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  • Oxford University Press (CrossRef)  (47)
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  • 1
    In: Neuro-Oncology, 2017, Vol. 19(11), pp.1427-1428
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 2
    Article
    Article
    In: Neuro-Oncology, 2018, Vol. 20(12), pp.1561-1562
    Keywords: Meningioma -- Genetics ; Telomerase -- Genetics;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 3
    In: Journal Of The National Cancer Institute, 2017, Vol. 109(3), pp.1-4
    Description: High-throughput analyses have revealed the presence of activating mutations in the AKT1 gene in a subpopulation of meningiomas. We report a female patient with multiple intracranial tumor manifestations and histologically verified meningotheliomatous meningioma in the lung. The tumor was continuously growing at multiple sites despite six surgical resections, radiotherapy, and two lines of systemic therapy. Following detection of an AKT1 E17K mutation in three independent tumor samples by sequencing, treatment with AZD5363, a selective AKT inhibitor, was initiated. Ex vivo cultured meningioma cells exhibited sensitivity to the drug as shown by pAKT accumulation on immunoblots. Treatment with AZD5363 resulted, for the first time, in stable disease and minor radiographic response. The patient has been on that treatment for more than one year with ongoing clinical and radiographic response. This is the first report of an AKT1-mutant meningioma responding to AKT inhibition, suggesting that molecular screening may result in clinical benefit.
    Keywords: Cancer Metastasis – Analysis ; Meningioma – Care and Treatment ; Gene Mutation – Research ; Gene Therapy – Analysis;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 4
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v42-v42
    Description: BACKGROUND: The recent identification of isocitrate dehydrogenase (IDH) mutations in gliomas and several other cancers suggests that this pathway is involved in oncogenesis; however effector functions are complex and yet incompletely understood. To study the regulatory effects of IDH on hypoxia-inducible-factor 1-alpha (HIF1A), a driving force in hypoxia-initiated angiogenesis, we performed mRNA-expression and functional, as well as genotype/imaging phenotype correlation analysis. METHODS: We studied differential mRNA-expression profiles from 288 samples with low-grade and anaplastic gliomas from The Cancer Genome Atlas (TCGA) of HIF1A and related downstream signaling on a single-gene and pathway level, as well as upstream biological causes and probable downstream effects between mutant and wild-type IDH tumors. Genotype/imaging phenotype correlation analysis was performed in a separate (local) dataset with relative cerebral blood volume (rCBV) MRI - an estimate of tumor angiogenesis - in 73 treatment-naive patients with low-grade and anaplastic gliomas. RESULTS: We show decreased expression of HIF1A-target genes on a single-gene and pathway level, strong inhibition of upstream regulators such as HIF1A and downstream biological functions such as angio- and vasculogenesis in IDH-mutant tumors. Our radiogenomic imaging approach revealed increased levels of rCBV in IDH wild-type tumors, where a one-unit increase in rCBV corresponded to a two-third decrease in the odds for an IDH-mutation and correctly predicted IDH mutation status in 88% of patients. CONCLUSION: Together, these findings show that IDH-mutation status is associated with a distinct angiogenesis transcriptome signature which is non-invasively predictable with rCBV-imaging.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 5
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi151-vi151
    Description: The World Health Organization (WHO) classification of brain tumors comprises 15 histological subtypes of meningioma, allotted to three WHO grades. While the current classification and grading approach is of prognostic value, it harbors shortcomings due to the necessarily subjective evaluation of histological criteria and potential sampling bias. In order to devise a molecular approach to meningioma classification, we previously identified six distinct Methylation Classes (MCs) of meningioma by DNA methylation profiling. These six MCs are termed MC benign-1, -2, -3, MC intermediate A, B, and MC malignant. Each MC shows typical mutational, cytogenetic, and gene expression patterns. Importantly, MCs are superior to WHO grading in predicting the risk of recurrence for individual patients. In order to translate these findings into diagnostic practice, we developed a meningioma classifier, assigning novel diagnostic samples to the respective MC of the reference cohort. This classifier is now being used on diagnostic cases for 2 years at the Dept. of Neuropathology Heidelberg and has recently been made available for external users through molecularneuropathology.org, alongside the brain tumor entity classifier. Over 200 diagnostic cases have been evaluated so far. Integrating histology, classifier results, and copy-number alterations provides a more robust basis for grading and the subsequent clinical decision whether to administer radiotherapy or not. In addition, the association of certain subgroups with druggable mutations informs about the potential to identify specific targets by additional sequencing. Collectively, this tool opens the opportunity for an integrated classification of meningioma samples in routine diagnostics.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 6
