Baseline and lifetime alcohol consumption and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend  = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend  = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend  = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend  = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17, Ptrend  = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend  = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend  = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31; Ptrend  = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer.

Food Processing and Risk of Crohn's Disease and Ulcerative Colitis: A European Prospective Cohort Study.

BACKGROUND & AIMS: Industrial foods have been associated with increased risks of several chronic conditions. We investigated the relationship between the degree of food processing and risks of Crohn's disease (CD) and ulcerative colitis (UC) in the European Prospective Investigation into Cancer and Nutrition cohort. METHODS: Analyses included 413,590 participants (68.6% women; mean baseline age, 51.7 y) from 8 European countries. Dietary data were collected at baseline from validated country-specific dietary questionnaires. Associations between proportions of unprocessed/minimally processed and ultraprocessed food intake and CD and UC risks were estimated using Cox models to obtain hazard ratios (HRs) and 95% CIs. Models were stratified by center, age, and sex, and adjusted for smoking status, body mass index, physical activity, energy intake, educational level, and alcohol consumption. RESULTS: During a mean follow-up period of 13.2 years, 179 incident cases of CD and 431 incident cases of UC were identified. The risk of CD was lower in people consuming high proportions of unprocessed/minimally processed foods (adjusted HR for the highest vs lowest quartile: 0.57; 95% CI, 0.35-0.93; P trend < .01), particularly fruits and vegetables (adjusted HRs, 0.54; 95% CI, 0.34-0.87 and 0.55; 95% CI, 0.34-0.91, respectively). There was no association between unprocessed/minimally processed food intake and the risk of UC. No association was detected between ultraprocessed food consumption and CD or UC risks. CONCLUSIONS: In the European Prospective Investigation into Cancer and Nutrition cohort, consumption of unprocessed/minimally processed foods was associated with a lower risk of CD. No association between UC risk and food processing was found.

Blood pressure, hypertension and the risk of atrial fibrillation: a systematic review and meta-analysis of cohort studies.

Elevated blood pressure and hypertension have been associated with increased risk of atrial fibrillation in a number of epidemiological studies, however, the strength of the association has differed between studies. We conducted a systematic review and meta-analysis of the association between blood pressure and hypertension and atrial fibrillation. PubMed and Embase databases were searched for studies of hypertension and blood pressure and atrial fibrillation up to June 6th 2022. Cohort studies reporting adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) of atrial fibrillation associated with hypertension or blood pressure were included. A random effects model was used to estimate summary RRs. Sixty eight cohort studies were included in the meta-analysis. The summary RR was 1.50 (95% CI: 1.42-1.58, I2 = 98.1%, n = 56 studies) for people with hypertension compared to those without hypertension (1,080,611 cases, 30,539,230 participants), 1.18 (95% CI: 1.16-1.21, I2 = 65.9%, n = 37 studies) per 20 mmHg increase in systolic blood pressure (346,471 cases, 14,569,396 participants), and 1.07 (95% CI: 1.03-1.11, I2 = 91.5%, n = 22 studies) per 10 mmHg increase in diastolic blood pressure (332,867 cases, 14,354,980 participants). There was evidence of a nonlinear association between diastolic blood pressure and atrial fibrillation with a steeper increase in risk at lower levels of diastolic blood pressure, but for systolic blood pressure the association appeared to be linear. For both systolic and diastolic blood pressure, the risk increased even within the normal range of blood pressure and persons at the high end of systolic and diastolic blood pressure around 180/110 mmHg had a 1.8-2.3 fold higher risk of atrial fibrillation compared to those with a blood pressure of 90/60 mmHg. These results suggest that elevated blood pressure and hypertension increases the risk of atrial fibrillation and there is some increase in risk even within the normal range of systolic and diastolic blood pressure.

Diabetes mellitus, prediabetes and the risk of Parkinson's disease: a systematic review and meta-analysis of 15 cohort studies with 29.9 million participants and 86,345 cases.

