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BACKGROUND: The association between protein intake and prostate cancer risk remains unclear.AIMS: To prospectively investigate the associations of dietary intakes of total protein, protein from different dietary sources, and amino acids with prostate cancer risk and mortality.METHODS: In 131,425 men from the European Prospective Investigation into Cancer and Nutrition, protein and amino acid intakes were estimated using validated dietary questionnaires. Multivariable-adjusted Cox regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).RESULTS: During a mean follow-up of 14.2 years, 6939 men were diagnosed with prostate cancer and 914 died of the disease. Dairy protein was positively associated with overall prostate cancer risk in the three highest fifths compared to the lowest (HR Q3 =1.14 (95% CI 1.05-1.23); HR Q 4=1.09 (1.01-1.18); HR Q5 =1.10 (1.02-1.19)); similar results were observed for yogurt protein (HR Q3 =1.14 (1.05-1.24); HR Q4 =1.09 (1.01-1.18); HR Q5 =1.12 (1.04-1.21)). For egg protein intake and prostate cancer mortality, no association was observed by fifths, but there was suggestive evidence of a positive association in the analysis per standard deviation increment. There was no strong evidence of associations with different tumour subtypes. DISCUSSION: Considering the weak associations and many tests, the results must be interpreted with caution.CONCLUSION: This study does not provide strong evidence for an association of intakes of total protein, protein from different dietary sources or amino acids with prostate cancer risk or mortality. However, our results may suggest some weak positive associations, which need to be confirmed in large-scale, pooled analyses of prospective data.

Malignant pleural mesothelioma (MPM) is a rare and aggressive cancer mainly caused by asbestos exposure. Specific and sensitive non-invasive biomarkers may facilitate and enhance screening programs for the early detection of cancer. We investigated DNA methylation (DNAm) profiles in MPM pre-diagnostic blood samples in a case-control study nested in the European Prospective Investigation into Cancer and nutrition (EPIC) cohort, aiming to characterise DNAm biomarkers associated with MPM. From the EPIC cohort, we included samples from 135 participants who developed MPM during 20 years of follow up and from 135 matched, cancer-free, controls. For the discovery phase we selected EPIC participants who developed MPM within five years from enrolment (n=36) with matched controls. We identified nine differentially methylated CpGs, selected by 10-fold cross-validation and correlation analyses: cg25755428 (MRI1), cg20389709 (KLF11), cg23870316, cg13862711 (LHX6), cg06417478 (HOOK2), cg00667948, cg01879420 (AMD1), cg25317025 (RPL17) and cg06205333 (RAP1A). Receiver operating characteristic (ROC) analysis showed that the model including baseline characteristics (age, sex, PC1wbc) along with the nine MPM-related CpGs has a better predictive value for MPM occurrence than the baseline model alone, maintaining some performance also at more than five years before diagnosis [AUC (area under the curve) 10 years=0.75; baseline AUC range=0.63-0.67)]. DNAm changes as non-invasive biomarkers in pre-diagnostic blood samples of MPM cases were investigated for the first time. Their application can improve the identification of asbestos-exposed individuals at higher MPM risk in order to possibly adopt more intensive monitoring for early disease identification.

Introduction: We investigated the impact of changes in lifestyle habits on colorectal cancer (CRC) risk in a multi-country European cohort. Methods: We used baseline and follow-up questionnaire data from the EPIC cohort to assess changes in lifestyle habits and their associations with CRC development. We calculated a healthy lifestyle index (HLI) score based on smoking status, alcohol consumption, body mass index and physical activity collected at the two timepoints. HLI ranged from 0 (most unfavourable) to 16 (most favourable). We estimated the association between HLI changes and CRC risk using Cox regression models and reported hazard ratios (HR) with 95% confidence intervals (CI). Results: Among 295,865 participants, 2,799 CRC cases were observed over a median of 7.8 years. Median time between questionnaires was 5.7 years. Each unit increase in HLI from the baseline to the follow-up assessment was associated with a statistically significant 3% lower CRC risk. Among participants in the top tertile at baseline (HLI>11), those in the bottom tertile at follow-up (HLI≤9) had a higher CRC risk (HR 1.34; 95%CI 1.02-1.75) than those remaining in the top tertile. Among individuals in the bottom tertile at baseline, those in the top tertile at follow-up had a lower risk (HR 0.77; 95%CI 0.59-1.00) than those remaining in the bottom tertile. Discussion: Improving adherence to a healthy lifestyle was inversely associated with CRC risk, while worsening adherence was positively associated with CRC risk. These results justify and support recommendations for healthy lifestyle changes and healthy lifestyle maintenance for CRC prevention.

Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk.Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk.Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases.Results: Mean age at baseline was 50.2years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite.Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk

Background: Nutrition and lifestyle have been long established as risk factors for colorectal cancer (CRC). Modifiable lifestyle behaviours bear potential to minimize long-term CRC risk; however, translation of lifestyle information into individualized CRC risk assessment has not been implemented. Lifestyle-based risk models may aid the identification of high-risk individuals, guide referral to screening and motivate behaviour change. We therefore developed and validated a lifestyle-based CRC risk prediction algorithm in an asymptomatic European population. Methods: The model was based on data from 255,482 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) study aged 19 to 70 years who were free of cancer at study baseline (1992–2000) and were followed up to 31 September 2010. The model was validated in a sample comprising 74,403 participants selected among five EPIC centres. Over a median follow-up time of 15 years, there were 3645 and 981 colorectal cancer cases in the derivation and validation samples, respectively. Variable selection algorithms in Cox proportional hazard regression and random survival forest (RSF) were used to identify the best predictors among plausible predictor variables. Measures of discrimination and calibration were calculated in derivation and validation samples. To facilitate model communication, a nomogram and a web-based application were developed. Results: The final selection model included age, waist circumference, height, smoking, alcohol consumption, physical activity, vegetables, dairy products, processed meat, and sugar and confectionary. The risk score demonstrated good discrimination overall and in sex-specific models. Harrell’s C-index was 0.710 in the derivation cohort and 0.714 in the validation cohort. The model was well calibrated and showed strong agreement between predicted and observed risk. Random survival forest analysis suggested high model robustness. Beyond age, lifestyle data led to improved model performance overall (continuous net reclassification improvement = 0.307 (95% CI 0.264–0.352)), and especially for young individuals below 45 years (continuous net reclassification improvement = 0.364 (95% CI 0.084–0.575)). Conclusions: LiFeCRC score based on age and lifestyle data accurately identifies individuals at risk for incident colorectal cancer in European populations and could contribute to improved prevention through motivating lifestyle change at an individual level., German Research Foundation (DFG) AL 1784/3-1, European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum (DKFZ) (Germany), Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Associazione Italiana per la Ricerca sul Cancro (AIRC), Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Regional Government of Asturias (Spain), Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain) 6236, Regional Government of Navarra (Spain), Regional Government of Catalonia (Catalan Institute of Oncology -ICO-IDIBELL) (Spain), Swedish Cancer Society, Swedish Research Council, County Council of Skane (Sweden), County Council of Vasterbotten (Sweden), Cancer Research UK C864/A14136 C8221/A19170, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) MR/N003284/1 MC-UU_12015/1 MR/M012190/1, Projekt DEAL

Previous studies have suggested that components of one-carbon metabolism, particularly circulating vitamin B6, have an etiological role in renal cell carcinoma (RCC). Vitamin B6 is a cofactor in the transsulfuration pathway. We sought to holistically investigate the role of the transsulfuration pathway in RCC risk. We conducted a nested case-control study (455 RCC cases and 455 matched controls) within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Plasma samples from the baseline visit were analyzed for metabolites of the transsulfuration pathway, including pyridoxal 5'-phosphate (PLP, the biologically active form of vitamin B6), homocysteine, serine, cystathionine, and cysteine, in addition to folate. Bayesian conditional logistic regression was used to estimate associations of metabolites with RCC risk as well as interactions with established RCC risk factors. Circulating PLP and cysteine were inversely associated with RCC risk, and these associations were not attenuated after adjustment for other transsulfuration metabolites (odds ratio (OR) and 90% credible interval (CrI) per 1 SD increase in log concentration: 0.76 [0.66, 0.87]; 0.81 [0.66, 0.96], respectively). A comparison of joint metabolite profiles suggested substantially greater RCC risk for the profile representative of low overall transsulfuration function compared to high function (OR 2.70 [90% CrI 1.26, 5.70]). We found some statistical evidence of interactions of cysteine with body mass index, and PLP and homocysteine with smoking status, on their associations with RCC risk. In conclusion, we found evidence suggesting that the transsulfuration pathway may play a role in metabolic dysregulation leading to RCC development. ispartof: INTERNATIONAL JOURNAL OF CANCER vol:151 issue:5 pages:708-716 ispartof: location:United States status: published

