Παγώνα Λάγιου

Lung cancer is the most common cause of cancer death worldwide, with over one million cases annually. To identify genetic factors that modify disease risk, we conducted a genome-wide association study by analysing 317,139 single-nucleotide polymorphisms in 1,989 lung cancer cases and 2,625 controls from six central European countries. We identified a locus in chromosome region 15q25 that was strongly associated with lung cancer (P = 9 x 10(-10)). This locus was replicated in five separate lung cancer studies comprising an additional 2,513 lung cancer cases and 4,752 controls (P = 5 x 10(-20) overall), and it was found to account for 14% (attributable risk) of lung cancer cases. Statistically similar risks were observed irrespective of smoking status or propensity to smoke tobacco. The association region contains several genes, including three that encode nicotinic acetylcholine receptor subunits (CHRNA5, CHRNA3 and CHRNB4). Such subunits are expressed in neurons and other tissues, in particular alveolar epithelial cells, pulmonary neuroendocrine cells and lung cancer cell lines, and they bind to N'-nitrosonornicotine and potential lung carcinogens. A non-synonymous variant of CHRNA5 that induces an amino acid substitution (D398N) at a highly conserved site in the second intracellular loop of the protein is among the markers with the strongest disease associations. Our results provide compelling evidence of a locus at 15q25 predisposing to lung cancer, and reinforce interest in nicotinic acetylcholine receptors as potential disease candidates and chemopreventative targets.

To assess the influence of a specific dietary pattern on overall survival.Cohort study.Three rural Greek villages, the data from which were collected as part of an international cross cultural study of food habits in later life.182 elderly residents of the three villages.Overall mortality.Diet was assessed with a validated extensive semiquantitative questionnaire on food intake. A one unit increase in diet score, devised a priori on the basis of eight component characteristics of the traditional common diet in the Mediterranean region, was associated with a significant 17% reduction in overall mortality (95% confidence interval 1% to 31%).A diet meeting currently understood health criteria does predict survival among people.

Low-risk limits recommended for alcohol consumption vary substantially across different national guidelines. To define thresholds associated with lowest risk for all-cause mortality and cardiovascular disease, we studied individual-participant data from 599 912 current drinkers without previous cardiovascular disease.We did a combined analysis of individual-participant data from three large-scale data sources in 19 high-income countries (the Emerging Risk Factors Collaboration, EPIC-CVD, and the UK Biobank). We characterised dose-response associations and calculated hazard ratios (HRs) per 100 g per week of alcohol (12·5 units per week) across 83 prospective studies, adjusting at least for study or centre, age, sex, smoking, and diabetes. To be eligible for the analysis, participants had to have information recorded about their alcohol consumption amount and status (ie, non-drinker vs current drinker), plus age, sex, history of diabetes and smoking status, at least 1 year of follow-up after baseline, and no baseline history of cardiovascular disease. The main analyses focused on current drinkers, whose baseline alcohol consumption was categorised into eight predefined groups according to the amount in grams consumed per week. We assessed alcohol consumption in relation to all-cause mortality, total cardiovascular disease, and several cardiovascular disease subtypes. We corrected HRs for estimated long-term variability in alcohol consumption using 152 640 serial alcohol assessments obtained some years apart (median interval 5·6 years [5th-95th percentile 1·04-13·5]) from 71 011 participants from 37 studies.In the 599 912 current drinkers included in the analysis, we recorded 40 310 deaths and 39 018 incident cardiovascular disease events during 5·4 million person-years of follow-up. For all-cause mortality, we recorded a positive and curvilinear association with the level of alcohol consumption, with the minimum mortality risk around or below 100 g per week. Alcohol consumption was roughly linearly associated with a higher risk of stroke (HR per 100 g per week higher consumption 1·14, 95% CI, 1·10-1·17), coronary disease excluding myocardial infarction (1·06, 1·00-1·11), heart failure (1·09, 1·03-1·15), fatal hypertensive disease (1·24, 1·15-1·33); and fatal aortic aneurysm (1·15, 1·03-1·28). By contrast, increased alcohol consumption was log-linearly associated with a lower risk of myocardial infarction (HR 0·94, 0·91-0·97). In comparison to those who reported drinking >0-≤100 g per week, those who reported drinking >100-≤200 g per week, >200-≤350 g per week, or >350 g per week had lower life expectancy at age 40 years of approximately 6 months, 1-2 years, or 4-5 years, respectively.In current drinkers of alcohol in high-income countries, the threshold for lowest risk of all-cause mortality was about 100 g/week. For cardiovascular disease subtypes other than myocardial infarction, there were no clear risk thresholds below which lower alcohol consumption stopped being associated with lower disease risk. These data support limits for alcohol consumption that are lower than those recommended in most current guidelines.UK Medical Research Council, British Heart Foundation, National Institute for Health Research, European Union Framework 7, and European Research Council.

Background. Recent epidemiologic investigations have suggested an association between increased blood levels of insulin-like growth factor 1 (IGF-1) and increased risk of prostate cancer Our goal was to determine whether an association exists between serum levels of IGF-1 and one of its binding proteins, insulin-like growth factorbinding protein 3 (IGFBP-3), and prostate cancer risk. Methods: An immunoradiometric assay was used to quantify IGF-1 levels and IGFBP-3 levels in serum samples as part of a populationbased, case-control study in Sweden. The study population comprised 210 patients with newly diagnosed, untreated prostate cancer and 224 frequency-matched control subjects. Data were analyzed by use of unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). Reported P values are twosided. Results: The mean serum IGF-1 level for case patients (158.4 ng/mL) was significantly higher than that for control subjects (147.4 ng/mL) (P =.02); corresponding mean serum IGFBP-3 levels were not significantly different between case patients (2668 ng/mL) and control subjects (2518 ng/ mL) (P =.09). We found a moderately strong and statistically significant (P = .04) positive association between serum levels of IGF-1 levels and risk of prostate cancer (OR = 1.51; 95% CI = 1.0-2.26 per 100 ng/mL increment); the association was particularly strong for men younger than 70 years of age (OR = 2.93; 95% CI = 1.43–5.97). No association was found between serum IGF-1 levels and disease stage. Serum IGFBP-3 levels were not significantly associated with increased risk of disease, and adjustment for IGFBP-3 had little effect on the association between IGF-1 levels and risk of prostate cancer. Conclusion Elevated serum IGF-1 levels may be an important predictor of risk for prostate cancer. However, our results do not support an important role for serum IGFBP-3 as a predictor of risk for this disease. [J Nall Cancer Inst 1998;90:911-5]

The term Mediterranean diet refers to dietary patterns found in olive-growing areas of the Mediterranean region and described in the 1960s and beyond. There are several variants of the Mediterranean diet, but some common components can be identified: high monounsaturated/saturated fat ratio; ethanol consumption at moderate levels and mainly in the form of wine; high consumption of vegetables, fruits, legumes, and grains; moderate consumption of milk and dairy products, mostly in the form of cheese; and low consumption of meat and meat products. Growing evidence demonstrates that the Mediterranean diet is beneficial to health; the evidence is stronger for coronary heart disease, but it also applies to some forms of cancer. Results from recent investigations provide a strong biomedical foundation for the beneficial effects of the Mediterranean diet.

It is widely believed that cancer can be prevented by high intake of fruits and vegetables. However, inconsistent results from many studies have not been able to conclusively establish an inverse association between fruit and vegetable intake and overall cancer risk.We conducted a prospective analysis of the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort to assess relationships between intake of total fruits, total vegetables, and total fruits and vegetables combined and cancer risk during 1992-2000. Detailed information on the dietary habit and lifestyle variables of the cohort was obtained. Cancer incidence and mortality data were ascertained, and hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models. Analyses were also conducted for cancers associated with tobacco and alcohol after stratification for tobacco smoking and alcohol drinking.Of the initial 142 605 men and 335 873 women included in the study, 9604 men and 21 000 women were identified with cancer after a median follow-up of 8.7 years. The crude cancer incidence rates were 7.9 per 1000 person-years in men and 7.1 per 1000 person-years in women. Associations between reduced cancer risk and increased intake of total fruits and vegetables combined and total vegetables for the entire cohort were similar (200 g/d increased intake of fruits and vegetables combined, HR = 0.97, 95% CI = 0.96 to 0.99; 100 g/d increased intake of total vegetables, HR = 0.98, 95% CI = 0.97 to 0.99); intake of fruits showed a weaker inverse association (100 g/d increased intake of total fruits, HR = 0.99, 95% CI = 0.98 to 1.00). The reduced risk of cancer associated with high vegetable intake was restricted to women (HR = 0.98, 95% CI = 0.97 to 0.99). Stratification by alcohol intake suggested a stronger reduction in risk in heavy drinkers and was confined to cancers caused by smoking and alcohol.A very small inverse association between intake of total fruits and vegetables and cancer risk was observed in this study. Given the small magnitude of the observed associations, caution should be applied in their interpretation.

<h3>Objective</h3> Examine the relationship between antibodies to 25 oral bacteria and pancreatic cancer risk in a prospective cohort study. <h3>Design</h3> We measured antibodies to oral bacteria in prediagnosis blood samples from 405 pancreatic cancer cases and 416 matched controls, nested within the European Prospective Investigation into Cancer and Nutrition study. Analyses were conducted using conditional logistic regression and additionally adjusted for smoking status and body mass index. <h3>Results</h3> Individuals with high levels of antibodies against <i>Porphyromonas gingivalis</i> ATTC 53978, a pathogenic periodontal bacteria, had a twofold higher risk of pancreatic cancer than individuals with lower levels of these antibodies (OR 2.14; 95% CI 1.05 to 4.36; &gt;200 ng/ml vs ≤200 ng/ml). To explore the association with commensal (non-pathogenic) oral bacteria, we performed a cluster analysis and identified two groups of individuals, based on their antibody profiles. A cluster with overall higher levels of antibodies had a 45% lower risk of pancreatic cancer than a cluster with overall lower levels of antibodies (OR 0.55; 95% CI 0.36 to 0.83). <h3>Conclusions</h3> Periodontal disease might increase the risk for pancreatic cancer. Moreover, increased levels of antibodies against specific commensal oral bacteria, which can inhibit growth of pathogenic bacteria, might reduce the risk of pancreatic cancer. Studies are needed to determine whether oral bacteria have direct effects on pancreatic cancer pathogenesis or serve as markers of the immune response.

Purpose Human papillomavirus type 16 (HPV16) infection is causing an increasing number of oropharyngeal cancers in the United States and Europe. The aim of our study was to investigate whether HPV antibodies are associated with head and neck cancer risk when measured in prediagnostic sera. Methods We identified 638 participants with incident head and neck cancers (patients; 180 oral cancers, 135 oropharynx cancers, and 247 hypopharynx/larynx cancers) and 300 patients with esophageal cancers as well as 1,599 comparable controls from within the European Prospective Investigation Into Cancer and Nutrition cohort. Prediagnostic plasma samples from patients (collected, on average, 6 years before diagnosis) and control participants were analyzed for antibodies against multiple proteins of HPV16 as well as HPV6, HPV11, HPV18, HPV31, HPV33, HPV45, and HPV52. Odds ratios (ORs) of cancer and 95% CIs were calculated, adjusting for potential confounders. All-cause mortality was evaluated among patients using Cox proportional hazards regression. Results HPV16 E6 seropositivity was present in prediagnostic samples for 34.8% of patients with oropharyngeal cancer and 0.6% of controls (OR, 274; 95% CI, 110 to 681) but was not associated with other cancer sites. The increased risk of oropharyngeal cancer among HPV16 E6 seropositive participants was independent of time between blood collection and diagnosis and was observed more than 10 years before diagnosis. The all-cause mortality ratio among patients with oropharyngeal cancer was 0.30 (95% CI, 0.13 to 0.67), for patients who were HPV16 E6 seropositive compared with seronegative. Conclusion HPV16 E6 seropositivity was present more than 10 years before diagnosis of oropharyngeal cancers.

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.

Self-reported dietary intake is assessed by methods of real-time recording (food diaries and the duplicate portion method) and methods of recall (dietary histories, food frequency questionnaires, and 24-hour dietary recalls). Being less labor intensive, recall methods are more frequently employed in nutritional epidemiological investigations. However, sources of error, which include the participants' inability to fully and accurately recall their intakes as well as limitations inherent in the food composition databases applied to convert the reported food consumption to energy and nutrient intakes, may limit the validity of the generated information. The use of dietary biomarkers is often recommended to overcome such errors and better capture intra-individual variability in intake; nevertheless, it has its own challenges. To address measurement error associated with dietary questionnaires, large epidemiological investigations often integrate sub-studies for the validation and calibration of the questionnaires and/or administer a combination of different assessment methods (e.g. administration of different questionnaires and assessment of biomarker levels). Recent advances in the omics field could enrich the list of reliable nutrition biomarkers, whereas new approaches employing web-based and smart phone applications could reduce respondent burden and, possibly, reporting bias. Novel technologies are increasingly integrated with traditional methods, but some sources of error still remain. In the analyses, food and nutrient intakes always need to be adjusted for total daily energy intake to account for errors related to reporting.

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.

A higher intake of fruits and vegetables has been associated with a lower risk of ischaemic heart disease (IHD), but there is some uncertainty about the interpretation of this association. The objective was to assess the relation between fruit and vegetable intake and risk of mortality from IHD in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Heart study.After an average of 8.4 years of follow-up, there were 1636 deaths from IHD among 313 074 men and women without previous myocardial infarction or stroke from eight European countries. Participants consuming at least eight portions (80 g each) of fruits and vegetables a day had a 22% lower risk of fatal IHD [relative risk (RR) = 0.78, 95% confidence interval (CI): 0.65-0.95] compared with those consuming fewer than three portions a day. After calibration of fruit and vegetable intake to account for differences in dietary assessment between the participating centres, a one portion (80 g) increment in fruit and vegetable intake was associated with a 4% lower risk of fatal IHD (RR = 0.96, 95% CI: 0.92-1.00, P for trend = 0.033).Results from this large observational study suggest that a higher intake of fruits and vegetables is associated with a reduced risk of IHD mortality. Whether this association is causal and, if so, the biological mechanism(s) by which fruits and vegetables operate to lower IHD risks remains unclear.

