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      Tumour-infiltrating lymphocytes predict for outcome in HPV-positive oropharyngeal cancer

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          Abstract

          Background:

          Human papillomavirus (HPV)-positive oropharyngeal cancer (OPSCC) is associated with improved survival compared with HPV-negative disease. However, a minority of HPV-positive patients have poor prognosis. Currently, there is no generally accepted strategy for identifying these patients.

          Methods:

          We retrospectively analysed 270 consecutively treated OPSCC patients from three centres for effects of clinical, pathological, immunological, and molecular features on disease mortality. We used Cox regression to examine associations between factors and OPSCC death, and developed a prognostic model for 3-year mortality using logistic regression analysis.

          Results:

          Patients with HPV-positive tumours showed improved survival (hazard ratio (HR), 0.33 (0.21–0.53)). High levels of tumour-infiltrating lymphocytes (TILs) stratified HPV-positive patients into high-risk and low-risk groups (3-year survival; HPV-positive/TIL high=96%, HPV-positive/TIL low=59%). Survival of HPV-positive/TIL low patients did not differ from HPV-negative patients (HR, 1.01; P=0.98). We developed a prognostic model for HPV-positive tumours using a ‘training' cohort from one centre; the combination of TIL levels, heavy smoking, and T-stage were significant (AUROC=0·87). This model was validated on patients from the other centres (detection rate 67% false-positive rate 5.6% AUROC=0·82).

          Interpretation:

          Our data suggest that an immune response, reflected by TIL levels in the primary tumour, has an important role in the improved survival seen in most HPV-positive patients, and is relevant for the clinical evaluation of HPV-positive OPSCC.

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          Most cited references29

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          Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.

          The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
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            Time-dependent ROC curves for censored survival data and a diagnostic marker.

            ROC curves are a popular method for displaying sensitivity and specificity of a continuous diagnostic marker, X, for a binary disease variable, D. However, many disease outcomes are time dependent, D(t), and ROC curves that vary as a function of time may be more appropriate. A common example of a time-dependent variable is vital status, where D(t) = 1 if a patient has died prior to time t and zero otherwise. We propose summarizing the discrimination potential of a marker X, measured at baseline (t = 0), by calculating ROC curves for cumulative disease or death incidence by time t, which we denote as ROC(t). A typical complexity with survival data is that observations may be censored. Two ROC curve estimators are proposed that can accommodate censored data. A simple estimator is based on using the Kaplan-Meier estimator for each possible subset X > c. However, this estimator does not guarantee the necessary condition that sensitivity and specificity are monotone in X. An alternative estimator that does guarantee monotonicity is based on a nearest neighbor estimator for the bivariate distribution function of (X, T), where T represents survival time (Akritas, M. J., 1994, Annals of Statistics 22, 1299-1327). We present an example where ROC(t) is used to compare a standard and a modified flow cytometry measurement for predicting survival after detection of breast cancer and an example where the ROC(t) curve displays the impact of modifying eligibility criteria for sample size and power in HIV prevention trials.
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              REporting recommendations for tumour MARKer prognostic studies (REMARK)

              Despite years of research and hundreds of reports on tumour markers in oncology, the number of markers that have emerged as clinically useful is pitifully small. Often initially reported studies of a marker show great promise, but subsequent studies on the same or related markers yield inconsistent conclusions or stand in direct contradiction to the promising results. It is imperative that we attempt to understand the reasons that multiple studies of the same marker lead to differing conclusions. A variety of methodological problems have been cited to explain these discrepancies. Unfortunately, many tumour marker studies have not been reported in a rigorous fashion, and published articles often lack sufficient information to allow adequate assessment of the quality of the study or the generalisability of the study results. The development of guidelines for the reporting of tumour marker studies was a major recommendation of the US National Cancer Institute and the European Organisation for Research and Treatment of Cancer (NCI-EORTC) First International Meeting on Cancer Diagnostics in 2000. Similar to the successful CONSORT initiative for randomised trials and the STARD statement for diagnostic studies, we suggest guidelines to provide relevant information about the study design, preplanned hypotheses, patient and specimen characteristics, assay methods, and statistical analysis methods. In addition, the guidelines suggest helpful presentations of data and important elements to include in discussions. The goal of these guidelines is to encourage transparent and complete reporting so that the relevant information will be available to others to help them to judge the usefulness of the data and understand the context in which the conclusions apply.
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                Author and article information

                Journal
                Br J Cancer
                Br. J. Cancer
                British Journal of Cancer
                Nature Publishing Group
                0007-0920
                1532-1827
                21 January 2014
                29 October 2013
                21 January 2014
                : 110
                : 2
                : 489-500
                Affiliations
                [1 ]Cancer Sciences Unit, Faculty of Medicine, University of Southampton , Tremona Road, Southampton SO16 6YD, UK
                [2 ]Department of Otolaryngology—Head and Neck Surgery, University Hospital Southampton NHS Foundation Trust , Tremona Road, Southampton SO16 6YD, UK
                [3 ]Department of Medical Statistics, University of Southampton , Tremona Road, Southampton SO16 6YD, UK
                [4 ]Department of Cellular Pathology, Bart's and The London School of Medicine and Dentistry , Garrod Building, Turner Street, Whitechapel, London E1 2AD, UK
                [5 ]Department of Oral and Maxillofacial Surgery, University Hospital Southampton NHS Foundation Trust , Tremona Road, Southampton SO16 6YD, UK
                [6 ]Macmillan Head, Neck and Thyroid Specialist Nurse Team, University Hospital Southampton NHS Foundation Trust , Tremona Road, Southampton SO16 6YD, UK
                [7 ]Department of Otolaryngology—Head and Neck Surgery, Poole NHS Foundation Trust , Longfleet Road, Poole BH15 2JB, UK
                [8 ]Department of Cellular Pathology, University Hospital Southampton NHS Foundation Trust , Tremona Road, Southampton SO16 6YD, UK
                [9 ]Department of Surgery, University Hospital Southampton NHS Foundation Trust , Tremona Road, Southampton SO16 6YD, UK
                [10 ]NIHR Experimental Cancer Medicine Centre Southampton , Tremona Road, Southampton SO16 6YD, UK
                Author notes
                [11]

                These authors contributed equally to this work.

                Article
                bjc2013639
                10.1038/bjc.2013.639
                3899750
                24169344
                9cf7a310-5fdc-4927-ae15-473471740769
                Copyright © 2014 Cancer Research UK

                This work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/

                History
                : 07 June 2013
                : 28 August 2013
                : 12 September 2013
                Categories
                Molecular Diagnostics

                Oncology & Radiotherapy
                tumour-infiltrating lymphocytes,survival,prognosis,oropharyngeal cancer,human papillomavirus

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