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  • Organic Chemistry  (12)
  • GLIOMAS  (7)
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  • 1
    Keywords: DIFFERENTIATION ; PROGRESSION ; PROGNOSTIC-SIGNIFICANCE ; GLIOMAS ; MULTIFORME ; astrocytoma ; SUBTYPES ; CODON 132 MUTATION ; INTEGRATED GENOMIC ANALYSIS ; IDH2 MUTATIONS
    Abstract: PURPOSE: The determinants of long-term survival in glioblastoma have remained largely obscure. Isocitrate dehydrogenase (IDH) 1 or 2 mutations are common in World Health Organization (WHO) grades II and III gliomas, but rare in primary glioblastomas, and associated with longer survival. EXPERIMENTAL DESIGN: We compared clinical and molecular characteristics of 69 patients with centrally confirmed glioblastoma and survival 〉36 months (LTS-36), including 33 patients surviving 〉60 months (LTS-60), with 257 patients surviving 〈36 months. MGMT promoter methylation, 1p/19q codeletions, EGFR amplification, TP53 mutations, and IDH1/2 mutations were determined by standard techniques. RESULTS: The rate of IDH1/2 mutations in LTS-36 patients was 34% (23 of 67 patients) as opposed to 4.3% in controls (11 of 257 patients). Long-term survivors with IDH1/2-mutant glioblastomas were younger, had almost no EGFR amplifications, but exhibited more often 1p/19q codeletions and TP53 mutations than LTS patients with IDH1/2 wild-type glioblastomas. Long-term survivors with IDH1/2 wild-type showed no distinguishing features from other patients with IDH1/2 wild-type glioblastomas except for a higher rate of MGMT promoter methylation. Similarly, among 11 patients with IDH1/2-mutant glioblastomas without long-term survival, the only difference to IDH1/2-mutant long-term survivors was less-frequent MGMT promoter methylation. Compared with LTS-36 patients, LTS-60 patients had less frequently TP53 mutations and radiotherapy alone as initial treatment. CONCLUSIONS: IDH1/2 mutations define a subgroup of tumors of LTS patients that exhibit molecular characteristics of WHO grade II/III gliomas and secondary glioblastomas. Determinants of LTS with IDH1/2 wild-type glioblastomas, which exhibit typical molecular features of primary glioblastomas, beyond MGMT promoter methylation, remain to be identified. Clin Cancer Res; 19(18); 5146-57. (c)2013 AACR.
    Type of Publication: Journal article published
    PubMed ID: 23918605
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  • 2
    Keywords: EXPRESSION ; radiotherapy ; SURVIVAL ; PROGRESSION ; ASTROCYTOMAS ; GLIOMAS ; MULTIFORME ; NEWLY-DIAGNOSED GLIOBLASTOMA ; EGFRVIII ; NEUROONCOLOGY
    Abstract: The epidermal growth factor receptor vIII mutant (EGFRvIII) is found in approximately 50% of all EGFR-amplified glioblastomas and constitutes a tumor-specific therapeutic target. To assess molecular testing approaches and the prognostic role of EGFRvIII in patients treated according to current standards of care, we compared different EGFRvIII detection methods and correlated EGFRvIII status with outcome in a prospective patient cohort of the German Glioma Network. In total, 184 newly diagnosed glioblastoma patients were investigated for EGFR amplification and for expression of EGFR and EGFRvIII by immunohistochemistry. Further, the EGFRvIII status was additionally studied by multiplex ligation-dependent probe amplification (MLPA) analysis and reverse transcription-PCR (RT-PCR). Immunohistochemistry demonstrated EGFRvIII in 34 of 184 patients (18%). RT-PCR or MLPA analysis detected 4 additional EGFRvIII-positive patients. Overall, RT-PCR and immunohistochemistry were more sensitive for EGFRvIII detection than MLPA. EGFRvIII status was not associated with progression-free and overall survival. EGFRvIII also had no prognostic significance in the subgroup of patients who were free from progression after concomitant radiochemotherapy and thus would be eligible for the ongoing ACT IV EGFRvIII vaccination trial. Age, extent of resection, and O6 -methylguanine DNA methyltransferase (MGMT) promoter methylation status appeared to be less prognostic in EGFRvIII-positive patients. Thus, EGFRvIII positivity is not a major negative prognostic factor in glioblastoma patients treated according to current standards of care. Data from phase II EGFRvIII-targeted vaccination trials compare favorably with the present contemporary results, supporting the further exploration of EGVRvIII vaccination in newly diagnosed glioblastoma. (c) 2013 Wiley Periodicals, Inc.
