mortality, after adjusting for tooth count, periodontitis and sociodemographic/lifestyle factors. Compared with those without untreated caries and with 25-28 teeth, individuals with untreated caries and 1-16 teeth had a 53% increased risk of all-cause mortality (HR: 1.53, 95% CI: 1.27, 1.85) and 96 % increased risk of heart disease mortality (HR: 1.96, 95% CI: 1.28, 3.01).Conclusions: In nationally representative cohorts, fewer permanent teeth and untreated caries were associated with all-cause and heart disease mortality. Fewer teeth were also associated with higher cancer mortality. [ABSTRACT FROM AUTHOR]

Background: The incidence of colorectal cancer (CRC) among individuals aged younger than 50 years has been increasing. As screening guidelines lower the recommended age of screening initiation, concerns including the burden on screening capacity and costs have been recognized, suggesting that an individualized approach may be warranted. We developed risk prediction models for early-onset CRC that incorporate an environmental risk score (ERS), including 16 lifestyle and environmental factors, and a polygenic risk score (PRS) of 141 variants.Methods: Relying on risk score weights for ERS and PRS derived from studies of CRC at all ages, we evaluated risks for early-onset CRC in 3486 cases and 3890 controls aged younger than 50 years. Relative and absolute risks for early-onset CRC were assessed according to values of the ERS and PRS. The discriminatory performance of these scores was estimated using the covariate-adjusted area under the receiver operating characteristic curve.Results: Increasing values of ERS and PRS were associated with increasing relative risks for early-onset CRC (odds ratio per SD of ERS = 1.14, 95% confidence interval [CI] = 1.08 to 1.20; odds ratio per SD of PRS = 1.59, 95% CI = 1.51 to 1.68), both contributing to case-control discrimination (area under the curve = 0.631, 95% CI = 0.615 to 0.647). Based on absolute risks, we can expect 26 excess cases per 10 000 men and 21 per 10 000 women among those scoring at the 90th percentile for both risk scores.Conclusions: Personal risk scores have the potential to identify individuals at differential relative and absolute risk for early-onset CRC. Improved discrimination may aid in targeted CRC screening of younger, high-risk individuals, potentially improving outcomes. [ABSTRACT FROM AUTHOR]

Background: Recent genome-wide association meta-analysis for melanoma doubled the number of previously identified variants. We assessed the performance of an updated polygenic risk score (PRS) in a population of older individuals, where melanoma incidence and cumulative ultraviolet radiation exposure is greatest.Methods: We assessed a PRS for cutaneous melanoma comprising 55 variants in a prospective study of 12 712 individuals in the ASPirin in Reducing Events in the Elderly Trial. We evaluated incident melanomas diagnosed during the trial and prevalent melanomas diagnosed preenrolment (self-reported). Multivariable models examined associations between PRS as a continuous variable (per SD) and categorical (low-risk [0%-20%], medium-risk [21%-80%], high-risk [81%-100%] groups) with incident melanoma. Logistic regression examined the association between PRS and prevalent melanoma.Results: At baseline, mean participant age was 75 years; 55.0% were female, and 528 (4.2%) had prevalent melanomas. During follow-up (median = 4.7 years), 120 (1.0%) incident cutaneous melanomas occurred, 98 of which were in participants with no history. PRS was associated with incident melanoma (hazard ratio = 1.46 per SD, 95% confidence interval [CI] = 1.20 to 1.77) and prevalent melanoma (odds ratio [OR] = 1.55 per SD, 95% CI = 1.42 to 1.69). Participants in the highest-risk PRS group had increased risk compared with the low-risk group for incident melanoma (OR = 2.51, 95% CI = 1.28 to 4.92) and prevalent melanoma (OR = 3.66, 95% CI = 2.69 to 5.05). When stratifying by sex, only males had an association between the PRS and incident melanoma, whereas both sexes had an association between the PRS and prevalent melanoma.Conclusions: A genomic risk score is associated with melanoma risk in older individuals and may contribute to targeted surveillance. [ABSTRACT FROM AUTHOR]

Background: Healthy plant-based diet index (hPDI) is associated with a lower risk of cardiometabolic conditions, but its association as well as interactions with microbiome have not been elucidated.Objectives: We aimed to investigate the interrelations between hPDI, gut microbiome, and cardiometabolic risk markers.Methods: hPDI was derived from dietary assessments by a validated FFQ and was examined in relation to metagenomic profiles of 911 fecal samples collected from 303 men aged 71 ± 4 y with an average BMI (in kg/m2) of 25.2 ± 3.6 in the Men's Lifestyle Validation Study. Principal coordinate (PCo) analysis based on Bray-Curtis dissimilarity was conducted, and interactions between hPDI and PCo were examined by using a metabolic risk score composed of blood lipids, BMI, and glycated hemoglobin.Results: After multivariable adjustment, hPDI was significantly associated with the relative abundance of 7 species and 9 pathways. In particular, higher hPDI was significantly associated with a higher relative abundance of Bacteroides cellulosilyticus and Eubacterium eligens, amino acid biosynthesis pathways (l-isoleucine biosynthesis I and III and l-valine biosynthesis), and the pathway of pyruvate fermentation to isobutanol. A favorable association between hPDI and the metabolic risk score was more pronounced among men with a higher PCo characterized by higher abundance of Bacteroides uniformis and lower abundance of Prevotella copri. At the individual species level, a similar interaction was also observed between hPDI and P. copri, as well as with Clostridium clostridioforme or Blautia hydrogenotrophica (all P-interaction < 0.01).Conclusion: A greater adherence to a healthy plant-based diet by older men was associated with a microbial profile characterized by a higher abundance of multiple species, including B. cellulosilyticus and E. eligens, as well as pathways in amino acid metabolism and pyruvate fermentation. In addition, inverse associations between healthy plant-based diet and human metabolic risk may partially depend on microbial compositions. [ABSTRACT FROM AUTHOR]

Background: The influence of a high sugar diet on colorectal cancer (CRC) survival is unclear.Methods: Among 1463 stage I-III CRC patients from the Nurses' Health Study and Health Professionals Follow-up Study, we estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for CRC-specific and all-cause mortality in relation to intake of post-diagnosis sugar-sweetened beverages (SSB), artificially sweetened beverages (ASB), fruit juice, fructose and other sugars.Results: Over a median 8.0 years, 781 cases died (173 CRC-specific deaths). Multivariable-adjusted HRs for post-diagnosis intake and CRC-specific mortality were 1.21 (95% CI: 0.87-1.68) per 1 serving SSBs per day (serving/day) and 1.24 (95% CI: 0.95-1.63) per 20 grams fructose per day. Significant positive associations for CRC-specific mortality were primarily observed ≤5 years from diagnosis (HR per 1 serving/day of SSBs = 1.59, 95% CI: 1.06-2.38). Significant inverse associations were observed between ASBs and CRC-specific and all-cause mortality (HR for ≥5 versus <1 serving/week = 0.44, 95% CI: 0.26-0.75 and 0.70, 95% CI: 0.55-0.89, respectively).Conclusions: Higher post-diagnosis intake of SSBs and sugars may be associated with higher CRC-specific mortality, but only up to 5 years from diagnosis, when more deaths were due to CRC. The inverse association between ASBs and CRC-specific mortality warrants further examination. [ABSTRACT FROM AUTHOR]

