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Background: Knowledge of the evolution of BMI and skeletal muscle index (SMI) measurements during advanced cancer and their relationships with disease progression (PD) is relevant to improve the timing of interventions that may improve cachexia-associated outcomes., Objectives: We investigated BMI and SMI trajectories and their associations with PD in metastatic colorectal cancer (mCRC) patients during consecutive palliative systemic regimens., Methods: In a secondary analysis of the primary CAIRO3 trial, we included 533 mCRC patients with BMI measurements repeated every 3 wk and 95 randomly selected patients with SMI measurements repeated every 9 wk. We studied 2 periods: p1, during first-line maintenance capecitabine + bevacizumab or observation until the first progression of disease (PD1); and p2, during capecitabine + oxaliplatin + bevacizumab or another reintroduction treatment from PD1 until the second progression of disease (PD2). BMI and SMI trajectories were modeled separately throughout both periods, and joint longitudinal-survival modeling was used to investigate the relationships between slopes in BMI and SMI with PD at 9 and 3 wk pre-PD. A multivariate longitudinal joint model was used to investigate the association between the BMI trajectory and PD at time of PD, independent of SMI., Results: During p1, the slopes in BMI and SMI were associated with early PD1 [HRs for 9-wk BMI: 1.54 (95% CI: 1.33, 1.76); 9-wk SMI: 1.38 (95% CI: 0.87, 1.89), NS; 3-wk BMI: 1.74 (95% CI: 1.48, 1.99); 3-wk SMI: 2.65 (95% CI: 1.97, 3.32)]. During p2, only the slope in SMI was related to PD2 [9-wk BMI: 1.09 (95%: CI: 0.73, 1.45), NS; 9-wk SMI: 1.64 (95% CI: 1.25, 2.04); 3-wk BMI: 1.17 (95% CI: 0.77, 1.57); 3-wk SMI: 1.11 (95% CI: 0.70, 1.53)]. In models mutually adjusting for BMI and SMI, SMI was associated with PD in p1 [p1 ( n = 95), HR BMI: 1.32 (95% CI: 0.74, 2.39), NS; p1, HR SMI: 1.50 (95% CI: 1.04, 2.14); p2 ( n = 50), BMI: 0.98 (95% CI: 0.55, 1.75), NS; p2, HR SMI: 1.11 (95% CI: 0.61, 2.05), NS]., Conclusions: In mCRC patients during palliative systemic treatment, SMI losses, irrespective of BMI losses, may be a marker for the early initiation of cachexia interventions., (Copyright © American Society for Nutrition 2019.)

Objectives: The Trials within Cohorts (TwiCs) design is an alternative for pragmatic randomized controlled trials (RCTs) and might overcome disadvantages such as difficult recruitment, dropout after randomization to control, and contamination. We investigated the applicability of the TwiCs design in an exercise oncology study regarding the recruitment process, representativeness of the study sample, contamination, participation, and dropout., Methods: The Utrecht cohort for Multiple BREast cancer intervention studies and Long-term evaLuAtion (UMBRELLA) Fit TwiCs evaluates an exercise intervention in inactive breast cancer patients. Eligible patients participating in the prospective UMBRELLA were identified and randomized. Patients randomized to the intervention (n = 130) were offered the intervention, whereas controls (n = 130) were not informed., Results: Fifty-two percent (n = 68) accepted the intervention. Because this rate was lower than expected, a larger sample size was required than initially estimated (n = 166). However, recruitment of 260 patients was still completed by one researcher within 30 months. Unselective eligibility screening and randomization before invitation improved representativeness. Disadvantage of the design might be inclusion of ineligible patients when cohort information is limited. Furthermore, the design faced higher noncompliance in the intervention group, but prevention of contamination., Conclusion: The TwiCs design improved logistics in recruitment and prevented contamination, but noncompliance due to refusal of the intervention was higher compared with conventional pragmatic exercise oncology RCTs, which may dilute the estimated intervention effect., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Chronic inflammation plays a critical role in the pathogenesis of the 2 major types of gastric cancer. Several foods, nutrients, and nonnutrient food components seem to be involved in the regulation of chronic inflammation., Objective: We assessed the association between the inflammatory potential of the diet and the risk of gastric carcinoma, overall and for the 2 major subsites: cardia cancers and noncardia cancers., Design: A total of 476,160 subjects (30% men, 70% women) from the European Investigation into Cancer and Nutrition (EPIC) study were followed for 14 y, during which 913 incident cases of gastric carcinoma were identified, including 236 located in the cardia, 341 in the distal part of the stomach (noncardia), and 336 with overlapping or unknown tumor site. The dietary inflammatory potential was assessed by means of an inflammatory score of the diet (ISD), calculated with the use of 28 dietary components and their corresponding inflammatory scores. The association between the ISD and gastric cancer risk was estimated by HRs and 95% CIs calculated by multivariate Cox regression models adjusted for confounders., Results: The inflammatory potential of the diet was associated with an increased risk of gastric cancer. The HR (95% CI) for each increase in 1 SD of the ISD were 1.25 (1.12, 1.39) for all gastric cancers, 1.30 (1.06, 1.59) for cardia cancers, and 1.07 (0.89, 1.28) for noncardia cancers. The corresponding values for the highest compared with the lowest quartiles of the ISD were 1.66 (1.26, 2.20), 1.94 (1.14, 3.30), and 1.07 (0.70, 1.70), respectively., Conclusions: Our results suggest that low-grade chronic inflammation induced by the diet may be associated with gastric cancer risk. This pattern seems to be more consistent for gastric carcinomas located in the cardia than for those located in the distal stomach. This study is listed on the ISRCTN registry as ISRCTN12136108.

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., Competing Interests: Author disclosures: RZ-R, JC, SR, VC, NS, EW, KKT, M-CB-R, KO, AKE, A Tjønneland, TK, VK, HB, A Trichopoulou, CLV, AK, DP, SG, AM, RT, VS, EL, SM, ES-F, PA, JMH, AB, UE, MA, JH, MS, HBB-d-M, PHMP, K-TK, NJW, JAS, AJC, ER, AS, IR, AA, and SF, no conflicts of interest., (© 2017 American Society for Nutrition.)

Background: The consumption of sweet beverages has been associated with greater risk of type 2 diabetes and obesity, which may be involved in the development of pancreatic cancer. Therefore, it has been hypothesized that sweet beverages may increase pancreatic cancer risk as well., Objective: We examined the association between sweet-beverage consumption (including total, sugar-sweetened, and artificially sweetened soft drink and juice and nectar consumption) and pancreatic cancer risk., Design: The study was conducted within the European Prospective Investigation into Cancer and Nutrition cohort. A total of 477,199 participants (70.2% women) with a mean age of 51 y at baseline were included, and 865 exocrine pancreatic cancers were diagnosed after a median follow-up of 11.60 y (IQR: 10.10-12.60 y). Sweet-beverage consumption was assessed with the use of validated dietary questionnaires at baseline. HRs and 95% CIs were obtained with the use of multivariable Cox regression models that were stratified by age, sex, and center and adjusted for educational level, physical activity, smoking status, and alcohol consumption. Associations with total soft-drink consumption were adjusted for juice and nectar consumption and vice versa., Results: Total soft-drink consumption (HR per 100 g/d: 1.03; 95% CI: 0.99, 1.07), sugar-sweetened soft-drink consumption (HR per 100 g/d: 1.02; 95% CI: 0.97, 1.08), and artificially sweetened soft-drink consumption (HR per 100 g/d: 1.04; 95% CI: 0.98, 1.10) were not associated with pancreatic cancer risk. Juice and nectar consumption was inversely associated with pancreatic cancer risk (HR per 100 g/d: 0.91; 95% CI: 0.84, 0.99); this association remained statistically significant after adjustment for body size, type 2 diabetes, and energy intake., Conclusions: Soft-drink consumption does not seem to be associated with pancreatic cancer risk. Juice and nectar consumption might be associated with a modest decreased pancreatic cancer risk. Additional studies with specific information on juice and nectar subtypes are warranted to clarify these results., (© 2016 American Society for Nutrition.)

