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      Elevated High-Sensitivity C-Reactive Protein Levels Predict Decreased Survival for Nasopharyngeal Carcinoma Patients in the Intensity-Modulated Radiotherapy Era

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          Abstract

          Purpose

          This study aimed to clarify the prognostic utility of high-sensitivity C-reactive protein (hs-CRP) in nasopharyngeal carcinoma (NPC) patients in the Intensity-Modulated Radiotherapy (IMRT) era.

          Patients and Methods

          In this observational study, 1,589 non-metastatic NPC patients treated with IMRT were recruited. Blood samples were collected before treatment for examination of hs-CRP levels. We evaluated the association of pretreatment hs-CRP levels with overall survival rate (OS), progression free survival rate (PFS), locoregional relapse free survival rate (LRFS) and distant metastasis free survival rate (DMFS).

          Results

          Baseline hs-CRP levels were correlated with sex, clinical stage, body mass index, smoking status, and EBV DNA level. Multivariate analysis showed that hs-CRP had significant association with OS (HR:1.723; 95%CI:1.238–2.398; p = 0.001), PFS (HR:1.621; 95%CI:1.273–2.064; p<0.001) and DMFS (HR:1.879; 95%CI:1.394–2.531; p<0.001). In subgroups such as advanced-stage group, low EBV DNA group and high EBV DNA group, elevated hs-CRP levels still predicted poor clinical outcomes. Furthermore, in patients with chronic HBV infection, decreased 4-year survival was observed in the cohort of high hs-CRP levels, with 87.4% vs. 94.9% (p = 0.023) for OS, 65.2% vs. 90.8% (p<0.001) for PFS, and 67.6% vs. 95.0% (p<0.001) for DMFS. A similar finding was observed for patients with cardiovascular disease, with 79.1% vs. 90.2% (p = 0.020) for PFS, and 71.4% vs. 97.6% (p = 0.002) for DMFS.

          Conclusion

          Elevated serum hs-CRP levels were correlated with poor survival for NPC patients in the IMRT era, playing a complementary role to TNM stage and EBV DNA. In addition, elevated hs-CRP level was still an effective indicator for patients with chronic HBV infection and cardiovascular disease.

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          Most cited references27

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          A prospective, randomized study comparing outcomes and toxicities of intensity-modulated radiotherapy vs. conventional two-dimensional radiotherapy for the treatment of nasopharyngeal carcinoma.

          To compare clinical outcomes and toxicities of two-dimensional conventional radiation therapy (2D-CRT) and intensity modulated radiation therapy (IMRT) for the treatment of nasopharyngeal carcinoma (NPC). Between July 2003 and October 2008, 616 patients with non-metastatic stage I to IVb NPC were prospectively randomized to receive 2D-CRT (n=310; mean age, 44.8±13.6 years) or IMRT (n=306; mean age, 46.7±12.5 years). Clinical outcomes and acute and late toxicities were determined and compared. The 2 groups were comparable with respect to all parameters of demographics and disease characteristics (all, p>0.05). Median follow-up was 42 months (range, 1-83 months). The 5-year actuarial local control rate was 90.5% in the IMRT group and 84.7% in the 2D-CRT group. The local control rates were 91% for stage T3 and 81.5% for stage T4 disease in the IMRT group and 80% and 62.2% in the 2D-CRT group, respectively. The 5-year actuarial nodal relapse-free survival (NRFS) rate was 92.4% in the IMRT and 92.9% in the 2D-CRT group (p>0.05). The NRFS was 93.9% for N2 disease in the IMRT group and 91.4% in the 2D-CRT group (p=0.02). The 5-year overall survival (OS) rate was 79.6% for the IMRT group and 67.1% for the 2D-CRT group (p=0.001). When stratified for stage, a significant difference was only noted for stage III disease. In terms of radiation-induced toxicities, patients in IMRT group had significantly lower radiation-induced toxicities than those in 2D-CRT group. IMRT provides improved local-recurrence free survival, especially in late-stage NPC patients and is associated with a lower incidence of toxicities. Copyright © 2012. Published by Elsevier Ireland Ltd.
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            Interferon beta 2/B-cell stimulatory factor type 2 shares identity with monocyte-derived hepatocyte-stimulating factor and regulates the major acute phase protein response in liver cells.