    Type of Publication: Journal article published
    PubMed ID: 24614983
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  • 3
    Keywords: brain ; GENE-EXPRESSION ; HYBRIDIZATION ; TUMORS ; UNITED-STATES ; GLIOMAS ; MULTIFORME ; temozolomide ; CODON 132 MUTATION ; IDH2 MUTATIONS
    Abstract: The prognosis of glioblastoma, the most malignant type of glioma, is still poor, with only a minority of patients showing long-term survival of more than three years after diagnosis. To elucidate the molecular aberrations in glioblastomas of long-term survivors, we performed genome- and/or transcriptome-wide molecular profiling of glioblastoma samples from 94 patients, including 28 long-term survivors with 〉36 months overall survival (OS), 20 short-term survivors with 〈12 months OS and 46 patients with intermediate OS. Integrative bioinformatic analyses were used to characterize molecular aberrations in the distinct survival groups considering established molecular markers such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, and O(6) -methylguanine DNA methyltransferase (MGMT) promoter methylation. Patients with long-term survival were younger and more often had IDH1/2-mutant and MGMT-methylated tumors. Gene expression profiling revealed over-representation of a distinct (proneural-like) expression signature in long-term survivors that was linked to IDH1/2 mutation. However, IDH1/2-wildtype glioblastomas from long-term survivors did not show distinct gene expression profiles and included proneural, classical and mesenchymal glioblastoma subtypes. Genomic imbalances also differed between IDH1/2-mutant and IDH1/2-wildtype tumors, but not between survival groups of IDH1/2-wildtype patients. Thus, our data support an important role for MGMT promoter methylation and IDH1/2 mutation in glioblastoma long-term survival and corroborate the association of IDH1/2 mutation with distinct genomic and transcriptional profiles. Importantly, however, IDH1/2-wildtype glioblastomas in our cohort of long-term survivors lacked distinctive DNA copy number changes and gene expression signatures, indicating that other factors might have been responsible for long survival in this particular subgroup of patients.(c) 2014 UICC.
    Type of Publication: Journal article published
    PubMed ID: 24615357
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  • 4
    Keywords: radiotherapy ; PATTERNS ; chemotherapy ; GLIOMAS ; MULTIFORME ; PHASE-II ; temozolomide ; GENETIC ALTERATIONS ; NEWLY-DIAGNOSED GLIOBLASTOMA ; IDH1 mutation
    Abstract: BackgroundThe number of patients age 〉65 years with malignant gliomas is increasing. Prognosis of these patients is worse compared with younger patients. To determine biological differences among malignant gliomas of different age groups and help to explain the survival heterogeneity seen in the NOA-08 trial, the prevalence and impact of recently established biomarkers for outcome in younger patients were characterized in elderly patients.MethodsPrevalences of mutations of isocitrate dehydrogenase 1 (IDH1) and histone H3.3 (H3F3A), the glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and methylation of alkylpurine DNA N-glycosylase (APNG) and peroxiredoxin 1 (PRDX1) promoters were determined in a representative biomarker subset (n = 126 patients with anaplastic astrocytoma or glioblastoma) from the NOA-08 trial.ResultsIDH1 mutations (R132H) were detected in only 3/126 patients, precluding determination of an association between IDH mutation and outcome. These 3 patients also displayed the G-CIMP phenotype. None of the IDH1 wild-type tumors were G-CIMP positive. Mutations in H3F3A were absent in all 103 patients sequenced for H3F3A. MassARRAY analysis of the APNG promoter revealed generally low methylation levels and failed to confirm any predictive properties for benefit from alkylating chemotherapy. Neither did PRDX1 promoter methylation show differential methylation or association with outcome in this cohort. In a 170-patient cohort from The Cancer Genome Atlas database matched for relevant prognostic factors, age 〉/=65 years was strongly associated with shorter survival.ConclusionsDespite an age-independent stable frequency of O6-methylguanine-DNA methyltransferase (MGMT) promoter hypermethylation, tumors in this age group largely lack prognostically favorable markers established in younger glioblastoma patients, which likely contributes to the overall worse prognosis of elderly patients. However, the survival differences hint at fundamental further differences among malignant gliomas of different age groups.