A diagnosis of diabetes mellitus and prediabetes has been associated with increased risk of Parkinson's disease (PD) in several studies, but results have not been entirely consistent. We conducted a systematic review and meta-analysis of cohort studies on diabetes mellitus, prediabetes and the risk of PD to provide an up-to-date assessment of the evidence. PubMed and Embase databases were searched for relevant studies up to 6th of February 2022. Cohort studies reporting adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between diabetes, prediabetes and Parkinson's disease were included. Summary RRs (95% CIs) were calculated using a random effects model. Fifteen cohort studies (29.9 million participants, 86,345 cases) were included in the meta-analysis. The summary RR (95% CI) of PD for persons with diabetes compared to persons without diabetes was 1.27 (1.20-1.35, I2 = 82%). There was no indication of publication bias, based on Egger's test (p = 0.41), Begg's test (p = 0.99), and inspection of the funnel plot. The association was consistent across geographic regions, by sex, and across several other subgroup and sensitivity analyses. There was some suggestion of a stronger association for diabetes patients reporting diabetes complications than for diabetes patients without complications (RR = 1.54, 1.32-1.80 [n = 3] vs. 1.26, 1.16-1.38 [n = 3]), vs. those without diabetes (pheterogeneity=0.18). The summary RR for prediabetes was 1.04 (95% CI: 1.02-1.07, I2 = 0%, n = 2). Our results suggest that patients with diabetes have a 27% increased relative risk of developing PD compared to persons without diabetes, and persons with prediabetes have a 4% increase in RR compared to persons with normal blood glucose. Further studies are warranted to clarify the specific role age of onset or duration of diabetes, diabetic complications, glycaemic level and its long-term variability and management may play in relation to PD risk.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Metabolic Syndrome and Risk of Gastrointestinal Cancers: An Investigation Using Large-scale Molecular Data.

BACKGROUND & AIMS: Gastrointestinal cancer risk is influenced by the presence of metabolic syndrome (MetS). However, previous epidemiologic studies lacked full serological biomarker data for the classification of MetS, and the interaction of MetS with germline cancer risk variants is unknown. METHODS: We investigated the associations between MetS and gastrointestinal cancer risk (overall, colorectal, pancreatic, esophageal adenocarcinoma, esophageal squamous cell carcinoma, stomach cardia, stomach non-cardia, hepatocellular carcinoma, and intrahepatic bile duct cancer) in 366,016 United Kingdom Biobank participants with comprehensive serum biomarker and genotype data. MetS status was determined by 3 different definitions at baseline, and, in 15,152 participants, at a repeat assessment after a median of 4.3 years of follow-up. Multivariable hazard ratios and 95% confidence intervals for cancer outcomes were estimated using Cox proportional hazards models. Analyses stratified by polygenic risk score were conducted for colorectal and pancreatic cancers. RESULTS: During a median follow-up of 7.1 years, 4238 incident cases of a gastrointestinal cancer occurred. MetS at baseline was associated with higher risk of overall gastrointestinal cancer by any definition (hazard ratio, 1.21; 95% confidence interval, 1.13-1.29, harmonized definition). MetS was associated with increased risks of colorectal cancer, colon cancer, rectal cancer, hepatocellular carcinoma, pancreatic cancer in women, and esophageal adenocarcinoma in men. Associations for colorectal cancer and pancreatic cancer did not differ by polygenic risk score strata (P-heterogeneity 0.70 and 0.69, respectively), and 80% of participants with MetS at baseline retained this status at the repeat assessment. CONCLUSIONS: These findings underscore the importance of maintaining good metabolic health in reducing the burden of gastrointestinal cancers, irrespective of genetic predisposition.

Does saffron supplementation have favorable effects on liver function indicators? A systematic review and meta-analysis of randomized controlled trials.

