María José Sánchez

Human papillomavirus (HPV), the causal agent of cervical cancer, appears to be involved in the etiology of cancer of the oral cavity and oropharynx. To investigate these associations, we conducted a multicenter case-control study of cancer of the oral cavity and oropharynx in nine countries.We recruited 1670 case patients (1415 with cancer of the oral cavity and 255 with cancer of the oropharynx) and 1732 control subjects and obtained an interview, oral exfoliated cells, and blood from all participants and fresh biopsy specimens from case patients. HPV DNA was detected by polymerase chain reaction (PCR). Antibodies against HPV16 L1, E6, and E7 proteins in plasma were detected with enzyme-linked immunosorbent assays. Multivariable models were used for case-control and case-case comparisons.HPV DNA was detected in biopsy specimens of 3.9% (95% confidence interval [CI] = 2.5% to 5.3%) of 766 cancers of the oral cavity with valid PCR results and 18.3% (95% CI = 12.0% to 24.7%) of 142 cancers of the oropharynx (oropharynx and tonsil combined) with valid PCR results. HPV DNA in cancer biopsy specimens was detected less frequently among tobacco smokers and paan chewers and more frequently among subjects who reported more than one sexual partner or who practiced oral sex. HPV16 DNA was found in 94.7% of HPV DNA-positive case patients. HPV DNA in exfoliated cells was not associated with cancer risk or with HPV DNA detection in biopsy specimens. Antibodies against HPV16 L1 were associated with risk for cancers of the oral cavity (odds ratio [OR] = 1.5, 95% CI = 1.1 to 2.1) and the oropharynx (OR = 3.5, 95% CI = 2.1 to 5.9). Antibodies against HPV16 E6 or E7 were also associated with risk for cancers of the oral cavity (OR = 2.9, 95% CI = 1.7 to 4.8) and the oropharynx (OR = 9.2, 95% CI = 4.8 to 17.7).HPV appears to play an etiologic role in many cancers of the oropharynx and possibly a small subgroup of cancers of the oral cavity. The most common HPV type in genital cancers (HPV16) was also the most common in these tumors. The mechanism of transmission of HPV to the oral cavity warrants further investigation.

Background: Current evidence suggests that high red meat intake is associated with increased colorectal cancer risk. High fish intake may be associated with a decreased risk, but the existing evidence is less convincing. Methods: We prospectively followed 478 040 men and women from 10 European countries who were free of cancer at enrollment between 1992 and 1998. Information on diet and lifestyle was collected at baseline. After a mean follow-up of 4.8 years, 1329 incident colorectal cancers were documented. We examined the relationship between intakes of red and processed meat, poultry, and fish and colorectal cancer risk using a proportional hazards model adjusted for age, sex, energy (nonfat and fat sources), height, weight, work-related physical activity, smoking status, dietary fiber and folate, and alcohol consumption, stratified by center. A calibration substudy based on 36 994 subjects was used to correct hazard ratios (HRs) and 95% confidence intervals (CIs) for diet measurement errors. All statistical tests were two-sided. Results: Colorectal cancer risk was positively associated with intake of red and processed meat (highest [>160 g/day] versus lowest [<20 g/day] intake, HR = 1.35, 95% CI = 0.96 to 1.88; Ptrend = .03) and inversely associated with intake of fish (>80 g/day versus <10 g/day, HR = 0.69, 95 % CI = 0.54 to 0.88; Ptrend <.001), but was not related to poultry intake. Correcting for measurement error strengthened the associations between colorectal cancer and red and processed meat intake (per 100-g increase HR = 1.25, 95% CI =1.09 to 1.41, Ptrend = .001 and HR = 1.55, 95% CI = 1.19 to 2.02, Ptrend = .001 before and after calibration, respectively) and for fish (per 100 g increase HR = 0.70, 95% CI = 0.57 to 0.87, Ptrend <.001 and HR = 0.46, 95% CI = 0.27 to 0.77, Ptrend = .003; before and after correction, respectively). In this study population, the absolute risk of development of colorectal cancer within 10 years for a study subject aged 50 years was 1.71% for the highest category of red and processed meat intake and 1.28% for the lowest category of intake and was 1.86% for subjects in the lowest category of fish intake and 1.28% for subjects in the highest category of fish intake. Conclusions: Our data confirm that colorectal cancer risk is positively associated with high consumption of red and processed meat and support an inverse association with fish intake.

BackgroundConflicting evidence exists regarding the association between saturated fatty acids (SFAs) and type 2 diabetes. In this longitudinal case-cohort study, we aimed to investigate the prospective associations between objectively measured individual plasma phospholipid SFAs and incident type 2 diabetes in EPIC-InterAct participants.MethodsThe EPIC-InterAct case-cohort study includes 12 403 people with incident type 2 diabetes and a representative subcohort of 16 154 individuals who were selected from a cohort of 340 234 European participants with 3·99 million person-years of follow-up (the EPIC study). Incident type 2 diabetes was ascertained until Dec 31, 2007, by a review of several sources of evidence. Gas chromatography was used to measure the distribution of fatty acids in plasma phospholipids (mol%); samples from people with type 2 diabetes and subcohort participants were processed in a random order by centre, and laboratory staff were masked to participant characteristics. We estimated country-specific hazard ratios (HRs) for associations per SD of each SFA with incident type 2 diabetes using Prentice-weighted Cox regression, which is weighted for case-cohort sampling, and pooled our findings using random-effects meta-analysis.FindingsSFAs accounted for 46% of total plasma phospholipid fatty acids. In adjusted analyses, different individual SFAs were associated with incident type 2 diabetes in opposing directions. Even-chain SFAs that were measured (14:0 [myristic acid], 16:0 [palmitic acid], and 18:0 [stearic acid]) were positively associated with incident type 2 diabetes (HR [95% CI] per SD difference: myristic acid 1·15 [95% CI 1·09–1·22], palmitic acid 1·26 [1·15–1·37], and stearic acid 1·06 [1·00–1·13]). By contrast, measured odd-chain SFAs (15:0 [pentadecanoic acid] and 17:0 [heptadecanoic acid]) were inversely associated with incident type 2 diabetes (HR [95% CI] per 1 SD difference: 0·79 [0·73–0·85] for pentadecanoic acid and 0·67 [0·63–0·71] for heptadecanoic acid), as were measured longer-chain SFAs (20:0 [arachidic acid], 22:0 [behenic acid], 23:0 [tricosanoic acid], and 24:0 [lignoceric acid]), with HRs ranging from 0·72 to 0·81 (95% CIs ranging between 0·61 and 0·92). Our findings were robust to a range of sensitivity analyses.InterpretationDifferent individual plasma phospholipid SFAs were associated with incident type 2 diabetes in opposite directions, which suggests that SFAs are not homogeneous in their effects. Our findings emphasise the importance of the recognition of subtypes of these fatty acids. An improved understanding of differences in sources of individual SFAs from dietary intake versus endogenous metabolism is needed.FundingEU FP6 programme, Medical Research Council Epidemiology Unit, Medical Research Council Human Nutrition Research, and Cambridge Lipidomics Biomarker Research Initiative.

Head and neck (H&N) cancers are a heterogeneous group of malignancies, affecting various sites, with different prognoses. The aims of this study are to analyse survival for patients with H&N cancers in relation to tumour location, to assess the change in survival between European countries, and to investigate whether survival improved over time.We analysed about 250,000 H&N cancer cases from 86 cancer registries (CRs). Relative survival (RS) was estimated by sex, age, country and stage. We described survival time trends over 1999-2007, using the period approach. Model based survival estimates of relative excess risks (RERs) of death were also provided by country, after adjusting for sex, age and sub-site.Five-year RS was the poorest for hypopharynx (25%) and the highest for larynx (59%). Outcome was significantly better in female than in male patients. In Europe, age-standardised 5-year survival remained stable from 1999-2001 to 2005-2007 for laryngeal cancer, while it increased for all the other H&N cancers. Five-year age-standardised RS was low in Eastern countries, 47% for larynx and 28% for all the other H&N cancers combined, and high in Ireland and the United Kingdom (UK), and Northern Europe (62% and 46%). Adjustment for sub-site narrowed the difference between countries. Fifty-four percent of patients was diagnosed at advanced stage (regional or metastatic). Five-year RS for localised cases ranged between 42% (hypopharynx) and 74% (larynx).This study shows survival progresses during the study period. However, slightly more than half of patients were diagnosed with regional or metastatic disease at diagnosis. Early diagnosis and timely start of treatment are crucial to reduce the European gap to further improve H&N cancers outcome.

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.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.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.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.Adherence to the WCRF/AICR recommendations for cancer prevention may lower the risk of developing most types of cancer.

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.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.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.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.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.

An improved model for risk stratification can be useful for guiding public health strategies of breast cancer prevention.To evaluate combined risk stratification utility of common low penetrant single nucleotide polymorphisms (SNPs) and epidemiologic risk factors.Using a total of 17 171 cases and 19 862 controls sampled from the Breast and Prostate Cancer Cohort Consortium (BPC3) and 5879 women participating in the 2010 National Health Interview Survey, a model for predicting absolute risk of breast cancer was developed combining information on individual level data on epidemiologic risk factors and 24 genotyped SNPs from prospective cohort studies, published estimate of odds ratios for 68 additional SNPs, population incidence rate from the National Cancer Institute-Surveillance, Epidemiology, and End Results Program cancer registry and data on risk factor distribution from nationally representative health survey. The model is used to project the distribution of absolute risk for the population of white women in the United States after adjustment for competing cause of mortality.Single nucleotide polymorphisms, family history, anthropometric factors, menstrual and/or reproductive factors, and lifestyle factors.Degree of stratification of absolute risk owing to nonmodifiable (SNPs, family history, height, and some components of menstrual and/or reproductive history) and modifiable factors (body mass index [BMI; calculated as weight in kilograms divided by height in meters squared], menopausal hormone therapy [MHT], alcohol, and smoking).The average absolute risk for a 30-year-old white woman in the United States developing invasive breast cancer by age 80 years is 11.3%. A model that includes all risk factors provided a range of average absolute risk from 4.4% to 23.5% for women in the bottom and top deciles of the risk distribution, respectively. For women who were at the lowest and highest deciles of nonmodifiable risks, the 5th and 95th percentile range of the risk distribution associated with 4 modifiable factors was 2.9% to 5.0% and 15.5% to 25.0%, respectively. For women in the highest decile of risk owing to nonmodifiable factors, those who had low BMI, did not drink or smoke, and did not use MHT had risks comparable to an average woman in the general population.This model for absolute risk of breast cancer including SNPs can provide stratification for the population of white women in the United States. The model can also identify subsets of the population at an elevated risk that would benefit most from risk-reduction strategies based on altering modifiable factors. The effectiveness of this model for individual risk communication needs further investigation.

A high consumption of fruit and vegetables is possibly associated with a decreased risk of colorectal cancer (CRC). However, the findings to date are inconsistent. We examined the relation between self-reported usual consumption of fruit and vegetables and the incidence of CRC. In the European Prospective Investigation into Cancer and Nutrition (EPIC), 452,755 subjects (131,985 men and 320,770 women) completed a dietary questionnaire in 1992–2000 and were followed up for cancer incidence and mortality until 2006. A multivariate Cox proportional hazard model was used to estimate adjusted hazard ratios (HRs) and 95% CIs. After an average follow-up of 8.8 y, 2,819 incident CRC cases were reported. Consumption of fruit and vegetables was inversely associated with CRC in a comparison of the highest with the lowest EPIC-wide quintile of consumption (HR: 0.86; 95% CI: 0.75, 1.00; P for trend = 0.04), particularly with colon cancer risk (HR: 0.76; 95% CI: 0.63, 0.91; P for trend < 0.01). Only after exclusion of the first 2 y of follow-up were these findings corroborated by calibrated continuous analyses for a 100-g increase in consumption: HRs of 0.95 (95% CI: 0.91, 1.00; P = 0.04) and 0.94 (95% CI: 0.89, 0.99; P = 0.02), respectively. The association between fruit and vegetable consumption and CRC risk was inverse in never and former smokers, but positive in current smokers. This modifying effect was found for fruit and vegetables combined and for vegetables alone (P for interaction < 0.01 for both). These findings suggest that a high consumption of fruit and vegetables is associated with a reduced risk of CRC, especially of colon cancer. This effect may depend on smoking status.

Although several studies have investigated the association of the Mediterranean diet with overall mortality or risk of specific cancers, data on overall cancer risk are sparse.We examined the association between adherence to Mediterranean dietary pattern and overall cancer risk using data from the European Prospective Investigation Into Cancer and nutrition, a multi-centre prospective cohort study including 142,605 men and 335,873. Adherence to Mediterranean diet was examined using a score (range: 0-9) considering the combined intake of fruits and nuts, vegetables, legumes, cereals, lipids, fish, dairy products, meat products, and alcohol. Association with cancer incidence was assessed through Cox regression modelling, controlling for potential confounders.In all, 9669 incident cancers in men and 21,062 in women were identified. A lower overall cancer risk was found among individuals with greater adherence to Mediterranean diet (hazard ratio=0.96, 95% CI 0.95-0.98) for a two-point increment of the Mediterranean diet score. The apparent inverse association was stronger for smoking-related cancers than for cancers not known to be related to tobacco (P (heterogeneity)=0.008). In all, 4.7% of cancers among men and 2.4% in women would be avoided in this population if study subjects had a greater adherence to Mediterranean dietary pattern.Greater adherence to a Mediterranean dietary pattern could reduce overall cancer risk.

Abstract Physical activity has been associated with lower risks of breast and colorectal cancer in epidemiological studies; however, it is unknown if these associations are causal or confounded. In two-sample Mendelian randomisation analyses, using summary genetic data from the UK Biobank and GWA consortia, we found that a one standard deviation increment in average acceleration was associated with lower risks of breast cancer (odds ratio [OR]: 0.51, 95% confidence interval [CI]: 0.27 to 0.98, P-value = 0.04) and colorectal cancer (OR: 0.66, 95% CI: 0.48 to 0.90, P-value = 0.01). We found similar magnitude inverse associations for estrogen positive (ER +ve ) breast cancer and for colon cancer. Our results support a potentially causal relationship between higher physical activity levels and lower risks of breast cancer and colorectal cancer. Based on these data, the promotion of physical activity is probably an effective strategy in the primary prevention of these commonly diagnosed cancers.

Background: Dairy product intake may be inversely associated with risk of type 2 diabetes, but the evidence is inconclusive for total dairy products and sparse for types of dairy products. Objective: The objective was to investigate the prospective association of total dairy products and different dairy subtypes with incidence of diabetes in populations with marked variation of intake of these food groups. Design: A nested case-cohort within 8 European countries of the European Prospective Investigation into Cancer and Nutrition Study (n = 340,234; 3.99 million person-years of follow-up) included a random subcohort (n = 16,835) and incident diabetes cases (n = 12,403). Baseline dairy product intake was assessed by using dietary questionnaires. Country-specific Prentice-weighted Cox regression HRs were calculated and pooled by using a random-effects meta-analysis. Results: Intake of total dairy products was not associated with diabetes (HR for the comparison of the highest with the lowest quintile of total dairy products: 1.01; 95% CI: 0.83, 1.34; P-trend = 0.92) in an analysis adjusted for age, sex, BMI, diabetes risk factors, education, and dietary factors. Of the dairy subtypes, cheese intake tended to have an inverse association with diabetes (HR: 0.88; 95% CI: 0.76, 1.02; P-trend = 0.01), and a higher combined intake of fermented dairy products (cheese, yogurt, and thick fermented milk) was inversely associated with diabetes (HR: 0.88; 95% CI: 0.78, 0.99; P-trend = 0.02) in adjusted analyses that compared extreme quintiles. Conclusions: This large prospective study found no association between total dairy product intake and diabetes risk. An inverse association of cheese intake and combined fermented dairy product intake with diabetes is suggested, which merits further study.

Abstract Epidemiological evidence suggests that the Mediterranean diet (MD) could reduce the risk of breast cancer (BC). As evidence from the prospective studies remains scarce and conflicting, we investigated the association between adherence to the MD and risk of BC among 335,062 women recruited from 1992 to 2000, in ten European countries, and followed for 11 years on average. Adherence to the MD was estimated through an adapted relative Mediterranean diet (arMED) score excluding alcohol. Cox proportional hazards regression models were used while adjusting for BC risk factors. A total of 9,009 postmenopausal and 1,216 premenopausal first primary incident invasive BC were identified (5,862 estrogen or progesterone receptor positive [ER+/PR+] and 1,018 estrogen and progesterone receptor negative [ER−/PR−]). The arMED was inversely associated with the risk of BC overall and in postmenopausal women (high vs. low arMED score; hazard ratio [HR] = 0.94 [95% confidence interval [CI]: 0.88, 1.00] p trend = 0.048, and HR = 0.93 [95% CI: 0.87, 0.99] p trend = 0.037, respectively). The association was more pronounced in ER−/PR− tumors (HR = 0.80 [95% CI: 0.65, 0.99] p trend = 0.043). The arMED score was not associated with BC in premenopausal women. Our findings show that adherence to a MD excluding alcohol was related to a modest reduced risk of BC in postmenopausal women, and this association was stronger in receptor‐negative tumors. The results support the potential scope for BC prevention through dietary modification.

OBJECTIVE Age at menopause is an important determinant of future health outcomes, but little is known about its relationship with type 2 diabetes. We examined the associations of menopausal age and reproductive life span (menopausal age minus menarcheal age) with diabetes risk. RESEARCH DESIGN AND METHODS Data were obtained from the InterAct study, a prospective case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition. A total of 3,691 postmenopausal type 2 diabetic case subjects and 4,408 subcohort members were included in the analysis, with a median follow-up of 11 years. Prentice weighted Cox proportional hazards models were adjusted for age, known risk factors for diabetes, and reproductive factors, and effect modification by BMI, waist circumference, and smoking was studied. RESULTS Mean (SD) age of the subcohort was 59.2 (5.8) years. After multivariable adjustment, hazard ratios (HRs) of type 2 diabetes were 1.32 (95% CI 1.04–1.69), 1.09 (0.90–1.31), 0.97 (0.86–1.10), and 0.85 (0.70–1.03) for women with menopause at ages &amp;lt;40, 40–44, 45–49, and ≥55 years, respectively, relative to those with menopause at age 50–54 years. The HR per SD younger age at menopause was 1.08 (1.02–1.14). Similarly, a shorter reproductive life span was associated with a higher diabetes risk (HR per SD lower reproductive life span 1.06 [1.01–1.12]). No effect modification by BMI, waist circumference, or smoking was observed (P interaction all &amp;gt; 0.05). CONCLUSIONS Early menopause is associated with a greater risk of type 2 diabetes.

A total of 308,036 women were selected from the European Prospective Investigation into Cancer and Nutrition (EPIC) study to evaluate the association between tobacco smoking and the risk of cervical intraepithelial neoplasia of grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). At baseline, participants completed a questionnaire and provided blood samples. During a mean follow-up time of 9 years, 261 ICC cases and 804 CIN3/CIS cases were reported. In a nested case–control study, the baseline sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11, 16, 18, 31, 33, 35, 45, 52, 58, and antibodies against Chlamydia trachomatis (CT), and Human Herpes Virus 2 (HHV-2). Cervical samples were not available for HPV-DNA analysis in this study. Multivariate analyses were used to estimate associations between smoking and risk of CIN3/CIS and ICC in the cohort and the case–control studies. In the cohort analyses smoking status, duration and intensity showed a two-fold increased risk of CIN3/CIS and ICC, while time since quitting was associated with a two-fold reduced risk. In the nested case–control study, consistent associations were observed after adjustment for HPV, CT and HHV-2 serostatus, in both HPV seronegative and seropositive women. Results from this large prospective study confirm the role of tobacco smoking as an important risk factor for both CIN3/CIS and ICC, even after taking into account HPV exposure as determined by HPV serology. The strong beneficial effect of quitting smoking is an important finding that will further support public health policies for smoking cessation.

Excess body weight, physical activity, smoking, alcohol consumption and certain dietary factors are individually related to colorectal cancer (CRC) risk; however, little is known about their joint effects. The aim of this study was to develop a healthy lifestyle index (HLI) composed of five potentially modifiable lifestyle factors - healthy weight, physical activity, non-smoking, limited alcohol consumption and a healthy diet, and to explore the association of this index with CRC incidence using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. In the EPIC cohort, a total of 347,237 men and women, 25- to 70-years old, provided dietary and lifestyle information at study baseline (1992 to 2000). Over a median follow-up time of 12 years, 3,759 incident CRC cases were identified. The association between a HLI and CRC risk was evaluated using Cox proportional hazards regression models and population attributable risks (PARs) have been calculated. After accounting for study centre, age, sex and education, compared with 0 or 1 healthy lifestyle factors, the hazard ratio (HR) for CRC was 0.87 (95% confidence interval (CI): 0.44 to 0.77) for two factors, 0.79 (95% CI: 0.70 to 0.89) for three factors, 0.66 (95% CI: 0.58 to 0.75) for four factors and 0.63 (95% CI: 0.54 to 0.74) for five factors; P-trend <0.0001. The associations were present for both colon and rectal cancers, HRs, 0.61 (95% CI: 0.50 to 0.74; P for trend <0.0001) for colon cancer and 0.68 (95% CI: 0.53 to 0.88; P-trend <0.0001) for rectal cancer, respectively (P-difference by cancer sub-site = 0.10). Overall, 16% of the new CRC cases (22% in men and 11% in women) were attributable to not adhering to a combination of all five healthy lifestyle behaviours included in the index. Combined lifestyle factors are associated with a lower incidence of CRC in European populations characterized by western lifestyles. Prevention strategies considering complex targeting of multiple lifestyle factors may provide practical means for improved CRC prevention.