    Type of Publication: Journal article published
    PubMed ID: 23595628
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  • 5
    Keywords: brain ; CELLS ; tumor ; CELL ; Germany ; human ; FOLLOW-UP ; HYBRIDIZATION ; COMPONENTS ; TUMORS ; NO ; IN-SITU ; PROGRESSION ; COMPARATIVE GENOMIC HYBRIDIZATION ; EXPRESSION ANALYSIS ; HEALTH ; DNA microarray ; ABERRATIONS ; FISH ; REGION ; RECURRENCE ; REGIONS ; SERIES ; FLUORESCENCE ; ORGANIZATION ; fluorescence in situ hybridization ; CHROMOSOMAL IMBALANCES ; GLIOMAS ; DMBT1 ; CLUSTER ; SUBPOPULATION ; GLIOMA ; MALIGNANT GLIOMAS ; ARRAY ; GRADE ; GENOMIC ABERRATIONS ; analysis ; PROFILES ; LOSSES ; FOCAL EPILEPSIES ; GANGLIOGLIOMAS ; NERVOUS-SYSTEM TUMORS ; ENGLAND ; ARRAY-CGH ; comparison ; LOW-GRADE ; PROFILE ; array-based CGH ; genomic aberration ; MOLECULAR CYTOGENETIC ANALYSIS ; tumor genetics
    Abstract: Gangliogliomas are generally benign neuroepithelial tumors composed of dysplastic neuronal and neoplastic glial elements. We screened 61 gangliogliomas [World Health Organization (WHO) grade I] for genomic alterations by chromosomal and array-based comparative genomic hybridization (CGH). Aberrations were detected in 66% of gangliogliomas (mean +/- SEM = 2.5 +/- 0.5 alterations/tumor). Frequent gains were on chromosomes 7 (21%), 5 (16%), 8 (13%), 12 (12%); frequent losses on 22q (16%), 9 (10%), 10 (8%). Recurrent partial imbalances comprised the minimal overlapping regions dim(10)(q25) and enh(12)(q13.3-q14.1). Unsupervised cluster analysis of genomic profiles detected two major subgroups (group I: complete gain of 7 and additional gains of 5, 8 or 12; group II: no major recurring imbalances, mainly losses). A comparison with low-grade gliomas (astrocytomas WHO grade II) showed chromosome 5 gain to be significantly more frequent in gangliogliomas. Interphase fluorescence in situ hybridization (FISH) identified the aberrations to be contained in a subpopulation of glial but not in neuronal cells. Two gangliogliomas and their anaplastic recurrences (WHO grade III) were analyzed. Losses of CDKN2A/B and DMBT1 or a gain/amplification of CDK4 found in the anaplastic tumors were already present in the respective gangliogliomas by array CGH and interphase FISH. In summary, genomic profiling in a large series of gangliogliomas could distinguish genetic subgroups even in this low-grade tumor
    Type of Publication: Journal article published
    PubMed ID: 18371186
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  • 6
    Keywords: CLASSIFICATION ; FOLLOW-UP ; PATTERNS ; GLIOMAS ; MULTIFORME ; OLDER PATIENTS ; ADJUVANT TEMOZOLOMIDE ; PROMOTER METHYLATION ; NEWLY-DIAGNOSED GLIOBLASTOMA ; CONCOMITANT
    Abstract: BACKGROUND: Radiotherapy is the standard care in elderly patients with malignant astrocytoma and the role of primary chemotherapy is poorly defined. We did a randomised trial to compare the efficacy and safety of dose-dense temozolomide alone versus radiotherapy alone in elderly patients with anaplastic astrocytoma or glioblastoma. METHODS: Between May 15, 2005, and Nov 2, 2009, we enrolled patients with confirmed anaplastic astrocytoma or glioblastoma, age older than 65 years, and a Karnofsky performance score of 60 or higher. Patients were randomly assigned 100 mg/m(2) temozolomide, given on days 1-7 of 1 week on, 1 week off cycles, or radiotherapy of 60.0 Gy, administered over 6-7 weeks in 30 fractions of 1.8-2.0 Gy. The primary endpoint was overall survival. We assessed non-inferiority with a 25% margin, analysed for all patients who received at least one dose of assigned treatment. This trial is registered with ClinicalTrials.gov, number NCT01502241. FINDINGS: Of 584 patients screened, we enrolled 412. 