Earlier analyses within the EPIC study showed that dietary fibre intake was inversely associated with colorectal cancer risk, but results from some large cohort studies do not support this finding. We explored whether the association remained after longer follow-up with a near threefold increase in colorectal cancer cases, and if the association varied by gender and tumour location.After a mean follow-up of 11.0 years, 4,517 incident cases of colorectal cancer were documented. Total, cereal, fruit, and vegetable fibre intakes were estimated from dietary questionnaires at baseline. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models stratified by age, sex, and centre, and adjusted for total energy intake, body mass index, physical activity, smoking, education, menopausal status, hormone replacement therapy, oral contraceptive use, and intakes of alcohol, folate, red and processed meats, and calcium. After multivariable adjustments, total dietary fibre was inversely associated with colorectal cancer (HR per 10 g/day increase in fibre 0.87, 95% CI: 0.79-0.96). Similar linear associations were observed for colon and rectal cancers. The association between total dietary fibre and risk of colorectal cancer risk did not differ by age, sex, or anthropometric, lifestyle, and dietary variables. Fibre from cereals and fibre from fruit and vegetables were similarly associated with colon cancer; but for rectal cancer, the inverse association was only evident for fibre from cereals.Our results strengthen the evidence for the role of high dietary fibre intake in colorectal cancer prevention.

ObjectiveTo study the long term consequences of low carbohydrate diets, generally characterised by concomitant increases in protein intake, on cardiovascular health.Design Prospective cohort study.Setting Uppsala, Sweden. ParticipantsFrom a random population sample, 43 396 Swedish women, aged 30-49 years at baseline, completed an extensive dietary questionnaire and were followed-up for an average of 15.7 years.Main outcome measures Association of incident cardiovascular diseases (ascertained by linkage with nationwide registries), overall and by diagnostic category, with decreasing carbohydrate intake (in tenths), increasing protein intake (in tenths), and an additive combination of these variables (low carbohydrate-high protein score, from 2 to 20), adjusted for intake of energy, intake of saturated and unsaturated fat, and several non-dietary variables.Results A one tenth decrease in carbohydrate intake or increase in protein intake or a 2 unit increase in the low carbohydrate-high protein score were all statistically significantly associated with increasing incidence of cardiovascular disease overall (n=1270)-incidence rate ratio estimates 1.04 (95% confidence interval 1.00 to 1.08), 1.04 (1.02 to 1.06), and 1.05 (1.02 to 1.08).No heterogeneity existed in the association of any of these scores with the five studied cardiovascular outcomes: ischaemic heart disease (n=703), ischaemic stroke (n=294), haemorrhagic stroke (n=70), subarachnoid haemorrhage (n=121), and peripheral arterial disease (n=82).Conclusions Low carbohydrate-high protein diets, used on a regular basis and without consideration of the nature of carbohydrates or the source of proteins, are associated with increased risk of cardiovascular disease.

BackgroundType 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time–risk relationship are unclear, and there is limited information on the role of antidiabetic medications.Patients and methodsWe analyzed individual-level data from 15 case–control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates.ResultsOverall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72–2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03–1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14–0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75–8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53–1.70, for ≥15 years).ConclusionThis study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration–risk relationship.

To date, no attempt has been made to systematically determine the apportionment of the hepatocellular carcinoma burden in Europe or North America among established risk factors.Using data collected from 1992 to 2006, which included 4,409,809 person-years in the European Prospective Investigation into Cancer and nutrition (EPIC), we identified 125 case patients with hepatocellular carcinoma, of whom 115 were matched to 229 control subjects. We calculated odds ratios (ORs) for the association of documented risk factors for hepatocellular carcinoma with incidence of this disease and estimated their importance in this European cohort.Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) infection (OR = 9.10, 95% confidence interval [CI] = 2.10 to 39.50 and OR = 13.36, 95% CI = 4.11 to 43.45, respectively), obesity (OR = 2.13, 95% CI = 1.06 to 4.29), former or current smoking (OR = 1.98, 95% CI = 0.90 to 4.39 and OR = 4.55, 95% CI = 1.90 to 10.91, respectively), and heavy alcohol intake (OR = 1.77, 95% CI = 0.73 to 4.27) were associated with hepatocellular carcinoma. Smoking contributed to almost half of all hepatocellular carcinomas (47.6%), whereas 13.2% and 20.9% were attributable to chronic HBV and HCV infection, respectively. Obesity and heavy alcohol intake contributed 16.1% and 10.2%, respectively. Almost two-thirds (65.7%, 95% CI = 50.6% to 79.3%) of hepatocellular carcinomas can be accounted for by exposure to at least one of these documented risk factors.Smoking contributed to more hepatocellular carcinomas in this Europe-wide cohort than chronic HBV and HCV infections. Heavy alcohol consumption and obesity also contributed to sizeable fractions of this disease burden. These contributions may be underestimates because EPIC volunteers are likely to be more health conscious than the general population.

Aim: Epigenetic changes may occur in response to environmental stressors, and an altered epigenome pattern may represent a stable signature of environmental exposure. Materials &amp; methods: Here, we examined the potential of DNA methylation changes in 910 prediagnostic peripheral blood samples as a marker of exposure to tobacco smoke in a large multinational cohort. Results: We identified 748 CpG sites that were differentially methylated between smokers and nonsmokers, among which we identified novel regionally clustered CpGs associated with active smoking. Importantly, we found a marked reversibility of methylation changes after smoking cessation, although specific genes remained differentially methylated up to 22 years after cessation. Conclusion: Our study has comprehensively cataloged the smoking-associated DNA methylation alterations and showed that these alterations are reversible after smoking cessation.

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.

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.

Obesity and associated metabolic disorders have been implicated in liver carcinogenesis; however, there are little data on the role of obesity-related biomarkers on liver cancer risk. We studied prospectively the association of inflammatory and metabolic biomarkers with risks of hepatocellular carcinoma (HCC), intrahepatic bile duct (IBD), and gallbladder and biliary tract cancers outside of the liver (GBTC) in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. Over an average of 7.7 years, 296 participants developed HCC (n=125), GBTC (n=137), or IBD (n=34). Using risk-set sampling, controls were selected in a 2:1 ratio and matched for recruitment center, age, sex, fasting status, and time of blood collection. Baseline serum concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), C-peptide, total high-molecular-weight (HMW) adiponectin, leptin, fetuin-a, and glutamatdehydrogenase (GLDH) were measured, and incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. After adjustment for lifestyle factors, diabetes, hepatitis infection, and adiposity measures, higher concentrations of CRP, IL-6, C-peptide, and non-HMW adiponectin were associated with higher risk of HCC (IRR per doubling of concentrations=1.22; 95% CI=1.02-1.46; P=0.03; 1.90; 95% CI=1.30-2.77; P=0.001; 2.25; 95% CI=1.43-3.54; P=0.0005; and 2.09; 95% CI=1.19-3.67; P=0.01, respectively). CRP was associated also with risk of GBTC (IRR=1.22; 95% CI=1.05-1.42; P=0.01). GLDH was associated with risks of HCC (IRR=1.62; 95% CI=1.25-2.11; P=0.0003) and IBD (IRR=10.5; 95% CI=2.20-50.90; P=0.003). The continuous net reclassification index was 0.63 for CRP, IL-6, C-peptide, and non-HMW adiponectin and 0.46 for GLDH, indicating good predictive ability of these biomarkers.Elevated levels of biomarkers of inflammation and hyperinsulinemia are associated with a higher risk of HCC, independent of obesity and established liver cancer risk factors.

The relationship between coffee consumption and mortality in diverse European populations with variable coffee preparation methods is unclear.To examine whether coffee consumption is associated with all-cause and cause-specific mortality.Prospective cohort study.10 European countries.521 330 persons enrolled in EPIC (European Prospective Investigation into Cancer and Nutrition).Hazard ratios (HRs) and 95% CIs estimated using multivariable Cox proportional hazards models. The association of coffee consumption with serum biomarkers of liver function, inflammation, and metabolic health was evaluated in the EPIC Biomarkers subcohort (n = 14 800).During a mean follow-up of 16.4 years, 41 693 deaths occurred. Compared with nonconsumers, participants in the highest quartile of coffee consumption had statistically significantly lower all-cause mortality (men: HR, 0.88 [95% CI, 0.82 to 0.95]; P for trend < 0.001; women: HR, 0.93 [CI, 0.87 to 0.98]; P for trend = 0.009). Inverse associations were also observed for digestive disease mortality for men (HR, 0.41 [CI, 0.32 to 0.54]; P for trend < 0.001) and women (HR, 0.60 [CI, 0.46 to 0.78]; P for trend < 0.001). Among women, there was a statistically significant inverse association of coffee drinking with circulatory disease mortality (HR, 0.78 [CI, 0.68 to 0.90]; P for trend < 0.001) and cerebrovascular disease mortality (HR, 0.70 [CI, 0.55 to 0.90]; P for trend = 0.002) and a positive association with ovarian cancer mortality (HR, 1.31 [CI, 1.07 to 1.61]; P for trend = 0.015). In the EPIC Biomarkers subcohort, higher coffee consumption was associated with lower serum alkaline phosphatase; alanine aminotransferase; aspartate aminotransferase; γ-glutamyltransferase; and, in women, C-reactive protein, lipoprotein(a), and glycated hemoglobin levels.Reverse causality may have biased the findings; however, results did not differ after exclusion of participants who died within 8 years of baseline. Coffee-drinking habits were assessed only once.Coffee drinking was associated with reduced risk for death from various causes. This relationship did not vary by country.European Commission Directorate-General for Health and Consumers and International Agency for Research on Cancer.

Suboptimal intakes of the micronutrient selenium (Se) are found in many parts of Europe. Low Se status may contribute to colorectal cancer (CRC) development. We assessed Se status by measuring serum levels of Se and Selenoprotein P (SePP) and examined the association with CRC risk in a nested case-control design (966 CRC cases; 966 matched controls) within the European Prospective Investigation into Cancer and Nutrition. Se was measured by total reflection X-ray fluorescence and SePP by immunoluminometric sandwich assay. Multivariable incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were calculated using conditional logistic regression. Respective mean Se and SePP levels were 84.0 μg/L and 4.3 mg/L in cases and 85.6 μg/L and 4.4 mg/L in controls. Higher Se concentrations were associated with a non-significant lower CRC risk (IRR = 0.92, 95% CI: 0.82-1.03 per 25 μg/L increase). However, sub-group analyses by sex showed a statistically significant association for women (p(trend) = 0.032; per 25 μg/L Se increase, IRR = 0.83, 95% CI: 0.70-0.97) but not for men. Higher SePP concentrations were inversely associated with CRC risk (p(trend) = 0.009; per 0.806 mg/L increase, IRR = 0.89, 95% CI: 0.82-0.98) with the association more apparent in women (p(trend) = 0.004; IRR = 0.82, 95% CI: 0.72-0.94 per 0.806 mg/L increase) than men (p(trend) = 0.485; IRR = 0.98, 95% CI: 0.86-1.12 per 0.806 mg/L increase). The findings indicate that Se status is suboptimal in many Europeans and suggest an inverse association between CRC risk and higher serum Se status, which is more evident in women.

Paul Brennan and colleagues perform genome-wide association analysis for oral cavity and pharyngeal cancer in trans-ancestry populations. They find seven new loci across different cancer subtypes, including a protective association in the HLA region that has a stronger effect in patients with human papillomavirus–positive cancers. We conducted a genome-wide association study of oral cavity and pharyngeal cancer in 6,034 cases and 6,585 controls from Europe, North America and South America. We detected eight significantly associated loci (P < 5 × 10−8), seven of which are new for these cancer sites. Oral and pharyngeal cancers combined were associated with loci at 6p21.32 (rs3828805, HLA-DQB1), 10q26.13 (rs201982221, LHPP) and 11p15.4 (rs1453414, OR52N2–TRIM5). Oral cancer was associated with two new regions, 2p23.3 (rs6547741, GPN1) and 9q34.12 (rs928674, LAMC3), and with known cancer-related loci—9p21.3 (rs8181047, CDKN2B-AS1) and 5p15.33 (rs10462706, CLPTM1L). Oropharyngeal cancer associations were limited to the human leukocyte antigen (HLA) region, and classical HLA allele imputation showed a protective association with the class II haplotype HLA-DRB1*1301–HLA-DQA1*0103–HLA-DQB1*0603 (odds ratio (OR) = 0.59, P = 2.7 × 10−9). Stratified analyses on a subgroup of oropharyngeal cases with information available on human papillomavirus (HPV) status indicated that this association was considerably stronger in HPV-positive (OR = 0.23, P = 1.6 × 10−6) than in HPV-negative (OR = 0.75, P = 0.16) cancers.