This work was funded by the Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund (WCRF) International grant program (WCRF 2015-1391, P.I. Mazda Jenab, International Agency for Research on Cancer). This work was partially financially supported by the Fondation de France (FDF grant no. 00081166 to H. Freisling and FDF grant no. 00089811 to A.-L. Mayen). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., The authors would like to thank the EPIC study participants and staff for their valuable contribution to this research. The authors would also like to thank Bertrand Hemon for the preparation of the databases. The coordination of EPIC is financially supported by the Inter national Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Insti tute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro (AIRC), Compagnia di San Paolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), Instituto de Salud Carlos III (ISCIII), Regional Govern ments of Andalucía, Asturias, the Basque Country, Murcia, and Navarra, and the Catalan Institute of Oncology (ICO) (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). We are grateful to all of the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. We acknowledge the use of data from the EPIC-Aarhus cohort, PI Kim Overvad. We thank the CERCA Programme/Generalitat de Catalunya for institutional support., Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: N-epsilon-carboxy-methyllysine (CML), N-epsilon-carboxyethyllysine (CEL), and N-delta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HRQ5vs.(Q1) = 0.92, 95% CI = 0.85-1.00) and MG-H1 (HRQ5vs.(Q1) = 0.92, 95% CI = 0.85-1.00), but not for CEL (HRQ5vs.(Q1) = 0.97, 95% CI = 0.89-1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development., Wereld Kanker Onderzoek Fonds (WKOF), World Cancer Research Fund (WCRF) International grant program (WCRF) 2015-1391, Fondation de France 00081166- 00089811

BACKGROUND & AIMS: Colorectal cancer risk can be lowered by adherence to the World Cancer Research Fund/ American Institute for Cancer Research (WCRF/AICR) guidelines. We derived metabolic signatures of adherence to these guidelines and tested their associations with colorectal cancer risk in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Scores reflecting adherence to the WCRF/AICR recommendations (scale, 1–5) were calculated from participant data on weight maintenance, physical activity, diet, and alcohol among a discovery set of 5738 cancer-free European Prospective Investigation into Cancer and Nutrition participants with metabolomics data. Partial least-squares regression was used to derive fatty acid and endogenous metabolite signatures of the WCRF/AICR score in this group. In an independent set of 1608 colorectal cancer cases and matched controls, odds ratios (ORs) and 95% CIs were calculated for colorectal cancer risk per unit increase in WCRF/AICR score and per the corresponding change in metabolic signatures using multivariable conditional logistic regression. RESULTS: Higher WCRF/AICR scores were characterized by metabolic signatures of increased odd-chain fatty acids, serine, glycine, and specific phosphatidylcholines. Signatures were inversely associated more strongly with colorectal cancer risk (fatty acids: OR, 0.51 per unit increase; 95% CI, 0.29–0.90; endogenous metabolites: OR, 0.62 per unit change; 95% CI, 0.50–0.78) than the WCRF/AICR score (OR, 0.93 per unit change; 95% CI, 0.86–1.00) overall. Signature associations were stronger in male compared with female participants. CONCLUSIONS: Metabolite profiles reflecting adherence to WCRF/AICR guidelines and additional lifestyle or biological risk factors were associated with colorectal cancer. Measuring a specific panel of metabolites representative of a healthy or unhealthy lifestyle may identify strata of the population at higher risk of colorectal cancer., World Cancer Research Fund International (WCRF) 20131002, European Commission grant EU-FP7/BBMRI-LPC 313010, International Agency for Research on Cancer, Danish Cancer Society, Ligue Contre le Cancer (France), General Electric, Institut Gustave-Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe German Cancer Research Center (Germany) Federal Ministry of Education & Research (BMBF) Deutsche Krebshilfe, Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro, Consiglio Nazionale delle Ricerche (CNR), Dutch Ministry of Public Health, Welfare and Sports (The Netherlands) Netherlands Cancer Registry (The Netherlands) Netherlands Government, Nordic Centre of Excellence Programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III PI13/00061 PI13/01162, Junta de Andalucia, Basque Government, Regional Government of Murcia, Regional Government of Navarra, Instituto de Salud Carlos III Cooperative Research in Health (Spain) RD06/0020, Swedish Cancer Society Swedish Research Council, County Council of Skane (Sweden) County Council of Vasterbotten (Sweden), Cancer Research UK 14136 C570/A16491 C8221/A19170, UK Research & Innovation (UKRI), Medical Research Council UK (MRC) 1000143 MR/M012190/1

Background & Aims: Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. Methods: The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. Results: In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04–1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04–1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93–0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90–0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90–0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92–0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93–0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. Conclusions: Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.

