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      Lower circulating platelet counts and antiplatelet therapy independently predict better outcomes in patients with head and neck squamous cell carcinoma

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          Abstract

          Background

          Head and neck squamous cell carcinoma (HNSCC) mortality rates have not shown significant reduction in decades. Platelets are being implicated in having cancer-promoting roles, an observation supported by the adverse outcomes associated with thrombocytosis in many malignancies associated with thrombocytosis. However, the prognostic significance of platelet counts in HNSCC is unknown. Here, we comprehensively investigate the predictive value of platelet counts at diagnosis and post-diagnosis antiplatelet treatment in the overall survival of HNSCC patients.

          Methods

          The study population consists of 1051 pathologically confirmed HNSCC cases diagnosed between years 2000 and 2012 in a tertiary medical center. Platelet count was investigated as a predictor of survival by fitting Cox Proportional Hazards (CPH) regression models to generate Hazard Ratios (HR) and 95% confidence intervals (CI), while adjusting for age, sex, race, stage, treatment and smoking status. Finally, we evaluated the association between overall survival and antiplatelet medication intake after diagnosis.

          Results

          Multivariable analysis showed an increased death rate in patients with thromobocytosis [HR 2.37, 95% CI 1.60-3.50)] and high normal platelet counts [HR 2.20, 95% CI 1.58-3.05] compared to the reference middle normal group. Post-diagnosis treatment with antiplatelet medications was inversely associated with death rate [HR 0.76, 95% CI 0.58-0.99].

          Conclusions

          Higher platelet counts were associated with poorer prognosis in HNSCC patients, whereas antiplatelet agents were associated with better prognosis. Antiplatelet agents warrant evaluation in preclinical and clinical settings as a way to improve survival in HNSCC.

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          Most cited references19

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          Interleukin-6 stimulates thrombopoiesis through thrombopoietin: role in inflammatory thrombocytosis.

          Baseline platelet production is dependent on thrombopoietin (TPO). TPO is constitutively produced and primarily regulated by receptor-mediated uptake by platelets. Inflammatory thrombocytosis is thought to be related to increased interleukin-6 (IL-6) levels. To address whether IL-6 might act through TPO to increase platelet counts, TPO was neutralized in vivo in C57BL/10 mice treated with IL-6, and hepatic TPO mRNA expression and TPO plasma levels were studied. Transcriptional regulation of TPO mRNA was studied in the hepatoblastoma cell line HepG2. Furthermore, TPO plasma levels were determined in IL-6-treated cancer patients. It is shown that IL-6-induced thrombocytosis in C57BL/10 mice is accompanied by enhanced hepatic TPO mRNA expression and elevated TPO plasma levels. Administration of IL-6 to cancer patients results in a corresponding increase in TPO plasma levels. IL-6 enhances TPO mRNA transcription in HepG2 cells. IL-6-induced thrombocytosis can be abrogated by neutralization of TPO, suggesting that IL-6 induces thrombocytosis through TPO. A novel pathway of TPO regulation by the inflammatory mediator IL-6 is proposed, indicating that the number of platelets by themselves might not be the sole determinant of circulating TPO levels and thus of thrombopoiesis. This regulatory pathway might be of relevance for the understanding of reactive thrombocytosis.
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            Platelets: physiology and biochemistry.

            Platelets are specialized blood cells that play central roles in physiologic and pathologic processes of hemostasis, inflammation, tumor metastasis, wound healing, and host defense. Activation of platelets is crucial for platelet function that includes a complex interplay of adhesion and signaling molecules. This article gives an overview of the activation processes involved in primary and secondary hemostasis, for example, platelet adhesion, platelet secretion, platelet aggregation, microvesicle formation, and clot retraction/stabilization. In addition, activated platelets are predominantly involved in cross talk to other blood and vascular cells. Stimulated "sticky" platelets enable recruitment of leukocytes at sites of vascular injury under high shear conditions. Platelet-derived microparticles as well as soluble adhesion molecules, sP-selectin and sCD40L, shed from the surface of activated platelets, are capable of activating, in turn, leukocytes and endothelial cells. This article focuses further on the new view of receptor-mediated thrombin generation of human platelets, necessary for the formation of a stable platelet-fibrin clot during secondary hemostasis. Finally, special emphasis is placed on important stimulatory and inhibitory signaling pathways that modulate platelet function.
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              Pretreatment levels of peripheral neutrophils and lymphocytes as independent prognostic factors in patients with nasopharyngeal carcinoma.

              The purpose of this study was to evaluate the counts and percentages of differential leukocytes as prognostic indicators in patients with nasopharyngeal carcinoma (NPC). This study consisted of 1410 cases identified from an established prospective cohort of 1533 patients with NPC between October 2005 and October 2007 in the Sun Yat-Sen University Cancer Center. Multivariate Cox proportional hazards analyses were applied. A high percentage of lymphocyte was significantly associated with a favorable prognosis of NPC (highest vs lowest quartile, hazard ratio [HR], 95% confidence interval [CI] for overall and progression-free survival, HR, 0.71; 95% CI, 0.48-1.06; HR, 0.61; 95% CI, 0.43-0.86, respectively), whereas a high neutrophil percentage (HR, 1.62; 95% CI, 1.06-2.46; HR, 1.55; 95% CI, 1.10-2.18, respectively), and a neutrophil/lymphocyte ratio (NLR; HR, 1.57; 95% CI, 1.04-2.39; HR, 1.68; 95% CI, 1.19-2.38, respectively), were significantly related to a poor prognosis of NPC. Pretreatment NLR and percentages of lymphocyte and neutrophil are independent prognostic factors and may serve as clinically convenient and useful biomarkers for survival of patients with NPC. Copyright © 2012 Wiley Periodicals, Inc.
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                Author and article information

                Contributors
                rachidi@musc.edu
                wallack@musc.edu
                dayt@musc.edu
                alberg@musc.edu
                zihai@musc.edu
                Journal
                J Hematol Oncol
                J Hematol Oncol
                Journal of Hematology & Oncology
                BioMed Central (London )
                1756-8722
                27 September 2014
                27 September 2014
                2014
                : 7
                : 1
                : 65
                Affiliations
                [ ]Department of Microbiology and Immunology, 86 Jonathan Lucas, Suite 612, Charleston, SC 29425 USA
                [ ]Hollings Cancer Center, 86 Jonathan Lucas, Suite 612, Charleston, SC 29425 USA
                [ ]Department of Public Health Sciences, 68 President Street, BE 103, Charleston, SC 29425 USA
                [ ]Head and Neck Tumor Center, Department of Otolaryngology-Head and Neck Surgery, Medical University of South Carolina, 171 Ashley Avenue, Charleston, SC 29425 USA
                Article
                65
                10.1186/s13045-014-0065-5
                4189675
                25260646
                563bbb03-14d0-42f6-8235-89d66e13998b
                © Rachidi et al.; licensee BioMed Central Ltd. 2014

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 28 May 2014
                : 6 August 2014
                Categories
                Research
                Custom metadata
                © The Author(s) 2014

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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