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  • 1
    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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  • 2
    Keywords: brain ; CELLS ; EXPRESSION ; tumor ; TUMOR-CELLS ; CELL ; Germany ; SYSTEM ; DISEASE ; PROTEIN ; DIFFERENTIATION ; SURGERY ; MARKER ; antibodies ; antibody ; LESIONS ; MUTATION ; etiology ; MARKERS ; p53 ; MUTATIONS ; vimentin ; CENTRAL-NERVOUS-SYSTEM ; FREQUENT ; sensitivity ; pathology ; GLIOMAS ; GLIOMA ; GFAP ; SPECIMENS ; GLIOBLASTOMA ; IMMUNOREACTIVITY ; IDH1 ; ASTROCYTES ; HUMAN-BRAIN-TUMORS ; GLIOBLASTOMAS ; P53 EXPRESSION ; IDH1 mutation ; PANEL ; mIDH1R132H ; NEUROPATHOLOGY ; NOGO-A EXPRESSION ; reactive gliosis ; WT1
    Abstract: Differentiation of gliomas and reactive gliosis may be challenging both at primary tumor occurrence and at posttherapy biopsy. The most frequent IDH1 mutation found in the majority of WHO grade II and III gliomas can be visualized with an antibody specifically detecting mutant IDH1(R132H) protein. In this study, mIDH1R132H immunoreactivity in 120 reactive gliosis specimens of various etiologies is compared with Wilms Tumor 1 (WT1) and p53 expression, both markers applied for the differentiation of reactive gliosis and glioma. Although WT1 and p53 positive glial cells were found in 17% and 63% of cases respectively, all samples were negative for mIDH1R132H. Furthermore, we investigated 19 posttherapy gliomas ( 6 WHO II, 13 WHO III) with extensive reactive changes and detected mIDH1R132H positive cells in 13 specimens. In 5 of these cases, tumor cells were missed by conventional staining, showing the improved sensitivity of mIDH1R132H. Thus, mIDH1R132H is a tumor-specific marker that is superior to other established markers to differentiate reactive from neoplastic cells in grade II and III gliomas and allows identifying tumor cells in posttherapy specimens with extensive reactive changes. As IDH mutations are not characteristic of grade IV primary glioblastomas, this antibody cannot differentiate primary glioblastoma from reactive gliosis. Thus, caution has to be taken and a combined panel with other markers is needed
    Type of Publication: Journal article published
    PubMed ID: 20661018
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  • 3
    Keywords: GLIOMAS ; 1p ; temozolomide ; GLIOBLASTOMA-MULTIFORME ; 19Q ; OLIGODENDROGLIAL TUMORS ; INTEGRATED GENOMIC ANALYSIS ; IDH2 MUTATIONS ; DEPENDENT PROBE AMPLIFICATION ; NEUROONCOLOGY
    Abstract: Background. Molecular biomarkers including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q codeletion, and O-6-methylguanine-DNA-methyltransferase (MGMT) promoter methylation may improve prognostication and guide treatment decisions for patients with World Health Organization (WHO) anaplastic gliomas. At present, each marker is individually tested by distinct assays. Illumina Infinium HumanMethylation450 BeadChip arrays (HM450) enable the determination of large-scale methylation profiles and genome-wide DNA copy number changes. Algorithms have been developed to detect the glioma CpG island methylator phenotype (G-CIMP) associated with IDH1/2 mutation, 1p/19q codeletion, and MGMT promoter methylation using a single assay. Methods. Here, we retrospectively investigated the diagnostic and prognostic performance of these algorithms in comparison to individual marker testing and patient outcome in the biomarker cohort (n = 115 patients) of the NOA-04 trial. Results. Concordance for IDH and 1p/19q status was very high: In 92% of samples, the HM450 and reference data agreed. In discordant samples, survival analysis by Kaplan-Meier and Cox regression analyses suggested a more accurate assessment of biological phenotype by the HM450 analysis. The HM450-derived MGMT-STP27 model to calculate MGMT promoter methylation probability revealed this aberration in a significantly higher fraction of samples than conventional methylation-specific PCR, with 87 of 91 G-CIMP tumors predicted as MGMT promoter-methylated. Pyrosequencing of discordant samples confirmed the HM450 assessment in 14 of 17 cases. Conclusions. G-CIMP and 1p/19q codeletion are reliably detectable by HM450 analysis and are associated with prognosis in the NOA-04 trial. For MGMT, HM450 suggests promoter methylation in the vast majority of G-CIMP tumors, which is supported by pyrosequencing.
    Type of Publication: Journal article published
    PubMed ID: 25028501
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