<h3>Importance</h3> Soft drinks are frequently consumed, but whether this consumption is associated with mortality risk is unknown and has been understudied in European populations to date. <h3>Objective</h3> To examine the association between total, sugar-sweetened, and artificially sweetened soft drink consumption and subsequent total and cause-specific mortality. <h3>Design, Setting, and Participants</h3> This population-based cohort study involved participants (n = 451 743 of the full cohort) in the European Prospective Investigation into Cancer and Nutrition (EPIC), an ongoing, large multinational cohort of people from 10 European countries (Denmark, France, Germany, Greece, Italy, the Netherlands, Norway, Spain, Sweden, and the United Kingdom), with participants recruited between January 1, 1992, and December 31, 2000. Excluded participants were those who reported cancer, heart disease, stroke, or diabetes at baseline; those with implausible dietary intake data; and those with missing soft drink consumption or follow-up information. Data analyses were performed from February 1, 2018, to October 1, 2018. <h3>Exposure</h3> Consumption of total, sugar-sweetened, and artificially sweetened soft drinks. <h3>Main Outcomes and Measures</h3> Total mortality and cause-specific mortality. Hazard ratios (HRs) and 95% CIs were estimated using multivariable Cox proportional hazards regression models adjusted for other mortality risk factors. <h3>Results</h3> In total, 521 330 individuals were enrolled. Of this total, 451 743 (86.7%) were included in the study, with a mean (SD) age of 50.8 (9.8) years and with 321 081 women (71.1%). During a mean (range) follow-up of 16.4 (11.1 in Greece to 19.2 in France) years, 41 693 deaths occurred. Higher all-cause mortality was found among participants who consumed 2 or more glasses per day (vs consumers of &lt;1 glass per month) of total soft drinks (hazard ratio [HR], 1.17; 95% CI, 1.11-1.22;<i>P</i> &lt; .001), sugar-sweetened soft drinks (HR, 1.08; 95% CI, 1.01-1.16;<i>P</i> = .004), and artificially sweetened soft drinks (HR, 1.26; 95% CI, 1.16-1.35;<i>P</i> &lt; .001). Positive associations were also observed between artificially sweetened soft drinks and deaths from circulatory diseases (≥2 glasses per day vs &lt;1 glass per month; HR, 1.52; 95% CI, 1.30-1.78;<i>P</i> &lt; .001) and between sugar-sweetened soft drinks and deaths from digestive diseases (≥1 glass per day vs &lt;1 glass per month; HR, 1.59; 95% CI, 1.24-2.05;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> This study found that consumption of total, sugar-sweetened, and artificially sweetened soft drinks was positively associated with all-cause deaths in this large European cohort; the results are supportive of public health campaigns aimed at limiting the consumption of soft drinks.

Abstract Background Although lifestyle factors have been studied in relation to individual non-communicable diseases (NCDs), their association with development of a subsequent NCD, defined as multimorbidity, has been scarcely investigated. The aim of this study was to investigate associations between five lifestyle factors and incident multimorbidity of cancer and cardiometabolic diseases. Methods In this prospective cohort study, 291,778 participants (64% women) from seven European countries, mostly aged 43 to 58 years and free of cancer, cardiovascular disease (CVD), and type 2 diabetes (T2D) at recruitment, were included. Incident multimorbidity of cancer and cardiometabolic diseases was defined as developing subsequently two diseases including first cancer at any site, CVD, and T2D in an individual. Multi-state modelling based on Cox regression was used to compute hazard ratios (HR) and 95% confidence intervals (95% CI) of developing cancer, CVD, or T2D, and subsequent transitions to multimorbidity, in relation to body mass index (BMI), smoking status, alcohol intake, physical activity, adherence to the Mediterranean diet, and their combination as a healthy lifestyle index (HLI) score. Cumulative incidence functions (CIFs) were estimated to compute 10-year absolute risks for transitions from healthy to cancer at any site, CVD (both fatal and non-fatal), or T2D, and to subsequent multimorbidity after each of the three NCDs. Results During a median follow-up of 11 years, 1910 men and 1334 women developed multimorbidity of cancer and cardiometabolic diseases. A higher HLI, reflecting healthy lifestyles, was strongly inversely associated with multimorbidity, with hazard ratios per 3-unit increment of 0.75 (95% CI, 0.71 to 0.81), 0.84 (0.79 to 0.90), and 0.82 (0.77 to 0.88) after cancer, CVD, and T2D, respectively. After T2D, the 10-year absolute risks of multimorbidity were 40% and 25% for men and women, respectively, with unhealthy lifestyle, and 30% and 18% for men and women with healthy lifestyles. Conclusion Pre-diagnostic healthy lifestyle behaviours were strongly inversely associated with the risk of cancer and cardiometabolic diseases, and with the prognosis of these diseases by reducing risk of multimorbidity.

We analysed trends in incidence for in situ and invasive melanoma in some European countries during the period 1995-2012, stratifying for lesion thickness.Individual anonymised data from population-based European cancer registries (CRs) were collected and combined in a common database, including information on age, sex, year of diagnosis, histological type, tumour location, behaviour (invasive, in situ) and lesion thickness. Mortality data were retrieved from the publicly available World Health Organization database.Our database covered a population of over 117 million inhabitants and included about 415,000 skin lesions, recorded by 18 European CRs (7 of them with national coverage). During the 1995-2012 period, we observed a statistically significant increase in incidence for both invasive (average annual percent change (AAPC) 4.0% men; 3.0% women) and in situ (AAPC 7.7% men; 6.2% women) cases.The increase in invasive lesions seemed mainly driven by thin melanomas (AAPC 10% men; 8.3% women). The incidence of thick melanomas also increased, although more slowly in recent years. Correction for lesions of unknown thickness enhanced the differences between thin and thick cases and flattened the trends. Incidence trends varied considerably across registries, but only Netherlands presented a marked increase above the boundaries of a funnel plot that weighted estimates by their precision. Mortality from invasive melanoma has continued to increase in Norway, Iceland (but only for elder people), the Netherlands and Slovenia.

Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings.However, generalisability of results to individuals with low vitamin D status is unclear.We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline.Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died.Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations.In population-wide genetic analyses, there were no associations of genetically-predicted 25(OH)D with coronary heart disease, stroke, or all-cause mortality.However, for the participants with vitamin D deficiency (25[OH]D concentration <25 nmol/L), genetic analyses provided strong evidence for an inverse association with all-cause mortality (odds ratio [OR] per 10 nmol/L increase in genetically-predicted 25[OH]D concentration 0•69 [95% CI 0•59-0•80]; p<0•0001) and nonsignificant inverse associations for stroke (0•85 [0•70-1•02], p=0•09) and coronary heart disease (0•89 [0•76-1•04]; p=0•14).A finer stratification of participants found inverse associations between genetically-predicted 25(OH)D concentrations and all-cause mortality up to around 40 nmol/L.Interpretation Stratified Mendelian randomisation analyses suggest a causal relationship between 25(OH)D concentrations and mortality for individuals with low vitamin D status.Our findings have implications for the design of vitamin D supplementation trials, and potential disease prevention strategies.

<h3>Background & Aims</h3> Early-onset colorectal cancer (CRC, in persons younger than 50 years old) is increasing in incidence; yet, in the absence of a family history of CRC, this population lacks harmonized recommendations for prevention. We aimed to determine whether a polygenic risk score (PRS) developed from 95 CRC-associated common genetic risk variants was associated with risk for early-onset CRC. <h3>Methods</h3> We studied risk for CRC associated with a weighted PRS in 12,197 participants younger than 50 years old vs 95,865 participants 50 years or older. PRS was calculated based on single nucleotide polymorphisms associated with CRC in a large-scale genome-wide association study as of January 2019. Participants were pooled from 3 large consortia that provided clinical and genotyping data: the Colon Cancer Family Registry, the Colorectal Transdisciplinary Study, and the Genetics and Epidemiology of Colorectal Cancer Consortium and were all of genetically defined European descent. Findings were replicated in an independent cohort of 72,573 participants. <h3>Results</h3> Overall associations with CRC per standard deviation of PRS were significant for early-onset cancer, and were stronger compared with late-onset cancer (<i>P</i> for interaction = .01); when we compared the highest PRS quartile with the lowest, risk increased 3.7-fold for early-onset CRC (95% CI 3.28–4.24) vs 2.9-fold for late-onset CRC (95% CI 2.80–3.04). This association was strongest for participants without a first-degree family history of CRC (<i>P</i> for interaction = 5.61 × 10^–5). When we compared the highest with the lowest quartiles in this group, risk increased 4.3-fold for early-onset CRC (95% CI 3.61–5.01) vs 2.9-fold for late-onset CRC (95% CI 2.70–3.00). Sensitivity analyses were consistent with these findings. <h3>Conclusions</h3> In an analysis of associations with CRC per standard deviation of PRS, we found the cumulative burden of CRC-associated common genetic variants to associate with early-onset cancer, and to be more strongly associated with early-onset than late-onset cancer, particularly in the absence of CRC family history. Analyses of PRS, along with environmental and lifestyle risk factors, might identify younger individuals who would benefit from preventive measures.

Background Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings.However, generalisability of results to individuals with low vitamin D status is unclear.We aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.Methods Observational analyses were undertaken using data from 33 prospective studies comprising 500 962 individuals with no known history of coronary heart disease or stroke at baseline.Mendelian randomisation analyses were performed in four population-based cohort studies (UK Biobank, EPIC-CVD, and two Copenhagen population-based studies) comprising 386 406 middle-aged individuals of European ancestries, including 33 546 people who developed coronary heart disease, 18 166 people who had a stroke, and 27 885 people who died.Primary outcomes were coronary heart disease, defined as fatal ischaemic heart disease (International Classification of Diseases 10th revision code I20-I25) or non-fatal myocardial infarction (I21-I23); stroke, defined as any cerebrovascular disease (I60-I69); and all-cause mortality.Findings Observational analyses suggested inverse associations between incident coronary heart disease, stroke, and all-cause mortality outcomes with 25(OH)D concentration at low 25(OH)D concentrations.In population-wide genetic analyses, there were no associations of genetically predicted 25(OH)D with coronary heart disease (odds ratio [OR] per 10 nmol/L higher genetically-predicted 25(OH)D concentration 0•98, 95% CI 0•95-1•01), stroke (1•01, [0•97-1•05]), or all-cause mortality (0•99, 0•95-1•02).Null findings were also observed in genetic analyses for causespecific mortality outcomes, and in stratified genetic analyses for all outcomes at all observed levels of 25(OH)D concentrations.Interpretation Stratified Mendelian randomisation analyses suggest a lack of causal relationship for 25(OH)D concentrations with both cardiovascular and mortality outcomes for individuals at all levels of 25(OH)D.Our findings suggest that substantial reductions in mortality and cardiovascular morbidity due to long-term low-dose vitamin D supplementation are unlikely even if targeted at individuals with low vitamin D status.

The phenotypic similarities between natural killer (NK) and T cells have led to the hypothesis that these distinctive lymphocyte subsets may be developmentally related and thus may share a common progenitor (Lanier, L. L., H. Spits, and J. H. Phillips, 1992. Immunol. Today. 13:392; Rodewald, H.-R., P. Moingeon, J. L. Lurich, C. Dosiou, P. Lopez, and E. L. Reinherz. 1992. Cell. 69:139). In this report, we have investigated the potential of human CD34+ triple negative thymocytes ([TN] CD3-, CD4-, CD8-) to generate both T cells and NK cells in murine fetal thymic organ cultures (mFTOC) and in vitro clonogenic assays. CD34+ TN thymocytes, the majority of which express prominent cytoplasmic CD3 epsilon (cytoCD3 epsilon) protein, can be divided into high (CD34Bright) and low (CD34Dim) surface expressing populations. CD34Bright TN thymocytes were capable of differentiating into T and NK cells when transferred into mFTOC, and demonstrated high NK cell clonogenic capabilities when cultured in interleukin (IL)-2, IL-7, and stem cell factor (SCF). Likewise, CD34Bright TN thymocyte clones after 5 d in culture were capable of generating NK and T cells when transferred into mFTOC but demonstrated clonogenic NK cell differentiation capabilities when maintained in culture with IL-2. CD34Dim TN thymocytes, however, possessed only T cell differentiation capabilities in mFTOC but were not expandable in clonogenic conditions containing IL-2, IL-7, and SCF. No significant differentiation of other cell lineage was detected in either mFTOC or in clonogenic assays from CD34+ TN thymocytes. These results represent the first definitive evidence of a common T/NK cell progenitor in the human fetal thymus and delineate the point in thymocyte differentiation where T and NK cells diverge.

Incidence rates of oral and oropharyngeal cancers (oral cancer) in Spain are among the highest in Europe. Spain has a population heavily exposed to various types of tobacco and alcoholic beverages but the role and impact of tobacco type and beverage type in oral carcinogenesis remain controversial. To estimate the independent and joint effects of tobacco smoking and alcohol drinking habits on the risk of developing oral cancer, we carried out a multicenter, hospital-based, case-control study in Spain. Data from 375 patients newly diagnosed with cancer of the oral cavity or oropharynx and 375 matched control subjects were analyzed using multivariate logistic regression procedures. All exposure characteristics of amount, duration and cessation of both tobacco smoking and alcohol drinking were strongly associated with cancer risk following a dose-dependent relationship. At equal intake or duration levels, black-tobacco smoking and drinking of spirits were both associated with a 2- to 4-fold increase in cancer risk compared to blond tobacco smoking or drinking of wine or beer, respectively. While ever exposure to smoking only or drinking only was associated with a moderate and nonsignificant increase in cancer risk, a history of simultaneous exposure to both habits was associated with a 13-fold increase that was compatible with a synergistic effect model (p-value for interaction: 0.008). Exposure to black tobacco smoking and/or drinking of spirits may account for up to 77% of oral cancer occurrence in Spain. Both black tobacco smoking and drinking of spirits place individuals at a very high risk of developing oral cancer. Simultaneous exposure to tobacco and alcohol consumption increases oral cancer risk in a synergistic fashion, even when consumption levels are moderate. These results underline the importance of type of tobacco and alcohol concentration in oral carcinogenesis.

Few studies have prospectively examined dietary patterns and adult weight change, and results to date are inconsistent. This study examines whether a Mediterranean diet (MD) pattern is associated with reduced 3-y incidence of obesity using data from the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The sample included 17,238 women and 10,589 men not obese and aged 29-65 y at baseline (1992-96). Height and weight were measured at baseline; weight was self-reported in a follow-up survey a mean of 3.3 y later. Detailed dietary history data, collected using a validated method, were used to construct a MD score. Logistic regression models were used to estimate odds of becoming overweight or obese. Among initially overweight subjects, 7.9% of women and 6.9% of men became obese, whereas 13.8% of normal weight men and 23.0% women became overweight. High MD adherence was associated with significantly lower likelihood of becoming obese among overweight subjects, with stronger associations after adjusting for underreporting of dietary data. Associations (odds ratios with 95% CI) were similar in women (0.69, 0.54-0.89) and men (0.68, 0.53-0.89). Adjusting for the plausibility of reported dietary intakes increased the magnitude of these associations, which were approximately 0.8 without this adjustment. MD adherence was not associated with incidence of overweight in initially normal-weight subjects. Nonetheless, results suggest that promoting eating habits consistent with MD patterns may be a useful part of efforts to combat obesity.

Epidemiologic data suggest that persons with diets rich in fruit and vegetables are at a lower risk of several chronic diseases and mortality than are persons with diets poor in fruit and vegetables. Often, this effect is attributed to antioxidant micronutrients found in plant foods.We aimed to assess the relation of mortality to the consumption of fruit, vegetables, and other plant foods and to the dietary intake of vitamin C, vitamin E, and carotenoids.The study was a prospective study in the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition. During 6.5 y of follow-up, 562 deaths occurred in 41 358 subjects aged 30-69 y. Proportional hazards regression analysis was used to assess the relation between dietary factors and total mortality.After adjustment for age, sex, and several potential confounders, the hazard ratio for the highest versus the lowest quartile of consumption was 0.79 (95% CI: 0.62, 1.00; P for trend = 0.029) for fresh fruit, 0.72 (0.56, 0.91; P for trend = 0.006) for root vegetables, and 0.77 (0.60, 0.98; P for trend = 0.015) for fruiting vegetables (ie, vegetables that contain the "fruit" part of the plant, the seeds). The corresponding figures for antioxidant nutrients were 0.74 (0.58, 0.94; P for trend = 0.009) for vitamin C, 0.68 (0.53, 0.87; P for trend = 0.006) for provitamin A carotenoids, and 0.65 (0.51, 0.84; P for trend 0.001) for lycopene. The effect of vitamin C and provitamin A disappeared after adjustment for total antioxidant capacity in plant foods.A high intake of fresh fruit, root vegetables, and fruiting vegetables is associated with reduced mortality, probably as a result of their high content of vitamin C, provitamin A carotenoids, and lycopene. Antioxidant capacity could partly explain the effect of ascorbic acid and provitamin A but not the association with lycopene.

The Mediterranean dietary pattern is believed to protect against cancer, although evidence from cohort studies that have examined particular cancer sites is limited.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.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.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).Greater adherence to an rMED is associated with a significant reduction in the risk of incident GC.

There is an association between a greater adherence to a Mediterranean diet and a reduced risk of developing chronic diseases. However, it is not clear whether this dietary pattern may be protective also against the development of obesity.We assessed the association between the adherence to the Mediterranean dietary pattern (MDP), prospective weight change, and the incidence of overweight or obesity.We conducted a prospective cohort study [the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol Consumption, Cessation of Smoking, Eating Out of Home, and Obesity (EPIC-PANACEA) project] in 373,803 individuals (103,455 men and 270,348 women; age range: 25-70 y) from 10 European countries. Anthropometric measurements were obtained at recruitment and after a median follow-up time of 5 y. The relative Mediterranean Diet Score (rMED; score range: 0-18) was used to assess adherence to the MDP according to the consumption of 9 dietary components that are characteristic of the Mediterranean diet. The association between the rMED and 5-y weight change was modeled through multiadjusted mixed-effects linear regression.Individuals with a high adherence to the MDP according to the rMED (11-18 points) showed a 5-y weight change of -0.16 kg (95% CI: -0.24, -0.07 kg) and were 10% (95% CI: 4%, 18%) less likely to develop overweight or obesity than were individuals with a low adherence to the MDP (0-6 points). The low meat content of the Mediterranean diet seemed to account for most of its positive effect against weight gain.This study shows that promoting the MDP as a model of healthy eating may help to prevent weight gain and the development of obesity.

Background Epidemiologic studies have suggested associations between flavonoid intake and health benefits. Traditional Mediterranean diets consist of a high consumption of plant products rich in flavonoids. Objective This study estimates dietary flavonoid intake and main food sources in a Mediterranean population (Spanish adults). Design The study included 40,683 subjects aged 35 to 64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition study Spanish cohort. Usual food intake was assessed by personal interviews using a computerized version of a validated diet history method. Expanded US Department of Agriculture databases for the flavonoid, isoflavone, and proanthocyanidin content were used. Results The median and mean of total flavonoids were 269.17 and 313.26 mg/day, respectively. The most abundant flavonoid subgroup was proanthocyanidins (60.1%), followed by flavanones (16.9%), flavan-3-ols (10.3%), flavonols (5.9%), anthocyanidins (5.8%), flavones (1.1%), and isoflavones (<0.01%). The main sources of total flavonoid intake were apples (23%), red wine (21%), unspecified fruit (12.8%), and oranges (9.3%). Conclusions These results should be very useful for evaluating the relationships between flavonoid intake and several diseases.

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.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.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.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.Our results suggest that a decrease in meat consumption may improve weight management.