Circulating tumor DNA (ctDNA) is emerging as a key potential biomarker for post-diagnosis surveillance but it may also play a crucial role in the detection of pre-clinical cancer. Small-cell lung cancer (SCLC) is an excellent candidate for early detection given there are no successful therapeutic options for late-stage disease, and it displays almost universal inactivation of TP53. We assessed the presence of TP53 mutations in the cell-free DNA (cfDNA) extracted from the plasma of 51 SCLC cases and 123 non-cancer controls. We identified mutations using a pipeline specifically designed to accurately detect variants at very low fractions. We detected TP53 mutations in the cfDNA of 49% SCLC patients and 11.4% of non-cancer controls. When stratifying the 51 initial SCLC cases by stage, TP53 mutations were detected in the cfDNA of 35.7% early-stage and 54.1% late-stage SCLC patients. The results in the controls were further replicated in 10.8% of an independent series of 102 non-cancer controls. The detection of TP53 mutations in 11% of the 225 non-cancer controls suggests that somatic mutations in cfDNA among individuals without any cancer diagnosis is a common occurrence, and poses serious challenges for the development of ctDNA screening tests.

<h2>Abstract</h2><h3>Aim of the study</h3> A vast majority of human malignancies are associated with ageing, and age is a strong predictor of cancer risk. Recently, DNA methylation-based marker of ageing, known as 'epigenetic clock', has been linked with cancer risk factors. This study aimed to evaluate whether the epigenetic clock is associated with breast cancer risk susceptibility and to identify potential epigenetics-based biomarkers for risk stratification. <h3>Methods</h3> Here, we profiled DNA methylation changes in a nested case–control study embedded in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort (n = 960) using the Illumina HumanMethylation 450K BeadChip arrays and used the Horvath age estimation method to calculate epigenetic age for these samples. Intrinsic epigenetic age acceleration (IEAA) was estimated as the residuals by regressing epigenetic age on chronological age. <h3>Results</h3> We observed an association between IEAA and breast cancer risk (OR, 1.04; 95% CI, 1.007–1.076, P = 0.016). One unit increase in IEAA was associated with a 4% increased odds of developing breast cancer (OR, 1.04; 95% CI, 1.007–1.076). Stratified analysis based on menopausal status revealed that IEAA was associated with development of postmenopausal breast cancers (OR, 1.07; 95% CI, 1.020–1.11, P = 0.003). In addition, methylome-wide analyses revealed that a higher mean DNA methylation at cytosine-phosphate-guanine (CpG) islands was associated with increased risk of breast cancer development (OR per 1 SD = 1.20; 95 %CI: 1.03–1.40, P = 0.02) whereas mean methylation levels at non-island CpGs were indistinguishable between cancer cases and controls. <h3>Conclusion</h3> Epigenetic age acceleration and CpG island methylation have a weak, but statistically significant, association with breast cancer susceptibility.

Tobacco smoking is a known cause of gastric cancer, but several aspects of the association remain imprecisely quantified. We examined the relation between cigarette smoking and the risk of gastric cancer using a uniquely large dataset of 23 epidemiological studies within the ‘Stomach cancer Pooling (StoP) Project’, including 10 290 cases and 26 145 controls. We estimated summary odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study-specific ORs using random-effects models. Compared with never smokers, the ORs were 1.20 (95% CI: 1.09–1.32) for ever, 1.12 (95% CI: 0.99–1.27) for former, and 1.25 (95% CI: 1.11–1.40) for current cigarette smokers. Among current smokers, the risk increased with number of cigarettes per day to reach an OR of 1.32 (95% CI: 1.10–1.58) for smokers of more than 20 cigarettes per day. The risk increased with duration of smoking, to reach an OR of 1.33 (95% CI: 1.14–1.54) for more than 40 years of smoking and decreased with increasing time since stopping cigarette smoking ( P for trend&lt;0.01) and became similar to that of never smokers 10 years after stopping. Risks were somewhat higher for cardia than noncardia gastric cancer. Risks were similar when considering only studies with information on Helicobacter pylori infection and comparing all cases to H. pylori + controls only. This study provides the most precise estimate of the detrimental effect of cigarette smoking on the risk of gastric cancer on the basis of individual data, including the relationship with dose and duration, and the decrease in risk following stopping smoking.

Colchicine has been utilized safely in a variety of cardiovascular clinical conditions. Among its potential mechanisms of action is the non-selective inhibition of NLRP3 inflammasome which is thought to be a major pathophysiologic component in the clinical course of patients with COVID-19. GRECCO-19 will be a prospective, randomized, open-labeled, controlled study to assess the effects of colchicine in COVID-19 complications prevention. Patients with laboratory confirmed SARS-CoV-2 infection (under RT PCR) and clinical picture that involves temperature >37.5 oC and at least two out of the: i. sustained coughing, ii. sustained throat pain, iii. Anosmia and/or ageusia, iv. fatigue/tiredness, v. PaO2<95 mmHg will be included. Patients will be randomised (1:1) in colchicine or control group. Trial results will be disseminated through peer-reviewed publications and conference presentations. GRECCO-19 trial aims to identify whether colchicine may positively intervene in the clinical course of COVID-19. (ClinicalTrials.gov Identifier: NCT04326790).

Emerging data indicate an increased risk of cerebrovascular events with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and highlight the potential impact of coronavirus disease (COVID-19) on the management and outcomes of acute stroke. We conducted a systematic review and meta-analysis to evaluate the aforementioned considerations.We performed a meta-analysis of observational cohort studies reporting on the occurrence and/or outcomes of patients with cerebrovascular events in association with their SARS-CoV-2 infection status. We used a random-effects model. Summary estimates were reported as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).We identified 18 cohort studies including 67,845 patients. Among patients with SARS-CoV-2, 1.3% (95% CI = 0.9-1.6%, I2 = 87%) were hospitalized for cerebrovascular events, 1.1% (95% CI = 0.8-1.3%, I2 = 85%) for ischemic stroke, and 0.2% (95% CI = 0.1-0.3%, I2 = 64%) for hemorrhagic stroke. Compared to noninfected contemporary or historical controls, patients with SARS-CoV-2 infection had increased odds of ischemic stroke (OR = 3.58, 95% CI = 1.43-8.92, I2 = 43%) and cryptogenic stroke (OR = 3.98, 95% CI = 1.62-9.77, I2 = 0%). Diabetes mellitus was found to be more prevalent among SARS-CoV-2 stroke patients compared to noninfected historical controls (OR = 1.39, 95% CI = 1.00-1.94, I2 = 0%). SARS-CoV-2 infection status was not associated with the likelihood of receiving intravenous thrombolysis (OR = 1.42, 95% CI = 0.65-3.10, I2 = 0%) or endovascular thrombectomy (OR = 0.78, 95% CI = 0.35-1.74, I2 = 0%) among hospitalized ischemic stroke patients during the COVID-19 pandemic. Odds of in-hospital mortality were higher among SARS-CoV-2 stroke patients compared to noninfected contemporary or historical stroke patients (OR = 5.60, 95% CI = 3.19-9.80, I2 = 45%).SARS-CoV-2 appears to be associated with an increased risk of ischemic stroke, and potentially cryptogenic stroke in particular. It may also be related to an increased mortality risk. ANN NEUROL 2021;89:380-388.

Abstract During a 4-year period from January 1995 to December 1998, blood samples and questionnaire data were obtained from 333 incident cases of hepatocellular carcinoma (HCC), as well as from 360 controls who were hospitalized for eye, ear, nose, throat or orthopedic conditions in Athens, Greece. Coded sera were tested for hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) by third-generation enzyme immunoassays, and information on smoking habits and beverage consumption was obtained. We found a significant dose-response, positive association between smoking and HCC risk [≥ 2 packs per day, odds ratio (OR)=2.5].This association was stronger in individuals without chronic infection with either HBV or HCV (≥ 2 packs per day, OR=2.8). Consumption of alcoholic beverages above a threshold of 40 glasses per week increased the risk of HCC (OR=1.9). We also found evidence of a strong, statistically significant and apparently super-multiplicative effect of heavy smoking and heavy drinking in the development of HCC (OR for both exposures=9.6). This interaction was particularly evident among individuals without either HBsAg or anti-HCV (OR for both exposures=10.9). Coffee intake was not positively associated with HCC risk, but the reverse could not be excluded for the subgroup of chronically infected individuals. In conclusion, tobacco smoking and heavy alcohol consumption are associated with increased risk of HCC, especially when these 2 exposures occur together. Int. J. Cancer 85:498–502, 2000. © 2000 Wiley-Liss, Inc.

The incidence of cancer overall in Mediterranean countries is lower than in Scandinavian countries, the United Kingdom, and the United States. This is mostly accounted for by the lower incidence among Mediterranean countries of cancer of the large bowel, breast, endometrium, and prostate. These forms of cancer have been linked to dietary factors, particularly low consumption of vegetables and fruit, and to a certain extent, high consumption of meat. The traditional Mediterranean diet is characterized by high consumption of foods of plant origin, relatively low consumption of red meat, and high consumption of olive oil, which in several studies has been reported to be more beneficial against cancer than other forms of added lipids. By taking into account the established or presumed nutritional causation of major forms of cancer and the composition of the traditional Mediterranean diet, estimates can be derived concerning the fraction of cancer occurrence in highly developed Western countries that could be attributed to their diets in comparison with the healthy traditional Mediterranean diet. Although estimates can only be crude, it can be calculated that up to 25% of the incidence of colorectal cancer, approximately 15% of the incidence of breast cancer, and approximately 10% of the incidence of prostate, pancreas, and endometrial cancer could be prevented if the populations of highly developed Western countries could shift to the traditional healthy Mediterranean diet.

We examined the associations of intake of vegetables, legumes and fruit with all-cause and cause-specific mortality in a population with prevalent diabetes in Europe. A cohort of 10,449 participants with self-reported diabetes within the European Prospective Investigation into Cancer and Nutrition study was followed for a mean of 9 y. Intakes of vegetables, legumes, and fruit were assessed at baseline between 1992 and 2000 using validated country-specific questionnaires. A total of 1346 deaths occurred. Multivariate relative risks (RR) for all-cause mortality were estimated in Cox regression models and RR for cause-specific mortality were derived in a competing risk model. An increment in intake of total vegetables, legumes, and fruit of 80 g/d was associated with a RR of death from all causes of 0.94 [95% CI 0.90-0.98]. Analyzed separately, vegetables and legumes were associated with a significantly reduced risk, whereas nonsignificant inverse associations for fruit intake were observed. Cardiovascular disease (CVD) mortality and mortality due to non-CVD/non-cancer causes were significantly inversely associated with intake of total vegetables, legumes, and fruit (RR 0.88 [95% CI 0.81-0.95] and 0.90 [0.82-0.99], respectively) but not cancer mortality (1.08 [0.99-1.17]). Intake of vegetables, legumes, and fruit was associated with reduced risks of all-cause and CVD mortality in a diabetic population. The findings support the current state of evidence from general population studies that the protective potential of vegetable and fruit intake is larger for CVD than for cancer and suggest that diabetes patients may benefit from a diet high in vegetables and fruits.

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.

Adherence to traditional Mediterranean diet (MD) has been reported to be inversely associated with total, as well as cardiovascular, mortality. We have examined the relation between degree of such adherence and incidence of cancer overall in a general population sample of 25 623 participants (10 582 men, 15 041 women) of the Greek segment of the European Prospective Investigation into Cancer and nutrition (EPIC). All subjects completed a validated, interviewer-administered, semi-quantitative food-frequency questionnaire at enrolment. Degree of adherence to the traditional MD was assessed through a 10-point scale (0 minimal; 9 maximal) that incorporated key dietary characteristics. During a median follow-up of 7.9 years and 188 042 total person-years, 851 medically confirmed incident cancer cases (421 men, 430 women) were recorded. Using proportional hazards regression with adjustment for potential confounders, we found that a higher degree of MD adherence was associated with lower overall cancer incidence. A two-point increase in the score corresponded to a 12% reduction in cancer incidence (adjusted hazard ratio, 0.88 (95% confidence interval 0.80, 0.95)). The association was exposure-dependent and stronger among women. This inverse association with MD adherence was considerably stronger than that predicted on the basis of the associations of the individual components of this diet and points to the value of analysing dietary patterns in cancer studies.

<h3>Objective</h3> To examine the association between serum concentrations of total cholesterol, high density lipoprotein cholesterol (HDL), low density lipoprotein cholesterol, triglycerides, apolipoprotein A-I (apoA), apolipoprotein B and the incidence of colorectal cancer (CRC). <h3>Design</h3> Nested case–control study. <h3>Setting</h3> The study was conducted within the European Prospective Investigation into Cancer and Nutrition (EPIC), a cohort of more than 520 000 participants from 10 western European countries. <h3>Participants</h3> 1238 cases of incident CRC, which developed after enrolment into the cohort, were matched with 1238 controls for age, sex, centre, follow-up time, time of blood collection and fasting status. <h3>Main outcome measures</h3> Serum concentrations were quantitatively determined by colorimetric and turbidimetric methods. Dietary and lifestyle data were obtained from questionnaires. Conditional logistic regression models were used to estimate incidence rate ratios (RRs) and 95% CIs which were adjusted for height, weight, smoking habits, physical activity, education, consumption of fruit, vegetables, meat, fish, alcohol, fibre and energy. <h3>Results</h3> After adjustments, the concentrations of HDL and apoA were inversely associated with the risk of colon cancer (RR for 1 SD increase of 16.6 mg/dl in HDL and 32.0 mg/dl in apoA of 0.78 (95% CI 0.68 to 0.89) and 0.82 (95% CI 0.72 to 0.94), respectively). No association was observed with the risk of rectal cancer. Additional adjustment for biomarkers of systemic inflammation, insulin resistance and oxidative stress or exclusion of the first 2 years of follow-up did not influence the association between HDL and risk of colon cancer. <h3>Conclusions</h3> These findings show that high concentrations of serum HDL are associated with a decreased risk of colon cancer. The mechanism behind this association needs further elucidation.