Background: Selenium status is suboptimal in many Europeans and may be a risk factor for the development of various cancers, including those of the liver and biliary tract., Objective: We wished to examine whether selenium status in advance of cancer onset is associated with hepatobiliary cancers in the EPIC (European Prospective Investigation into Cancer and Nutrition) study., Design: We assessed prediagnostic selenium status by measuring serum concentrations of selenium and selenoprotein P (SePP; the major circulating selenium transfer protein) and examined the association with hepatocellular carcinoma (HCC; n = 121), gallbladder and biliary tract cancers (GBTCs; n = 100), and intrahepatic bile duct cancer (IHBC; n = 40) risk in a nested case-control design within the EPIC study. Selenium was measured by total reflection X-ray fluorescence, and SePP was determined by a colorimetric sandwich ELISA. Multivariable ORs and 95% CIs were calculated by using conditional logistic regression., Results: HCC and GBTC cases, but not IHBC cases, showed significantly lower circulating selenium and SePP concentrations than their matched controls. Higher circulating selenium was associated with a significantly lower HCC risk (OR per 20-μg/L increase: 0.41; 95% CI: 0.23, 0.72) but not with the risk of GBTC or IHBC. Similarly, higher SePP concentrations were associated with lowered HCC risk only in both the categorical and continuous analyses (HCC: P-trend ≤ 0.0001; OR per 1.5-mg/L increase: 0.37; 95% CI: 0.21, 0.63)., Conclusion: These findings from a large prospective cohort provide evidence that suboptimal selenium status in Europeans may be associated with an appreciably increased risk of HCC development., (© 2016 American Society for Nutrition.)

Introduction: Serum liver biomarkers (gamma-glutamyl transferase, GGT; alanine aminotransferase, ALT; aspartate aminotransferase, AST; alkaline phosphatase, ALP; total bilirubin) are used as indicators of liver disease, but there is currently little data on their prospective association with risk of hepatobiliary cancers., Methods: A nested-case control study was conducted within the prospective EPIC cohort (>520,000 participants, 10 European countries). After a mean 7.5 mean years of follow-up, 121 hepatocellular carcinoma (HCC), 34 intrahepatic bile duct (IHBC) and 131 gallbladder and biliary tract (GBTC) cases were identified and matched to 2 controls each. Circulating biomarkers were measured in serum taken at recruitment into the cohort, prior to cancer diagnosis. Multivariable adjusted conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI)., Results: In multivariable models, 1SD increase of each log-transformed biomarker was positively associated with HCC risk (OR(GGT)=4.23, 95%CI:2.72-6.59; OR(ALP)=3.43, 95%CI:2.31-5.10;OR(AST)=3.00, 95%CI:2.04-4.42; OR(ALT)=2.69, 95%CI:1.89-3.84; OR(Bilirubin)=2.25, 95%CI:1.58-3.20). Each liver enzyme (OR(GGT)=4.98; 95%CI:1.75-14.17; OR(AST)=3.10, 95%CI:1.04-9.30; OR(ALT)=2.86, 95%CI:1.26-6.48, OR(ALP)=2.31, 95%CI:1.10-4.86) but not bilirubin (OR(Bilirubin)=1.46,95%CI:0.85-2.51) showed a significant association with IHBC. Only ALP was significantly associated with GBTC risk (OR(ALP)=1.59, 95%CI:1.20-2.09)., Conclusion: This study shows positive associations between circulating liver biomarkers in sera collected prior to cancer diagnoses and the risks of developing HCC or IHBC, but not GBTC., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: The recent literature indicates that a high vegetable intake and not a high fruit intake could be associated with decreased steroid hormone receptor-negative breast cancer risk., Objective: This study aimed to investigate the association between vegetable and fruit intake and steroid hormone receptor-defined breast cancer risk., Design: A total of 335,054 female participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were included in this study (mean ± SD age: 50.8 ± 9.8 y). Vegetable and fruit intake was measured by country-specific questionnaires filled out at recruitment between 1992 and 2000 with the use of standardized procedures. Cox proportional hazards models were stratified by age at recruitment and study center and were adjusted for breast cancer risk factors., Results: After a median follow-up of 11.5 y (IQR: 10.1-12.3 y), 10,197 incident invasive breast cancers were diagnosed [3479 estrogen and progesterone receptor positive (ER+PR+); 1021 ER and PR negative (ER-PR-)]. Compared with the lowest quintile, the highest quintile of vegetable intake was associated with a lower risk of overall breast cancer (HRquintile 5-quintile 1: 0.87; 95% CI: 0.80, 0.94). Although the inverse association was most apparent for ER-PR- breast cancer (ER-PR-: HRquintile 5-quintile 1: 0.74; 95% CI: 0.57, 0.96; P-trend = 0.03; ER+PR+: HRquintile 5-quintile 1: 0.91; 95% CI: 0.79, 1.05; P-trend = 0.14), the test for heterogeneity by hormone receptor status was not significant (P-heterogeneity = 0.09). Fruit intake was not significantly associated with total and hormone receptor-defined breast cancer risk., Conclusion: This study supports evidence that a high vegetable intake is associated with lower (mainly hormone receptor-negative) breast cancer risk., (© 2016 American Society for Nutrition.)

Background: Studies of the role of dietary factors in epithelial ovarian cancer (EOC) development have been limited, and no specific dietary factors have been consistently associated with EOC risk., Objective: We used a nutrient-wide association study approach to systematically test the association between dietary factors and invasive EOC risk while accounting for multiple hypothesis testing by using the false discovery rate and evaluated the findings in an independent cohort., Design: We assessed dietary intake amounts of 28 foods/food groups and 29 nutrients estimated by using dietary questionnaires in the EPIC (European Prospective Investigation into Cancer and Nutrition) study (n = 1095 cases). We selected 4 foods/nutrients that were statistically significantly associated with EOC risk when comparing the extreme quartiles of intake in the EPIC study (false discovery rate = 0.43) and evaluated these factors in the NLCS (Netherlands Cohort Study; n = 383 cases). Cox regression models were used to estimate HRs and 95% CIs., Results: None of the 4 dietary factors that were associated with EOC risk in the EPIC study (cholesterol, polyunsaturated and saturated fat, and bananas) were statistically significantly associated with EOC risk in the NLCS; however, in meta-analysis of the EPIC study and the NLCS, we observed a higher risk of EOC with a high than with a low intake of saturated fat (quartile 4 compared with quartile 1; overall HR: 1.21; 95% CI: 1.04, 1.41)., Conclusion: In the meta-analysis of both studies, there was a higher risk of EOC with a high than with a low intake of saturated fat., (© 2016 American Society for Nutrition.)

Background: Higher coffee intake has been purportedly related to a lower risk of liver cancer. However, it remains unclear whether this association may be accounted for by specific biological mechanisms., Objective: We aimed to evaluate the potential mediating roles of inflammatory, metabolic, liver injury, and iron metabolism biomarkers on the association between coffee intake and the primary form of liver cancer-hepatocellular carcinoma (HCC)., Design: We conducted a prospective nested case-control study within the European Prospective Investigation into Cancer and Nutrition among 125 incident HCC cases matched to 250 controls using an incidence-density sampling procedure. The association of coffee intake with HCC risk was evaluated by using multivariable-adjusted conditional logistic regression that accounted for smoking, alcohol consumption, hepatitis infection, and other established liver cancer risk factors. The mediating effects of 21 biomarkers were evaluated on the basis of percentage changes and associated 95% CIs in the estimated regression coefficients of models with and without adjustment for biomarkers individually and in combination., Results: The multivariable-adjusted RR of having ≥4 cups (600 mL) coffee/d compared with <2 cups (300 mL)/d was 0.25 (95% CI: 0.11, 0.62; P-trend = 0.006). A statistically significant attenuation of the association between coffee intake and HCC risk and thereby suspected mediation was confirmed for the inflammatory biomarker IL-6 and for the biomarkers of hepatocellular injury glutamate dehydrogenase, alanine aminotransferase, aspartate aminotransferase (AST), γ-glutamyltransferase (GGT), and total bilirubin, which-in combination-attenuated the regression coefficients by 72% (95% CI: 7%, 239%). Of the investigated biomarkers, IL-6, AST, and GGT produced the highest change in the regression coefficients: 40%, 56%, and 60%, respectively., Conclusion: These data suggest that the inverse association of coffee intake with HCC risk was partly accounted for by biomarkers of inflammation and hepatocellular injury.