Misreporting characterized by the reporting of implausible energy intakes may undermine the valid estimation of diet-disease relations, but the methods to best identify and account for misreporting are unknown. The present study compared how alternate approaches affected associations between selected dietary factors and body mass index (BMI) by using data from the European Prospective Investigation Into Cancer and Nutrition-Spain. A total of 24,332 women and 15,061 men 29-65 years of age recruited from 1992 to 1996 for whom measured height and weight and validated diet history data were available were included. Misreporters were identified on the basis of disparities between reported energy intakes and estimated requirements calculated using the original Goldberg method and 2 alternatives: one that substituted basal metabolic rate equations that are more valid at higher BMIs and another that used doubly labeled water-predicted total energy expenditure equations. Compared with results obtained using the original method, underreporting was considerably lower and overreporting higher with alternative methods, which were highly concordant. Accounting for misreporters with all methods yielded diet-BMI relations that were more consistent with expectations; alternative methods often strengthened associations. For example, among women, multivariable-adjusted differences in BMI for the highest versus lowest vegetable intake tertile (β = 0.37 (standard error, 0.07)) were neutral after adjusting with the original method (β = 0.01 (standard error, 07)) and negative using the predicted total energy expenditure method with stringent cutoffs (β = -0.15 (standard error, 0.07)). Alternative methods may yield more valid associations between diet and obesity-related outcomes.

Studying gene-lifestyle interaction may help to identify lifestyle factors that modify genetic susceptibility and uncover genetic loci exerting important subgroup effects. Adequately powered studies with prospective, unbiased, standardised assessment of key behavioural factors for gene-lifestyle studies are lacking. This case-cohort study aims to investigate how genetic and potentially modifiable lifestyle and behavioural factors, particularly diet and physical activity, interact in their influence on the risk of developing type 2 diabetes.Incident cases of type 2 diabetes occurring in European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts between 1991 and 2007 from eight of the ten EPIC countries were ascertained and verified. Prentice-weighted Cox regression and random-effects meta-analyses were used to investigate differences in diabetes incidence by age and sex.A total of 12,403 verified incident cases of type 2 diabetes occurred during 3.99 million person-years of follow-up of 340,234 EPIC participants eligible for InterAct. We defined a centre-stratified subcohort of 16,154 individuals for comparative analyses. Individuals with incident diabetes who were randomly selected into the subcohort (n = 778) were included as cases in the analyses. All prevalent diabetes cases were excluded from the study. InterAct cases were followed-up for an average of 6.9 years; 49.7% were men. Mean baseline age and age at diagnosis were 55.6 and 62.5 years, mean BMI and waist circumference values were 29.4 kg/m(2) and 102.7 cm in men, and 30.1 kg/m(2) and 92.8 cm in women, respectively. Risk of type 2 diabetes increased linearly with age, with an overall HR of 1.56 (95% CI 1.48-1.64) for a 10 year age difference, adjusted for sex. A male excess in the risk of incident diabetes was consistently observed across all countries, with a pooled HR of 1.51 (95% CI 1.39-1.64), adjusted for age.InterAct is a large, well-powered, prospective study that will inform our understanding of the interplay between genes and lifestyle factors on the risk of type 2 diabetes development.

The risk of gastric cancer (GC) associated with dietary intake of nitrosodimethylamine (NDMA) and endogenous formation of nitroso compounds (NOCs) was investigated in the European Prospective Investigation into Cancer and Nutrition (EPIC). The study included 521,457 individuals and 314 incident cases of GC that had occurred after 6.6 average years of follow-up. An index of endogenous NOC (ENOC) formation was estimated using data of the iron content from meat intake and faecal apparent total NOC formation according to previous published studies. Antibodies to Helicobacter pylori and vitamin C levels were measured in a sub-sample of cases and matched controls included in a nested case-control within the cohort. Exposure to NDMA was < 1 microg on average compared with 93 mug on average from ENOC. There was no association between NDMA intake and GC risk (HR, 1.00; 95% CI, 0.7-1.43). ENOC was significantly associated with non-cardia cancer risk (HR, 1.42; 95% CI, 1.14-1.78 for an increase of 40 microg/day) but not with cardia cancer (HR, 0.96; 95% CI, 0.69-1.33). Although the number of not infected cases is low, our data suggest a possible interaction between ENOC and H.pylori infection (P for interaction = 0.09). Moreover, we observed an interaction between plasma vitamin C and ENOC (P < 0.02). ENOC formation may account for our previously reported association between red and processed meat consumption and gastric cancer risk.

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.

<h3>Context</h3>B vitamins and factors related to 1-carbon metabolism help to maintain DNA integrity and regulate gene expression and may affect cancer risk.<h3>Objective</h3>To investigate if 1-carbon metabolism factors are associated with onset of lung cancer.<h3>Design, Setting, and Participants</h3>The European Prospective Investigation into Cancer and Nutrition (EPIC) recruited 519 978 participants from 10 countries between 1992 and 2000, of whom 385 747 donated blood. By 2006, 899 lung cancer cases were identified and 1770 control participants were individually matched by country, sex, date of birth, and date of blood collection. Serum levels were measured for 6 factors of 1-carbon metabolism and cotinine.<h3>Main Outcome Measure</h3>Odds ratios (ORs) of lung cancer by serum levels of 4 B vitamins (B₂, B₆, folate [B₉], and B₁₂), methionine, and homocysteine.<h3>Results</h3>Within the entire EPIC cohort, the age-standardized incidence rates of lung cancer (standardized to the world population, aged 35-79 years) were 6.6, 44.9, and 156.1 per 100 000 person-years among never, former, and current smokers for men, respectively. The corresponding incidence rates for women were 7.1, 23.9, and 100.9 per 100 000 person-years, respectively. After accounting for smoking, a lower risk for lung cancer was seen for elevated serum levels of B₆ (fourth vs first quartile OR, 0.44; 95% confidence interval [CI], 0.33-0.60; P for trend &lt;.000001), as well as for serum methionine (fourth vs first quartile OR, 0.52; 95% CI, 0.39-0.69; P for trend &lt;.000001). Similar and consistent decreases in risk were observed in never, former, and current smokers, indicating that results were not due to confounding by smoking. The magnitude of risk was also constant with increasing length of follow-up, indicating that the associations were not explained by preclinical disease. A lower risk was also seen for serum folate (fourth vs first quartile OR, 0.68; 95% CI, 0.51-0.90; P for trend = .001), although this was apparent only for former and current smokers. When participants were classified by median levels of serum methionine and B₆, having above-median levels of both was associated with a lower lung cancer risk overall (OR, 0.41; 95% CI, 0.31-0.54), as well as separately among never (OR, 0.36; 95% CI, 0.18-0.72), former (OR, 0.51; 95% CI, 0.34-0.76), and current smokers (OR, 0.42; 95% CI, 0.27-0.65).<h3>Conclusion</h3>Serum levels of vitamin B₆ and methionine were inversely associated with risk of lung cancer.

Recently, several genome-wide association studies have identified various genetic susceptibility loci for breast cancer. Relatively little is known about the possible interactions between these loci and the established risk factors for breast cancer.To assess interactions between single-nucleotide polymorphisms (SNPs) and established risk factors, we prospectively collected DNA samples and questionnaire data from 8576 breast cancer case subjects and 11 892 control subjects nested within the National Cancer Institute's Breast and Prostate Cancer Cohort Consortium (BPC3). We genotyped 17 germline SNPs (FGFR2-rs2981582, FGFR2-rs3750817, TNRC9-rs3803662, 2q35-rs13387042, MAP3K1-rs889312, 8q24-rs13281615, CASP8-rs1045485, LSP1-rs3817198, COL1A1-rs2075555, COX11-rs6504950, RNF146-rs2180341, 6q25-rs2046210, SLC4A7-rs4973768, NOTCH2-rs11249433, 5p12-rs4415084, 5p12-rs10941679, RAD51L1-rs999737), and odds ratios were estimated by logistic regression to confirm previously reported associations with breast cancer risk. We performed likelihood ratio test to assess interactions between 17 SNPs and nine established risk factors (age at menarche, parity, age at menopause, use of hormone replacement therapy, family history, height, body mass index, smoking status, and alcohol consumption), and a correction for multiple testing of 153 tests (adjusted P value threshold = .05/153 = 3 × 10(-4)) was done. Case-case comparisons were performed for possible differential associations of polymorphisms by subgroups of tumor stage, estrogen and progesterone receptor status, and age at diagnosis. All statistical tests were two-sided.We confirmed the association of 14 SNPs with breast cancer risk (P(trend) = 2.57 × 10(-3) -3.96 × 10(-19)). Three SNPs (LSP1-rs3817198, COL1A1-rs2075555, and RNF146-rs2180341) did not show association with breast cancer risk. After accounting for multiple testing, no statistically significant interactions were detected between the 17 SNPs and the nine risk factors. We also confirmed that SNPs in FGFR2 and TNRC9 were associated with greater risk of estrogen receptor-positive than estrogen receptor-negative breast cancer (P(heterogeneity) = .0016 for FGFR2-rs2981582 and P(heterogeneity) = .0053 for TNRC9-rs3803662). SNP 5p12-rs10941679 was statistically significantly associated with greater risk of progesterone receptor-positive than progesterone receptor-negative breast cancer (P(heterogeneity) = .0028).This study does not support the hypothesis that known common breast cancer susceptibility loci strongly modify the associations between established risk factors and breast cancer.

Obesity, a major risk factor for endometrial cancer, is a low-grade inflammatory state characterized by elevated concentrations of cytokines and acute phase reactants. The current study had two aims: first to investigate the associations of C-reactive protein (CRP), interleukin 6 (IL6), and IL1 receptor antagonist (IL1Ra) with endometrial cancer risk and second to examine to which extent these markers can influence the association between obesity and endometrial cancer. We conducted a case–control study, nested within the European Prospective Investigation into Cancer and Nutrition, which comprised 305 incident cases of endometrial cancer and 574 matched controls. CRP, IL6, and IL1Ra were measured in prospectively collected blood specimens by immunoassays. Data were analyzed using conditional logistic regression. All statistical tests were two-sided, and P values &lt;0.05 were considered statistically significant. We observed a significant increase in risk of endometrial cancer with elevated levels of CRP (odds ratio (OR) for top versus bottom quartile: 1.58, 95% confidence interval (CI): 1.03–2.41, P trend =0.02), IL6 (OR for top versus bottom quartile: 1.66, 95% CI: 1.08–2.54, P trend =0.008), and IL1Ra (OR for top versus bottom quartile: 1.82, 95% CI: 1.22–2.73, P trend =0.004). After adjustment for body mass index (BMI), the estimates were strongly reduced and became non-significant. The association between BMI and endometrial cancer was also substantially attenuated (∼10–20%) after adjustment for inflammatory markers, even when the effects of C-peptide or estrone had already been taken into account. We provided epidemiological evidence that chronic inflammation might mediate the association between obesity and endometrial cancer and that endometrial carcinogenesis could be promoted by an inflammatory milieu.

OBJECTIVE The long-term association between dietary protein and type 2 diabetes incidence is uncertain. We aimed to investigate the association between total, animal, and plant protein intake and the incidence of type 2 diabetes. RESEARCH DESIGN AND METHODS The prospective European Prospective Investigation into Cancer and Nutrition (EPIC)-InterAct case-cohort study consists of 12,403 incident type 2 diabetes cases and a stratified subcohort of 16,154 individuals from eight European countries, with an average follow-up time of 12.0 years. Pooled country-specific hazard ratios (HRs) and 95% CI of prentice-weighted Cox regression analyses were used to estimate type 2 diabetes incidence according to protein intake. RESULTS After adjustment for important diabetes risk factors and dietary factors, the incidence of type 2 diabetes was higher in those with high intake of total protein (per 10 g: HR 1.06 [95% CI 1.02–1.09], Ptrend &amp;lt; 0.001) and animal protein (per 10 g: 1.05 [1.02–1.08], Ptrend = 0.001). Effect modification by sex (P &amp;lt; 0.001) and BMI among women (P &amp;lt; 0.001) was observed. Compared with the overall analyses, associations were stronger in women, more specifically obese women with a BMI &amp;gt;30 kg/m2 (per 10 g animal protein: 1.19 [1.09–1.32]), and nonsignificant in men. Plant protein intake was not associated with type 2 diabetes (per 10 g: 1.04 [0.93–1.16], Ptrend = 0.098). CONCLUSIONS High total and animal protein intake was associated with a modest elevated risk of type 2 diabetes in a large cohort of European adults. In view of the rapidly increasing prevalence of type 2 diabetes, limiting iso-energetic diets high in dietary proteins, particularly from animal sources, should be considered.

In this study, the relation between fruit and vegetable consumption and mortality was investigated within the European Prospective Investigation Into Cancer and Nutrition. Survival analyses were performed, including 451,151 participants from 10 European countries, recruited between 1992 and 2000 and followed until 2010. Hazard ratios, rate advancement periods, and preventable proportions to respectively compare risk of death between quartiles of consumption, to estimate the period by which the risk of death was postponed among high consumers, and to estimate proportions of deaths that could be prevented if all participants would shift their consumption 1 quartile upward. Consumption of fruits and vegetables was inversely associated with all-cause mortality (for the highest quartile, hazard ratio = 0.90, 95% confidence interval (CI): 0.86, 0.94), with a rate advancement period of 1.12 years (95% CI: 0.70, 1.54), and with a preventable proportion of 2.95%. This association was driven mainly by cardiovascular disease mortality (for the highest quartile, hazard ratio = 0.85, 95% CI: 0.77, 0.93). Stronger inverse associations were observed for participants with high alcohol consumption or high body mass index and suggested in smokers. Inverse associations were stronger for raw than for cooked vegetable consumption. These results support the evidence that fruit and vegetable consumption is associated with a lower risk of death.

La obesidad es un importante factor de riesgo cardiovascular. En España son pocos los estudios que hayan realizado una medición física del peso y la estatura para estimar la magnitud del problema. El objetivo de este estudio es determinar la prevalencia de obesidad infantil y juvenil en España en 2012. Estudio transversal sobre una muestra probabilística, representativa de la población española, de 978 niños entre los 8 y los 17 años. Se midió objetivamente el peso y la estatura del menor, junto con otras variables sociodemográficas. Se calcularon las prevalencias de sobrepeso y obesidad siguiendo criterios de la Organización Mundial de la Salud, la International Obesity Task Force y el estudio español enKid. En el grupo de edad de 8 a 17 años, en 2012 la prevalencia de sobrepeso es del 26% y la de obesidad, del 12,6%; 4 de cada 10 jóvenes sufren exceso de peso. En el grupo comprendido entre los 8 y los 13 años, el exceso de peso supera el 45%, mientras que para el grupo de 14 a 17 años, el exceso de peso es del 25,5%. Este factor de riesgo cardiovascular aparece asociado a las clases sociales más desfavorecidas y con menos estudios. La prevalencia de sobrepeso y obesidad infantil y juvenil en España sigue siendo muy alta (cercana al 40%), pero no ha crecido en los últimos 12 años. Obesity is a major cardiovascular risk factor. In Spain, few studies have physically measured height and weight to estimate the magnitude of the problem. The aim of this study was to determine the prevalence of child and adolescent obesity in Spain in 2012. We performed a cross-sectional probability sample of 1018 children, representative of the Spanish population aged between 8 and 17 years old, with objectively measured height and weight, along with other sociodemographic variables. We calculated the prevalence of overweight and obesity according to the criteria of the World Health Organization, the International Obesity Task Force, and the enKid study. In the group aged 8 to 17 years old, the prevalence of overweight and obesity was 26% and 12.6%, respectively; 4 in 10 young people were overweight or obese. Excess weight was found in 45% of the group aged 8 to 13 years and in 25.5% of that aged 14 to 17 years. This cardiovascular risk factor was associated with lower social class and lower educational level. The prevalence of overweight and obesity in children and adolescents in Spain remains high (close to 40%), but has not increased in the last 12 years. Full English text available from: www.revespcardiol.org/en.

Resveratrol has been shown to have beneficial effects on diseases related to oxidant and/or inflammatory processes and extends the lifespan of simple organisms including rodents. The objective of the present study was to estimate the dietary intake of resveratrol and piceid (R&amp;P) present in foods, and to identify the principal dietary sources of these compounds in the Spanish adult population. For this purpose, a food composition database (FCDB) of R&amp;P in Spanish foods was compiled. The study included 40 685 subjects aged 35–64 years from northern and southern regions of Spain who were included in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Spain cohort. Usual food intake was assessed by personal interviews using a computerised version of a validated diet history method. An FCDB with 160 items was compiled. The estimated median and mean of R&amp;P intake were 100 and 933 μg/d respectively. Approximately, 32 % of the population did not consume R&amp;P. The most abundant of the four stilbenes studied was trans -piceid (53·6 %), followed by trans -resveratrol (20·9 %), cis -piceid (19·3 %) and cis -resveratrol (6·2 %). The most important source of R&amp;P was wines (98·4 %) and grape and grape juices (1·6 %), whereas peanuts, pistachios and berries contributed to less than 0·01 %. For this reason the pattern of intake of R&amp;P was similar to the wine pattern. This is the first time that R&amp;P intake has been estimated in a Mediterranean country.

Epidemiological studies show that adherence to a Mediterranean diet (MD) increases longevity; however, few studies are restricted to Mediterranean populations or explore the effect of a MD pattern that directly incorporates olive oil. Therefore the relationship between adherence to the MD and mortality was studied within the the Spanish cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC-Spain). The EPIC-Spain analysis included 40 622 participants (37·7 % males) aged 29–69 years who were recruited from five Spanish regions in 1992–1996. During a mean follow-up of 13·4 years, 1855 deaths were documented: 913 from cancer, 399 from CVD, 425 from other causes and 118 from unknown causes of death. Risk of all-cause and cause-specific mortality was assessed according to the level of adherence to a relative MD (rMED) score, measured using an 18-unit scale incorporating nine selected dietary components. A high compared with a low rMED score was associated with a significant reduction in mortality from all causes (hazard ratio (HR) 0·79; 95 % CI 0·69, 0·91), from CVD (HR 0·66; 95 % CI 0·49, 0·89), but not from overall cancer (HR 0·92; 95 % CI 0·75, 1·12). A 2-unit increase in rMED score was associated with a 6 % ( P &lt; 0·001) decreased risk of all-cause mortality. A high olive oil intake and moderate alcohol consumption contributed most to this association. In this Spanish cohort, following an olive oil-rich MD was related to a significant reduction in all-cause mortality, and reduced the risk of mortality from CVD. These results support the important role that the MD pattern has on reducing mortality in Mediterranean countries.

Plausible biological mechanisms underlie possible associations between fatty acids in blood and risk of prostate cancer; epidemiologic evidence for an association, however, is inconsistent.The objectives were to assess the association between plasma phospholipid fatty acids and risk of total prostate cancer by stage and grade.This was a nested case-control analysis of 962 men with a diagnosis of prostate cancer after a median follow-up time of 4.2 y and 1061 matched controls who were taking part in the European Prospective Investigation into Cancer and Nutrition. The fatty acid composition of plasma phospholipids was measured by gas chromatography, and the risk of prostate cancer was estimated by using conditional logistic regression with adjustment for lifestyle variables.We found a positive association between palmitic acid and risk of total, localized, and low-grade prostate cancer. The risk of prostate cancer for men in the highest quintile compared with the lowest quintile of palmitic acid was 1.47 (95% CI: 0.97, 2.23; P for trend = 0.032). We found an inverse association between stearic acid and the risk of total, localized, and low-grade prostate cancer; men in the highest quintile of stearic acid had a relative risk of 0.77 (95% CI: 0.56, 1.06; P for trend = 0.03). There were significant positive associations between myristic, alpha-linolenic, and eicosapentaenoic acids and risk of high-grade prostate cancer.The associations between palmitic, stearic, myristic, alpha-linolenic, and eicosapentaenoic acids and prostate cancer risk may reflect differences in intake or metabolism of these fatty acids between the precancer cases and controls and should be explored further.

BackgroundThe comparative performance of existing models for prediction of type 2 diabetes across populations has not been investigated. We validated existing non-laboratory-based models and assessed variability in predictive performance in European populations.MethodsWe selected non-invasive prediction models for incident diabetes developed in populations of European ancestry and validated them using data from the EPIC-InterAct case-cohort sample (27 779 individuals from eight European countries, of whom 12 403 had incident diabetes). We assessed model discrimination and calibration for the first 10 years of follow-up. The models were first adjusted to the country-specific diabetes incidence. We did the main analyses for each country and for subgroups defined by sex, age (<60 years vs ≥60 years), BMI (<25 kg/m2 vs ≥25 kg/m2), and waist circumference (men <102 cm vs ≥102 cm; women <88 cm vs ≥88 cm).FindingsWe validated 12 prediction models. Discrimination was acceptable to good: C statistics ranged from 0·76 (95% CI 0·72–0·80) to 0·81 (0·77–0·84) overall, from 0·73 (0·70–0·76) to 0·79 (0·74–0·83) in men, and from 0·78 (0·74–0·82) to 0·81 (0·80–0·82) in women. We noted significant heterogeneity in discrimination (pheterogeneity<0·0001) in all but one model. Calibration was good for most models, and consistent across countries (pheterogeneity>0·05) except for three models. However, two models overestimated risk, DPoRT by 34% (95% CI 29–39%) and Cambridge by 40% (28–52%). Discrimination was always better in individuals younger than 60 years or with a low waist circumference than in those aged at least 60 years or with a large waist circumference. Patterns were inconsistent for BMI. All models overestimated risks for individuals with a BMI of <25 kg/m2. Calibration patterns were inconsistent for age and waist-circumference subgroups.InterpretationExisting diabetes prediction models can be used to identify individuals at high risk of type 2 diabetes in the general population. However, the performance of each model varies with country, age, sex, and adiposity.FundingThe European Union.