    In: Neuro-Oncology, 2018, Vol. 20(suppl6), pp.vi155-vi155
    Description: Abstract BACKGROUND Meningioma is a heterogenous disease and precise molecular characterization may support clinical decision-making. Several recurring gene mutations as well as prognostic relevant DNA-methylation classes were recently identified in meningioma. We aimed to validate the recent findings in an independent cohort. METHODS Formalin fixed and paraffin emended samples of 127 meningioma patients (Grade I 40.9%; Grade II: 37.8%; Grade III: 21.3%) were retrieved from the Neuro-Biobank, Institute of Neurology, Medical University of Vienna. Methylation classes (MC) were analyzed using 850k EPIC (Illumina, San Diego, CA, USA) according to the Heidelberg Meningioma Classifier. Panel sequencing for genes reported to impact meningioma, namely NF2, TRAF7, KLF4, ARID, SMO, AKT, TERT, PIK3CA and SUFU was performed as previously outlined. The TRAKLS mutation type was characterized by presence of TRAF7, AKT1, KLF4 or/and SMO mutation. Survival data including progression free survival was retrieved from chart review. RESULTS Meningioma relevant mutations were evident in 96/127 (75.5%) specimens. NF2 (42/127; 33.1%), TRAF7 (40/127; 31.5%), KLF4 (27/127; 21.3%) and ARID (25/127; 19.7%) mutation were the most frequently observed ones. Two or more mutations were observed in 51/127 (40.2%) specimens. MC correlated with presence of target mutations as well as clinical characteristics (p〈0.05; Chi Square test). TRAF7, KLF4 and TERT mutations as well as TRAKLS mutation type associated with progression free survival in univariate analysis (〈0.05; log rank test), however in multivariable analysis only MC (HR 1.9; 95% CI 1.3–2.8; p=0.001; cox regression model) and presence of TERT mutation HR 24.9; 95% CI 3.9–159.8; p=0.001; cox regression model) remained statically significant. CONCLUSIONS Molecular profiling including methylation class and genetic aberrations and may facilitate more precise prognostic assessment and identification of potential targets for targeted therapy in meningioma patients.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 7
    In: Journal Of The National Cancer Institute, 2016, Vol. 108(5)
    Description: The World Health Organization (WHO) classification and grading system attempts to predict the clinical course of meningiomas based on morphological parameters. However, because of high interobserver variation of some criteria, more reliable prognostic markers are required. Here, we assessed the TERT promoter for mutations in the hotspot regions C228T and C250T in meningioma samples from 252 patients. Mutations were detected in 16 samples (6.4% across the cohort, 1.7%, 5.7%, and 20.0% of WHO grade I, II, and III cases, respectively). Data were analyzed by t test, Fisher’s exact test, log-rank test, and Cox proportional hazard model. All statistical tests were two-sided. Within a mean follow-up time in surviving patients of 68.1 months, TERT promoter mutations were statistically significantly associated with shorter time to progression ( P 〈 .001). Median time to progression among mutant cases was 10.1 months compared with 179.0 months among wild-type cases. Our results indicate that the inclusion of molecular data (ie, analysis of TERT promoter status) into a histologically and genetically integrated classification and grading system for meningiomas increases prognostic power. Consequently, we propose to incorporate the assessment of TERT promoter status in upcoming grading schemes for meningioma.
    Keywords: Meningioma – Genetic Aspects ; Recurrence (Disease) – Genetic Aspects;
    ISSN: 0027-8874
    E-ISSN: 1460-2105
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  • 8
    In: Journal of Neuropathology & Experimental Neurology, 2017, Vol.76(12), pp.997-999
    Description: Abstract We report a novel case of a World Health Organization grade 3 anaplastic meningioma arising from the olfactory groove in an 83-year-old woman. Molecular and methylation profiling confirm this lesion to be an NF2 subtype, methylation class intermediate type B meningioma. As most meningiomas in this location are indolent SMO subtype lesions, our report suggests that even though rare, aggressive NF2 subtype meningiomas can also occur along the midline anterior skull base.