Abstract Endometrial cancer risk has been associated with reproductive factors (age at menarche, age at menopause, parity, age at first and last birth, time since last birth and use of oral contraceptives (OCs)]. However, these factors are closely interrelated and whether they act independently still requires clarification. We conducted a study to examine the association of menstrual and reproductive variables with the risk of endometrial cancer among the European Prospective Investigation into Cancer and Nutrition (EPIC). Among the 302,618 women eligible for the study, 1,017 incident endometrial cancer cases were identified. A reduction in endometrial cancer risk was observed in women with late menarche, early menopause, past OC use, high parity and a shorter time since last full‐term pregnancy (FTP). No association was observed for duration of breast feeding after adjustment for number of FTP or for abortion (spontaneous or induced). After mutual adjustment, late age at menarche, early age at menopause and duration of OC use showed similar risk reductions of 7–8% per year of menstrual life, whereas the decreased risk associated with cumulative duration of FTPs was stronger (22% per year). In conclusion, our findings confirmed a reduction in risk of endometrial cancer with factors associated with a lower cumulative exposure to estrogen and/or higher exposure to progesterone, such as increasing number of FTPs and shorter menstrual lifespan and, therefore, support an important role of hormonal mechanisms in endometrial carcinogenesis.

Alcohol is an important risk factor for upper aerodigestive cancers and is principally metabolized by alcohol dehydrogenase (ADH) enzymes. We have investigated six ADH genetic variants in over 3,800 aerodigestive cancer cases and 5,200 controls from three individual studies. Gene variants rs1229984 (ADH1B) and rs1573496 (ADH7) were significantly protective against aerodigestive cancer in each individual study and overall (P = 10(-10) and 10(-9), respectively). These effects became more apparent with increasing alcohol consumption (P for trend = 0.0002 and 0.065, respectively). Both gene effects were independent of each other, implying that multiple ADH genes may be involved in upper aerodigestive cancer etiology.

Few epidemiologic studies have investigated the potential relation between flavonoids and breast cancer risk. We have applied recently published data on the composition of foods and beverages in terms of six principal classes of flavonoids (i.e., flavanones, flavan-3-ols, flavonols, flavones, anthocyanidines, and isoflavones) on dietary information collected in a large-case control study of breast cancer conducted in Italy between 1991 and 1994. The study included 2,569 women with incident, histologically confirmed breast cancer, and 2,588 hospital controls. Odds ratios (OR) and 95% confidence intervals were estimated by multiple logistic regression models. After allowance for major confounding factors and energy intake, a reduced risk of breast cancer was found for increasing intake of flavones (OR, 0.81, for the highest versus the lowest quintile; P-trend, 0.02), and flavonols (OR, 0.80; P-trend, 0.06). No significant association was found for other flavonoids, including flavanones (OR, 0.95), flavan-3-ols (OR, 0.86), anthocyanidins (OR, 1.09), as well as for isoflavones (OR, 1.05). The findings of this large study of an inverse association between flavones and breast cancer risk confirm the results of a Greek study.

The birth weight of boys is about 100 g heavier than the birth weight of girls, and this seems to be consistent across populations. No study, has examined whether the difference is because the pregnant woman has a higher energy intake or more efficient energy utilisation if she is carrying a male embryo than if she is carrying a female embryo. We report data to support the first hypothesis—that the pregnant woman carrying a boy has a higher energy intake. We analysed data from an international prospective study on dietary and non-dietary predictors of pregnancy hormones and outcomes among women in Boston, United States, and Shanghai, China.1 Because the database of nutrients for the Chinese diet is incomplete, we present data on dietary intakes for the US women only. Between March 1994 and October 1995, we identified 402 eligible pregnant women during their first routine prenatal visit at the Beth Israel Hospital in …

Genome-wide association studies (GWAS) have been successful in identifying common genetic variation involved in susceptibility to etiologically complex disease. We conducted a GWAS to identify common genetic variation involved in susceptibility to upper aero-digestive tract (UADT) cancers. Genome-wide genotyping was carried out using the Illumina HumanHap300 beadchips in 2,091 UADT cancer cases and 3,513 controls from two large European multi-centre UADT cancer studies, as well as 4,821 generic controls. The 19 top-ranked variants were investigated further in an additional 6,514 UADT cancer cases and 7,892 controls of European descent from an additional 13 UADT cancer studies participating in the INHANCE consortium. Five common variants presented evidence for significant association in the combined analysis (p ≤ 5 × 10⁻⁷). Two novel variants were identified, a 4q21 variant (rs1494961, p = 1×10⁻⁸) located near DNA repair related genes HEL308 and FAM175A (or Abraxas) and a 12q24 variant (rs4767364, p =2 × 10⁻⁸) located in an extended linkage disequilibrium region that contains multiple genes including the aldehyde dehydrogenase 2 (ALDH2) gene. Three remaining variants are located in the ADH gene cluster and were identified previously in a candidate gene study involving some of these samples. The association between these three variants and UADT cancers was independently replicated in 5,092 UADT cancer cases and 6,794 controls non-overlapping samples presented here (rs1573496-ADH7, p = 5 × 10⁻⁸); rs1229984-ADH1B, p = 7 × 10⁻⁹; and rs698-ADH1C, p = 0.02). These results implicate two variants at 4q21 and 12q24 and further highlight three ADH variants in UADT cancer susceptibility.

The long-term health consequences of diets used for weight control are not established. We have evaluated the association of the frequently recommended low carbohydrate diets - usually characterized by concomitant increase in protein intake - with long-term mortality.The Women's Lifestyle and Health cohort study initiated in Sweden during 1991-1992, with a 12-year almost complete follow up.The Uppsala Health Care Region.42,237 women, 30-49 years old at baseline, volunteers from a random sample, who completed an extensive questionnaire and were traced through linkages to national registries until 2003.We evaluated the association of mortality with: decreasing carbohydrate intake (in deciles); increasing protein intake (in deciles) and an additive combination of these variables (low carbohydrate-high protein score from 2 to 20), in Cox models controlling for energy intake, saturated fat intake and several nondietary covariates.Decreasing carbohydrate or increasing protein intake by one decile were associated with increase in total mortality by 6% (95% CI: 0-12%) and 2% (95% CI: -1 to 5%), respectively. For cardiovascular mortality, amongst women 40-49 years old at enrolment, the corresponding increases were, respectively, 13% (95% CI: -4 to 32%) and 16% (95% CI: 5-29%), with the additive score being even more predictive.A diet characterized by low carbohydrate and high protein intake was associated with increased total and particularly cardiovascular mortality amongst women. Vigilance with respect to long-term adherence to such weight control regimes is advisable.

Abstract General obesity has been positively associated with risk of liver and probably with biliary tract cancer, but little is known about abdominal obesity or weight gain during adulthood. We used multivariable Cox proportional hazard models to investigate associations between weight, body mass index, waist and hip circumference, waist‐to‐hip and waist‐to‐height ratio (WHtR), weight change during adulthood and risk of hepatocellular carcinoma (HCC), intrahepatic (IBDC) and extrahepatic bile duct system cancer [EBDSC including gallbladder cancer (GBC)] among 359,525 men and women in the European Prospective Investigation into Cancer and Nutrition study. Hepatitis B and C virus status was measured in a nested case–control subset. During a mean follow‐up of 8.6 years, 177 cases of HCC, 58 cases of IBDC and 210 cases of EBDSC, including 76 cases of GBC, occurred. All anthropometric measures were positively associated with risk of HCC and GBC. WHtR showed the strongest association with HCC [relative risk (RR) comparing extreme tertiles 3.51, 95% confidence interval (95% CI): 2.09–5.87; p trend &lt; 0.0001] and with GBC (RR: 1.56, 95% CI: 1.12–2.16 for an increment of one unit in WHtR). Weight gain during adulthood was also positively associated with HCC when comparing extreme tertiles (RR: 2.48, 95% CI: 1.49–4.13; &lt;0.001). No statistically significant association was observed between obesity and risk of IBDC and EBDSC. Our results provide evidence of an association between obesity, particularly abdominal obesity, and risk of HCC and GBC. Our findings support public health recommendations to reduce the prevalence of obesity and weight gain in adulthood for HCC and GBC prevention in Western populations.

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

The authors aimed to evaluate the association of the traditional Mediterranean diet and major food groups with incidence of and mortality from cerebrovascular disease (CBVD) in a Mediterranean population. The study population was a cohort of 23,601 participants from the Greek segment of the EPIC Study (European Prospective Investigation into Cancer and Nutrition) who were free of cardiovascular diseases and cancer at baseline (1994–1999). Diet was assessed by means of a validated food frequency questionnaire. A 10-point scale integrating key Mediterranean diet characteristics was used to assess the participants’ degree of adherence to this diet. During a median follow-up period of 10.6 years (1994–2009), 395 confirmed incident cases and 196 deaths from CBVD were recorded. Using Cox proportional hazards regression and adjusting for potential confounders, increased adherence to the Mediterranean diet, as measured by 2-point increments in score, was inversely associated with CBVD incidence (adjusted hazard ratio = 0.85, 95% confidence interval: 0.74, 0.96) and mortality (adjusted hazard ratio = 0.88, 95% CI: 0.73, 1.06). These inverse trends were mostly evident among women and with respect to ischemic rather than hemorrhagic CBVD and were largely driven by consumption of vegetables, legumes, and olive oil. These data provide support for an inverse association of adherence to the Mediterranean diet with CBVD incidence and mortality.

<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.

We examined prospectively the association between weight change during adulthood and breast cancer risk, using data on 1358 incident cases that developed during 5.8 years of follow-up among 40,429 premenopausal and 57,923 postmenopausal women from six European countries, taking part in the European prospective investigation into cancer and nutrition study. Multivariate Cox regression models were used to calculate hazard ratios according to weight change (kg), defined as the weight difference between age at enrollment and age 20 adjusted for other risk factors. Changes in weight were not associated with premenopausal breast cancer risk. In postmenopausal women, weight gain was positively associated with breast cancer risk only among noncurrent hormone replacement therapy (HRT) users (P-trend < or = 0.0002). Compared to women with a stable weight (+/-2 kg), the relative risk for women who gained 15-20 kg was 1.50 (95% confidence interval (CI) 1.06-2.13). The pooled RR per weight gain increment of 5 kg was 1.08 (95% CI 1.04-1.12). Weight gain was not associated with breast cancer risk in current HRT users, although, overall, these women experienced a much higher risk of breast cancer compared with nonusers. Our findings suggest that large adult weight gain was a significant predictor of breast cancer in postmenopausal women not taking exogenous hormones.

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.

Studies of diet and health focus increasingly on dietary patterns. Although the traditional Mediterranean diet is perceived as being healthy, there is little information on its possible benefit to young people. We studied whether closer adherence to the traditional Mediterranean dietary pattern was associated with overall and cancer mortality in a cohort of 42,237 young women, aged 30-49 years at enrollment, who were recruited in 1991-2 from the general population in the Uppsala Health Care Region, Sweden, and followed up, almost completely, for about 12 years. Adherence to the Mediterranean diet was assessed by a 10-point score incorporating the characteristics of this diet. Among women less than 40 years old at enrollment--whose causes of death are mainly cancer with probable genetic influences, injuries or suicide--there was no association of the Mediterranean diet score with total or cancer mortality. Among women 40-49 years old at enrollment, a 2-point increase in the score was associated with considerable reductions in overall mortality (13%; 95% CI 1%, 23%; P approximately 0.05) and cancer mortality (16%; 95% CI -1%, 29%; P approximately 0.06). Few cardiovascular deaths occurred in this cohort of young women. The findings of the present study in a northern European population of young women indicate that closer adherence to a Mediterranean dietary pattern reduces mortality even among young persons.

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.

Tobacco and alcohol are major risk factors for upper aerodigestive tract (UADT) cancer and significant variation is observed in UADT cancer rates across Europe. We have estimated the proportion of UADT cancer burden explained by tobacco and alcohol and how this varies with the incidence rates across Europe, cancer sub-site, gender and age. This should help estimate the minimum residual burden of other risk factors to UADT cancer, including human papillomavirus. We analysed 1981 UADT cancer cases and 1993 controls from the ARCAGE multicentre study. We estimated the population attributable risk (PAR) of tobacco alone, alcohol alone and their joint effect. Tobacco and alcohol together explained 73% of UADT cancer burden of which nearly 29% was explained by smoking alone, less than 1% due to alcohol on its own and 44% by the joint effect of tobacco and alcohol. Tobacco and alcohol together explained a larger proportion of hypopharyngeal/laryngeal cancer (PAR=85%) than oropharyngeal (PAR=74%), esophageal (PAR=67%) and oral cancer (PAR=61%). Tobacco and alcohol together explain only about half of the total UADT cancer burden among women. Geographically, tobacco and alcohol explained a larger proportion of UADT cancer in central (PAR=84%) than southern (PAR=72%) and western Europe (PAR=67%). While the majority of the UADT cancers in Europe are due to tobacco or the joint effect of tobacco and alcohol, our results support a significant role for other risk factors in particular, for oral and oropharyngeal cancers and also for UADT cancers in southern and western Europe.

Our aim was to assess the impact of cigarette smoking on the risk of the tumors classified by the International Agency for Research on Cancer as causally associated with smoking, referred to as tobacco-related cancers (TRC).The study population included 441,211 participants (133,018 men and 308,193 women) from the European Prospective Investigation Into Cancer and Nutrition. We investigated 14,563 participants who developed a TRC during an average follow-up of 11 years. The impact of smoking cigarettes on cancer risk was assessed by the population attributable fraction (AF(p)), calculated using the adjusted hazard ratios and 95% CI for current and former smokers, plus either the prevalence of smoking among cancer cases or estimates from surveys in representative samples of the population in each country.The proportion of all TRC attributable to cigarette smoking was 34.9% (95% CI, 32.5 to 37.4) using the smoking prevalence among cases and 36.2% (95% CI, 33.7 to 38.6) using the smoking prevalence from the population. The AF(p) were above 80% for cancers of the lung and larynx, between 20% and 50% for most respiratory and digestive cancers and tumors from the lower urinary tract, and below 20% for the remaining TRC.Using data on cancer incidence for 2008 and our AF(p) estimates, about 270,000 new cancer diagnoses per year can be considered attributable to cigarette smoking in the eight European countries with available data for both men and women (Italy, Spain, United Kingdom, the Netherlands, Greece, Germany, Sweden, Denmark).

