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      • Record: found
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      Tumor-Associated Neutrophils as a New Prognostic Factor in Cancer: A Systematic Review and Meta-Analysis

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          Abstract

          Purpose

          Tumor-associated neutrophils (TAN) have been reported in a variety of malignancies. We conducted an up-to-date meta-analysis to evaluate the prognostic role of TAN in cancer.

          Method

          Pubmed, Embase and web of science databases were searched for studies published up to April 2013. Pooled hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) were calculated. The impact of neutrophils localization and primary antibody were also assessed.

          Results

          A total of 3946 patients with various solid tumors from 20 studies were included. High density of intratumoral neutrophils were independently associated with unfavorable survival; the pooled HRs were 1.68 (95%CI: 1.36–2.07, I 2 = 55.8%, p<0.001) for recurrence-free survival (RFS)/disease-free survival (DFS), 3.36 (95%CI: 2.08–5.42, I 2 = 0%, p<0.001) for cancer-specific survival (CSS) and 1.66 (95%CI: 1.37–2.01, I 2 = 70.5%, p<0.001) for overall survival (OS). Peritumoral and stromal neutrophils were not statistically significantly associated with survival. When grouped by primary antibody, the pooled HRs were 1.80 (95%CI: 1.47–2.22, I 2 = 67.7%, p<0.001) for CD66b, and 1.44 (95%CI: 0.90–2.30, I 2 = 45.9%, p = 0.125) for CD15, suggesting that CD66b positive TAN might have a better prognostic value than CD15.

          Conclusion

          High levels of intratumoral neutrophils are associated with unfavorable recurrence-free, cancer-specific and overall survival.

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          Most cited references30

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          Language bias in randomised controlled trials published in English and German.

          M. Egger, T Zellweger-Zähner, M. Schneider … (1997)
          Some randomised controlled trials (RCTs) done in German-speaking Europe are published in international English-language journals and others in national German-language journals. We assessed whether authors are more likely to report trials with statistically significant results in English than in German. We studied pairs of RCT reports, matched for first author and time of publication, with one report published in German and the other in English. Pairs were identified from reports round in a manual search of five leading German-language journals and from reports published by the same authors in English found on Medline. Quality of methods and reporting were assessed with two different scales by two investigators who were unaware of authors' identities, affiliations, and other characteristics of trial reports. Main study endpoints were selected by two investigators who were unaware of trial results. Our main outcome was the number of pairs of studies in which the levels of significance (shown by p values) were discordant. 62 eligible pairs of reports were identified but 19 (31%) were excluded because they were duplicate publications. A further three pairs (5%) were excluded because no p values were given. The remaining 40 pairs were analysed. Design characteristics and quality features were similar for reports in both languages. Only 35% of German-language articles, compared with 62% of English-language articles, reported significant (p < 0.05) differences in the main endpoint between study and control groups (p = 0.002 by McNemar's test). Logistic regression showed that the only characteristic that predicted publication in an English-language journal was a significant result. The odds ratio for publication of trials with significant results in English was 3.75 (95% CI 1.25-11.3). Authors were more likely to publish RCTs in an English-language journal if the results were statistically significant. English language bias may, therefore, be introduced in reviews and meta-analyses if they include only trials reported in English. The effort of the Cochrane Collaboration to identify as many controlled trials as possible, through the manual search of many medical journals published in different languages will help to reduce such bias.
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            Estrogen plus progestin and breast cancer incidence and mortality in postmenopausal women.

            Rowan Chlebowski, Garnet Anderson, Margery Gass … (2010)
            In the Women's Health Initiative randomized, placebo-controlled trial of estrogen plus progestin, after a mean intervention time of 5.6 (SD, 1.3) years (range, 3.7-8.6 years) and a mean follow-up of 7.9 (SD, 1.4) years, breast cancer incidence was increased among women who received combined hormone therapy. Breast cancer mortality among participants in the trial has not been previously reported. To determine the effects of therapy with estrogen plus progestin on cumulative breast cancer incidence and mortality after a total mean follow-up of 11.0 (SD, 2.7) years, through August 14, 2009. A total of 16,608 postmenopausal women aged 50 to 79 years with no prior hysterectomy from 40 US clinical centers were randomly assigned to receive combined conjugated equine estrogens, 0.625 mg/d, plus medroxyprogesterone acetate, 2.5 mg/d, or placebo pill. After the original trial completion date (March 31, 2005), reconsent was required for continued follow-up for breast cancer incidence and was obtained from 12,788 (83%) of the surviving participants. Invasive breast cancer incidence and breast cancer mortality. In intention-to-treat analyses including all randomized participants and censoring those not consenting to additional follow-up on March 31, 2005, estrogen plus progestin was associated with more invasive breast cancers compared with placebo (385 cases [0.42% per year] vs 293 cases [0.34% per year]; hazard ratio [HR], 1.25; 95% confidence interval [CI], 1.07-1.46; P = .004). Breast cancers in the estrogen-plus-progestin group were similar in histology and grade to breast cancers in the placebo group but were more likely to be node-positive (81 [23.7%] vs 43 [16.2%], respectively; HR, 1.78; 95% CI, 1.23-2.58; P = .03). There were more deaths directly attributed to breast cancer (25 deaths [0.03% per year] vs 12 deaths [0.01% per year]; HR, 1.96; 95% CI, 1.00-4.04; P = .049) as well as more deaths from all causes occurring after a breast cancer diagnosis (51 deaths [0.05% per year] vs 31 deaths [0.03% per year]; HR, 1.57; 95% CI, 1.01-2.48; P = .045) among women who received estrogen plus progestin compared with women in the placebo group. Estrogen plus progestin was associated with greater breast cancer incidence, and the cancers are more commonly node-positive. Breast cancer mortality also appears to be increased with combined use of estrogen plus progestin. clinicaltrials.gov Identifier: NCT00000611.
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              Intratumoral neutrophils: a poor prognostic factor for hepatocellular carcinoma following resection.