Background: The higher risk of death resulting from excess adiposity may be attenuated by physical activity (PA). However, the theoretical number of deaths reduced by eliminating physical inactivity compared with overall and abdominal obesity remains unclear., Objective: We examined whether overall and abdominal adiposity modified the association between PA and all-cause mortality and estimated the population attributable fraction (PAF) and the years of life gained for these exposures., Design: This was a cohort study in 334,161 European men and women. The mean follow-up time was 12.4 y, corresponding to 4,154,915 person-years. Height, weight, and waist circumference (WC) were measured in the clinic. PA was assessed with a validated self-report instrument. The combined associations between PA, BMI, and WC with mortality were examined with Cox proportional hazards models, stratified by center and age group, and adjusted for sex, education, smoking, and alcohol intake. Center-specific PAF associated with inactivity, body mass index (BMI; in kg/m²) (>30), and WC (≥102 cm for men, ≥88 cm for women) were calculated and combined in random-effects meta-analysis. Life-tables analyses were used to estimate gains in life expectancy for the exposures., Results: Significant interactions (PA × BMI and PA × WC) were observed, so HRs were estimated within BMI and WC strata. The hazards of all-cause mortality were reduced by 16-30% in moderately inactive individuals compared with those categorized as inactive in different strata of BMI and WC. Avoiding all inactivity would theoretically reduce all-cause mortality by 7.35% (95% CI: 5.88%, 8.83%). Corresponding estimates for avoiding obesity (BMI >30) were 3.66% (95% CI: 2.30%, 5.01%). The estimates for avoiding high WC were similar to those for physical inactivity., Conclusion: The greatest reductions in mortality risk were observed between the 2 lowest activity groups across levels of general and abdominal adiposity, which suggests that efforts to encourage even small increases in activity in inactive individuals may be beneficial to public health.

Background: Previous studies suggest that elevated resting heart rate (RHR) is related to an increased risk of cancer mortality. The aim of this study was to evaluate the relation between RHR and cancer incidence and mortality in patients with vascular disease., Methods: Patients with manifest vascular disease (n=6007) were prospectively followed-up for cancer incidence and mortality. At baseline, RHR was obtained from an electrocardiogram. The relation between RHR and cancer incidence, cancer mortality and total mortality was assessed using competing risks models., Results: During a median follow-up of 6.0 years (interquartile range: 3.1-9.3) 491 patients (8%) were diagnosed with cancer and 907 (15%) patients died, 248 (27%) died from cancer. After adjustment for potential confounders, the hazard ratio (HR) for incident cancer per 10 beats/min increase in RHR was 1.00 (95% confidence interval [CI]: 0.93-1.07). There was a trend toward an increased risk of colorectal cancer in patients with higher RHR (HR 1.15, 95% CI 0.97-1.36). The risk of all-cause mortality was increased in patients in the highest quartile of RHR compared to the lowest quartile (HR 1.86, 95% CI 1.53-2.27), but no effect of RHR on cancer mortality was observed (HR 1.01, 95% CI 0.70-1.46)., Conclusions: In patients with manifest vascular disease, elevated RHR was related to a higher risk of premature all-cause mortality, but this was not due to increased cancer mortality. RHR was not related to risk of overall cancer incidence, although a relation between elevated RHR and incident colorectal cancer risk could not be ruled out., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Although diet is related to chronic disease risk and mortality, its association with total disease burden is not clear., Objective: We investigated the minimum impact of different dietary patterns on disability-adjusted life years (DALYs) by using individual longitudinal data., Design: A prospective cohort study was conducted in 33,066 healthy men and women aged 20-70 y recruited into the European Prospective Investigation into Cancer and Nutrition-Netherlands study during 1993-1997. We measured adherence to 3 a priori dietary patterns [the modified Mediterranean diet score (mMDS), the WHO-based Healthy Diet Indicator, and the Dutch Healthy Diet index] and 2 a posteriori dietary patterns. Two a posteriori methods were used to extract Western and prudent patterns. Participants were followed until the end of 2007 for the occurrence of and mortality from the most important chronic diseases. The disease burden was expressed in DALYs, which are the sum of Years Lost due to Disability and Years of Life Lost because of premature mortality. The associations between dietary patterns (per SD change in score) and DALYs were estimated by using a 2-part model and adjusted for relevant confounders (sex, age at recruitment, smoking status and intensity, educational level, marital status, job status, energy intake, and physical activity)., Results: After an average follow-up of 12.4 y, higher adherence to the mMDS or prudent pattern was most strongly associated with healthy survival; per SD higher adherence to the mMDS or prudent pattern, fewer healthy life years were lost [51 d (-0.14 DALYs; 95% CI: -0.21, -0.08 DALYs) and 58 d (-0.16 DALYs; 95% CI: -0.23, -0.09 DALYs), respectively]., Conclusion: In this Dutch study, of various dietary patterns evaluated, higher adherence to the mMDS or prudent dietary pattern was associated with a lower disease burden as assessed by DALYs., (© 2014 American Society for Nutrition.)

There are inconsistent and limited data available to assess the relationship between fat intake and risk of epithelial ovarian cancer (EOC). We examined the consumption of total fat, fat sources and fat subtypes in relation to risk of EOC and its major histologic subtypes in the European Prospective Investigation into Cancer and Nutrition which includes incident invasive (n=1095) and borderline (n=96) EOC. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). In multivariate models, we observed no association with consumption of total fat, animal or plant fat, saturated fat, cholesterol, monounsaturated fat, or fatty fish and risk of invasive EOC. There was, however, an increased risk of invasive EOC in the highest category of intake (Quartile 4 vs. Quartile 1) of polyunsaturated fat (HR=1.22, 95% CI=1.02-1.48, P(trend)=0.02). We did not observe heterogeneity in the risk associations in comparisons of serous and endometrioid histologic subtypes. This study does not support an etiological role for total fat intake in relation to EOC risk; however, based on observations of a positive association between intake of polyunsaturated fat and invasive EOC risk in the current and previous studies, this fat subtype warrants further investigation to determine its potential role in EOC development., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Principal component analysis (PCA) and cluster analysis are used frequently to derive dietary patterns. Decisions on how many patterns to extract are primarily based on subjective criteria, whereas different solutions vary in their food-group composition and perhaps association with disease outcome. Literature on reliability of dietary patterns is scarce, and previous studies validated only 1 preselected solution. Therefore, we assessed reliability of different pattern solutions ranging from 2 to 6 patterns, derived from the aforementioned methods. A validated food frequency questionnaire was administered at baseline (1993-1997) to 39,678 participants in the European Prospective Investigation into Cancer and Nutrition-The Netherlands (EPIC-NL) cohort. Food items were grouped into 31 food groups for dietary pattern analysis. The cohort was randomly divided into 2 halves, and dietary pattern solutions derived in 1 sample through PCA were replicated through confirmatory factor analysis in sample 2. For cluster analysis, cluster stability and split-half reproducibility were assessed for various solutions. With PCA, we found the 3-component solution to be best replicated, although all solutions contained ≥1 poorly confirmed component. No quantitative criterion was in agreement with the results. Associations with disease outcome (coronary heart disease) differed between the component solutions. For all cluster solutions, stability was excellent and deviations between samples was negligible, indicating good reproducibility. All quantitative criteria identified the 2-cluster solution as optimal. Associations with disease outcome were comparable for different cluster solutions. In conclusion, reliability of obtained dietary patterns differed considerably for different solutions using PCA, whereas cluster analysis derived generally stable, reproducible clusters across different solutions. Quantitative criteria for determining the number of patterns to retain were valuable for cluster analysis but not for PCA. Associations with disease risk were influenced by the number of patterns that are retained, especially when using PCA. Therefore, studies on associations between dietary patterns and disease risk should report reasons to choose the number of retained patterns., (© 2014 American Society for Nutrition.)

It has been suggested that mitochondrial dysfunction and DNA damage are involved in lymphomagenesis. Increased copy number of mitochondrial DNA (mtDNA) as a compensatory mechanism of mitochondrial dysfunction previously has been associated with B-cell lymphomas, in particular chronic lymphocytic leukemia (CLL). However, current evidence is limited and based on a relatively small number of cases. Using a nested case-control study, we extended these findings with a focus on subtype-specific analyses. Relative mtDNA copy number was measured in the buffy coat of prospectively collected blood of 469 lymphoma cases and 469 matched controls. The association between mtDNA copy number and the risk of developing lymphoma and histologic subtypes was examined using logistic regression models. We found no overall association between mtDNA and risk of lymphoma. Subtype analyses revealed significant increased risks of CLL (n = 102) with increasing mtDNA copy number (odds ratio = 1.34, 1.44, and 1.80 for quartiles 2-4, respectively; P trend = .001). mtDNA copy number was not associated with follow-up time, suggesting that this observation is not strongly influenced by indolent disease status. This study substantially strengthens the evidence that mtDNA copy number is related to risk of CLL and supports the importance of mitochondrial dysfunction as a possible mechanistic pathway in CLL ontogenesis.

