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Background Current risk models for renal cell carcinoma (RCC) based on clinicopathological factors are sub-optimal in accurately identifying high-risk patients. Here, we perform a head-to-head comparison of previously published DNA methylation markers and propose a potential prognostic model for clear cell RCC (ccRCC). Patients and methods Promoter methylation of PCDH8, BNC1, SCUBE3, GREM1, LAD1, NEFH, RASSF1A, GATA5, SFRP1, CDO1, and NEURL was determined by nested methylation-specific PCR. To identify clinically relevant methylated regions, The Cancer Genome Atlas (TCGA) was used to guide primer design. Formalin-fixed paraffin-embedded (FFPE) tissue samples from 336 non-metastatic ccRCC patients from the prospective Netherlands Cohort Study (NLCS) were used to develop a Cox proportional hazards model using stepwise backward elimination and bootstrapping to correct for optimism. For validation purposes, FFPE ccRCC tissue of 64 patients from the University Hospitals Leuven and a series of 232 cases from The Cancer Genome Atlas (TCGA) were used. Results Methylation of GREM1, GATA5, LAD1, NEFH, NEURL, and SFRP1 was associated with poor ccRCC-specific survival, independent of age, sex, tumor size, TNM stage or tumor grade. Moreover, the association between GREM1, NEFH, and NEURL methylation and outcome was shown to be dependent on the genomic region. A prognostic biomarker model containing GREM1, GATA5, LAD1, NEFH and NEURL methylation in combination with clinicopathological characteristics, performed better compared to the model with clinicopathological characteristics only (clinical model), in both the NLCS and the validation population with a c-statistic of 0.71 versus 0.65 and a c-statistic of 0.95 versus 0.86 consecutively. However, the biomarker model had limited added prognostic value in the TCGA series with a c-statistic of 0.76 versus 0.75 for the clinical model. Conclusion In this study we performed a head-to-head comparison of potential prognostic methylation markers for ccRCC using a novel approach to guide primers design which utilizes the optimal location for measuring DNA methylation. Using this approach, we identified five methylation markers that potentially show prognostic value in addition to currently known clinicopathological factors.

BACKGROUND AND PURPOSE: Caffeine is associated with a lower risk of some neurological diseases, but few prospective studies have investigated caffeine intake and risk of amyotrophic lateral sclerosis (ALS) mortality. We therefore determined associations between coffee, tea and caffeine intake, and risk of ALS mortality. METHODS: We conducted pooled analyses of eight international, prospective cohort studies, including 351 565 individuals (120 688 men and 230 877 women). We assessed coffee, tea and caffeine intake using validated food-frequency questionnaires administered at baseline. We used Cox regression to estimate study- and sex-specific risk ratios and 95% confidence intervals (CI) for ALS mortality, which were then pooled using a random-effects model. We conducted analyses using cohort-specific tertiles, absolute common cut-points and continuous measures of all exposures. RESULTS: During follow-up, 545 ALS deaths were documented. We did not observe statistically significant associations between coffee, tea or caffeine intake and risk of ALS mortality. The pooled multivariable risk ratio (MVRR) for ≥3 cups per day vs. >0 to

Purpose Evidence from cross-sectional studies suggests that higher levels of light-intensity physical activity (LPA) are associated with better health-related quality of life (HRQoL) in colorectal cancer (CRC) survivors. However, these associations have not been investigated in longitudinal studies that provide the opportunity to analyse how within-individual changes in LPA affect HRQoL. We investigated longitudinal associations of LPA with HRQoL outcomes in CRC survivors, from 6 weeks to 2 years post-treatment. Methods Data were used of a prospective cohort study among 325 stage I–III CRC survivors (67% men, mean age: 67 years), recruited between 2012 and 2016. Validated questionnaires were used to assess hours/week of LPA (SQUASH) and HRQoL outcomes (EORTC QLQ-C30, Checklist Individual Strength) at 6 weeks, and 6, 12 and 24 months post-treatment. We applied linear mixed regression to analyse longitudinal confounder-adjusted associations of LPA with HRQoL. Results We observed statistically significant longitudinal associations between more LPA and better global quality of life and physical, role and social functioning, and less fatigue over time. Intra-individual analysis showed that within-person increases in LPA (per 8 h/week) were related to improved HRQoL, including better global quality of life (β = 1.67, 95% CI 0.71; 2.63; total range scale: 0–100) and less fatigue (β = − 1.22, 95% CI − 2.37; − 0.07; scale: 20–140). Stratified analyses indicated stronger associations among participants below the median of moderate-to-vigorous physical activity (MVPA) at diagnosis. Conclusion Higher levels of LPA were longitudinally associated with better HRQoL and less fatigue in CRC survivors up to two years post-treatment. Further prospective studies using accelerometer data are necessary to inform development of interventions targeting LPA.

Insulin-like growth factors (IGFs) have been associated with growth, body size, physical activity, and colorectal cancer (CRC). We hypothesized that variants in IGF-related genes increase the CRC susceptibility associated with a larger body size and a lack of physical activity. We assessed this in the Netherlands Cohort Study (NLCS). Participants (n=120 852) completed a baseline questionnaire on diet and cancer. ~75% returned toenail clippings. Using a case-cohort approach and 16.3 years of follow-up, toenail DNA from 3768 subcohort members and 2580 CRC cases was genotyped. We aggregated unfavorable alleles (potentially increasing CRC risk) for 18 single nucleotide polymorphisms in 8 genes into a sum score. The sum score (in tertiles) and an IGF1 19-CA repeat polymorphism (19/19, 19/non-19, and non-19/non-19 repeats) in combination with body size (mostly in tertiles) and (non-)occupational physical activity (>12, 8-12, and 90, >60-90

Background:Prostate cancer is the most commonly diagnosed cancer in men in Europe and the United States. Numerous studies have indicated genetics to have a major role in the aetiology of this disease; as much as 42% of the risk may be explained by heritable factors. Genome-wide association studies have detected an association between prostate cancer and chromosome 8p21-23. In this study, we analysed eight microsatellite (MS) markers in that region in order to confirm previous results and narrow down the location of candidate prostate cancer genes.Methods:292 cases and 278 controls were selected from the Netherlands Cohort Study (NLCS). The following MSs were used in the analyses: D8S136, D8S1734, D8S1742, D8S261, D8S262, D8S351, D8S511 and D8S520. Associations were evaluated using a χ 2 test and logistic regression. We checked for any effects on the association by tumour stage.Results:Associations that were found confirmed previous research that pointed to the 8p21-23 region. Two MSs: D8S136 (odds ratio (OR), 0.69; P=4.00 × 10 -28), and D8S520 (OR, 0.80; P=3.37 × 10 -11), were consistently and strongly related with prostate cancer. Genotype analysis showed an additive effect for D8S136 (P-trend=6.22 × 10 -03) and D8S520 (P-trend=2.62 × 10 -22), suggesting an increased risk for people with a short number of repeats on both alleles at those markers.Conclusions:This study provides strong evidence that the 8p21-23 region is likely to harbour prostate cancer genes.© 2013 Macmillan Publishers Limited All rights reserved. Chemicals/CAS: lipoprotein lipase, 83137-80-8, 9004-02-8