Several pharmaceutical and non-pharmaceutical approaches have been suggested to improve liver health. There is a large discrepancy in the effects of saffron supplementation on liver function in adults. To fill this knowledge gap, this systematic review and meta-analysis of randomized controlled trials (RCTs) assess the effects of saffron supplementation on liver enzymes alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase (ALP). A systematic search current to August 2020 was performed in PubMed/Medline, Scopus, Web of Science, and Google Scholar using relevant keywords to detect eligible articles. A random-effects model was used to estimate the weighted mean difference (WMD) and 95% confidence (95% CI). Nine eligible trials were included in the final analysis. The pooled analysis revealed that serum ALT concentrations were significantly reduced using saffron compared to placebo (WMD: -2.39 U/L; 95% CI: -4.57 to -0.22; P = 0.03, I2= 87.9%, P < 0.001). However, saffron supplementation did not affect levels of serum AST (WMD: 1.12 U/L; 95% CI: -1.42 to 3.65; P = 0.39) or ALP (WMD: 4.32 U/L; 95% CI: -6.91 to 15.54; P = 0.78). In the dose-response analysis, we did not find a significant dose-response relationship between dosage and duration of saffron supplementation on serum levels of ALT, AST, and ALP. We found that saffron supplementation can reduce ALT serum concentrations without significant effects on other liver function indicators, including AST and ALP. Nevertheless, future large RCTs on diverse populations are needed to understand better the effects of saffron and its constituents on these enzymes.

Dietary antioxidant supplements and risk of keratinocyte cancers in women: a prospective cohort study.

PURPOSE: Experimental studies suggested that antioxidants could protect against skin carcinomas. However, epidemiological studies on antioxidant supplement use in relation to basal-cell carcinoma (BCC) and squamous-cell carcinoma (SCC) risks yielded inconsistent findings, and few prospective studies have been conducted to date. We aimed to investigate the associations between antioxidant supplement intake and keratinocyte cancer (KC) risk. METHODS: E3N is an ongoing prospective cohort initiated in 1990 and involving 98,995 French women aged 40-65 years at recruitment. Intakes of dietary antioxidants were estimated via a validated dietary questionnaire in 1993 and self-reported antioxidant supplement use was collected in 1995. We used Cox models to compute hazard ratios (HRs) and 95% confidence intervals (CIs) adjusted for age and skin cancer risk factors. RESULTS: Over 1995-2014, 2426 BCC and 451 SCC cases were diagnosed among 63,063 women. We found positive relationships between vitamin A supplement use and KC risk (HR = 1.37, 95% CI 1.15-1.62), particularly with BCC (HR = 1.40, 95% CI 1.17-1.69); and between vitamin E supplement use and risks of both BCC (HR = 1.21, 95% CI 1.03-1.52) and SCC (HR = 1.43, 95% CI 1.03-1.99). Intake of beta-carotene supplements was associated with an increased SCC risk (HR = 1.59, 95% CI 1.00-2.54). Vitamin C supplement use was not associated with KC risk. We found similar results when considering total antioxidant intake. CONCLUSIONS: Intakes of vitamin A or E supplements were associated with an increased KC risk in women. Further studies with information on doses and duration of supplement use and the ability to examine their underlying mechanisms are needed.

Metabolic perturbations prior to hepatocellular carcinoma diagnosis: Findings from a prospective observational cohort study.

Hepatocellular carcinoma (HCC) development entails changes in liver metabolism. Current knowledge on metabolic perturbations in HCC is derived mostly from case-control designs, with sparse information from prospective cohorts. Our objective was to apply comprehensive metabolite profiling to detect metabolites whose serum concentrations are associated with HCC development, using biological samples from within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (>520 000 participants), where we identified 129 HCC cases matched 1:1 to controls. We conducted high-resolution untargeted liquid chromatography-mass spectrometry-based metabolomics on serum samples collected at recruitment prior to cancer diagnosis. Multivariable conditional logistic regression was applied controlling for dietary habits, alcohol consumption, smoking, body size, hepatitis infection and liver dysfunction. Corrections for multiple comparisons were applied. Of 9206 molecular features detected, 220 discriminated HCC cases from controls. Detailed feature annotation revealed 92 metabolites associated with HCC risk, of which 14 were unambiguously identified using pure reference standards. Positive HCC-risk associations were observed for N1-acetylspermidine, isatin, p-hydroxyphenyllactic acid, tyrosine, sphingosine, l,l-cyclo(leucylprolyl), glycochenodeoxycholic acid, glycocholic acid and 7-methylguanine. Inverse risk associations were observed for retinol, dehydroepiandrosterone sulfate, glycerophosphocholine, γ-carboxyethyl hydroxychroman and creatine. Discernible differences for these metabolites were observed between cases and controls up to 10 years prior to diagnosis. Our observations highlight the diversity of metabolic perturbations involved in HCC development and replicate previous observations (metabolism of bile acids, amino acids and phospholipids) made in Asian and Scandinavian populations. These findings emphasize the role of metabolic pathways associated with steroid metabolism and immunity and specific dietary and environmental exposures in HCC development.