373 patients (195 randomly allocated to the temozolomide group and 178 to the radiotherapy group) received at least one dose of treatment and were included in efficacy analyses. Median overall survival was 8.6 months (95% CI 7.3-10.2) in the temozolomide group versus 9.6 months (8.2-10.8) in the radiotherapy group (hazard ratio [HR] 1.09, 95% CI 0.84-1.42, p(non-inferiority)=0.033). Median event-free survival (EFS) did not differ significantly between the temozolomide and radiotherapy groups (3.3 months [95% CI 3.2-4.1] vs 4.7 [4.2-5.2]; HR 1.15, 95% CI 0.92-1.43, p(non-inferiority)=0.043). Tumour MGMT promoter methylation was seen in 73 (35%) of 209 patients tested. MGMT promoter methylation was associated with longer overall survival than was unmethylated status (11.9 months [95% CI 9.0 to not reached] vs 8.2 months [7.0-10.0]; HR 0.62, 95% CI 0.42-0.91, p=0.014). EFS was longer in patients with MGMT promoter methylation who received temozolomide than in those who underwent radiotherapy (8.4 months [95e% CI 5.5-11.7] vs 4.6 [4.2-5.0]), whereas the opposite was true for patients with no methylation of the MGMT promoter (3.3 months [3.0-3.5] vs 4.6 months [3.7-6.3]). The most frequent grade 3-4 intervention-related adverse events were neutropenia (16 patients in the temozolomide group vs two in the radiotherapy group), lymphocytopenia (46 vs one), thrombocytopenia (14 vs four), raised liver-enzyme concentrations (30 vs 16), infections (35 vs 23), and thromboembolic events (24 vs eight). INTERPRETATION: Temozolomide alone is non-inferior to radiotherapy alone in the treatment of elderly patients with malignant astrocytoma. MGMT promoter methylation seems to be a useful biomarker for outcomes by treatment and could aid decision-making. FUNDING: Merck Sharp & Dohme.
    Type of Publication: Journal article published
    PubMed ID: 22578793
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  • 7
    Keywords: CANCER ; radiotherapy ; SURVIVAL ; tumor ; CLASSIFICATION ; ASSOCIATION ; chemotherapy ; GLIOMAS ; EUROPEAN ORGANIZATION ; temozolomide ; GLIOBLASTOMA ; IDH1 ; ADJUVANT PROCARBAZINE ; PHASE-3 TRIAL ; 1p/19q ; BRAIN-TUMOR GROUP
    Abstract: OBJECTIVE: To explore whether the isocitrate dehydrogenase 1 (IDH1) or 1p/19q status determines the prognostic vs predictive role of O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation in the Neuro-Oncology Working Group of the German Cancer Society (NOA)-04 trial anaplastic glioma biomarker cohort. METHODS: Patients (n = 183) of the NOA-04 trial with known MGMT and IDH1 status were analyzed for interdependency of the prognostic vs predictive role of MGMT promoter methylation from IDH1 or 1p/19q status and treatment, using progression-free survival (PFS) as an endpoint. An independent validation cohort of the German Glioma Network (n = 75) and the NOA-08 trial (n = 34) served as a confirmation cohort. RESULTS: In tumors with IDH1 mutation, MGMT promoter methylation was associated with prolonged PFS with chemotherapy +/- radiotherapy (RT) or RT-only groups, and is thus prognostic. In tumors without IDH1 mutation, MGMT promoter methylation was associated with increased PFS in patients treated with chemotherapy, but not in those who received RT alone as the first-line treatment, and is thus chemotherapy-predictive. In contrast, 1p/19q codeletions showed no such association with the prognostic vs predictive value of MGMT. CONCLUSIONS: MGMT promoter methylation is a predictive biomarker for benefit from alkylating agent chemotherapy in patients with IDH1-wild-type, but not IDH1-mutant, malignant gliomas of World Health Organization grades III/IV. Combined IDH1/MGMT assessment may help to individualize clinical decision-making in neuro-oncology.
