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      Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all‐cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer

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          Abstract

          Tobacco smoking and alcohol consumption are well‐established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all‐cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully‐adjusted HR for current versus never‐smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non‐drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all‐cause mortality in models adjusted for important prognostic factors.

          Abstract

          What's new?

          Smoking and alcohol use are risk factors for developing head‐and‐neck cancer (HNC) and are known to influence mortality in general. However, the prognostic role of smoking status and alcohol intake at time of diagnosis on HNC survival is less clear. In this study, the authors provide a comprehensive, prospective analysis of mortality risk in different tumour sites, adjusting for important prognostic factors such as stage, comorbidity, and HPV infection. These results may provide insight to inform and improve prediction of clinical outcomes.

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          'Mendelian randomization': can genetic epidemiology contribute to understanding environmental determinants of disease?

          Associations between modifiable exposures and disease seen in observational epidemiology are sometimes confounded and thus misleading, despite our best efforts to improve the design and analysis of studies. Mendelian randomization-the random assortment of genes from parents to offspring that occurs during gamete formation and conception-provides one method for assessing the causal nature of some environmental exposures. The association between a disease and a polymorphism that mimics the biological link between a proposed exposure and disease is not generally susceptible to the reverse causation or confounding that may distort interpretations of conventional observational studies. Several examples where the phenotypic effects of polymorphisms are well documented provide encouraging evidence of the explanatory power of Mendelian randomization and are described. The limitations of the approach include confounding by polymorphisms in linkage disequilibrium with the polymorphism under study, that polymorphisms may have several phenotypic effects associated with disease, the lack of suitable polymorphisms for studying modifiable exposures of interest, and canalization-the buffering of the effects of genetic variation during development. Nevertheless, Mendelian randomization provides new opportunities to test causality and demonstrates how investment in the human genome project may contribute to understanding and preventing the adverse effects on human health of modifiable exposures.
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            When the entire population is the sample: strengths and limitations in register-based epidemiology.

            Studies based on databases, medical records and registers are used extensively today in epidemiological research. Despite the increasing use, no developed methodological literature on use and evaluation of population-based registers is available, even though data collection in register-based studies differs from researcher-collected data, all persons in a population are available and traditional statistical analyses focusing on sampling error as the main source of uncertainty may not be relevant. We present the main strengths and limitations of register-based studies, biases especially important in register-based studies and methods for evaluating completeness and validity of registers. The main strengths are that data already exist and valuable time has passed, complete study populations minimizing selection bias and independently collected data. Main limitations are that necessary information may be unavailable, data collection is not done by the researcher, confounder information is lacking, missing information on data quality, truncation at start of follow-up making it difficult to differentiate between prevalent and incident cases and the risk of data dredging. We conclude that epidemiological studies with inclusion of all persons in a population followed for decades available relatively fast are important data sources for modern epidemiology, but it is important to acknowledge the data limitations.
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              Multiplex human papillomavirus serology based on in situ-purified glutathione s-transferase fusion proteins.

              More than 100 different human papillomaviruses (HPVs) can cause proliferative diseases, many of which are malignant, such as cervical cancer. HPV serology is complex because infection and disease lead to distinct type-specific antibody responses. Using bead-based technology, we have developed an assay platform that allows the simultaneous detection of antibodies against up to 100 in situ affinity-purified recombinant HPV proteins. Twenty-seven HPV proteins were expressed as glutathione S-transferase fusion proteins and affinity-purified in one step by incubation of glutathione-displaying beads in bacterial lysate. Spectrally distinct bead sets, each carrying one particular antigen, were mixed, incubated with serum, and differentiated in a flow cytometer-like analyzer (xMAP; Luminex Corp). Antibodies bound to the antigens were detected via fluorescent secondary reagents. We studied 756 sera from 2 case-control studies of cervical cancer. Glutathione S-transferase fusion proteins bound with high affinity to glutathione-displaying beads (Kd = 6.9 x 10(-9) mol/L). The dynamic range of multiplex serology covered 1.5 orders of magnitude, and antibodies were detected at serum dilutions >1:1,000,000. Imprecision (median CV) was < or = 5.4%, and assay reproducibility was high (R2 = 0.97). Results on clinical samples showed high concordance with ELISA (kappa = 0.846), but multiplex serology exhibited increased detection of weak antibody responses. Antibodies to the E6 oncoproteins of the rare HPV types 52 and 58 were associated with cervical cancer (P < 0.001). Multiplex serology enables antibody analyses of large numbers of sera against up to 100 antigens in parallel and has the potential to replace ELISA technology.
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                Author and article information

                Contributors
                rhona.beynon@bristol.ac.uk
                Journal
                Int J Cancer
                Int. J. Cancer
                10.1002/(ISSN)1097-0215
                IJC
                International Journal of Cancer
                John Wiley and Sons Inc. (Hoboken )
                0020-7136
                1097-0215
                23 April 2018
                01 September 2018
                : 143
                : 5 ( doiID: 10.1002/ijc.v143.5 )
                : 1114-1127
                Affiliations
                [ 1 ] Population Health Sciences Bristol Medical School, University of Bristol, Canynge Hall Bristol BS8 2PS United Kingdom
                [ 2 ] MRC Integrative Epidemiology Unit (IEU) Bristol BS8 2BN United Kingdom
                [ 3 ] National Institute for Health Research (NIHR) Bristol Biomedical Research Centre, University Hospitals Bristol NHS Foundation Trust and University of Bristol
                [ 4 ] School of Oral and Dental Sciences, University of Bristol BS1 2LY United Kingdom
                [ 5 ] Molecular Diagnostics of Oncogenic Infections Division German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 Heidelberg 69120 Germany
                [ 6 ] Infections and Cancer Epidemiology German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280 Heidelberg 69120 Germany
                Author notes
                [*] [* ] Correspondence to: Rhona Beynon, Department of Population Health Sciences, Bristol Medical School, University of Bristol, Canynge Hall, 39 Whatley Road, Bristol, BS8 2PS, United Kingdom, Tel: +[44‐(0)117‐928‐7211], E‐mail: rhona.beynon@ 123456bristol.ac.uk
                [†]

                R.M.M., M.M. and A.R.N. contributed equally to this work

                Author information
                http://orcid.org/0000-0001-5494-9519
                Article
                IJC31416
                10.1002/ijc.31416
                6099366
                29607493
                553e3c9b-8481-49ef-b6b0-b5be390fe64b
                © 2018 The Authors International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 05 October 2017
                : 16 February 2018
                : 13 March 2018
                Page count
                Figures: 1, Tables: 5, Pages: 14, Words: 6914
                Funding
                Funded by: National Institute for Health Research (NIHR) under its Programme Grants for Applied Research scheme
                Award ID: RP‐PG‐0707‐10034
                Funded by: The MRC/University of Bristol Integrative Epidemiology Unit (IEU) is supported by the MRC and the University of Bristol
                Award ID: MC‐UU‐12013/1-9
                Funded by: Cancer Research UK Programme Grant
                Funded by: Integrative Cancer Epidemiology Programme
                Award ID: C18281/A19169
                Funded by: Wellcome Trust
                Award ID: 110021/Z/15/Z
                Categories
                Cancer Epidemiology
                Cancer Epidemiology
                Custom metadata
                2.0
                ijc31416
                1 September 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:version=5.4.4 mode:remove_FC converted:20.08.2018

                Oncology & Radiotherapy
                head and neck cancer,smoking,alcohol,human papillomavirus,survival
                Oncology & Radiotherapy
                head and neck cancer, smoking, alcohol, human papillomavirus, survival

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