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Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glioblastoma is both the most common and most aggressive primary brain tumor. Until recently, the standard of care involved maximal safe surgical resection followed by radiation therapy with or without nitrosourea-based chemotherapy. In 2005, the results of a large clinical trial examining the role of adjuvant chemotherapy in management of newly diagnosed glioblastoma were published. This study created a new standard of adjuvant treatment, using concurrent and sequential temozolomide in the initial therapy of glioblastoma. A companion tumor biology study identified the prognostic role of O(6)-methylguanine-DNA methyltransferase (MGMT) status in patients with newly diagnosed glioblastoma. Several preliminary studies have been initiated to address the issue of resistance and suppression of MGMT activity, and have used alternative temozolomide dosing schedules and O(6)-guanine mimetic agents as substrates for MGMT. In addition, recent studies have attempted to define mechanisms responsible for the apparent synergy between temozolomide and radiotherapy. Lastly, an increased understanding of the molecular biology of glioblastoma has provided new leads for the adjuvant treatment of this disease. This Review summarizes new developments in treatment of glioblastoma and speculates on possible future treatment strategies for managing this aggressive cancer.
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PMID:Mechanisms of disease: temozolomide and glioblastoma--look to the future. 1854 16

Uveal melanoma is associated with a high mortality rate once metastases occur, with over >90% of metastatic patients dying within less than 1 year from metastases to the liver. The intraarterial hepatic (iah) administration of the alkylating agent fotemustine holds some promise with response rates of 36% and median survival of 15 months. Here, we investigated whether the DNA-repair-protein MGMT may be involved in the variability of response to fotemustine and temozolomide in uveal melanoma. Epigenetic inactivation of MGMT has been demonstrated to be a predictive marker for benefit from alkylating agent therapy in glioblastoma. We found a methylated MGMT promoter in 6% of liver metastases from 34 uveal melanoma patients. The mean MGMT activity measured in liver metastases with negligible liver tissue content was significantly lower than in liver tissue (146 versus 523 fmol/mg protein, p = 0.002). Expression of the MGMT protein was detectable in 50% of 88 metastases by immunohistochemistry on a tissue microarray. Expression was heterogeneous, and in accordance with MGMT activity data, usually lower than in the surrounding liver. Differential MGMT activity/expression between metastasis and liver tissue and more efficient depletion of MGMT with higher doses of alkylating agent therapy using iah delivery may provide the pharmacologic window for the higher response rate. However, these results do not support MGMT methylation status or protein expression as predictive markers for treatment outcome to iah chemotherapy with alkylating agents.
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PMID:Infrequent promoter methylation of the MGMT gene in liver metastases from uveal melanoma. 1854 61

Epigenetic silencing of the DNA repair protein O(6)-methylguanine-DNA methyltransferase (MGMT) by promoter methylation predicts successful alkylating agent therapy, such as with temozolomide, in glioblastoma patients. Stratified therapy assignment of patients in prospective clinical trials according to tumor MGMT status requires a standardized diagnostic test, suitable for high-throughput analysis of small amounts of formalin-fixed, paraffin-embedded tumor tissue. A direct, real-time methylation-specific PCR (MSP) assay was developed to determine methylation status of the MGMT gene promoter. Assay specificity was obtained by selective amplification of methylated DNA sequences of sodium bisulfite-modified DNA. The copy number of the methylated MGMT promoter, normalized to the beta-actin gene, provides a quantitative test result. We analyzed 134 clinical glioma samples, comparing the new test with the previously validated nested gel-based MSP assay, which yields a binary readout. A cut-off value for the MGMT methylation status was suggested by fitting a bimodal normal mixture model to the real-time results, supporting the hypothesis that there are two distinct populations within the test samples. Comparison of the tests showed high concordance of the results (82/91 [90%]; Cohen's kappa = 0.80; 95% confidence interval, 0.82-0.95). The direct, real-time MSP assay was highly reproducible (Pearson correlation 0.996) and showed valid test results for 93% (125/134) of samples compared with 75% (94/125) for the nested, gel-based MSP assay. This high-throughput test provides an important pharmacogenomic tool for individualized management of alkylating agent chemotherapy.
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PMID:Validation of real-time methylation-specific PCR to determine O6-methylguanine-DNA methyltransferase gene promoter methylation in glioma. 1855 68