Background. The Collaborative Group on Hormonal Factors in Breast Cancer has brought together and reanalysed about 90% of the worldwide epidemiological evidence on the relation between risk of breast cancer and use of hormone replacement therapy (HRT). Methods. Individual data on 52,705 women with breast cancer and 108,411 women without breast cancer from 51 studies in 21 countries were collected, checked, and analysed centrally. The main analyses are based on 53,865 postmenopausal women with a known age at menopause, of whom 17,830 (33%) had used HRT at some time. The median age at first use was 48 years, and 34% of ever-users had used HRT for 5 years or longer. Estimates of the relative risk of breast cancer associated with the use of HRT were obtained after stratification of all analyses by study, age at diagnosis, time since menopause, body-mass index, parity, and the age a woman was when her first child was born. Findings. Among current users of HRT or those who ceased use 1-4 years previously, the relative risk of having breast cancer diagnosed increased by a factor of 1.023 (95% CI 1.011-1.036; 2p = 0.0002) for each year of use; the relative risk was 1.35 (1.21-1.49; 2p = 0.00001) for women who had used HRT for 5 years or longer (average duration of use in this group 11 years). This increase is comparable with the effect on breast cancer of delaying menopause, since among never-users of HRT the relative risk of breast cancer increases by a factor of 1.028 (95% CI 1.021-1.034) for each year older at menopause. 5 or more years after cessation of HRT use, there was no significant excess of breast cancer overall or in relation to duration of use. These main findings did not vary between individual studies. Of the many factors examined that might affect the relation between breast cancer risk and use of HRT, only a woman's weight and body-mass index had a material effect: the increase in the relative risk of breast dancer associated with long durations of use in current and recent users was greater for women of lower than of higher weight or body-mass index. There was no marked variation in the results according to hormonal type or dose but little information was available about long durations of use of any specific preparation. Cancers diagnosed in women who had ever used HRT tended to be less advanced clinically than those diagnosed in never-users. In North America and Europe the cumulative incidence of breast cancer between the ages of 50 and 70 in never-users of HRT is about 45 per 1000 women. The cumulative excess numbers of breast cancers diagnosed between these ages per 1000 women who began use of HRT at age 50 and used it for 5, 10, and 15 years, respectively, are estimated to be 2 (95% CI 1-3), 6 (3-9), and 12 (5-20). Whether HRT affects mortality from breast cancer is not known. Interpretation. The risk of having breast cancer diagnosed is increased in women using HRT and increases with increasing duration of use. This effect is reduced after cessation of use of HRT and has largely, if not wholly, disappeared after about 5 years. These findings should be considered in the context of the benefits and other risks associated with the use of HRT.

BACKGROUND/OBJECTIVES: The few prospective studies that examined lung, female breast and prostate cancer risk in vegetarians have yielded mixed results, whereas none have studied the effects of low meat diets. Moreover, little is known about the explanatory role of (non-) dietary factors associated with these diets. SUBJECTS/METHODS: The Netherlands Cohort Study-Meat Investigation Cohort (NLCS-MIC)-is an analytical cohort of 11 082 individuals including 1133 self-reported vegetarians (aged 55-69 years at baseline). At baseline (1986), subjects completed a questionnaire on dietary habits and other risk factors for cancer and were classified into vegetarians (n = 691), pescetarians (n = 389), 1 day per week (n = 1388), 2-5 days per week (n = 2965) and 6-7 days per week meat consumers (n = 5649). RESULTS: After 20.3 years of follow-up, 279 lung, 312 postmenopausal breast and 399 prostate cancer cases (including 136 advanced) were available for analyses. After adjustment for confounding variables, we found no statistically significant association between meat consumption groups and the risk of lung cancer. As well, no significant associations were observed for postmenopausal breast and overall prostate cancer. After adjustment for confounders, individuals consuming meat 1 day per week were at a 75% increased risk of advanced prostate cancer compared with 6-7 days per week meat consumers (95% CI 1.03-2.97). CONCLUSIONS: Vegetarians, pescetarians and 1 day per week meat consumers did not have a reduced risk of lung, postmenopausal breast and overall prostate cancer compared with individuals consuming meat on a daily basis after taking confounders into account.

Introduction To study the properties of a screening instrument in predicting long-term sickness absence among employees with depressive complaints. Methods Employees at high risk of future sickness absence were selected by the screening instrument Balansmeter (BM). Depressive complaints were assessed with the depression scale of the Hospital Anxiety and Depression Scale. The total study population consisted of 7,401 employees. Sickness absence was assessed objectively and analyzed at 12 and 18 months of follow-up using company registers on certified sick leave. Results The relative risk (RR) for long-term sickness absence, for employees at high risk versus not at high risk, was 3.26 (95% CI 2.54-4.22) in men and 2.55 (1.98-3.35) in women, when the BM was applied in the total study population. The RR of long-term sickness absence of employees with depressive complaints compared with employees without depressive complaints was 3.13 (2.41-4.09) in men and 2.45 (2.00-3.00) in women. The RR of long-term sickness absence for the BM applied in employees with depressive complaints was 5.23 in men and 3.87 in women. When the BM with a cut-off point with a higher sensitivity was applied in employees with depressive complaints, the RR for long-term sickness absence was 4.88 in men and 3.80 in women. Conclusions The screening instrument Balansmeter is able to predict long-term sickness absence within employees with depressive complaints. The total prediction of long-term sickness absence proved better in employees with depressive complaints compared with employees of a general working population.

Ovarian cancer is a highly lethal disease. Many researchers have, therefore, attempted to identify high risk populations. In this perspective, numerous genetic association studies have been performed to discover common ovarian cancer susceptibility variants. Accordingly, there is an increasing need to synthesize the evidence in order to identify true associations. A comprehensive and systematic assessment of all available data on genetic susceptibility to sporadic ovarian cancer was carried out. The evidence of statistically significant findings was evaluated based on the number of positive replications, the ratio of positive and negative studies, and the false-positive report probability (FPRP). The authors reviewed three genome-wide association studies (GWAS) and 147 candidate gene studies, published from 1990 to October 2010, including around 1100 genetic variants in more than 200 candidate genes and 20 intergenic regions. Genetic variants with the strongest evidence for an association with ovarian cancer include the rs2854344 in the RB1 gene and SNPs on chromosomes 9p22.2, 8q24, 2q31, and 19p13. Promising genetic pathways for ovarian cancer include the cell cycle, DNA repair, sex steroid hormone and oncogenic pathway. Concluding, this review shows that many genetic association studies have been performed, but only a few genetic variants show strong evidence for an association with ovarian cancer. More research is needed to elucidate causal genetic variants, taking into consideration gene-gene and gene-environment interactions, combined effects of common and rare variants, and differences between histological subtypes of this cancer.

Objective To investigate the association between selenium and the risk of Barrett’s esophagus (BE), the precursor lesion of esophageal adenocarcinoma. Methods Data from the prospective Netherlands Cohort Study were used. This cohort study was initiated in 1986, when 120,852 subjects aged 55–69 years completed a questionnaire on dietary habits and lifestyle, and provided toenail clippings for the determination of baseline selenium status. After 16.3 years of follow-up, 253 BE cases (identified through linkage with the nationwide Dutch pathology registry) and 2,039 subcohort members were available for case–cohort analysis. Cox proportional hazards models were used to calculate incidence rate ratios (RR). Results The multivariable-adjusted RR for the highest versus the lowest quartile of toenail selenium was 1.06 (95% CI 0.71–1.57). No dose–response trend was seen (p trend = 0.99). No association was found in subgroups defined by sex, smoking status, body mass index (BMI), or intake of antioxidants. For BE cases that later progressed to high-grade dysplasia or adenocarcinoma, the RR for a selenium level above the median vs. below the median was 0.64 (95% CI 0.24–1.76). Conclusions In this large prospective cohort study, we found no evidence of an association between selenium and risk of BE. Electronic supplementary material The online version of this article (doi:10.1007/s10552-010-9651-1) contains supplementary material, which is available to authorized users.

Background/Objectives: Acrylamide, a probable human carcinogen, was detected in various heat-treated foods such as French fries and potato crisps. Recently, positive associations have been found between dietary acrylamide intakes, as estimated with a food frequency questionnaire using an acrylamide database, and cancer risk in some epidemiological studies. As acrylamide levels vary considerably within the same type of foods, a validation study was performed to investigate whether use of an acrylamide food database containing calculated mean acrylamide content, based on extensive sampling and chemical analysis of Dutch foods (several samples per food), can classify subjects with respect to true acrylamide intake. Subjects/Methods: We used the data from a 24-h duplicate diet study. The acrylamide content of 39 Dutch 24-h duplicate diets collected in 2004 was estimated using the mean acrylamide levels of foods available from the database and the menu list, on which the participants of the duplicate diet study had listed the amounts of individual foods and drinks in household units. Next, the acrylamide content of the total duplicate diets was analytically measured and correlated to the estimated acrylamide contents. Results: The Spearman's correlation coefficient between chemically determined acrylamide content and the calculated acrylamide content of the duplicate diets was 0.82 (P