One hundred goitrous school children received 475 mg iodized oil by mouth, while 100 controls received mineral oil, on a double-blind basis. On follow-up 22 months later the urinary iodine had increased and goiter size had decreased in both groups, more strikingly in the iodine-treated children. There were no consistent differences between the two treatment groups in rate of somatic growth or performance on the Stanford-Binet and Bender tests. Because of the complexities introduced by increases in urinary iodine in the controls, we compared goiter reduction with improvement in IQ score in all children, regardless of group, and found a significant relationship (p = 0.014), particularly in girls (p = 0.029). We conclude that oral iodized oil is an attractive alternative to its injection but we recommend an approximate doubling of the dose used here for more effective control. Also, while our data are not conclusive, they support the possibility that correction of iodine deficiency may improve mental performance in school age children, particularly girls.

The protective effect of physical activity (PA) on abdominal adiposity is unclear.We examined whether PA independently predicted gains in body weight and abdominal adiposity.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).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.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.

International Journal of CancerVolume 134, Issue 8 p. 1871-1888 EpidemiologyFree Access Active and passive cigarette smoking and breast cancer risk: Results from the EPIC cohort Laure Dossus, Laure Dossus Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorMarie-Christine Boutron-Ruault, Marie-Christine Boutron-Ruault Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorRudolf Kaaks, Rudolf Kaaks Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorInger T. Gram, Inger T. Gram Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, NorwaySearch for more papers by this authorAlice Vilier, Alice Vilier Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorBéatrice Fervers, Béatrice Fervers Cancer and Environment Unit, Centre Léon Bérard, Lyon, FranceSearch for more papers by this authorJonas Manjer, Jonas Manjer Department of Plastic Surgery, Skane University Hospital Malmo, Lund University, Malmo, SwedenSearch for more papers by this authorAnne Tjonneland, Anne Tjonneland Danish Cancer Society Research Center, Copenhagen, DenmarkSearch for more papers by this authorAnja Olsen, Anja Olsen Danish Cancer Society Research Center, Copenhagen, DenmarkSearch for more papers by this authorKim Overvad, Kim Overvad Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, DenmarkSearch for more papers by this authorJenny Chang-Claude, Jenny Chang-Claude Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorHeiner Boeing, Heiner Boeing Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, GermanySearch for more papers by this authorAnnika Steffen, Annika Steffen Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, GermanySearch for more papers by this authorAntonia Trichopoulou, Antonia Trichopoulou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorPagona Lagiou, Pagona Lagiou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Department of Epidemiology, Harvard School of Public Health, Boston, MA Bureau of Epidemiologic Research, Academy of Athens, Athens, GreeceSearch for more papers by this authorMaria Sarantopoulou, Maria Sarantopoulou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorDomenico Palli, Domenico Palli Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, ItalySearch for more papers by this authorFranco Berrino, Franco Berrino Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalySearch for more papers by this authorRosario Tumino, Rosario Tumino Cancer Registry and Histopathology Unit, "Civile - M.P. Arezzo" Hospital, ASP Ragusa, ItalySearch for more papers by this authorPaolo Vineis, Paolo Vineis MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom HuGeF Foundation, Torino, ItalySearch for more papers by this authorAmalia Mattiello, Amalia Mattiello Department of Clinical and Experimental Medicine, Federico II University, Naples, ItalySearch for more papers by this authorH. Bas Bueno-de-Mesquita, H. Bas Bueno-de-Mesquita National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The NetherlandsSearch for more papers by this authorFranzel J.B. van Duijnhoven, Franzel J.B. van Duijnhoven National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Division of Human Nutrition, Wageningen University, Wageningen, The NetherlandsSearch for more papers by this authorMarieke F. Bakker, Marieke F. Bakker Julius Center for Health Sciences and Primary Care Epidemiology, UMC Utrecht, The NetherlandsSearch for more papers by this authorPetra HM Peeters, Petra HM Peeters Julius Center for Health Sciences and Primary Care Epidemiology, UMC Utrecht, The Netherlands Department of Epidemiology and Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorElisabete Weiderpass, Elisabete Weiderpass Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway Department of Research, Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Samfundet Folkhälsan, Helsinki, FinlandSearch for more papers by this authorEivind Bjerkaas, Eivind Bjerkaas Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, NorwaySearch for more papers by this authorTonje Braaten, Tonje Braaten Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, NorwaySearch for more papers by this authorVirginia Menéndez, Virginia Menéndez Public Health Directorate, Asturias, SpainSearch for more papers by this authorAntonio Agudo, Antonio Agudo Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, SpainSearch for more papers by this authorMaria-Jose Sanchez, Maria-Jose Sanchez Andalusian School of Public Health, Granada, Spain CIBER Epidemiología y Salud Pública CIBERESP, SpainSearch for more papers by this authorPilar Amiano, Pilar Amiano CIBER Epidemiología y Salud Pública CIBERESP, Spain Department of Health of the Regional Government of the Basque Country, Public Health Division of Gipuzkoa, BIODonostia Research Institute, San Sebastian, SpainSearch for more papers by this authorMaria-Jose Tormo, Maria-Jose Tormo CIBER Epidemiología y Salud Pública CIBERESP, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, SpainSearch for more papers by this authorAurelio Barricarte, Aurelio Barricarte CIBER Epidemiología y Salud Pública CIBERESP, Spain Navarre Public Health Institute, Pamplona, SpainSearch for more papers by this authorSalma Butt, Salma Butt Department of Surgery, Skane University Hospital Malmo, Lund University, Malmo, SwedenSearch for more papers by this authorKay-Tee Khaw, Kay-Tee Khaw University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorNicholas Wareham, Nicholas Wareham MRC Epidemiology Unit, Cambridge, United KingdomSearch for more papers by this authorTim J. Key, Tim J. Key Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorRuth C. Travis, Ruth C. Travis Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorSabina Rinaldi, Sabina Rinaldi Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorValerie McCormack, Valerie McCormack Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorIsabelle Romieu, Isabelle Romieu Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorDavid G. Cox, David G. Cox School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorTeresa Norat, Teresa Norat School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorElio Riboli, Elio Riboli School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorFrançoise Clavel-Chapelon, Corresponding Author Françoise Clavel-Chapelon Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceCorrespondence to: Dr. Françoise Clavel-Chapelon, Inserm U1018, Team 9: Nutrition, Hormones et Santé de la Femme, Institut Gustave Roussy, Espace Maurice Tubiana, 114 rue Edouard Vaillant, F-94805 Villejuif Cedex, France, Tel.: +33-1-4211-4148, Fax: +33-1-4211-4000, E-mail: [email protected]Search for more papers by this author Laure Dossus, Laure Dossus Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorMarie-Christine Boutron-Ruault, Marie-Christine Boutron-Ruault Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorRudolf Kaaks, Rudolf Kaaks Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorInger T. Gram, Inger T. Gram Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway Norwegian Centre for Integrated Care and Telemedicine, University Hospital of North Norway, Tromsø, NorwaySearch for more papers by this authorAlice Vilier, Alice Vilier Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceSearch for more papers by this authorBéatrice Fervers, Béatrice Fervers Cancer and Environment Unit, Centre Léon Bérard, Lyon, FranceSearch for more papers by this authorJonas Manjer, Jonas Manjer Department of Plastic Surgery, Skane University Hospital Malmo, Lund University, Malmo, SwedenSearch for more papers by this authorAnne Tjonneland, Anne Tjonneland Danish Cancer Society Research Center, Copenhagen, DenmarkSearch for more papers by this authorAnja Olsen, Anja Olsen Danish Cancer Society Research Center, Copenhagen, DenmarkSearch for more papers by this authorKim Overvad, Kim Overvad Section for Epidemiology, Department of Public Health, Aarhus University, Aarhus, DenmarkSearch for more papers by this authorJenny Chang-Claude, Jenny Chang-Claude Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorHeiner Boeing, Heiner Boeing Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, GermanySearch for more papers by this authorAnnika Steffen, Annika Steffen Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbruecke, Nuthetal, GermanySearch for more papers by this authorAntonia Trichopoulou, Antonia Trichopoulou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorPagona Lagiou, Pagona Lagiou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Department of Epidemiology, Harvard School of Public Health, Boston, MA Bureau of Epidemiologic Research, Academy of Athens, Athens, GreeceSearch for more papers by this authorMaria Sarantopoulou, Maria Sarantopoulou WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorDomenico Palli, Domenico Palli Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Florence, ItalySearch for more papers by this authorFranco Berrino, Franco Berrino Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalySearch for more papers by this authorRosario Tumino, Rosario Tumino Cancer Registry and Histopathology Unit, "Civile - M.P. Arezzo" Hospital, ASP Ragusa, ItalySearch for more papers by this authorPaolo Vineis, Paolo Vineis MRC/HPA Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom HuGeF Foundation, Torino, ItalySearch for more papers by this authorAmalia Mattiello, Amalia Mattiello Department of Clinical and Experimental Medicine, Federico II University, Naples, ItalySearch for more papers by this authorH. Bas Bueno-de-Mesquita, H. Bas Bueno-de-Mesquita National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The NetherlandsSearch for more papers by this authorFranzel J.B. van Duijnhoven, Franzel J.B. van Duijnhoven National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Division of Human Nutrition, Wageningen University, Wageningen, The NetherlandsSearch for more papers by this authorMarieke F. Bakker, Marieke F. Bakker Julius Center for Health Sciences and Primary Care Epidemiology, UMC Utrecht, The NetherlandsSearch for more papers by this authorPetra HM Peeters, Petra HM Peeters Julius Center for Health Sciences and Primary Care Epidemiology, UMC Utrecht, The Netherlands Department of Epidemiology and Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorElisabete Weiderpass, Elisabete Weiderpass Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, Norway Department of Research, Cancer Registry of Norway, Oslo, Norway Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden Samfundet Folkhälsan, Helsinki, FinlandSearch for more papers by this authorEivind Bjerkaas, Eivind Bjerkaas Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, NorwaySearch for more papers by this authorTonje Braaten, Tonje Braaten Institute of Community Medicine Faculty of Health Sciences, UiT The Arctic University of Norway, Tromsø, NorwaySearch for more papers by this authorVirginia Menéndez, Virginia Menéndez Public Health Directorate, Asturias, SpainSearch for more papers by this authorAntonio Agudo, Antonio Agudo Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Program, Catalan Institute of Oncology, L'Hospitalet de Llobregat, SpainSearch for more papers by this authorMaria-Jose Sanchez, Maria-Jose Sanchez Andalusian School of Public Health, Granada, Spain CIBER Epidemiología y Salud Pública CIBERESP, SpainSearch for more papers by this authorPilar Amiano, Pilar Amiano CIBER Epidemiología y Salud Pública CIBERESP, Spain Department of Health of the Regional Government of the Basque Country, Public Health Division of Gipuzkoa, BIODonostia Research Institute, San Sebastian, SpainSearch for more papers by this authorMaria-Jose Tormo, Maria-Jose Tormo CIBER Epidemiología y Salud Pública CIBERESP, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, SpainSearch for more papers by this authorAurelio Barricarte, Aurelio Barricarte CIBER Epidemiología y Salud Pública CIBERESP, Spain Navarre Public Health Institute, Pamplona, SpainSearch for more papers by this authorSalma Butt, Salma Butt Department of Surgery, Skane University Hospital Malmo, Lund University, Malmo, SwedenSearch for more papers by this authorKay-Tee Khaw, Kay-Tee Khaw University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorNicholas Wareham, Nicholas Wareham MRC Epidemiology Unit, Cambridge, United KingdomSearch for more papers by this authorTim J. Key, Tim J. Key Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorRuth C. Travis, Ruth C. Travis Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorSabina Rinaldi, Sabina Rinaldi Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorValerie McCormack, Valerie McCormack Section of Environment and Radiation, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorIsabelle Romieu, Isabelle Romieu Section of Nutrition and Metabolism, International Agency for Research on Cancer, Lyon, FranceSearch for more papers by this authorDavid G. Cox, David G. Cox School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorTeresa Norat, Teresa Norat School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorElio Riboli, Elio Riboli School of Public Health, Imperial College, London, United KingdomSearch for more papers by this authorFrançoise Clavel-Chapelon, Corresponding Author Françoise Clavel-Chapelon Inserm U1018, Centre for Research in Epidemiology and Population Health (CESP), Institut Gustave Roussy, Villejuif, France Paris South University, Villejuif, FranceCorrespondence to: Dr. Françoise Clavel-Chapelon, Inserm U1018, Team 9: Nutrition, Hormones et Santé de la Femme, Institut Gustave Roussy, Espace Maurice Tubiana, 114 rue Edouard Vaillant, F-94805 Villejuif Cedex, France, Tel.: +33-1-4211-4148, Fax: +33-1-4211-4000, E-mail: [email protected]Search for more papers by this author First published: 06 October 2013 https://doi.org/10.1002/ijc.28508Citations: 95AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract Recent cohort studies suggest that increased breast cancer risks were associated with longer smoking duration, higher pack-years and a dose-response relationship with increasing pack-years of smoking between menarche and first full-term pregnancy (FFTP). Studies with comprehensive quantitative life-time measures of passive smoking suggest an association between passive smoking dose and breast cancer risk. We conducted a study within the European Prospective Investigation into Cancer and Nutrition to examine the association between passive and active smoking and risk of invasive breast cancer and possible effect modification by known breast cancer risk factors. Among the 322,988 women eligible for the study, 9,822 developed breast cancer (183,608 women with passive smoking information including 6,264 cases). When compared to women who never smoked and were not being exposed to passive smoking at home or work at the time of study registration, current, former and currently exposed passive smokers were at increased risk of breast cancer (hazard ratios (HR) [95% confidence interval (CI)] 1.16 [1.05–1.28], 1.14 [1.04–1.25] and 1.10 [1.01–1.20], respectively). Analyses exploring associations in different periods of life showed the most important increase in risk with pack-years from menarche to FFTP (1.73 [1.29–2.32] for every increase of 20 pack-years) while pack-years smoked after menopause were associated with a significant decrease in breast cancer risk (HR = 0.53, 95% CI: 0.34–0.82 for every increase of 20 pack-years). Our results provide an important replication, in the largest cohort to date, that smoking (passively or actively) increases breast cancer risk and that smoking between menarche and FFTP is particularly deleterious. Abstract What's new? The EPIC study is the largest cohort analysis on smoking and breast cancer to date. In this analysis of data from that study, the authors have confirmed that both active and passive exposure to cigarette smoke increases breast cancer risk. These results emphasize that it's important to distinguish between passive exposure and no exposure when analyzing the relationship between smoking and breast cancer. The authors also confirm that the most potent window of exposure for smoking and breast cancer risk is between menarche and first full term pregnancy. Abbreviations BMI body mass index CI confidence interval EPIC European Prospective Investigation into Cancer and Nutrition ER estrogen receptor FFTP first full-term pregnancy HR hazard ratio IARC International Agency for Research on Cancer MHT menopausal hormone therapy OC oral contraceptive PAH polycyclic hydrocarbons PR progesterone receptor Tobacco smoking is among the leading preventable risk factors for a variety of diseases.1 The biological plausibility of an association with breast cancer risk has been long suggested because carcinogens found in tobacco smoke may pass into the blood stream and be transported to the breast.2 Most epidemiological studies concluded to a weak positive association and suggested that there may be an increased risk with heavy smoking, smoking of long duration, smoking before a first full-term pregnancy (FFTP) and passive smoking.3-11 A number of reports also raised the hypothesis that this increase may be stronger in women with high levels of estrogens.12, 13 Previously published reviews of the literature that included measures of passive smoking concluded that passive smokers (and particularly premenopausal women) may be at increased risk of developing breast cancer when compared to women never regularly exposed to tobacco smoke in any form.4, 14-17 In 2000, Morabia et al. demonstrated that separating passive smokers from never exposed had a major impact on associations observed for active smokers.18 Since then, studies that included comprehensive measures of lifetime occupational and residential passive smoking consistently observed an increased risk, whereas studies with less comprehensive measures saw no effect or a much weaker effect.4, 7, 14, 16, 17 However, a recent meta-analysis showed an increased breast cancer risk for passive smokers in retrospectively collected data but not in prospectively collected data,19 possibly because of poorer assessment of lifetime passive smoking exposure in prospective cohort studies. In addition, two recent large cohort studies showed that the increase in breast cancer risk with active smoking is concentrated in the period between menarche and first pregnancy, following a dose-response relationship with pack-years, and observed a reduced risk after first pregnancy or after menopause.7, 11, 20 The European Prospective Investigation into Cancer and Nutrition (EPIC) is a multicenter prospective study initiated in 1992 in ten European countries.21 With close to 10,000 breast cancer cases (including over 6,000 cases in the population with available data on passive smoking) EPIC offers a unique opportunity to examine in depth whether, after account of passive exposure at recruitment, smoking affects breast cancer risk differently (i) in current, former and passive smokers, (ii) in different periods of a woman's life, (iii) in different subgroups exposed to specific breast cancer risk factors, in particular according to menopausal status, hormone receptor status of the tumor, to BMI and to alcohol intake. Material and Methods Study population Eligible study subjects were from the general population residing in a given geographical area, i.e., a town or a province. There were, however, a few exceptions as follows: the French cohort was based on members of a health insurance plan covering state school employees; the Italian and Spanish cohorts included members of local blood donor associations; the Utrecht and Florence cohorts were based on women attending breast cancer screening and part of the Oxford cohort consisted of vegetarians and healthy eaters. Eligible subjects were invited by mail to participate in the study. In some cases (e.g., blood donors) the first invitation was by personal contact. Those who accepted signed an informed consent and completed questionnaires on their diet, lifestyle and medical history. The study was approved by the IARC Ethical Review Committee and by the Ethical Committees of the participating centers. From the initial pool of 367,903 subjects, we excluded women who reported a history of cancer (N = 19,853), women with incomplete follow-up data (N = 3,862), women with no information on smoking status (N = 8,687) and women from the Swedish centre Umea (N = 12,513) where data on reproductive factors were not available. This left 322,988 women originating from Denmark (29,262), France (64,864), Germany (27,843), Greece (14,617), Italy (31,111), The Netherlands (26,848), Norway (33,856), Spain (25,343), Sweden (14,394) and the United Kingdom (54,850). Data collection Data were collected on a large number of lifestyle and health factors that are of interest in studies on nutrition and cancer because they may be related to nutritional status or may be known or suspected cancer risk factors. A common set of questions was agreed on and translated into national questionnaires, including those addressing cigarette smoking status (current, former and never), amount and duration of cigarettes smoked and age at initiation. Information on smoking habits was not updated after baseline; therefore, duration among current smokers refers to duration between initiation and recruitment into the study (from 1992 in France until 2000 in Norway). Daily number of cigarettes usually smoked was requested for current smokers. Information on the number of cigarettes smoked per day over an individual's lifetime was also collected (except in France and Sweden, and these countries were therefore excluded from analyses on this variable and from analyses on pack-years at different periods of life, N = 79,258). Age at initiation was recorded as a categorical variable in two countries (France and Norway) and as a continuous variable elsewhere. Questions on passive smoking were asked in 16 centers, from seven countries (France, Italy, The Netherlands, Germany, Denmark, Sweden and Norway) corresponding to 183,608 women. Information was collected on adult residential exposure and adult occupational exposure (except in France, whose cohort population is mainly composed of teachers). The following question was asked about adult passive smoking exposure: "Does someone regularly smoke in your presence at home/work?" In three countries [France, Italy (except Naples) and Denmark], childhood exposure from parents was also registered and taken into account, so that in other countries, women defined as never exposed to tobacco may include subjects with passive childhood exposure to tobacco smoke. The following questions were asked about childhood smoking exposure: "Did any of your parents smoke when you grew up?" or "When you were a child, did you spend time where smoking was present." Questions about passive smoking intensity (time spent around smokers and number of cigarettes smoked by the partner) were only asked in France and Italy and were therefore not considered in this analysis. As only menopausal status at baseline was recorded, further classification of women who were premenopausal at baseline was based on age, considering as premenopausal a woman until age 50, and as postmenopausal a woman after age 55. Thus, women who were premenopausal at baseline contributed to the premenopausal group for the period between enrolment and age 50, and to the post-menopausal group from age 55 until the end of follow-up. Premenopausal women at baseline did not contribute person-years while aged between age 50 and 55. Follow-up and ascertainment of breast cancer Incident breast cancer cases were identified through population cancer registries (Denmark, Italy, The Netherlands, Spain, UK and Norway) or active follow-up (France, Germany and Greece), depending on the follow-up procedures in each of the participating countries. Active follow-up used a combination of methods including active follow-up through participants and their next-of-kin, and use of health insurance records and existing pathology registries. Mortality data were also obtained at the regional or national level. The 10th Revision of the International Statistical Classification of Diseases, Injuries and Causes of Death (ICD) was used to classify mortality and cancer incidence data and ICD-O-3 to define breast tumor. In our analysis, women were followed from study entry (1992–2000) until first breast cancer diagnosis, death or last known date of contact (between 2005 and 2010 depending on the center). Overall, among the 322,988 women followed for a mean duration of 11 years, 9,822 first invasive breast cancer cases o

A "Western" lifestyle characterized by physical inactivity and excess weight is associated with a number of metabolic and hormonal dysregulations, including increased circulating estrogen levels, hyperinsulinemia, hyperglycemia, and chronic inflammation. The same hormonal and metabolic axes might mediate the association between this lifestyle and the development of endometrial cancer. Using data collected within the European Prospective Investigation into Cancer and Nutrition (EPIC), a prospective cohort study carried out in 10 European countries during 1992-2000, we conducted a factor analysis to delineate important components that summarize the variation explained by a set of biomarkers and to examine their association with endometrial cancer risk. Prediagnostic levels of testosterone, androstenedione, dehydroepiandrosterone sulfate, sex hormone-binding globulin, estrone, estradiol, C-peptide, insulin-like growth factor-binding proteins 1 and 2, adiponectin, high- and low-density lipoprotein cholesterol, glucose, triglycerides, tumor necrosis factor (TNF) α, soluble TNF receptors 1 and 2, C-reactive protein, interleukin-6, and interleukin-1 receptor antagonist were measured in 233 incident endometrial cancer cases and 446 matched controls. Factor analysis identified 3 components associated with postmenopausal endometrial cancer risk that could be labeled "insulin resistance/metabolic syndrome," "steroids," and "inflammation" factors. A fourth component, "lipids," was not significantly associated with endometrial cancer. In conclusion, besides the well-known associations of risk with sex hormones and insulin-regulated physiological axes, our data further support the hypothesis that inflammation factors play a role in endometrial carcinogenesis.