Background: It remains unknown whether the benefit of colonoscopy screening against colorectal cancer (CRC) and the optimal age to start screening differ by CRC risk profile.Methods: Among 75 873 women and 42 875 men, we defined a CRC risk score (0-8) based on family history, aspirin, height, body mass index, smoking, physical activity, alcohol, and diet. We calculated colonoscopy screening-associated hazard ratios and absolute risk reductions (ARRs) for CRC incidence and mortality and age-specific CRC cumulative incidence according to risk score. All statistical tests were 2-sided.Results: During a median of 26 years of follow-up, we documented 2407 CRC cases and 874 CRC deaths. Although the screening-associated hazard ratio did not vary by risk score, the ARRs in multivariable-adjusted 10-year CRC incidence more than doubled for individuals with scores 6-8 (ARR = 0.34%, 95% confidence interval [CI] = 0.26% to 0.42%) compared with 0-2 (ARR = 0.15%, 95% CI = 0.12% to 0.18%, Ptrend < .001). Similar results were found for CRC mortality (ARR = 0.22%, 95% CI = 0.21% to 0.24% vs 0.08%, 95% CI = 0.07% to 0.08%, Ptrend < .001). The ARR in mortality of distal colon and rectal cancers was fourfold higher for scores 6-8 than 0-2 (distal colon cancer: ARR = 0.08%, 95% CI = 0.07% to 0.08% vs 0.02%, 95% CI = 0.02% to 0.02%, Ptrend < .001; rectal cancer: ARR = 0.08%, 95% CI = 0.08% to 0.09% vs 0.02%, 95% CI = 0.02% to 0.03%, Ptrend < .001). When using age 45 years as the benchmark to start screening, individuals with risk scores of 0-2, 3, 4, 5, and 6-8 attained the threshold CRC risk level (10-year cumulative risk of 0.47%) at age 51 years, 48 years, 45 years, 42 years, and 38 years, respectively.Conclusions: The absolute benefit of colonoscopy screening is more than twice higher for individuals with the highest than lowest CRC risk profile. Individuals with a high- and low-risk profile may start screening up to 6-7 years earlier and later, respectively, than the recommended age of 45 years. [ABSTRACT FROM AUTHOR]

Background: Prior epidemiological and intervention studies have not been able to separate independent effects of dose, timing, and duration of aspirin use in colorectal cancer (CRC) chemoprevention. We examined aspirin-based CRC chemoprevention according to timing in the Nurses' Health Study and Health Professionals Follow-Up Study.Methods: The exposures include cumulative average dose and total duration of aspirin use in more than 10 years before follow-up started (remote period) and in the immediate 10 years before follow-up started (recent period). Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for exposures and CRC risk.Results: Aspirin use of longer than 10 years before follow-up started (HR = 0.88, 95% CI = 0.83 to 0.94) per 5-year increment and the immediate 10 years before follow-up started (HR = 0.90, 95% CI = 0.84 to 0.96) were similarly important in CRC chemoprevention, though a 5-year lag was required for a clear benefit in the recent period. In the remote period, the association was not dose dependent; compared with less than 0.5 standard-dose (325 mg) tablets per week; hazard ratios were 0.78 (95% CI = 0.63 to 0.98), 0.81 (95% CI = 0.72 to 0.91), and 0.74 (95% CI = 0.64 to 0.86) for doses of 0.5 to less than 1.5, 1.5 to less than 5, and 5 and more tablets per week, respectively. However, there was dose dependency in the recent period (with respective HR = 0.91, 95% CI = 0.79 to 1.06; HR = 0.87, 95% CI = 0.77 to 0.98; and HR = 0.76, 95% CI = 0.64 to 0.91).Conclusions: A suggestive benefit necessitates at least 6-10 years and most clearly after approximately 10 years since initiation of aspirin. Remote use and use within the previous 10 years both contribute independently to decrease risk, though a lower dose may be required for a benefit with longer term use. [ABSTRACT FROM AUTHOR]

Background: The role of poor diet quality in the rising incidence of colorectal cancer (CRC) diagnosed younger than age 50 years has not been explored. Based on molecular features of early-onset CRC, early-onset adenomas are emerging surrogate endpoints.Methods: In a prospective cohort study (Nurses' Health Study II), we evaluated 2 empirical dietary patterns (Western and prudent) and 3 recommendation-based indexes (Dietary Approaches to Stop Hypertension [DASH], Alternative Mediterranean Diet [AMED], and Alternative Healthy Eating Index [AHEI]-2010) with risk of early-onset adenoma overall and by malignant potential (high-risk: ≥1 cm, tubulovillous or villous histology, high-grade dysplasia, or ≥3 adenomas), among 29 474 women with 1 or more lower endoscopy before age 50 years (1991-2011). Multivariable logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: We documented 1157 early-onset adenomas with 375 at high risk. Western diet was positively associated, whereas prudent diet, DASH, AMED, and AHEI-2010 were inversely associated with risk of early-onset adenoma. The associations were largely confined to high-risk adenomas (the highest vs lowest quintile: Western, OR = 1.67, 95% CI = 1.18 to 2.37; prudent, OR = 0.69, 95% CI = 0.48 to 0.98; DASH, OR = 0.65, 95% CI = 0.45 to 0.93; AMED, OR = 0.55, 95% CI = 0.38 to 0.79; AHEI-2010, OR = 0.71, 95% CI = 0.51 to 1.01; all Ptrend ≤ .03), driven by those identified in the distal colon and rectum (all Ptrend ≤ .04, except AMED: Ptrend = .14).Conclusion: Poor diet quality was associated with an increased risk of early-onset distal and rectal adenomas of high malignant potential. These findings provide preliminary but strong support to the role of diet in early-onset CRC. [ABSTRACT FROM AUTHOR]

Background: Higher dairy intake during adulthood has been associated with lower colorectal cancer risk. As colorectal carcinogenesis spans several decades, we hypothesised that higher dairy intake during adolescence is associated with lower risk of colorectal adenoma, a colorectal cancer precursor.Methods: In 27,196 females from the Nurses' Health Study 2, aged 25-42 years at recruitment (1989), who had completed a validated high school diet questionnaire in 1998 and undergone at least one lower bowel endoscopy between 1998 and 2011, logistic regression for clustered data was used to calculate odds ratios (ORs) and 95% confidence intervals (CI).Results: Colorectal adenomas were diagnosed in 2239 women. Dairy consumption during adolescence was not associated with colorectal adenoma risk (OR highest vs. lowest [≥4 vs. ≤1.42 servings/day] quintile [95% CI] 0.94 [0.80, 1.11]). By anatomical site, higher adolescent dairy intake was associated with lower rectal (0.63 [0.42, 0.95]), but not proximal (1.01 [0.80, 1.28]) or distal (0.97 [0.76, 1.24]) colon adenoma risk. An inverse association was observed with histologically advanced (0.72 [0.51, 1.00]) but not non-advanced (1.07 [0.86, 1.33]) adenoma.Conclusions: In this large cohort of younger women, higher adolescent dairy intake was associated with lower rectal and advanced adenoma risk later in life. [ABSTRACT FROM AUTHOR]