Aberrant DNA methylation affects carcinogenesis of colorectal cancer. Folate metabolizing enzymes may influence the bioavailability of methyl groups, whereas DNA and histone methyltransferases are involved in epigenetic regulation of gene expression. We studied associations of genetic variants of folate metabolizing enzymes (MTHFR, MTR, and MTRR), DNA methyltransferase DNMT3b, and histone methyltransferases (EHMT1, EHMT2, and PRDM2), with colorectal cancers, with or without the CpG island methylator phenotype (CIMP), MLH1 hypermethylation, or microsatellite instability. Incidence rate ratios were calculated in case-cohort analyses, with common homozygotes as reference, among 659 cases and 1,736 subcohort members of the Netherlands Cohort Study on diet and cancer (n = 120,852). Men with the MTHFR 677TT genotype were at decreased colorectal cancer risk (incidence rate ratio, 0.49; P = 0.01), but the T allele was associated with increased risk in women (incidence rate ratio, 1.39; P = 0.02). The MTR 2756GG genotype was associated with increased colorectal cancer risk (incidence rate ratio, 1.58; P = 0.04), and inverse associations were observed among women carrying DNMT3b C→T (rs406193; incidence rate ratio, 0.72; P = 0.04) or EHMT2 G→A (rs535586; incidence rate ratio, 0.76; P = 0.05) polymorphisms. Although significantly correlated (P < 0.001), only 41.5% and 33.3% of CIMP tumors harbored MLH1 hypermethylation or microsatellite instability, respectively. We observed inverse associations between MTR A2756G and CIMP among men (incidence rate ratio, 0.58; P = 0.04), and between MTRR A66G and MLH1 hypermethylation among women (incidence rate ratio, 0.55; P = 0.02). In conclusion, MTHFR, MTR, DNMT3b, and EHMT2 polymorphisms are associated with colorectal cancer, and rare variants of MTR and MTRR may reduce promoter hypermethylation. The incomplete overlap between CIMP, MLH1 hypermethylation, and microsatellite instability indicates that these related “methylation phenotypes” may not be similar and should be investigated separately. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3086–96)

The prevalence of atopic diseases, including eczema, allergic rhinoconjunctivitis and asthma, has increased worldwide, predominantly in westernized countries. Recent epidemiological studies and experimental research suggest that microbial stimulation of the immune system influences the development of tolerance to innocuous allergens. The gastrointestinal microbiota composition may be of particular interest, as it provides an early and major source of immune stimulation and seems to be a prerequisite for the development of oral tolerance. In this review the observational studies of the association between the gut microbiota and atopic diseases are discussed. Although most studies indicated an association between the gut microbiota composition and atopic sensitization or symptoms, no specific harmful or protective microbes can be identified yet. Some important methodological issues that have to be considered are the microbiological methods used (traditional culture vs molecular techniques), the timing of examining the gut microbiota, the definition of atopic outcomes, confounding and reverse causation. In conclusion, the microbiota hypothesis in atopic diseases is promising and deserves further attention. To gain more insight into the role of the gut microbiota in the etiology of atopy, large-scale prospective birth cohort studies using molecular methods to study the gut microbiota are needed.

Ovary cancer risk in relation to consumption of dairy products was investigated using a self-administered questionnaire on dietary habits and other risk factors for cancer, which was completed in 1986 by 62 573 postmenopausal women participating in the Netherlands Cohort Study. Follow-up for cancer was implemented by annual record linkage with the Netherlands Cancer Registry and a nationwide pathology registry. After 11.3 years of follow-up, data of 252 incident epithelial ovarian cancer cases and 2216 subcohort members were available for analysis. No association was seen between consumption of milk yoghurt, cheese or fermented dairy products and ovarian cancer risk. The multivariable adjusted relative risk of epithelial ovarian cancer for women in the highest compared to the lowest quintile of intake of lactose or dairy fat was 0.93 (95% confidence interval (CI) = 0.60-1.45; Ptrend = 0.32) and 1.53 (95% CI = 1.00-2.36; Ptrend = 0.11), respectively. Lactose or dairy fat intakes were not associated with serous ovarian cancer risk. Our results do not support an association between consumption of dairy products or lactose intake and ovarian cancer. © 2006 Cancer Research. Chemicals / CAS: lactose, 10039-26-6, 16984-38-6, 63-42-3, 64044-51-5; Dietary Fats; Lactose, 63-42-3

Summary Background The rise in atopic diseases has been linked to disturbances in the intestinal microbiota composition. Objective The purpose of this study was to investigate the intestinal microbiota composition in infants in whom atopic (IgE-associated) eczema was or was not developing, using a molecular fingerprinting technique. Methods Within a prospective birth cohort study, fecal samples have been collected at the infant's age of 1 month. Within the context of this cohort, we conducted a nested case–control study comparing fecal samples of 26 infants who became sensitized and developed eczema within the first year of life with 52 non-sensitized non-eczematous infants. The composition of the fecal samples was examined using PCR combined with denaturing gradient gel electrophoresis. Using real-time PCR, total bacterial counts and bifidobacterial counts were enumerated. Results Neither total bacterial profiles nor the type and proportion of bifidobacteria in the feces were associated with the development of atopic eczema. The similarity of bacterial profiles was low; mean similarity was approximately 33% in both infants with or without atopic eczema. The prevalence of one specific band in total bacterial profiles was significantly higher in infants with atopic eczema compared with controls (96% vs. 71%, P=0.01). Identification of this band revealed that it represented Escherichia coli. Conclusion Although no association was found between the development of IgE-associated eczema and the dominant gut microbiota as a whole or with the bifdobacterial microbiota, the association with E. coli indicates that differences in gut microbiota do precede the development of atopy.

We reviewed 37 prospective cohort and four intervention studies on potential dietary risk factors for prostate cancer, published between 1966 and September 2003. Some studies were limited by small size, crude measurement of dietary exposure and limited control for confounders. Intervention and prospective cohort studies support a protective role against prostate cancer for selenium, and possibly for vitamin E, pulses and tomatoes/lycopene. Overall consumption of meat, eggs, vegetables, fruit, coffee, tea, carotenoids and vitamins A, C and D was not consistently related to prostate cancer risk. Intervention studies also indicate that supplementation with beta-carotene does not lower prostate cancer risk, except possibly in men with low beta-carotene status at baseline. For specific types of meat, alcoholic drinks, dairy products, fat and anthropometric measures, most cohort studies suggest either an increased risk or no relation with prostate cancer. For calcium, two cohort studies suggest an increased risk at very high calcium intakes (>2000 mg/day). In conclusion, prospective studies are consistent with a protective role for selenium, and possibly vitamin E, pulses and tomatoes/lycopene, in the aetiology of prostate cancer. Studies are inconclusive on the role of meat, dairy products, fat, vegetables, fruits, alcohol and anthropometric measures, whereas a very high calcium intake appears to be positively associated with prostate cancer risk.

Epidemiologic studies directly contribute data on risk (or benefit) in humans as the investigated species, and in the full food intake range normally encountered by humans. This paper starts with introducing the epidemiologic approach, followed by a discussion of perceived differences between toxicological and epidemiologic risk assessment. Areas of contribution of epidemiology to the risk assessment process are identified, and ideas for tailoring epidemiologic studies to the risk assessment procedures are suggested, dealing with data collection, analyses and reporting of both existing and new epidemiologic studies. The dietary habits and subsequent disease occurrence of over three million people are currently under observation worldwide in cohort studies, offering great potential for use in risk assessment. The use of biomarkers and data on genetic susceptibility are discussed. The paper describes a scheme to classify epidemiologic studies for use in risk assessment, and deals with combining evidence from multiple studies. Using a matrix approach, the potential contribution to each of the steps in the risk assessment process is evaluated for categories of food substances. The contribution to risk assessment of specific food substances depends on the quality of the exposure information. Strengths and weaknesses are summarized. It is concluded that epidemiology can contribute significantly to hazard identification, hazard characterisation and exposure assessment.

Item does not contain fulltext This study examined the prevalence of common infections among employees in different work schedules. Self-administered questionnaire data from the Maastricht Cohort Study on "Fatigue at Work" (n = 12,140) were used. Job title was used as a matching variable between day and shift workers to control for their different work environment. We used a multilevel analysis of a two-level structure, in which the individual employees (level 1) were nested within job titles (level 2), adjusted for demographics, longstanding disease, health behavior, work-related factors, fatigue and sleep quality. Results from the multilevel analyses showed that, compared to day work, shift work was associated with a higher risk for common infections, with the highest risk in three-shift workers. Compared to day work, shift work was further associated with differences in health, health behavior, sleep, fatigue and perceived job characteristics, factors that may influence the occurrence of infections and should be taken into account in future studies as well.