Abstract Background: Individuals with higher blood 25-hydroxyvitamin D [25(OH)D] levels have a lower risk of developing colorectal cancer (CRC), but the influence of 25(OH)D on mortality after CRC diagnosis is unknown. Methods: The association between prediagnostic 25(OH)D levels and CRC-specific (N = 444) and overall mortality (N = 541) was prospectively examined among 1,202 participants diagnosed with CRC between 1992 and 2003 in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Multivariable Cox proportional hazards models were used to calculate HRs and corresponding 95% CIs according to 25(OH)D quintiles and genetic variation within the VDR and CASR genes. Potential dietary, lifestyle, and metabolic effect modifiers were also investigated. Results: There were 541 deaths, 444 (82%) due to CRC. Mean follow-up was 73 months. In multivariable analysis, higher 25(OH)D levels were associated with a statistically significant reduction in CRC-specific (Ptrend = 0.04) and overall mortality (Ptrend = 0.01). Participants with 25(OH)D levels in the highest quintile had an adjusted HR of 0.69 (95% CI: 0.50–0.93) for CRC-specific mortality and 0.67 (95% CI: 0.50–0.88) for overall mortality, compared with the lowest quintile. Except for a possible interaction by prediagnostic dietary calcium intake (Pinteraction = 0.01), no other potential modifying factors related to CRC survival were noted. The VDR (FokI and BsmI) and CASR (rs1801725) genotypes were not associated with survival. Conclusions: High prediagnostic 25(OH)D levels are associated with improved survival of patients with CRC. Impact: Our findings may stimulate further research directed at investigating the effects of blood vitamin D levels before, at, and after CRC diagnosis on outcomes in CRC patients. Cancer Epidemiol Biomarkers Prev; 21(4); 582–93. ©2012 AACR.

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 (HRper 10-g/d increase: 0.90; 95% CI: 0.88, 0.92); with mortality from circulatory (HRper 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 addition to HPV, high parity and hormonal contraceptives have been associated with cervical cancer (CC). However, most of the evidence comes from retrospective case-control studies. The aim of this study is to prospectively evaluate associations between hormonal factors and risk of developing cervical intraepithelial neoplasia grade 3 (CIN3)/carcinoma in situ (CIS) and invasive cervical cancer (ICC). Methods and Findings We followed a cohort of 308,036 women recruited in the European Prospective Investigation into Cancer and Nutrition (EPIC) Study. At enrollment, participants completed a questionnaire and provided serum. After a 9-year median follow-up, 261 ICC and 804 CIN3/CIS cases were reported. In a nested case-control study, the sera from 609 cases and 1,218 matched controls were tested for L1 antibodies against HPV types 11,16,18,31,33,35,45,52,58, and antibodies against Chlamydia trachomatis and Human herpesvirus 2. Multivariate analyses were performed to estimate hazard ratios (HR), odds ratios (OR) and corresponding 95% confidence intervals (CI). The cohort analysis showed that number of full-term pregnancies was positively associated with CIN3/CIS risk (p-trend = 0.03). Duration of oral contraceptives use was associated with a significantly increased risk of both CIN3/CIS and ICC (HR = 1.6 and HR = 1.8 respectively for ≥15 years versus never use). Ever use of menopausal hormone therapy was associated with a reduced risk of ICC (HR = 0.5, 95%CI: 0.4–0.8). A non-significant reduced risk of ICC with ever use of intrauterine devices (IUD) was found in the nested case-control analysis (OR = 0.6). Analyses restricted to all cases and HPV seropositive controls yielded similar results, revealing a significant inverse association with IUD for combined CIN3/CIS and ICC (OR = 0.7). Conclusions Even though HPV is the necessary cause of CC, our results suggest that several hormonal factors are risk factors for cervical carcinogenesis. Adherence to current cervical cancer screening guidelines should minimize the increased risk of CC associated with these hormonal risk factors.

The (14;18) translocation constitutes both a genetic hallmark and critical early event in the natural history of follicular lymphoma (FL). However, t(14;18) is also detectable in the blood of otherwise healthy persons, and its relationship with progression to disease remains unclear. Here we sought to determine whether t(14;18)-positive cells in healthy individuals represent tumor precursors and whether their detection could be used as an early predictor for FL.Among 520,000 healthy participants enrolled onto the EPIC (European Prospective Investigation Into Cancer and Nutrition) cohort, we identified 100 who developed FL 2 to 161 months after enrollment. Prediagnostic blood from these and 218 controls were screened for t(14;18) using sensitive polymerase chain reaction-based assays. Results were subsequently validated in an independent cohort (65 case participants; 128 controls). Clonal relationships between t(14;18) cells and FL were also assessed by molecular backtracking of paired prediagnostic blood and tumor samples.Clonal analysis of t(14;18) junctions in paired prediagnostic blood versus tumor samples demonstrated that progression to FL occurred from t(14;18)-positive committed precursors. Furthermore, healthy participants at enrollment who developed FL up to 15 years later showed a markedly higher t(14;18) prevalence and frequency than controls (P < .001). Altogether, we estimated a 23-fold higher risk of subsequent FL in blood samples associated with a frequency > 10(-4) (odds ratio, 23.17; 95% CI, 9.98 to 67.31; P < .001). Remarkably, risk estimates remained high and significant up to 15 years before diagnosis.High t(14;18) frequency in blood from healthy individuals defines the first predictive biomarker for FL, effective years before diagnosis.

Abstract Background: The etiologies of glioma and meningioma tumors are largely unknown. Although reproductive hormones are thought to influence the risk of these tumors, epidemiologic data are not supportive of this hypothesis; however, few cohort studies have published on this topic. We examined the relation between reproductive factors and the risk of glioma and meningioma among women in the European Prospective Investigation into Cancer and Nutrition (EPIC). Methods: After a mean of 8.4 years of follow-up, 193 glioma and 194 meningioma cases were identified among 276,212 women. Information on reproductive factors and hormone use was collected at baseline. Cox proportional hazard regression was used to determine hazard ratios (HR) and 95% confidence intervals (95% CI). Results: No associations were observed between glioma or meningioma risk and reproductive factors, including age at menarche, parity, age at first birth, menopausal status, and age at menopause. A higher risk of meningioma was observed among postmenopausal women who were current users of hormone replacement therapy (HR, 1.79; 95% CI, 1.18-2.71) compared with never users. Similarly, current users of oral contraceptives were at higher risk of meningioma than never users (HR, 3.61; 95% CI, 1.75-7.46). Conclusion: Our results do not support a role for estrogens and glioma risk. Use of exogenous hormones, especially current use, seems to increase meningioma risk. However, these findings could be due to diagnostic bias and require confirmation. Impact: Elucidating the role of hormones in brain tumor development has important implications and needs to be further examined using biological measurements. Cancer Epidemiol Biomarkers Prev; 19(10); 2562–9. ©2010 AACR.

The authors investigated associations between serum C-reactive protein (CRP) concentrations and colon and rectal cancer risk in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (1992-2003) among 1,096 incident cases and 1,096 controls selected using risk-set sampling and matched on study center, age, sex, time of blood collection, fasting status, menopausal status, menstrual cycle phase, and hormone replacement therapy. In conditional logistic regression with adjustment for education, smoking, nutritional factors, body mass index, and waist circumference, CRP showed a significant nonlinear association with colon cancer risk but not rectal cancer risk. Multivariable-adjusted relative risks for CRP concentrations of > or = 3.0 mg/L versus <1.0 mg/L were 1.36 (95% confidence interval (CI): 1.00, 1.85; P-trend = 0.01) for colon cancer and 1.02 (95% CI: 0.67, 1.57; P-trend = 0.65) for rectal cancer. Colon cancer risk was significantly increased in men (relative risk = 1.74, 95% CI: 1.11, 2.73; P-trend = 0.01) but not in women (relative risk = 1.06, 95% CI: 0.67, 1.68; P-trend = 0.13). Additional adjustment for C-peptide, glycated hemoglobin, and high density lipoprotein cholesterol did not attenuate these results. These data provide evidence that elevated CRP concentrations are related to a higher risk of colon cancer but not rectal cancer, predominantly among men and independently of obesity, insulin resistance, and dyslipidemia.

Abstract Several modifiable lifestyle factors, including smoking, alcohol, certain dietary factors and weight are independently associated with gastric cancer (GC); however, their combined impact on GC risk is unknown. We constructed a healthy lifestyle index to investigate the joint influence of these behaviors on GC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. The analysis included 461,550 participants (662 first incident GC cases) with a mean follow-up of 11.4 years. A healthy lifestyle index was constructed, assigning 1 point for each healthy behavior related to smoking status, alcohol consumption and diet quality (represented by the Mediterranean diet) for assessing overall GC and also body mass index for cardia GC and 0 points otherwise. Risk of GC was calculated using Cox proportional hazards regression models while adjusting for relevant confounders. The highest versus lowest score in the healthy lifestyle index was associated with a significant lower risk of GC, by 51% overall (HR 0.49 95% CI 0.35, 0.70), by 77% for cardia GC (HR 0.23 95% CI 0.08, 0.68) and by 47% for noncardia GC (HR 0.53 (95% CI 0.32, 0.87), p-trends<0.001. Population attributable risk calculations showed that 18.8% of all GC and 62.4% of cardia GC cases could have been prevented if participants in this population had followed the healthy lifestyle behaviors of this index. Adopting several healthy lifestyle behaviors including not smoking, limiting alcohol consumption, eating a healthy diet and maintaining a normal weight is associated with a large decreased risk of GC.

Breast cancer survival is reportedly higher in the US than in Europe. The first worldwide study (CONCORD) found wide international differences in age-standardized survival. The aim of this study is to explain these survival differences. Population-based data on stage at diagnosis, diagnostic procedures, treatment and follow-up were collected for about 20,000 women diagnosed with breast cancer aged 15-99 years during 1996-98 in 7 US states and 12 European countries. Age-standardized net survival and the excess hazard of death up to 5 years after diagnosis were estimated by jurisdiction (registry, country, European region), age and stage with flexible parametric models. Breast cancers were generally less advanced in the US than in Europe. Stage also varied less between US states than between European jurisdictions. Early, node-negative tumors were more frequent in the US (39%) than in Europe (32%), while locally advanced tumors were twice as frequent in Europe (8%), and metastatic tumors of similar frequency (5-6%). Net survival in Northern, Western and Southern Europe (81-84%) was similar to that in the US (84%), but lower in Eastern Europe (69%). For the first 3 years after diagnosis the mean excess hazard was higher in Eastern Europe than elsewhere: the difference was most marked for women aged 70-99 years, and mainly confined to women with locally advanced or metastatic tumors. Differences in breast cancer survival between Europe and the US in the late 1990s were mainly explained by lower survival in Eastern Europe, where low healthcare expenditure may have constrained the quality of treatment.

Abstract Identifying genetic variants with pleiotropic associations can uncover common pathways influencing multiple cancers. We took a two-stage approach to conduct genome-wide association studies for lung, ovary, breast, prostate, and colorectal cancer from the GAME-ON/GECCO Network (61,851 cases, 61,820 controls) to identify pleiotropic loci. Findings were replicated in independent association studies (55,789 cases, 330,490 controls). We identified a novel pleiotropic association at 1q22 involving breast and lung squamous cell carcinoma, with eQTL analysis showing an association with ADAM15/THBS3 gene expression in lung. We also identified a known breast cancer locus CASP8/ALS2CR12 associated with prostate cancer, a known cancer locus at CDKN2B-AS1 with different variants associated with lung adenocarcinoma and prostate cancer, and confirmed the associations of a breast BRCA2 locus with lung and serous ovarian cancer. This is the largest study to date examining pleiotropy across multiple cancer-associated loci, identifying common mechanisms of cancer development and progression. Cancer Res; 76(17); 5103–14. ©2016 AACR.

The type and quantity of dietary carbohydrate as quantified by glycemic index (GI) and glycemic load (GL), and dietary fiber may influence the risk of liver and biliary tract cancers, but convincing evidence is lacking.The association between dietary GI/GL and carbohydrate intake with hepatocellular carcinoma (HCC; N = 191), intrahepatic bile duct (IBD; N = 66), and biliary tract (N = 236) cancer risk was investigated in 477 206 participants of the European Prospective Investigation into Cancer and Nutrition cohort. Dietary intake was assessed by country-specific, validated dietary questionnaires. Hazard ratios and 95% confidence intervals were estimated from proportional hazard models. HBV/HCV status was measured in a nested case-control subset.Higher dietary GI, GL, or increased intake of total carbohydrate was not associated with liver or biliary tract cancer risk. For HCC, divergent risk estimates were observed for total sugar = 1.43 (1.17-1.74) per 50 g/day, total starch = 0.70 (0.55-0.90) per 50 g/day, and total dietary fiber = 0.70 (0.52-0.93) per 10 g/day. The findings for dietary fiber were confirmed among HBV/HCV-free participants [0.48 (0.23-1.01)]. Similar associations were observed for IBD [dietary fiber = 0.59 (0.37-0.99) per 10 g/day], but not biliary tract cancer.Findings suggest that higher consumption of dietary fiber and lower consumption of total sugars are associated with lower HCC risk. In addition, high dietary fiber intake could be associated with lower IBD cancer risk.

Abstract Abdominal and general adiposity are independently associated with mortality, but there is no consensus on how best to assess abdominal adiposity. We compared the ability of alternative waist indices to complement body mass index (BMI) when assessing all-cause mortality. We used data from 352,985 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) and Cox proportional hazards models adjusted for other risk factors. During a mean follow-up of 16.1 years, 38,178 participants died. Combining in one model BMI and a strongly correlated waist index altered the association patterns with mortality, to a predominantly negative association for BMI and a stronger positive association for the waist index, while combining BMI with the uncorrelated A Body Shape Index (ABSI) preserved the association patterns. Sex-specific cohort-wide quartiles of waist indices correlated with BMI could not separate high-risk from low-risk individuals within underweight (BMI &lt; 18.5 kg/m 2 ) or obese (BMI ≥ 30 kg/m 2 ) categories, while the highest quartile of ABSI separated 18–39% of the individuals within each BMI category, which had 22–55% higher risk of death. In conclusion, only a waist index independent of BMI by design, such as ABSI, complements BMI and enables efficient risk stratification, which could facilitate personalisation of screening, treatment and monitoring.

The association between vitamin D status and hepatocellular carcinoma (HCC) has not been well investigated, despite experimental evidence supporting an important role of vitamin D in liver pathophysiology. Our objective was to investigate the association between prediagnostic circulating 25-hydroxyvitamin D [25(OH)D] serum levels and the risk of HCC in a prospective, nested case-control study among 520,000 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Each case (n = 138) diagnosed between 1992 and 2010 was matched to one control by age, sex, study center, date and time of blood collection, and fasting status. Serum baseline levels of 25(OH)D were measured by liquid chromatography/tandem mass spectrometry. Multivariable incident rate ratios (IRRs) of HCC associated with continuous (per 10 nmol/L) or categorical levels (tertiles or a priori-defined categories) of prediagnostic 25(OH)D were calculated using conditional logistic regression. Higher 25(OH)D levels were associated with a 49% reduction in the risk of HCC (highest versus lowest tertile: multivariable IRR = 0.51, 95% confidence interval [CI], 0.26 to 0.99; Ptrend = 0.04; per 10 nmol/L increase: IRR = 0.80, 95% CI, 0.68-0.94). The finding did not vary substantially by time from enrolment to diagnosis, and did not change after adjustment for biomarkers of preexisting liver damage, nor chronic infection with hepatitis B or C viruses. The findings were not modified by body size or smoking status. Conclusion: In this prospective study on western European populations, serum levels of 25(OH)D were inversely associated with the risk of HCC. Given the rising incidence of this cancer in low-risk developed countries and the strong public health interest surrounding the potentially cancer-protective roles of vitamin D, additional studies in different populations are required. (Hepatology 2014;60:1222–1230)

There is an unclear association between intake of fish and long-chain n-3 polyunsaturated fatty acids (n-3 LC-PUFAs) and colorectal cancer (CRC). We examined the association between fish consumption, dietary and circulating levels of n-3 LC-PUFAs, and ratio of n-6:n-3 LC-PUFA with CRC using data from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.Dietary intake of fish (total, fatty/oily, lean/white) and n-3 LC-PUFA were estimated by food frequency questionnaires given to 521,324 participants in the EPIC study; among these, 6291 individuals developed CRC (median follow up, 14.9 years). Levels of phospholipid LC-PUFA were measured by gas chromatography in plasma samples from a sub-group of 461 CRC cases and 461 matched individuals without CRC (controls). Multivariable Cox proportional hazards and conditional logistic regression models were used to calculate hazard ratios (HRs) and odds ratios (ORs), respectively, with 95% CIs.Total intake of fish (HR for quintile 5 vs 1, 0.88; 95% CI, 0.80-0.96; Ptrend = .005), fatty fish (HR for quintile 5 vs 1, 0.90; 95% CI, 0.82-0.98; Ptrend = .009), and lean fish (HR for quintile 5 vs 1, 0.91; 95% CI, 0.83-1.00; Ptrend = .016) were inversely associated with CRC incidence. Intake of total n-3 LC-PUFA (HR for quintile 5 vs 1, 0.86; 95% CI, 0.78-0.95; Ptrend = .010) was also associated with reduced risk of CRC, whereas dietary ratio of n-6:n-3 LC-PUFA was associated with increased risk of CRC (HR for quintile 5 vs 1, 1.31; 95% CI, 1.18-1.45; Ptrend < .001). Plasma levels of phospholipid n-3 LC-PUFA was not associated with overall CRC risk, but an inverse trend was observed for proximal compared with distal colon cancer (Pheterogeneity = .026).In an analysis of dietary patterns of participants in the EPIC study, we found regular consumption of fish, at recommended levels, to be associated with a lower risk of CRC, possibly through exposure to n-3 LC-PUFA. Levels of n-3 LC-PUFA in plasma were not associated with CRC risk, but there may be differences in risk at different regions of the colon.