Background: Poor lifestyles have been linked to insulin insensitivity/hyperinsulinemia, which may contribute to downstream changes such as inflammation and oxidative damage and the development of chronic diseases. As a biomarker of intracellular oxidative stress, leukocyte mitochondrial DNA copy number (mtDNA-CN) has been related to lifestyle factors including diet and weight. No epidemiologic study has examined the relation between combined insulinemic potential of lifestyle and mtDNA-CN.Objectives: Our aim was to examine the association between Empirical Lifestyle Index for Hyperinsulinemia (ELIH) and leukocyte mtDNA-CN in US men and women.Methods: This cross-sectional analysis included 2835 white adults without cancers, diabetes, or cardiovascular disease at blood collection, including 2160 women from the Nurses' Health Study and 675 men from the Health Professionals Follow-Up Study. ELIH is an index based on plasma C-peptide that characterizes the insulinemic potential of lifestyle (diet, body weight, and physical activity). Relative mtDNA-CN in peripheral blood leukocytes was measured by qPCR-based assay.Results: We found a significant inverse association between ELIH and mtDNA-CN. In multivariable-adjusted linear models, absolute least squares means ± SDs of mtDNA-CN z score across ELIH quintiles in women were as follows: Q1: 0.14 ± 0.05; Q2: 0.04 ± 0.06; Q3: 0.008 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.06 ± 0.05 (P-trend = 0.006). Means ± SDs in men were as follows: Q1: 0.25 ± 0.09; Q2: 0.23 ± 0.09; Q3: 0.07 ± 0.09; Q4: 0.02 ± 0.09; and Q5: -0.04 ± 0.09 (P-trend = 0.007). Means ± SDs in all participants were as follows: Q1: 0.16 ± 0.05; Q2: 0.07 ± 0.05; Q3: 0.01 ± 0.05; Q4: 0.01 ± 0.05; and Q5: -0.05 ± 0.05 (P-trend = 0.0004).Conclusions: Hyperinsulinemic lifestyles (i.e., higher ELIH) were associated with lower leukocyte mtDNA-CN among subjects without major diseases, suggesting that the difference in lifestyle insulinemic potential may be related to excessive oxidative stress damage. [ABSTRACT FROM AUTHOR]

Introduction: The relationships among PIK3CA mutations, medication use and tumor progression remains poorly understood. Aspirin use post-diagnosis may modify components of the PI3K pathway, including AKT and mTOR, and has been associated with lower risk of breast cancer recurrence and mortality. We assessed time to metastasis (TTM) and survival with respect to aspirin use and tumor PIK3CA mutations among women with metastatic breast cancer.Methods: Patients with hormone receptor positive, HER2 negative (HR+/HER2-) metastatic breast cancer treated in 2009-2016 who received tumor genotyping were included. Aspirin use between primary and metastatic diagnosis was extracted from electronic medical records. TTM and survival were estimated using Cox proportional hazards regression.Results: Among 267 women with metastatic breast cancer, women with PIK3CA mutated tumors had longer TTM than women with PIK3CA wildtype tumors (7.1 vs. 4.7 years, p = 0.008). There was a significant interaction between PIK3CA mutations and aspirin use on TTM (p = 0.006) and survival (p = 0.026). PIK3CA mutations were associated with longer TTM among aspirin non-users (HR = 0.60 95% CI:0.44-0.82 p = 0.001) but not among aspirin users (HR = 1.57 0.86-2.84 p = 0.139). Similarly, PIK3CA mutations were associated with reduced mortality among aspirin non-users (HR = 0.70 95% CI:0.48-1.02 p = 0.066) but not among aspirin users (HR = 1.75 95% CI:0.88-3.49 p = 0.110).Conclusions: Among women who develop metastatic breast cancer, tumor PIK3CA mutations are associated with slower time to progression and mortality only among aspirin non-users. Larger studies are needed to confirm this finding and examine the relationship among aspirin use, tumor mutation profile, and the overall risk of breast cancer progression. [ABSTRACT FROM AUTHOR]

Background: Increasing evidence suggests that conventional adenomas (CAs) and serrated polyps (SPs) represent two distinct groups of precursor lesions for colorectal cancer (CRC). The influence of common genetic variants on risk of CAs and SPs remain largely unknown.Methods: Among 27 426 participants within three prospective cohort studies, we created a weighted genetic risk score (GRS) based on 40 CRC-related single nucleotide polymorphisms (SNPs) identified in previous genome-wide association studies; and we examined the association of GRS (per one standard deviation increment) with risk of CAs, SPs and synchronous CAs and SPs, by multivariable logistic regression. We also analysed individual variants in the secondary analysis.Results: During 18-20 years of follow-up, we documented 2952 CAs, 1585 SPs and 794 synchronous CAs and SPs. Higher GRS was associated with increased risk of CAs [odds ratio (OR) = 1.17, 95% confidence interval (CI): 1.12-1.21] and SPs (OR = 1.09, 95% CI: 1.03-1.14), with a stronger association for CAs than SPs (Pheterogeneity=0.01). An even stronger association was found for patients with synchronous CAs and SPs (OR = 1.32), advanced CAs (OR = 1.22) and multiple CAs (OR = 1.25). Different sets of variants were associated with CAs and SPs, with a Spearman correlation coefficient of 0.02 between the ORs associating the 40 SNPs with the two lesions. After correcting for multiple testing, three variants were associated with CAs (rs3802842, rs6983267 and rs7136702) and two with SPs (rs16892766 and rs4779584).Conclusions: Common genetic variants play a potential role in the conventional and serrated pathways of CRC. Different sets of variants are identified for the two pathways, further supporting the aetiological heterogeneity of CRC. [ABSTRACT FROM AUTHOR]