Pancreatic cancer has few early symptoms, is usually diagnosed at late stages, and has a high case-fatality rate. Identifying modifiable risk factors is crucial to reducing pancreatic cancer morbidity and mortality. Prior studies have suggested that specific foods and nutrients, such as dairy products and constituents, may play a role in pancreatic carcinogenesis. In this pooled analysis of the primary data from 14 prospective cohort studies, 2212 incident pancreatic cancer cases were identified during follow-up among 862 680 individuals. Adjusting for smoking habits, personal history of diabetes, alcohol intake, body mass index (BMI), and energy intake, multivariable study-specific hazard ratios (MVHR) and 95% confidence intervals (CIs) were calculated using the Cox proportional hazards models and then pooled using a random effects model. There was no association between total milk intake and pancreatic cancer risk (MVHR = 0.98, 95% CI = 0.82-1.18 comparing ≥500 with 1-69.9 g/day). Similarly, intakes of low-fat milk, whole milk, cheese, cottage cheese, yogurt, and icecream were not associated with pancreatic cancer risk. No statistically significant association was observed between dietary (MVHR = 0.96, 95% CI = 0.77-1.19) and total calcium (MVHR = 0.89, 95% CI = 0.71-1.12) intake and pancreatic cancer risk overall when comparing intakes ≥1300 with

There are few epidemiological data on the dietary risk factors of Barrett's oesophagus, a precursor of oesophageal adenocarcinoma. The present study investigated the association between vegetable, fruit and nitrate intake and Barrett's oesophagus risk in a large prospective cohort. The Netherlands Cohort Study recruited 120852 individuals aged 55-69 years in 1986. Vegetable and fruit intake was assessed using a 150-item FFQ, and nitrate intake from dietary sources and drinking water was determined. After 16 center dot 3 years of follow-up, 433 cases (241 men and 192 women) of Barrett's oesophagus with specialised intestinal metaplasia and 3717 subcohort members were analysed in a case-cohort design using Cox proportional hazards models while adjusting for potential confounders. Men exhibited a lower risk of Barrett's oesophagus in the highest v. the lowest quintile of total (multivariable-adjusted hazard ratio (HR): 0 center dot 66, 95% CI 0 center dot 43, 1 center dot 01), raw (HR 0 center dot 63, 95% CI 0 center dot 40, 0 center dot 99), raw leafy (HR 0 center dot 55, 95% CI 0 center dot 36, 0 center dot 86) and Brassica (HR 0 center dot 64, 95% CI 0 center dot 41, 1 center dot 00) vegetable intake. No association was found for other vegetable groups and fruits. No significant associations were found between vegetable and fruit intake and Barrett's oesophagus risk among women. Total nitrate intake was inversely associated with Barrett's disease risk in men (HR 0 center dot 50, 95% CI 0 center dot 25, 0 center dot 99) and positively associated with it in women (HR 3 center dot 77, 95% CI 1 center dot 68, 8 center dot 45) (P for interaction=0 center dot 04). These results suggest that vegetable intake may contribute to the prevention of Barrett's oesophagus. The possible differential effect in men and women should be evaluated further.

Am J Epidemiol 2001 Sep 15;154(6):530-7 Related Articles, Books, LinkOut Energy restriction in childhood and adolescence and risk of prostate cancer: results from the Netherlands Cohort Study.Dirx MJ, van den Brandt PA, Goldbohm RA, Lumey LH.Department of Epidemiology, Faculty of Health Sciences, Maastricht University, Maastricht, the Netherlands. MJM.Dirx@epid.unimaas.nlThis study investigated the association between prostate cancer risk and energy restriction during childhood. The authors examined the hypothesis among 58,279 men aged 55-69 years enrolled in the Netherlands Cohort Study on Diet and Cancer. Information on diet and risk factors was collected by questionnaire in 1986. Additional information was collected on residence during the Dutch Hunger Winter (1944-1945) and the World War II years (1940-1944) and father's employment status during the economic depression of 1932-1940, used as indicators of exposure. A case-cohort approach was used. After 7.3 years of follow-up (through December 1993), 903 prostate cancer cases were available for analysis. Analyses were carried out for all prostate cancer cases. The prostate cancer rate ratio for men who had lived in a western Netherlands city in 1944-1945 was 1.15 (95% confidence interval (CI): 0.80, 1.31), and the rate ratio for men who had lived in a western rural area in 1944-1945 was 1.30 (95% CI: 0.97, 1.73). Residence during the war years (1940-1944) and father's employment in 1932-1940 showed no relation to prostate cancer risk. In subgroup analyses in which exposure before, during, and after the adolescent growth spurt was evaluated, the same pattern as that of the overall data was shown. The authors found no evidence for the hypothesis that energy restriction early in life decreases prostate cancer risk later in life.

The relation between vegetable and fruit consumption and colorectal cancer risk was comprehensively assessed in the Netherlands Cohort Study on Diet and Cancer using a validated 150-item food frequency questionnaire. After 6.3 years of follow-up (1986-1992), over 1,000 incident cases of colorectal cancer were registered. Using case-cohort analysis, the authors calculated rate ratios and 95% confidence intervals adjusted for age, alcohol intake, and family history of colorectal cancer. For colon cancer, no statistically significant associations with total vegetable intake or total fruit intake were found. However, among women, an inverse association was observed with vegetables and fruits combined (for the highest quintile vs. the lowest, the rate ratio was 0.66 (95% confidence interval: 0.44, 1.01)). Brassica vegetables and cooked leafy vegetables showed inverse associations for both men and women. Among women and, to a lesser extent, among men, inverse associations were stronger for distal colonic tumors than for proximal colonic tumors. For rectal cancer, no statistically significant associations were found for vegetable consumption or fruit consumption or for specific groups of vegetables and fruits; only Brassica vegetables showed a positive association in women. As in other cohort studies, the observed inverse relation between vegetable and fruit consumption and occurrence of colorectal cancer was less strong than relations reported in case-control studies.

University Masstricht, Department of Epidemiology, The Netherlands.The association between the intake of nitrate or nitrite and gastric cancer risk was investigated in a prospective cohort study started in 1986 in the Netherlands, of 120,852 men and women aged 55-69 years. At baseline, data on dietary intake, smoking habits and other covariates were collected by means of a self-administered questionnaire. For data analysis, a case-cohort approach was used, in which the person-years at risk were estimated from a randomly selected subcohort (1688 men and 1812 women). After 6.3 years of follow-up, 282 microscopically confirmed incident cases of stomach cancer were detected: 219 men and 63 women. We did not find a higher risk of gastric cancer among people with a higher nitrate intake from food [rate ratio (RR) highest/lowest quintile = 0.80, 95% CI 0.47-1.37, trend-P = 0.18], a higher nitrate intake from drinking water (RR highest/lowest quintile = 0.88, 95% CI 0.59-1.32, trend-P = 0.39) or a higher intake of nitrite (RR highest/lowest quintile = 1.44, 95% CI 0.95-2.18, trend-P = 0.24). Rate ratios for gastric cancer were also computed for each tertile of nitrate intake from foods within tertiles of vitamin C intake and intake of beta-carotene, but no consistent pattern was found. Therefore, our study does not support a positive association between the intake of nitrate or nitrite and gastric cancer risk.

Socioeconomic status and breast cancer incidence: a prospective cohort study.Van Loon AJ, Goldbohm RA, Van den Brandt PA.University of Limburg, Department of Epidemiology, Maastricht, The Netherlands.BACKGROUND. To gain more insight into the relation between socioeconomic status (SES) and breast cancer risk, we have studied that association, before and after adjustment for traditional risk factors for breast cancer, in a prospective cohort study on lifestyle and cancer that started in 1986 in the Netherlands amongst 62,573 women aged 55-69 years. METHODS. At baseline, data on SES, diet, reproductive factors and other covariates were collected by means of a self-administered questionnaire. For data-analysis a case-cohort approach was used. After 3.3 years of follow-up, 471 incident cases were available for analysis. RESULTS. We did not find a higher age-adjusted risk of breast cancer for those with a higher level of education (RR highest/lowest level of education = 0.94, 95% confidence interval [CI]: 0.63-1.39, trend-P = 0.15). Although upper white-collar workers had a slightly higher breast cancer risk than blue-collar workers (RR = 1.16, 95% CI: 0.83-1.62, trend-P = 0.34), women with a profession of higher social standing did not have a higher risk (RR highest/lowest social standing = 0.73, 95% CI: 0.24-2.23, trend-P = 0.86). Additional adjustment for traditional risk factors did not alter the association between SES and breast cancer risk. CONCLUSIONS. We did not find an association between SES and breast cancer risk. This is not in agreement with studies conducted in other European countries and North America