Background: Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants., Methods: We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 μm (PM2.5), less than 10 μm (PM10), and between 10 μm and 2.5 μm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis., Findings: The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 μg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 μg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 μg/m(3) (1.07, 1.01-1.13)., Interpretation: Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value., Funding: European Community's Seventh Framework Program (FP7/2007-2011)., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: A moderate association exists between body mass index (BMI) and colorectal cancer. Less is known about the effect of weight change., Objective: We investigated the relation between BMI and weight change and subsequent colon and rectal cancer risk., Design: This was studied among 328,781 participants in the prospective European Prospective Investigation into Cancer-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating study (mean age: 50 y). Body weight was assessed at recruitment and on average 5 y later. Self-reported weight change (kg/y) was categorized in sex-specific quintiles, with quintiles 2 and 3 combined as the reference category (men: -0.6 to 0.3 kg/y; women: -0.4 to 0.4 kg/y). In the subsequent years, participants were followed for the occurrence of colon and rectal cancer (median period: 6.8 y). Multivariable Cox proportional hazards regression analyses were used to study the association., Results: A total of 1261 incident colon cancer and 747 rectal cancer cases were identified. BMI at recruitment was statistically significantly associated with colon cancer risk in men (HR: 1.04; 95% CI: 1.02, 1.07). Moderate weight gain (quintile 4) in men increased risk further (HR: 1.32; 95% CI: 1.04, 1.68), but this relation did not show a clear trend. In women, BMI or weight gain was not related to subsequent risk of colon cancer. No statistically significant associations for weight loss and colon cancer or for BMI and weight changes and rectal cancer were found., Conclusions: BMI attained at adulthood was associated with colon cancer risk. Subsequent weight gain or loss was not related to colon or rectal cancer risk in men or women.

Background: The relation between vitamin D status and lymphoma risk is inconclusive., Objective: We examined the association between prediagnostic plasma 25-hydroxyvitamin D [25(OH)D] and lymphoid cancer risk., Design: We conducted a study nested within the European Prospective Investigation into Cancer and Nutrition cohort of 1127 lymphoma cases and 1127 matched controls with a mean follow-up time of 7.1 y. Conditional logistic regression was used to estimate multivariable-adjusted incidence rate ratios of lymphoma risk in relation to plasma 25(OH)D. Season-standardized and season-specific 25(OH)D quartiles were used. We also analyzed 25(OH)D as a continuous variable and used predefined cutoffs., Results: No statistically significant association between plasma 25(OH)D and overall lymphoid cancer risk was observed. A positive association for B-cell non-Hodgkin lymphoma was noted only in those with a diagnosis made during the first 2 y of follow-up (P-heterogeneity = 0.03), which suggests the possibility of reverse causality. Further analysis restricted to participants with ≥2 y of follow-up time showed a significant association between 25(OH)D and chronic lymphocytic leukemia (CLL) (n = 161): adjusted incidence rate ratios were 0.40 (95% CI: 0.18, 0.90; P-trend = 0.05) and 0.31 (95% CI: 0.13, 0.76; P-trend = 0.03) for the top compared with the bottom season-standardized and season-specific quartiles, respectively. Data on dietary vitamin D intake provided further support for the observed association (incidence rate ratio: 0.33; 95% CI = 0.12, 0.89; P-trend = 0.006)., Conclusions: Our findings do not support a protective role of high 25(OH)D concentration in lymphoid cancers overall. However, they suggest that higher concentrations of 25(OH)D are associated with a reduced risk of CLL.

Background: In 2007, the World Cancer Research Fund (WCRF) and the American Institute for Cancer Research (AICR) issued recommendations on diet, physical activity, and weight management for cancer prevention on the basis of the most comprehensive collection of available evidence., Objective: We investigated whether concordance with WCRF/AICR recommendations is related to risk of death., Design: The current study included 378,864 participants from 9 European countries enrolled in the European Prospective Investigation into Cancer and Nutrition study. At recruitment (1992-1998), dietary, anthropometric, and lifestyle information was collected. A WCRF/AICR score, which incorporated 6 of the WCRF/AICR recommendations for men [regarding body fatness, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, and alcoholic drinks (score range: 0-6)] and 7 WCRF/AICR recommendations for women [plus breastfeeding (score range: 0-7)], was constructed. Higher scores indicated greater concordance with WCRF/AICR recommendations. Associations between the WCRF/AICR score and risks of total and cause-specific death were estimated by using Cox regression analysis., Results: After a median follow-up time of 12.8 y, 23,828 deaths were identified. Participants within the highest category of the WCRF/AICR score (5-6 points in men; 6-7 points in women) had a 34% lower hazard of death (95% CI: 0.59, 0.75) compared with participants within the lowest category of the WCRF/AICR score (0-2 points in men; 0-3 points in women). Significant inverse associations were observed in all countries. The WCRF/AICR score was also significantly associated with a lower hazard of dying from cancer, circulatory disease, and respiratory disease., Conclusion: Results of this study suggest that following WCRF/AICR recommendations could significantly increase longevity.

Purpose: Alcohol intake may adversely affect the concentrations of endogenous sex hormones, and thus increase the risk of endometrial cancer. However, epidemiologic studies have provided conflicting results. Therefore, we investigated the association between alcohol intake and endometrial cancer risk a large, multicenter, prospective study., Methods: From 1992 through 2010, 301,051 women in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort were followed for incident endometrial cancer (n = 1382). Baseline alcohol consumption was assessed by country-specific, validated dietary questionnaires. Information on past alcohol consumption was collected by lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated from Cox proportional hazard models., Results: The multivariable HRs (and 95% CIs) compared with light drinkers (0.1-6 g/d) were 1.03 (0.88-1.20) for 0 g of alcohol per day at baseline, 1.01 (0.86-1.17) for 6.1-12 g/d, 1.03 (0.87-1.22) for 12.1-24 g/d, 1.07 (0.87-1.38) for 24.1-36 g/d, and 0.85 (0.61-1.18) for more than 36 g/d (p(trend) = 0.77). No association was observed among former drinkers (OR, 1.28; 95% CI, 0.98-1.68 compared with light drinkers). Null associations were also found between alcohol consumption at age 20 years, lifetime pattern of alcohol drinking, and baseline alcohol intake from specific alcoholic beverages and endometrial cancer risk., Conclusions: Our findings suggest no association between alcohol intake and endometrial cancer risk., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Several experimental studies have suggested potential anticarcinogenic effects of flavonoids, although epidemiologic evidence for the impact of dietary flavonoids on risk of gastric cancer (GC) is limited., Objective: We investigated the association between intake of dietary flavonoids and lignans and incident GC., Design: The study followed 477,312 subjects (29.8% men) aged 35-70 y from 10 European countries who participated in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Validated dietary questionnaires and lifestyle information were collected at baseline. A food-composition database on flavonoids and lignans was compiled by using data from USDA and Phenol-Explorer databases., Results: During an average follow-up of 11 y, 683 incident GC cases (57.8% men) were mostly validated by a panel of pathologists and used in this analysis. We observed a significant inverse association between total flavonoid intake and GC risk in women (HR: 0.81; 95% CI: 0.70, 0.94; for the continuous variable after log₂ transformation) but not in men (HR: 0.97; 95% CI: 0.85, 1.09). In women, significant inverse associations with GC risk were also observed for intakes of some flavonoid subgroups (anthocyanidins, flavonols, flavones, and flavanols), particularly with intestinal type tumors for total flavonoid and flavanol intakes (P-heterogeneity < 0.1). After stratification by smoking status and sex, there was no significant heterogeneity in these associations between ever- and never-smokers., Conclusion: Total dietary flavonoid intake is associated with a significant reduction in the risk of GC in women.

Background: Published associations between dietary carotenoids and vitamin C and bladder cancer risk are inconsistent. Biomarkers may provide more accurate measures of nutrient status., Objective: We investigated the association between plasma carotenoids and vitamin C and risk of urothelial cell carcinoma (UCC) in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition., Design: A total of 856 patients with newly diagnosed UCC were matched with 856 cohort members by sex, age at baseline, study center, date and time of blood collection, and fasting status. Plasma carotenoids (α- and β-carotene, β-cryptoxanthin, lycopene, lutein, and zeaxanthin) were measured by using reverse-phase HPLC, and plasma vitamin C was measured by using a colorimetric assay. Incidence rate ratios (IRRs) were estimated by using conditional logistic regression with adjustment for smoking status, duration, and intensity., Results: UCC risk decreased with higher concentrations of the sum of plasma carotenoids (IRR for the highest compared with the lowest quartile: 0.64; 95% CI: 0.44, 0.93; P-trend = 0.04). Plasma β-carotene was inversely associated with aggressive UCC (IRR: 0.51; 95% CI: 0.30, 0.88; P-trend = 0.02). Plasma lutein was inversely associated with risk of nonaggressive UCC (IRR: 0.56; 95% CI: 0.32, 0.98; P-trend = 0.05). No association was observed between plasma vitamin C and risk of UCC., Conclusions: Although residual confounding by smoking or other factors cannot be excluded, higher concentrations of plasma carotenoids may reduce risk of UCC, in particular aggressive UCC. Plasma lutein may reduce risk of nonaggressive UCC.