Gliomas are the most frequent tumors of the central nervous system. The WHO classification, based on the presumed cell origin, distinguishes astrocytic, oligodendrocytic and mixed gliomas. A grading system is based on the presence of the following criteria: increased cellular density, nuclear atypias, mitosis, vascular proliferation and necrosis. The main histological subtype of grade I gliomas are pilocytic astrocytomas, which are benign. Diffuse astrocytomas, oligodendrogliomas and oligoastrocytomas are low-grade (II) or high-grade (III and IV) tumors. Glioblastomas correspond to grade IV astrocytomas. C. Daumas-Duport et al. have proposed another classification based on histology and imaging data, which distinguishes oligodendrogliomas and mixed gliomas of grade A (without endothelial proliferation and/or contrast enhancement), oligodendrogliomas and mixed gliomas of grade B (with endothelial proliferation or contrast enhancement), glioblastomas and glioneuronal malignant tumors. Both classifications lack reproducibility. Many studies have searched for a molecular classification. Recurrent abnormalities in gliomas have been found. They encompassed recurrent chromosomal alterations, such as lost of chromosome 10, gain of chromosome 7, deletion of chromosome 1p and 19q, but also activation of the Akt pathway (amplification of EGFR), dysregulation of the cell cycle (deletion of p16, p53). These studies have enabled the description of two molecular subtypes for glioblastomas. De novo glioblastomas, which occur in young patients without of a prior history of brain tumor and harbor frequent amplification of EGFR, deletion of p16 and mutation of PTEN while mutation of p53 is infrequent. Secondary glioblastomas occur in the context of a preexisting low-grade glioma and are characterized by more frequent mutation of p53. On the other side, combined complete deletion of 1p and 19q as the result of the translocation t(1;19)(q10;p10) is highly specific of oligodendrogliomas. However, histological and molecular classifications do not always correspond as many alterations are shared by high-grade tumors, whatever their histological type. Besides, few molecular alterations have a prognostic value. Among them combined 1p19q loss is associated with a better prognosis and response to treatment for oligodendrogliomas. Another promising marker is MGMT, a DNA repairing enzyme. If inactivated (by methylation of the promoter of the gene) a better sensitivity is observed with nitrosoure agents. However, some concerns exist for the method of detection of this abnormality. Quality control for molecular techniques is also required before using them for therapeutic strategy. In the future, studies of gene expression profiles by cDNA-microarray as well as works in the field of neural progenitor cells will probably provide new insights in gliomagenesis.
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PMID:[Histological and molecular classification of gliomas]. 1856 48

A new adjuvant therapy, individual adjuvant therapy (IAT), which is individualized according to the results of real-time reverse-transcription polymerase chain-reaction (RT-PCR) for O6-methylguanine-DNA methyltransferase (MGMT), was used to treat malignant gliomas. Immediately after the operation, mRNA expression for drug-resistance genes was investigated in frozen samples of malignant gliomas from 55 patients (30 glioblastoma multiformes, 20 anaplastic astrocytomas and 5 anaplastic oligodendroglial tumors) by real-time quantitative RT-PCR with specific primers for MGMT. Forty-two patients were treated with 1-(4-amino-2-methyl-5-pyrimidynyl) methyl-3-(2-chloroethyl)-3-nitrosourea hydrochloride (ACNU)-based chemotherapies since the relative quantitation value (RQV) of MGMT in real-time RT-PCR with SYBR-Green I was <1.0 or the absolute value of MGMT mRNA as measured by Taq Man probe methods normalized to the level of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was <6.0x10(3) copies/microg RNA. Thirteen patients, whose tumors had an RQV of >1.0 or who had an absolute value of MGMT of >6.0x10(3) copies/microg RNA, were treated by platinum-based chemotherapy using cisplatin or carboplatin. The response rate was 40.9% for glioblastoma multiformes, 60.0% for anaplastic astrocytomas and 80.0% for anaplastic oligodendroglial tumors. The median survival period of 30 patients with glioblastoma treated by IAT was 21.7 months. The 2-year survival rate of glioblastoma patients treated by IAT was 70.9%. Our IAT, based on the results of real-time RT-PCR, may lead to a beneficial glioma therapy.
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PMID:Individual adjuvant therapy for malignant gliomas based on O6-methylguanine-DNA methyltransferase messenger RNA quantitation by real-time reverse-transcription polymerase chain-reaction. 1857 33

Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas (TCGA) pilot project aims to assess the value of large-scale multi-dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas--the most common type of adult brain cancer--and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.
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PMID:Comprehensive genomic characterization defines human glioblastoma genes and core pathways. 1877 90