Background:High intakes of whole-grains and cereal fiber have been consistently associated with lower risk of cardiometabolic diseases in observational studies. Yet, improved understanding about the underlying mechanisms is needed. We hypothesized that cereal fiber and whole-grain are associated with beneficial metabolic marker profiles.Aim:To investigate if cereal fiber intake, estimated by food frequency questionnaires and plasma total alkylresorcinols concentrations as well as the C17:0/C21:0-ratio in plasma as biomarkers of whole-grain wheat and rye intake or the relative whole-grain rye to wheat intake, respectively, were associated with metabolic biomarkers.Design:A cross-sectional study conducted to investigate the associations between alkylresorcinols as biomarker of whole-grain wheat and rye intake, cereal fiber and selected metabolic biomarkers among 954 participants of the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Cereal fiber intake was assessed by FFQ and whole grain wheat and rye were reflected by biomarkers analyzed in plasma samples, i.e. total alkylresorcinol (AR). Moreover, the ratio of two of the five measured alkylresorcinols (AR C17:0/C21:0 ratio) was used as an indicator of whole-grain source (wheat or rye). Metabolic biomarkers (HbA1c, C-peptide, IGFBP-1, IGFBP-2, total cholesterol, LDL, HDL, triglycerides, apolipoprotein A-I (apoA), apolipoprotein B (ApoB) and CRP) were measured in blood samples. All biomarkers were already measured for nested case-control studies of colorectal cancer matched based on sex, study center, age at blood collection, date and time of blood collection, fasting status. Women were further matched by menopausal status, phase of menstrual cycle, and use of oral contraceptives or hormone replacement therapy at time of blood collection. Multivariable linear regression analysis was used to investigate the relationship between exposure variables metabolic biomarkers adjusted for case-control status and common confounders.Results:No associations were found between cereal fiber intake and the metabolic markers. However, whole-grain wheat and rye intake, reflected by total AR, was associated with a lower concentration of the inflammation marker CRP. The alkylresorcinol C17:0/C21:0 ratio was not associated with any of the measured metabolic markers in this cohort.Conclusion:Overall, we found no support for an association between cereal fibre intake, whole grain wheat and rye intake reflected by biomarkers and metabolic markers in the present cohort. One exception was the finding of an inverse association between whole grain biomarkers and CRP. Prospective studies or RCTs are warranted to confirm our findings.

Fruit and vegetable (FV 95% CI: 0.68-1.15; p-trend = 0.44), vegetables (HR: 0.89; 95% CI: 0.69-1.14; p-trend = 0.56), or fruit (HR: 1.00; 95% CI: 0.79-1.26; p-trend = 0.64). No significant association was observed with any individual type of vegetable or fruit. However, there was a positive borderline trend with fruit juice intake (HR: 1.23; 95% CI: 0.98-1.53; p-trend = 0.06). This study did not find any significant association between FV however a positive trend with fruit juice intake was observed, possibly related to its high sugar content.

A whole-grain (WG)-rich diet has shown to have potential for both prevention and treatment of the metabolic syndrome (MetS), which is a cluster of risk factors that increase the risk of type 2 diabetes and cardiovascular disease. Different WGs may have different health effects. WG rye, in particular, may improve glucose homeostasis and blood lipids, possibly mediated through fermentable dietary fiber and lignans. Recent studies have also suggested a crucial role of the gut microbiota in response to WG. Objectives: The aim was to investigate WG rye, alone and with lignan supplements [secoisolariciresinol diglucoside (SDG)], and WG wheat diets on glucose tolerance [oral-glucose-tolerance test (OGTT)], other cardiometabolic outcomes, enterolignans, and microbiota composition. Moreover, we exploratively evaluated the role of gut microbiota enterotypes in response to intervention diets. Methods: Forty men with MetS risk profile were randomly assigned to WG diets in an 8-wk crossover study. The rye diet was supplemented with 280 mg SDG at weeks 4-8. Effects of treatment were evaluated by mixed-effects modeling, and effects on microbiota composition and the role of gut microbiota as a predictor of response to treatment were analyzed by random forest plots. Results: The WG rye diet (± SDG supplements) did not affect the OGTT compared with WG wheat. Total and LDL cholesterol were lowered (-0.06 and -0.09 mmol/L, respectively; P < 0.05) after WG rye compared with WG wheat after 4 wk but not after 8 wk. WG rye resulted in higher abundance of Bifidobacterium [fold-change (FC) = 2.58, P < 0.001] compared with baseline and lower abundance of Clostridium genus compared with WG wheat (FC = 0.54, P = 0.02). The explorative analyses suggest that baseline enterotype is associated with total and LDL-cholesterol response to diet. Conclusions: WG rye, alone or with SDG supplementation, compared with WG wheat did not affect glucose metabolism but caused transient LDL-cholesterol reduction. The effect of WG diets appeared to differ according to enterotype. This trial was registered at www.clinicaltrials.gov as NCT02987595.

