Gliomas: Current Concepts in Biology, Diagnosis and Therapy (Recent Results in Cancer Research)

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The objective of this ESMO-led study is to provide health authorities with data on the availability of licensed anti-neoplastic medicines. ESMO seeks to eradicate cancer at its earliest stages through effective cancer prevention awareness and advocacy campaigns. Rare Cancers Europe is a multi-stakeholder initiative dedicated to putting rare cancers firmly on the European policy agenda. Published in Ann Oncol 25 suppl 3 : iiiiii Stupp, M. Brada, M. Tonn, G. This update covers recommendations for glioblastoma; anaplastic astrocytoma, oligoastrocytoma and oligodendroglioma; and diffuse glioma.

The recommendations cover clinically relevant problems in: diagnosis and pathology, molecular markers, staging and risk assessment, treatment of newly diagnosed patients, treatment of patients with recurrent disease, personalised medicine, response evaluation plus follow-up and long-term implications. Careers at ESMO. ESMO Oncology Journals Our journals offer ESMO members and the oncology community a globally visible platform to publish scientific studies, and a highly credible source of educational updates.

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A recent report has suggested that glioma patients at the Karolinska University Hospital receiving 6 months of antiviral therapy as an add-on to standard radiation and temozolamide therapy exhibited marked increases in survival rates 95 , though the study design and mathematics used have been questioned 23 , Some other studies, but not all, have also shown improved outcomes in cancer patients on antiviral therapy 32 , These data may imply that the oncogenic effects of EBV—at least in B-cell lymphomas—are not affected by antiretroviral drugs.

For example, Zakaria et al. A corollary of this is the idea that stress resulting from co-infections may also be important in viral reactivation and oncogenesis. Although the low levels of EBV infections reported in gliomas, by themselves may not be sufficient, they likely require additional stress-causing risk factors, such as the co-presence of other oncoviruses, to influence oncogenesis or oncomodulation.

Tumor biology and cancer therapy – an evolving relationship

Vaccines against specific viruses may, therefore, offer a more targeted approach for association studies and clinical therapy [for review see Cohen ]. For example, an EBV vaccine has been tested in a phase I clinical trial on Chinese nasopharyngeal carcinoma patients to determine the safe and immunogenic dose In that study, it was concluded that the vaccine is both safe and immunogenic, thus paving the way for further clinical testing of the EBV vaccine that may be of clinical benefit in EBV-positive tumors including glioma patients.

The first prophylactic EBV vaccine based on virus-like particles VLPs that mimic the structure of the EBV virus, but lack its genome has also been reported to be effective in preclinical models and may represent a safer alternative. Finally, could it be that by looking for EBV and other herpes viruses like CMV, in gliomas we might have been focusing on the wrong viruses? Recent NGS sequencing data seems to suggest that most of the viruses especially CMV are completely absent from gliomas and many of the positive associations reported are likely artifactual as they may be rationally explained otherwise [e.

The reported low level presence of EBV does not completely rule it out from being associated with oncogenesis or oncomodulation in gliomas [indeed, it may not even need to be present to exert its effects as suggested by the study of Shumilov et al. Understanding the role of EBV and other oncoviruses in the etiology of gliomas, that generally have a poor prognosis, would likely open up new avenues for the treatment and management of these, often fatal, CNS tumors.

SA and A-EM conceived the review. SA and SV searched the literature. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Brain tumors. Am J Med Cancer statistics, CA Cancer J Clin — The pathobiology of glioma tumors.

Annu Rev Pathol — Wen PY, Kesari S. Malignant gliomas in adults. N Engl J Med — Maintenance therapy with tumor-treating fields plus temozolomide vs temozolomide alone for glioblastoma: a randomized clinical trial.

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JAMA — Neuro Oncol — Glioblastoma multiforme: a review of its epidemiology and pathogenesis through clinical presentation and treatment. Asian Pac J Cancer Prev —9. Cell-based immunotherapy against gliomas: from bench to bedside. Mol Ther — Diamandis P, Aldape KD. Insights from molecular profiling of adult glioma. J Clin Oncol — Bush NA, Butowski N. The effect of molecular diagnostics on the treatment of glioma.


Curr Oncol Rep Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol — Glioblastoma targeted therapy: updated approaches from recent biological insights. Ann Oncol — Lieberman F.

Glioblastoma update: molecular biology, diagnosis, treatment, response assessment, and translational clinical trials. FRes Isocitrate dehydrogenase mutations in gliomas. Reitman ZJ, Yan H. Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism.

J Natl Cancer Inst — Glioblastoma: pathology, molecular mechanisms and markers. Acta Neuropathol — Genomic alterations of ERBB receptors in cancer: clinical implications. Oncotarget — The somatic genomic landscape of glioblastoma. Cell — Epidermal growth factor receptor in glioblastoma.

Oncol Lett —6. Front Oncol Dullea A, Marignol L. MGMT testing allows for personalised therapy in the temozolomide era.

Glioblastoma - an Osmosis Knowledge shot.

Tumour Biol — MGMT testing — the challenges for biomarker-based glioma treatment. Nat Rev Neurol — MGMT gene silencing and benefit from temozolomide in glioblastoma. Therapeutic targeting of replicative immortality. Semin Cancer Biol 35 Suppl :S— Current state and future prospects of immunotherapy for glioma. Immunotherapy — The role of microglia and macrophages in CNS homeostasis, autoimmunity, and cancer. J Immunol Res MicroRNAs as biomarkers for human glioblastoma: progress and potential. Acta Pharmacol Sin Viral carcinogenesis beyond malignant transformation: EBV in the progression of human cancers.