Genetic variants in 15q25 have been identified as potential risk markers for lung cancer (LC), but controversy exists as to whether this is a direct association, or whether the 15q variant is simply a proxy for increased exposure to tobacco carcinogens.We performed a detailed analysis of one 15q single nucleotide polymorphism (SNP) (rs16969968) with smoking behaviour and cancer risk in a total of 17 300 subjects from five LC studies and four upper aerodigestive tract (UADT) cancer studies.Subjects with one minor allele smoked on average 0.3 cigarettes per day (CPD) more, whereas subjects with the homozygous minor AA genotype smoked on average 1.2 CPD more than subjects with a GG genotype (P < 0.001). The variant was associated with heavy smoking (>20 CPD) [odds ratio (OR) = 1.13, 95% confidence interval (CI) 0.96-1.34, P = 0.13 for heterozygotes and 1.81, 95% CI 1.39-2.35 for homozygotes, P < 0.0001]. The strong association between the variant and LC risk (OR = 1.30, 95% CI 1.23-1.38, P = 1 x 10(-18)), was virtually unchanged after adjusting for this smoking association (smoking adjusted OR = 1.27, 95% CI 1.19-1.35, P = 5 x 10(-13)). Furthermore, we found an association between the variant allele and an earlier age of LC onset (P = 0.02). The association was also noted in UADT cancers (OR = 1.08, 95% CI 1.01-1.15, P = 0.02). Genome wide association (GWA) analysis of over 300 000 SNPs on 11 219 subjects did not identify any additional variants related to smoking behaviour.This study confirms the strong association between 15q gene variants and LC and shows an independent association with smoking quantity, as well as an association with UADT cancers.

Increasing incidence of head and neck cancer (HNC) in young adults has been reported. We aimed to compare the role of major risk factors and family history of cancer in HNC in young adults and older patients.We pooled data from 25 case-control studies and conducted separate analyses for adults ≤ 45 years old ('young adults', 2010 cases and 4042 controls) and >45 years old ('older adults', 17700 cases and 22 704 controls). Using logistic regression with studies treated as random effects, we estimated adjusted odds ratios (ORs) and 95% confidence intervals (CIs).The young group of cases had a higher proportion of oral tongue cancer (16.0% in women; 11.0% in men) and unspecified oral cavity / oropharynx cancer (16.2%; 11.1%) and a lower proportion of larynx cancer (12.1%; 16.6%) than older adult cases. The proportions of never smokers or never drinkers among female cases were higher than among male cases in both age groups. Positive associations with HNC and duration or pack-years of smoking and drinking were similar across age groups. However, the attributable fractions (AFs) for smoking and drinking were lower in young when compared with older adults (AFs for smoking in young women, older women, young men and older men, respectively, = 19.9% (95% CI=9.8%, 27.9%), 48.9% (46.6%, 50.8%), 46.2% (38.5%, 52.5%), 64.3% (62.2%, 66.4%); AFs for drinking=5.3% (-11.2%, 18.0%), 20.0% (14.5%, 25.0%), 21.5% (5.0%, 34.9%) and 50.4% (46.1%, 54.3%). A family history of early-onset cancer was associated with HNC risk in the young [OR=2.27 (95% CI=1.26, 4.10)], but not in the older adults [OR=1.10 (0.91, 1.31)]. The attributable fraction for family history of early-onset cancer was 23.2% (8.60% to 31.4%) in young compared with 2.20% (-2.41%, 5.80%) in older adults.Differences in HNC aetiology according to age group may exist. The lower AF of cigarette smoking and alcohol drinking in young adults may be due to the reduced length of exposure due to the lower age. Other characteristics, such as those that are inherited, may play a more important role in HNC in young adults compared with older adults.

Studies in the United States report inverse associations of the Mediterranean dietary pattern with breast cancer risk, and several studies in Mediterranean countries indicate inverse associations of breast cancer risk with intake of olive oil, a constitutional component of this diet. No study, however, has evaluated the association of the traditional Mediterranean diet with breast cancer in a Mediterranean country.We studied the relation of conformity to the Mediterranean diet with breast cancer risk in the context of the European Prospective Investigation into Cancer and Nutrition cohort in Greece.We followed up 14,807 women for an average of 9.8 y and identified 240 incident breast cancer cases. Diet was assessed through a validated food-frequency questionnaire, and conformity to the Mediterranean diet was evaluated through a score (range = 0-9 points) incorporating the characteristics of this diet.Increasing conformity to the Mediterranean diet was not associated with lower breast cancer risk in the entire cohort [hazard ratio (HR) = 0.88 for every 2 points; 95% CI: 0.75, 1.03] or in premenopausal women (HR = 1.01 for every 2 points; 95% CI: 0.80, 1.28), but there was a marginally significant inverse association among postmenopausal women (HR = 0.78 for every 2 points; 95% CI: 0.62, 0.98; P for interaction by menopausal status = 0.05).Conformity to the traditional Mediterranean diet may be associated with lower breast cancer risk among postmenopausal women and could explain, in part, the lower incidence of this disease in Mediterranean countries.

We investigated the association between diet and head and neck cancer (HNC) risk using data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium. The INHANCE pooled data included 22 case-control studies with 14,520 cases and 22,737 controls. Center-specific quartiles among the controls were used for food groups, and frequencies per week were used for single food items. A dietary pattern score combining high fruit and vegetable intake and low red meat intake was created. Odds ratios (OR) and 95% confidence intervals (CI) for the dietary items on the risk of HNC were estimated with a two-stage random-effects logistic regression model. An inverse association was observed for higher-frequency intake of fruit (4th vs. 1st quartile OR = 0.52, 95% CI = 0.43-0.62, p (trend) < 0.01) and vegetables (OR = 0.66, 95% CI = 0.49-0.90, p (trend) = 0.01). Intake of red meat (OR = 1.40, 95% CI = 1.13-1.74, p (trend) = 0.13) and processed meat (OR = 1.37, 95% CI = 1.14-1.65, p (trend) < 0.01) was positively associated with HNC risk. Higher dietary pattern scores, reflecting high fruit/vegetable and low red meat intake, were associated with reduced HNC risk (per score increment OR = 0.90, 95% CI = 0.84-0.97).

Low socioeconomic status has been reported to be associated with head and neck cancer risk. However, previous studies have been too small to examine the associations by cancer subsite, age, sex, global region and calendar time and to explain the association in terms of behavioral risk factors. Individual participant data of 23,964 cases with head and neck cancer and 31,954 controls from 31 studies in 27 countries pooled with random effects models. Overall, low education was associated with an increased risk of head and neck cancer (OR = 2.50; 95% CI = 2.02 - 3.09). Overall one-third of the increased risk was not explained by differences in the distribution of cigarette smoking and alcohol behaviors; and it remained elevated among never users of tobacco and nondrinkers (OR = 1.61; 95% CI = 1.13 - 2.31). More of the estimated education effect was not explained by cigarette smoking and alcohol behaviors: in women than in men, in older than younger groups, in the oropharynx than in other sites, in South/Central America than in Europe/North America and was strongest in countries with greater income inequality. Similar findings were observed for the estimated effect of low versus high household income. The lowest levels of income and educational attainment were associated with more than 2-fold increased risk of head and neck cancer, which is not entirely explained by differences in the distributions of behavioral risk factors for these cancers and which varies across cancer sites, sexes, countries and country income inequality levels.

Human papillomavirus (HPV) is causally implicated in a subset of cancers of the upper aero-digestive tract (UADT).Associations between type-specific HPV antibodies were examined among 1496 UADT cancer case subjects and 1425 control subjects by estimating odds ratios (ORs) in logistic regression analyses adjusted for potential confounders. The agreement between serology and tumor markers of HPV infection, including presence of HPV DNA and p16 expression, were examined in a subset of tumors.HPV16 L1 seropositivity was associated with increased risk of oral cavity and oropharyngeal cancer (OR = 1.94, 95% confidence interval [CI] = 1.03 to 3.65; OR = 8.60, 95% CI = 5.21 to 14.20, respectively). HPV16 E6 antibodies were present in 30.2% of oropharyngeal case subjects and only 0.8% of control subjects (OR = 132.0, 95% CI = 65.29 to 266.86). Combined seropositivity to HPV16 E6 and E7 was rare (n = 1 of 1425 control subjects). An agreement of 67% was observed between HPV16 E6 serology and the corresponding presence of an HPV-related cancer: four of six HPV DNA-positive/p16-overexpressing tumors were HPV16 E6 antibody positive. An HPV16 independent association was observed for HPV18 and oropharyngeal cancer (OR = 8.14, 95% CI = 2.21 to 29.99 for HPV18 E6 seropositivity) and HPV6 and laryngeal cancer (OR = 3.25, 95% CI = 1.46 to 7.24 for HPV6 E7 seropositivity).These results confirm an important role for HPV16 infection in oropharyngeal cancer. HPV16 E6 antibodies are strongly associated with HPV16-related oropharyngeal cancers. Continuing efforts are needed to consider both HPV serology and p16 staining as biomarkers relevant to the etiology and natural history of HPV16-related oropharyngeal tumors. These results also support a marginal role for HPV18 in oropharyngeal cancer and HPV6 in laryngeal cancer.

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

An improved understanding of the contribution of the diet to health and disease risks requires accurate assessments of dietary exposure in nutritional epidemiologic studies. The use of dietary biomarkers may improve the accuracy of estimates.We applied a metabolomic approach in a large cohort study to identify novel biomarkers of intake for a selection of polyphenol-containing foods. The large chemical diversity of polyphenols and their wide distribution over many foods make them ideal biomarker candidates for such foods.Metabolic profiles were measured with the use of high-resolution mass spectrometry in 24-h urine samples from 481 subjects from the large European Prospective Investigation on Cancer and Nutrition cohort. Peak intensities were correlated to acute and habitual dietary intakes of 6 polyphenol-rich foods (coffee, tea, red wine, citrus fruit, apples and pears, and chocolate products) measured with the use of 24-h dietary recalls and food-frequency questionnaires, respectively.Correlation (r > 0.3, P < 0.01 after correction for multiple testing) and discriminant [pcorr (1) > 0.3, VIP > 1.5] analyses showed that >2000 mass spectral features from urine metabolic profiles were significantly associated with the consumption of the 6 selected foods. More than 80 polyphenol metabolites associated with the consumption of the selected foods could be identified, and large differences in their concentrations reflecting individual food intakes were observed within and between 4 European countries. Receiver operating characteristic curves showed that 5 polyphenol metabolites, which are characteristic of 5 of the 6 selected foods, had a high predicting ability of food intake.Highly diverse food-derived metabolites (the so-called food metabolome) can be characterized in human biospecimens through this powerful metabolomic approach and screened to identify novel biomarkers for dietary exposures, which are ultimately essential to better understand the role of the diet in the cause of chronic diseases.

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.

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.

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.

<h3>Importance</h3> There is an urgent need to improve lung cancer risk assessment because current screening criteria miss a large proportion of cases. <h3>Objective</h3> To investigate whether a lung cancer risk prediction model based on a panel of selected circulating protein biomarkers can outperform a traditional risk prediction model and current US screening criteria. <h3>Design, Setting, and Participants</h3> Prediagnostic samples from 108 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and samples from 216 smoking-matched controls from the Carotene and Retinol Efficacy Trial (CARET) cohort were used to develop a biomarker risk score based on 4 proteins (cancer antigen 125 [CA125], carcinoembryonic antigen [CEA], cytokeratin-19 fragment [CYFRA 21-1], and the precursor form of surfactant protein B [Pro-SFTPB]). The biomarker score was subsequently validated blindly using absolute risk estimates among 63 ever-smoking patients with lung cancer diagnosed within 1 year after blood collection and 90 matched controls from 2 large European population-based cohorts, the European Prospective Investigation into Cancer and Nutrition (EPIC) and the Northern Sweden Health and Disease Study (NSHDS). <h3>Main Outcomes and Measures</h3> Model validity in discriminating between future lung cancer cases and controls. Discrimination estimates were weighted to reflect the background populations of EPIC and NSHDS validation studies (area under the receiver-operating characteristics curve [AUC], sensitivity, and specificity). <h3>Results</h3> In the validation study of 63 ever-smoking patients with lung cancer and 90 matched controls (mean [SD] age, 57.7 [8.7] years; 68.6% men) from EPIC and NSHDS, an integrated risk prediction model that combined smoking exposure with the biomarker score yielded an AUC of 0.83 (95% CI, 0.76-0.90) compared with 0.73 (95% CI, 0.64-0.82) for a model based on smoking exposure alone (<i>P</i> = .003 for difference in AUC). At an overall specificity of 0.83, based on the US Preventive Services Task Force screening criteria, the sensitivity of the integrated risk prediction (biomarker) model was 0.63 compared with 0.43 for the smoking model. Conversely, at an overall sensitivity of 0.42, based on the US Preventive Services Task Force screening criteria, the integrated risk prediction model yielded a specificity of 0.95 compared with 0.86 for the smoking model. <h3>Conclusions and Relevance</h3> This study provided a proof of principle in showing that a panel of circulating protein biomarkers may improve lung cancer risk assessment and may be used to define eligibility for computed tomography screening.