Background: Epidemiological evidence on the associations between meat intake and risk of hepatocellular carcinoma (HCC) was limited and inconsistent.Methods: We prospectively examined the association between consumption of meats and meat mutagens with HCC risk using data from the Nurses' Health Study and the Health Professionals Follow-up Study. Cox proportional-hazards regression models were used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for known liver-cancer risk factors.Results: During up to 32 years of follow-up, we documented 163 incident HCC cases. The HRs of HCC for the highest vs the lowest tertile intake levels were 1.84 (95% CI: 1.16-2.92, Ptrend = 0.04) for processed red meats and 0.61 (95% CI: 0.40-0.91, Ptrend = 0.02) for total white meats. There was a null association between unprocessed red meats and HCC risk (HR = 1.06, 95% CI: 0.68-1.63, Ptrend = 0.85). We found both poultry (HR = 0.60, 95% CI: 0.40-0.90, Ptrend = 0.01) and fish (HR = 0.70, 95% CI: 0.47-1.05, Ptrend = 0.10) were inversely associated with HCC risk. The HR for HCC risk was 0.79 (95% CI: 0.61-1.02) when 1 standard deviation of processed red meats was substituted with an equivalent amount of poultry or fish intake. We also found a suggestive positive association of intake of meat-derived mutagenicity or heterocyclic amines with risk of HCC.Conclusions: Processed red meat intake might be associated with higher, whereas poultry or possibly fish intake might be associated with lower, risk of HCC. Replacing processed red meat with poultry or fish might be associated with reduced HCC risk. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation is a risk factor for colorectal cancer (CRC). Circulating C-reactive protein (CRP) is also moderately associated with CRC risk. However, observational studies are susceptible to unmeasured confounding or reverse causality. Using genetic risk variants as instrumental variables, we investigated the causal relationship between genetically elevated CRP concentration and CRC risk, using a Mendelian randomization approach.Methods: Individual-level data from 30 480 CRC cases and 22 844 controls from 33 participating studies in three international consortia were used: the Genetics and Epidemiology of Colorectal Cancer Consortium (GECCO), the Colorectal Transdisciplinary Study (CORECT) and the Colon Cancer Family Registry (CCFR). As instrumental variables, we included 19 single nucleotide polymorphisms (SNPs) previously associated with CRP concentration. The SNP-CRC associations were estimated using a logistic regression model adjusted for age, sex, principal components and genotyping phases. An inverse-variance weighted method was applied to estimate the causal effect of CRP on CRC risk.Results: Among the 19 CRP-associated SNPs, rs1260326 and rs6734238 were significantly associated with CRC risk (P = 7.5 × 10-4, and P = 0.003, respectively). A genetically predicted one-unit increase in the log-transformed CRP concentrations (mg/l) was not associated with increased risk of CRC [odds ratio (OR) = 1.04; 95% confidence interval (CI): 0.97, 1.12; P = 0.256). No evidence of association was observed in subgroup analyses stratified by other risk factors.Conclusions: In spite of adequate statistical power to detect moderate association, we found genetically elevated CRP concentration was not associated with increased risk of CRC among individuals of European ancestry. Our findings suggested that circulating CRP is unlikely to be a causal factor in CRC development. [ABSTRACT FROM AUTHOR]

Background: While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type.Methods: The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression.Results: Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57-2.20) and ICC (HR = 1.47, 95% CI: 1.07-2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74-1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR≥7 drinks/day = 1.87, 95% CI: 1.41-2.47) and a 68% increased ICC risk (HR≥5 drinks/day = 1.68, 95% CI: 0.99-2.86). However, light-to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR>0-<0.5 drinks/day = 0.77, 95% CI: 0.67-0.89; HR>0.5-<1 drinks/day = 0.57, 95% CI: 0.44-0.73; HR1-<3 drinks/day = 0.71, 95% CI: 0.58-0.87), but not ICC.Conclusions: These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC. [ABSTRACT FROM AUTHOR]

Little is known about the genetic influence on BMI trajectory throughout adulthood. We created a genetic risk score (GRS) comprising 97 adult BMI-associated variants among 9,971 women and 6,405 men of European ancestry. Serial measures of BMI were assessed from 18 (women) or 21 (men) years to 85 years of age. We also examined BMI change in early (from 18 or 21 to 45 years of age), middle (from 45 to 65 years of age), and late adulthood (from 65 to 80 years of age). GRS was positively associated with BMI across all ages, with stronger associations in women than in men. The associations increased from early to middle adulthood, peaked at 45 years of age in men and at 60 years of age in women (0.91 and 1.35 kg/m2 per 10-allele increment, respectively) and subsequently declined in late adulthood. For women, each 10-allele increment in the GRS was associated with an average BMI gain of 0.54 kg/m2 in early adulthood, whereas no statistically significant association was found for BMI change in middle or late adulthood or for BMI change in any life period in men. Our findings indicate that genetic predisposition exerts a persistent effect on adiposity throughout adult life and increases early adulthood weight gain in women. [ABSTRACT FROM AUTHOR]

BACKGROUND: Heterocyclic amines (HCAs) in cooked meats may play a role in colorectal cancer (CRC) development. OBJECTIVES: We aimed to prospectively examine the association between estimated intakes of HCAs and meat-derived mutagenicity (MDM) in two cohorts of health professionals, the Health Professionals Follow-up Study (HPFS) and the Nurses' Health Study (NHS). METHODS: In 29,615 men and 65,875 women, intake of the HCAs 2-amino- 3,8-dimethylimidazo(4,5-/)quinoxaline (MeIQx), 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine (PhIP), 2-amino-3,4,8-trimethylimidazo(4,5-/)quinoxaline (DiMeIQx), and MDM was estimated using a 1996 cooking questionnaire, the 1994 food frequency questionnaire, and an online database. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) and to adjust for potential confounders. Estimates for both cohorts were pooled using random-effects meta-analysis. RESULTS: Between 1996 and 2010, 418 male and 790 female CRC cases were identified. Meat mutagen intake was not statistically significantly associated with risk of CRC [highest vs. lowest quintile, pooled HR (95% CI) for MeIQx: 1.12 (0.93, 1.34), p for trend 0.23; PhIP: 1.10 (0.90, 1.33), p for trend 0.35; MDM: 1.03 (0.86, 1.24), p for trend 0.75] or subtypes of CRC defined by tumor location (proximal or distal colon, or rectum). When analyzed by source of meat, PhIP from red but not from white meat was nonsignificantly positively associated with CRC and significantly positively associated with proximal cancers [HR (95% CI) per standard deviation increase of log-transformed intake: PhIP red meat: CRC: 1.06 (0.99, 1.12), proximal: 1.11 (1.02, 1.21); PhIP white meat: CRC: 0.99 (0.94, 1.04), proximal: 1.00 (0.93, 1.09)]. CONCLUSIONS: Estimated intakes of meat mutagens were not significantly associated with CRC risk over 14 years of follow-up in the NHS and HPFS cohorts. Results for PhIP from red but not from white meat warrant further investigation. CITATION: Le NT, Michels FA, Song M, Zhang X, Bernstein AM, Giovannucci EL, Fuchs CS, Ogino S, Chan AT, Sinha R, Willett WC, Wu K. 2016. A prospective analysis of meat mutagens and colorectal cancer in the Nurses' Health Study and Health Professionals Follow-up Study. Environ Health Perspect 124:1529-1536; http://dx.doi.org/10.1289/EHP238 [ABSTRACT FROM AUTHOR]