BMI in the Associations of Plant-Based Diets with Type 2 Diabetes and Hypertension Risks in Women: The E3N Prospective Cohort Study.

BACKGROUND: Few studies have evaluated the quality of plant-based diets in relation to chronic diseases, and the potential role of BMI is not clearly explored. OBJECTIVES: To study the associations between plant-based diet indices and type 2 diabetes (T2D) and hypertension risks, as well as the extent to which the associations were modified and/or mediated by BMI. METHODS: The study included 74,522 women from the Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale prospective cohort [mean (SD): age, 52.94 (6.7) years; BMI, 22.970 (3.328) kg/m2]. Dietary data were collected at baseline (1993) via an FFQ. Overall plant-based diet index (PDI), healthful PDI (hPDI), and unhealthful PDI (uPDI) were developed. Multivariable Cox regression models were used to derive HRs and 95% CIs. Effect modification and mediation by BMI were explored. RESULTS: There were 3292 (4.64%) incident cases of T2D and 12,504 (27.14%) incident cases of hypertension over ∼20 years of follow-up. In the multivariable model further adjusted for BMI, higher adherence to PDI and hPDI was associated with lower T2D and hypertension risks, with an HR per 1-SD increase (95% CI) of 0.88 (0.85, 0.91) and 0.96 (0.94, 0.98) for PDI and 0.88 (0.85, 0.92) and 0.94 (0.92, 0.95) for hPDI, respectively. uPDI was not associated with T2D [0.98 (0.94, 1.01)], whereas a positive association was observed with hypertension: 1.04 (1.02, 1.06). There was interaction between PDI and uPDI, as well as BMI, on T2D (P-interaction < 0.001) but not on hypertension (P-interaction > 0.05). In addition, BMI mediated 26-59% and 0.2-59% of diet-T2D and diet-hypertension associations, respectively. CONCLUSIONS: Differential associations between plant-based diets and T2D and hypertension risks were observed among women in this large prospective study. Only healthier plant foods were associated with lower risks, partly through decreasing BMI. The protocol was registered at clinicaltrials.gov as NCT03285230.

The associations of the Palaeolithic diet alone and in combination with lifestyle factors with type 2 diabetes and hypertension risks in women in the E3N prospective cohort.

PURPOSE: Patterns of change from the traditional Palaeolithic lifestyle to the modern lifestyle may partly explain the epidemic proportions of non-communicable diseases (NCDs). We investigated to what extent adherence to the Palaeolithic diet (PD) and the Palaeolithic-like lifestyle was associated with type 2 diabetes (T2D) and hypertension risks. METHODS: A study of 70,991 women from the E3N (Etude Epidémiologique auprès de femmes de la Mutuelle Générale de l'Education Nationale) cohort, followed up for nearly 20 years. There were 3292 incident T2D and 12,504 incident hypertension cases that were validated. Dietary data were collected at baseline in 1993 via a food frequency questionnaire. The PD score and the Palaeolithic-like lifestyle score (PD, physical activity, smoking status, and body mass index [BMI]) were derived and considered in quintiles. Multivariable Cox regression models were employed to estimate hazard ratios (HR) and 95% confidence intervals (CI) for incident T2D and hypertension. RESULTS: In the fully adjusted models, a 1-SD increase of the PD score was associated with 4% and 3% lower risks of T2D and hypertension, respectively. Those in the highest versus the lowest quintile of the score had HR (95% CI) of 0.88 (0.79, 0.98) and 0.91 (0.86, 0.96) for T2D and hypertension, respectively (P-trend < 0.0001). Associations were stronger for the Palaeolithic-like lifestyle score; in the fully adjusted model, a 1-SD increase of the score was associated with 19% and 6% lower risks of T2D and hypertension, respectively. Risks lowered successively with each increase in quintile; those in the highest versus the lowest quintile had HR (95% CI) of 0.58 (0.52, 0.65) and 0.85 (0.80, 0.90) for T2D and hypertension, respectively (P-trend < 0.0001). CONCLUSIONS: Our data suggest that adhering to a PD based on fruit, vegetables, lean meats, fish, and nuts, and incorporating a Palaeolithic-like lifestyle could be promising options to prevent T2D and hypertension.