In a previous paper published in this journal, we reported on the role of the intestinal microbiota in the development of atopic manifestations, as examined in a prospective birth cohort (KOALA).1 We showed that infants colonised with Clostridium difficile were at increased risk of developing eczema, wheeze and sensitisation. An association between C difficile and atopic diseases has also been reported by others.2 3 A possible underlying mechanism could be through breaking oral tolerance, as C difficile can cause inflammation in gut tissues, leading to increased permeability of the mucosal barrier and thus facilitating the penetration of allergens.4 The enteropathogenicity of C difficile is associated with the production of toxins A and B, encoded by the genes tcdA and tcdB . Both toxins disrupt epithelial cell tight junctions and thereby ablate epithelial barrier function.5 According to the hypothesised mechanism, it is expected that …

Contains fulltext : 69626.pdf (Publisher’s version ) (Closed access) Alcohol consumption has been associated with a decreased risk for renal cell cancer in several studies. We investigated whether alcohol is associated with (epi)genetic changes of the von Hippel-Lindau (VHL) gene in renal cell cancer. The Netherlands Cohort Study (NLCS) on Diet and Cancer started in 1986 (n = 120,852) and uses the case-cohort method. After 11.3 years of follow-up, 314 renal cell cancer cases and 4,511 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumor tissue from 235 cases. VHL mutations were analyzed by sequencing, whereas VHL promoter methylation was analyzed using methylation-specific PCR. In multivariate analysis, hazard ratios of renal cell cancer for cohort members who consumed up to 5, 15, 30, and > or = 30 g of alcohol per day were 0.72, 0.64, 0.81, and 0.69, respectively, compared with nondrinkers [95% confidence interval (95% CI) for the > or = 30 category, 0.44-1.07; P for trend, 0.17]. Alcohol intake from beer, wine, and liquor was associated with decreased risks for renal cell cancer, although not statistically significant. Hazard ratios were not different for clear-cell renal cell cancer with and without VHL mutations, except for alcohol from beer, which was associated with an increased risk for clear-cell renal cell cancer without VHL mutations (hazard ratio for > or = 5 g of alcohol from beer compared with nondrinkers, 2.74; 95% CI, 1.35-5.57). Alcohol was associated with a decreased risk for clear-cell renal cell cancer without VHL gene promoter methylation (hazard ratio for >15 g compared with nondrinkers, 0.58; 95% CI, 0.34-0.99). In this study, a not statistically significant inverse association was observed between alcohol and renal cell cancer. There was no statistical significant heterogeneity by VHL mutation or methylation status.

Since a KRAS oncogene mutation is an early event in colorectal cancer development and cigarette smoking is thought to have an effect on early stages of colorectal tumorigenesis, smoking, especially long-term smoking, may be associated with the risk for colorectal cancer with KRAS oncogene mutations. In the Netherlands Cohort Study on diet and cancer (n=120,852 men and women), using a case-cohort design, adjusted incidence rate ratios (RR) and 95% confidence intervals (CI) were computed for colorectal tumors with wild-type and with mutated KRAS gene, and with specific G:C-->T:A or G:C-->A:T point mutations in KRAS, according to cigarette smoking status, frequency, duration, pack years, age at first exposure, years since cessation, inhalation and filter usage. After 7.3 years and excluding the first 2.3 years, 648 cases and 4083 sub-cohort members were included in the analyses. Ex-smokers, but not current smokers, were at increased risk for colorectal cancer with wild-type KRAS gene tumors when compared with never smokers, albeit not statistically significant (RR 1.26, 95% CI 0.96-1.66). This was not observed for KRAS mutated tumors when comparing ex-smokers with never smokers (RR 1.15, 95% CI 0.79-1.66). The highest category of smoking frequency (>20 cigarettes/day) and inhalation of smoke were associated with an increased risk for colorectal cancer with wild-type KRAS gene tumors, though not statistically significant, when compared with never smoking (frequency: RR 1.24, 95% CI 0.90-1.71 and inhalation: RR 1.25, 95% CI 0.94-1.67). These associations were strongest in men (ex-smokers: RR 1.79, 95% CI 1.00-3.20; frequency: RR 1.91, 95% CI 1.03-3.52; inhalation: RR 1.69, 95% CI 0.94-3.04). No associations were observed between any of the smoking characteristics and the risk for colorectal cancer with mutated KRAS gene tumors, nor where there any clear associations with tumors with specific G:C-->A:T transitions or G:C-->T:A transversions. These results suggest that, in contrast to the hypothesis, smoking does not increase the risk for colorectal tumors with a mutated KRAS gene. Some smoking characteristics, i.e. being an ex-smoker, frequency and inhalation, may be associated with risk for colorectal cancer characterized by the wild-type KRAS gene, especially in men.

In a cohort study, ovarian cancer (280 cases) showed no significant association with tea or coffee, the multivariable rate ratios being 0.94 (95% confidence interval (CI): 0.89, 1.00) and 1.04 (95% CI: 0.97, 1.12) per cup per day, respectively. A meta-analysis also produced no significant findings overall, though the cohort studies showed a significant inverse association for tea.British Journal of Cancer (2007) 97, 1291-1294. doi:10.1038/sj.bjc.6604008 www.bjcancer.com Published online 9 October 2007.

We investigated whether smoking is associated with mutations in the Von Hippel-Lindau (VHL) gene in 337 cases of sporadic renal cell carcinoma (RCC) among 120 852 people followed for 11.3 years; the findings suggest that smoking causes RCC independently of VHL gene mutations. © 2006 Cancer Research. Chemicals / CAS: adenine, 22177-51-1, 2922-28-3, 73-24-5; cytosine, 71-30-7; guanine, 69257-39-2, 73-40-5; thymine, 65-71-4; Von Hippel-Lindau Tumor Suppressor Protein, EC 6.3.2.19

PG - 1002-8 AB - BACKGROUND AND OBJECTIVE: To estimate the effects of reducing the prevalence of smoking in lower educated groups on educational differences in life expectancy. METHODS: A dynamic Markov-type multistate transition model estimated the effects on life expectancy of two scenarios. A "maximum scenario" where educational differences in prevalence of smoking disappear immediately, and a "policy target-scenario" where difference in prevalence of smoking is halved over a 20-year period. The two scenarios were compared to a reference scenario, where smoking prevalences do not change. Five Dutch cohort studies, involving over 67,000 participants aged 20 to 90 years, provided relative mortality risks by educational level, and smoking habits were assessed using national data of more than 120,000 persons. RESULTS: In the reference scenario, the difference in life expectancy at age 40 between highest and lowest educated groups was 5.1 years for men and 2.7 years for women. In the "maximum scenario" these differences were reduced to 3.6 years for men and 1.7 years for women (reduction approximately 30%), and in the "policy target-scenario" differences were 4.7 years for men and 2.4 years for women (reduction approximately 10%). CONCLUSION: Theoretically, educational differences in life expectancy would be reduced by 30% at maximum, if variations in smoking prevalence were eliminated completely. In practice, tobacco control policies that are targeted at the lower educated may reduce the differences in life expectancy by approximately 10%

Case-cohort analyses were performed on meat and fish consumption in relation to K-ras mutations in 448 colon and 160 rectal cancers that occurred during 7.3 years of follow-up, excluding the first 2.3 years, and 2948 subcohort members of The Netherlands Cohort Study on diet and cancer. Adjusted incidence rate ratios and 95% confidence intervals were computed for colon and rectal cancer and for K-ras mutation status subgroups. Total fresh meat, most types of fresh meat and fish were not associated with colon or rectal cancer, neither overall nor with K-ras mutation status. However, several weak associations were observed for tumours with a wild-type K-ras, including beef and colon tumours, and an inverse association for pork with colon and rectal tumours; for meat products, an increased association was observed with wild-type K-ras tumours in the colon and possibly with G > A transitions in rectal tumours. © 2005 Cancer Research UK.