Background: Knowledge on specific biological pathways mediating disease occurrence (e.g., inflammation) may be utilized to construct hypotheses-driven dietary patterns that take advantage of current evidence on disease-related hypotheses and the statistical methods of a posteriori patterns.Objective: We developed and validated an empirical dietary inflammatory index (EDII) based on food groups.Methods: We entered 39 pre-defined food groups in reduced rank regression models followed by stepwise linear regression analyses in the Nurses' Health Study (NHS, n = 5230) to identify a dietary pattern most predictive of 3 plasma inflammatory markers: interleukin-6 (IL-6), C-reactive protein (CRP), and tumor necrosis factor α receptor 2 (TNFαR2). We evaluated the construct validity of the EDII in 2 independent samples from NHS-II (n = 1002) and Health Professionals Follow-up Study (HPFS, n = 2632) using multivariable-adjusted linear regression models to examine how well the EDII predicted concentrations of IL-6, CRP, TNFαR2, adiponectin, and an overall inflammatory marker score combining all biomarkers.Results: The EDII is the weighted sum of 18 food groups; 9 are anti-inflammatory and 9 proinflammatory. In NHS-II and HPFS, the EDII significantly predicted concentrations of all biomarkers. For example, the relative concentrations comparing extreme EDII quintiles in NHS-II were: adiponectin, 0.88 (95% CI, 0.80, 0.96), P-trend = 0.003; and CRP, 1.52 (95% CI, 1.18, 1.97), P-trend = 0.002. Corresponding associations in HPFS were: 0.87 (95% CI, 0.82, 0.92), P-trend < 0.0001; and 1.23 (95% CI, 1.09, 1.40), P-trend = 0.002.Conclusion: The EDII represents, to our knowledge, a novel, hypothesis-driven, empirically derived dietary pattern that assesses diet quality based on its inflammatory potential. Its strong construct validity in independent samples of women and men indicates its usefulness in assessing the inflammatory potential of whole diets. Additionally, the EDII may be calculated in a standardized and reproducible manner across different populations thus circumventing a major limitation of dietary patterns derived from the same study in which they are applied. [ABSTRACT FROM AUTHOR]

Purpose: The influence of reproductive factors on colorectal cancer, including oral contraceptive (OC) use, has been examined, but less research is available on OC use and adenomas.Methods: Participants of the Nurses' Health Study who had a lower bowel endoscopy between 1986 (when endoscopies were first assessed) and 2008 were included in this study. Multivariable logistic regression models for clustered data were used to estimate odds ratios and 95 % confidence intervals [OR (95 % CIs)].Results: Among 73,058 participants, 51 % (n = 37,382) reported ever using OCs. Ever OC use was associated with a slight increase in non-advanced adenomas [OR 1.11, 95 % CI (1.02, 1.21)] but not with any other endpoints. Duration of OC use was not associated with adenomas, but longer times since last OC use were associated with increased odds of adenomas [e.g., compared to never use, 15+ years since last use: OR 1.17 (1.07, 1.27)]. Shorter times since last OC use were inversely associated [e.g., ≤4 years since last use: OR 0.74 (0.65, 0.84)].Conclusions: We observed a modest borderline increase in risk of colorectal adenomas with any prior OC use. Additionally, more recent OC use may decrease risk, while exposure in the distant past may modestly increase risk of adenomas. [ABSTRACT FROM AUTHOR]

Background: Although obesity has been linked to an increased risk of colorectal cancer (CRC), the risk associated with long-term status or change of body fat distribution has not been fully elucidated.Methods: Using repeated anthropometric assessments in the Nurses' Health Study and Health Professionals Follow-up Study, we prospectively investigated cumulative average waist circumference, hip circumference and waist-to-hip ratio, as well as their 10-year changes over adulthood, in relation to CRC risk over 23-24 years of follow-up. Cox proportional hazards models were used to calculate the hazard ratio (HR) and 95% confidence interval (CI).Results: High waist circumference, hip circumference and waist-to-hip ratio were all associated with a higher CRC risk in men, even after adjusting for body mass index. The association was attenuated to null in women after adjusting for body mass index. Ten-year gain of waist circumference was positively associated with CRC risk in men (P for trend = 0.03), but not in women (P for trend = 0.34).Compared with men maintaining their waist circumference, those gaining waist circumference by ≥ 10 cm were at a higher risk of CRC, with a multivariable-adjusted HR of 1.59 (95% CI, 1.01-2.49). This association appeared to be independent of weight change.Conclusions: Abdominal adiposity, independent of overall obesity, is associated with an increased CRC risk in men but not in women. Our findings also provide the first prospective evidence that waist circumference gain during adulthood may be associated with higher CRC risk in men, thus highlighting the importance of maintaining a healthy waist for CRC prevention. [ABSTRACT FROM AUTHOR]

Background: Chronic inflammation may play a role in colorectal cancer (CRC) pathogenesis. The relationship between soluble tumour necrosis factor receptor type II (sTNF-RII) and survival among CRC patients is not well defined.Methods: We prospectively evaluated the association between pre-diagnosis plasma levels of sTNF-RII and mortality in 544 CRC patients from the Nurses' Health Study and Health Professionals Follow-Up Study diagnosed from 1990 to 2010. Primary and secondary end points were overall and CRC-specific mortality, respectively. Cox proportional hazards models were used to calculate multivariate hazard ratios for mortality.Results: Higher sTNF-RII levels were significantly associated with increased overall mortality (multivariate HR=1.48, 95% CI 1.02-2.16, P-trend=0.006), but not with CRC-specific mortality (HR=1.23, 95% CI 0.72-2.08, P-trend=0.34). In subgroup analyses, among regular aspirin users, those with higher sTNF-RII levels had an adjusted HR of 0.52 (95% CI 0.20-1.33) for overall mortality compared with those with lower sTNF-RII levels, whereas among nonregular aspirin users the adjusted HR was 2.26 (95% CI 1.23-4.01, P for interaction=0.53).Conclusions: Among CRC patients, higher sTNF-RII levels are associated with a significant increase in overall mortality, but not CRC-specific mortality. The role of inflammation and anti-inflammatory medications in survival of CRC patients warrants further exploration. [ABSTRACT FROM AUTHOR]

Background: Low levels of adiponectin (ADIPOQ; HGNC ID; HGNC:13633), an adipokine, are associated with obesity, adiposity, excess energy balance, and increased risk of colorectal neoplasia. Given the reported association of increased body mass index (BMI) and low-level physical activity with KRAS-mutated colorectal tumor, we hypothesized that low-level plasma adiponectin might be associated with increased risk of KRAS-mutant colorectal carcinoma but not with risk of KRAS wild-type carcinoma.Methods: We conducted molecular pathological epidemiology research using a nested case-control study design (307 incident rectal and colon cancer case patients and 593 matched control individuals) within prospective cohort studies, the Nurses' Health Study (152 case patients and 297 control individuals, with blood collection in 1989-1990) and the Health Professionals Follow-up Study (155 case patients and 296 control individuals, with blood collection in 1993-1995). Multivariable conditional logistic regression models and two-sided likelihood ratio tests were used to assess etiologic heterogeneity of the associations.Results: The association of low-level plasma adiponectin with colorectal cancer risk statistically significantly differed by KRAS mutation status (P heterogeneity = .004). Low levels of plasma adiponectin were associated with KRAS-mutant colorectal cancer (for the lowest vs highest tertile: multivariable odds ratio [OR] = 2.83, 95% confidence interval [CI] = 1.50 to 5.34, P trend = .002) but not with KRAS wild-type cancer (for the lowest vs highest tertile: multivariable OR = 0.83, 95% CI = 0.49 to 1.43, P trend = .48). In secondary analyses, the association between plasma adiponectin and colorectal cancer did not appreciably differ by BRAF or PIK3CA oncogene mutation status.Conclusions: Low-level plasma adiponectin is associated with KRAS-mutant colorectal cancer risk but not with KRAS wild-type cancer risk. [ABSTRACT FROM AUTHOR]

