BACKGROUND: In 2004, a randomised phase III trial by the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) reported improved median and 2-year survival for patients with glioblastoma treated with concomitant and adjuvant temozolomide and radiotherapy. We report the final results with a median follow-up of more than 5 years. METHODS: Adult patients with newly diagnosed glioblastoma were randomly assigned to receive either standard radiotherapy or identical radiotherapy with concomitant temozolomide followed by up to six cycles of adjuvant temozolomide. The methylation status of the methyl-guanine methyl transferase gene, MGMT, was determined retrospectively from the tumour tissue of 206 patients. The primary endpoint was overall survival. Analyses were by intention to treat. This trial is registered with Clinicaltrials.gov, number NCT00006353. FINDINGS: Between Aug 17, 2000, and March 22, 2002, 573 patients were assigned to treatment. 278 (97%) of 286 patients in the radiotherapy alone group and 254 (89%) of 287 in the combined-treatment group died during 5 years of follow-up. Overall survival was 27.2% (95% CI 22.2-32.5) at 2 years, 16.0% (12.0-20.6) at 3 years, 12.1% (8.5-16.4) at 4 years, and 9.8% (6.4-14.0) at 5 years with temozolomide, versus 10.9% (7.6-14.8), 4.4% (2.4-7.2), 3.0% (1.4-5.7), and 1.9% (0.6-4.4) with radiotherapy alone (hazard ratio 0.6, 95% CI 0.5-0.7; p<0.0001). A benefit of combined therapy was recorded in all clinical prognostic subgroups, including patients aged 60-70 years. Methylation of the MGMT promoter was the strongest predictor for outcome and benefit from temozolomide chemotherapy. INTERPRETATION: Benefits of adjuvant temozolomide with radiotherapy lasted throughout 5 years of follow-up. A few patients in favourable prognostic categories survive longer than 5 years. MGMT methylation status identifies patients most likely to benefit from the addition of temozolomide. FUNDING: EORTC, NCIC, Nelia and Amadeo Barletta Foundation, Schering-Plough.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(09)70025-7.pdf

Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial

background Epigenetic silencing of the MGMT (O 6 -methylguanine–DNA methyltransferase) DNArepair gene by promoter methylation compromises DNA repair and has been associated with longer survival in patients with glioblastoma who receive alkylating agents. methods We tested the relationship between MGMT silencing in the tumor and the survival of patients who were enrolled in a randomized trial comparing radiotherapy alone with radiotherapy combined with concomitant and adjuvant treatment with temozolomide. The methylation status of the MGMT promoter was determined by methylation-specific polymerase-chain-reaction analysis. results The MGMT promoter was methylated in 45 percent of 206 assessable cases. Irrespective of treatment, MGMT promoter methylation was an independent favorable prognostic factor (P<0.001 by the log-rank test; hazard ratio, 0.45; 95 percent confidence interval, 0.32 to 0.61). Among patients whose tumor contained a methylated MGMT promoter, a survival benefit was observed in patients treated with temozolomide and radiotherapy; their median survival was 21.7 months (95 percent confidence interval, 17.4 to 30.4), as compared with 15.3 months (95 percent confidence interval, 13.0 to 20.9) among those who were assigned to only radiotherapy (P=0.007 by the log-rank test). In the absence of methylation of the MGMT promoter, there was a smaller and statistically insignificant difference in survival between the treatment groups. conclusions Patients with glioblastoma containing a methylated MGMT promoter benefited from temozolomide, whereas those who did not have a methylated MGMT promoter did not have such a benefit.

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MGMT Gene Silencing and Benefit from Temozolomide in Glioblastoma

Glioblastoma multiforme (GBM) is the most common and lethal type of brain cancer. To identify the genetic alterations in GBMs, we sequenced 20,661 protein coding genes, determined the presence of amplifications and deletions using high-density oligonucleotide arrays, and performed gene expression analyses using next-generation sequencing technologies in 22 human tumor samples. This comprehensive analysis led to the discovery of a variety of genes that were not known to be altered in GBMs. Most notably, we found recurrent mutations in the active site of isocitrate dehydrogenase 1 (IDH1) in 12% of GBM patients. Mutations in IDH1 occurred in a large fraction of young patients and in most patients with secondary GBMs and were associated with an increase in overall survival. These studies demonstrate the value of unbiased genomic analyses in the characterization of human brain cancer and identify a potentially useful genetic alteration for the classification and targeted therapy of GBMs.

http://science.sciencemag.org/content/sci/321/5897/1807.full.pdf

An Integrated Genomic Analysis of Human Glioblastoma Multiforme

Background A recent genomewide mutational analysis of glioblastomas (World Health Organization [WHO] grade IV glioma) revealed somatic mutations of the isocitrate dehydrogenase 1 gene (IDH1) in a fraction of such tumors, most frequently in tumors that were known to have evolved from lower-grade gliomas (secondary glioblastomas). Methods We determined the sequence of the IDH1 gene and the related IDH2 gene in 445 central nervous system (CNS) tumors and 494 non-CNS tumors. The enzymatic activity of the proteins that were produced from normal and mutant IDH1 and IDH2 genes was determined in cultured glioma cells that were transfected with these genes. Results We identified mutations that affected amino acid 132 of IDH1 in more than 70% of WHO grade II and III astrocytomas and oligodendrogliomas and in glioblastomas that developed from these lower-grade lesions. Tumors without mutations in IDH1 often had mutations affecting the analogous amino acid (R172) of the IDH2 gene. Tumors with IDH1 or IDH2 mutations h...