High Body Mass Index and Central Adiposity Is Associated with Increased Risk of Acute Pancreatitis: A Meta-Analysis.

BACKGROUND: Higher body mass index and waist circumference have been associated with increased risk of pancreatitis in several prospective studies; however, the results have not been entirely consistent. AIMS: We conducted a systematic review and dose-response meta-analysis of prospective studies on adiposity and risk of pancreatitis to clarify this association. METHODS: PubMed and Embase databases were searched for studies on adiposity and pancreatitis up to January 27, 2020. Prospective studies reporting adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between adiposity and risk of pancreatitis were included, and summary RRs (95% CIs) were calculated using a random effects model. RESULTS: Ten prospective studies with 5129 cases and 1,693,657 participants were included. The summary RR (95% CI) of acute pancreatitis was 1.18 (95% CI: 1.03-1.35, I2 = 91%, n = 10 studies) per 5 kg/m2 increase in BMI and 1.36 (95% CI: 1.29-1.43, I2 = 0%, n = 3) per 10 cm increase in waist circumference. There was evidence of a nonlinear association between BMI and acute pancreatitis, pnonlinearity < 0.0001, with a steeper association at higher levels of BMI, but not for waist circumference, pnonlinearity = 0.19. Comparing a BMI of 35 with a BMI of 22, there was a 58% increase in the RR and there was a fourfold increase in the RR comparing a waist circumference of 110 cm with 69 cm. There was no evidence of publication bias. CONCLUSIONS: This meta-analysis suggests that both increasing BMI and waist circumference are associated with a dose-response-related increase in the risk of acute pancreatitis.

Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study.

Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a large-scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow-up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1-standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1-SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition.

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992-2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00-1.26), with no detected heterogeneity across countries (phomogeneity = 0.42). This risk increased linearly with duration of use (ptrend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97-1.43), which was heterogeneous across countries (phomogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.

Inflammatory potential of the diet and risk of colorectal cancer in the European Prospective Investigation into Cancer and Nutrition study.

Proinflammatory diets are associated with risk of developing colorectal cancer (CRC), however, inconsistencies exist in subsite- and sex-specific associations. The relationship between CRC and combined lifestyle-related factors that contribute toward a low-grade inflammatory profile has not yet been explored. We examined the association between the dietary inflammatory potential and an inflammatory profile and CRC risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. This cohort included 476,160 participants followed-up of 14 years and 5,991 incident CRC cases (3,897 colon and 2,094 rectal tumors). Dietary inflammatory potential was estimated using an Inflammatory Score of the Diet (ISD). An Inflammatory Profile Score (IPS) was constructed, incorporating the ISD, physical activity level and abdominal obesity. The associations between the ISD and CRC and IPS and CRC were assessed using multivariable regression models. More proinflammatory diets were related to a higher CRC risk, particularly for colon cancer; hazard ratio (HR) for highest versus lowest ISD quartile was 1.15 (95% confidence interval [CI] 1.04-1.27) for CRC, 1.24 (95% CI 1.09-1.41) for colon cancer and 0.99 (95% CI 0.83-1.17) for rectal cancer. Associations were more pronounced in men and not significant in women. The IPS was associated with CRC risk, particularly colon cancer among men; HRs for the highest versus lowest IPS was 1.62 (95% CI 1.31-2.01) for colon cancer overall and 2.11 (95% CI 1.50-2.97) for colon cancer in men. Our study shows that more proinflammatory diets and a more inflammatory profile are associated with higher risk of CRC, principally colon cancer and in men.

Premenopausal Use of Progestogens and Cutaneous Melanoma Risk: A French Prospective Cohort Study.

