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      Plasma and dietary carotenoid, retinol and tocopherol levels and the risk of gastric adenocarcinomas in the European prospective investigation into cancer and nutrition

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      1 , * , 1 , 1 , 1 , 1 , 2 , 1 , 1 , 3 ,   3 ,   4 , 5 , 5 , 6 , 6 , 7 , 7 , 8 , 8 , 8 , 9 , 10 , 11 ,   12 , 13 , 14 , 14 , 15 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 23 , 24 , 25 , 26 , 27 , 27 , 28 , 29 , 30 , 31 , 1 , 17
      British Journal of Cancer
      carotenoids, tocopherol, retinol, gastric cancer, diet, EPIC

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          Abstract

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

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          Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease.

          Observational studies suggest that people who consume more fruits and vegetables containing beta carotene have somewhat lower risks of cancer and cardiovascular disease, and earlier basic research suggested plausible mechanisms. Because large randomized trials of long duration were necessary to test this hypothesis directly, we conducted a trial of beta carotene supplementation. In a randomized, double-blind, placebo-controlled trial of beta carotene (50 mg on alternate days), we enrolled 22,071 male physicians, 40 to 84 years of age, in the United States; 11 percent were current smokers and 39 percent were former smokers at the beginning of the study in 1982. By December 31, 1995, the scheduled end of the study, fewer than 1 percent had been lost to follow-up, and compliance was 78 percent in the group that received beta carotene. Among 11,036 physicians randomly assigned to receive beta carotene and 11,035 assigned to receive placebo, there were virtually no early or late differences in the overall incidence of malignant neoplasms or cardiovascular disease, or in overall mortality. In the beta carotene group, 1273 men had any malignant neoplasm (except nonmelanoma skin cancer), as compared with 1293 in the placebo group (relative risk, 0.98; 95 percent confidence interval, 0.91 to 1.06). There were also no significant differences in the number of cases of lung cancer (82 in the beta carotene group vs. 88 in the placebo group); the number of deaths from cancer (386 vs. 380), deaths from any cause (979 vs. 968), or deaths from cardiovascular disease (338 vs. 313); the number of men with myocardial infarction (468 vs. 489); the number with stroke (367 vs. 382); or the number with any one of the previous three end points (967 vs. 972). Among current and former smokers, there were also no significant early or late differences in any of these end points. In this trial among healthy men, 12 years of supplementation with beta carotene produced neither benefit nor harm in terms of the incidence of malignant neoplasms, cardiovascular disease, or death from all causes.
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            The EPIC Project: rationale and study design. European Prospective Investigation into Cancer and Nutrition.

            The most consistent result of epidemiological studies on diet and cancer is that a diet rich in vegetables, fruit and, more generally, in plant foods is associated with a reduced risk of cancer at several anatomical sites. Epidemiological studies have been less consistent regarding the putative increase in risk related to consumption of fat or meat. In addition it has not been possible to identify clearly the biological role of specific nutrients or non-nutrient food components in the prevention or causation of cancer. Limitations in the precision and validity of traditional dietary intake measurements and limited use of biomarkers combined with narrow ranges of variations in dietary habits within single populations, have been the main reasons for the limited success in identifying more specific diet and cancer links. EPIC is a multi-centre prospective cohort study designed to investigate the relation between diet, nutritional and metabolic characteristics, various lifestyle factors and the risk of cancer. The study is based in 22 collaborating centres in nine European countries and includes populations characterized by large variations in dietary habits and cancer risk. Data are collected on diet, physical activity, sexual maturation and reproductive history, lifetime consumption of alcohol and tobacco, previous and current illnesses and current medication. Following a common protocol and using identical equipment, blood samples are collected, aliquoted into plasma, serum, white blood cells and erythrocytes, and stored in liquid nitrogen at -196 degrees C for future laboratory analyses on cancer cases and matched healthy controls. Anthropometric measurements are taken according to a standard protocol. It is planned to include around 400,000 middle-aged men and women. The collection of questionnaire data, anthropometric measurements and blood samples is under way. Almost 340,000 subjects had been included in the study by mid-1996, and recruitment is expected to be almost complete by 1997. Follow-up for cancer incidence and total mortality has started and it is expected that about 23000 cancer cases will be identified during the first 10 years of follow-up.
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              Chemoprevention of gastric dysplasia: randomized trial of antioxidant supplements and anti-helicobacter pylori therapy.