Abstract Prediagnostic endogenous sex steroid hormone levels have well established associations with overall risk of breast cancer. While evidence toward the existence of distinct subtypes of breast cancer accumulates, few studies have investigated the associations of sex steroid hormone levels with risk of hormone receptor [estrogen receptor (ER) and/or progesterone receptor (PR)] defined breast cancer. In a case–control study nested within the EPIC cohort (European Prospective Investigation into Cancer and Nutrition), estradiol, testosterone, and sex hormone–binding globulin levels were measured in prediagnostic serum samples from postmenopausal women not using hormone replacement therapy at blood donation. A total of 554 women who developed invasive breast cancer with information on receptor status were matched with 821 control subjects. Conditional logistic regression models estimated breast cancer risk with hormone concentrations according to hormone receptor status of the tumor. Sex steroid hormones were associated with risks of not only ER+PR+ breast cancer [estradiol OR for highest vs. lowest tertile = 2.91 (95% CI: 1.62–5.23), Ptrend = 0.002; testosterone OR = 2.27 (95% CI: 1.35–3.81), Ptrend = 0.002] but also of ER-PR- breast cancer [estradiol OR = 2.11 (95% CI: 1.00–4.46), Ptrend = 0.05; testosterone OR = 2.06 (95% CI: 0.95–4.46), Ptrend = 0.03], with associations appearing somewhat stronger in the receptor-positive disease. Serum androgens and estrogens are associated with risks of both hormone receptor–negative as well as receptor–positive breast tumors. Further research is needed to establish through which molecular pathways, and during which evolutionary stages of development, androgens and estrogens can promote the occurrence of both receptor-positive and -negative clinical breast tumors. Cancer Prev Res; 4(10); 1626–35. ©2011 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.

Adherence to the Mediterranean diet (MD) has been reported to improve CHD prognosis and to be inversely associated with CHD mortality. The aim of the present study was to investigate the association of adherence to the MD with CHD incidence and mortality in the Greek European Prospective Investigation into Cancer and Nutrition cohort, a population with traditional Mediterranean roots. In a general population sample of 23 929 adult men and women with no CVD or cancer at enrolment, a validated FFQ was interviewer-administered, sociodemographic, physical activity and other characteristics were recorded, and arterial blood pressure and anthropometric characteristics were measured. In a median period of 10 years, 636 incident CHD cases and 240 CHD deaths were recorded. Associations of adherence to the MD, operationalised through a nine-component score (0, poor; 9, excellent), with CHD incidence and mortality were evaluated through Cox regression controlling for potentially confounding variables. A two-point increase in the MD score was associated with lower CHD mortality by 25 % (95 % CI 0·57, 0·98) among women and 19 % (95 % CI 0·67, 0·99) among men. The association of adherence to the MD with CHD incidence was again inverse, but weaker (hazard ratios 0·85 (95 % CI 0·71, 1·02) among women and 0·98 (95 % CI 0·87, 1·10) among men). With respect to score components, only meat among men (positively) and fruits and nuts among women (inversely) were associated with both the incidence of and mortality from CHD. The MD, as an integral entity, is inversely associated with CHD incidence and, particularly, mortality.

The mechanisms underlying the strong association between percentage dense area on a mammogram and the risk of breast cancer are unknown. We investigated separately the absolute dense area and the absolute nondense area on mammograms in relation to breast cancer risk. We conducted a nested case-control study on prediagnostic mammographic density measurements and risk of breast cancer in the Nurses' Health Study and the Nurses' Health Study II. Premenopausal mammograms were available from 464 cases and 998 controls, and postmenopausal mammograms were available from 960 cases and 1,662 controls. We used a computer-assisted thresholding technique to measure mammographic density, and we used unconditional logistic regression to calculate OR and 95% CI data. Higher absolute dense area was associated with a greater risk of breast cancer among premenopausal women (ORtertile 3 vs 1 = 2.01, 95% CI = 1.45 to 2.77) and among postmenopausal women (ORquintile 5 vs 1 = 2.19, 95% CI = 1.65 to 2.89). However, increasing absolute nondense area was associated with a decreased risk of breast cancer among premenopausal women (ORtertile 3 vs 1 = 0.51, 95% CI = 0.36 to 0.72) and among postmenopausal women (ORquintile 5 vs 1 = 0.46, 95% CI = 0.34 to 0.62). These associations changed minimally when we included both absolute dense area and absolute nondense area in the same statistical model. As expected, the percentage dense area was the strongest risk factor for breast cancer in both groups. Our results indicate that absolute dense area is independently and positively associated with breast cancer risk, whereas absolute nondense area is independently and inversely associated with breast cancer risk. Since adipose tissue is radiographically nondense, these results suggest that adipose breast tissue may have a protective role in breast carcinogenesis.

Background & Aims Hepatocellular carcinoma (HCC) has a very poor prognosis and any effort to identify additional risk factors, besides those already established, would be important for the prevention of the disease. Data on the role of diet on HCC risk are still controversial. Methods We have evaluated the association of adherence to the Mediterranean diet with HCC risk, as well as the interaction of this dietary pattern with chronic hepatitis infection, by combining two case-control studies undertaken in Italy and Greece, including overall 518 cases of HCC and 772 controls. Adherence to the traditional Mediterranean diet was assessed through the Mediterranean diet score (MDS), which ranges between 0 (lowest adherence) and 9 (highest adherence). Odds ratios (OR) for HCC were obtained through multiple logistic regression models, controlling for potentially confounding factors, including chronic infection with hepatitis B/C viruses. Results Compared to MDS of 0–3, the ORs for HCC were 0.66 (95% confidence interval (CI), 0.41–1.04) for MDS equal to 4 and 0.51 (95% CI, 0.34–0.75) for MDS ⩾5, with a significant trend (p <0.001). The detrimental effect of poor adherence to Mediterranean diet on HCC risk was disproportionally high among those chronically infected with hepatitis B and/or C viruses, with a suggestion of super-additive interaction, albeit statistically non-significant. Conclusions Closer adherence to the Mediterranean diet appears to be protective against HCC. Our results also point to potential benefits from adhering to a Mediterranean dietary pattern for patients chronically infected with hepatitis viruses. Hepatocellular carcinoma (HCC) has a very poor prognosis and any effort to identify additional risk factors, besides those already established, would be important for the prevention of the disease. Data on the role of diet on HCC risk are still controversial. We have evaluated the association of adherence to the Mediterranean diet with HCC risk, as well as the interaction of this dietary pattern with chronic hepatitis infection, by combining two case-control studies undertaken in Italy and Greece, including overall 518 cases of HCC and 772 controls. Adherence to the traditional Mediterranean diet was assessed through the Mediterranean diet score (MDS), which ranges between 0 (lowest adherence) and 9 (highest adherence). Odds ratios (OR) for HCC were obtained through multiple logistic regression models, controlling for potentially confounding factors, including chronic infection with hepatitis B/C viruses. Compared to MDS of 0–3, the ORs for HCC were 0.66 (95% confidence interval (CI), 0.41–1.04) for MDS equal to 4 and 0.51 (95% CI, 0.34–0.75) for MDS ⩾5, with a significant trend (p <0.001). The detrimental effect of poor adherence to Mediterranean diet on HCC risk was disproportionally high among those chronically infected with hepatitis B and/or C viruses, with a suggestion of super-additive interaction, albeit statistically non-significant. Closer adherence to the Mediterranean diet appears to be protective against HCC. Our results also point to potential benefits from adhering to a Mediterranean dietary pattern for patients chronically infected with hepatitis viruses.

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.

BackgroundIn epidemiological studies, Helicobacter pylori infection is usually detected by enzyme-linked immunosorbent assay (ELISA). However, infection can spontaneously clear from the mucosa during the progression of atrophy and could lead to substantial under-detection of infection and underestimation of its effect on gastric cancer (GC) risk. Antibodies detected by western blot are known to persist longer after the loss of the infection.MethodsIn a nested case–control study from the Eurogast-EPIC cohort, including 88 noncardia GC cases and 338 controls, we assessed the association between noncardia GC and H. pylori infection comparing antibodies detected by western blot (HELICOBLOT2.1) to those detected by ELISA (Pyloriset EIA-GIII®).ResultsBy immunoblot, 82 cases (93.2%) were H. pylori positive, 10 of these cases (11.4%) were negative by ELISA and only 6 cases (6.8%) were negative by both ELISA and immunoblot. Multivariable odds ratio (OR) for noncardia GC comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.0–15.1], and by immunoblot, the OR was 21.4 (95% CI 7.1–64.4).ConclusionsUsing a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is a necessary condition for noncardia GC.

We aimed to assess the association of oral health (OH), dental care (DC) and mouthwash with upper-aerodigestive tract (UADT) cancer risk, and to examine the extent that enzymes involved in the metabolism of alcohol modify the effect of mouthwash. The study included 1963 patients with incident cancer of the oral cavity, oropharynx, hypopharynx, larynx or esophagus and 1993 controls. Subjects were interviewed about their oral health and dental care behaviors (which were converted to scores of OH and DC respectively), as well as smoking, alcohol drinking, diet, occupations, medical conditions and socio-economic status. Blood samples were taken for genetic analyses. Mouthwash use was analyzed in relation to the presence of polymorphisms of alcohol-metabolizing genes known to be associated with UADT. Adjusted odds ratios (ORs) and 95%-confidence intervals [CI] were estimated with multiple logistic regression models adjusting for multiple confounders. Fully adjusted ORs of low versus high scores of DC and OH were 2.36[CI = 1.51–3.67] and 2.22[CI = 1.45–3.41], respectively, for all UADT sites combined. The OR for frequent use of mouthwash use (3 or more times/day) was 3.23[CI = 1.68–6.19]. The OR for the rare variant ADH7 (coding for fast ethanol metabolism) was lower in mouthwash-users (OR = 0.53[CI = 0.35–0.81]) as compared to never-users (OR = 0.97[CI = 0.73–1.29]) indicating effect modification (pheterogeneity = 0.065) while no relevant differences were observed between users and non-users for the variant alleles of ADH1B, ADH1C or ALDH2. Poor OH and DC seem to be independent risk factors for UADT because corresponding risk estimates remain substantially elevated after detailed adjustment for multiple confounders. Whether mouthwash use may entail some risk through the alcohol content in most formulations on the market remains to be fully clarified.

Associations of hormone-receptor positive breast cancer with excess adiposity are reasonably well characterized; however, uncertainty remains regarding the association of body mass index (BMI) with hormone-receptor negative malignancies, and possible interactions by hormone replacement therapy (HRT) use. Within the European EPIC cohort, Cox proportional hazards models were used to describe the relationship of BMI, waist and hip circumferences with risk of estrogen-receptor (ER) negative and progesterone-receptor (PR) negative (n = 1,021) and ER+PR+ (n = 3,586) breast tumors within five-year age bands. Among postmenopausal women, the joint effects of BMI and HRT use were analyzed. For risk of ER-PR- tumors, there was no association of BMI across the age bands. However, when analyses were restricted to postmenopausal HRT never users, a positive risk association with BMI (third versus first tertile HR = 1.47 (1.01 to 2.15)) was observed. BMI was inversely associated with ER+PR+ tumors among women aged ≤49 years (per 5 kg/m2 increase, HR = 0.79 (95%CI 0.68 to 0.91)), and positively associated with risk among women ≥65 years (HR = 1.25 (1.16 to 1.34)). Adjusting for BMI, waist and hip circumferences showed no further associations with risks of breast cancer subtypes. Current use of HRT was significantly associated with an increased risk of receptor-negative (HRT current use compared to HRT never use HR: 1.30 (1.05 to 1.62)) and positive tumors (HR: 1.74 (1.56 to 1.95)), although this risk increase was weaker for ER-PR- disease (Phet = 0.035). The association of HRT was significantly stronger in the leaner women (BMI ≤22.5 kg/m2) than for more overweight women (BMI ≥25.9 kg/m2) for, both, ER-PR- (HR: 1.74 (1.15 to 2.63)) and ER+PR+ (HR: 2.33 (1.84 to 2.92)) breast cancer and was not restricted to any particular HRT regime. An elevated BMI may be positively associated with risk of ER-PR- tumors among postmenopausal women who never used HRT. Furthermore, postmenopausal HRT users were at an increased risk of ER-PR- as well as ER+PR+ tumors, especially among leaner women. For hormone-receptor positive tumors, but not for hormone-receptor negative tumors, our study confirms an inverse association of risk with BMI among young women of premenopausal age. Our data provide evidence for a possible role of sex hormones in the etiology of hormone-receptor negative tumors.

The role of diet in the prevention of diabetes remains uncertain. The aim of this study was to investigate two different dietary aspects, i.e. adherence to the Mediterranean diet and glycaemic load (GL), in relation to diabetes occurrence.We analysed data from the Greek cohort of the population-based European Prospective Investigation into Cancer and Nutrition (EPIC). From a total of 22,295 participants, actively followed for a median of 11.34 years, 2,330 cases of incident type 2 diabetes were recorded. All participants completed a validated, interviewer-administered semi-quantitative food frequency questionnaire at enrolment. From this information, we calculated a ten point Mediterranean diet score (MDS), reflecting adherence to the traditional Mediterranean diet, as well as the dietary GL. We estimated HRs and the corresponding 95% CIs of diabetes using Cox proportional hazards regression models adjusted for potential confounders.A higher MDS was inversely associated with diabetes risk (HR 0.88 [95% CI 0.78, 0.99] for MDS ≥ 6 vs MDS ≤ 3). GL was positively associated with diabetes (HR 1.21 [95% CI 1.05, 1.40] for the highest vs the lowest GL quartile). A significant protection of about 20% was found for a diet with a high MDS and a low GL.A low GL diet that also adequately adheres to the principles of the traditional Mediterranean diet may reduce the incidence of type 2 diabetes.

