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      Tumour necrosis factor-alpha expression in tumour islets confers a survival advantage in non-small cell lung cancer

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          Abstract

          Background

          The role of TNFα in cancer is complex with both pro-tumourigenic and anti-tumourigenic roles proposed. We hypothesised that anatomical microlocalisation is critical for its function.

          Methods

          This study used immunohistochemistry to investigate the expression of TNFα in the tumour islets and stroma with respect to survival in 133 patients with surgically resected NSCLC.

          Results

          TNFα expression was increased in the tumour islets of patients with above median survival (AMS) compared to those with below median survival (BMS)(p = 0.006), but similar in the stroma of both groups. Increasing tumour islet TNFα density was a favorable independent prognostic indicator (p = 0.048) while stromal TNFα density was an independent predictor of reduced survival (p = 0.007). Patients with high TNFα expression (upper tertile) had a significantly higher 5-year survival compared to patients in the lower tertile (43% versus 22%, p = 0.01). In patients with AMS, 100% of TNFα + cells were macrophages and mast cells, compared to only 28% in the islets and 50% in the stroma of BMS patients (p < 0.001).

          Conclusions

          The expression of TNFα in the tumour islets of patients with NSCLC is associated with improved survival suggesting a role in the host anti-tumour immunological response. The expression of TNFα by macrophages and mast cells is critical for this relationship.

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          Most cited references19

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          Revisions in the International System for Staging Lung Cancer.

          Revisions in stage grouping of the TNM subsets (T=primary tumor, N=regional lymph nodes, M=distant metastasis) in the International System for Staging Lung Cancer have been adopted by the American Joint Committee on Cancer and the Union Internationale Contre le Cancer. These revisions were made to provide greater specificity for identifying patient groups with similar prognoses and treatment options with the least disruption of the present classification: T1N0M0, stage IA; T2N0M0, stage IB; T1N1M0, stage IIA; T2N1M0 and T3N0M0, stage IIB; and T3N1M0, T1N2M0, T2N2M0, T3N2M0, stage IIIA. The TNM subsets in stage IIIB-T4 any N M0, any T N3M0, and in stage IV-any T any N M1, remain the same. Analysis of a collected database representing all clinical, surgical-pathologic, and follow-up information for 5,319 patients treated for primary lung cancer confirmed the validity of the TNM and stage grouping classification schema.
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            Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial.

            Tumor necrosis factor (TNF) is an important proinflammatory cytokine that mediates inflammatory synovitis and articular matrix degradation in rheumatoid arthritis (RA). We investigated the ability of adalimumab, a human anti-TNF monoclonal antibody, to inhibit the progression of structural joint damage, reduce the signs and symptoms, and improve physical function in patients with active RA receiving concomitant treatment with methotrexate (MTX). In this multicenter, 52-week, double-blind, placebo-controlled study, 619 patients with active RA who had an inadequate response to MTX were randomized to receive adalimumab 40 mg subcutaneously every other week (n = 207), adalimumab 20 mg subcutaneously every week (n = 212), or placebo (n = 200) plus concomitant MTX. The primary efficacy end points were radiographic progression at week 52 (total Sharp score by a modified method [TSS]), clinical response at week 24 (improvements of at least 20% in the American College of Rheumatology core criteria [ACR20]), and physical function at week 52 (disability index of the Health Assessment Questionnaire [HAQ]). At week 52, there was statistically significantly less radiographic progression, as measured by the change in TSS, in the patients receiving adalimumab either 40 mg every other week (mean +/- SD change 0.1 +/- 4.8) or 20 mg weekly (0.8 +/- 4.9) as compared with that in the placebo group (2.7 +/- 6.8) (P < or = 0.001 for each comparison). In addition, there were statistically significant changes in the components of the TSS. At week 24, ACR20 responses were achieved by 63% and 61% of patients in the adalimumab 40 mg every other week and 20 mg weekly groups, respectively, versus 30% of patients in the placebo group (P < or = 0.001 for each comparison). At week 52, ACR20 responses were achieved by 59% and 55% of patients taking adalimumab 40 mg every other week and 20 mg weekly, respectively, versus 24% of patients taking placebo (P < or = 0.001 for each comparison). At week 52, physical function as measured by the HAQ demonstrated statistically significant improvement with adalimumab 40 mg every other week and 20 mg weekly compared with placebo (mean change in HAQ score -0.59 and -0.61, respectively, versus -0.25; P < or = 0.001 for each comparison). A total of 467 patients (75.4%) completed 52 weeks of treatment. Adalimumab was generally well tolerated. Discontinuations occurred in 22.0% of adalimumab-treated patients and in 30.0% of placebo-treated patients. The rate of adverse events (both serious and nonserious) was comparable in the adalimumab and placebo groups, although the proportion of patients reporting serious infections was higher in patients receiving adalimumab (3.8%) than in those receiving placebo (0.5%) (P < or = 0.02), and was highest in the patients receiving 40 mg every other week. In this 52-week trial, adalimumab was more effective than placebo at inhibiting the progression of structural joint damage, reducing the signs and symptoms, and improving physical function in patients with active RA who had demonstrated an incomplete response to MTX.
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              Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer.

              The role played by the innate immune system in determining survival from non-small-cell lung cancer (NSCLC) is unclear. The aim of this study was to investigate the prognostic significance of macrophage and mast-cell infiltration in NSCLC. We used immunohistochemistry to identify tryptase+ mast cells and CD68+ macrophages in the tumor stroma and tumor islets in 175 patients with surgically resected NSCLC. 5-year survival was 52.9% in patients with an islet macrophage density greater than the median versus 7.7% when less than the median (P < .0001). In the same groups, respectively, median survival was 2,244 versus 334 days (P < .0001). Patients with a high islet macrophage density but incomplete resection survived markedly longer than patients with a low islet macrophage density but complete resection. The tumor islet CD68+ macrophage density is a powerful independent predictor of survival from surgically resected NSCLC. The biologic explanation for this and its implications for the use of adjunctive treatment requires further study.
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                Author and article information

                Journal
                BMC Cancer
                BMC Cancer
                BioMed Central
                1471-2407
                2010
                23 June 2010
                : 10
                : 323
                Affiliations
                [1 ]Institute for Lung Health, Glenfield Hospital, Leicester, UK
                [2 ]Department of Infection, Immunity and Inflammation, University of Leicester, UK
                [3 ]Department of Thoracic Surgery, Glenfield Hospital, Leicester, UK
                Article
                1471-2407-10-323
                10.1186/1471-2407-10-323
                2909205
                20573209
                b196f7e2-0898-4226-91c8-cbd267d2569a
                Copyright ©2010 Ohri et al; licensee BioMed Central Ltd.

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 January 2010
                : 23 June 2010
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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