The Experts below are selected from a list of 2898 Experts worldwide ranked by ideXlab platform
Nicolas De Tribolet - One of the best experts on this subject based on the ideXlab platform.
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clinical trial substantiates the predictive value of o 6 methylguanine dna Methyltransferase promoter methylation in glioblastoma patients treated with temozolomide
Clinical Cancer Research, 2004Co-Authors: Monika E Hegi, Annie Claire Diserens, Sophie Godard, Philippe Otten, Guy Van Melle, Luca Regli, Pierre-yves Dietrich, Nicolas De Tribolet, Sandrine OstermannAbstract:Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-Methylguanine-DNA Methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.
Monika E Hegi - One of the best experts on this subject based on the ideXlab platform.
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Expression of O 6 -methylguanine-DNA Methyltransferase in childhood medulloblastoma Denis FaoroAndreO. von BuerenTarek ShalabyDavide Sciuscio • Marie-Louise HurlimannLucia ArnoldNicolas U. GerberJohannes Haybaeck • Michel MittelbronnStefan RutkowskiM
2020Co-Authors: D. Faoro, Monika E Hegi, Tarek Shalaby, Lucia Arnold, Nicolas U. Gerber, Michael A. Grotzer, A. O. Von Bueren, Stefan Rutkowski, Johannes Haybaeck, Michel MittelbronnAbstract:Medulloblastomas (MB) are the most common malignant brain tumors in childhood. Alkylator-based drugs are effective agents in the treatment of patients with MB. In several tumors, including malignant glioma, elevated O 6 -methylguanine-DNA Methyltransferase (MGMT) expres- sion levels or lack of MGMT promoter methylation have been found to be associated with resistance to alkylating chemotherapeutic agents such as temozolomide (TMZ). In this study, we examined the MGMT status of MB and central nervous system primitive neuroectodermal tumor (PNET) cells and two large sets of primary MB. In seven MB/PNET cell lines investigated, MGMT promoter methylation was detected only in D425 human MB cells as assayed by the qualitative methylation-specific PCR and the more quantitative pyrosequencing assay. In D425 human MB cells, MGMT mRNA and protein expression was clearly lower when compared with the MGMT expression in the other MB/PNET cell lines. In MB/PNET cells, sen- sitivity towards TMZ and 1-(2-chloroethyl)-3-cyclohexyl- 1-nitrosourea (CCNU) correlated with MGMT methylation and MGMT mRNA expression. Pyrosequencing in 67 pri- mary MB samples revealed a mean percentage of MGMT methylation of 3.7-92% (mean: 13.25%, median: 10.67%). Percentage of MGMT methylation and MGMT mRNA expression as determined by quantitative RT-PCR corre- lated inversely (n = 46; Pearson correlation r 2 = 0.14, P = 0.01). We then analyzed MGMT mRNA expression in a second set of 47 formalin-fixed paraffin-embedded pri- mary MB samples from clinically well-documented patients treated within the prospective randomized multicenter trial HIT'91. No association was found between MGMT mRNA expression and progression-free or overall survival. There- fore, it is not currently recommended to use MGMT mRNA expression analysis to determine who should receive alkylating agents and who should not.
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dose dense temozolomide for newly diagnosed glioblastoma a randomized phase iii clinical trial
Journal of Clinical Oncology, 2013Co-Authors: Mark R Gilbert, Monika E Hegi, Meihua Wang, Kenneth D Aldape, Roger Stupp, Kurt A Jaeckle, Terri S Armstrong, Jeffrey Scott Wefel, Minhee WonAbstract:Purpose Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O 6 -methylguanine-DNA Methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM. Patients and Methods This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
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clinical trial substantiates the predictive value of o 6 methylguanine dna Methyltransferase promoter methylation in glioblastoma patients treated with temozolomide
Clinical Cancer Research, 2004Co-Authors: Monika E Hegi, Annie Claire Diserens, Sophie Godard, Philippe Otten, Guy Van Melle, Luca Regli, Pierre-yves Dietrich, Nicolas De Tribolet, Sandrine OstermannAbstract:Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-Methylguanine-DNA Methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.
James G Herman - One of the best experts on this subject based on the ideXlab platform.
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Generating mutations but providing chemosensitivity: the role of O^6-methylguanine DNA Methyltransferase in human cancer
Oncogene, 2004Co-Authors: Manel Esteller, James G HermanAbstract:O^6-methylguanine DNA Methyltransferase (MGMT) is a key enzyme in the DNA repair network. MGMT removes mutagenic and cytotoxic adducts from O^6-guanine in DNA, the preferred point of attack of many carcinogens (i.e. methylnitrosourea) and alkylating chemotherapeutic agents (i.e. BCNU, temozolamide, etc.). Hypermethylation of the CpG island located in the promoter region of MGMT is primarily responsible for the loss of MGMT function in many tumor types. The methylation-mediated silencing of MGMT has two consequences for cancer. First, tumors with MGMT methylation have a new mutator phenotype characterized by the generation of transition point mutations in genes involved in cancer etiology, such as the tumor suppressor p53 and the oncogene K-ras. Second, MGMT hypermethylation demonstrates the possibility of pharmacoepigenomics: methylated tumors are more sensitive to the killing effects of alkylating drugs used in chemotherapy. These recent results underscore the importance of MGMT in basic and translational cancer research.