Breast cancer is the most common cancer among women and prevention strategies are needed to reduce incidence worldwide. A healthy lifestyle index score (HLIS) was generated to investigate the joint effect of modifiable lifestyle factors on postmenopausal breast cancer risk. The study included 242,918 postmenopausal women from the multinational European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, with detailed information on diet and lifestyle assessed at baseline. The HLIS was constructed from five factors (diet, physical activity, smoking, alcohol consumption and anthropometry) by assigning scores of 0–4 to categories of each component, for which higher values indicate healthier behaviours. Hazard ratios (HR) were estimated by Cox proportional regression models. During 10.9 years of median follow‐up, 7,756 incident breast cancer cases were identified. There was a 3% lower risk of breast cancer per point increase of the HLIS. Breast cancer risk was inversely associated with a high HLIS when fourth versus second (reference) categories were compared [adjusted HR = 0.74; 95% confidence interval (CI): 0.66–0.83]. The fourth versus the second category of the HLIS was associated with a lower risk for hormone receptor double positive (adjusted HR = 0.81, 95% CI: 0.67–0.98) and hormone receptor double negative breast cancer (adjusted HR = 0.60, 95% CI: 0.40–0.90). Findings suggest having a high score on an index of combined healthy behaviours reduces the risk of developing breast cancer among postmenopausal women. Programmes which engage women in long term health behaviours should be supported.

Hepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.To address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.A metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.Our results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.

Increased levels of thyroglobulin (Tg) and thyroid-stimulating hormone (TSH) are associated with differentiated thyroid carcinoma (TC) risk, but strong epidemiological evidence is lacking.Three hundred fifty-seven incident TC case patients (n = 300 women and 57 men; mean age at blood collection = 51.5 years) were identified in the EPIC cohort study and matched with 2 (women) or 3 (men) control subjects using incidence density sampling. Matching included study center, sex, age, date, time, and fasting status at blood collection. Levels of total and free (f) thyroxine (T4) and triiodo-thyronine (T3), TSH, Tg, and anti-Tg antibodies (TgAb) were measured by commercially available immunoassays. Odds ratios (ORs) and 95% confidence intervals (CIs) were computed using conditional logistic regression. All statistical tests were two-sided.TC risk was positively associated with Tg (OR for the highest vs lowest quartile = 9.15; 95% CI = 5.28 to 15.90; P < .001) and negatively associated with TSH level (OR = 0.56; 95% CI = 0.38 to 0.81; P = .001). Odds ratios were not modified by adjustment for weight and height and were consistent across sexes, age groups, and countries. The association with Tg was stronger in follicular than papillary TC. The odds ratio for TgAb-positivity was 1.50 (95% CI = 1.05 to 2.15; P = .03). Among case patients, TSH level was stable over time, whereas Tg level was higher in proximity to TC diagnosis. Areas under the receiver operating characteristic curve were 57% and 74% for TSH and Tg level, respectively.High Tg levels precede by up to 8 years the detection of TC, pointing to a long sojourn time of the disease. Low TSH levels may predispose to TC onset. Neither marker has sufficient accuracy to be a screening test.

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)

An association between heavy alcohol drinking and gastric cancer risk has been recently reported, but the issue is still open to discussion and quantification. We investigated the role of alcohol drinking on gastric cancer risk in the “Stomach cancer Pooling (StoP) Project,” a consortium of epidemiological studies. A total of 9,669 cases and 25,336 controls from 20 studies from Europe, Asia and North America were included. We estimated summary odds‐ratios (ORs) and the corresponding 95% confidence intervals (CIs) by pooling study‐specific ORs using random‐effects meta‐regression models. Compared with abstainers, drinkers of up to 4 drinks/day of alcohol had no increase in gastric cancer risk, while the ORs were 1.26 (95% CI, 1.08–1.48) for heavy (&gt;4 to 6 drinks/day) and 1.48 (95% CI 1.29–1.70) for very heavy (&gt;6 drinks/day) drinkers. The risk for drinkers of &gt;4 drinks/day was higher in never smokers (OR 1.87, 95% CI 1.35–2.58) as compared with current smokers (OR 1.14, 95% CI 0.93–1.40). Somewhat stronger associations emerged with heavy drinking in cardia (OR 1.61, 95% CI 1.11–2.34) than in non‐cardia (OR 1.28, 95% CI 1.13–1.45) gastric cancers, and in intestinal‐type (OR 1.54, 95% CI 1.20–1.97) than in diffuse‐type (OR 1.29, 95% CI 1.05–1.58) cancers. The association was similar in strata of H. pylori infected (OR = 1.52, 95% CI 1.16–2.00) and noninfected subjects (OR = 1.69, 95% CI 0.95–3.01). Our collaborative pooled‐analysis provides definite, more precise quantitative evidence than previously available of an association between heavy alcohol drinking and gastric cancer risk.

General obesity, as reflected by BMI, is an established risk factor for esophageal adenocarcinoma (EAC), a suspected risk factor for gastric cardia adenocarcinoma (GCC) and appears unrelated to gastric non-cardia adenocarcinoma (GNCC). How abdominal obesity, as commonly measured by waist circumference (WC), relates to these cancers remains largely unexplored. Using measured anthropometric data from 391,456 individuals from the European Prospective Investigation into Cancer and Nutrition (EPIC) study and 11 years of follow-up, we comprehensively assessed the association of anthropometric measures with risk of EAC, GCC and GNCC using multivariable proportional hazards regression. One hundred twenty-four incident EAC, 193 GCC and 224 GNCC were accrued. After mutual adjustment, BMI was unrelated to EAC, while WC showed a strong positive association (highest vs. lowest quintile HR = 1.19; 95% CI, 0.63-2.22 and HR = 3.76; 1.72-8.22, respectively). Hip circumference (HC) was inversely related to EAC after controlling for WC, while WC remained positively associated (HR = 0.35; 0.18-0.68, and HR=4.10; 1.94-8.63, respectively). BMI was not associated with GCC or GNCC. WC was related to higher risks of GCC after adjustment for BMI and more strongly after adjustment for HC (highest vs. lowest quintile HR = 1.91; 1.09-3.37, and HR = 2.23; 1.28-3.90, respectively). Our study demonstrates that abdominal, rather than general, obesity is an indisputable risk factor for EAC and also provides evidence for a protective effect of gluteofemoral (subcutaneous) adipose tissue in EAC. Our study further shows that general obesity is not a risk factor for GCC and GNCC, while the role of abdominal obesity in GCC needs further investigation.

Obesity is positively associated with colorectal cancer. Recently, body size subtypes categorised by the prevalence of hyperinsulinaemia have been defined, and metabolically healthy overweight/obese individuals (without hyperinsulinaemia) have been suggested to be at lower risk of cardiovascular disease than their metabolically unhealthy (hyperinsulinaemic) overweight/obese counterparts. Whether similarly variable relationships exist for metabolically defined body size phenotypes and colorectal cancer risk is unknown.The association of metabolically defined body size phenotypes with colorectal cancer was investigated in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Metabolic health/body size phenotypes were defined according to hyperinsulinaemia status using serum concentrations of C-peptide, a marker of insulin secretion. A total of 737 incident colorectal cancer cases and 737 matched controls were divided into tertiles based on the distribution of C-peptide concentration amongst the control population, and participants were classified as metabolically healthy if below the first tertile of C-peptide and metabolically unhealthy if above the first tertile. These metabolic health definitions were then combined with body mass index (BMI) measurements to create four metabolic health/body size phenotype categories: (1) metabolically healthy/normal weight (BMI < 25 kg/m2), (2) metabolically healthy/overweight (BMI ≥ 25 kg/m2), (3) metabolically unhealthy/normal weight (BMI < 25 kg/m2), and (4) metabolically unhealthy/overweight (BMI ≥ 25 kg/m2). Additionally, in separate models, waist circumference measurements (using the International Diabetes Federation cut-points [≥80 cm for women and ≥94 cm for men]) were used (instead of BMI) to create the four metabolic health/body size phenotype categories. Statistical tests used in the analysis were all two-sided, and a p-value of <0.05 was considered statistically significant. In multivariable-adjusted conditional logistic regression models with BMI used to define adiposity, compared with metabolically healthy/normal weight individuals, we observed a higher colorectal cancer risk among metabolically unhealthy/normal weight (odds ratio [OR] = 1.59, 95% CI 1.10-2.28) and metabolically unhealthy/overweight (OR = 1.40, 95% CI 1.01-1.94) participants, but not among metabolically healthy/overweight individuals (OR = 0.96, 95% CI 0.65-1.42). Among the overweight individuals, lower colorectal cancer risk was observed for metabolically healthy/overweight individuals compared with metabolically unhealthy/overweight individuals (OR = 0.69, 95% CI 0.49-0.96). These associations were generally consistent when waist circumference was used as the measure of adiposity. To our knowledge, there is no universally accepted clinical definition for using C-peptide level as an indication of hyperinsulinaemia. Therefore, a possible limitation of our analysis was that the classification of individuals as being hyperinsulinaemic-based on their C-peptide level-was arbitrary. However, when we used quartiles or the median of C-peptide, instead of tertiles, as the cut-point of hyperinsulinaemia, a similar pattern of associations was observed.These results support the idea that individuals with the metabolically healthy/overweight phenotype (with normal insulin levels) are at lower colorectal cancer risk than those with hyperinsulinaemia. The combination of anthropometric measures with metabolic parameters, such as C-peptide, may be useful for defining strata of the population at greater risk of colorectal cancer.

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 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

Perturbations in levels of amino acids (AA) and their derivatives are observed in hepatocellular carcinoma (HCC). Yet, it is unclear whether these alterations precede or are a consequence of the disease, nor whether they pertain to anatomically related cancers of the intrahepatic bile duct (IHBC), and gallbladder and extrahepatic biliary tract (GBTC). Circulating standard AA, biogenic amines and hexoses were measured (Biocrates AbsoluteIDQ‐p180Kit) in a case‐control study nested within a large prospective cohort (147 HCC, 43 IHBC and 134 GBTC cases). Liver function and hepatitis status biomarkers were determined separately. Multivariable conditional logistic regression was used to calculate odds ratios and 95% confidence intervals (OR; 95%CI) for log‐transformed standardised (mean = 0, SD = 1) serum metabolite levels and relevant ratios in relation to HCC, IHBC or GBTC risk. Fourteen metabolites were significantly associated with HCC risk, of which seven metabolites and four ratios were the strongest predictors in continuous models. Leucine, lysine, glutamine and the ratio of branched chain to aromatic AA (Fischer's ratio) were inversely, while phenylalanine, tyrosine and their ratio, glutamate, glutamate/glutamine ratio, kynurenine and its ratio to tryptophan were positively associated with HCC risk. Confounding by hepatitis status and liver enzyme levels was observed. For the other cancers no significant associations were observed. In conclusion, imbalances of specific AA and biogenic amines may be involved in HCC development.

Scores of overall diet quality have received increasing attention in relation to disease aetiology; however, their value in risk prediction has been little examined. The objective was to assess and compare the association and predictive performance of 10 diet quality scores on 10-year risk of all-cause, CVD and cancer mortality in 451,256 healthy participants to the European Prospective Investigation into Cancer and Nutrition, followed-up for a median of 12.8y. All dietary scores studied showed significant inverse associations with all outcomes. The range of HRs (95% CI) in the top vs. lowest quartile of dietary scores in a composite model including non-invasive factors (age, sex, smoking, body mass index, education, physical activity and study centre) was 0.75 (0.72-0.79) to 0.88 (0.84-0.92) for all-cause, 0.76 (0.69-0.83) to 0.84 (0.76-0.92) for CVD and 0.78 (0.73-0.83) to 0.91 (0.85-0.97) for cancer mortality. Models with dietary scores alone showed low discrimination, but composite models also including age, sex and other non-invasive factors showed good discrimination and calibration, which varied little between different diet scores examined. Mean C-statistic of full models was 0.73, 0.80 and 0.71 for all-cause, CVD and cancer mortality. Dietary scores have poor predictive performance for 10-year mortality risk when used in isolation but display good predictive ability in combination with other non-invasive common risk factors.

Reliable biomarkers of apatinib response in gastric cancer (GC) are lacking. We investigated the association between early presence of common adverse events (AEs) and clinical outcomes in metastatic GC patients.We conducted a retrospective cohort study using data on 269 apatinib-treated GC patients in two clinical trials. AEs were assessed at baseline until 28 days after the last dose of apatinib. Clinical outcomes were compared between patients with and without hypertension (HTN), proteinuria, or hand and foot syndrome (HFS) in the first 4 weeks. Time-to-event variables were assessed using Kaplan-Meier methods and Cox proportional hazard regression models. Binary endpoints were assessed using logistic regression models. Landmark analyses were performed as sensitivity analyses. Predictive model was analyzed, and risk scores were calculated to predict overall survival.Presence of AEs in the first 4 weeks was associated with prolonged median overall survival (169 vs. 103 days, log-rank p = 0.0039; adjusted hazard ratio (HR) 0.64, 95% confidence interval [CI] 0.64-0.84, p = 0.001), prolonged median progression-free survival (86.5 vs. 62 days, log-rank p = 0.0309; adjusted HR 0.69, 95% CI 0.53-0.91, p = 0.007), and increased disease control rate (54.67 vs. 32.77%; adjusted odds ratio 2.67, p < 0.001). Results remained significant in landmark analyses. The onset of any single AE or any combinations of the AEs were all statistically significantly associated with prolonged OS, except for the presence of proteinuria. An AE-based prediction model and subsequently derived scoring system showed high calibration and discrimination in predicting overall survival.Presence of HTN, proteinuria, or HFS during the first cycle of apatinib treatment was a viable biomarker of antitumor efficacy in metastatic GC patients.