Contains fulltext : 47661.pdf (Publisher’s version ) (Closed access) OBJECTIVES: Hypertension and/or antihypertensive medication are reported to be risk factors of renal cell carcinoma (RCC). We investigated whether these risk factors are associated with von Hippel-Lindau gene (VHL) mutations in RCC. METHODS: The Netherlands Cohort Study on Diet and Cancer (NLCS) started in 1986 (n = 120 852 men and women) and uses the case-cohort methodology. After 11.3 years of follow-up, 337 RCC cases and 4774 subcohort members were available for analysis. DNA was isolated from paraffin-embedded tumour tissue for VHL analysis. RESULTS: Cohort members who reported hypertension or use of antihypertensive medication had a slightly (non-significant) increased risk of RCC: rate ratios (RR) 1.22 [95% confidence interval (CI), 0.94-1.58] and 1.14 (95% CI, 0.85-1.52), respectively. RRs were adjusted for sex, age, body mass index (BMI) and cigarette smoking. Of the 235 patients for whom tumour tissue specimens were collected, 187 had a clear-cell RCC, of whom 114 had a VHL mutation. History of hypertension was associated with a non-significantly increased risk of clear-cell RCC with VHL mutations: RR = 1.34 (95% CI, 0.87-2.07), and was not associated with the risk of clear-cell RCC without VHL mutations; RR = 0.88 (95% CI, 0.51-1.53). Use of diuretics was associated with clear-cell RCC without VHL mutations; RR = 2.11 (95% CI, 1.16-3.83). CONCLUSIONS: In this study non-significantly increased risks for history of hypertension and use of antihypertensive medication with RCC were observed. The association with hypertension was stronger in RCC patients with VHL mutations, while there was a positive association of diuretics use and risk of RCC without VHL mutations.

Aims: To investigate the relation between exposure to pesticides, polycyclic aromatic hydrocarbons (PAHs), diesel exhaust, metal dust, metal fumes, and mineral oil in relation to prostate cancer incidence in a large prospective study. Methods: This cohort study was conducted among 58 279 men in the Netherlands. In September 1986, cohort members (55–69 years) completed a self-administered questionnaire on potential cancer risk factors, including job history. Follow up for prostate cancer incidence was established by linkage to cancer registries until December 1995 (9.3 years of follow up). The analyses included 1386 cases of prostate cancer and 2335 subcohort members. A blinded case-by-case expert exposure assessment was carried out to assign cases and subcohort members a cumulative probability of exposure for each potential carcinogenic exposure. Results: In multivariate analyses there was a significant negative association for pesticides (RR 0.60; 95% CI 0.37 to 0.95) when comparing the highest tertile of exposure to pesticides with no exposure. No association was found for occupational exposure to PAHs (RR 0.75; 95% CI 0.42 to 1.31), diesel exhaust (RR 0.81; 95% CI 0.62 to 1.06), metal dust (RR 1.01; 95% CI 0.72 to 1.40), metal fumes (RR 1.11; 95% CI 0.80 to 1.54), or mineral oil (RR 0.99; 95% CI 0.66 to 1.48) when comparing the highest tertile of exposure with no exposure. In subgroup analysis, with respect to tumour invasiveness and morphology, null results were found for occupational exposure to pesticides, PAH, diesel exhaust, metal dust, metal fumes, and mineral oil. Conclusions: These results suggest a negative association between occupational exposure to pesticides and prostate cancer. For other carcinogenic exposures results suggest no association between occupational exposure to PAHs, diesel exhaust, metal dust, metal fumes, or mineral oil and prostate cancer.

OBJECTIVE: The hygiene hypothesis suggests that the protective 'siblings effect' against atopic diseases such as atopic dermatitis, allergic asthma and hay fever is a result of recurrent infections during early childhood. A recent study and review have indicated that this protective effect may already arise in utero. Lower n-3 essential fatty acid (EFA) status is associated with increased parity, and EFA status has also been related to atopy. The present study confirms the negative association between parity and neonatal immunoglobulin E (IgE) levels and further unravel the role of perinatal EFA status. METHODOLOGY: In a prospective cohort study in 184 atopic mothers and their neonates, we simultaneously measured serum total IgE and EFA levels in plasma phospholipids, both in the mother at 34-36 weeks of gestation and in the neonate at the age of 1 week. Linear regression analysis was used to estimate the effect of parity on maternal and neonatal IgE and EFA status, and the independent effects of parity and EFA status on IgE, controlling for confounding factors such as maternal age and birth season. RESULTS: Parity was associated with lower neonatal IgE level (P < 0.01), as well as with lower docosahexanoic acid (DHA, 22:6n-3) status of the mother (P = 0.01) but not of the neonate (P > 0.69). In the multivariate analysis, higher parity, higher maternal IgE, lower maternal age and birth in the first 3 months of the year were independently associated with neonatal IgE level. No association was detected between maternal or neonatal EFA status and neonatal IgE. CONCLUSIONS: As neonatal total serum IgE is predictive of later atopy, our results support the hypothesis that the sibling effect in atopy is already being programmed in utero. Our data also confirm earlier findings that DHA status is lower in multiparous women, but this did not confound the relation between parity and neonatal IgE.

Although obesity is an established risk factor for endometrial cancer, evidence linking risk to height, weight change since age 20, and physical activity is limited. In this case-cohort study, 62 573 women from The Netherlands Cohort Study on Diet and Cancer were followed up from 1986 to 1995, and 226 endometrial cancer case patients were identified. In Cox proportional hazards analyses, women 175 cm or taller had an increased risk of endometrial cancer compared with those less than 160 cm (rate ratio [RR] = 2.57, 95% confidence interval [CI] = 1.32 to 4.99). Compared with women with a body mass index (BMI; kg/m2 between 20 and 22.9, women with a BMI of 30 or greater had a higher risk (RR = 4.50, 95% CI = 2.62 to 7.72; Ptrend

This study examined the concept of need for recovery, that is the need to recuperate from work-induced fatigue, experienced after a day of work. The study explored the relationship between need for recovery from work, prolonged fatigue, and psychological distress in the working population. A cross-sectional study was carried out. Data of the Maastricht Cohort Study on fatigue at work were used (n = 12,095). Some degree of need for recovery was found in nearly all employees. Need for recovery from work was associated with demographic, work-related, and health factors. Principal Components Analysis revealed obvious separation between need for recovery items and both fatigue items and psychological distress items, supporting the notion that need for recovery, fatigue, and psychological distress represent different underlying concepts. Although need for recovery, fatigue, and psychological distress were frequently comorbid, they also clearly occurred as separate entities.

Both carcinogenic and anticarcinogenic properties have been reported for the synthetic antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT). The association between dietary intake of BHA and BHT and stomach cancer risk was investigated in the Netherlands Cohort Study (NLCS) that started in 1986 among 120,852 men and women aged 55 to 69 years. A semi-quantitative food frequency questionnaire was used to assess food consumption. Information on BHA or BHT content of cooking fats, oils, mayonnaise and other creamy salad dressings and dried soups was obtained by chemical analysis, a Dutch database of food additives (ALBA) and the Dutch Compendium of Foods and Diet Products. After 6.3 years of follow-up, complete data on BHA and BHT intake of 192 incident stomach cancer cases and 2035 subcohort members were available for case-cohort analysis. Mean intake of BHA or BHT among subcohort members was 105 and 351 μg/day, respectively. For consumption of mayonnaise and other creamy salad dressings with BHA or BHT no association with stomach cancer risk was observed. A statistically non-significant decrease in stomach cancer risk was observed with increasing BHA and BHT intake [rate ratio (RR) highest/lowest intake of BHA=0.57 (95% confidence interval (CI): 0.25-1.30] and BHT=0.74 (95% CI: 0.38-1.43). In this study, no significant association with stomach cancer risk was found for usual intake of low levels of BHA and BHT. Copyright (C) 2000 Elsevier Science Ltd. Chemicals/CAS: Antioxidants; Butylated Hydroxyanisole, 25013-16-5; Butylated Hydroxytoluene, 128-37-0; Food Additives

Objective: To evaluate whether levels of n-6 long chain polyunsaturated fatty acids (LCPs) in human breast milli. are related to the mother's atopic constitution, and whether a decreased level can be restored by gamma-linolenic acid supplementation. Design: Cross-sectional study and dietary supplementation trial. Subjects: 20 atopic mothers and 20 non-atopic mothers (controls), all lactating. Setting: General population. Interventions: The atopic mothers were randomly assigned to low (n = 10) or high (n = 10) dosage oral supplementation with oral borage oil for one week (230 or 460 mg gamma-linolenic acid (18:3n-6) per day). Main outcome measures: Essential fatty acid composition of the breast milli. total fat fraction, determined by gas liquid chromatography. Results: Arachidonic acid (20:4n-6) was lower in breast milk of atopic mothers compared with non-atopic mothers (0.39 wt% vs 0.46 wt%. difference -0.07% wt% (95% confidence limits -0.13, -0.01 wt%; P

Department of Epidemiology, Maastricht University, The Netherlands.Prostate cancer risk in relation to consumption of animal products, and intake of calcium and protein was investigated in the Netherlands Cohort Study. At baseline in 1986, 58,279 men aged 55-69 years completed a self-administered 150-item food frequency questionnaire and a questionnaire on other risk factors for cancer. After 6.3 years of follow-up, 642 prostate cancer cases were available for analysis. In multivariate case-cohort analyses adjusted for age, family history of prostate cancer and socioeconomic status, no associations were found for consumption of fresh meat, fish, cheese and eggs. Positive trends in risk were found for consumption of cured meat and milk products (P-values 0.04 and 0.02 respectively). For calcium and protein intake, no associations were observed. The hypothesis that dietary factors might be more strongly related to advanced prostate tumours could not be confirmed in our study. We conclude that, in this study, animal products are not strongly related to prostate cancer risk.

