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  • PROMOTER METHYLATION  (3)
  • 1
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; Germany ; TOXICITY ; FOLLOW-UP ; imaging ; GENE ; TISSUE ; PATIENT ; CONTRAST ; TRIAL ; PROMOTER ; AGE ; EFFICACY ; inactivation ; ORGANIZATION ; METHYLATION ; MULTIFORME ; O-6-METHYLGUANINE-DNA METHYLTRANSFERASE ; PHASE-II ; ONCOLOGY ; ADULT ; METHYLTRANSFERASE ; GLIOMA ; overall survival ; SCIENCE ; MGMT ; methods ; PLUS ; temozolomide ; PROMOTER METHYLATION ; GLIOBLASTOMA ; indomethacin ; MGMT GENE ; EORTC ; BENEFIT ; Follow up
    Abstract: Purpose: To evaluate the toxicity and efficacy of chemoradiotherapy with temozolomide (TMZ) administered in an intensified 1-week on/1-week off schedule plus indomethacin in patients with newly diagnosed glioblastoma. Patients and Methods: A total of 41 adult patients (median Karnofsky performance status, 90%; median age, 56 years) were treated with preirradiation TMZ at 150 mg/m(2) (1 week on/1 week off), involved-field radiotherapy combined with concomitant low-dose TMZ (50 mg/m(2)), maintenance TMZ starting at 150 mg/m(2) using a 1-week on/1-week off schedule, plus maintenance indomethacin (25 mg twice daily). Results: The median follow-up interval was 21.7 months. Grade 4 hematologic toxicity was observed in 15 patients (36.6%). Treatment-related nonhematologic Grade 4-5 toxicity was reported for 2 patients (4.9%). The median progression-free survival was 7.6 months (95% confidence interval, 6.2-10.4). The 1-year survival rate was 73.2% (95% confidence interval, 56.8-84.2%). The presence of O-6-methylguanine-DNA methyltransferase (MGMT) gene promoter methylation in the tumor tissue was associated with significantly superior progression-free survival. Conclusion: The dose-dense regimen of TMZ administered in a 1-week on/1-week off schedule resulted in acceptable nonhematologic toxicity. Compared with data from the European Organization for Research and Treatment of Cancer/National Cancer Institute of Canada trial 26981-22981/CE.3, patients with an unmethylated MGMT gene promoter appeared not to benefit from intensifying the TMZ schedule regarding the median progression-free survival and overall survival. In contrast, data are promising for patients with a methylated MGMT promoter. (C) 2010 Elsevier Inc
    Type of Publication: Journal article published
    PubMed ID: 19836157
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  • 2
    Keywords: ANGIOGENESIS ; CELLS ; EXPRESSION ; ENDOTHELIAL GROWTH-FACTOR ; INHIBITION ; POPULATION ; PROTEIN ; mechanisms ; DOWN-REGULATION ; HYPERMETHYLATION ; MALIGNANT GLIOMAS ; astrocytoma ; SUBTYPES ; PROMOTER METHYLATION ; GLIOBLASTOMA ; AKAP12 ; Gravin ; SSeCKS ; SSECKS/GRAVIN/AKAP12
    Abstract: The scaffold protein A-kinase anchor protein 12 (AKAP12) exerts tumor suppressor activity and is downregulated in several tumor entities. We characterized AKAP12 expression and regulation in astrocytomas, including pilocytic and diffusely infiltrating astrocytomas. We examined 194 human gliomas and 23 normal brain white matter samples by immunohistochemistry or immunoblotting for AKAP12 expression. We further performed quantitative methylation analysis of the AKAP12 promoter by MassARRAY (R) of normal brain, World Health Organization (WHO) grade I to IV astrocytomas, and glioma cell lines. Our results show that AKAP12 is expressed in a perivascular distribution in normal CNS, strongly upregulated in tumor cells in pilocytic astrocytomas, and weakly expressed in diffuse astrocytomas of WHO grade II to IV. Methylation analyses revealed specific hypermethylation of AKAP12 alpha promoter in WHO grade II to IV astrocytomas. Restoration experiments using 5-aza-2'-deoxycytidine in primary glioblastoma cells decreased AKAP12 alpha promoter methylation and markedly increased AKAP12 alpha mRNA levels. In summary, we demonstrate that AKAP12 is differentially expressed in human astrocytomas showing high expression in pilocytic but low expression in diffuse astrocytomas of all WHO-grades. Our results further indicate that epigenetic mechanisms are involved in silencing AKAP12 in diffuse astrocytomas; however, a tumor suppressive role of AKAP12 in distinct astrocytoma subtypes remains to be determined
    Type of Publication: Journal article published
    PubMed ID: 24042196
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  • 3
    Keywords: radiotherapy ; SURVIVAL ; tumor ; evaluation ; Germany ; TOXICITY ; COMMON ; DIAGNOSIS ; GENE ; TISSUE ; TUMORS ; TIME ; PATIENT ; DNA ; INFECTION ; treatment ; PROGRESSION ; PROMOTER ; EFFICACY ; chemotherapy ; INFECTIONS ; RECURRENT ; METHYLATION ; GLIOMAS ; DNA methyltransferase ; LACKING ; PHASE-II ; ONCOLOGY ; ADULT ; METHYLTRANSFERASE ; GLIOMA ; MALIGNANT GLIOMA ; GRADE ; GENE PROMOTER ; MGMT ; TUMOR TISSUE ; methods ; EVENTS ; temozolomide ; GLIOBLASTOMA-MULTIFORME ; CRITERIA ; USA ; PROMOTER METHYLATION ; O-6-methylguanine ; survival rate ; GLIOBLASTOMA ; PROGRESSION-FREE SURVIVAL ; REGIMEN ; evidence ; MGMT GENE ; O-6-methylguanine-DNA-methyltransferase
    Abstract: Purpose Evaluation of toxicity and efficacy of an alternating weekly regimen of temozolomide administered 1 week on and 1 week off in patients with recurrent glioma. Patients and Methods Ninety adult patients with recurrent gliomas accrued in one center received chemotherapy with temozolomide at 150 mg/ m(2)/ d ( days 1 through 7 and 15 through 21 every 4 weeks) with individual dose adjustments according to hematologic toxicity. Results A total of 906 treatment weeks were delivered. Grade 4 hematotoxicity according to the Common Terminology Criteria for Adverse Events ( CTCAE; version 3.0) was observed in 24 treatment weeks ( 2.6%). CTCAE grade 4 lymphopenia eventually developed in 11 patients ( 12%). There were neither cumulative lymphopenias nor opportunistic infections. The progression-free survival ( PFS) rate at 6 months for glioblastoma patients was 43.8%. The median PFS in these patients was 24 weeks ( 95% Cl, 17 to 26 weeks), the median survival time from diagnosis of progression was 38 weeks ( 95% Cl, 30 to 46 weeks), and the 1-year survival rate from progression was 23%. O-6-methylguanine DNA methyltransferase ( MGMT) gene promoter methylation in the tumor tissue was not associated with longer PFS ( log-rank P = .37). Conclusion These data imply that the alternating weekly schedule is feasible, safe, and effective and clearly warrants investigation in randomized studies. Compared with more protracted low-dose temozolomide schedules, the 1-week-on/ 1-week-off schedule may be less toxic. We provide preliminary evidence that this dose-dense schedule is also active in patients with tumors lacking MGMT gene promoter methylation
    Type of Publication: Journal article published
    PubMed ID: 17664483
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