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      Tobacco, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project

      research-article
      1 , , 2 , 1 , 1 , 1 , 1 , 3 , 4 , 4 , 5 , 6 , 7 , 1 , 2 , 3 , 8 , 9 , 1 , 3 , 9 , 1 , 1 , 10 , 11 , 1 , 12 , 10 , 1 , 3 , 9 , 1 , 4 , 9 , 13 , 14 , 15 , 4 , 16 , 1 , 1
      British Journal of Cancer
      Nature Publishing Group UK

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          Abstract

          Background

          While tobacco and alcohol are established risk factors for hepatocellular carcinoma (HCC), the most common type of primary liver cancer, it is unknown whether they also increase the risk of intrahepatic cholangiocarcinoma (ICC). Thus, we examined the association between tobacco and alcohol use by primary liver cancer type.

          Methods

          The Liver Cancer Pooling Project is a consortium of 14 US-based prospective cohort studies that includes data from 1,518,741 individuals (HCC n = 1423, ICC n = 410). Multivariable-adjusted hazards ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression.

          Results

          Current smokers at baseline had an increased risk of HCC (hazard ratio (HR) = 1.86, 95% confidence interval (CI): 1.57–2.20) and ICC (HR = 1.47, 95% CI: 1.07–2.02). Among individuals who quit smoking >30 years ago, HCC risk was almost equivalent to never smokers (HR = 1.09, 95% CI: 0.74–1.61). Compared to non-drinkers, heavy alcohol consumption was associated with an 87% increased HCC risk (HR ≥7 drinks/day = 1.87, 95% CI: 1.41–2.47) and a 68% increased ICC risk (HR ≥5 drinks/day = 1.68, 95% CI: 0.99–2.86). However, light-to-moderate alcohol consumption of <3 drinks/day appeared to be inversely associated with HCC risk (HR >0–<0.5 drinks/day = 0.77, 95% CI: 0.67–0.89; HR >0.5–<1 drinks/day = 0.57, 95% CI: 0.44–0.73; HR 1–<3 drinks/day = 0.71, 95% CI: 0.58–0.87), but not ICC.

          Conclusions

          These findings suggest that, in this relatively healthy population, smoking cessation and light-to-moderate drinking may reduce the risk of HCC.

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          Most cited references40

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          Final report on the aspirin component of the ongoing Physicians' Health Study. Steering Committee of the Physicians' Health Study Research Group.

          The Physicians' Health Study is a randomized, double-blind, placebo-controlled trial designed to determine whether low-dose aspirin (325 mg every other day) decreases cardiovascular mortality and whether beta carotene reduces the incidence of cancer. The aspirin component was terminated earlier than scheduled, and the preliminary findings were published. We now present detailed analyses of the cardiovascular component for 22,071 participants, at an average follow-up time of 60.2 months. There was a 44 percent reduction in the risk of myocardial infarction (relative risk, 0.56; 95 percent confidence interval, 0.45 to 0.70; P less than 0.00001) in the aspirin group (254.8 per 100,000 per year as compared with 439.7 in the placebo group). A slightly increased risk of stroke among those taking aspirin was not statistically significant; this trend was observed primarily in the subgroup with hemorrhagic stroke (relative risk, 2.14; 95 percent confidence interval, 0.96 to 4.77; P = 0.06). No reduction in mortality from all cardiovascular causes was associated with aspirin (relative risk, 0.96; 95 percent confidence interval, 0.60 to 1.54). Further analyses showed that the reduction in the risk of myocardial infarction was apparent only among those who were 50 years of age and older. The benefit was present at all levels of cholesterol, but appeared greatest at low levels. The relative risk of ulcer in the aspirin group was 1.22 (169 in the aspirin group as compared with 138 in the placebo group; 95 percent confidence interval, 0.98 to 1.53; P = 0.08), and the relative risk of requiring a blood transfusion was 1.71. This trial of aspirin for the primary prevention of cardiovascular disease demonstrates a conclusive reduction in the risk of myocardial infarction, but the evidence concerning stroke and total cardiovascular deaths remains inconclusive because of the inadequate numbers of physicians with these end points.
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            Nicotine chemistry, metabolism, kinetics and biomarkers.

            Nicotine underlies tobacco addiction, influences tobacco use patterns, and is used as a pharmacological aid to smoking cessation. The absorption, distribution and disposition characteristics of nicotine from tobacco and medicinal products are reviewed. Nicotine is metabolized primarily by the liver enzymes CYP2A6, UDPglucuronosyltransferase (UGT), and flavin-containing monooxygenase (FMO). In addition to genetic factors, nicotine metabolism is influenced by diet and meals, age, sex, use of estrogen-containing hormone preparations, pregnancy and kidney disease, other medications, and smoking itself. Substantial racial/ethnic differences are observed in nicotine metabolism, which are likely influenced by both genetic and environmental factors. The most widely used biomarker of nicotine intake is cotinine, which may be measured in blood, urine, saliva, hair, or nails. The current optimal plasma cotinine cut-point to distinguish smokers from non-smokers in the general US population is 3 ng ml(-1). This cut-point is much lower than that established 20 years ago, reflecting less secondhand smoke exposure due to clear air policies and more light or occasional smoking.
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              The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence.

