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201. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers

Author

Korshunov, Andrey, Ryzhova, Marina, Hovestadt, Volker, Bender, Sebastian, Sturm, Dominik, Capper, David, Meyer, Jochen, Schrimpf, Daniel, Kool, Marcel, Northcott, Paul A., Zheludkova, Olga, Milde, Till, Witt, Olaf, Kulozik, Andreas E., Reifenberger, Guido, Jabado, Nada, Perry, Arie, Lichter, Peter, von Deimling, Andreas, Pfister, Stefan M., and Jones, David T. W.

Published
2015
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204. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial

Author

Wick, Wolfgang, Platten, Michael, Meisner, Christoph, Felsberg, Jörg, Tabatabai, Ghazaleh, Simon, Matthias, Nikkhah, Guido, Papsdorf, Kirsten, Steinbach, Joachim P, Sabel, Michael, Combs, Stephanie E, Vesper, Jan, Braun, Christian, Meixensberger, Jürgen, Ketter, Ralf, Mayer-Steinacker, Regine, Reifenberger, Guido, and Weller, Michael

Published
2012
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205. Intratumoral heterogeneity of MYC drives medulloblastoma metastasis and angiogenesis

Author

Qin, Nan, primary, Paisana, Eunice, additional, Langini, Maike, additional, Picard, Daniel, additional, Malzkorn, Bastian, additional, Custódia, Carlos, additional, Cascão, Rita, additional, Meyer, Frauke-Dorothee, additional, Blümel, Lena, additional, Göbbels, Sarah, additional, Taban, Kübra, additional, Bartl, Jasmin, additional, Bechmann, Nicole, additional, Conrad, Catleen, additional, Gravemeyer, Jan, additional, Becker, Jürgen C, additional, Stefanski, Anja, additional, Puget, Stéphanie, additional, Barata, João T, additional, Stühler, Kai, additional, Fischer, Ute, additional, Felsberg, Jörg, additional, Ayrault, Olivier, additional, Reifenberger, Guido, additional, Borkhardt, Arndt, additional, Eisenhofer, Graeme, additional, Faria, Claudia C, additional, and Remke, Marc, additional

Published
2022
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207. The who classification of tumors of the central nervous system 2021 changes in the diagnostics of diffuse gliomas and implications for clinical practice

Author

Weller, Michael, Knobbe-Thomsen, Christiane B., Le Rhun, Emilie, Reifenberger, Guido, INSERM, Université de Lille, Universität Zürich [Zürich] = University of Zurich [UZH], University hospital of Zurich [Zurich], Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], and Universität Zürich [Zürich] = University of Zurich (UZH)

Subjects
Glioblastoma, Isocitrate dehydrogenase, TERT, EGFR, Glioma, [SDV]Life Sciences [q-bio]
Abstract

International audience; Background: The World Health Organization (WHO) classification of tumors of the central nervous system (CNS) was revised in 2016 to incorporate molecular biomarkers of importance for tumor diagnostics and clinical decision making. Thereafter, the cIMPACT-NOW consortium published a series of recommendations for the future classification of CNS tumors that have subsequently been incorporated into the new WHO classification 2021. Objectives: Which changes in the WHO classification 2021 directly affect the diagnosis and treatment of adult patients with diffuse gliomas? Materials and methods: The criteria of the WHO classification 2021 for diffuse gliomas were examined with regard to this question. Results: Mutations in the isocitrate dehydrogenase (IDH) genes 1 or 2 remain important for the classification of diffuse gliomas. Among IDH-mutant gliomas, loss of nuclear ATRX expression identifies IDH-mutant astrocytomas, while 1p/19q codeletion is diagnostic for IDH-mutant and 1p/19q-codeleted oligodendrogliomas. The nomenclature for IDH-mutant glioblastoma was changed to astrocytoma, IDH-mutant, CNS WHO grade 4. Homozygous deletion of the CDKN2A/B gene locus is a novel molecular biomarker for these tumors. IDH-wildtype diffuse astrocytomas carrying a telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor (EGFR) gene amplification, and/or combined gains of chromosome 7 and losses of chromosome 10 (+7/−10) are now classified as IDH-wildtype glioblastomas, even when histology shows no microvascular proliferation and/or necrosis. In addition, several new pediatric-type diffuse gliomas have been introduced that must be distinguished from the more common adult-type diffuse gliomas. Conclusions: The 2021 WHO classification 2021 introduces new tumor types and implements fundamental conceptual changes based on new molecular findings, which increase diagnostic precision and improve clinical care through modified treatment recommendations. The new WHO classification also has a major impact on the design of future clinical trials in neuro-oncology.