Lignans are diphenolic plant compounds with potential health modulating properties that are absorbed to the circulation and metabolized to the enterolignans enterodiol (END) and enterolactone (ENL) by gut microbiota. Epidemiological studies have inconsistently shown that a high lignan intake and circulating ENL are associated with reduced risk of breast‐, prostate‐, and colorectal cancer as well as cardiovascular disease and total and cause‐specific mortality. Inconsistencies can be due to interpersonal variation of ENL formation or responses. The aim of this review is to identify and evaluate the impact of factors influencing variability in plasma concentrations of the main enterolignan, ENL. The main determinants of plasma ENL concentrations are intake of lignan and lignan‐rich foods, composition and activity of intestinal microflora, antimicrobial use, nutrient intake, BMI, smoking, sex, and age. Composition and activity of the intestinal microbiota appear to be the most critical factor governing interpersonal variability in plasma ENL concentration followed by the use of antibiotics. Future studies with combined data from gut microbiota and metabolomics with food intake and life style data can be used to estimate the relative contribution of the different factors to ENL concentration in quantitative terms., Lignans are bioactive compounds from plants with potential health modulating properties. Plant lignans are absorbed or passed through the colon and metabolized to the enterolignans enterodiol (END) and enterolactone (ENL) by gut microbiota. Studies on the role of lignans in human health, and ENL in particular, have been inconsistent. One reason for inconsistency can be due to large interpersonal variability in the factors that affect lignan concentrations and their activity in vivo. The current study describes the most important factors that determine the plasma ENL concentrations as well as the most important sources of interpersonal variability.

Aims: The hypothesis of ‘metabolically healthy obesity’ implies that, in the absence of metabolic dysfunction, individuals with excess adiposity are not at greater cardiovascular risk. We tested this hypothesis in a large pan-European prospective study. Methods and results: We conducted a case-cohort analysis in the 520 000-person European Prospective Investigation into Cancer and Nutrition study (‘EPIC-CVD’). During a median follow-up of 12.2 years, we recorded 7637 incident coronary heart disease (CHD) cases. Using cut-offs recommended by guidelines, we defined obesity and overweight using body mass index (BMI), and metabolic dysfunction (‘unhealthy’) as >_ 3 of elevated blood pressure, hypertriglyceridaemia, low HDL-cholesterol, hyperglycaemia, and elevated waist circumference. We calculated hazard ratios (HRs) and 95% confidence intervals (95% CI) within each country using Prentice-weighted Cox proportional hazard regressions, accounting for age, sex, centre, education, smoking, diet, and physical activity. Compared with metabolically healthy normal weight people (reference), HRs were 2.15 (95% CI: 1.79; 2.57) for unhealthy normal weight, 2.33 (1.97; 2.76) for unhealthy overweight, and 2.54 (2.21; 2.92) for unhealthy obese people. Compared with the reference group, HRs were 1.26 (1.14; 1.40) and 1.28 (1.03; 1.58) for metabolically healthy overweight and obese people, respectively. These results were robust to various sensitivity analyses. Conclusion: Irrespective of BMI, metabolically unhealthy individuals had higher CHD risk than their healthy counterparts. Conversely, irrespective of metabolic health, overweight and obese people had higher CHD risk than lean people. These findings challenge the concept of ‘metabolically healthy obesity’, encouraging population-wide strategies to tackle obesity., European Union (EU) HEALTH-F2-2012-279233, European Research Council (ERC) 268834, Medical Research Council UK (MRC) G0800270 MR/L003120/1 MR/M012190/1, British Heart Foundation SP/09/002 RG/08/014 RG13/13/30194, National Institute for Health Research (NIHR), Regional Government of Asturias, Hellenic Health Foundation, German Cancer Aid, German Cancer Research Centre, German Federal Ministry of Education and Research, Cancer Research UK 570/A16491, Regione Sicilia, Associazione Iblea per la Ricerca Epidemiologica (A.I.R.E.) - ONLUS Ragusa, Associazione Volontari Italiani Sangue AVIS Ragusa, Compagnia di San Paolo, Human Genetics Foundation-Torino (HuGeF), British Heart Foundation RG/13/13/30194 RG/08/014/24067, Cancer Research UK 16491, Medical Research Council UK (MRC) MR/L003120/1 G0800270 MC_UU_12015/1, National Institute for Health Research (NIHR) NF-SI-0512-10135 NF-SI-0512-10165, Novo Nordisk Foundation NNF17OC0026936