The median overall survival and, more importantly, the 2-year survival rate of patients with newly diagnosed glioblastoma are increased by the administration of combined temozolomide and radiotherapy, which has recently become the new standard of treatment in patients with a histological confirmation of diagnosis. Moreover, the assessment of O(6)-methylguanine-DNA methyltransferase gene promoter methylation has clarified the impact of this approach, and improved upon the interpretation of doubtful cases after concurrent radiotherapy/temozolomide treatment. Therefore, future strategies in the treatment of glioblastoma patients will include stratification for MGMT methylation status, and various approaches based on epigenetic features are currently under investigation.
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PMID:Association between response to primary treatments and MGMT status in glioblastoma. 1898 38

Meningiomas are usually cured by surgical resection. However, approximately 10% are characterized by more aggressive clinical behavior and higher risk of recurrence. Typically, recurrent meningiomas require further surgical resection followed, in some cases, by radiotherapy. To date, no chemotherapeutic agent has proven to be effective in either preventing or treating recurrence. The alkylating chemotherapeutic agent, Temozolomide (TMZ) has shown to increase overall survival in patients with glioblastoma (GBM) but its effectiveness for other types of brain tumor is less known. The clinical benefit of TMZ seems to be limited to those GBM tumors with promoter methylation of the MGMT gene. In this study, we assessed if a biologic rationale exists to support the use of TMZ as a treatment for meningiomas by assessing the MGMT promoter methylation status in these tumors using methylation specific PCR. We investigated the MGMT promoter methylation status in 36 tumors (32 newly diagnosed; 4 recurrent). Histologically, the majority were grade I. Patients were primarily female (64%) with a mean age of 52. None of the meningiomas in our series showed MGMT gene promoter methylation. Based on these data, we conclude that there is no biological rational to suggest that TMZ might have significant anti-meningioma activity.
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PMID:Methylation status of MGMT gene promoter in meningiomas. 1899 37

We studied the expression of O(6)-methylguanine-DNA methyltransferase (O(6)-MGMT), P-glycoprotein (Pgp), and multidrug resistance protein-1 (MRP-1) in 23 glioblastomas using RT-PCR, methylation-specific PCR, and immunohistochemistry, and analyzed their association with overall patient survival. Univariate analysis of collected data demonstrated that the expressions of O(6)-MGMT and MRP-1 detected by immunohistochemistry, in addition to the consistent factors, including preoperative Karnofsky performance scale (KPS), radical surgery, and tumor location and extension, were significant prognostic factors for the overall survival (OS) of patients with glioblastoma, who received nimustine (ACNU)-based chemotherapy in association with surgery and radiotherapy. Among them, following multivariate analysis, preoperative KPS, radical surgery, tumor location, and the expression of O(6)-MGMT remained as significant prognostic factors. These findings suggest that immunohistochemical analysis of O(6)-MGMT in patients with glioblastoma can be a useful method to predict the effects of chemotherapy and identify alternative chemotherapeutic regimens for O(6)-MGMT-positive patients.
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PMID:Prognostic significance of the immunohistochemical expression of O6-methylguanine-DNA methyltransferase, P-glycoprotein, and multidrug resistance protein-1 in glioblastomas. 1901 75

Liver-type glutaminase (LGA) is a glutaminase isoform that has been implicated in transcription modulation. LGA mRNA is absent from postoperative samples of primary gliomas and is low in cultured astrocytes. In this study, stable transfection of T98G cells with a vector carrying human LGA sequence increased the expression of LGA mRNA and protein, and the ability of the cells to degrade glutamine (Gln), as manifested by a three-fold reduction of their steady-state Gln content and a 2.5-fold increase of their glutamate (Glu) content. The transfected cells (TLGA cells) showed a 40% decrease of cell survival as assessed by colony formation, well correlated with significant reduction of mitochondrial activity as demonstrated with MTT test. Also, a 45% reduction of cell migration and a 47% decrease of proliferation index (Ki67 immunostaining) were found as compared with sham-transfected cells. Microarray analysis, which included over 47,000 transcripts, revealed a significantly altered expression of 85 genes in TLGA, but not in sham-transfected or control cells (P < 0.005). Microarray data were confirmed with real-time PCR analysis for eight genes potentially relevant to malignancy: S100A16, CAPN2, FNDC3B, DYNC1LI1, TIMP4, MGMT, ADM, and TIMP1. Of these changes, decreased expression of S100A16 and MGMT can be best reconciled with the current views on the role of their protein products in glioma malignancy. Malignancy-reducing effect of newly inserted LGA mRNA in glioblastoma cells can be reconciled with a hypothesis that absence of such a modulatory mechanism in glia-derived tumors deprived of LGA mRNA may facilitate some aspects of their progression.
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PMID:Transfection with liver-type glutaminase cDNA alters gene expression and reduces survival, migration and proliferation of T98G glioma cells. 1906 76


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