Published
2022

208. Additional file 1 of Droplet digital PCR-based analyses for robust, rapid, and sensitive molecular diagnostics of gliomas

Author

Wolter, Marietta, Felsberg, Jörg, Malzkorn, Bastian, Kaulich, Kerstin, and Reifenberger, Guido

Abstract

Additional file1. Table S1 Overview of the primer and probe sequences used for the individual ddPCR assays in this study including both previously published and newly designed assays. Table S2 Commercially available assays used for ddPCR-based single nucleotide variant (SNV) and copy number variation (CNV) analyses of certain biomarkers. Table S3 Primers and probes used for ddPCR-based single nucleotide polymorphism (SNP) analysis on chromosomal arms 1p and 19q. Table S4 Primers and probes used for ddPCR-based SNP analysis on chromosome 10. Table S5 Thermocycler conditions used for ddPCR assays. Table S6 Sensitivity, specificity, accuracy, and precision of each ddPCR assay investigated in relation to the respective method used for validation. Table S7 Detection of IDH1 and IDH2 mutations using duplex and multiplex ddPCR assays. Table S8 Detection of BRAF V600E and BRAF V600K mutations using duplex ddPCR assays. Table S9 Detection of H3-3A p.K28M and H3-3A p.G35R mutations using duplex ddPCR assays. Table S10 Comparison of the experimentally detected mean allele frequency (AF) of deleted SNP loci on 1p and 19q versus the AF calculated from the mutant allele frequency (MAF) of TERTp (a) or IDH1/2 (b) mutations. Table S11 Comparison of the experimentally detected mean allele frequency (AF) of deleted SNP loci on chromosome 10 versus the AF calculated from the mutant allele frequency (MAF) of TERTp mutations. Table S12 Detection of the EGFRvIII variant using ddPCR as well as comparison of a commercially available PrimePCR™ ddPCR (a) and a self-designed (b) copy number assay for EGFR exon 28. Table S13 Determination of CDKN2A copy number in 66 glioma samples using a PrimePCR™ ddPCR CDKN2A copy number assay. Fig. S1 Detection of IDH1 and IDH2 hotspot mutations in FFPE DNA using ddPCR. Fig. S2 Sensitivity of ddPCR to detect IDH1 R132H (a), BRAF V600E (b) as well as H3-3A p.K28M (c.83A>T) (c) and H3-3A p.G35R (c.103G>A) (d) mutations in FFPE DNA. Fig. S3 Detection of BRAF V600E (a) and BRAF V600K (b) mutations in FFPE DNA using ddPCR. Fig. S4 Detection of H3-3A p.K28M and H3-3A p.G35R/V mutations in FFPE DNA using ddPCR. Fig. S5 Detection of the PRKCA D463H mutation in chordoid glioma FFPE tissue samples using ddPCR. Fig. S6 Analysis of copy number variations on chromosomal arms 1p and 19q in 15 glioma samples using ddPCR. Fig. S7 Loss of heterozygosity (LOH) on chromosomal arms 1p and 19q (a, b) as well as on chromosome 10 (c) detected by ddPCR-based SNP analysis. Fig. S8 Detection of BRAF duplication in 20 pilocytic astrocytomas by ddPCR analysis of UBN2 and BRAF copy number using the assay reported by Appay et al. [8]. Fig. S9 Job Report file of case 1 using the ARCHER® FusionPlex Panel and Archer Analysis software v6.2.7. Fig. S10 The general workflow for the ddPCR-based molecular diagnostics

Published
2022
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209. Additional file 3 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 3. Composition of cohorts mcPXA and histPXA in numbers.