              Shuang Qiu, Jian Zhou, FAN-FAN XING … (2011)
              Neutrophil infiltration has been linked to clinical outcome of various cancer types. However, its role in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated prognostic values for intratumoral and peritumoral neutrophils in HCC patients undergoing curative resection. The expression of CD66b, CD8, TGF-beta, and CD34 was assessed by immunohistochemistry in tissue microarrays containing paired intratumoral and peritumoral tissues from 197 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated. Intratumoral CD66b(+) neutrophils significantly correlated with CD8(+) T cells (r=0.240, p=0.004), TGF-beta expression (p=0.012), BCLC stage (p=0.016), and early recurrence (p=0.041). Increased intratumoral neutrophils were significantly associated with decreased RFS/OS (p=0.001 and p<0.001, respectively) in univariate analysis and were identified as an independent prognostic factor (HR=1.845, 95% CI=1.169-2.911, p=0.008 for RFS; HR=2.578, 95% CI=1.618-4.106, p<0.001 for OS) in multivariate analysis. Intratumoral neutrophil-to-CD8(+) T cell ratio (iNTR) better predicted the outcome in terms of minimum p values. Intratumoral neutrophils were also demonstrated to be statistically predictive for RFS/OS in the normal AFP subgroup, small HCC subgroup, and validation cohort. However, peritumoral neutrophils were not associated with the outcome of HCC. The presence of intratumoral neutrophils was a poor prognostic factor for HCC after resection. Intratumoral neutrophil-to-CD8(+) T cell ratio was a better predictor of outcome. Copyright © 2010 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
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                Author and article information

                Contributors
                William B. Coleman: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, USA )
                ISSN (Electronic): 1932-6203
                Publication date Collection: 2014
                Publication date (Electronic): 6 June 2014
                Volume: 9
                Issue: 6
                Electronic Location Identifier: e98259
                Affiliations
                [1 ]Institute of Oncology, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P. R. China
                [2 ]Department of Oncology, Aarhus University Hospital, Aarhus, Denmark
                [3 ]Department of Thoracic Surgery, Provincial Hospital Affiliated to Shandong University, Shandong University, Jinan, P. R. China
                University of North Carolina School of Medicine, United States of America
                Author notes

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

                Conceived and designed the experiments: MS PH QL JD. Performed the experiments: MS PH JD. Analyzed the data: MS PH FD GW QL. Contributed reagents/materials/analysis tools: MS PH FD. Wrote the paper: MS PH FD. Final approval of manuscript: MS PH FD GW QL JD.

                Article
                Publisher ID: PONE-D-14-05474
                DOI: 10.1371/journal.pone.0098259
                PMC ID: 4048155
                PubMed ID: 24906014
                SO-VID: c92c96c6-dce4-497d-9e75-f5d91aebcbbf
                Copyright statement: Copyright @ 2014
                License:

                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
                Date received : 6 February 2014
                Date accepted : 30 April 2014
                Page count
                Pages: 10
                Funding
                The work was supported by Provincial science and technology development plan of Shandong (2012GG0021836), Provincial Natural Science Foundation of Shandong (ZR2013HZ001). FD has received research grant from Health Research Fund of Central Denmark Region and the Danish Cancer Society. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cellular Types
                Subject: Animal Cells
                Subject: Blood Cells
                Subject: White Blood Cells
                Subject: Neutrophils
                Subject: Immune Cells
                Subject: Immunology
                Subject: Medicine and Health Sciences
                Subject: Oncology

                ScienceOpen disciplines: Uncategorized
                Data availability:
                ScienceOpen disciplines: Uncategorized

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