            One of the oldest and most preserved of the homeostatic responses of the body to injury is the acute phase protein response associated with inflammation. The liver responds to hormone-like mediators by the increased synthesis of a series of plasma proteins called acute phase reactants. In these studies, we examined the relationship of hepatocyte-stimulating factor derived from peripheral blood monocytes to interferon beta 2 (IFN-beta 2), which has been cloned. Antibodies raised against fibroblast-derived IFN-beta having neutralizing activity against both IFN-beta 1 and -beta 2 inhibited the major hepatocyte-stimulating activity derived from monocytes. Fibroblast-derived mediator elicited the identical stimulated response in human HepG2 cells and primary rat hepatocytes as the monocyte cytokine. Finally, recombinant-derived human B-cell stimulatory factor type 2 (IFN-beta 2) from Escherichia coli induced the synthesis of all major acute phase proteins studied in human hepatoma HepG2 and primary rat hepatocyte cultures. These data demonstrate that monocyte-derived hepatocyte-stimulating factor and IFN-beta 2 share immunological and functional identity and that IFN-beta 2, also known as B-cell stimulatory factor and hybridoma plasmacytoma growth factor, has the hepatocyte as a major physiologic target and thereby is essential in controlling the hepatic acute phase response.
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              Plasma Epstein-Barr viral deoxyribonucleic acid quantitation complements tumor-node-metastasis staging prognostication in nasopharyngeal carcinoma.

              To evaluate the effect of combining circulating Epstein-Barr viral (EBV) DNA load data with TNM staging data in pretherapy prognostication of nasopharyngeal carcinoma (NPC). Three hundred seventy-six patients with all stages of NPC were studied. Pretreatment plasma/serum EBV DNA concentrations were quantified by a polymerase chain reaction assay. Determinants of overall survival were assessed by multivariate analysis. Survival probabilities of patient groups, segregated by clinical stage (I, II, III, or IV) alone and also according to EBV DNA load (low or high), were compared. Pretherapy circulating EBV DNA load is an independent prognostic factor for overall survival in NPC. Patients with early-stage disease were segregated by EBV DNA levels into a poor-risk subgroup with survival similar to that of stage III disease and a good-risk subgroup with survival similar to stage I disease. Pretherapy circulating EBV DNA load is an independent prognostic factor to International Union Against Cancer (UICC) staging in NPC. Combined interpretation of EBV DNA data with UICC staging data leads to alteration of risk definition of patient subsets, with improved risk discrimination in early-stage disease. Validation studies are awaited.
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                13 April 2015
                2015
                : 10
                : 4
                : e0122965
                Affiliations
                [1 ]State Key Laboratory of Oncology in South China and Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
                [2 ]Department of Nasopharyngeal Carcinoma, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China
                [3 ]ZhongShan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China
                National Cancer Centre, SINGAPORE
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: LQT DPH. Performed the experiments: DPH QYC LZ XPL YH YXXX SHW YTP WHC SSG LTL. Analyzed the data: DPH. Contributed reagents/materials/analysis tools: MSZ HQM CNQ XG. Wrote the paper: DPH.

                Article
                PONE-D-14-35159
                10.1371/journal.pone.0122965
                4395211
                25874450
                d0cba110-abb2-45b9-98f5-25a5cdbb16a0
                Copyright @ 2015

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

                History
                : 8 August 2014
                : 16 February 2015
                Page count
                Figures: 4, Tables: 3, Pages: 17
                Funding
                This research was supported by grants from the National Natural Science Foundation of China (No: 81072226, http://www.nsfc.gov.cn), the 863 Project (No: 2012AA02A501, http://www.863.gov.cn/), the National Key Basic Research Program of China (No: 2013CB910304, http://www.973.gov.cn), the Sci-Tech Project Foundation of Guangdong Province (No: 2011B080701034, and 2011B031800161, http://www.gdstc.gov.cn/), the Sci-Tech Project Foundation of Guangzhou City (No: 2011J4300100, http://www.gzsi.gov.cn), the Sun Yat-sen University Clinical Research 5010 Program, and the Fundamental Research Funds for the central universities ( http://www.sysu.edu.cn). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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