              Previous research has identified a high risk of gastric carcinoma as well as a high prevalence of cancer precursor lesions in rural populations living in the province of Nariño, Colombia, in the Andes Mountains. A randomized, controlled chemoprevention trial was conducted in subjects with confirmed histologic diagnoses of multifocal nonmetaplastic atrophy and/or intestinal metaplasia, two precancerous lesions. Individuals were assigned to receive anti-Helicobacter pylori triple therapy and/or dietary supplementation with ascorbic acid, beta-carotene, or their corresponding placebos. Gastric biopsy specimens taken at baseline were compared with those taken at 72 months. Relative risks of progression, no change, and regression from multifocal nonmetaplastic atrophy and intestinal metaplasia were analyzed with multivariate polytomous logistic regression models to estimate treatment effects. All statistical tests were two-sided. All three basic interventions resulted in statistically significant increases in the rates of regression: Relative risks were 4.8 (95% confidence interval [CI] = 1.6-14.2) for anti-H. pylori treatment, 5. 1 (95% CI = 1.7-15.0) for beta-carotene treatment, and 5.0 (95% CI = 1.7-14.4) for ascorbic acid treatment in subjects with atrophy. Corresponding relative risks of regression in subjects with intestinal metaplasia were 3.1 (95% CI = 1.0-9.3), 3.4 (95% CI = 1.1-9.8), and 3.3 (95% CI = 1.1-9.5). Combinations of treatments did not statistically significantly increase the regression rates. Curing the H. pylori infection (which occurred in 74% of the treated subjects) produced a marked and statistically significant increase in the rate of regression of the precursor lesions (relative risks = 8.7 [95% CI = 2.7-28.2] for subjects with atrophy and 5.4 [95% CI = 1.7-17.6] for subjects with intestinal metaplasia). In the very high-risk population studied, effective anti-H. pylori treatment and dietary supplementation with antioxidant micronutrients may interfere with the precancerous process, mostly by increasing the rate of regression of cancer precursor lesions, and may be an effective strategy to prevent gastric carcinoma.
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                Author and article information

                Journal
                Br J Cancer
                British Journal of Cancer
                0007-0920
                1532-1827
                01 August 2006
                07 August 2006
                : 95
                : 3
                : 406-415
                Affiliations
                [1 ]Nutrition and Hormones Group, IARC-WHO , Lyon, France
                [2 ]Department of Nutrition, Loma Linda University , Loma Linda, CA, USA
                [3 ]Institute of Cancer Epidemiology, Danish Cancer Society , Copenhagen, Denmark
                [4 ]Department of Clinical Epidemiology, Aalborg Hospital, Aarhus University Hospital , Aalborg, Denmark
                [5 ]INSERM Department ER120, Institut Gustave Roussy , Villejuif, France
                [6 ]Department of Epidemiology, German Institute of Human Nutrition , Potsdam-Rehbücke, Germany
                [7 ]Department of Clinical Epidemiology, Deutsches Krebsforschungszentrum , Heidelberg, Germany
                [8 ]Department of Hygiene and Epidemiology, Medical School, University of Athens , Athens, Greece
                [9 ]Epidemiology Unit, Istituto Tumori , Milan, Italy
                [10 ]Department of Clinical and Experimental Medicine, Federico II University , Naples, Italy
                [11 ]Molecular and Nutritional Epidemiology Unit, CSPO-Scientific Institute of Tuscany , Florence, Italy
                [12 ]University of Turin and CPO-Piemonte , Turin, Italy
                [13 ]Cancer Registry, Azienda Ospedaliera ‘Civile MP Arezzo' , Ragusa, Italy
                [14 ]Julius Centre for Health Sciences and Primary Care, University Medical Center , Utrecht, The Netherlands
                [15 ]Centre for Nutrition and Health, National Institute for Public Health and the Environment , Bilthoven, The Netherlands
                [16 ]Institute of Community Medicine, University of Tromso , Tromso, Norway
                [17 ]Department of Epidemiology, Catalan Institute of Oncology , Barcelona (ICO-IDIBELL), Spain
                [18 ]Servicio de Epidemiología, Consejería de Sanidad y Consumo , Murcia, Spain
                [19 ]Andalusian School of Public Health , Granada, Spain
                [20 ]Public Health Department of Guipuzkoa , San Sebastian, Spain
                [21 ]Public Health Institute of Navarra , Pamplona, Spain
                [22 ]Sección Información Sanitaria, Consejería de Salud y Servicios Sanitarios de Asturias , Asturias, Spain
                [23 ]Department of Odontology, Faculty of Medicine, Umeå University , Umeå, Sweden
                [24 ]Department of Medical Epidemiology, Karolinska Instututet , Stockholm, Sweden
                [25 ]Department of Public Health and Primary Care, Centre for Nutrition and Cancer Prevention and Survival, University of Cambridge , Cambridge, UK
                [26 ]Clinical Gerontology Unit, University of Cambridge , Cambridge, UK
                [27 ]Cancer Epidemiology Unit, University of Oxford , Oxford, UK
                [28 ]Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP) and Medical Faculty of Porto/HS Joao , Porto, Portugal
                [29 ]Department of Histopathology, Addenbrooke's Hospital , Cambridge, UK
                [30 ]Novartis Vaccines, Research Center , Siena, Italy
                [31 ]Servizio di Medicina di Laboratorio, Azienda Ospedaliera di Padova , Padova, Italy
                Author notes
                [* ]Author for correspondence: Jenab@ 123456iarc.fr
                Article
                6603266
                10.1038/sj.bjc.6603266
                2360629
                16832408
                a8243542-3187-45ad-8f6f-31612b0a6ee0
                Copyright 2006, Cancer Research UK
                History
                : 20 March 2006
                : 09 June 2006
                : 14 June 2006
                Categories
                Epidemiology

                Oncology & Radiotherapy
                diet,carotenoids,tocopherol,retinol,gastric cancer,epic
                Oncology & Radiotherapy
                diet, carotenoids, tocopherol, retinol, gastric cancer, epic

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