    Type of Publication: Journal article published
    PubMed ID: 24068788
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  • 8
    Electronic Resource
    Electronic Resource
    Weinheim : Wiley-Blackwell
    Liebigs Annalen 342 (1905), S. 1-13 
    ISSN: 0075-4617
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: 15N-Labelled 3-(Dimethylamino)-2,2-dimethyl-2H-azirine for Mechanistic Studies of Reactions with NH-Acidic HeterocyclesThe synthesis of 3-(dimethylamino)-2,2-dimethyl(1-15N)-2H-azirine (1*) was accomplished via reaction of 1-chloro-N,N,2-trimethyl-1-propenylamine (9) and sodium (1-15N) azide (Scheme 3). The earlier reported reactions of 1 with saccharin (10, Scheme 4), phthalimide (12, Scheme 5), and 2H-1,3-benzoxazin-2,4(3H)-dione (16, Scheme 6) were repeated with 1*, and the position of the 15N-label in the products was determined by 15N-NMR spectroscopy. Whereas the postulated reaction mechanisms for 10 and 12 were confirmed by these experiments, the mechanism for the reaction of 16 had to be revised. With respect to the position of 15N in the products 17 and 18, a new mechanism is formulated in Scheme 7. Treatment of 5,5-dimethyl-1,3-oxazolidine-2,4-dione (19) with 1* led to 3,4-dihydro-2H-imidazol-2-on 20 in which only N(3) was labelled. The mechanism of a ring expansion and transannular ring contraction as shown in Scheme 8 is in agreement with this finding.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 0018-019X
    Keywords: Chemistry ; Organic Chemistry
    Source: Wiley InterScience Backfile Collection 1832-2000
    Topics: Chemistry and Pharmacology
    Notes: Dipolar 1:1 Adducts from the Reaction of 3-Amino-2H-azirines with 1,3,4-Oxadiazol- and 1,3,4-Thiadiazol-2(3H)-ones3-Amino-2H-azirines 1 react with 5-(trifluoromethyl)-1,3,4-oxadiazol-2(3H)-one (2) as well as with different 5-substituted 1,3,4-thiadiazol-2(3H)-ones (5a-e) in 2-propanol at room temperature to give dipolar 1:1 adducts of type 3 and 6, respectively, in reasonable-to-good yields (Schemes 3 and 6, Tab. 1 and 2). The structure of two of these dipolar adducts, 6a and 6e, which are formally donor-acceptor-stabilized azomethin imines, have been elucidated by X-ray crystallography (Figs. 1-4). In the reaction of 2 and sterically crowded 3-amino-2H-azirines 1c-e with a 2-propyl and 2-propenyl substituent, respectively, at C(2), a 4,5-dihydro-1,2,4-triazin-3(2H)-one of type 4 is formed as minor product (Scheme 3 and Table 1). Independent syntheses of these products proved the structure of 4. Several reaction mechanisms for the formation of compounds 3 and 4 are discussed, the most likely ones are described in Scheme 4: reaction of 2 as an NH-acidic compound leads, via a bicyclic zwitterion of type A, to 3 as well as to 4. In the latter reaction, a ring-expanded intermediate B is most probable.
    Additional Material: 4 Ill.
    Type of Medium: Electronic Resource
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