We investigated the influence of premenopausal use of progestogens on melanoma using data from E3N (Etude Epidémiologique Auprès de Femmes de l'Education Nationale), a prospective cohort of 98,995 French women, aged 40-65 years at inclusion. We used Cox models to adjust for age and melanoma risk factors. Over 1992-2008, 540 melanoma cases were ascertained among 79,558 women. We found a modest association between self-reported progestogen use and melanoma risk (hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 1.02, 1.47), which was reduced after adjustment for melanoma risk factors (HR = 1.15, 95% CI: 0.95, 1.39). There was no heterogeneity across types of progestogens (P = 0.22), and use of multiple progestogens was positively associated with melanoma risk (HR = 1.33, 95% CI: 1.04, 1.70). Among users, we found no relationship with duration of progestogen use, age at start and last use, and time since first and last use. Although our results did not show evidence of a confounding effect of sun exposure, progestogen users had lower levels of residential sun exposure and were more likely to report sunscreen use, suggesting specific sun exposure profiles in users. Our findings do not support a strong influence of progestogens on melanoma risk. Further research is needed to confirm these results.

Diabetes mellitus and the risk of pancreatitis: A systematic review and meta-analysis of cohort studies.

BACKGROUND: Diabetes mellitus has been associated with increased risk of pancreatitis in several studies, however, not all studies have found an association. We conducted a systematic review and meta-analysis of prospective studies on diabetes mellitus and pancreatitis to clarify the association. METHODS: PubMed and Embase databases were searched for studies on diabetes mellitus and pancreatitis up to 8th of January 2020. Cohort studies that reported adjusted relative risk (RR) estimates and 95% confidence intervals (CIs) for the association between diabetes diagnosis and pancreatitis were included and summary RRs (95% CIs) were calculated using a random effects model. RESULTS: Eight cohort studies were included in the meta-analysis, and seven of these were included in the analysis of diabetes mellitus and acute pancreatitis (14124 cases, 5.7 million participants). Comparing diabetes patients with persons without diabetes the summary RRs (95% CIs) were 1.74 (95% CI: 1.33-2.29, I2 = 95%) for acute pancreatitis, 1.40 (95% CI: 0.88-2.22, I2 = 0%, n = 2) for chronic pancreatitis, and 1.39 (95% CI: 1.07-1.80, I2 = 54%, n = 3) for pancreatitis overall. Although there was some indication of publication bias in the analysis of acute pancreatitis this appeared to be explained by one outlying study which when excluded did not substantially alter the association. The results persisted in several subgroup and sensitivity analyses. CONCLUSIONS: These results suggest that diabetes patients are at an increased risk of acute pancreatitis. Further studies are needed on diabetes and risk of chronic pancreatitis, pancreatitis overall and on gallstone-related and non-gallstone-related pancreatitis.

Urinary flavanone concentrations as biomarkers of dietary flavanone intakes in the European Prospective Investigation into Cancer and Nutrition (EPIC) study.

In the present study, the aim was to investigate the correlation between the acute and habitual dietary intake of flavanones, their main food sources and the concentrations of aglycones naringenin and hesperetin in 24 h urine in a European population. A 24-h dietary recall (24-HDR) and a 24-h urine sample were collected the same day from a subsample of 475 people from four different countries of the European Prospective Investigation into Cancer and Nutrition study. Acute and habitual dietary data were captured through a standardised 24-HDR and a country/centre-specific validated dietary questionnaire (DQ). The intake of dietary flavanones was estimated using the Phenol-Explorer database. Urinary flavanones (naringenin and hesperetin) were analysed using tandem MS with a previous enzymatic hydrolysis. Weak partial correlation coefficients were found between urinary flavanone concentrations and both acute and habitual dietary flavanone intakes (Rpartial = 0·14-0·17). Partial correlations were stronger between urinary excretions and acute intakes of citrus fruit and juices (Rpartial ∼ 0·6) than with habitual intakes of citrus fruit and juices (Rpartial ∼ 0·24). In conclusion, according to our results, urinary excretion of flavanones can be considered a good biomarker of acute citrus intake. However, low associations between habitual flavanone intake and urinary excretion suggest a possible inaccurate estimation of their intake or a too sporadic intake. For assessing habitual exposures, multiple urinary collections may be needed. These results show that none of the approaches tested is ideal, and the use of both DQ and biomarkers can be recommended.