Published
2022
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210. Additional file 5 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 5. Histological features observed in pleomorphic xanthoastrocytomas, (a) classical giant pleomorphic cells with multiple nuclei and prominent nucleolus, (b) extensive perivascular inflammatory infiltrates, (c) endothelial proliferations, (d) extensive myxoid matrix, (e) pseudopalisading necrosis, (f) pseudopapillary growth pattern, (g) biphasic pattern with spindle cell component and giant pleomorphic cell component, (h) extensive calcification, (i) small round blue cell morphology, (j) a thrombosed vessel; all depicted tumors had a maximum calibrated score above 0.9 for mcPXA; Supplementary figure 2 Overall survival (Kaplan-Meier curve) of patients in cohort mcPXA stratified after initial histological diagnosis (a) and BRAF V600E status (b); Supplementary figure 3 Typical copy number profile of mcPXA (upper panel) compared to that of mcGBM (lower panel); Supplementary figure 4 Copy number summary of cohort mcPXA altogether and stratified after WHO grade; Supplementary figure 5: The composition of cohorts histPXA and mcPXA, (a) 220 mcPXA cases with their histological composition, (b) 144 histPXA cases with their methylation class assignments (v11b4).

Published
2022
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211. Additional file 6 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Subjects
TheoryofComputation_MATHEMATICALLOGICANDFORMALLANGUAGES, ComputingMethodologies_SYMBOLICANDALGEBRAICMANIPULATION, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Data_FILES, GeneralLiterature_REFERENCE(e.g.,dictionaries,encyclopedias,glossaries)
Abstract

Additional file 6. List of abbreviations.

Published
2022
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212. Additional file 4 of Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival

Author

Ebrahimi, Azadeh, Korshunov, Andrey, Reifenberger, Guido, Capper, David, Felsberg, Joerg, Trisolini, Elena, Pollo, Bianca, Calatozzolo, Chiara, Prinz, Marco, Staszewski, Ori, Schweizer, Leonille, Schittenhelm, Jens, Harter, Patrick N., Paulus, Werner, Thomas, Christian, Kohlhof-Meinecke, Patricia, Seiz-Rosenhagen, Marcel, Milde, Till, Casalini, Bel��n M., Suwala, Abigail, Wefers, Annika K., Reinhardt, Annekathrin, Sievers, Philipp, Kramm, Christof M., Etminam, Nima, Unterberg, Andreas, Wick, Wolfgang, Herold-Mende, Christel, Sturm, Dominik, Pfister, Stefan M., Sill, Martin, Jones, David T. W., Schrimpf, Daniel, Reuss, David E., Aldape, Ken, Abdullaev, Zied, Sahm, Felix, von Deimling, Andreas, and Stichel, Damian

Abstract

Additional file 4. tSNE plot of histPXA cases with the set of reference samples underlying the classifier version v11b4; ���histPXA a��� represents cases with a calibrated score less than 0.9 in v11b4 classifier, ���histPXA b��� represents cases with a calibrated score of 0.9 or higher in v11b4 classifier.

Published
2022
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215. Glutaredoxin 2 promotes SP-1-dependent CSPG4 transcription and migration of wound healing NG2 glia and glioma cells: Enzymatic Taoism

Author

Wilms, Christina, primary, Lepka, Klaudia, additional, Häberlein, Felix, additional, Edwards, Steven, additional, Felsberg, Jörg, additional, Pudelko, Linda, additional, Lindenberg, Tobias T., additional, Poschmann, Gereon, additional, Qin, Nan, additional, Volbracht, Katrin, additional, Prozorovski, Tim, additional, Meuth, Sven G., additional, Kahlert, Ulf D., additional, Remke, Marc, additional, Aktas, Orhan, additional, Reifenberger, Guido, additional, Bräutigam, Lars, additional, Odermatt, Benjamin, additional, and Berndt, Carsten, additional