Background: The glycemic potential of a diet is associated with chronically elevated insulin concentrations, which may augment breast cancer (BC) risk by stimulating insulin receptor or by affecting insulin-like growth factor I (IGF-I)-mediated mitogenesis. It is unclear whether this effect differs by BC phenotype., Objective: The objective was to investigate the relation between glycemic index (GI), glycemic load (GL), and total carbohydrate intake with BC by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC)., Design: We identified 11,576 women with invasive BC among 334,849 EPIC women aged 34-66 y (5th to 95th percentiles) at baseline over a median follow-up of 11.5 y. Dietary GI and GL were calculated from country-specific dietary questionnaires. We used multivariable Cox proportional hazards models to quantify the association between GI, GL, and carbohydrate intake and BC risk. BC tumors were classified by receptor status., Results: Overall GI, GL, and carbohydrates were not related to BC. Among postmenopausal women, GL and carbohydate intake were significantly associated with an increased risk of estrogen receptor-negative (ER(-)) BC when extreme quintiles (Q) were compared [multivariable HR(Q5-Q1) (95% CI) = 1.36 (1.02, 1.82; P-trend = 0.010) and HR(Q5-Q1) = 1.41 (1.05, 1.89; P-trend = 0.009), respectively]. Further stratification by progesterone receptor (PR) status showed slightly stronger associations with ER(-)/PR(-) BC [HR(Q5-Q1) (95% CI) = 1.48 (1.07, 2.05; P-trend = 0.010) for GL and HR(Q5-Q1) = 1.62 (1.15, 2.30; P-trend = 0.005) for carbohydrates]. No significant association with ER-positive BC was observed., Conclusion: Our results indicate that a diet with a high GL and carbohydrate intake is positively associated with an increased risk of developing ER(-) and ER(-)/PR(-) BC among postmenopausal women.

Background: Previous studies have shown that high fiber intake is associated with lower mortality. However, little is known about the association of dietary fiber with specific causes of death other than cardiovascular disease (CVD)., Objective: The aim of this study was to assess the relation between fiber intake, mortality, and cause-specific mortality in a large European prospective study of 452,717 men and women., Design: HRs and 95% CIs were estimated by using Cox proportional hazards models, stratified by age, sex, and center and adjusted for education, smoking, alcohol consumption, BMI, physical activity, total energy intake, and, in women, ever use of menopausal hormone therapy., Results: During a mean follow-up of 12.7 y, a total of 23,582 deaths were recorded. Fiber intake was inversely associated with total mortality (HR(per 10-g/d increase): 0.90; 95% CI: 0.88, 0.92); with mortality from circulatory (HR(per 10-g/d increase): 0.90 and 0.88 for men and women, respectively), digestive (HR: 0.61 and 0.64), respiratory (HR: 0.77 and 0.62), and non-CVD noncancer inflammatory (HR: 0.85 and 0.80) diseases; and with smoking-related cancers (HR: 0.86 and 0.89) but not with non-smoking-related cancers (HR: 1.05 and 0.97). The associations were more evident for fiber from cereals and vegetables than from fruit. The associations were similar across BMI and physical activity categories but were stronger in smokers and participants who consumed >18 g alcohol/d., Conclusions: Higher fiber intake is associated with lower mortality, particularly from circulatory, digestive, and non-CVD noncancer inflammatory diseases. Our results support current recommendations of high dietary fiber intake for health maintenance.

Background: In 2007 the World Cancer Research Fund (WCRF) and the American Institute of Cancer Research (AICR) issued 8 recommendations (plus 2 special recommendations) on diet, physical activity, and weight management for cancer prevention on the basis of the most comprehensive collection of available evidence., Objective: We aimed to investigate whether concordance with the WCRF/AICR recommendations was related to cancer risk in the European Prospective Investigation into Cancer and Nutrition (EPIC) study., Design: The present study included 386,355 EPIC participants from 9 European countries. At recruitment, dietary, anthropometric, and lifestyle information was collected. A score was constructed based on the WCRF/AICR recommendations on weight management, physical activity, foods and drinks that promote weight gain, plant foods, animal foods, alcoholic drinks, and breastfeeding for women; the score range was 0-6 for men and 0-7 for women. Higher scores indicated greater concordance with WCRF/AICR recommendations. The association between the score and cancer risk was estimated by using multivariable Cox regression models., Results: Concordance with the score was significantly associated with decreased risk of cancer. A 1-point increment in the score was associated with a risk reduction of 5% (95% CI: 3%, 7%) for total cancer, 12% (95% CI: 9%, 16%) for colorectal cancer, and 16% (95% CI: 9%, 22%) for stomach cancer. Significant associations were also observed for cancers of the breast, endometrium, lung, kidney, upper aerodigestive tract, liver, and esophagus but not for prostate, ovarian, pancreatic, and bladder cancers., Conclusion: Adherence to the WCRF/AICR recommendations for cancer prevention may lower the risk of developing most types of cancer.

Background: In 2007 the World Cancer Research Fund Report concluded that there was limited and inconsistent evidence for an effect of coffee and tea consumption on the risk of epithelial ovarian cancer (EOC)., Objective: In the European Prospective Investigation into Cancer and Nutrition (EPIC), we aimed to investigate whether coffee intakes, tea intakes, or both are associated with the risk of EOC., Design: All women participating in the EPIC (n = 330,849) were included in this study. Data on coffee and tea consumption were collected through validated food-frequency questionnaires at baseline. HRs and 95% CIs were estimated by using Cox proportional hazards models. Furthermore, we performed an updated meta-analysis of all previous prospective studies until April 2011 by comparing the highest and lowest coffee- and tea-consumption categories as well as by using dose-response random-effects meta-regression analyses., Results: During a median follow-up of 11.7 y, 1244 women developed EOC. No association was observed between the risk of EOC and coffee consumption [HR: 1.05 (95% CI: 0.75, 1.46) for the top quintile compared with no intake] or tea consumption [HR: 1.07 (95% CI: 0.78, 1.45) for the top quintile compared with no intake]. This lack of association between coffee and tea intake and EOC risk was confirmed by the results of our meta-analysis., Conclusion: Epidemiologic studies do not provide sufficient evidence to support an association between coffee and tea consumption and risk of ovarian cancer.

Objective: Assessing effects of lifestyle interventions in cancer patients has some specific challenges. Although randomization is urgently needed for evidence-based knowledge, sometimes it is difficult to apply conventional randomization (i.e., consent preceding randomization and intervention) in daily settings. Randomization before seeking consent was proposed by Zelen, and additional modifications were proposed since. We discuss four alternatives for conventional randomization: single and double randomized consent design, two-stage randomized consent design, and the design with consent to postponed information., Study Design and Setting: We considered these designs when designing a study to assess the impact of physical activity on cancer-related fatigue and quality of life. We tested the modified Zelen design with consent to postponed information in a pilot. The design was chosen to prevent drop out of participants in the control group because of disappointment about the allocation., Results: The result was a low overall participation rate most likely because of perceived lack of information by eligible patients and a relatively high dropout in the intervention group., Conclusion: We conclude that the alternatives were not better than conventional randomization., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Fruit and vegetable consumption might prevent weight gain through their low energy density and high dietary fiber content., Objective: We assessed the association between the baseline consumption of fruit and vegetables and weight change in participants from 10 European countries participating in the European Prospective Investigation into Cancer and Nutrition study., Design: Diet was assessed at baseline in 373,803 participants by using country-specific validated questionnaires. Weight was measured at baseline and self-reported at follow-up in most centers. Associations between baseline fruit and vegetable intakes (per 100 g/d) and weight change (g/y) after a mean follow-up of 5 y were assessed by using linear mixed-models, with age, sex, total energy intake, and other potential confounders controlled for., Results: After exclusion of subjects with chronic diseases at baseline and subjects who were likely to misreport energy intakes, baseline fruit and vegetable intakes were not associated with weight change overall. However, baseline fruit and vegetable intakes were inversely associated with weight change in men and women who quit smoking during follow-up. We observed weak positive associations between vegetable intake and weight change in women who were overweight, were former smokers, or had high prudent dietary pattern scores and weak inverse associations between fruit intake and weight change in women who were >50 y of age, were of normal weight, were never smokers, or had low prudent dietary pattern scores., Conclusions: In this large study, higher baseline fruit and vegetable intakes, while maintaining total energy intakes constant, did not substantially influence midterm weight change overall but could help to reduce risk of weight gain in persons who stop smoking. The interactions observed in women deserve additional attention.