A fundamental goal of epidemiologic research is to investigate the relationship between exposures and disease risk. Cases of the disease are often considered a single outcome and assumed to share a common etiology. However, evidence indicates that many human diseases arise and evolve through a range of heterogeneous molecular pathologic processes, influenced by diverse exposures. Pathogenic heterogeneity has been considered in various neoplasms such as colorectal, lung, prostate, and breast cancers, leukemia and lymphoma, and non-neoplastic diseases, including obesity, type II diabetes, glaucoma, stroke, cardiovascular disease, autism, and autoimmune disease. In this article, we discuss analytic options for studying disease subtype heterogeneity, emphasizing methods for evaluating whether the association of a potential risk factor with disease varies by disease subtype. Methods are described for scenarios where disease subtypes are categorical and ordinal and for cohort studies, matched and unmatched case-control studies, and case-case study designs. For illustration, we apply the methods to a molecular pathological epidemiology study of alcohol intake and colon cancer risk by tumor LINE-1 methylation subtypes. User-friendly software to implement the methods is publicly available. [ABSTRACT FROM AUTHOR]

Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a secondary analysis of a randomized controlled trial, the Polyp Prevention Trial, a higher intake of one subclass, flavonols, was statistically significantly associated with a reduced risk of recurrent advanced adenoma. Most previous prospective studies on colorectal cancer evaluated only a limited number of flavonoid subclasses and intake ranges, yielding inconsistent results. Objective: In this study, we examined whether higher habitual dietary intakes of flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols, and anthocyanins) were associated with a lower risk of colorectal cancer. Design: Using data from validated food-frequency questionnaires administered every 4 y and an updated flavonoid food composition database, we calculated flavonoid intakes for 42,478 male participants from the Health Professionals Follow-Up Study and for 76,364 female participants from the Nurses' Health Study. Results: During up to 26 y of follow-up, 2519 colorectal cancer cases (1061 in men, 1458 in women) were documented. Intakes of flavonoid subclasses were not associated with risk of colorectal cancer in either cohort. Pooled multivariable adjusted RRs (95% CIs) comparing the highest with the lowest quintiles were 1.04 (0.91, 1.18) for flavonols, 1.01 (0.89, 1.15) for flavones, 0.96 (0.84, 1.10) for flavanones, 1.07 (0.95, 1.21) for flavan-3-ols, and 0.98 (0.81, 1.19) for anthocyanins (all P values for heterogeneity by sex >0.19). In subsite analyses, flavonoid intake was also not associated with colon or rectal cancer risk. Conclusion: Our findings do not support the hypothesis that a higher habitual intake of any flavonoid subclass decreases the risk of colorectal cancer. [ABSTRACT FROM AUTHOR]

Background: Diet plays a role in the pathogenesis of Crohn’s disease (CD) and ulcerative colitis (UC). Dietary zinc may influence risk of disease through effects on autophagy, innate and adaptive immune response and maintenance of the intestinal barrier.Methods: We analysed data from 170 776 women from the Nurses Health Study I and Nurses Health Study II, who were followed for 26 years. Zinc intake was assessed using semi-quantitative food frequency questionnaires administered every 4 years. Incident CD and UC were ascertained by medical record review. Cox proportional hazards models adjusting for potential confounders determined the independent association between zinc intake and incident disease.Results: Over 3 317 550 person-years (p-y) of follow-up, we identified 269 incident cases of CD and 338 incident cases of UC. Zinc intake ranged from 9 mg/day in the lowest quintile to 27 mg/day in the highest quintile. Compared with women with the lowest quintile of intake, the multivariate hazard ratios (HR) for CD were 0.92 [95% confidence interval (CI), 0.65 – 1.29) for women in the second quintile of intake, 0.60 (95% CI, 0.40 – 0.89) for the third quintile, 0.57 (95% CI, 0.38 – 0.86) for fourth quintile and 0.74 (95% CI, 0.50 – 1.10) for the highest quintile (Ptrend = 0.003). The association was stronger for dietary zinc (HR 0.63, 95% CI, 0.43 – 0.93, comparing extreme quintiles) than for zinc intake from supplements. Neither dietary nor supplemental zinc modified risk of UC.Conclusions: In two large prospective cohorts of women, intake of zinc was inversely associated with risk of CD but not UC. [ABSTRACT FROM AUTHOR]

Importance: It is important to document patterns of prescription drug use to inform both clinical practice and research.Objective: To evaluate trends in prescription drug use among adults living in the United States.Design, Setting, and Participants: Temporal trends in prescription drug use were evaluated using nationally representative data from the National Health and Nutrition Examination Survey (NHANES). Participants included 37,959 noninstitutionalized US adults, aged 20 years and older. Seven NHANES cycles were included (1999-2000 to 2011-2012), and the sample size per cycle ranged from 4861 to 6212.Exposures: Calendar year, as represented by continuous NHANES cycle.Main Outcomes and Measures: Within each NHANES cycle, use of prescription drugs in the prior 30 days was assessed overall and by drug class. Temporal trends across cycles were evaluated. Analyses were weighted to represent the US adult population.Results: Results indicate an increase in overall use of prescription drugs among US adults between 1999-2000 and 2011-2012 with an estimated 51% of US adults reporting use of any prescription drugs in 1999-2000 and an estimated 59% reporting use of any prescription drugs in 2011-2012 (difference, 8% [95% CI, 3.8%-12%]; P for trend <.001). The prevalence of polypharmacy (use of ≥5 prescription drugs) increased from an estimated 8.2% in 1999-2000 to 15% in 2011-2012 (difference, 6.6% [95% CI, 4.4%-8.2%]; P for trend <.001). These trends remained statistically significant with age adjustment. Among the 18 drug classes used by more than 2.5% of the population at any point over the study period, the prevalence of use increased in 11 drug classes including antihyperlipidemic agents, antidepressants, prescription proton-pump inhibitors, and muscle relaxants.Conclusions and Relevance: In this nationally representative survey, significant increases in overall prescription drug use and polypharmacy were observed. These increases persisted after accounting for changes in the age distribution of the population. The prevalence of prescription drug use increased in the majority of, but not all, drug classes. [ABSTRACT FROM AUTHOR]

Background: Inflammation has been hypothesized to increase the risk of cancer development as an initiator or promoter, yet no large-scale study of inherited variation across cancer sites has been conducted.Methods: We conducted a cross-cancer genomic analysis for the inflammation pathway based on 48 genome-wide association studies within the National Cancer Institute GAME-ON Network across five common cancer sites, with a total of 64 591 cancer patients and 74 467 control patients. Subset-based meta-analysis was used to account for possible disease heterogeneity, and hierarchical modeling was employed to estimate the effect of the subcomponents within the inflammation pathway. The network was visualized by enrichment map. All statistical tests were two-sided.Results: We identified three pleiotropic loci within the inflammation pathway, including one novel locus in Ch12q24 encoding SH2B3 (rs3184504), which reached GWAS significance with a P value of 1.78 x 10(-8), and it showed an association with lung cancer (P = 2.01 x 10(-6)), colorectal cancer (GECCO P = 6.72x10(-6); CORECT P = 3.32x10(-5)), and breast cancer (P = .009). We also identified five key subpathway components with genetic variants that are relevant for the risk of these five cancer sites: inflammatory response for colorectal cancer (P = .006), inflammation related cell cycle gene for lung cancer (P = 1.35x10(-6)), and activation of immune response for ovarian cancer (P = .009). In addition, sequence variations in immune system development played a role in breast cancer etiology (P = .001) and innate immune response was involved in the risk of both colorectal (P = .022) and ovarian cancer (P = .003).Conclusions: Genetic variations in inflammation and its related subpathway components are keys to the development of lung, colorectal, ovary, and breast cancer, including SH2B3, which is associated with lung, colorectal, and breast cancer. [ABSTRACT FROM AUTHOR]