    Keywords: Medicine;
    ISSN: 0022-3069
    E-ISSN: 15546578
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  • 9
    In: Neuro-Oncology, 2017, Vol. 19(8), pp.1088-1096
    Description: Background: Skull base meningiomas are considered to be difficult for surgical treatment. We wondered whether genetic alterations recently identified in benign non-NF2-mutated World Health Organization (WHO) grade I meningiomas are related to clinical features of skull base meningiomas and whether druggable signaling pathways are activated.Methods: We analyzed 93 skull base meningiomas (82 WHO grade I, 11 WHO grade II) for mutations of hot spots or the most relevant exons of AKT1, KLF4/TRAF7, SMO, PI3K, and the TERT promoter.Results: The AKT1E17K mutation was present in 31% of patients and was related to meningothelial histology. AKT1E17K had a negative effect on the time to tumor recurrence. Analyses of activated signaling proteins revealed among AKT1E17K tumors a significantly higher rate of phospho-mammalian target of rapamycin (mTOR) and phospho-p70S6K+ tumors. AKT1E17K tumors with immunoexpression of phospho-extracellular signal-regulated kinase 1 or 2 (ERK1/2) were characterized by significantly shorter time to tumor recurrence compared with AKT1wt tumors expressing phospho-ERK1/2 (P = .046). KLF4 mutations (K409Q) were present in 11.8% of cases, with significant association to the secretory/transitional subtype (P 〈 .001). The presence of the KLF4 K409Q mutation was associated with favorable outcome. One phosphatidylinositol-3 kinase (PI3K) mutation but no SMO or TERT promoter mutation was found.Conclusions: AKT1E17K mutation is frequent in skull base meningiomas, results in activation of the mTOR and ERK1/2 signaling pathways, and has negative impact on tumor recurrence. Patients with skull base meningiomas with AKT1E17K mutation might benefit from additional treatment targeting the mTOR pathway. Generally, the PI3K-Akt-mTOR axis might be a potential target for kinase inhibitors in these tumors.
    Keywords: 〈Kwd〉 〈Italic Toggle="Yes"〉Akt1〈/Italic〉 〈/Kwd〉 ; 〈Kwd〉 〈Italic Toggle="Yes"〉Klf4〈/Italic〉 〈/Kwd〉 ; Meningioma ; Skull Base
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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  • 10
    In: Neuro-Oncology, 2015, Vol. 17(suppl5), pp.v116-v116
    Description: Although aggressive meningiomas WHO II and III are rare tumors, more effective therapies are urgently needed as reflected by a 5-year-recurrence rate of 50-80% in WHO III meningiomas. In the present study we aimed to learn more about the immunological situation of meningioma and thus a potential suitability of immunotherapeutic approaches. Occurrence of tumor-infiltrating lymphocytes (TILs) was studied in 114 primary and recurrent meningiomas WHO°I – III and quantified by multicolor immunofluorescence stainings using the markers CD3, CD8, and FOXP3 by using the semi-automated analysis method TissueFAXS. Although similar levels of TILs (CD3+) were found in all WHO grades, TIL numbers were higher in primary as compared to recurrent meningiomas. Phenotypic subclassification into effector and regulatory T-cells revealed elevated levels of T helper cells (CD8−) but not cytotoxic T-cells (CD8+). In contrast to effector T-cells, we found a significant increase of regulatory (FOXP3+) T-cells, which is mainly based on the CD8+ Treg cell phenotype. In contrast to all other T-cell phenotypes analyzed, solely FOXP3+ and in particular the CD8+ Treg cell subpopulation were increasing when comparing primary and recurrent meningioma and were further found to be correlated with a poor overall survival. Moreover, detection of Treg cells in primary meningioma is more frequently in patients developing recurrent tumors and might therefore serve as a negative prognostic marker. Furthermore, microarray analyses hint to profound changes in the tumor microenvironment with increasing WHO grade and recurrent tumors. Altogether, our results suggest a higher impact of quality than quantity of TILs, highlighting the importance of the microenvironment on the functional immune status, which needs to be considered for developing novel therapy approaches.
    Keywords: Medicine;
    ISSN: 1522-8517
    E-ISSN: 1523-5866
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