Background: Gastric cancer (GC) is the second leading cause of cancer death worldwide. The association between alcohol consumption and GC has been investigated in numerous epidemiologic studies with inconsistent results., Objective: We evaluated the association between alcohol consumption and GC risk., Design: We conducted a prospective analysis in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, which included 444 cases of first primary gastric adenocarcinoma. HRs and 95% CIs for GC were estimated by using multivariable Cox proportional hazards regression for consumption of pure ethanol in grams per day, with stratification by smoking status, anatomic subsite (cardia, noncardia), and histologic subtype (diffuse, intestinal). In a subset of participants, results were further adjusted for baseline Helicobacter pylori serostatus., Results: Heavy (compared with very light) alcohol consumption (≥60 compared with 0.1-4.9 g/d) at baseline was positively associated with GC risk (HR: 1.65; 95% CI: 1.06, 2.58), whereas lower consumption amounts (<60 g/d) were not. When we analyzed GC risk by type of alcoholic beverage, there was a positive association for beer (≥30 g/d; HR: 1.75; 95% CI: 1.13, 2.73) but not for wine or liquor. Associations were primarily observed at the highest amounts of drinking in men and limited to noncardia subsite and intestinal histology; no statistically significant linear dose-response trends with GC risk were observed., Conclusion: Heavy (but not light or moderate) consumption of alcohol at baseline (mainly from beer) is associated with intestinal-type noncardia GC risk in men from the EPIC cohort.

Background: Epidemiologic data suggest that diet is a risk factor in the etiology of gastric cancer. However, the role of dietary fatty acids, a modifiable risk factor, remains relatively unexplored., Objective: The objective of this study was to determine the association of plasma phospholipid fatty acid concentrations, as biomarkers of exogenous and endogenously derived fatty acids, with the risk of gastric adenocarcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition-Europe Gastric Cancer (EPIC-EURGAST)., Design: Fatty acids were measured by gas chromatography in prediagnostic plasma phospholipids from 238 cases matched to 626 controls by age, sex, study center, and date of blood donation. Conditional logistic regression models adjusted for Helicobacter pylori infection status, BMI, smoking, physical activity, education, and energy intake were used to estimate relative cancer risks., Results: Positive risk associations for gastric cancer were observed in the highest compared with the lowest quartiles of plasma oleic acid (OR: 1.72; 95% CI: 1.01, 2.94), di-homo-γ-linolenic acid (OR: 1.92; 95% CI: 1.10, 3.35), α-linolenic acid (OR: 3.20; 95% CI: 1.70, 6.06), and the ratio of MUFAs to saturated fatty acids, as an indicator of stearoyl-CoA desaturase-1 enzyme activity (OR: 1.40; 95% CI: 0.81, 2.43). An inverse risk association was observed with the ratio of linoleic to α-linolenic acid (OR: 0.37; 95% CI: 0.20, 0.66)., Conclusion: These data suggest that a specific prediagnostic plasma phospholipid fatty acid profile, characterized mainly by high concentrations of oleic acid, α-linolenic acid, and di-homo-γ-linolenic acid, which presumably reflect both a complex dietary pattern and altered fatty acid metabolism, may be related to increased gastric cancer risk.

Background: The protective effect of physical activity (PA) on abdominal adiposity is unclear., Objective: We examined whether PA independently predicted gains in body weight and abdominal adiposity., Design: In a prospective cohort study [the EPIC (European Prospective Investigation into Cancer and Nutrition)], we followed 84,511 men and 203,987 women for 5.1 y. PA was assessed by a validated questionnaire, and individuals were categorized into 4 groups (inactive, moderately inactive, moderately active, and active). Body weight and waist circumference were measured at baseline and self-reported at follow-up. We used multilevel mixed-effects linear regression models and stratified our analyses by sex with adjustments for age, smoking status, alcohol consumption, educational level, total energy intake, duration of follow-up, baseline body weight, change in body weight, and waist circumference (when applicable)., Results: PA significantly predicted a lower waist circumference (in cm) in men (β = -0.045; 95% CI: -0.057, -0.034) and in women (β = -0.035; 95% CI: -0.056, -0.015) independent of baseline body weight, baseline waist circumference, and other confounding factors. The magnitude of associations was materially unchanged after adjustment for change in body weight. PA was not significantly associated with annual weight gain (in kg) in men (β = -0.008; 95% CI: -0.02, 0.003) and women (β = -0.01; 95% CI: -0.02, 0.0006). The odds of becoming obese were reduced by 7% (P < 0.001) and 10% (P < 0.001) for a one-category difference in baseline PA in men and women, respectively., Conclusion: Our results suggest that a higher level of PA reduces abdominal adiposity independent of baseline and changes in body weight and is thus a useful strategy for preventing chronic diseases and premature deaths.

Introduction: Hip fractures constitute a major and growing public health problem amongst the elderly worldwide. We examined the association of anthropometry and physical activity with hip fracture incidence in a cohort of elderly Europeans, participants in the European Prospective Investigation into Cancer and nutrition (EPIC) study., Materials and Methods: The study population consisted of 27 982 volunteers (10 553 men and 17 429 women) aged 60 years and above from five European countries. Information on anthropometry, physical activity, medical history and other characteristics was collected at baseline. During a median follow-up of 8 years, 261 incident hip fractures (203 women and 58 men) were recorded. Data were analysed through Cox proportional hazard regression with adjustment for potential confounders., Results: A higher body mass index (BMI) was associated with lower hip fracture risk (hazard ratio (HR)per increasing sex-specific-quintile: 0.85, 95% confidence interval (95% CI): 0.77–0.94). Body height was associated with increased hip fracture risk (HR per 5 cm: 1.13, 95% CI: 1.01–1.25). Waist-to-hip ratio was not related to hip fracture risk. Increasing levels of leisure-time physical activity were related to lower risk (HR per increasing tertile: 0.84, 95% CI: 0.70–0.99, p for trend: 0.039)., Conclusions: In a prospective cohort study of elderly Europeans, we found evidence that high body stature increased and high BMI decreased the incidence of hip fractures. After adjustment for BMI,waist to-hip ratio was not associated with hip fracture risk. Leisure-time physical activity appears to play a beneficial role in the prevention of hip fractures., (2010 Elsevier Ltd. All rights reserved.)

Introduction: Until now, studies examining the relationship between socioeconomic status and pancreatic cancer incidence have been inconclusive., Aim: To prospectively investigate to what extent pancreatic cancer incidence varies according to educational level within the European Prospective Investigation into Cancer and Nutrition (EPIC) study., Methods: In the EPIC study, socioeconomic status at baseline was measured using the highest level of education attained. Hazard ratios by educational level and a summary index, the relative indices of inequality (RII), were estimated using Cox regression models stratified by age, gender, and center and adjusted for known risk factors. In addition, we conducted separate analyses by age, gender and geographical region., Results: Within the source population of 407, 944 individuals at baseline, 490 first incident primary pancreatic adenocarcinoma cases were identified in 9 European countries. The crude difference in risk of pancreatic cancer according to level of education was small and not statistically significant (RII=1.14, 95% CI 0.80-1.62). Adjustment for known risk factors reduced the inequality estimates to only a small extent. In addition, no statistically significant associations were observed for age groups (adjusted RII(≤ 60 years)=0.85, 95% CI 0.44-1.64, adjusted RII(>60 years)=1.18, 95% CI 0.73-1.90), gender (adjusted RII(male)=1.20, 95% CI 0.68-2.10, adjusted RII(female)=0.96, 95% CI 0.56-1.62) or geographical region (adjusted RII(Northern Europe)=1.14, 95% CI 0.81-1.61, adjusted RII(Middle Europe)=1.72, 95% CI 0.93-3.19, adjusted RII(Southern Europe)=0.75, 95% CI 0.32-1.80)., Conclusion: Despite large educational inequalities in many risk factors within the EPIC study, we found no evidence for an association between educational level and the risk of developing pancreatic cancer in this European cohort., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Background: In a recent US cohort study, total coffee and tea consumption was inversely associated with risk of glioma, and experimental studies showed that caffeine can slow the invasive growth of glioblastoma., Objective: The objective was to examine the relation between coffee and tea intake and the risk of glioma and meningioma in a large European cohort study, the European Prospective Investigation into Cancer and Nutrition (EPIC)., Design: Data on coffee and tea intake were collected from men and women recruited into the EPIC cohort study. Over an average of 8.5 y of follow-up, 343 cases of glioma and 245 cases of meningioma were newly diagnosed in 9 countries. We used Cox proportional hazards models to examine the relation between coffee and tea and brain tumors., Results: We observed no associations between coffee, tea, or combined coffee and tea consumption and risk of either type of brain tumor when using quantiles based on country-specific distributions of intake. However, a significant inverse association was observed for glioma risk among those consuming ≥100 mL coffee and tea per day compared with those consuming <100 mL/d (hazard ratio: 0.66; 95% CI: 0.44, 0.97; P = 0.03). The association was slightly stronger in men (hazard ratio: 0.59; 95% CI: 0.34, 1.01) than in women (hazard ratio: 0.74; 95% CI: 0.42, 1.31), although neither was statistically significant., Conclusions: In this large cohort study, we observed an inverse association between total coffee and tea consumption and risk of glioma that was consistent with the findings of a recent study. These findings, if further replicated in other studies, may provide new avenues of research on gliomas.

