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Thromboembolic disease in patients with high-grade glioma.

ABSTRACT: Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced during the postoperative period with adherence to the use of mechanical and medical thromboprophylaxis. Activation of the coagulation cascade occurs throughout the course of disease because of a variety of complex interactions, including tumor hypoxia, upregulation of VEGR expression, and increases in both tumor cell-specific tissue factor (TF) expression and inducible TF expression in numerous intrinsic regulatory pathways. Long-term anticoagulation to prevent VTE is an attractive therapy; however, the therapeutic window is narrow and current data do not support its routine use. Most patients with proven symptomatic VTE can be safely anticoagulated, including those receiving anti-VEGF therapy, such as bevacizumab. Initial therapy should include low molecular weight heparin (LMWH), and protracted anticoagulant treatment, perhaps indefinitely, is indicated for patients with HGG because of the ongoing risk of thrombosis. A variety of coagulation- and tumor-related proteins, such as TF and circulating microparticles, may serve as potential disease-specific biomarkers in relation to disease recurrence, monitoring of therapy, and as potential therapeutic targets.

SUBMITTER: Perry JR

PROVIDER: S-EPMC3480243 | biostudies-literature | 2012 Sep

REPOSITORIES: biostudies-literature

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Thromboembolic disease in patients with high-grade glioma.

Perry James R JR

Neuro-oncology 20120901

Venous thromboembolism (VTE) is common throughout the course of disease in high-grade glioma (HGG). The interactions between the coagulation cascade, endothelium, and regulation of angiogenesis are complex and drive glioblastoma growth and invasion. We reviewed the incidence of VTE in HGG, the biology of the coagulome as related to glioblastoma progression, prevention and treatment of thrombosis, and the putative role of anticoagulants as anti-cancer therapy. VTE can be significantly reduced dur ...[more]

PMID: 23095833

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Project description:Glioblastoma is a dreadful disease with very poor prognosis, median overall survival being <2 years despite standard-of-care treatment. This has led to the development of alternative strategies, among which immunotherapy is being actively tested. In particular, many clinical trials of therapeutic vaccination using peptides or tumor cells are ongoing. A major issue in implementing therapeutic vaccines in patients with high-grade glioma is that immune responses have to be elicited in the context of immunosuppressive treatments. Indeed, radiotherapy, chemotherapy, and steroids, which are part of the standard of care for patients with glioblastoma, are known to deplete leukocytes. Whether lymphopenia is beneficial or detrimental to elicitation of efficient immune responses is still debated. Here, in order to determine the impact of standard radiochemotherapy on immune cell subsets, we analyzed the phenotype and function of immune populations in 25 patients with high-grade glioma along concomitant radiochemotherapy and adjuvant chemotherapy with temozolomide. Thirteen healthy individuals were studied along the same period. We show that absolute T and B cell counts are reduced upon concomitant radiochemotherapy. Importantly, T cell counts were not restored long-term after discontinuation of treatment. In addition, the percentage of T regulatory cells among CD4 T cells was increased during the same period and was not decreased upon treatment discontinuation. Finally, we show that the ability of T cells to proliferate is transiently reduced after concomitant radiochemotherapy but is restored at the time of adjuvant TMZ cycles. Although not experimentally validated, transient reduction in proliferation associated with strong lymphopenia during radiochemotherapy may suggest that vaccine-induced T cell stimulation would be suboptimal in that period and that therapeutic vaccination should be performed outside radiochemotherapy administration. In addition, strategies aiming at depleting Treg cells should be implemented in future trials.

Project description:Background:Malignant glioma is the second leading cause of cancer-related death worldwide, and is known to exhibit a high degree of heterogeneity in its deregulation of different oncogenic pathways. The molecular subclasses of human glioma are not well known. Thus, it is crucial to identify vital oncogenic pathways in glioma with significant relationships to patient survival. Methods:In this study, we devised a bioinformatics strategy to map patterns of oncogenic pathway activation in glioma, from the Gene Expression Omnibus (GEO). Bioinformatics analysis revealed that 749 genes were differentially expressed and classified into different glioma grades. Results:Using gene expression signatures, we identified three oncogenic pathways (MAPK signaling pathway, Wnt signaling pathway, and ErbB signaling pathway) deregulated in the majority of human glioma. Following gene microarray analysis, the gene expression profile in the differential grade glioma was further validated by bioinformatic analyses, with coexpression network construction. Furthermore, we found that cytochrome c oxidase subunit Vb (COX5B), the terminal enzyme of the electron transport chain, was the central gene in a coexpression network that transfers electrons from reduced cytochrome c to oxygen and, in the process, generates an electrochemical gradient across the mitochondrial inner membrane. The expression level of COX5B was then detected in 87 glioma tissues as well as adjacent normal tissues using immunohistochemistry. We found that COX5B was significantly upregulated in 67 of 87 (77.0%) glioma and glioblastoma tissues, compared with adjacent tissue (p<0.01). Furthermore, statistical analysis showed the COX5B expression level was significantly associated with clinical stage and lymph node status, while there were no correlations between COX5B expression and age or tumor size. Conclusion:These data indicate that COX5B may be implicated in glioma pathogenesis and as a biomarker for identification of the pathological grade of glioma.

Dataset Information

Thromboembolic disease in patients with high-grade glioma.

Publications

Thromboembolic disease in patients with high-grade glioma.

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