Background: Observational data have suggested that intakes of nutrients involved in one-carbon metabolism are inversely associated with risk of colorectal carcinoma and adenomas. In contrast, results from some preclinical studies and cardiovascular and chemoprevention trials have raised concerns that high folate intake may promote carcinogenesis by facilitating the progression of established neoplasia. Objective: We tested the hypothesis that higher total folate intake (including food folate and folic acid from fortified foods and supplements) or other one-carbon nutrient intakes might be associated with poorer survival after a diagnosis of colorectal cancer. Design: We used rectal and colon cancer cases within the following 2 US prospective cohort studies: the Nurses' Health Study and the Health Professionals Follow-Up Study. Biennial questionnaires were used to gather information on medical history and lifestyle factors, including smoking and alcohol consumption. B-vitamin and methionine intakes were derived from food-frequency questionnaires. Data on tumor molecular characteristics (including microsatellite instability, CpG island methylator phenotype, KRAS, BRAF, and PIK3CA mutations, and long interspersed nucleotide element 1 methylation level) were available for a subset of cases. We assessed colorectal cancer-specific mortality according to postdiagnostic intakes of one-carbon nutrients with the use of multivariable Cox proportional hazards regression models. Results: In 1550 stage I--III colorectal cancer cases with a median follow-up of 14.9 y, we documented 641 deaths including 176 colorectal cancer-specific deaths. No statistically significant associations were observed between postdiagnostic intakes of folate or other one-carbon nutrients and colorectal cancer-specific mortality (multivariate P-trend ≥ 0.21). In an exploratory molecular pathologic epidemiology survival analysis, there was no significant interaction between one-carbon nutrients or alcohol and any of the tumor molecular biomarkers examined. Conclusions: Higher postdiagnostic intakes of one-carbon nutrients are not associated with the prognosis in stage I--III colorectal cancer. Our findings do not support the hypothesis that higher folate intake after colorectal cancer diagnosis might increase risk of cancer-related death. [ABSTRACT FROM AUTHOR]

Background: Although a higher consumption of alcohol, which is a methyl-group antagonist, was previously associated with colorectal cancer risk, mechanisms remain poorly understood. Objective: We hypothesized that excess alcohol consumption might increase risk of colorectal carcinoma with hypomethylation of insulin-like growth factor 2 (IGF2) differentially methylated region-0 (DMR0), which was previously associated with a worse prognosis. Design: With the use of a molecular pathologic epidemiology database in 2 prospective cohort studies, the Nurses' Health Study and Health Professionals Follow-up Study, we examined the association between alcohol intake and incident colorectal cancer according to the tumor methylation level of IGF2 DMR0. Duplication-method Cox proportional cause-specific hazards regression for competing risk data were used to compute HRs and 95% CIs. In addition, we investigated intakes of vitamin B-6, vitamin B-12, methionine, and folate as exposures. Results: During 3,206,985 person-years of follow-up, we identified 993 rectal and colon cancer cases with an available tumor DNA methylation status. Compared with no alcohol consumption, the consumption of =15 g alcohol/d was associated with elevated risk of colorectal cancer with lower levels of IGF2 DMR0 methylation [within the first and second quartiles: HRs of 1.55 (95% CI: 1.08, 2.24) and 2.11 (95% CI: 1.44, 3.07), respectively]. By contrast, alcohol consumption was not associated with cancer with higher levels of IGF2 DMR0 methylation. The association between alcohol and cancer risk differed significantly by IGF2 DMR0 methylation level (P-heterogeneity = 0.006). The association of vitamin B-6, vitamin B-12, and folate intakes with cancer risk did not significantly differ according to IGF2 DMR0 methylation level (P-heterogeneity > 0.2). Conclusions: Higher alcohol consumption was associated with risk of colorectal cancer with IGF2 DMR0 hypomethylation but not risk of cancer with high-level IGF2 DMR0 methylation. The association between alcohol intake and colorectal cancer risk may differ by tumor epigenetic features. [ABSTRACT FROM AUTHOR]

Background: Association studies have suggested that lower circulating 25-hydroxyvitamin D [25(OH)D] in African Americans may partially underlie higher rates of cardiovascular disease and cancer in this population. Nonetheless, the relation between vitamin D supplementation and 25(OH)D concentrations in African Americans remains undefined. Objective: Our primary objective was to determine the doseresponse relation between vitamin D and plasma 25(OH)D. Design: A total of 328 African Americans in Boston, MA, were enrolled over 3 winters from 2007 to 2010 and randomly assigned to receive a placebo or 1000, 2000, or 4000 IU vitamin D3/d for 3 mo. Subjects completed sociodemographic and dietary questionnaires, and plasma samples were drawn at baseline and 3 and 6 mo. Results: Median plasma 25(OH)D concentrations at baseline were 15.1, 16.2, 13.9, and 15.7 ng/mL for subjects randomly assigned to receive the placebo or 1000, 2000, or 4000 IU/d, respectively (P = 0.63). The median plasma 25(OH)D concentration at 3 mo differed significantly between supplementation arms at 13.7, 29.7, 34.8, and 45.9 ng/mL, respectively (P < 0.001). An estimated 1640 IU vitamin D3/d was needed to raise the plasma 25(OH)D concentration to ≥20 ng/mL in ≥97.5% of participants, whereas a dose of 4000 IU/d was needed to achieve concentrations ≥33 ng/mL in ≥80% of subjects. No significant hypercalcemia was seen in a subset of participants. Conclusions: Within African Americans, an estimated 1640 IU vitamin D3/d was required to achieve concentrations of plasma 25(OH)D recommended by the Institute of Medicine, whereas 4000 IU/d was needed to reach concentrations predicted to reduce cancer and cardiovascular disease risk in prospective observational studies. These results may be helpful for informing future trials of disease prevention. This trial was registered at clinicaltrials.gov as NCT00585637. [ABSTRACT FROM AUTHOR]