Background: Obesity is related to many adverse health-related outcomes., Objective: We investigated whether changes in physical activity were related to less gain in either body weight or waist circumference (WC)., Design: The association between prospectively assessed physical activity and either body weight or WC was examined in 4944 participants of the Doetinchem Study (men and women aged between 26 and 66 y at baseline). Information on physical activity (derived from a validated physical activity index), body weight, and WC, measured according to standardized procedures, was collected at baseline and at the 5- and 10-y follow-ups., Results: Random mixed-effects models showed that a single measurement of physical activity was not clearly related to change in body weight and WC over a 5-y period. However, analyses of repeated measures showed that compared with those who maintained their activity level, those who increased their physical activity over a 5-y period had less gain in WC ( minus 0.35 cm; 95% CI: minus 0.65, minus 0.05 cm) and possibly in body weight ( minus 280 g; 95% CI: minus 620, 5 g). Most importantly, these effects were sustained (although not significantly) in the consecutive 5 y for WC ( minus 0.56 cm; 95% CI: minus 108, 0.04 cm) and for body weight ( minus 590 g; 95% CI: minus 1005, minus 130 g), which indicated that physical activity was truly a determinant of body size changes., Conclusions: An increase in physical activity was associated with a statistically significant lower gain in body weight and in WC, which was maintained during the following 5 y. These findings support the need for public health programs that promote physical activity.

Background: Meat intake may be related to weight gain because of its high energy and fat content. Some observational studies have shown that meat consumption is positively associated with weight gain, but intervention studies have shown mixed results., Objective: Our objective was to assess the association between consumption of total meat, red meat, poultry, and processed meat and weight gain after 5 y of follow-up, on average, in the large European population who participated in the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of Smoking, Eating Out of Home and Obesity (EPIC-PANACEA) project., Design: A total of 103,455 men and 270,348 women aged 25-70 y were recruited between 1992 and 2000 in 10 European countries. Diet was assessed at baseline with the use of country-specific validated questionnaires. A dietary calibration study was conducted in a representative subsample of the cohort. Weight and height were measured at baseline and self-reported at follow-up in most centers. Associations between energy from meat (kcal/d) and annual weight change (g/y) were assessed with the use of linear mixed models, controlled for age, sex, total energy intake, physical activity, dietary patterns, and other potential confounders., Results: Total meat consumption was positively associated with weight gain in men and women, in normal-weight and overweight subjects, and in smokers and nonsmokers. With adjustment for estimated energy intake, an increase in meat intake of 250 g/d (eg, one steak at approximately 450 kcal) would lead to a 2-kg higher weight gain after 5 y (95% CI: 1.5, 2.7 kg). Positive associations were observed for red meat, poultry, and processed meat., Conclusion: Our results suggest that a decrease in meat consumption may improve weight management.

Objective: In lifestyle intervention trials, participants of the control group often change their behavior despite the request to maintain their usual lifestyle pattern. These changes in the control group and changes in addition to the intended in the intervention group can lead to undesirable confounding effects., Study Design and Setting: We address several considerations for study design to prevent noncompliance or minimize its effects. Furthermore, we demonstrate how the instrumental variable method can give insight into the extent of bias introduced by noncompliance in randomized trials, within the context of the Sex Hormones and Physical Exercise study., Results: Noncompliance can be prevented by measures taken in the design phase of a study, for example, limited duration of the study, clear recommendations, power calculation, intensity of the intervention, involvement of the control group, waiting-list control group, and single-consent design nested within an observational study. When nevertheless noncompliance does occur, the instrumental variable method estimates the intervention effect of treatment among the compliers., Conclusion: Noncompliance can seriously affect validity of lifestyle trial results. Its occurrence should be prevented by taking measures during the design phase of a study. The instrumental variable method can give insight into confounding by noncompliance in randomized trials., (Copyright (c) 2010 Elsevier Inc. All rights reserved.)

Objective: To investigate whether Escherichia coli bacteriuria is associated with the development of hypertension during a long-term follow-up., Methods: A prospective cohort study was performed among the participants of two population-based studies. Between 1974 and 1986 all women aged 39 to 68 years old, who lived in Utrecht, the Netherlands, were invited to participate in a breast cancer screening program. The participants completed a questionnaire, underwent a medical examination, and collected a morning urine sample that remained stored. From 1993 to 1997 another population-based study was performed. We performed a full cohort analysis for 444 women who participated in both studies. E. coli bacteriuria was diagnosed by a real-time PCR. Hypertension was defined as the use of antihypertensive medication and/or a measured systolic blood pressure of at least 160 mmHg or a diastolic blood pressure of 95 mmHg or higher. The mean follow-up was 11.5+/-1.7 years., Results: Forty women (9%) had E. coli bacteriuria at baseline. Women who had bacteriuria at baseline had a mean blood pressure at study endpoint of 133+/-20 mmHg systolic and 78+/-11 mmHg diastolic, and women without bacteriuria had values of 129+/-20 and 78+/-11 mmHg, respectively (p-values for difference 0.33 and 0.88). Although E. coli bacteriuria was not associated with the blood pressure as a continuous variable, it was associated with the development of hypertension during follow-up (OR 2.8, 95% CI 1.4-5.5)., Conclusion: E. coli bacteriuria may increase the risk of future hypertension.

Background: The Mediterranean dietary pattern is believed to protect against cancer, although evidence from cohort studies that have examined particular cancer sites is limited., Objective: We aimed to explore the association between adherence to a relative Mediterranean diet (rMED) and incident gastric adenocarcinoma (GC) within the European Prospective Investigation into Cancer and Nutrition study., Design: The study included 485,044 subjects (144,577 men) aged 35-70 y from 10 European countries. At recruitment, dietary and lifestyle information was collected. An 18-unit rMED score, incorporating 9 key components of the Mediterranean diet, was used to estimate rMED adherence. The association between rMED and GC with respect to anatomic location (cardia and noncardia) and histologic types (diffuse and intestinal) was investigated. A calibration study in a subsample was used to control for dietary measurement error., Results: After a mean follow-up of 8.9 y, 449 validated incident GC cases were identified and used in the analysis. After stratification by center and age and adjustment for recognized cancer risk factors, high compared with low rMED adherence was associated with a significant reduction in GC risk (hazard ratio: 0.67; 95% CI: 0.47, 0.94). A 1-unit increase in the rMED score was associated with a decreased risk of GC of 5% (95% CI: 0.91, 0.99). There was no evidence of heterogeneity between different anatomic locations or histologic types. The calibrated results showed similar trends (overall hazard ratio for GC: 0.93; 95% CI: 0.89, 0.99)., Conclusion: Greater adherence to an rMED is associated with a significant reduction in the risk of incident GC.

Given the lack of consistent evidence of the relationship between Mediterranean dietary patterns and body fat, we assessed the cross-sectional association between adherence to a modified Mediterranean diet, BMI, and waist circumference (WC). A total of 497,308 individuals (70.7% women) aged 25-70 y from 10 European countries participated in this study. Diet was assessed at baseline using detailed validated country-specific questionnaires, and anthropometrical measurements were collected using standardized procedures. The association between the degree of adherence to the modified-Mediterranean Diet Score (mMDS) (including high consumption of vegetables, legumes, fruits and nuts, cereals, fish and seafood, and unsaturated:saturated fatty acids ratio; moderate alcohol intake; and low consumption of meat and meat products and dairy products) and BMI (kg.m(-2)) or WC (cm) was modeled through mixed-effects linear regression, controlling for potential confounders. Overall, the mMDS was not significantly associated with BMI. Higher adherence to the Mediterranean diet was significantly associated with lower WC, for a given BMI, in both men (-0.09; 95% CI -0.14 to -0.04) and women (-0.06; 95% CI -0.10 to -0.01). The association was stronger in men (-0.20; 95% CI -0.23 to -0.17) and women (-0.17; 95% CI -0.21 to -0.13) from Northern European countries. Despite the observed heterogeneity among regions, results of this study suggest that adherence to a modified Mediterranean diet, high in foods of vegetable origin and unsaturated fatty acids, is associated with lower abdominal adiposity measured by WC in European men and women.

