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      The Prognostic Value of Tumor-Infiltrating Neutrophils in Gastric Adenocarcinoma after Resection

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          Abstract

          Background

          Several pieces of evidence indicate that tumor-infiltrating neutrophils (TINs) are correlated to tumor progression. In the current study, we explore the relationship between TINs and clinicopathological features of gastric adenocarcinoma patients. Furthermore, we investigated the prognostic value of TINs.

          Patients and Methods

          The study was comprised of two groups, training group (115 patients) and test group (97 patients). Biomarkers (intratumoral CD15+ neutrophils) were assessed by immunohistochemistry. The relationship between clinicopathological features and patient outcome were evaluated using Cox regression and Kaplan-Meier analysis.

          Results

          Immunohistochemical detection showed that the tumor-infiltrating neutrophils (TINs) in the training group ranged from 0.00–115.70 cells/high-power microscopic field (HPF) and the median number was 21.60 cells/HPF. Based on the median number, the patients were divided into high and low TINs groups. Chi-square test analysis revealed that the density of CD15+ TINs was positively associated with lymph node metastasis (p = 0.024), distance metastasis (p = 0.004) and UICC (International Union Against Cancer) staging (p = 0.028). Kaplan-Meier analysis showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.002). Multivariate Cox's analysis showed that the density of CD15+ TINs was an independent prognostic factor for overall survival of gastric adenocarcinoma patients. Using another 97 patients as a test group and basing on the median number of TINs (21.60 cells/HPF) coming from the training group, Kaplan-Meier analysis also showed that patients with a lower density of TINs had a better prognosis than patients with a higher density of TINs (p = 0.032). The results verify that the number of CD15+ TINs can predict the survival of gastric adenocarcinoma surgical patients.

          Conclusions

          The presence of CD15+ TINs is an independent and unfavorable factor in the prognosis of gastric adenocarcinoma patients. Targeting CD15+ TINs may be a potential intervenient therapy in the future.

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          Most cited references 19

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          Infiltrating neutrophils mediate the initial angiogenic switch in a mouse model of multistage carcinogenesis.

          Matrix metalloprotease type 9 (MMP-9) has been functionally implicated in VEGF activation, the induction and maintenance of chronic angiogenesis, and early stage tumor growth in a number of mouse models of cancer. In this article, we have identified two inflammatory cell types that are major sources of MMP-9 in the angiogenic stages of pancreatic islet carcinogenesis that unfold in RIP1-Tag2 transgenic mice. MMP-9-expressing neutrophils were predominantly found inside angiogenic islet dysplasias and tumors, whereas MMP-9-expressing macrophages were localized along the periphery of such lesions. Transient depletion of neutrophils significantly suppressed VEGF:VEGF-receptor association, a signature of MMP-9 activity, and markedly reduced the frequency of initial angiogenic switching in dysplasias. Thus infiltrating neutrophils can play a crucial role in activating angiogenesis in a previously quiescent tissue vasculature during the early stages of carcinogenesis.
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            The Baseline Ratio of Neutrophils to Lymphocytes Is Associated with Patient Prognosis in Advanced Gastric Cancer

            Objective: In cancer patients, the balance between neutrophil (N) and lymphocyte (L) cell counts fluctuates with advancing disease. The objective of our study was to determine the prognostic implications of the N/L ratio in the peripheral blood of gastric cancer patients. Methods: Study participants were identified from a prospective cohort of patients with advanced gastric cancer in Japan (n = 1,220). Results: The median baseline N/L was 2.58 (range, 0.63–12.7). Univariate analysis revealed that patients with an N/L ≧2.5 (n = 644) had a significantly poorer prognosis than those with an N/L –12 ). The median survival times for these two groups were 239 (95% confidence interval, CI, 217–251 days) and 363 days (95% CI, 334–406 days), respectively, while the 1-year survival rates were 30 (95% CI, 26–34%) and 50% (95% CI, 45–54%), respectively. A multivariate Cox model established a significant relationship between the N/L ratio and survival (adjusted hazard ratio = 1.52; 95% CI, 1.32–1.75; p = 0.077 × 10 –8 ). Conclusions: These results suggest that the N/L ratio is an independent prognostic factor in advanced gastric cancer. Measurement of this ratio may serve as a clinically accessible and useful biomarker for patient survival.
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              High preoperative neutrophil-lymphocyte ratio predicts poor survival in patients with gastric cancer.

              The neutrophil-lymphocyte ratio (NLR) reflects inflammatory status. An elevated NLR has been reported to be a prognostic indicator in some malignant tumors. The aim of this study was to evaluate the clinical significance of the preoperative NLR in patients with primary gastric cancer. A total of 709 men and 319 women, with a mean age of 64.4 years, who underwent gastrectomy were included. The numbers of patients in each pathological stage were as follows: stage I, 584; stage II, 132; stage III, 153; and stage IV, 159. The mean NLR was 2.62 +/- 1.68. A total of 127 patients (12.4%) with an NLR of 4.0 or more were classified as high NLR individuals in this study. The prognostic significance of a high NLR, together with various clinicopathological factors, was evaluated by multivariate analysis. The 5-year survival of patients with a high NLR was significantly worse than that of patients with a low NLR (57% vs 82%, P < 0.001). Univariate and multivariate analyses of clinicopathological factors affecting survival revealed that high NLR, depth of tumor, positive lymph nodes, distant metastasis, peritoneal metastasis, poorly differentiated type, and high platelet count were significant risk factors for reduced survival. On multivariate analysis, after adjusting for tumor stage, a high NLR was an independent risk factor for reduced survival (P = 0.003; adjusted hazard ratio, 1.845; 95% confidence interval, 1.236-2.747). A high preoperative NLR may be a convenient biomarker to identify patients with a poor prognosis after resection for primary gastric cancer.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2012
                19 March 2012
                : 7
                : 3
                Affiliations
                [1 ]State Key Laboratory of Oncology in Southern China and Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [2 ]Department of Gastric and Pancreatic Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [3 ]Department of Thoracic Oncology, Sun Yat-sen University Cancer Center, Guangzhou, People's Republic of China
                [4 ]First Affiliated Hospital of Jinan University, Jinan University, Guangzhou, People's Republic of China
                Tufts University, United States of America
                Author notes

                Conceived and designed the experiments: KP XDL JCX. Performed the experiments: JJZ KP WW JGC. Analyzed the data: JJZ YHW LL JJL YBC DDW QZP. Contributed reagents/materials/analysis tools: WW. Wrote the paper: JJZ KP.

                Article
                PONE-D-11-17116
                10.1371/journal.pone.0033655
                3307751
                22442706
                Zhao et al. 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.
                Page count
                Pages: 6
                Categories
                Research Article
                Biology
                Anatomy and Physiology
                Immune Physiology
                Immunology
                Molecular Cell Biology
                Cellular Types
                Medicine
                Anatomy and Physiology
                Immune Physiology
                Clinical Immunology
                Diagnostic Medicine
                Pathology
                General Pathology
                Gastroenterology and Hepatology
                Oncology
                Basic Cancer Research
                Cancers and Neoplasms
                Gastrointestinal Tumors

                Uncategorized

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