Background: Carotenoids and vitamin C are thought to be associated with reduced cancer risk because of their antioxidative capacity. Objective: This study evaluated the associations of plasma carotenoid, retinol, tocopherol, and vitamin C concentrations and risk of breast cancer. Design: In a nested case-control study within the European Prospective Investigation into Cancer and Nutrition cohort, 1502 female incident breast cancer cases were included, with an oversampling of premenopausal (n = 582) and estrogen receptor–negative (ER-) cases (n = 462). Controls (n = 1502) were individually matched to cases by using incidence density sampling. Prediagnostic samples were analyzed for α-carotene, β-carotene, lycopene, lutein, zeaxanthin, β-cryptoxanthin, retinol, α-tocopherol, γ-tocopherol, and vitamin C. Breast cancer risk was computed according to hormone receptor status and age at diagnosis (proxy for menopausal status) by using conditional logistic regression and was further stratified by smoking status, alcohol consumption, and body mass index (BMI). All statistical tests were 2-sided. Results: In quintile 5 compared with quintile 1, α-carotene (OR: 0.61; 95% CI: 0.39, 0.98) and β-carotene (OR: 0.41; 95% CI: 0.26, 0.65) were inversely associated with risk of ER- breast tumors. The other analytes were not statistically associated with ER- breast cancer. For estrogen receptor–positive (ER+) tumors, no statistically significant associations were found. The test for heterogeneity between ER- and ER+ tumors was statistically significant only for β-carotene (P-heterogeneity = 0.03). A higher risk of breast cancer was found for retinol in relation to ER-/progesterone receptor–negative tumors (OR: 2.37; 95% CI: 1.20, 4.67;P-heterogeneity with ER+/progesterone receptor positive = 0.06). We observed no statistically significant interaction between smoking, alcohol, or BMI and all investigated plasma analytes (based on tertile distribution). Conclusion: Our results indicate that higher concentrations of plasma β-carotene and α-carotene are associated with lower breast cancer risk of ER- tumors.

Abstract Background Metabolomics is a promising molecular tool to identify novel etiologic pathways leading to cancer. Using a targeted approach, we prospectively investigated the associations between metabolite concentrations in plasma and breast cancer risk. Methods A nested case-control study was established within the European Prospective Investigation into Cancer cohort, which included 1624 first primary incident invasive breast cancer cases (with known estrogen and progesterone receptor and HER2 status) and 1624 matched controls. Metabolites ( n = 127, acylcarnitines, amino acids, biogenic amines, glycerophospholipids, hexose, sphingolipids) were measured by mass spectrometry in pre-diagnostic plasma samples and tested for associations with breast cancer incidence using multivariable conditional logistic regression. Results Among women not using hormones at baseline ( n = 2248), and after control for multiple tests, concentrations of arginine (odds ratio [OR] per SD = 0.79, 95% confidence interval [CI] = 0.70–0.90), asparagine (OR = 0.83 (0.74–0.92)), and phosphatidylcholines (PCs) ae C36:3 (OR = 0.83 (0.76–0.90)), aa C36:3 (OR = 0.84 (0.77–0.93)), ae C34:2 (OR = 0.85 (0.78–0.94)), ae C36:2 (OR = 0.85 (0.78–0.88)), and ae C38:2 (OR = 0.84 (0.76–0.93)) were inversely associated with breast cancer risk, while the acylcarnitine C2 (OR = 1.23 (1.11–1.35)) was positively associated with disease risk. In the overall population, C2 (OR = 1.15 (1.06–1.24)) and PC ae C36:3 (OR = 0.88 (0.82–0.95)) were associated with risk of breast cancer, and these relationships did not differ by breast cancer subtype, age at diagnosis, fasting status, menopausal status, or adiposity. Conclusions These findings point to potentially novel pathways and biomarkers of breast cancer development. Results warrant replication in other epidemiological studies.

Abstract Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study. Experimental Design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis. Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker. Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664–75. ©2016 AACR. See related commentary by Skates, p. 4542

To investigate the association between alcohol consumption (at baseline and over lifetime) and non-fatal and fatal coronary heart disease (CHD) and stroke.Multicentre case-cohort study.A study of cardiovascular disease (CVD) determinants within the European Prospective Investigation into Cancer and nutrition cohort (EPIC-CVD) from eight European countries.32 549 participants without baseline CVD, comprised of incident CVD cases and a subcohort for comparison.Non-fatal and fatal CHD and stroke (including ischaemic and haemorrhagic stroke).There were 9307 non-fatal CHD events, 1699 fatal CHD, 5855 non-fatal stroke, and 733 fatal stroke. Baseline alcohol intake was inversely associated with non-fatal CHD, with a hazard ratio of 0.94 (95% confidence interval 0.92 to 0.96) per 12 g/day higher intake. There was a J shaped association between baseline alcohol intake and risk of fatal CHD. The hazard ratios were 0.83 (0.70 to 0.98), 0.65 (0.53 to 0.81), and 0.82 (0.65 to 1.03) for categories 5.0-14.9 g/day, 15.0-29.9 g/day, and 30.0-59.9 g/day of total alcohol intake, respectively, compared with 0.1-4.9 g/day. In contrast, hazard ratios for non-fatal and fatal stroke risk were 1.04 (1.02 to 1.07), and 1.05 (0.98 to 1.13) per 12 g/day increase in baseline alcohol intake, respectively, including broadly similar findings for ischaemic and haemorrhagic stroke. Associations with cardiovascular outcomes were broadly similar with average lifetime alcohol consumption as for baseline alcohol intake, and across the eight countries studied. There was no strong evidence for interactions of alcohol consumption with smoking status on the risk of CVD events.Alcohol intake was inversely associated with non-fatal CHD risk but positively associated with the risk of different stroke subtypes. This highlights the opposing associations of alcohol intake with different CVD types and strengthens the evidence for policies to reduce alcohol consumption.

Bile acids have been proposed to promote colon carcinogenesis. However, there are limited prospective data on circulating bile acid levels and colon cancer risk in humans.Associations between prediagnostic plasma levels of 17 primary, secondary, and tertiary bile acid metabolites (conjugated and unconjugated) and colon cancer risk were evaluated in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Bile acid levels were quantified by tandem mass spectrometry in samples from 569 incident colon cancer cases and 569 matched controls. Multivariable logistic regression analyses were used to estimate odds ratios (ORs) for colon cancer risk across quartiles of bile acid concentrations.Positive associations were observed between colon cancer risk and plasma levels of seven conjugated bile acid metabolites: the primary bile acids glycocholic acid (ORquartile 4 vs quartile 1= 2.22, 95% confidence interval [CI] = 1.52 to 3.26), taurocholic acid (OR = 1.78, 95% CI = 1.23 to 2.58), glycochenodeoxycholic acid (OR = 1.68, 95% CI = 1.13 to 2.48), taurochenodeoxycholic acid (OR = 1.62, 95% CI = 1.11 to 2.36), and glycohyocholic acid (OR = 1.65, 95% CI = 1.13 to 2.40), and the secondary bile acids glycodeoxycholic acid (OR = 1.68, 95% CI = 1.12 to 2.54) and taurodeoxycholic acid (OR = 1.54, 95% CI = 1.02 to 2.31). By contrast, unconjugated bile acids and tertiary bile acids were not associated with risk.This prospective study showed that prediagnostic levels of certain conjugated primary and secondary bile acids were positively associated with risk of colon cancer. Our findings support experimental data to suggest that a high bile acid load is colon cancer promotive.

OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P &amp;lt; 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

Varios artículos recientes sugieren que la obesidad es un factor de riesgo para una enfermedad más grave por coronavirus. En este artículo se resume la evidencia científica disponible sobre el papel de la obesidad en COVID-19, con especial atención en las personas más jóvenes y los mecanismos biológicos propuestos para explicar tanto el mayor riesgo observado como la posible mayor contagiosidad de esta población. Se consideran varias implicaciones de la pandemia sobre las personas con obesidad, en relación con las posibles dificultades en el manejo de los pacientes ingresados, las implicaciones del confinamiento sobre el control y tratamiento de la obesidad, y el estigma que sufren estas personas por su condición, y que puede verse aumentado si se confirma la relación de la obesidad con COVID-19. Comprender el papel de la obesidad en COVID-19 debería ser una prioridad de salud pública, dada la alta prevalencia de esta condición en nuestro país. Recent reports suggest that obesity is a risk factor for more severe coronavirus disease. This article summarizes the available scientific evidence on the role of obesity in COVID-19. We focus on implications for younger patients and the proposed biological mechanisms that could explain both the higher risk observed and the possible higher contagiousness of people with obesity. We consider implications of the pandemic for people with obesity in relation to: difficulties in managing hospitalized patients, implications of confinement for the control and treatment of obesity, and the stigma people with obesity suffer, that could increase should the relationship between obesity and COVID-19 be confirmed. Understanding the role of obesity in COVID-19 should be a public health priority, given the high prevalence of this condition in our country.

It is unclear whether obesity is associated with the development of inflammatory bowel disease despite compelling data from basic science studies. We therefore examined the association between obesity and risk of Crohn's disease (CD) and ulcerative colitis (UC).We conducted pooled analyses of 5 prospective cohorts with validated anthropometric measurements for body mass index (BMI) and waist-hip ratio and other lifestyle factors. Diagnoses of CD and UC were confirmed through medical records or ascertained using validated definitions. We used Cox proportional hazards modeling to calculate pooled multivariable-adjusted HRs (aHRs) and 95% confidence intervals (CIs).Among 601,009 participants (age range, 18-98 years) with 10,110,018 person-years of follow-up, we confirmed 563 incident cases of CD and 1047 incident cases of UC. Obesity (baseline BMI ≥30 kg/m2) was associated with an increased risk of CD (pooled aHR, 1.34; 95% CI, 1.05-1.71, I2 = 0%) compared with normal BMI (18.5 to <25 kg/m2). Each 5 kg/m2 increment in baseline BMI was associated with a 16% increase in risk of CD (pooled aHR, 1.16; 95% CI, 1.05-1.22; I2 = 0%). Similarly, with each 5 kg/m2 increment in early adulthood BMI (age, 18-20 years), there was a 22% increase in risk of CD (pooled aHR, 1.22; 95% CI, 1.05-1.40; I2 = 13.6%). An increase in waist-hip ratio was associated with an increased risk of CD that did not reach statistical significance (pooled aHR across quartiles, 1.08; 95% CI, 0.97-1.19; I2 = 0%). No associations were observed between measures of obesity and risk of UC.In an adult population, obesity as measured by BMI was associated with an increased risk of older-onset CD but not UC.

The vascular endothelium has several important functions, including hemostasis. The homeostasis of hemostasis is based on a fine balance between procoagulant and anticoagulant proteins and between fibrinolytic and antifibrinolytic ones. Coagulopathies are characterized by a mutation-induced alteration of the function of certain coagulation factors or by a disturbed balance between the mechanisms responsible for regulating coagulation. Homeostatic therapies consist in replacement and nonreplacement treatments or in the administration of antifibrinolytic agents. Rebalancing products reestablish hemostasis by inhibiting natural anticoagulant pathways. These agents include monoclonal antibodies, such as concizumab and marstacimab, which target the tissue factor pathway inhibitor; interfering RNA therapies, such as fitusiran, which targets antithrombin III; and protease inhibitors, such as serpinPC, which targets active protein C. In cases of thrombophilia (deficiency of protein C, protein S, or factor V Leiden), treatment may consist in direct oral anticoagulants, replacement therapy (plasma or recombinant ADAMTS13) in cases of a congenital deficiency of ADAMTS13, or immunomodulators (prednisone) if the thrombophilia is autoimmune. Monoclonal-antibody-based anti-vWF immunotherapy (caplacizumab) is used in the context of severe thrombophilia, regardless of the cause of the disorder. In cases of disseminated intravascular coagulation, the treatment of choice consists in administration of antifibrinolytics, all-trans-retinoic acid, and recombinant soluble human thrombomodulin.

<h3>Background & Aims</h3> Evidence regarding the association of dietary exposures with colorectal cancer (CRC) risk is not consistent with a few exceptions. Therefore, we conducted a diet-wide association study (DWAS) in the European Prospective Investigation into Cancer and Nutrition (EPIC) to evaluate the associations between several dietary exposures with CRC risk. <h3>Methods</h3> The association of 92 food and nutrient intakes with CRC risk was assessed in 386,792 participants, 5069 of whom developed incident CRC. Correction for multiple comparisons was performed using the false discovery rate, and emerging associations were examined in the Netherlands Cohort Study (NLCS). Multiplicative gene-nutrient interactions were also tested in EPIC based on known CRC-associated loci. <h3>Results</h3> In EPIC, alcohol, liquor/spirits, wine, beer/cider, soft drinks, and pork were positively associated with CRC, whereas milk, cheese, calcium, phosphorus, magnesium, potassium, riboflavin, vitamin B6, beta carotene, fruit, fiber, nonwhite bread, banana, and total protein intakes were inversely associated. Of these 20 associations, 13 were replicated in the NLCS, for which a meta-analysis was performed, namely alcohol (summary hazard ratio [HR] per 1-SD increment in intake: 1.07; 95% confidence interval [CI], 1.04–1.09), liquor/spirits (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.06), wine (HR per 1-SD increment in intake, 1.04; 95% CI, 1.02–1.07), beer/cider (HR per 1-SD increment in intake, 1.06; 95% CI, 1.04–1.08), milk (HR per 1-SD increment in intake, 0.95; 95% CI, 0.93–0.98), cheese (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), calcium (HR per 1-SD increment in intake, 0.93; 95% CI, 0.90–0.95), phosphorus (HR per 1-SD increment in intake, 0.92; 95% CI, 0.90–0.95), magnesium (HR per 1-SD increment in intake, 0.95; 95% CI, 0.92–0.98), potassium (HR per 1-SD increment in intake, 0.96; 95% CI, 0.94–0.99), riboflavin (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97), beta carotene (HR per 1-SD increment in intake, 0.96; 95% CI, 0.93–0.98), and total protein (HR per 1-SD increment in intake, 0.94; 95% CI, 0.92–0.97). None of the gene-nutrient interactions were significant after adjustment for multiple comparisons. <h3>Conclusions</h3> Our findings confirm a positive association for alcohol and an inverse association for dairy products and calcium with CRC risk, and also suggest a lower risk at higher dietary intakes of phosphorus, magnesium, potassium, riboflavin, beta carotene, and total protein.

A cross-sectional study was conducted within the Spanish cohort of the European Prospective Investigation in Cancer and Nutrition to assess the principal food sources of vitamin C, vitamin E, alpha-carotene, beta-carotene, lycopene, lutein, beta-cryptoxanthin and zeaxanthin in an adult Spanish population. The study included 41446 healthy volunteers (25812 women and 15634 men), aged 29-69 years, from three Spanish regions in the north (Asturias, Navarra and Guipúzcoa) and two in the south (Murcia and Granada). Usual food intake was estimated by personal interview through a computerized version of a dietary history questionnaire. Foods that provided at least two-thirds of the studied nutrients were: fruits (mainly oranges) (51 %) and fruiting vegetables (mainly tomato and sweet pepper) (20 %) for vitamin C; vegetable oils (sunflower and olive) (40 %), non-citrus fruits (10 %), and nuts and seeds (8 %) for vitamin E; root vegetables (carrots) (82 %) for alpha-carotene; green leafy (28 %), root (24 %) and fruiting vegetables (22 %) for beta-carotene; fruiting vegetables (fresh tomato) (72 %) for lycopene; green leafy vegetables (64 %) for lutein; citrus fruits (68 %) for beta-cryptoxanthin; citrus fruits (43 %) and green leafy vegetables (20 %) for zeaxanthin. In conclusion, the main food sources of nutrients with redox properties have been identified in a Mediterranean country. This could provide an insight into the interpretation of epidemiological studies investigating the role of diet in health and disease.

Epidemiologic studies suggest that a high intake of fruits and vegetables is associated with decreased risk of cancers of the upper aero-digestive tract. We studied data from 345,904 subjects of the prospective European Investigation into Cancer and Nutrition (EPIC) recruited in seven European countries, who had completed a dietary questionnaire in 1992–1998. During 2,182,560 person years of observation 352 histologically verified incident squamous cell cancer (SCC) cases (255 males; 97 females) of the oral cavity, pharynx, larynx, and esophagus were identified. Linear and restricted cubic spline Cox regressions were fitted on variables of intake of fruits and vegetables and adjusted for potential confounders. We observed a significant inverse association with combined total fruits and vegetables intake (estimated relative risk (RR) = 0.91; 95% confidence interval (95% CI) 0.83–1.00 per 80 g/d of consumption), and nearly significant inverse associations in separate analyses with total fruits and total vegetables intake (RR: 0.97 (95% CI: 0.92–1.02) and RR = 0.89 (95% CI: 0.78–1.02) per 40 g/d of consumption). Overall, vegetable subgroups were not related to risk with the exception of intake of root vegetables in men. Restricted cubic spline regression did not improve the linear model fits except for total fruits and vegetables and total fruits with a significant decrease in risk at low intake levels (<120 g/d) for fruits. Dietary recommendations should consider the potential benefit of increasing fruits and vegetables consumption for reducing the risk of cancers of the upper aero-digestive tract, particularly at low intake.

Vitamin C is an antioxidant and inhibitor of carcinogenic N -nitroso compound production in the stomach. Higher dietary vitamin C consumption is associated with decreased risk of gastric cancer (GC) in numerous case–control studies, but data from prospective studies are limited, particularly so for blood measures of vitamin C. The objective of this study was to determine the association of plasma and dietary vitamin C levels with the risk of GC in a case–control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 European countries. Using a fluorometric method, vitamin C was measured in pre-diagnostic plasma from 215 GC cases (matched controls = 416). Conditional logistic regression models adjusted by body mass index, total energy intake, smoking status/duration/intensity and Helicobacter pylori infection status were used to estimate relative cancer risks. No association with GC risk was observed for dietary vitamin C, whereas an inverse GC risk was observed in the highest versus lowest quartile of plasma vitamin C [odds ratio (OR) = 0.55, 95% confidence interval (CI) = 0.31–0.97, Ptrend = 0.043], which was maintained after exclusion of cases with ≤2 years follow-up (OR = 0.40, 95% CI = 0.19–0.83, Ptrend = 0.064). The inverse association was more pronounced in subjects consuming higher levels of red and processed meats, a factor that may increase endogenous N -nitroso compound production. The effect of plasma vitamin C was not different by GC anatomical subsite (cardia/non-cardia) or histological subtype (diffuse/intestinal), and there was no significant interaction of effect with H.pylori . The results of this study show, in a prospective setting, an inverse association of GC risk with high levels of plasma vitamin C and suggest an interaction with the intake of red and processed meats, whose consumption may elevate endogenous N -nitroso compound production.

Background: Consumption of fried food has been suggested to promote obesity, but this association has seldom been studied.

Despite declining incidence rates, gastric cancer (GC) is a major cause of death worldwide. Its aetiology may involve dietary antioxidant micronutrients such as carotenoids and tocopherols. The objective of this study was to determine the association of plasma levels of seven common carotenoids, their total plasma concentration, retinol and alpha- and gamma-tocopherol, with the risk of gastric adenocarcinoma in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC), a large cohort involving 10 countries. A secondary objective was to determine the association of total sum of carotenoids, retinol and alpha-tocopherol on GCs by anatomical subsite (cardia/noncardia) and histological subtype (diffuse/intestinal). Analytes were measured by high-performance liquid chromatography in prediagnostic plasma from 244 GC cases and 645 controls matched by age, gender, study centre and date of blood donation. Conditional logistic regression models adjusted by body mass index, total energy intake, smoking and Helicobacter pylori infection status were used to estimate relative cancer risks. After an average 3.2 years of follow-up, a negative association with GC risk was observed in the highest vs the lowest quartiles of plasma beta-cryptoxanthin (odds ratio (OR) = 0.53, 95% confidence intervals (CI) = 0.30-0.94, P(trend) = 0.006), zeaxanthin (OR = 0.39, 95% CI = 0.22-0.69, P(trend) = 0.005), retinol (OR = 0.55, 95% CI = 0.33-0.93, P(trend) = 0.005) and lipid-unadjusted alpha-tocopherol (OR = 0.59, 95% CI = 0.37-0.94, P(trend) = 0.022). For all analytes, no heterogeneity of risk estimates or significant associations were observed by anatomical subsite. In the diffuse histological subtype, an inverse association was observed with the highest vs lowest quartile of lipid-unadjusted alpha-tocopherol (OR = 0.26, 95% CI = 0.11-0.65, P(trend) = 0.003). These results show that higher plasma concentrations of some carotenoids, retinol and alpha-tocopherol are associated with reduced risk of GC.

Polychlorinated biphenyls (PCBs) are persistent compounds that may pose an environmental hazard to humans, food being the main source of exposure for the general population. To measure the serum concentrations of the main PCBs in subjects from the general population in Spain, and to assess potential determinants of such concentrations. Serum was obtained from blood samples of 953 subjects aged 35–64 years, residents in five Spanish regions (three from the North and two from the South), randomly selected from the EPIC-Spain cohort. Blood collection took place during 1992–1996 and four PCB congeners (118, 138, 153 and 180) were determined by means of gas chromatography with electron-capture detection (GC-ECD). The concentration of total PCBs was 459 ng/g lipids (or 3.1 μg/l); the corresponding figures for PCB 153 were 186 ng/g lipids and 1.25 μg/l. Men had higher values than women, PCB levels increased with age, and serum concentration of PCBs was higher in northern regions. Body mass index (BMI) was inversely related to PCB concentrations, and fish intake was the dietary factor showing the greatest association with serum PCBs. The pattern described was similar for each congener separately. We found concentrations similar to those reported in European countries where blood collection was carried during the same period. Regional differences within Spain are not fully explained by anthropometric or dietary factors. The inverse association with BMI suggests that in the mid-1990s there was still ongoing or recent exposure to PCBs in Spain.

