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      Association between plasma fibrinogen and survival in patients with small‐cell lung carcinoma

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          Abstract

          Background

          Elevated plasma fibrinogen (Fbg) levels contribute to tumor progression and metastasis; however, limited research on Fbg in small cell lung cancer (SCLC) has been conducted. This study evaluated the prognostic value of Fbg levels in patients with SCLC.

          Methods

          Data on plasma Fbg level, clinical features, and overall survival were retrospectively collected. Kaplan–Meier estimates and log‐rank tests were used to analyze the relationship between Fbg level and survival. Multivariate analyses were performed to determine independent prognostic factors. Subgroup analyses were performed based on extensive/limited disease and Eastern Cooperative Oncology Group status.

          Results

          A total of 120 patients with SCLC were included. The one, three, and five‐year survival rates for the entire cohort were 48.3%, 9.2%, and 1.7%, respectively. Univariate analyses revealed that age, alcohol use, clinical stage, pleural effusion, Eastern Cooperative Oncology Group grade, and Fbg and lactate dehydrogenase levels were associated with survival ( P < 0.05). The median survival time for patients with high Fbg levels (> 400 mg/dL) was shorter than for those with low Fbg levels (8 vs. 14 months; P = 0.013). Furthermore, multivariate analysis revealed that Fbg was negatively and independently associated with SCLC prognosis (hazard ratio 1.505, 95% confidence interval 1.018–2.226; P = 0.041). Higher Fbg levels were associated with shorter survival in the extensive disease subgroup (7 vs. 12 months; P = 0.004).

          Conclusions

          Elevated plasma Fbg was an independent factor associated with poor outcomes in SCLC patients and could serve as a prognostic biomarker.

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          Most cited references27

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          High D-dimer levels are associated with poor prognosis in cancer patients.

          Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1(st), 2(nd) and 3(rd) quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4-1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.
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            Vascular endothelial growth factor binds to fibrinogen and fibrin and stimulates endothelial cell proliferation.

            Vascular development and response to injury are regulated by several cytokines and growth factors including the members of the fibroblast growth factor and vascular endothelial cell growth factor (VEGF) families. Fibrinogen and fibrin are also important in these processes and affect many endothelial cell properties. Possible specific interactions between VEGF and fibrinogen that could play a role in coordinating vascular responses to injury are investigated. Binding studies using the 165 amino acid form of VEGF immobilized on Sepharose beads and soluble iodine 125 ((125)I)-labeled fibrinogen demonstrated saturable and specific binding. Scatchard analysis indicated 2 classes of binding sites with dissociation constants (K(d)s) of 5.9 and 462 nmol/L. The maximum molar binding ratio of VEGF:fibrinogen was 3.8:1. Further studies characterized binding to fibrin using (125)I-labeled VEGF- and Sepharose-immobilized fibrin monomer. These also demonstrated specific and saturable binding with 2 classes of sites having K(d)s of 0.13 and 97 nmol/L and a molar binding ratio of 3.6:1. Binding to polymerized fibrin demonstrated one binding site with a K(d) of 9.3 nmol/L. Binding of VEGF to fibrin(ogen) was independent of FGF-2, indicating that there are distinct binding sites for each angiogenic peptide. VEGF bound to soluble fibrinogen in medium and to surface immobilized fibrinogen or fibrin retained its capacity to support endothelial cell proliferation. VEGF binds specifically and saturably to fibrinogen and fibrin with high affinity, and this may affect the localization and activity of VEGF at sites of tissue injury. (Blood. 2000;96:3772-3778)
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              Fibrinogen synthesized by cancer cells augments the proliferative effect of fibroblast growth factor-2 (FGF-2).

              Fibroblast growth factor (FGF)-2 is a critical growth factor in normal and malignant cell proliferation and tumor-associated angiogenesis. Fibrinogen and fibrin bind to FGF-2 and modulate FGF-2 functions. Furthermore, we have shown that extrahepatic epithelial cells are capable of endogenous production of fibrinogen. Herein we examined the role of fibrinogen and FGF-2 interactions on prostate and lung adenocarcinoma cell growth in vitro. Cell proliferation was measured by (3)H-thymidine uptake and the specificity of FGF-2-fibrinogen interactions was measured using wild-type and mutant FGF-2s, fibrinogen gamma-chain (FGG) RNAi and co-immunoprecipitation. Metabolic labeling, immunopurification and fluorography demonstrated de novo fibrinogen production. FGF-2 stimulated DU-145 cell proliferation, whereas neither FGF-2 nor fibrinogen affected the growth of PC-3 or A549 cells. Fibrinogen augmented the proliferative effect of FGF-2 on DU-145 cells. The role of fibrinogen in FGF-2-enhanced DNA synthesis was confirmed using an FGF-2 mutant that exhibits no binding affinity for fibrinogen. FGG transcripts were present in PC-3, A549 and DU-145 cells, but only PC-3 and A549 cells produced detectable levels of intact protein. RNAi-mediated knockdown of FGG expression resulted in decreased production of fibrinogen protein and inhibited (3)H-thymidine uptake in A549 and PC-3 cells by 60%, which was restored by exogenously added fibrinogen. FGF-2 and fibrinogen secreted by the cells were present in the medium as a soluble complex, as determined by coimmunoprecipitation studies. These data indicate that endogenously synthesized fibrinogen promotes the growth of lung and prostate cancer cells through interaction with FGF-2.
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                Author and article information

                Contributors
                fss_and_yx@163.com
                agy23104464@163.com
                Journal
                Thorac Cancer
                Thorac Cancer
                10.1111/(ISSN)1759-7714
                TCA
                Thoracic Cancer
                John Wiley & Sons Australia, Ltd (Melbourne )
                1759-7706
                1759-7714
                13 November 2017
                January 2018
                : 9
                : 1 ( doiID: 10.1111/tca.2018.9.issue-1 )
                : 146-151
                Affiliations
                [ 1 ] Department of Oncology, Beijing Chao‐Yang Hospital Capital Medical University Beijing China
                [ 2 ] Clinical Laboratory, Beijing Chao‐Yang Hospital Capital Medical University Beijing China
                Author notes
                [*] [* ] Correspondence

                Guangyu An, Department of Oncology, Beijing Chao‐Yang Hospital, Capital Medical University, 8 Gongren Tiyuchang Nanlu, Beijing 100020, China.

                Tel: +86 10 8523 1570

                Fax: +86 10 8523 1570

                Email: agy23104464@ 123456163.com

                Author information
                http://orcid.org/0000-0003-2234-3146
                Article
                TCA12556
                10.1111/1759-7714.12556
                5754299
                29131503
                2a759a52-d4e9-47e4-b32f-162dc0bd492a
                © 2017 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd

                This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

                History
                : 28 August 2017
                : 12 October 2017
                : 15 October 2017
                Page count
                Figures: 2, Tables: 3, Pages: 6, Words: 3728
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                tca12556
                January 2018
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.2.8 mode:remove_FC converted:04.01.2018

                fibrinogen,prognosis,small‐cell lung carcinoma,survival

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