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inactivation of the dna repair gene mgmt and the clinical response of gliomas to alkylating agents
The New England Journal of Medicine, 2000Co-Authors: Manel Esteller, J Garciafoncillas, Esther Andion, Steven N Goodman, Oscar F Hidalgo, V Vanaclocha, Stephen B Baylin, James G HermanAbstract:Background The DNA-repair enzyme O 6-methylguanine-DNA Methyltransferase (MGMT) inhibits the killing of tumor cells by alkylating agents. MGMT activity is controlled by a promoter; methylation of t...
Annie Claire Diserens - One of the best experts on this subject based on the ideXlab platform.
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MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, a
Acta Neuropathologica, 2012Co-Authors: Pierre Bady, Davide Sciuscio, Jocelyne Bloch, Martin J. Den Bent, Christine Marosi, Annie Claire Diserens, Luigi Mariani, Pierre-yves Dietrich, Michael Weller, Frank L. HeppnerAbstract:The methylation status of the O^6-methylguanine-DNA Methyltransferase ( MGMT ) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM - 450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p
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clinical trial substantiates the predictive value of o 6 methylguanine dna Methyltransferase promoter methylation in glioblastoma patients treated with temozolomide
Clinical Cancer Research, 2004Co-Authors: Monika E Hegi, Annie Claire Diserens, Sophie Godard, Philippe Otten, Guy Van Melle, Luca Regli, Pierre-yves Dietrich, Nicolas De Tribolet, Sandrine OstermannAbstract:Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-Methylguanine-DNA Methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.
Pierre-yves Dietrich - One of the best experts on this subject based on the ideXlab platform.
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MGMT methylation analysis of glioblastoma on the Infinium methylation BeadChip identifies two distinct CpG regions associated with gene silencing and outcome, yielding a prediction model for comparisons across datasets, tumor grades, a
Acta Neuropathologica, 2012Co-Authors: Pierre Bady, Davide Sciuscio, Jocelyne Bloch, Martin J. Den Bent, Christine Marosi, Annie Claire Diserens, Luigi Mariani, Pierre-yves Dietrich, Michael Weller, Frank L. HeppnerAbstract:The methylation status of the O^6-methylguanine-DNA Methyltransferase ( MGMT ) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM - 450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137 provided good classification properties and prognostic value (kappa = 0.85; log-rank p
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clinical trial substantiates the predictive value of o 6 methylguanine dna Methyltransferase promoter methylation in glioblastoma patients treated with temozolomide
Clinical Cancer Research, 2004Co-Authors: Monika E Hegi, Annie Claire Diserens, Sophie Godard, Philippe Otten, Guy Van Melle, Luca Regli, Pierre-yves Dietrich, Nicolas De Tribolet, Sandrine OstermannAbstract:Purpose: In the setting of a prospective clinical trial, we determined the predictive value of the methylation status of the O-6-Methylguanine-DNA Methyltransferase ( MGMT ) promoter for outcome in glioblastoma patients treated with the alkylating agent temozolomide. Expression of this excision repair enzyme has been associated with resistance to alkylating chemotherapy. Experimental Design: The methylation status of MGMT in the tumor biopsies was evaluated in 38 patients undergoing resection for newly diagnosed glioblastoma and enrolled in a Phase II trial testing concomitant and adjuvant temozolomide and radiation. The epigenetic silencing of the MGMT gene was determined using methylation-specific PCR. Results: Inactivation of the MGMT gene by promoter methylation was associated with longer survival ( P = 0.0051; Log-rank test). At 18 months, survival was 62% (16 of 26) for patients testing positive for a methylated MGMT promoter but reached only 8% (1 of 12) in absence of methylation ( P = 0.002; Fisher’s exact test). In the presence of other clinically relevant factors, methylation of the MGMT promoter remains the only significant predictor ( P = 0.017; Cox regression). Conclusions: This prospective clinical trial identifies MGMT -methylation status as an independent predictor for glioblastoma patients treated with a methylating agent. The association of the epigenetic inactivation of the DNA repair gene MGMT with better outcome in this homogenous cohort may have important implications for the design of future trials and supports efforts to deplete MGMT by O -6-benzylguanine, a noncytotoxic substrate of this enzyme.