Recent studies have demonstrated that mature natural killer (NK) cells can be grown from human triple negative (TN; CD3-, CD4-, CD8-) thymocytes, suggesting that a common NK/T cell precursor exists within the thymus that can give rise to both NK cells and T cells under appropriate conditions. In the present study, we have investigated human fetal and postnatal thymus to determine whether NK cells and their precursors exist within this tissue and whether NK cells can be distinguished from T cell progenitors. Based on the surface expression of CD56 (an NK cell-associated antigen) and CD5 (a T cell-associated antigen), three phenotypically distinctive populations of TN thymocytes were identified. CD56+, CD5-; CD56-, CD5-, and CD56-, CD5+. The CD56+, CD5- population of TN thymocytes, although displaying a low cytolytic function against NK sensitive tumor cell targets, were similar in antigenic phenotype to fetal liver NK cells, gave rise to NK cell clones, and were unable to generate T cells in mouse fetal thymic organ cultures (mFTOC). This population of thymocytes represents a relatively mature population of lineage-committed NK cells. The CD56-, CD5- population of TN thymocytes were similar to thymic NK cells in antigenic phenotype and NK cell clonogenic potential. Clones derived from this population of TN thymocytes acquired CD56 surface expression and NK cell cytolytic function. CD56-, CD5- TN thymocytes thus contain a novel population of NK cell-committed precursors. The CD56-, CD5- population of TN thymocytes also contains a small percentage of CD34+ cells, which demonstrate no in vitro clonogenic potential, but possess T cell reconstituting capabilities in mFTOC. The majority of TN thymocytes do not express CD56, but coexpress CD34 and CD5. These CD56-, CD5+, CD34+ cells demonstrate no NK or T cell clonogenic potential, but are extremely efficient in repopulating mFTOC and differentiating into CD3+, CD4+, CD8+ T cells. The results of this investigation have identified NK cells and NK cell precursors in the human thymus and have shown that these cell types are unable to differentiate along the T cell lineage pathway. Thus, while a common NK/T cell progenitor likely exists, once committed to the NK cell lineage these cells no longer have the capacity to develop along the T cell developmental pathway.

A Western diet is associated with breast cancer risk.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).Between 1992 and 2003, information on diet was collected from 319,826 women. Disease hazard ratios were estimated with multivariate Cox proportional hazard models.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.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.

Background: National indicators of cancer burden are essential information for cancer surveillance and health planning, so that in countries with partial registration coverage and geographically variable risk patterns, such as Spain, this is even more relevant. This article provides estimates of cancer incidence in Spain for all cancers combined, with the single exception of non-melanoma skin cancer, and for major cancer sites over the period 1981–2006, with projections up to 2012.Patients and methods: Estimates were obtained by applying the MIAMOD method, a statistical back-calculation approach, to derive incidence from mortality and relative survival data.Results: During the period 1981–2012, age-standardised incidence rates for all cancers rose from the beginning of the period and started to decline from 2000 onwards among men, and increased across the whole period among women. Differences in incidence trends between men and women might be attributable to the gender-specific case-mix of sites for all cancers, and to differences in risk factors specific to certain cancer sites in men and women, with smoking being the main factor accounting for these differences between the sexes.Conclusions: Estimates and projections of cancer incidence and mortality show divergent trends in Spain by sex and tumour type. This information is basic for planning and enhancing public health strategies and resources.

Flavonols, flavanones and flavones (FLAV) are sub-classes of flavonoids that exert cardioprotective and anti-carcinogenic properties in vitro and in vivo . We aimed to estimate the FLAV dietary intake, their food sources and associated lifestyle factors in ten European countries participating in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. FLAV intake and their food sources for 36 037 subjects, aged between 35 and 74 years, in twenty-seven study centres were obtained using standardised 24 h dietary recall software (EPIC-SOFT). An ad hoc food composition database on FLAV was compiled using data from US Department of Agriculture and Phenol-Explorer databases and was expanded using recipes, estimations and flavonoid retention factors in order to increase its correspondence with the 24 h dietary recall. Our results showed that the highest FLAV-consuming centre was the UK health-conscious group, with 130·9 and 97·0 mg/d for men and women, respectively. The lowest FLAV intakes were 36·8 mg/d in men from Umeå and 37·2 mg/d in women from Malmö (Sweden). The flavanone sub-class was the main contributor to the total FLAV intake ranging from 46·6 to 52·9 % depending on the region. Flavonols ranged from 38·5 to 47·3 % and flavones from 5·8 to 8·6 %. FLAV intake was higher in women, non-smokers, increased with level of education and physical activity. The major food sources were citrus fruits and citrus-based juices (especially for flavanones), tea, wine, other fruits and some vegetables. We concluded that the present study shows heterogeneity in intake of these three sub-classes of flavonoids across European regions and highlights differences by sex and other sociodemographic and lifestyle factors.

Mediterranean diet is associated with lower incidence of coronary heart disease, and two randomised trials indicated that it improves prognosis of coronary patients. These trials, however, relied on a total of 100 deaths and evaluated designer diets in the clinical context. We have evaluated the association of adherence to the modified Mediterranean diet, in which unsaturates were substituted for monounsaturates, with survival among elderly with previous myocardial infarction within the European Prospective Investigation into Cancer and nutrition (EPIC) study. As of December 2003, after a median follow-up of 6.7 years, 2671 EPIC participants from nine countries were 60 years or older and had prevalent myocardial infarction but no stroke or cancer at enrolment, complete information on dietary intakes and important covariates and known survival status. Adherence to the modified Mediterranean diet was assessed through a 10-unit-scale. Mortality ratio in relation to modified Mediterranean diet was estimated through Cox regression controlling for possible confounding. Increased adherence to modified Mediterranean diet by two units was associated with 18% lower overall mortality rate (95% confidence interval 7–27%, fixed effects model). There was no significant heterogeneity by sex, age at enrolment, or country, although the association tended to be less evident among northern Europeans. Associations between food groups contributing to the modified Mediterranean diet and mortality were generally weak. A diet inspired by the Mediterranean pattern that can be easily adopted by Western populations is associated with substantial reduction of total mortality of coronary patients in the community.

Fruit and vegetable consumption might prevent weight gain through their low energy density and high dietary fiber content.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.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.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.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.

To assess the extent to which stage at diagnosis and adherence to treatment guidelines may explain the persistent differences in colorectal cancer survival between the USA and Europe.A high-resolution study using detailed clinical data on Dukes' stage, diagnostic procedures, treatment and follow-up, collected directly from medical records by trained abstractors under a single protocol, with standardised quality control and central statistical analysis.21 population-based registries in seven US states and nine European countries provided data for random samples comprising 12 523 adults (15-99 years) diagnosed with colorectal cancer during 1996-1998.Logistic regression models were used to compare adherence to 'standard care' in the USA and Europe. Net survival and excess risk of death were estimated with flexible parametric models.The proportion of Dukes' A and B tumours was similar in the USA and Europe, while that of Dukes' C was more frequent in the USA (38% vs 21%) and of Dukes' D more frequent in Europe (22% vs 10%). Resection with curative intent was more frequent in the USA (85% vs 75%). Elderly patients (75-99 years) were 70-90% less likely to receive radiotherapy and chemotherapy. Age-standardised 5-year net survival was similar in the USA (58%) and Northern and Western Europe (54-56%) and lowest in Eastern Europe (42%). The mean excess hazard up to 5 years after diagnosis was highest in Eastern Europe, especially among elderly patients and those with Dukes' D tumours.The wide differences in colorectal cancer survival between Europe and the USA in the late 1990s are probably attributable to earlier stage and more extensive use of surgery and adjuvant treatment in the USA. Elderly patients with colorectal cancer received surgery, chemotherapy or radiotherapy less often than younger patients, despite evidence that they could also have benefited.

Limited scientific evidence has characterized the association between dietary fiber intake and risk of breast cancer (BC) by menopausal status and hormone receptor expression in tumors.We investigated the relation between total dietary fiber and its main food sources (vegetables, fruit, cereals, and legumes) and BC risk by using data from the European Prospective Investigation into Cancer and Nutrition (EPIC).A total of 11,576 invasive BC cases in 334,849 EPIC women mostly aged 35-70 y at baseline were identified over a median follow-up of 11.5 y. Dietary fiber was estimated from country-specific dietary questionnaires. Multivariable Cox proportional hazards regression models were used to quantify the association between dietary variables and BC risk with energy adjustment by using the residual method. Subgroup analyses were performed by menopausal status and estrogen receptor (ER) and progesterone receptor (PR) expression in tumors.BC risk was inversely associated with intakes of total dietary fiber [hazard ratio comparing fifth quintile to first quintile (HR(Q5-Q1)): 0.95; 95% CI: 0.89, 1.01; P-trend = 0.03] and fiber from vegetables (0.90; 0.84, 0.96; P-trend < 0.01) but not with fiber from fruit, cereals, or legumes. Overall, associations were homogeneous by menopausal status and ER and PR expression in tumors. For vegetable fiber, stronger associations were observed for estrogen receptor-negative and progesterone receptor-negative (HR(Q5-Q1):0.74; 95% CI: 0.59, 0.93; P-trend = 0.01) than for estrogen receptor-positive and progesterone receptor-positive tumors (0.92: 0.81, 1.03; P-trend = 0.05), with P-heterogeneity = 0.09.Diets rich in dietary fiber and, particularly, fiber from vegetables may be associated with a small reduction in risk of BC, independently of menopausal status.

Objective To assess the association between consumption of fried foods and risk of coronary heart disease.Design Prospective cohort study.Setting Spanish cohort of the European Prospective Investigation into Cancer and Nutrition.Participants 40 757 adults aged 29-69 and free of coronary heart disease at baseline (1992-6), followed up until 2004. Main outcome measuresCoronary heart disease events and vital status identified by record linkage with hospital discharge registers, population based registers of myocardial infarction, and mortality registers. ResultsDuring a median follow-up of 11 years, 606 coronary heart disease events and 1135 deaths from all causes occurred.Compared with being in the first (lowest) quarter of fried food consumption, the multivariate hazard ratio of coronary heart disease in the second quarter was 1.15 (95% confidence interval 0.91 to 1.45), in the third quarter was 1.07 (0.83 to 1.38), and in the fourth quarter was 1.08 (0.82 to 1.43; P for trend 0.74).The results did not vary between those who used olive oil for frying and those who used sunflower oil.Likewise, no association was observed between fried food consumption and all cause mortality: multivariate hazard ratio for the highest versus the lowest quarter of fried food consumption was 0.93 (95% confidence interval 0.77 to 1.14; P for trend 0.98). ConclusionIn Spain, a Mediterranean country where olive or sunflower oil is used for frying, the consumption of fried foods was not associated with coronary heart disease or with all cause mortality.

While higher intake of fish and lower consumption of red/processed meats have been suggested to play a protective role in the etiology of several cancers, prospective evidence for hepatocellular carcinoma (HCC) is limited, particularly in Western European populations.The associations of fish and meats with HCC risk were analyzed in the EPIC cohort. Between 1992 and 2010, 191 incident HCC were identified among 477 206 participants. Baseline diet was assessed using validated dietary questionnaires. A single 24-h diet recall from a cohort subsample was used for calibration. Multivariable proportional hazard regression was utilized to estimate hazard ratios (HR) and 95% confidence intervals (CI). In a nested case-control subset (HCC = 122), HBV/HCV status and liver function biomarkers were measured.HCC risk was inversely associated with intake of total fish (per 20 g/day increase, HR = 0.83, 95% CI 0.74-0.95 and HR = 0.80, 95% CI 0.69-0.97 before and after calibration, respectively). This inverse association was also suggested after adjusting for HBV/HCV status and liver function score (per 20-g/day increase, RR = 0.86, 95% CI 0.66-1.11 and RR = 0.74, 95% CI 0.50-1.09, respectively) in a nested case-control subset. Intakes of total meats or subgroups of red/processed meats, and poultry were not associated with HCC risk.In this large European cohort, total fish intake is associated with lower HCC risk.

Women with a diagnosis of breast cancer are at increased risk of second primary cancers, and the identification of risk factors for the latter may have clinical implications. We have followed-up for 11 years 10,045 women with invasive breast cancer from a European cohort, and identified 492 second primary cancers, including 140 contralateral breast cancers. Expected and observed cases and Standardized Incidence Ratios (SIR) were estimated using Aalen-Johansen Markovian methods. Information on various risk factors was obtained from detailed questionnaires and anthropometric measurements. Cox proportional hazards regression models were used to estimate the role of risk factors. Women with breast cancer had a 30% excess risk for second malignancies (95% confidence interval—CI 18–42) after excluding contralateral breast cancers. Risk was particularly elevated for colorectal cancer (SIR, 1.71, 95% CI 1.43–2.00), lymphoma (SIR 1.80, 95% CI 1.31–2.40), melanoma (2.12; 1.63–2.70), endometrium (2.18; 1.75–2.70) and kidney cancers (2.40; 1.57–3.52). Risk of second malignancies was positively associated with age at first cancer, body mass index and smoking status, while it was inversely associated with education, post-menopausal status and a history of full-term pregnancy. We describe in a large cohort of women with breast cancer a 30% excess of second primaries. Among risk factors for breast cancer, a history of full-term pregnancy was inversely associated with the risk of second primary cancer.

Results from prospective studies on premenopausal serum hormone levels in relation to breast cancer risk have been inconclusive, especially with regard to tumor subtypes. Using a case-control study nested within the prospective European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (801 breast cancer cases and 1,132 matched control subjects), we analyzed the relationships of prediagnostic serum estradiol, free estradiol, progesterone, testosterone, free testosterone and sex hormone-binding globulin (SHBG) levels with the risk of breast cancer by estrogen and progesterone receptor-positive and -negative breast tumors and by age at diagnoses. Higher prediagnostic serum levels of testosterone and free testosterone were associated with an increased overall risk of breast cancer [ORQ4-Q1 = 1.56 (95% CI 1.15-2.13), ptrend = 0.02 for testosterone and ORQ4-Q1 = 1.33 (95% CI 0.99-1.79), ptrend = 0.04 for free testosterone], but no significant risk association was observed for estradiol, free estradiol, progesterone and SHBG. Tests for heterogeneity between receptor-positive and -negative tumors were not significant. When analysis were stratified by age at tumor diagnosis, the odds ratios observed for estradiol were stronger and borderline significant for breast cancer diagnosed at age less than 50 [ORQ4-Q1 = 1.32 (95% CI 0.87-2.01), ptrend = 0.05] compared to breast cancer diagnosed at age 50 or above [ORQ4-Q1 = 0.94 (95% CI 0.60-1.47), ptrend = 0.34, phet = 0.04]. In conclusion, our data indicate that higher premenopausal circulating testosterone levels are associated with an increased risk of developing breast cancer, but do not show a significant association of estradiol or progesterone with breast cancer risk, overall, by menstrual cycle phase or by tumor receptor status, although a possible risk increase with higher estradiol levels for tumors diagnosed before age 50 was seen.

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.

Abstract Background: Case–control studies suggested a moderate, but consistent, association of hepatitis C virus (HCV) infection with lymphoid tissue malignancies, especially non–Hodgkin lymphoma (NHL). More limited data suggested that hepatitis B virus (HBV) infection might also be associated with NHL. However, prospective studies on the topic are few. Methods: A nested case–control study was conducted in eight countries participating in the EPIC prospective study. Seven hundred thirty-nine incident cases of NHL, 238 multiple myeloma (MM), and 46 Hodgkin lymphoma (HL) were matched with 2,028 controls. Seropositivity to anti-HCV, anti-HBc, and HBsAg was evaluated and conditional logistic regression was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (CI) for NHL, MM, or HL, and their combination. Results: Anti-HCV seropositivity among controls in different countries ranged from 0% to 5.3%; HBsAg from 0% to 2.7%; and anti-HBc from 1.9% to 45.9%. Similar nonsignificant associations were found with seropositivity to HBsAg for NHL (OR = 1.78; 95% CI: 0.78–4.04), MM (OR = 4.00; 95% CI: 1.00–16.0), and HL (OR = 2.00; 95% CI: 0.13–32.0). The association between HBsAg and the combination of NHL, MM, and HL (OR = 2.21; 95% CI: 1.12–4.33) was similar for cancer diagnosed less than 3 and 3 or more years after blood collection. No significant association was found between anti-HCV and NHL, MM, or HL risk, but the corresponding CIs were very broad. Conclusions: Chronic HBV infection may increase the risk of lymphoid malignancies among healthy European volunteers. Impact: Treatment directed at control of HBV infection should be evaluated in HBsAg-seropositive patients with lymphoid tissue malignancies. Cancer Epidemiol Biomarkers Prev; 20(1); 208–14. ©2011 AACR.

Although smoking and HPV infection are recognized as important risk factors for oropharyngeal cancer, how their joint exposure impacts on oropharyngeal cancer risk is unclear. Specifically, whether smoking confers any additional risk to HPV-positive oropharyngeal cancer is not understood.Using HPV serology as a marker of HPV-related cancer, we examined the interaction between smoking and HPV16 in 459 oropharyngeal (and 1445 oral cavity and laryngeal) cancer patients and 3024 control participants from two large European multi-centre studies. Odds ratios and credible intervals [CrI], adjusted for potential confounders, were estimated using Bayesian logistic regression.Both smoking [odds ratio (OR [CrI]: 6.82 [4.52, 10.29]) and HPV seropositivity (OR [CrI]: 235.69 [99.95, 555.74]) were independently associated with oropharyngeal cancer. The joint association of smoking and HPV seropositivity was consistent with that expected on the additive scale (synergy index [CrI]: 1.32 [0.51, 3.45]), suggesting they act as independent risk factors for oropharyngeal cancer.Smoking was consistently associated with increase in oropharyngeal cancer risk in models stratified by HPV16 seropositivity. In addition, we report that the prevalence of oropharyngeal cancer increases with smoking for both HPV16-positive and HPV16-negative persons. The impact of smoking on HPV16-positive oropharyngeal cancer highlights the continued need for smoking cessation programmes for primary prevention of head and neck cancer.

Alcohol intake has been associated to breast cancer in pre and postmenopausal women; however results are inconclusive regarding tumor hormonal receptor status, and potential modifying factors like age at start drinking. Therefore, we investigated the relation between alcohol intake and the risk of breast cancer using prospective observational data from the European Prospective Investigation into Cancer and Nutrition (EPIC). Up to 334,850 women, aged 35–70 years at baseline, were recruited in ten European countries and followed up an average of 11 years. Alcohol intake at baseline and average lifetime alcohol intake were calculated from country‐specific dietary and lifestyle questionnaires. The study outcomes were the Hazard ratios (HR) of developing breast cancer according to hormonal receptor status. During 3,670,439 person‐years, 11,576 incident breast cancer cases were diagnosed. Alcohol intake was significantly related to breast cancer risk, for each 10 g/day increase in alcohol intake the HR increased by 4.2% (95% CI: 2.7–5.8%). Taking 0 to 5 g/day as reference, alcohol intake of &gt;5 to 15 g/day was related to a 5.9% increase in breast cancer risk (95% CI: 1–11%). Significant increasing trends were observed between alcohol intake and ER+/PR+, ER−/PR−, HER2− and ER−/PR−HER2− tumors. Breast cancer risk was stronger among women who started drinking prior to first full‐time pregnancy. Overall, our results confirm the association between alcohol intake and both hormone receptor positive and hormone receptor negative breast tumors, suggesting that timing of exposure to alcohol drinking may affect the risk. Therefore, women should be advised to control their alcohol consumption.