Published
2022
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216. First report from the meta-analysis of the randomized trials NORDIC, NOA-8 and CE.6 on elderly patients with glioblastoma

Author

Malmstrom, Annika, primary, Cantagallo, Eva, additional, Callaghan, Chris O, additional, Wick, Wolfgang, additional, Gronberg, Bjorn Henning, additional, Laperriere, Normand, additional, Rosell, Johan, additional, Marosi, Christine, additional, Weller, Michael, additional, Perry, James, additional, Brandes, Alba A, additional, Reifenberger, Guido, additional, Menten, Johan, additional, Meisner, Christoph, additional, Oppong, Felix, additional, and Gorlia, Thierry, additional

Published
2022
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217. EIF4EBP1 is transcriptionally upregulated by MYCN and associates with poor prognosis in neuroblastoma

Author

Voeltzke, Kai, primary, Scharov, Katerina, additional, Funk, Cornelius, additional, Kahler, Alisa, additional, Picard, Daniel, additional, Hauffe, Laura, additional, Orth, Martin F., additional, Remke, Marc, additional, Esposito, Irene, additional, Kirchner, Thomas, additional, Schramm, Alexander, additional, Rotblat, Barak, additional, Grünewald, Thomas G. P., additional, Reifenberger, Guido, additional, and Leprivier, Gabriel, additional

Published
2021
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218. Cross-Species Genomics Reveals Oncogenic Dependencies in ZFTA/C11orf95 Fusion-Positive Supratentorial Ependymomas

Author

Zheng, Tuyu, Ghasemi, David R, Okonechnikov, Konstantin, Korshunov, Andrey, Sill, Martin, Maass, Kendra K, da Silva, Patricia Benites Goncalves, Ryzhova, Marina, Gojo, Johannes, Stichel, Damian, Arabzade, Amir, Kupp, Robert, Benzel, Julia, Taya, Shinichiro, Adachi, Toma, Shiraishi, Ryo, Gerber, Nicolas U, Sturm, Dominik, Ecker, Jonas, Sievers, Philipp, Selt, Florian, Chapman, Rebecca, Haberler, Christine, Figarella-Branger, Dominique, Reifenberger, Guido, Fleischhack, Gudrun, Rutkowski, Stefan, Donson, Andrew M, Ramaswamy, Vijay, Capper, David, et al, and University of Zurich

Subjects
10036 Medical Clinic, 610 Medicine & health, 2730 Oncology
Published
2021

219. Integrated DNA methylation and copy-number profiling identify three clinically and biologically relevant groups of anaplastic glioma

Author

Wiestler, Benedikt, Capper, David, Sill, Martin, Jones, David T. W., Hovestadt, Volker, Sturm, Dominik, Koelsche, Christian, Bertoni, Anna, Schweizer, Leonille, Korshunov, Andrey, Weiß, Elisa K., Schliesser, Maximilian G., Radbruch, Alexander, Herold-Mende, Christel, Roth, Patrick, Unterberg, Andreas, Hartmann, Christian, Pietsch, Torsten, Reifenberger, Guido, Lichter, Peter, Radlwimmer, Bernhard, Platten, Michael, Pfister, Stefan M., von Deimling, Andreas, Weller, Michael, and Wick, Wolfgang

Published
2014
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220. Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort

Author

Pietsch, Torsten, Schmidt, Rene, Remke, Marc, Korshunov, Andrey, Hovestadt, Volker, Jones, David T. W., Felsberg, Jörg, Kaulich, Kerstin, Goschzik, Tobias, Kool, Marcel, Northcott, Paul A., von Hoff, Katja, von Bueren, André O., Friedrich, Carsten, Mynarek, Martin, Skladny, Heyko, Fleischhack, Gudrun, Taylor, Michael D., Cremer, Friedrich, Lichter, Peter, Faldum, Andreas, Reifenberger, Guido, Rutkowski, Stefan, and Pfister, Stefan M.