Plasma polyphenols associated with lower high-sensitivity C-reactive protein concentrations: a cross-sectional study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

Experimental studies have reported on the anti-inflammatory properties of polyphenols. However, results from epidemiological investigations have been inconsistent and especially studies using biomarkers for assessment of polyphenol intake have been scant. We aimed to characterise the association between plasma concentrations of thirty-five polyphenol compounds and low-grade systemic inflammation state as measured by high-sensitivity C-reactive protein (hsCRP). A cross-sectional data analysis was performed based on 315 participants in the European Prospective Investigation into Cancer and Nutrition cohort with available measurements of plasma polyphenols and hsCRP. In logistic regression analysis, the OR and 95 % CI of elevated serum hsCRP (>3 mg/l) were calculated within quartiles and per standard deviation higher level of plasma polyphenol concentrations. In a multivariable-adjusted model, the sum of plasma concentrations of all polyphenols measured (per standard deviation) was associated with 29 (95 % CI 50, 1) % lower odds of elevated hsCRP. In the class of flavonoids, daidzein was inversely associated with elevated hsCRP (OR 0·66, 95 % CI 0·46, 0·96). Among phenolic acids, statistically significant associations were observed for 3,5-dihydroxyphenylpropionic acid (OR 0·58, 95 % CI 0·39, 0·86), 3,4-dihydroxyphenylpropionic acid (OR 0·63, 95 % CI 0·46, 0·87), ferulic acid (OR 0·65, 95 % CI 0·44, 0·96) and caffeic acid (OR 0·69, 95 % CI 0·51, 0·93). The odds of elevated hsCRP were significantly reduced for hydroxytyrosol (OR 0·67, 95 % CI 0·48, 0·93). The present study showed that polyphenol biomarkers are associated with lower odds of elevated hsCRP. Whether diet rich in bioactive polyphenol compounds could be an effective strategy to prevent or modulate deleterious health effects of inflammation should be addressed by further well-powered longitudinal studies.

Citrus intake and risk of skin cancer in the European Prospective Investigation into Cancer and Nutrition cohort (EPIC).

Citrus intake has been suggested to increase the risk of skin cancer. Although this relation is highly plausible biologically, epidemiologic evidence is lacking. We aimed to examine the potential association between citrus intake and skin cancer risk. EPIC is an ongoing multi-center prospective cohort initiated in 1992 and involving ~ 520,000 participants who have been followed-up in 23 centers from 10 European countries. Dietary data were collected at baseline using validated country-specific dietary questionnaires. We used Cox proportional hazards regression models to compute hazard ratios (HR) and 95% confidence intervals (CI). During a mean follow-up of 13.7 years, 8448 skin cancer cases were identified among 270,112 participants. We observed a positive linear dose-response relationship between total citrus intake and skin cancer risk (HR = 1.10, 95% CI 1.03-1.18 in the highest vs. lowest quartile; Ptrend = 0.001), particularly with basal cell carcinoma (BCC) (HR = 1.11, 95% CI 1.02-1.20, Ptrend = 0.007) and squamous cell carcinoma (SCC) (HR = 1.23, 95% CI 1.04-1.47, Ptrend = 0.01). Citrus fruit intake was positively associated with skin cancer risk (HR = 1.08, 95% CI 1.01-1.16, Ptrend = 0.01), particularly with melanoma (HR = 1.23, 95% CI 1.02-1.48; Ptrend = 0.01), although with no heterogeneity across skin cancer types (Phomogeneity = 0.21). Citrus juice was positively associated with skin cancer risk (Ptrend = 0.004), particularly with BCC (Ptrend = 0.008) and SCC (Ptrend = 0.004), but not with melanoma (Phomogeneity = 0.02). Our study suggests moderate positive linear dose-response relationships between citrus intake and skin cancer risk. Studies with available biomarker data and the ability to examine sun exposure behaviors are warranted to clarify these associations and examine the phototoxicity mechanisms of furocoumarin-rich foods.