Adiponectin-an adipose tissue-derived protein-may provide a molecular link between obesity and colorectal cancer (CRC), but evidence from large prospective studies is limited. In particular, no epidemiological study explored high-molecular weight (HMW) and non-HMW adiponectin fractions in relation to CRC risk, despite them being hypothesized to have differential biological activities, i.e. regulating insulin sensitivity (HMW adiponectin) versus inflammatory response (non-HMW adiponectin). In a prospective, nested case-control study, we investigated whether prediagnostic serum concentrations of total, HMW and non-HMW adiponectin are associated with risk of CRC, independent of obesity and other known CRC risk factors. A total of 1206 incident cases (755 colon and 451 rectal) were matched to 1206 controls using incidence-density sampling. In conditional logistic regression, adjusted for dietary and lifestyle factors, total adiponectin and non-HMW adiponectin concentrations were inversely associated with risk of CRC [relative risk (RR) comparing highest versus lowest quintile = 0.71, 95% confidence interval (CI) = 0.53-0.95, P(trend) = 0.03 for total adiponectin and RR = 0.45, 95% CI = 0.34-0.61, P(trend) < 0.0001 for non-HMW adiponectin]. HMW adiponectin concentrations were not associated with CRC risk (RR = 0.91, 95% CI = 0.68-1.22, P(trend) = 0.55). Non-HMW adiponectin was associated with CRC risk even after adjustment for body mass index and waist circumference (RR = 0.39, 95% CI = 0.26-0.60, P(trend) < 0.0001), whereas the association with total adiponectin was no longer significant (RR = 0.81, 95% CI = 0.60-1.09, P(trend) = 0.23). When stratified by cancer site, non-HMW adiponectin was inversely associated with both colon and rectal cancer. These findings suggest an important role of the relative proportion of non-HMW adiponectin in CRC pathogenesis. Future studies are warranted to confirm these results and to elucidate the underlying mechanisms.

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.

International Journal of CancerVolume 135, Issue 12 p. 2887-2899 EpidemiologyFree Access Weight change in middle adulthood and breast cancer risk in the EPIC-PANACEA study Marleen J. Emaus, Marleen J. Emaus Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorCarla H. van Gils, Carla H. van Gils Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorMarije F. Bakker, Marije F. Bakker Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorCharlotte N. Steins Bisschop, Charlotte N. Steins Bisschop Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorEvelyn M. Monninkhof, Evelyn M. Monninkhof Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorH. B(as) Bueno-de-Mesquita, H. B(as) Bueno-de-Mesquita National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, the Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorNoémie Travier, Noémie Travier Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Barcelona, SpainSearch for more papers by this authorTina Landsvig Berentzen, Tina Landsvig Berentzen Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals—A part of Copenhagen University Hospital, The Capital Region, Copenhagen, DenmarkSearch for more papers by this authorKim Overvad, Kim Overvad Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, DenmarkSearch for more papers by this authorAnne Tjønneland, Anne Tjønneland The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, DenmarkSearch for more papers by this authorIsabelle Romieu, Isabelle Romieu International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorSabina Rinaldi, Sabina Rinaldi International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorVeronique Chajes, Veronique Chajes International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorMarc J. Gunter, Marc J. Gunter Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorFrançoise Clavel-Chapelon, Françoise Clavel-Chapelon Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorGuy Fagherazzi, Guy Fagherazzi Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorSylvie Mesrine, Sylvie Mesrine Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorJenny Chang-Claude, Jenny Chang-Claude German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorRudolf Kaaks, Rudolf Kaaks German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorHeiner Boeing, Heiner Boeing Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, GermanySearch for more papers by this authorKrasimira Aleksandrova, Krasimira Aleksandrova Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, GermanySearch for more papers by this authorAntonia Trichopoulou, Antonia Trichopoulou Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorAndroniki Naska, Androniki Naska Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorPhilippos Orfanos, Philippos Orfanos Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorDomenico Palli, Domenico Palli Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, ItalySearch for more papers by this authorClaudia Agnoli, Claudia Agnoli Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalySearch for more papers by this authorRosario Tumino, Rosario Tumino Cancer Registry and Histopathology Unit, "Civile M.P. Arezzo" Hospital, ASP Ragusa, ItalySearch for more papers by this authorPaolo Vineis, Paolo Vineis Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom HuGeF Foundation, Torino, ItalySearch for more papers by this authorAmalia Mattiello, Amalia Mattiello Dipartimento Di Medicina Clinica E Chirurgia Federico II University, Naples, ItalySearch for more papers by this authorTonje Braaten, Tonje Braaten Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorKristin Benjaminsen Borch, Kristin Benjaminsen Borch Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorEiliv Lund, Eiliv Lund Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorVirginia Menéndez, Virginia Menéndez Public Health Directorate, Asturias, SpainSearch for more papers by this authorMaría-José Sánchez, María-José Sánchez Andalusian School of Public Health, Granada, Spain CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, SpainSearch for more papers by this authorCarmen Navarro, Carmen Navarro CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain Department of Health and Social Sciences, Universidad de Murcia, Murcia, SpainSearch for more papers by this authorAurelio Barricarte, Aurelio Barricarte CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Navarre Public Health Institute, Pamplona, SpainSearch for more papers by this authorPilar Amiano, Pilar Amiano Public Health Division of Gipuzkoa, San Sebastian, SpainSearch for more papers by this authorMalin Sund, Malin Sund Department of Surgical and Perioperative Sciences/Surgery, Umeå University, Umeå, SwedenSearch for more papers by this authorAnne Andersson, Anne Andersson Department of radiation sciences, oncology, Umeå University, Umeå, SwedenSearch for more papers by this authorSigne Borgquist, Signe Borgquist Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden Department of Oncology, Skåne University Hospital, Lund, SwedenSearch for more papers by this authorÅsa Olsson, Åsa Olsson Department of Surgery, Lund University, Skåne University Hospital, Malmö, SwedenSearch for more papers by this authorKay-Tee Khaw, Kay-Tee Khaw University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorNick Wareham, Nick Wareham University of Cambridge, Cambridge, United Kingdom MRC Epidemiology Unit, Cambridge, United KingdomSearch for more papers by this authorRuth C. Travis, Ruth C. Travis Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorElio Riboli, Elio Riboli Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorPetra H.M. Peeters, Petra H.M. Peeters Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorAnne M. May, Corresponding Author Anne M. May Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsCorrespondence to: Anne M. May, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, the Netherlands, Tel.: +31-88-755-1132, Fax: +31-88-755-5480, E-mail: a.m.may@umcutrecht.nlSearch for more papers by this author Marleen J. Emaus, Marleen J. Emaus Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorCarla H. van Gils, Carla H. van Gils Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorMarije F. Bakker, Marije F. Bakker Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorCharlotte N. Steins Bisschop, Charlotte N. Steins Bisschop Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorEvelyn M. Monninkhof, Evelyn M. Monninkhof Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsSearch for more papers by this authorH. B(as) Bueno-de-Mesquita, H. B(as) Bueno-de-Mesquita National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands Department of Gastroenterology and Hepatology, University Medical Center, Utrecht, the Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorNoémie Travier, Noémie Travier Unit of Nutrition, Environment and Cancer, Cancer Epidemiology Research Programme, Catalan Institute of Oncology, Barcelona, SpainSearch for more papers by this authorTina Landsvig Berentzen, Tina Landsvig Berentzen Institute of Preventive Medicine, Bispebjerg and Frederiksberg Hospitals—A part of Copenhagen University Hospital, The Capital Region, Copenhagen, DenmarkSearch for more papers by this authorKim Overvad, Kim Overvad Department of Public Health, Section for Epidemiology, Aarhus University, Aarhus, DenmarkSearch for more papers by this authorAnne Tjønneland, Anne Tjønneland The Danish Cancer Society, Institute of Cancer Epidemiology, Copenhagen, DenmarkSearch for more papers by this authorIsabelle Romieu, Isabelle Romieu International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorSabina Rinaldi, Sabina Rinaldi International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorVeronique Chajes, Veronique Chajes International Agency for Research on Cancer (IARC-WHO), Lyon, FranceSearch for more papers by this authorMarc J. Gunter, Marc J. Gunter Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorFrançoise Clavel-Chapelon, Françoise Clavel-Chapelon Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorGuy Fagherazzi, Guy Fagherazzi Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorSylvie Mesrine, Sylvie Mesrine Inserm, Centre for research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health team, F-94805 Villejuif, France Univ Paris Sud, UMRS 1018, F-94805 Villejuif, France IGR, F-94805 Villejuif, FranceSearch for more papers by this authorJenny Chang-Claude, Jenny Chang-Claude German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorRudolf Kaaks, Rudolf Kaaks German Cancer Research Center (DKFZ), Heidelberg, GermanySearch for more papers by this authorHeiner Boeing, Heiner Boeing Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, GermanySearch for more papers by this authorKrasimira Aleksandrova, Krasimira Aleksandrova Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrücke, Nuthetal, GermanySearch for more papers by this authorAntonia Trichopoulou, Antonia Trichopoulou Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorAndroniki Naska, Androniki Naska Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorPhilippos Orfanos, Philippos Orfanos Department of Hygiene, Epidemiology and Medical Statistics, WHO Collaborating Center for Food and Nutrition Policies, University of Athens Medical School, Athens, Greece Hellenic Health Foundation, Athens, GreeceSearch for more papers by this authorDomenico Palli, Domenico Palli Molecular and Nutritional Epidemiology Unit, Cancer Research and Prevention Institute—ISPO, Florence, ItalySearch for more papers by this authorClaudia Agnoli, Claudia Agnoli Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, ItalySearch for more papers by this authorRosario Tumino, Rosario Tumino Cancer Registry and Histopathology Unit, "Civile M.P. Arezzo" Hospital, ASP Ragusa, ItalySearch for more papers by this authorPaolo Vineis, Paolo Vineis Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom HuGeF Foundation, Torino, ItalySearch for more papers by this authorAmalia Mattiello, Amalia Mattiello Dipartimento Di Medicina Clinica E Chirurgia Federico II University, Naples, ItalySearch for more papers by this authorTonje Braaten, Tonje Braaten Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorKristin Benjaminsen Borch, Kristin Benjaminsen Borch Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorEiliv Lund, Eiliv Lund Department of Community Medicine, University of Tromsø, Tromsø, NorwaySearch for more papers by this authorVirginia Menéndez, Virginia Menéndez Public Health Directorate, Asturias, SpainSearch for more papers by this authorMaría-José Sánchez, María-José Sánchez Andalusian School of Public Health, Granada, Spain CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, SpainSearch for more papers by this authorCarmen Navarro, Carmen Navarro CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Department of Epidemiology, Murcia Regional Health Council, Murcia, Spain Department of Health and Social Sciences, Universidad de Murcia, Murcia, SpainSearch for more papers by this authorAurelio Barricarte, Aurelio Barricarte CIBER de Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain Navarre Public Health Institute, Pamplona, SpainSearch for more papers by this authorPilar Amiano, Pilar Amiano Public Health Division of Gipuzkoa, San Sebastian, SpainSearch for more papers by this authorMalin Sund, Malin Sund Department of Surgical and Perioperative Sciences/Surgery, Umeå University, Umeå, SwedenSearch for more papers by this authorAnne Andersson, Anne Andersson Department of radiation sciences, oncology, Umeå University, Umeå, SwedenSearch for more papers by this authorSigne Borgquist, Signe Borgquist Division of Oncology, Department of Clinical Sciences, Lund University, Lund, Sweden Department of Oncology, Skåne University Hospital, Lund, SwedenSearch for more papers by this authorÅsa Olsson, Åsa Olsson Department of Surgery, Lund University, Skåne University Hospital, Malmö, SwedenSearch for more papers by this authorKay-Tee Khaw, Kay-Tee Khaw University of Cambridge, Cambridge, United KingdomSearch for more papers by this authorNick Wareham, Nick Wareham University of Cambridge, Cambridge, United Kingdom MRC Epidemiology Unit, Cambridge, United KingdomSearch for more papers by this authorRuth C. Travis, Ruth C. Travis Cancer Epidemiology Unit, University of Oxford, Oxford, United KingdomSearch for more papers by this authorElio Riboli, Elio Riboli Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorPetra H.M. Peeters, Petra H.M. Peeters Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United KingdomSearch for more papers by this authorAnne M. May, Corresponding Author Anne M. May Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the NetherlandsCorrespondence to: Anne M. May, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX, the Netherlands, Tel.: +31-88-755-1132, Fax: +31-88-755-5480, E-mail: a.m.may@umcutrecht.nlSearch for more papers by this author First published: 26 April 2014 https://doi.org/10.1002/ijc.28926Citations: 43AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Abstract Long-term weight gain (i.e., weight gain since age 20) has been related to higher risk of postmenopausal breast cancer, but a lower risk of premenopausal breast cancer. The effect of weight change in middle adulthood is unclear. We investigated the association between weight change in middle adulthood (i.e., women aged 40–50 years) and the risk of breast cancer before and after the age of 50. We included female participants of the European Prospective Investigation into Cancer and Nutrition cohort, with information on anthropometric measures at recruitment and after a median follow-up of 4.3 years. Annual weight change was categorized using quintiles taking quintile 2 and 3 as the reference category (−0.44 to 0.36 kg/year). Multivariable Cox proportional hazards regression analysis was used to examine the association. 205,723 women were included and 4,663 incident breast cancer cases were diagnosed during a median follow-up of 7.5 years (from second weight assessment onward). High weight gain (Q5: 0.83–4.98 kg/year) was related to a slightly, but significantly higher breast cancer risk (HRQ5_versus_Q2/3: 1.09, 95% CI: 1.01−1.18). The association was more pronounced for breast cancer diagnosed before or at age 50 (HRQ5_versus_Q2/3: 1.37, 95% CI: 1.02−1.85). Weight loss was not associated with breast cancer risk. There was no evidence for heterogeneity by hormone receptor status. In conclusion, high weight gain in middle adulthood increases the risk of breast cancer. The association seems to be more pronounced for breast cancer diagnosed before or at age 50. Our results illustrate the importance of avoiding weight gain in middle adulthood. Abstract What's new? This is one of the first studies that investigated the effect of prospectively measured weight change in middle adulthood in relation to breast cancer. We used data from the EPIC-PANACEA study which is a large multicenter cohort study. Although it is well known that BMI protects against premenopausal breast cancer, this study found evidence that weight gain in middle adulthood increases breast cancer risk, especially breast cancer diagnosed before or at age 50. Abbreviations EPIC European Prospective Investigation into Cancer and Nutrition ER estrogen receptor HRT hormone replacement therapy PANACEA Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home And obesity PR progesterone receptor Based on the results of cohort1-11 and case–control studies,12-17 the World Cancer Research Fund states that long-term adult weight gain (i.e., recalled weight gain since age 20) increases the risk of postmenopausal breast cancer and grades this relation as "probable".18 Most studies investigated the association between long-term weight gain and breast cancer risk without a focus on a particular period in life. Only two cohort studies have examined prospective changes in weight in middle adulthood as well (i.e., weight change since menopause,4 and between age 45–55 and after age 555). Although both studies showed an increased postmenopausal breast cancer risk for long-term weight gain (defined as weight gain since age 184 and since age 255), the results for weight gain in middle adulthood varied from no association5 to a slightly increased risk of postmenopausal breast cancer.4 A third study investigated the association between weight change before (<45 years), between (≥45 and <55 years) and after menopause (≥55 years) and the risk of postmenopausal breast cancer.19 This prospective study observed an increased risk for postmenopausal breast cancer in relation to weight gain before and around menopause. In line with these findings, one would expect that the association of weight loss and breast cancer is in the opposite direction of the association of weight gain and breast cancer. However, previous studies did not provide sufficient evidence for this hypothesis.1, 3, 12, 16, 17, 20 The effect of weight change has been proposed to be modified by BMI15 and the use of postmenopausal hormone replacement therapy (HRT).4, 6-8, 11 Studies suggest that the relationship is more pronounced or only present in leaner women and non-HRT users. In the European Prospective Investigation into Cancer and Nutrition (EPIC), the association between weight change since age 20 until EPIC recruitment and breast cancer risk has been investigated showing a higher breast cancer risk in postmenopausal non-current HRT users only.6 Here, we evaluated the association between weight change in middle adulthood (i.e., after recruitment into the cohort, when the majority of participants was between 46 and 58 years old) and the occurrence of primary invasive breast cancer diagnosed before and after the age of 50 years. For this, we use data from the European Prospective Investigation into Cancer and Nutrition-Physical Activity, Nutrition, Alcohol, Cessation of smoking, Eating out of home And obesity (EPIC-PANACEA) study, which is a subcohort of EPIC that includes all participants with repeated assessment of anthropometry.21, 22 We further investigated whether associations differ by the timing of weight change, i.e., occurring either in the period before, around or after the age of 50 years, or by hormone receptor status of the breast tumors. Potential effect modification by BMI and use of HRT at recruitment was explored as well. Material and Methods Subjects The EPIC study is an on-going multi-center prospective cohort study designed to investigate the relation between nutrition and cancer occurrence. The design of EPIC is described in detail elsewhere.23 The cohort consists of 23 centers in ten European countries (i.e., Denmark, France, Germany, Greece, Italy, Netherlands, Norway, Spain, Sweden and United Kingdom). From 1992–2000, more than 500,000 individuals aged between 25 and 70 years were recruited in ten European countries. All participants gave written or oral informed consent. The study was approved by the International Agency for Research on Cancer ethical review committee and by local ethical committees at the participating centers. The EPIC-PANACEA study is a subcohort of EPIC where repeated data of anthropometry are available, and is originally designed to investigate determinants of obesity and weight changes in Europe.21, 22 For EPIC-PANACEA, 147,103 participants were excluded according to the PANACEA exclusion criteria, i.e., missing dietary and non-dietary questionnaires, in the top or bottom 1% of the ratio of energy intake to energy requirement (estimated from age, sex, and body weight and height), pregnant women, missing weight at recruitment or extreme anthropometric values (i.e., height <1.3 m, BMI <16 kg/m2, waist circumference >160 cm and waist circumference <60 cm in combination with BMI >25 kg/m2), missing follow-up weight (this included the cohorts of Turin and Ragusa (both Italy) and parts of cohorts from Norway and Naples (Italy)) or participants with a weight change of ≤5 or >5 kg/year over several years. For the present study, we further excluded male participants (N = 91,390) and women without any follow-up information after the second weight assessment, or women with (prevalent or incident) cancer other than non-melanoma skin cancers before the second weight assessment (N = 45,404). Furthermore, women with a breast cancer in situ diagnosis after the second weight assessment, or with missing information on breast cancer occurrence or on breast cancer behavior were excluded (N = 697). Participants of the centers Norway and Umeå (Sweden) were excluded (N = 31,131), because in these centers different questionnaires were used to assess physical activity. The final study population comprised 205,723 women from nine countries. Assessment of anthropometric measures and weight change At recruitment, anthropometry was assessed by trained staff using a standard examination protocol which has been described in detail.24 Weight was measured to the nearest 0.1 kg and height was measured without shoes, to the nearest 0.1, 0.5 or 1.0 cm depending on the study center. The measurements were corrected to account for protocol differences between centers.24 The centers in Oxford (United Kingdom) and France collected self-reported weight and height. The second weight assessment took place after a median follow-up of 4.3 years (IQR: 3.5−5.4 years), and was conducted through self-report in all centers, with the exception of Cambridge (United Kingdom) and Doetinchem (Netherlands) where weight was measured by trained staff. To account for differences in follow-up time between first and second weight assessment (varying from 2 to 11 years), annual weight change was calculated by dividing absolute weight change by follow-up time between two weight assessments. Assessment of end point The outcome of interest was first incident of primary invasive breast cancer diagnosed after the second weight assessment (Fig. 1), identified through population cancer registries or by active follow-up. The active follow-up procedure used a combination of methods including health insurance records, cancer and pathology registries, and active follow-up through study participants and their next-of-kin. Cancer incidence data were classified according to the International Classification of Disease, 10th Revision. Breast cancer was defined as C50. Censoring dates for each center were established depending on the dates at which cancer registries were considered complete. In case of active follow-up, the end of follow-up was the last known contact, date of diagnosis, or date of death, whichever came first. Loss to follow-up was 3.7%. Information on hormone receptor status was provided by each center based on pathology reports and was routinely available for tumors diagnosed after 1997–2006, depending on center. Figure 1Open in figure viewerPowerPoint Overview of EPIC-PANACEA (N = 205,723). *For EPIC-PANACEA, 147,103 participants were excluded according to the PANACEA exclusion criteria, i.e., missing dietary and non-dietary questionnaires, in the top or bottom 1% of the ratio of energy intake to energy requirement (estimated from age, sex and body weight and height), pregnant women, missing weight at recruitment or extreme anthropometric values, missing follow-up weight or participants with a weight change of ≤5 or >5 kg/year over several years. For the present study, we further excluded male participants (N = 91,390). Additionally, women without any follow-up information after the second weight assessment, or women with (preval

Obesity is a major cardiovascular risk factor. In Spain, few studies have physically measured height and weight to estimate the magnitude of the problem. The aim of this study was to determine the prevalence of child and adolescent obesity in Spain in 2012.We performed a cross-sectional probability sample of 1018 children, representative of the Spanish population aged between 8 and 17 years old, with objectively measured height and weight, along with other sociodemographic variables. We calculated the prevalence of overweight and obesity according to the criteria of the World Health Organization, the International Obesity Task Force, and the enKid study.In the group aged 8 to 17 years old, the prevalence of overweight and obesity was 26% and 12.6%, respectively; 4 in 10 young people were overweight or obese. Excess weight was found in 45% of the group aged 8 to 13 years and in 25.5% of that aged 14 to 17 years. This cardiovascular risk factor was associated with lower social class and lower educational level.The prevalence of overweight and obesity in children and adolescents in Spain remains high (close to 40%), but has not increased in the last 12 years.