Published
2014
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222. Quantitative proteomic landscapes of primary and recurrent glioblastoma reveal a protumorigeneic role for FBXO2-dependent glioma-microenvironment interactions.

Author

Buehler, Marcel, Yi, Xiao, Ge, Weigang, Blattmann, Peter, Rushing, Elisabeth, Reifenberger, Guido, Felsberg, Joerg, Yeh, Charles, Corn, Jacob E, Regli, Luca, Zhang, Junyi, Cloos, Ann, Ravi, Vidhya M, Wiestler, Benedikt, Heiland, Dieter Henrik, Aebersold, Ruedi, Weller, Michael, Guo, Tiannan, and Weiss, Tobias

Published
2023
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223. AMPLIFY-NEOVAC: a randomized, 3-arm multicenter phase I trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with an immune checkpoint inhibitor targeting programmed death-ligand 1 in isocitrate dehydrogenase 1 mutant gliomas.

Author

Bunse, Lukas, Rupp, Anne-Kathleen, Poschke, Isabel, Bunse, Theresa, Lindner, Katharina, Wick, Antje, Blobner, Jens, Misch, Martin, Tabatabai, Ghazaleh, Glas, Martin, Schnell, Oliver, Gempt, Jens, Denk, Monika, Reifenberger, Guido, Bendszus, Martin, Wuchter, Patrick, Steinbach, Joachim P, Wick, Wolfgang, and Platten, Michael

Abstract

Introduction: Isocitrate dehydrogenase (IDH) mutations are disease-defining mutations in IDH-mutant astrocytomas and IDH-mutant and 1p/19q-codeleted oligodendrogliomas. In more than 80% of these tumors, point mutations in IDH type 1 (IDH1) lead to expression of the tumor-specific protein IDH1R132H. IDH1R132H harbors a major histocompatibility complex class II (MHCII)-restricted neoantigen that was safely and successfully targeted in a first-in human clinical phase 1 trial evaluating an IDH1R132H 20-mer peptide vaccine (IDH1-vac) in newly diagnosed astrocytomas concomitant to standard of care (SOC). Methods: AMPLIFY-NEOVAC is a randomized, 3-arm, window-of-opportunity, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of IDH1-vac combined with avelumab (AVE), an immune checkpoint inhibitor (ICI) targeting programmed death-ligand 1 (PD-L1). The target population includes patients with resectable IDH1R132H-mutant recurrent astrocytoma or oligodendroglioma after SOC. Neoadjuvant and adjuvant immunotherapy will be administered to 48 evaluable patients. In arm 1, 12 patients will receive IDH1-vac; in arm 2, 12 patients will receive the combination of IDH1-vac and AVE, and in arm 3, 24 patients will receive AVE only. Until disease progression according to immunotherapy response assessment for neuro-oncology (iRANO) criteria, treatment will be administered over a period of maximum 43 weeks (primary treatment phase) followed by facultative maintenance treatment. Perspective: IDH1R132H 20-mer peptide is a shared clonal driver mutation-derived neoepitope in diffuse gliomas. IDH1-vac safely targets IDH1R132H in newly diagnosed astrocytomas. AMPLIFY-NEOVAC aims at (1) demonstrating safety of enhanced peripheral IDH1-vac-induced T cell responses by combined therapy with AVE compared to IDH1-vac only and (2) investigating intra-glioma abundance and phenotypes of IDH1-vac induced T cells in exploratory post-treatment tissue analyses. In an exploratory analysis, both will be correlated with clinical outcome. Trial registration: NCT03893903. [ABSTRACT FROM AUTHOR]

Published
2022
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224. Chemotherapy for adult patients with spinal cord gliomas