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 is a well-established risk factor for head and neck cancer (HNC). This study aims to explore the effect of alcohol intensity and duration, as joint continuous exposures, on HNC risk.Data from 26 case-control studies in the INHANCE Consortium were used, including never and current drinkers who drunk ≤10 drinks/day for ≤54 years (24234 controls, 4085 oral cavity, 3359 oropharyngeal, 983 hypopharyngeal and 3340 laryngeal cancers). The dose-response relationship between the risk and the joint exposure to drinking intensity and duration was investigated through bivariate regression spline models, adjusting for potential confounders, including tobacco smoking.For all subsites, cancer risk steeply increased with increasing drinks/day, with no appreciable threshold effect at lower intensities. For each intensity level, the risk of oral cavity, hypopharyngeal and laryngeal cancers did not vary according to years of drinking, suggesting no effect of duration. For oropharyngeal cancer, the risk increased with durations up to 28 years, flattening thereafter. The risk peaked at the higher levels of intensity and duration for all subsites (odds ratio = 7.95 for oral cavity, 12.86 for oropharynx, 24.96 for hypopharynx and 6.60 for larynx).Present results further encourage the reduction of alcohol intensity to mitigate HNC risk.

Throughout the coronavirus disease 2019 (COVID-19) pandemic, countries have relied on a variety of ad hoc border control protocols to allow for non-essential travel while safeguarding public health, from quarantining all travellers to restricting entry from select nations on the basis of population-level epidemiological metrics such as cases, deaths or testing positivity rates1,2. Here we report the design and performance of a reinforcement learning system, nicknamed Eva. In the summer of 2020, Eva was deployed across all Greek borders to limit the influx of asymptomatic travellers infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and to inform border policies through real-time estimates of COVID-19 prevalence. In contrast to country-wide protocols, Eva allocated Greece's limited testing resources on the basis of incoming travellers' demographic information and testing results from previous travellers. By comparing Eva's performance against modelled counterfactual scenarios, we show that Eva identified 1.85 times as many asymptomatic, infected travellers as random surveillance testing, with up to 2-4 times as many during peak travel, and 1.25-1.45 times as many asymptomatic, infected travellers as testing policies that utilize only epidemiological metrics. We demonstrate that this latter benefit arises, at least partially, because population-level epidemiological metrics had limited predictive value for the actual prevalence of SARS-CoV-2 among asymptomatic travellers and exhibited strong country-specific idiosyncrasies in the summer of 2020. Our results raise serious concerns on the effectiveness of country-agnostic internationally proposed border control policies3 that are based on population-level epidemiological metrics. Instead, our work represents a successful example of the potential of reinforcement learning and real-time data for safeguarding public health.

There is accumulating evidence supporting an association between the thrombosis and thrombocytopenia syndrome (TTS) and adenovirus vector-based vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Yet TTS and TTS-associated cerebral venous sinus thrombosis (CVST) remain poorly characterized. We aim to systematically evaluate the proportion of CVST among TTS cases and assess its characteristics and outcomes.We performed a systematic review and meta-analysis of clinical trials, cohorts, case series, and registry-based studies with the aim to assess (1) the pooled mortality rate of CVST, TTS-associated CVST, and TTS and (2) the pooled proportion of patients with CVST among patients with any thrombotic event and TTS. Secondary outcomes comprised clinical characteristics of patients with postvaccination thrombotic event. This meta-analysis is reported according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines and was written according to the Meta-analysis of Observational Studies in Epidemiology proposal.Sixty-nine studies were included in the qualitative analysis comprising 370 patients with CVST out of 4,182 patients with any thrombotic event associated with SARS-CoV-2 vector-based vaccine administration. Twenty-three studies were included further in quantitative meta-analysis. Among TTS cases, the pooled proportion of CVST was 51% (95% confidence interval [CI] 36%-66%; I2 = 61%). TTS was independently associated with a higher likelihood of CVST when compared to patients without TTS with thrombotic events after vaccination (odds ratio 13.8; 95% CI 2.0-97.3; I2 = 78%). The pooled mortality rates of TTS and TTS-associated CVST were 28% (95% CI 21%-36%) and 38% (95% CI 27%-49%), respectively. Thrombotic complications developed within 2 weeks of exposure to vector-based SARS-CoV-2 vaccines (mean interval 10 days; 95% CI 8-12) and affected predominantly women (69%; 95% CI 60%-77%) under age 45, even in the absence of prothrombotic risk factors.Approximately half of patients with TTS present with CVST; almost one-third of patients with TTS do not survive. Further research is required to identify independent predictors of TTS following adenovirus vector-based vaccination.The prespecified study protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO (CRD42021250709).

Randomized controlled trials (RCTs) testing supplementation with eicosapentaenoic (EPA) and docosahexaenoic (DHA) fatty acids have failed to provide evidence supporting a suggested inverse association between fish intake and dementia risk.Dose-response analyses were conducted to evaluate associations between fish intake, all-cause dementia or Alzheimer's Disease (AD), and the effect of EPA/DHA supplementation on cognitive performance.PubMed, Scopus and Web of Science databases were searched for original research evaluating either associations between fish intake and dementia or AD, or the impact of EPA and/or DHA supplementation on the risk of cognitive decline.Data were collected on study characteristics and methods; number of cases/deaths (for observational studies); categories of exposure; model covariates; risk estimates from the most-adjusted model; type and dosage of supplementation (from RCTs); fatty acid levels in blood; and differences in cognition test results before and after supplementation. Risk of bias was assessed through the ROBINS-E and RoB2.0 tools for observational and experimental studies, respectively.Weighted mixed-effects models were applied, allowing for the inclusion of studies with 2 levels of exposure. Based on findings with low/moderate risk of bias, fish intake of up to 2 portions (250 g) per week was associated with a 10% reduction (95% confidence interval [CI]: 0.79, 1.02, Ν = 5) in all-cause dementia and a 30% reduction (95% CI: 0.54, 0.89, Ν = 3) in AD risk. Changes in EPA and DHA body status had a positive impact on participants' executive functions, but not on their overall cognitive performance.The protection offered by fish intake against cognitive decline levels off at intakes higher than 2 portions/week and likely relates to the impact of EPA and DHA on the individual's executive functions, although there remain questions about the mechanisms linking the short- and long-term effects.PROSPERO registration no. CRD42019139528.

Long-term exposure to air pollution has been associated with increased natural-cause mortality, but the evidence on diagnoses-specific mortality outcomes is limited. Few studies have examined the potential synergistic effects of exposure to pollutants and greenness. We investigated the association between exposure to air pollution and greenness with nervous system related mortality, cardiometabolic and chronic obstructive pulmonary diseases (COPD) mortality in Greece, using an ecological study design. We collected socioeconomic and mortality data for 1035 municipal units from the 2011 Census. Annual PM2.5, NO2, BC and O3 concentrations for 2010 were predicted at 100 × 100 m grids by hybrid land use regression models. The normalized difference vegetation index (NDVI) was used for greenness. We applied single and two-exposure Poisson regression models on standardized mortality rates accounting for spatial autocorrelation. We assessed interactions between pollutants and greenness. An interquartile range increase in PM2.5, NO2 and BC was associated with increased risk in mortality from diseases of the nervous system (relative risk (RR): 1.14, 95% confidence interval (CI): 1.01, 1.28); 1.03 (95% CI: 0.99, 1.07); 1.05 (95% CI: 1.00, 1.10) respectively) and from cerebrovascular disease (RR: 1.14, 95% CI: 1.10, 1.18); 1.02 (95% CI: 1.01, 1.04); 1.02 (95% CI: 1.00, 1.04) respectively). PM2.5 was associated with ischemic heart disease mortality (RR: 1.05, 95% CI: 1.01, 1.10). We estimated inverse associations for all outcomes with O3 and for mortality from diseases of the nervous system or COPD with greenness. Estimates were mostly robust to co-exposure adjustment. Interactions were identified between NDVI and O3 or PM2.5 on mortality from the diseases of the nervous system, with higher effect estimates in greener areas. Our findings support the adverse effects of air pollution and the beneficial role of greenness on cardiovascular and nervous system related mortality. Further research is needed on diabetes mellitus.

Meat intake has been positively associated with risk of digestive tract cancers in several epidemiological studies, while data on the relation of meat intake with cancer risk at most other sites are inconsistent. The overall data set, derived from an integrated series of case-control studies conducted in northern Italy between 1983 and 1996, included the following incident, histologically confirmed neoplasms: oral cavity, pharynx and esophagus (n = 497), stomach (n = 745), colon (n = 828), rectum (n = 498), liver (n = 428), gallbladder (n = 60), pancreas (n = 362), larynx (n = 242), breast (n = 3,412), endometrium (n = 750), ovary (n = 971), prostate (n = 127), bladder (n = 431), kidney (n = 190), thyroid (n = 208), Hodgkin's disease (n = 80), non-Hodgkin's lymphomas (n = 200) and multiple myelomas (n = 120). Controls were 7,990 patients admitted to hospital for acute, non-neoplastic conditions unrelated to long-term modifications in diet. The multivariate odds ratios (ORs) for the highest tertile of red meat intake (≥7 times/week) compared with the lowest (≤3 times/week) were 1.6 for stomach, 1.9 for colon, 1.7 for rectal, 1.6 for pancreatic, 1.6 for bladder, 1.2 for breast, 1.5 for endometrial and 1.3 for ovarian cancer. ORs showed no significant heterogeneity across strata of age at diagnosis and sex. No convincing relation with red meat intake emerged for cancers of the oral cavity, pharynx and esophagus, liver, gallbladder, larynx, kidney, thyroid, prostate, Hodgkin's disease, non-Hodgkin's lymphomas and multiple myeloma. For none of the neoplasms considered was there a significant inverse relationship with red meat intake. Thus, reducing red meat intake might lower the risk for several common neoplasms. Int. J. Cancer 86:425–428, 2000. © 2000 Wiley-Liss, Inc.

To better understand the nutritional etiology of squamous cell esophageal cancer, we conducted a case-control study in 3 areas of northern Italy. A total of 304 incident, histologically confirmed cases of squamous cell carcinoma of the esophagus (275 men, 29 women) and 743 hospital controls (593 men, 150 women) with acute, non-neoplastic conditions, not related to smoking, alcohol consumption or long-term diet modification, were interviewed during 1992 to 1997. The validated food-frequency questionnaire included 78 questions on food items or recipes, which were then categorized into 19 main food groups, and 10 questions on fat intake pattern. After allowance for age, sex, education, area of residence, tobacco smoking, alcohol drinking and non-alcohol energy, a significant increased risk emerged for high consumption of soups (OR=2.1 for the highest vs. lowest quintile), whereas inverse associations with esophageal cancer risk were observed for pasta and rice (OR=0.7), poultry (OR=0.4), raw vegetables (OR=0.3), citrus fruit (OR=0.4) and other fruit (OR=0.5). The associations with dietary habits were consistent in different strata of tobacco smoking and alcohol drinking. Among added lipids, olive oil intake showed a significant reduction of esophageal cancer risk, even after allowance for total vegetable consumption (OR=0.4), while butter consumption was directly associated with this risk (OR=2.2). Our results thus provide further support to the evidence that raw vegetables and citrus fruit are inversely related to the risk of squamous cell esophageal cancer and suggest that olive oil may also reduce this risk.

The nutritional aetiology of prostate cancer was evaluated in Athens, Greece, through a case-control study that included 320 patients with histologically confirmed incident prostate cancer and 246 controls without history or symptomatology of benign prostatic hyperplasia or prostate cancer, treated in the same hospital as the cases for minor diseases or conditions. Among major food groups, milk and dairy products as well as added lipids were marginally positively associated with risk for prostate cancer. Among added lipids, seed oils were significantly and butter and margarine non-significantly positively associated with prostate cancer risk, whereas olive oil was unrelated to this risk. Cooked tomatoes and to a lesser extent raw tomatoes were inversely associated with the risk for prostate cancer. In analyses focusing on nutrients, rather than foods, polyunsaturated fats were positively and vitamin E inversely associated with prostate cancer. We conclude that several nutrition-related processes jointly contribute to prostate carcinogenesis.

Abstract Objective: To evaluate meat intake patterns in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohorts. Design and setting: 24-Hour dietary recalls were assessed within the framework of a prospective cohort study in 27 centres across 10 European countries by means of standardised computer-assisted interviews. Subjects: In total, 22 924 women and 13 031 men aged 35–74 years. Results: Mean total meat intake was lowest in the ‘health-conscious’ cohort in the UK (15 and 21 g day −1 in women and men, respectively) and highest in the north of Spain, especially in San Sebastian (124 and 234 g day −1 , respectively). In the southern Spanish centres and in Naples (Italy), meat consumption was distinctly lower than in the north of these countries. Central and northern European centres/countries showed rather similar meat consumption patterns, except for the British and French cohorts. Differences in the intake of meat sub-groups (e.g. red meat, processed meat) across EPIC were even higher than found for total meat intake. With a few exceptions, the Mediterranean EPIC centres revealed a higher proportion of beef/veal and poultry and less pork or processed meat than observed in central or northern European centres. The highest sausage consumption was observed for the German EPIC participants, followed by the Norwegians, Swedish, Danish and Dutch. Conclusions: The results demonstrate distinct differences in meat consumption patterns between EPIC centres across Europe. This is an important prerequisite for obtaining further insight into the relationship between meat intake and the development of chronic diseases.