The effect of duration of cigarette smoking cessation on colorectal cancer risk by molecular subtypes remains unclear. Using duplication-method Cox proportional-hazards regression analyses, we examined associations between duration of smoking cessation and colorectal cancer risk according to status of CpG island methylator phenotype (CIMP), microsatellite instability, v-raf murine sarcoma viral oncogene homolog B1 (BRAF) mutation, or DNA methyltransferase-3B (DNMT3B) expression. Follow-up of 134,204 individuals in 2 US nationwide prospective cohorts (Nurses' Health Study (1980–2008) and Health Professionals Follow-up Study (1986–2008)) resulted in 1,260 incident rectal and colon cancers with available molecular data. Compared with current smoking, 10–19, 20–39, and ≥40 years of smoking cessation were associated with a lower risk of CIMP-high colorectal cancer, with multivariate hazard ratios (95% confidence intervals) of 0.53 (0.29, 0.95), 0.52 (0.32, 0.85), and 0.50 (0.27, 0.94), respectively (Ptrend = 0.001), but not with the risk of CIMP-low/CIMP-negative cancer (Ptrend = 0.25) (Pheterogeneity = 0.02, between CIMP-high and CIMP-low/CIMP-negative cancer risks). Differential associations between smoking cessation and cancer risks by microsatellite instability (Pheterogeneity = 0.02), DNMT3B expression (Pheterogeneity = 0.03), and BRAF (Pheterogeneity = 0.10) status appeared to be driven by the associations of CIMP-high cancer with microsatellite instability–high, DNMT3B-positive, and BRAF-mutated cancers. These molecular pathological epidemiology data suggest a protective effect of smoking cessation on a DNA methylation–related carcinogenesis pathway leading to CIMP-high colorectal cancer. [ABSTRACT FROM PUBLISHER]

Aspirin use decreases colon cancer risk, but this association may vary among population subgroups. The aspirin-colon cancer association was evaluated according to body mass index and physical activity in 1,701 incident colon cancer cases diagnosed during follow-up of 139,310 participants for up to 26 years in 2 US prospective cohort studies that began in 1980 and 1992, respectively. Whether plasma C-peptide levels modified the association was examined by using a nested case-control design (n = 384 cases, 749 controls). Multiplicative and additive interactions were tested. Body mass index did not modify the association; pooled multivariable relative risks for regular aspirin use versus nonuse ranged from 0.74 to 0.75 in the normal weight and obese groups (test for multiplicative interaction, P = 0.75; test for additive interaction, P = 0.66). Pooled multivariable relative risks for regular aspirin use were 0.86 (95% confidence interval (CI): 0.66, 1.11) in the low and 0.67 (95% CI: 0.58, 0.77) in the high physical activity groups with no interaction evident on either the multiplicative or additive scale (P > 0.10). Plasma C-peptide levels also did not modify the aspirin-colon cancer association, with multivariable relative risks of 0.74 (95% CI: 0.50, 1.10) for the low and 0.65 (95% CI: 0.46, 0.92) for the high group. Reductions in colon cancer risk associated with aspirin use were not significantly modified by body mass index, physical activity, or plasma C-peptide level in this study. [ABSTRACT FROM AUTHOR]

There is a wealth of experimental, epidemiological, and most recently, randomized trial evidence that suggests that aspirin and other NSAIDs can reduce the risk of colorectal adenoma and cancer. As a result, these medications have emerged as promising chemopreventative agents. However, routine use has not been recommended in large part due to a lack of information on the optimal dose and duration of treatment. In this issue, observational data drawn from a cohort within the Polyp Prevention Trial strongly support the effectiveness of aspirin and NSAIDs in reducing the risk of recurrent colorectal adenoma, including those with morphologically or histologically advanced features. In particular, the investigators demonstrate that participants who consumed more than one standard aspirin tablet per day had the greatest reduction in risk. Because much potential toxicity of these agents are dose-related, these findings highlight the need for further investigation into the optimal dose and duration of the medications before consideration of their use in widespread chemoprevention efforts. The combination of future epidemiological data, in concert with continuing experimental developments, will guide further research initiatives and better inform cost-benefit and decision analyses. Hopefully, interpretation of this large body of evidence ultimately will lead to concrete clinical guidelines which will define a role, if any, for these medications as anticancer agents. [ABSTRACT FROM AUTHOR]

The article discusses research on link between physical activity and inflammatory bowel disease risk. It reports study details including gathering of data on physical activity of women enrolled in Nurses' Health Studies and documentation of cases of Crohn's disease and ulcerative colitis. It concludes that high levels of physical activity can contribute to reduced Crohn's disease risk but not ulcerative colitis. A chart listing updated physical activity information collected is also given.

STUDY QUESTION: Do proton pump inhibitors (PPIs) increase the risk of hip fracture in postmenopausal women even after accounting for other lifestyle and dietary risk factors? SUMMARY ANSWER: Regular use of PPIs was associated with an increased risk of hip fracture in postmenopausal women, particularly among those with a history of smoking. WHAT IS KNOWN AND WHAT THIS PAPER ADDS: Previous studies of the association between PPI use and hip fracture have had limited information on important lifestyle and dietary factors associated with fracture. This study shows an increased risk of hip fracture even after controlling for these other factors, and risk seems limited to women with history of smoking. [ABSTRACT FROM AUTHOR]

Background: More information is needed about the long-term effects of low-dose aspirin (≤160 mg) on incident hepatocellular carcinoma, liver-related mortality, and gastrointestinal bleeding in persons with chronic hepatitis B or hepatitis C virus infection.Methods: Using nationwide Swedish registries, we identified all adults who received a diagnosis of chronic hepatitis B or hepatitis C from 2005 through 2015 and who did not have a history of aspirin use (50,275 patients). Patients who were starting to take low-dose aspirin (14,205 patients) were identified by their first filled prescriptions for 90 or more consecutive doses of aspirin. We constructed a propensity score and applied inverse probability of treatment weighting to balance baseline characteristics between groups. Using Cox proportional-hazards regression modeling, we estimated the risk of hepatocellular carcinoma and liver-related mortality, accounting for competing events.Results: With a median of 7.9 years of follow-up, the estimated cumulative incidence of hepatocellular carcinoma was 4.0% among aspirin users and 8.3% among nonusers of aspirin (difference, -4.3 percentage points; 95% confidence interval [CI], -5.0 to -3.6; adjusted hazard ratio, 0.69; 95% CI, 0.62 to 0.76). This inverse association appeared to be duration-dependent; as compared with short-term use (3 months to <1 year), the adjusted hazard ratios were 0.90 (95% CI, 0.76 to 1.06) for 1 to less than 3 years of use, 0.66 (95% CI, 0.56 to 0.78) for 3 to less than 5 years of use, and 0.57 (95% CI, 0.42 to 0.70) for 5 or more years of use. Ten-year liver-related mortality was 11.0% among aspirin users and 17.9% among nonusers (difference, -6.9 percentage points [95% CI, -8.1 to -5.7]; adjusted hazard ratio, 0.73 [95% CI, 0.67 to 0.81]). However, the 10-year risk of gastrointestinal bleeding did not differ significantly between users and nonusers of aspirin (7.8% and 6.9%, respectively; difference, 0.9 percentage points; 95% CI, -0.6 to 2.4).Conclusions: In a nationwide study of patients with chronic viral hepatitis in Sweden, use of low-dose aspirin was associated with a significantly lower risk of hepatocellular carcinoma and lower liver-related mortality than no use of aspirin, without a significantly higher risk of gastrointestinal bleeding. (Funded by the National Institutes of Health and others.). [ABSTRACT FROM AUTHOR]