              We conducted a systematic review and a meta-analysis to estimate the magnitude and determinants of association between diabetes and hepatocellular carcinoma (HCC). MEDLINE searches were conducted for published full studies (between January 1966 and February 2005) that provided risk estimates and met criteria concerning the definition of exposure and outcomes. Two investigators independently performed standardized search and data abstraction. Unadjusted and adjusted odds ratios for individual outcomes were obtained or calculated for each study and were synthesized using a random-effects model. A total of 26 studies met our inclusion and exclusion criteria. Among 13 case-control studies, diabetes was associated significantly with HCC in 9 studies (pooled odds ratio, 2.5; 95% confidence interval, 1.8-3.5). Among 13 cohort studies, diabetes was associated significantly with HCC in 7 studies (pooled risk ratio, 2.5; 95% confidence interval, 1.9-3.2). The results were relatively consistent in different populations, different geographic locations, and a variety of control groups. The significant association between HCC and diabetes was independent of alcohol use or viral hepatitis in the 10 studies that examined these factors. Few studies adjusted for diet and obesity. Diabetes is associated with an increased risk for HCC. However, more research is required to examine issues related to the duration and treatment of diabetes, and confounding by diet and obesity.
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                Author and article information

                Contributors
                +240.276.7321 , jessica.petrick@nih.gov
                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group UK (London )
                0007-0920
                1532-1827
                9 March 2018
                3 April 2018
                : 118
                : 7
                : 1005-1012
                Affiliations
                [1 ]ISNI 0000 0004 1936 8075, GRID grid.48336.3a, Division of Cancer Epidemiology and Genetics, , National Cancer Institute, ; Bethesda, MD USA
                [2 ]ISNI 0000 0004 0371 6485, GRID grid.422418.9, Epidemiology Research Program, , American Cancer Society, ; Atlanta, GA USA
                [3 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Division of Preventive Medicine, Department of Medicine, , Brigham and Women’s Hospital, ; Boston, MA USA
                [4 ]ISNI 0000 0004 0378 8294, GRID grid.62560.37, Channing Division of Network Medicine, Department of Medicine, , Brigham and Women’s Hospital, ; Boston, MA USA
                [5 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Division of Gastroenterology, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [6 ]ISNI 0000 0004 0386 9924, GRID grid.32224.35, Clinical and Translational Epidemiology Unit, , Massachusetts General Hospital and Harvard Medical School, ; Boston, MA USA
                [7 ]ISNI 0000 0004 0620 9745, GRID grid.410724.4, Division of Medical Oncology, , National Cancer Centre Singapore, ; Singapore, Singapore
                [8 ]ISNI 0000 0004 4657 1992, GRID grid.410370.1, VA Boston Healthcare System, ; Boston, MA USA
                [9 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Epidemiology, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [10 ]ISNI 0000 0004 1936 7558, GRID grid.189504.1, Slone Epidemiology Center at Boston University, ; Boston, MA USA
                [11 ]ISNI 0000000419368657, GRID grid.17635.36, Department of Pediatrics, , University of Minnesota, ; Minneapolis, MN USA
                [12 ]ISNI 0000 0004 1936 9510, GRID grid.253615.6, Exercise and Nutrition Sciences, Milken Institute School of Public Health, , George Washington University, ; Washington, DC USA
                [13 ]ISNI 000000041936754X, GRID grid.38142.3c, Department of Nutrition, , Harvard T.H. Chan School of Public Health, ; Boston, MA USA
                [14 ]ISNI 0000000419368956, GRID grid.168010.e, Department of Medicine and Obstetrics & Gynecology, , Stanford University School of Medicine, ; Stanford, CA USA
                [15 ]ISNI 0000 0004 1936 9887, GRID grid.273335.3, Department of Epidemiology and Environmental Health, , University at Buffalo, ; Buffalo, NY USA
                [16 ]ISNI 0000 0004 1936 8753, GRID grid.137628.9, Department of Population Health, , New York University School of Medicine, ; New York, NY USA
                Article
                7
                10.1038/s41416-018-0007-z
                5931109
                29520041
                8ab775f1-6084-419a-8b29-82e67b98285a
                © Cancer Research UK 2018

                Note: his work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 4.0 Unported License." Please change this instead to read: "Note: This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International licence (CC BY 4.0).

                History
                : 30 September 2017
                : 4 January 2018
                : 5 January 2018
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                © Cancer Research UK 2018

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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