Background: A Western diet is associated with breast cancer risk., Objective: We investigated the relation of meat, egg, and dairy product consumption with breast cancer risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC)., Design: Between 1992 and 2003, information on diet was collected from 319,826 women. Disease hazard ratios were estimated with multivariate Cox proportional hazard models., Results: Breast cancer cases (n = 7119) were observed during 8.8 y (median) of follow-up. No consistent association was found between breast cancer risk and the consumption of any of the food groups under study, when analyzed by both categorical and continuous exposure variable models. High processed meat consumption was associated with a modest increase in breast cancer risk in the categorical model (hazard ratio: 1.10; 95% CI: 1.00, 1.20; highest compared with lowest quintile: P for trend = 0.07). Subgroup analyses suggested an association with butter consumption, limited to premenopausal women (hazard ratio: 1.28; 95% CI: 1.06, 1.53; highest compared with lowest quintile: P for trend = 0.21). Between-country heterogeneity was found for red meat (Q statistic = 18.03; P = 0.05) and was significantly explained (P = 0.023) by the proportion of meat cooked at high temperature., Conclusions: We have not consistently identified intakes of meat, eggs, or dairy products as risk factors for breast cancer. Future studies should investigate the possible role of high-temperature cooking in the relation of red meat intake with breast cancer risk.

We followed-up for mortality and cancer incidence 1088 healthy non-smokers from a population-based study, who were characterized for 22 variants in 16 genes involved in DNA repair pathways. Follow-up was 100% complete. The association between polymorphism and mortality or cancer incidence was analyzed using Cox Proportional Hazard regression models. Ninety-five subjects had died in a median follow-up time of 78 months (inter-quartile range 59-93 months). None of the genotypes was clearly associated with total mortality, except variants for two Double-Strand Break DNA repair genes, XRCC3 18067 C>T (rs#861539) and XRCC2 31479 G>A (rs#3218536). Adjusted hazard ratios were 2.25 (1.32-3.83) for the XRCC3 C/T genotype and 2.04 (1.00-4.13) for the T/T genotype (reference C/C), and 2.12 (1.14-3.97) for the XRCC2 G/A genotype (reference G/G). For total cancer mortality, the adjusted hazard ratios were 3.29 (1.23-7.82) for XRCC3 C/T, 2.84 (0.81-9.90) for XRCC3 T/T and 3.17 (1.21-8.30) for XRCC2 G/A. With combinations of three or more adverse alleles, the adjusted hazard ratio for all cause mortality was 17.29 (95% C.I. 8.13-36.74), and for all incident cancers the HR was 5.28 (95% C.I. 2.17-12.85). Observations from this prospective study suggest that polymorphisms of genes involved in the repair of DNA double-strand breaks significantly influence the risk of cancer and non-cancer disease, and can influence mortality.

Background: Plasma phospholipid fatty acids have been correlated with food intakes in populations with homogeneous dietary patterns. However, few data are available on populations with heterogeneous dietary patterns., Objective: The objective was to investigate whether plasma phospholipid fatty acids are suitable biomarkers of dietary intakes across populations involved in a large European multicenter study., Design: A cross-sectional study design nested to the European Prospective Investigation into Cancer and Nutrition (EPIC) was conducted to determine plasma fatty acid profiles in >3,000 subjects from 16 centers, who had also completed 24-h dietary recalls and dietary questionnaires. Plasma fatty acids were assessed by capillary gas chromatography. Ecological and individual correlations were calculated between fatty acids and select food groups., Results: The most important determinant of plasma fatty acids was region, which suggests that the variations across regions are largely due to different food intakes. Strong ecological correlations were observed between fish intake and long-chain n-3 polyunsaturated fatty acids (r = 0.78, P < 0.01), olive oil and oleic acid (r = 0.73, P < 0.01), and margarine and elaidic acid (r = 0.76, P < 0.01). Individual correlations varied across the regions, particularly between olive oil and oleic acid and between alcohol and the saturation index, as an indicator of stearoyl CoA desaturase activity., Conclusions: These findings indicate that specific plasma phospholipid fatty acids are suitable biomarkers of some food intakes in the EPIC Study. Moreover, these findings suggest complex interactions between alcohol intake and fatty acid metabolism, which warrants further attention in epidemiologic studies relating dietary fatty acids to alcohol-related cancers and other chronic diseases.

Background: Epidemiologic studies have produced conflicting results with respect to an association of dietary fat with breast cancer., Objective: We aimed to investigate the association between fat consumption and breast cancer., Design: We prospectively investigated fat consumption in a large (n = 319,826), geographically and culturally heterogeneous cohort of European women enrolled in the European Prospective Investigation into Cancer and Nutrition who completed a dietary questionnaire. After a mean of 8.8 y of follow-up, 7119 women developed breast cancer. Cox proportional hazard models, stratified by age and center and adjusted for energy intake and confounders, were used to estimate hazard ratios (HRs) for breast cancer., Results: An association between high saturated fat intake and greater breast cancer risk was found [HR = 1.13 (95% CI: 1.00, 1.27; P for trend = 0.038) for the highest quintile of saturated fat intake compared with the lowest quintile: 1.02 (1.00, 1.04) for a 20% increase in saturated fat consumption (continuous variable)]. No significant association of breast cancer with total, monounsaturated, or polyunsaturated fat was found, although trends were for a direct association of risk with monounsaturated fat and an inverse association with polyunsaturated fat. In menopausal women, the positive association with saturated fat was confined to nonusers of hormone therapy at baseline [1.21 (0.99, 1.48) for the highest quintile compared with the lowest quintile; P for trend = 0.044; and 1.03 (1.00, 1.07) for a 20% increase in saturated fat as a continuous variable]., Conclusions: Evidence indicates a weak positive association between saturated fat intake and breast cancer risk. This association was more pronounced for postmenopausal women who never used hormone therapy.

There is strong evidence from both animal- and in vitro-models that paraoxonase (PON1) is involved in the onset of cardiovascular disease. In humans there is no consensus on this issue and therefore we investigated the effect of PON1 genotype and activity on the incidence of coronary heart disease (CHD) and acute myocardial infarction (AMI) in a large prospective cohort of 17,357 middle-aged women. We applied a case-cohort design using the CHD (n=211) and AMI cases (n=71) and a random sample from the baseline cohort (n=1527). A weighted Cox proportional hazards model was used to estimate age- and multivariate-adjusted hazard ratios (HR) for the PON1 genetic variants (192Q > R and -107C > T) and tertiles of the PON1 arylesterase- and paraoxonase activities. Neither the PON1 genetic variants, nor the PON1 activities affected the incidence of CHD in general, but, an increased paraoxonase activity was associated with a higher risk of AMI: the second and third tertile HR were 1.31 and 2.07, respectively (P-trend=0.029, multivariate model). In the subgroup of never-smokers, paraoxonase activity was associated with an increased risk for AMI: the second and third tertile HR were 4.1 and 4.7, respectively (P-trend=0.009, multivariate model). Additionally, when compared to the lowest paraoxonase tertile in never-smokers, the highest paraoxonase tertile in current-smokers showed a 19.2-fold higher risk for AMI (95%CI: 5.3-69.5, P < 0.0001, multivariate model). In conclusion, this study shows that in middle-aged women paraoxonase activity was associated with an increased risk for AMI and that the risk was modified by the effects of smoking.

Background: F2-isoprostanes are prostaglandin-like compounds formed via arachidonic acid oxidation during oxidative stress., Objective: To study the relation between urinary concentrations of 8-iso-prostaglandin F2α (8-iso PGF2α) and mortality due to cardiovascular disease (CVD) in a nested case-cohort design., Methods: Follow-up duration of this prospective study among postmenopausal women was 18 years. Cases included 141 women who died of coronary heart disease and 109 women who died of stroke, whereas controls were a random cohort sample of 142 women. The concentration of 8-iso PGF2α was determined with liquid chromatography/tandem mass spectrometry in urine samples collected at baseline., Results: Smokers had 34.8% higher urinary 8-iso PGF2α concentrations than nonsmokers (P < 0.001). High levels of urinary 8-iso PGF2α were associated with increased incidence of fatal CVD. Women who were in the highest quartile of urinary 8-iso PGF2α levels had, independently of age, an odds ratio of 1.8 (95% confidence interval, 1.1-3.1, P < 0.05) for CVD mortality. Further adjustment by systolic blood pressure, history of CVD, diabetes, smoking, and body mass index did not attenuate this association., Conclusion: Women with high levels of urinary 8-iso PGF2α had an 80% increased risk of dying of coronary heart disease or stroke, supporting involvement of oxidative stress in the pathophysiology of cardiovascular disease.