Department of Epidemiology, Maastricht University, Maastricht, The Netherlands.BACKGROUND: The roles of energy and fat intake as risk factors for prostate carcinoma are still questionable. Therefore, these factors were evaluated in the Netherlands Cohort Study described in this article. METHODS: The cohort study consisted of 58,279 men ages 55-69 years at baseline in 1986. After 6.3 years of follow-up, 642 incident prostate carcinoma cases were available for analysis. Intake of energy, fat, and separate fatty acids were measured by means of a self-administered questionnaire; fat intake was adjusted for energy by regression analysis. The case-cohort method was used to calculate rate ratios (RRs). Analyses were conducted for all prostate carcinoma cases together as well as for case subgroups (latent vs. nonlatent and localized vs. advanced). RESULTS: No associations were found in multivariate analyses between prostate carcinoma and intake of energy, total fat, total saturated fatty acids, or total trans unsaturated fatty acids (RR highest vs. lowest quintile: 0.99, 1.10, 1.19, and 0.99, respectively). Oleic acid intake showed a nonsignificant positive association (RR = 1.38, 95% CI: 0.88-2.19). Positive associations were also observed for intake of oleic acid in subgroup analyses. Linoleic (RR = 0.78, 95% CI: 0. 56-1.09) and linolenic (RR = 0.76, 95% CI: 0.66-1.04) acid intake were associated with nonsignificantly decreased risks; only for linolenic acid did these associations persist in subgroup analyses. No associations were found for intake of arachidonic acid, eicosapentaenoic acid, or docosahexaenoic acid. CONCLUSIONS: These data suggest that certain fatty acids might be involved in prostate carcinoma occurrence, although the possibility that these were chance findings cannot be ruled out. Copyright 1999 American Cancer Society.

Department of Nutrition, Harvard School of Public Health, Boston, Mass 02115, USA.OBJECTIVE: To assess the risk of invasive breast cancer associated with total and beverage-specific alcohol consumption and to evaluate whether dietary and nondietary factors modify the association. DATA SOURCES: We included in these analyses 6 prospective studies that had at least 200 incident breast cancer cases, assessed long-term intake of food and nutrients, and used a validated diet assessment instrument. The studies were conducted in Canada, the Netherlands, Sweden, and the United States. Alcohol intake was estimated by food frequency questionnaires in each study. The studies included a total of 322647 women evaluated for up to 11 years, including 4335 participants with a diagnosis of incident invasive breast cancer. DATA EXTRACTION: Pooled analysis of primary data using analyses consistent with each study's original design and the random-effects model for the overall pooled analyses. DATA SYNTHESIS: For alcohol intakes less than 60 g/d (reported by >99% of participants), risk increased linearly with increasing intake; the pooled multivariate relative risk for an increment of 10 g/d of alcohol (about 0.75-1 drink) was 1.09 (95% confidence interval [CI], 1.04-1.13; P for heterogeneity among studies, .71). The multivariate-adjusted relative risk for total alcohol intakes of 30 to less than 60 g/d (about 2-5 drinks) vs nondrinkers was 1.41 (95% CI, 1.18-1.69). Limited data suggested that alcohol intakes of at least 60 g/d were not associated with further increased risk. The specific type of alcoholic beverage did not strongly influence risk estimates. The association between alcohol intake and breast cancer was not modified by other factors. CONCLUSIONS: Alcohol consumption is associated with a linear increase in breast cancer incidence in women over the range of consumption reported by most women. Among women who consume alcohol regularly, reducing alcohol consumption is a potential means to reduce breast cancer risk.Publication Types: Meta-Analysis

Study objective - To evaluate the influence of occupational exposure to carcinogens in explaining the association between socioeconomic status and lung cancer. Design - A prospective cohort study. Data on diet, other lifestyle factors, sociodemographic characteristics and job history were collected by means of a self administered questionnaire. Follow up for incident cancer was established by record linkage with a national pathology register and with regional cancer registries. Setting - Population originating from 204 municipalities in The Netherlands. Participants - These comprised 58,279 men aged 55-69 years in September 1986. After 4.3 years of follow up there were 470 microscopically confirmed incident lung cancer cases with complete data on dietary habits and job history. Measurements and main results - Estimation of occupational exposure to asbestos, paint dust, polycyclic aromatic hydrocarbons, and welding fumes was carried out by two experts, using information on job history from the baseline questionnaire. Socioeconomic status was measured by means of highest attained level of education and two indicators based on occupation. In the initial multivariate analyses of socioeconomic status and lung cancer, adjustment was made for age, smoking habits, intake of vitamin C, betacarotene and retinol, and history of chronic obstructive pulmonary disease or asthma. Additional adjustment for occupational exposure to the four carcinogens mentioned above did not change the inverse association between the level of education and lung cancer risk (initial model: RR highest/lowest level of education = 0.53; 95% CI 0.34,0.82; additional model: RR highest/lowest level of education = 0.53; 95% CI 0.34,0.84). Nor was the association between the two occupation based indicators of socioeconomic status and lung cancer risk influenced by occupational exposure to carcinogens. The effect of occupational exposure on the association between the level of education and lung cancer risk did not differ between ex-smokers and current smokers. Conclusions - Occupational exposure to asbestos, paint dust, polycyclic aromatic hydrocarbons, and welding fumes could not explain the inverse association between socioeconomic status and lung cancer risk. More research which explicitly addresses possible explanations for the association between socioeconomic status and lung cancer risk is needed.

A prospective cohort study on the relationship between onion and leek consumption, garlic supplement use and the risk of colorectal carcinoma in The Netherlands.Dorant E, van den Brandt PA, Goldbohm RA.Department of Epidemiology, University of Limburg, Maastricht, The Netherlands.The association between onion and leek consumption, garlic supplement use and colon and rectum carcinoma among men and women was evaluated in the Netherlands Cohort Study, a large-scale prospective cohort study on diet and cancer. Onions, leeks, and garlic belong to the Allium genus and contain large amounts of potentially chemopreventive compounds. The Netherlands Cohort Study was started in 1986 among 120 852 men and women, aged 55-69 years. Dietary intake was measured with a 150-item food frequency questionnaire. After 3.3 years of follow-up, 150 and 143 incident male and female cases of colon carcinoma, and 93 and 57 cases of rectum carcinoma, respectively, with complete dietary data were available for analysis. Dietary data were available for 1525 men and 1598 women of a randomly selected subcohort, that was followed up to estimate person-time in the entire cohort. In men, the adjusted rate ratios (RRs) in multivariable analysis for colon and rectum carcinoma in the highest compared to the lowest onion consumption categories were 0.87 (95% confidence interval [CI] = 0.48-1.65), and 0.66 (95% CI = 0.28-1.52), respectively. The RRs for proximal colon carcinoma were lower than for distal colon carcinoma. Leek consumption was not associated with colon and rectum carcinoma incidence in men. None of the RRs were significantly different from unity and no trends in the RRs were detected. A lower risk was found for rectum carcinoma in women consuming less than 0.25 onions per day (RR=0.36, 95% CI = 0.13-0.99), but the trend in the RRs was not statistically significant (P = 0.25). All other RRs for colon and rectum carcinoma associated with onion consumption were slightly higher than one. Leek consumption was not associated with colon and rectum carcinoma incidence. The use of garlic supplements was not associated with colon and rectum carcinoma in men and women combined. This study does not support an inverse association between the consumption of onions and leeks, or the use of garlic supplements and the incidence of male and female colon and rectum carcinoma.