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IDH1 and IDH2 Mutations in Gliomas

Glioblastoma tumour cells release microvesicles (exosomes) containing mRNA, miRNA and angiogenic proteins. These microvesicles are taken up by normal host cells, such as brain microvascular endothelial cells. By incorporating an mRNA for a reporter protein into these microvesicles, we demonstrate that messages delivered by microvesicles are translated by recipient cells. These microvesicles are also enriched in angiogenic proteins and stimulate tubule formation by endothelial cells. Tumour-derived microvesicles therefore serve as a means of delivering genetic information and proteins to recipient cells in the tumour environment. Glioblastoma microvesicles also stimulated proliferation of a human glioma cell line, indicating a self-promoting aspect. Messenger RNA mutant/variants and miRNAs characteristic of gliomas could be detected in serum microvesicles of glioblastoma patients. The tumour-specific EGFRvIII was detected in serum microvesicles from 7 out of 25 glioblastoma patients. Thus, tumour-derived microvesicles may provide diagnostic information and aid in therapeutic decisions for cancer patients through a blood test.

https://www.ym.edu.tw/bps/paper/0317Glioblastoma.pdf

Glioblastoma microvesicles transport RNA and proteins that promote tumour growth and provide diagnostic biomarkers

In recent years, the time honored concept that the adult mammalian central nervous system is incapable of regeneration has been seriously challenged. Much of this work has been directed towards studying the regenerative capability of neurons and axons, and there has been some evidence to show that even mature neurons may be capable of cell division (1). The regeneration of neuroglia and their products, specifically myelin, has also been the subject of renewed interest. Central nervous system remyelination has always been contrasted with the situation in the peripheral nervous system where remyelination rapidly follows both Wallerian and primary demyelination, and where the remyelination is preceeded by a brisk proliferation of Schwann cells. At a clinical level the potential importance of remyelination is great, not only in the primary demyelinating diseases such as multiple sclerosis, but also in other destructive diseases where any future advances in stimulating a neuronal regeneration will have to be accompanied by remyelination. These problems of central nervous system remyelination and oligodendroglial proliferation are intimately associated. In the peripheral nervous system Schwann cell proliferation is an important aspect of remyelination. These problems of central nervous system remyelination and oligodendroglial proliferation are intimately associated. In the peripheral nervous system Schwann cell proliferation is an important aspect of remyelination. Common dogma has accepted that mature postmyelinated oligodendrocytes are incapable of division although it is well established that proliferation occurs not only in differentiated astrocytes (2) and microglia (3, 4, 5) but in certain mammals in the undifferentiated cells of the subependymal plate (6). This failure of oligodendrocyte proliferation has been cited as one of the reasons accounting for the limited remyelinative capacity of the central nervous system.

Oligodendrocyte Proliferation: Its Relationship to Central Nervous System Remyelination

/pdf/autobiography-series-in-search-of-knowledge-and-joy-my-life-25u8nnh537.pdf

Autobiography Series: In Search of Knowledge and Joy: My Life as a Neuropathologist

The oligodendrocyte is a cell of great complexity, manufacturing a large quantity of lipids and proteins. It supports myelin sheaths many times larger than its own cell body, and contains a sophisticated cytoskeletal transport mechanism for the delivery of these constituents to distant sites. These hnctions show many analogies to those occurring in the neuron, and as in the neuron, the metabolic and transport demands on the cell render it susceptible to damage and dysfunction.

The reactions of the oligodendrocyte

Plenas et al. are to be congratulated on the application of cutting edge cell and molecular biologic techniques to address central issues regarding the immune-pathogenesis multiple sclerosis (MS) of lesions.1 This was a demanding study with regard to acquisition of patient material, experimental design, quality and quantity of labor involved, and cost. As emphasized in this report, a challenge in MS is to define the immunologic events ongoing in actual lesions and then determine whether and how these may be reflected or monitored by analysis of more readily available tissue samples such as cerebrospinal fluid (CSF) or blood. The authors specifically address the concept of there being distinct phenotypes of early lesions among MS patients, categorized as patterns 1–4.2 Pattern 2 lesions have been described to feature immunoglobulin (Ig) and complement deposition in addition to inflammatory cell infiltration and myelin destruction and were the most frequent lesion pattern observed in the initial combined biopsy and autopsy sample. Data supporting the distinct features of pattern 2 lesions include therapeutic responses to plasma exchange therapy3 and potentially presence of unique serum autoantibody signatures.4 The authors acknowledge the controversy that exists regarding this concept, providing rationale for generating more direct evidence as in this study.

Samuel K. Ludwin

Papers

Oligodendrocyte Proliferation: Its Relationship to Central Nervous System Remyelination

Autobiography Series: In Search of Knowledge and Joy: My Life as a Neuropathologist

The reactions of the oligodendrocyte

Sequencing the immunopathologic heterogeneity in multiple sclerosis.

How international is the International Society of Neuropathology