Trends Microbiol — The roles of viruses in brain tumor initiation and oncomodulation. J Neurooncol — Viruses and human cancers: a long road of discovery of molecular paradigms. Clin Microbiol Rev — Role of infectious agents in the carcinogenesis of brain and head and neck cancers. Infect Agent Cancer The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia —9. Prevalence of neurotropic viruses in malignant glioma and their onco-modulatory potential.

In Vivo —9. A comprehensive next generation sequencing-based virome assessment in brain tissue suggests no major virus-tumor association. Acta Neuropathol Commun Activation of telomerase by human cytomegalovirus. Soderberg-Naucler C. HCMV microinfections in inflammatory diseases and cancer. J Clin Virol — Human cytomegalovirus infection and expression in human malignant glioma.

Cancer Res — PubMed Abstract Google Scholar. Sensitive detection of human cytomegalovirus in tumors and peri-pheral blood of patients diagnosed with glioblastoma. Neuro Oncol —8. Detection of human cytomegalovirus in different histological types of gliomas. Human herpesvirus multiplex ddPCR detection in brain tissue from low- and high-grade astrocytoma cases and controls. Lancet —3. Epstein-Barr virus infection and human malignancies. Int J Exp Pathol — Viral oncology: molecular biology and pathogenesis.

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J Clin Med 6 Progress and problems in understanding and managing primary Epstein-Barr virus infections. The interaction between human papillomavirus and other viruses. Virus Res — Crit Rev Oncol Hematol — Epstein-Barr virus: 40 years on. Nat Rev Cancer — Murata T, Tsurumi T.

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  4. Switching of EBV cycles between latent and lytic states. Rev Med Virol — Several other promising tumor vaccine strategies are also being used in clinical trials. Dendritic cells are professional antigen-presenting cells that can be primed with tumor antigen ex vivo 30 and then readministered to the patient, where they mediate T-cell activation. Numerous preclinical studies demonstrate that dendritic cells pulsed with glioma antigens can prime a cytotoxic lymphocyte response that is tumor specific; phase 1 and 2 clinical trials have been completed using dendritic cell strategies, with encouraging results.

    Antibody-mediated drug delivery is a strategy designed with the dual purpose of increasing the local drug concentration while minimizing nonspecific systemic exposure. Monoclonal antibodies targeting glioma-specific structures have been coupled to radionuclides radioimmunoconjugates , exotoxins immunotoxins , or chemotherapeutic agents and are administrated locally. Antigens that are overexpressed in tumors relative to normal tissue are typically used, such as mutant EGFR, tenascin, and interleukin 4 or interleukin 13 receptors.

    Gene therapy is based on the insertion or modification of genes into a cell to treat a disease. Gene delivery can be accomplished using a variety of vectors, from viruses to cell-based systems to synthetic vectors. In gliomas, viral vectors have been used to deliver suicide genes, proapoptotic genes, p53, cytokines, and caspases. Synthetic vector research has focused on the use of nanoparticles.

    Liposomal vectors, for example, have been used to deliver therapeutic genes in the preclinical setting. A variety of other novel therapeutic approaches are also currently being researched, including the use of alternating electrical fields to disrupt cell division via a device called NovoTTFA NovoCure Ltd, Haifa, Israel , 34 currently in phase 3 trials, and the use of thermal lasers to denature tumor tissue. In conclusion, the survival of patients with GBM continues to improve, albeit more slowly than we would like. A wide variety of new techniques and agents are currently under study, alone and in combination.

    Increased collective experience in their use and improved understanding of the complex biology of GBM may allow for more rational and effective therapy selection for patients, further extending survival in the years to come. Drafting of the manuscript : Clarke and Butowski. Critical revision of the manuscript for important intellectual content : Clarke, Butowski, and Chang.

    Administrative, technical, and material support : Clarke and Butowski. Study supervision : Butowski and Chang. Additional Contributions: Ilona Garner, BS, provided editorial assistance in the preparation of this manuscript. All Rights Reserved. View Large Download. Accessed October 1, MGMT gene silencing and benefit from temozolomide in glioblastoma. Intensity-modulated radiotherapy in high-grade gliomas: clinical and dosimetric results.

    Randomized phase II trial of chemoradiotherapy followed by either dose-dense or metronomic temozolomide for newly diagnosed glioblastoma. Phase II trial of temozolomide plus O 6 -benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma.

    Phase II study of erlotinib plus temozolomide during and after radiation therapy in patients with newly diagnosed glioblastoma multiforme or gliosarcoma. Molecular determinants of the response of glioblastomas to EGFR kinase inhibitors. Phase II study of imatinib mesylate plus hydroxyurea in adults with recurrent glioblastoma multiforme [published correction appears in J Clin Oncol. Phase II trial of tipifarnib in patients with recurrent malignant glioma either receiving or not receiving enzyme-inducing antiepileptic drugs: a North American Brain Tumor Consortium Study.

    Gliadel BCNU wafer plus concomitant temozolomide therapy after primary resection of glioblastoma multiforme. Long-term treatment of malignant gliomas with intramuscularly administered polyinosinic-polycytidylic acid stabilized with polylysine and carboxymethylcellulose: an open pilot study. Alternating electric fields arrest cell proliferation in animal tumor models and human brain tumors. Save Preferences. Privacy Policy Terms of Use. This Issue. Citations View Metrics.

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