Summary Background & aims High intakes of the phytoestrogen lignans and high blood concentrations of its main biomarker, enterolactone, has been associated with a better breast cancer prognosis. We investigated the association between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis (i.e. recurrence, breast cancer-specific mortality and all-cause mortality). Methods Plasma and data was available from the Danish Diet, Cancer and Health cohort. Information on treatment and clinical characteristics from registries and clinical databases and both pre-diagnostic and diagnostic plasma measurement of enterolactone on a sub-set. Enterolactone was quantified in plasma using a high-throughput LC−MS/MS method. We followed 1457 breast cancer cases from date of diagnosis and until censoring or end-of-follow-up (median 9 years), during this time 404 died (250 of breast cancer) and 267 experienced recurrence. Cox proportional hazards models were used to estimate hazard ratios (HR) with 95% confidence intervals (CI). Results Plasma enterolactone were borderline significantly associated with lower breast cancer-specific mortality (HRdoubling = 0.93, 95% CI:0.86, 1.00, P = 0.0501), but not associated with all-cause mortality (HRdoubling = 0.95, 95% CI:0.89, 1.01) and recurrence (HRdoubling = 0.96, 95% CI: 0.89, 1.04) in the models adjusted for smoking, schooling, BMI, physical activity and use of menopausal hormones. Adjusting further for clinical characteristics and treatment did not change the results considerably. In the sensitivity analyses, an inverse association was found with all-cause and breast cancer-specific mortality for those where blood was collected ≤5 years before diagnosis. Conclusions Overall, no clear association was found between pre-diagnostic plasma concentrations of enterolactone and breast cancer prognosis.

cope High enterolactone levels may have health benefits in relation to risk of noncommunicable diseases. Enterolactone is produced by the colonic microbiota after intake of lignans and treatment with antimicrobials may result in altered enterolactone production. This study investigates the association between antibiotic use and enterolactone concentration. Methods and results Using LC–MS/MS, enterolactone concentrations were quantified in plasma samples from 2237 participants from the Diet, Cancer and Health cohort. The participants were healthy at enrollment, but were later diagnosed with cancer. At enrollment, participants had blood drawn and completed a food frequency questionnaire and lifestyle questionnaire. Antibiotic use was assessed as reimbursed antibiotic prescriptions up to 12 months before enrollment. Antibiotic use ≤3 months before enrollment was associated with a 41% (Δcrude: –41; 95% CI: –52, –28) lower enterolactone concentration in women and 12% in men (Δcrude: –12; 95% CI: –31, 11), while antibiotic use >3–12 months before enrollment was associated with 26% lower enterolactone in women (Δcrude: –26; 95% CI: –37, –14) and 14% in men (Δcrude: –14; 95% CI: –28, 1). Conclusion Use of antibiotics up to 12 months before enrollment was associated with lower plasma enterolactone levels, especially among women.