Consumption of black tea and cancer risk: a prospective cohort study.Goldbohm RA, Hertog MG, Brants HA, van Poppel G, van den Brandt PA.Department of Epidemiology, Netherlands Organization for Applied Scientific Research [TNO] Nutrition and Food Research Institute, Zeist, The Netherlands.BACKGROUND: Tea is one of the most frequently consumed beverages in the world. Antioxidant polyphenol compounds (such as catechins and flavonols) are abundantly present in both green and black teas and have been observed to have anticarcinogenic properties in cell and animal model studies. In black tea, however, most of the catechins have been oxidized to forms that may have reduced anticarcinogenic properties. Despite indications from experimental studies that tea may protect against cancer, epidemiologic evidence has been inconclusive. PURPOSE: The association between black tea consumption and the subsequent risk of stomach, colorectal, lung, and breast cancers was investigated in The Netherlands Cohort Study on Diet and Cancer among 58,279 men and 62,573 women aged 55-69 years. METHODS: Subjects in the cohort completed a self-administered questionnaire on dietary habits and other risk factors for cancer at base line in 1986. Follow-up for cancer was done by means of computerized record linkage with all nine regional cancer registries in The Netherlands and the national pathology database. During 4.3 years of follow-up, 200, 650, 764, and 650 cases of stomach, colorectal, lung, and breast cancers were diagnosed, respectively. The questionnaire data of case subjects and those of a random subcohort (n = 3500) were used to calculate rate ratios (RRs) of cancer in categories of consumers of black tea compared with nonconsumers. RESULTS: Tea was not used by 13% of the subjects in the cohort, whereas 37%, 34%, and 16% consumed one to two, three to four, and five or more cups of tea per day, respectively. No association was observed between tea consumption and risk of colorectal cancer: The risk among tea drinkers in each consumption category was similar to that among nondrinkers. The RR of breast cancer among consumers of five or more cups of tea per day was 1.3 (95% confidence interval = 0.9-2.0); no dose-response association was observed. In age- and sex-adjusted analyses, consumption of tea was inversely associated with stomach (two-sided P for trend = .147) and lung (two-sided P for trend < .001) cancers. However, tea drinkers appeared to smoke less and to eat more vegetables and fruits than nondrinkers. When smoking and dietary factors were taken into account, tea in itself did not appear to protect against stomach and lung cancers: The RRs in all consumption categories were close to unity. Analysis of the tea and cancer relationship in a subgroup that included subjects in the lowest two quintiles of consumption of vegetables and fruits also failed to reveal a protective effect of tea consumption on the risk of three cancer types studied (colorectal, lung, and breast cancers). CONCLUSIONS: This investigation does not support the hypothesis that consumption of black tea protects against four of the major cancers in humans; a cancer-enhancing effect was not evident, either.

Consumption of onions and a reduced risk of stomach carcinoma.Dorant E, van den Brandt PA, Goldbohm RA, Sturmans F.Department of Epidemiology, University of Limburg, Maastricht, The Netherlands.BACKGROUND & AIMS: Results from case-control studies and laboratory tests indicate that consumption of allium vegetables may considerably reduce the risk of stomach cancer. The association between onion and leek consumption, garlic supplement use, and the incidence of stomach carcinoma was studied. METHODS: The association was investigated in the Netherlands Cohort Study on diet and cancer, which started in 1986 with 120,852 men and women ranging in age from 55 to 69 years. Dietary data were available for 139 stomach carcinoma cases diagnosed during 3.3 years of follow-up and for 3123 subjects of the randomly selected subcohort. RESULTS: The rate ratio for stomach carcinoma in the highest onion consumption category (> or = 0.5 onions/day) was 0.50 (95% confidence interval, 0.26-0.95) compared with the lowest category (0 onions/day) after adjustment for other risk factors. The reduction in risk was restricted to carcinoma in the noncardia part of the stomach (P = 0.002) and was also found among subjects without a history of stomach disorders (P = 0.01). The consumption of leeks and the use of garlic supplements were not associated with stomach carcinoma risk. CONCLUSIONS: The Netherlands Cohort Study provides evidence for a strong inverse association between onion consumption and stomach carcinoma incidence.

The association between socioeconomic status and colon cancer was investigated in a prospective cohort study that started in 1986 in The Netherlands among 120,852 men and women aged 55-69 years. At baseline, data on socioeconomic status, alcohol consumption and other dietary and non-dietary covariates were collected by means of a self-administered questionnaire. For data analysis a case-cohort approach was used, in which the person-years at risk were estimated using a randomly selected subcohort (1688 men and 1812 women). After 3.3 years of follow-up, 312 incident colon cancer cases were detected: 157 men and 155 women. After adjustment for age, we found a positive association between colon cancer risk and highest level of education (trend P = 0.13) and social standing (trend P = 0.008) for men. Also, male, upper white-collar workers had a higher colon cancer risk than blue-collar workers (RR = 1.42, 95% CI 0.95-2.11). Only the significant association between social standing and colon cancer risk persisted after additional adjustment for other risk factors for colon cancer (trend P = 0.005), but the higher risk was only found in the highest social standing category (RR highest/lowest social standing = 2.60, 95% CI 1.31-5.14). In women, there were no clear associations between the socioeconomic status indicators and colon cancer.

Prospective study on alcohol consumption and the risk of cancer of the colon and rectum in the Netherlands.Goldbohm RA, Van den Brandt PA, Van 't Veer P, Dorant E, Sturmans F, Hermus RJ.TNO Toxicology and Nutrition Institute, Zeist, Netherlands.The association between alcohol consumption and cancer of the colon and rectum was investigated in a prospective cohort study, conducted in the Netherlands from 1986 onwards among 120,852 men and women, aged 55 to 69 years. During 3.3 years of follow-up, 312 and 166 cases of colon and rectal cancer had accumulated, respectively. After exclusion of cases diagnosed in the first year of follow-up, the analysis was based on 217 incident cases of colon cancer (107 men and 110 women) and 113 cases of rectal cancer (75 men and 38 women). For colon cancer, no association with total intake of alcohol nor with the consumption of beer and wine, specifically, could be demonstrated; for liquor intake, a significant (P = 0.04) decreasing risk with increasing consumption was observed. For rectal cancer in men, positive trends were observed for total alcohol intake (P = 0.04), beer (P = 0.05), and liquor (P = 0.06). Results for rectal cancer in women were consistent with those in men, but data were too sparse to provide stable estimates. Simultaneous adjustment for beverage type and quantity appeared to strengthen the association of rectal cancer with drinking beer (relative rate (yes/no) = 2.0, 95 percent confidence interval = 1.1-3.9), although a dose-response effect was not observed. When alcohol intake from beer, wine, and liquor were included as continuous variables, the association was somewhat stronger for liquor than for beer, but none of the associations were statistically significant. It is concluded that consumption of alcoholic beverages (beer, in particular) is associated with an increased risk for rectal but not colon cancer

A risk assessment has been made on nitrate, nitrite and N-nitroso compounds encountered in the human diet. Vegetables constitute a major source of nitrate providing over 85% of the average daily human dietary intake. Nitrite and N-nitroso compounds present in the diet contribute relatively small amounts to the body burden and the major source of these biologically reactive compounds is derived from the bacterial and mammalian metabolism of ingested nitrate. Additionally, endogenous synthesis provides an important source contributing to the body burden of nitrate. Data from animal toxicological studies, human effects and epidemiological surveys have been reviewed and evaluated. It is concluded that there is no firm scientific evidence at present to recommend drastic reductions beyond the average levels of nitrate encountered in vegetables grown in keeping with good agricultural practice. Recommendations have also been made for further animal and human studies to be carried out to elucidate the potential risks to man from ingested nitrate.

Twenty habitually omnivorous subjects and 19 habitually lactoovovegetarian subjects aged 59-65 y collected feces during 4 consecutive days. The concentrations of bile acids in total feces did not differ between the omnivores and vegetarians, but the bile acid concentrations in fecal water were significantly lower in the vegetarians. The concentration of the colorectal cancer-predicting bile acid deoxycholic acid in fecal water was explained by the intake of saturated fat and the daily fecal wet weight (r2 = 0.50). Fecal pH did not differ between the omnivores and vegetarians. This variable was significantly (P < 0.05) explained by the intake of calcium (r2 = 0.30); 24-h fecal wet weight and defecation frequency were significantly higher in the vegetarians. In conclusion, our vegetarian subjects had a lower concentration of deoxycholic acid in fecal water, higher fecal wet weight, and higher defecation frequency than the omnivorous subjects.