BACKGROUND/OBJECTIVES: Evidence on the role of diet in relation to prostate cancer progression is sparse. Foods rich in lignans have shown beneficial effects on prostate cancer progression in both animal studies and small human intervention studies, including beneficial effects on prostate-specific antigen levels and tumour growth. The lignan metabolite, enterolactone, has further shown to slow prostate cancer cell growth in vitro. The aim was to investigate the association between prediagnostic enterolactone concentrations and mortality among men with prostate cancer. SSUBLJECTS/METHODS: Prediagnostic plasma concentrations of enterolactone from 1390 men diagnosed with prostate cancer from the Danish Diet, Cancer and Health cohort were related to all-cause or prostate cancer-specific death, using Cox proportional hazards models with follow-up time (from the date of diagnose until the date of death, emigration or end of follow-up by December 2013) as the underlying time axis. RESULTS: The hazard ratios for enterolactone concentrations assessed linearly by 20 nmol/l increments was 0.95 (0.90, 1.02) for all-cause mortality and 0.98 (0.92, 1.05) for prostate cancer-specific mortality. Categorisation of enterolactone concentrations into quartiles did not reveal a different pattern. No effect modifications by smoking, body mass index or sport were observed, and the associations did not differ by prostate cancer aggressiveness. CONCLUSIONS: We found no association between enterolactone concentrations and mortality among men diagnosed with prostate cancer.

Background: Differentiated thyroid cancer (TC) is the most common endocrine cancer. Fish can be an important source of iodine and other micronutrients and contaminants that may affect the thyroid gland and TC risk.Objective: We prospectively evaluated the relations between the consumption of total fish and different fish types and shellfish and TC risk in the EPIC (European Prospective Investigation into Cancer and Nutrition) study.Methods: EPIC is a cohort of >500,000 men and women, mostly aged 35-70 y, who were recruited in 10 European countries. After a mean follow-up of 14 y, 748 primary differentiated TC cases were diagnosed; 666 were in women and 601 were papillary TC. Data on intakes of lean fish, fatty fish, fish products, and shellfish were collected by using country-specific validated dietary questionnaires at recruitment. Multivariable Cox regression was used to calculate HRs and 95% CIs adjusted for many potential confounders, including dietary and nondietary factors.Results: No significant association was observed between total fish consumption and differentiated TC risk for the highest compared with the lowest quartile (HR: 1.03; 95% CI: 0.81, 1.32; P-trend = 0.67). Likewise, no significant association was observed with the intake of any specific type of fish, fish product, or shellfish. No significant heterogeneity was found by TC subtype (papillary or follicular tumors), by sex, or between countries with low and high TC incidence.Conclusion: This large study shows that the intake of fish and shellfish was not associated with differentiated TC risk in Europe, a region in which iodine deficiency or excess is rare.

BACKGROUND: The prognosis for men with non-aggressive prostate cancer is good, and several studies have investigated the impact of lifestyle changes including physical activity and diet on the prognosis. Despite positive results in animal studies and a few human interventions with whole-grain rye on markers of prostate cancer progression, the feasibility of trials investigating such dietary changes in combination with physical activity remains largely unstudied. The primary aim was to investigate the feasibility of an intervention with high whole-grain rye intake and vigorous physical activity for 6 months in men diagnosed with prostate cancer.METHODS: In total, 26 men (53-72 years) recently diagnosed with non-aggressive prostate cancer and on active surveillance, were enrolled in 2011-2012 and randomly assigned to an intervention or a control group. The intervention included 170 g/day of whole-grain rye and 3 × 45 minutes/week of vigorous physical activity. The duration of the intervention was 6 months and end of follow-up 12 months after baseline. Clinic visits were scheduled at baseline and 3, 6 and 12 months after baseline. Compliance with the intervention was evaluated by diaries, food frequency questionnaires, biomarkers, and heart rate monitor data. The effect of the intervention was evaluated by linear multiple regression analysis.RESULTS: In the intervention group, the mean daily intake of whole-grain rye measured from diaries was 146 g (SD: 19) for the first 3 months and 125 g (SD: 40) for the last 3 months of the intervention. The median level (5(th) and 95(th) percentiles) of vigorous physical activity was 91 (17, 193) min/week for the first 3 months and 66 (13, 259) min/week for the last 3 months. No recordings of physical activity were done for the control group. Aerobic fitness (VO2 peak) increased in the intervention group compared to the control group after the intervention. No effects were found on other cardio-metabolic outcomes or prostate cancer progression.CONCLUSIONS: The lifestyle intervention appeared feasible for 6 months among Danish men and the results are encouraging for conducting full-scale studies, where the impact of whole-grain rye and vigorous physical activity on prostate cancer progression and metabolic parameters can be evaluated.TRIAL REGISTRATION: ClinicalTrials.gov, NCT01300104 . Registered on 18 February 2011.