Author

Gramatzki, Dorothee, Felsberg, Jörg, Hentschel, Bettina, Bähr, Oliver, Westphal, Manfred, Schackert, Gabriele, Tonn, Jörg Christian, Herrlinger, Ulrich, Loeffler, Markus, Pietsch, Torsten, Steinbach, Joachim Peter, Reifenberger, Guido, Roth, Patrick, Weller, Michael, University of Zurich, and Gramatzki, Dorothee

Subjects
2808 Neurology, 610 Medicine & health, 2701 Medicine (miscellaneous), 2730 Oncology, 10040 Clinic for Neurology
Published
2021

225. Molekulare und funktionelle Stabilität von Langzeit Glioblastom-Sphäroidkulturen unterstützten ihre Nützlichkeit als reproduzierbare In-vitro-Modelle

Author

Nickel, Ann-Christin, Picard, Daniel, Wolters, Marietta, Kaulich, Kerstin, Muhammad, Sajjad, Reifenberger, Guido, Hänggi, Daniel, Carro, Maria Stella, Remke, Marc, and Kahlert, Ulf Dietrich

Subjects
ddc: 610, 610 Medical sciences, Medicine
Abstract

Objective: Reproducible and clinically relevant in vitro drug testing of gliomas depends on appropriate cell models. Glioma stem-like cell-based 3D cultures emerged as an alternative to monolayer cell lines as 3D cultures may better represent tumor biology and hence also be more suitable for cancer [for full text, please go to the a.m. URL], 72. Jahrestagung der Deutschen Gesellschaft für Neurochirurgie (DGNC), Joint Meeting mit der Polnischen Gesellschaft für Neurochirurgie

Published
2021

226. PATH-39. INTEGRATED MOLECULAR-MORPHOLOGICAL MENINGIOMA CLASSIFICATION: A MULTICENTER RETROSPECTIVE ANALYSIS, RETRO- AND PROSPECTIVELY VALIDATED

Author

Maas, Sybren, primary, Stichel, Damian, additional, Hielscher, Thomas, additional, Sievers, Philipp, additional, Berghoff, Anna, additional, Schrimpf, Daniel, additional, Sill, Martin, additional, Euskirchen, Philipp, additional, Reuss, David, additional, Dohmen, Hildegard, additional, Stein, Marco, additional, Baumgarten, Peter, additional, Ricklefs, Franz, additional, Rushing, Elizabeth, additional, Bewerunge-Hudler, Melanie, additional, Ketter, Ralf, additional, Schittenhelm, Jens, additional, Jaunmuktane, Zane, additional, Leu, Severina, additional, Grady, Conor, additional, Serrano, Jonathan, additional, Golfinos, John, additional, Sen, Chandra, additional, Mawrin, Christian, additional, Jungk, Christine, additional, Hänggi, Daniel, additional, Westphal, Manfred, additional, Lamszus, Katrin, additional, Etminan, Nima, additional, Unterberg, Andreas, additional, Harter, Patrick, additional, Wirsching, Hans-Georg, additional, Neidert, Marian Christoph, additional, Ratliff, Miriam, additional, Platten, Michael, additional, Snuderl, Matija, additional, Aldape, Kenneth, additional, Brandner, Sebastian, additional, Hench, Jürgen, additional, Frank, Stephan, additional, Pfister, Stefan, additional, Jones, David, additional, Reifenberger, Guido, additional, Acker, Till, additional, Wick, Wolfgang, additional, Weller, Michael, additional, Preusser, Matthias, additional, von Deimling, Andreas, additional, and Sahm, Felix, additional

Published
2021
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228. The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma

Author

Ahmadov, Ulvi, primary, Picard, Daniel, additional, Bartl, Jasmin, additional, Silginer, Manuela, additional, Trajkovic-Arsic, Marija, additional, Qin, Nan, additional, Blümel, Lena, additional, Wolter, Marietta, additional, Lim, Jonathan K. M., additional, Pauck, David, additional, Winkelkotte, Alina Marie, additional, Melcher, Marlen, additional, Langini, Maike, additional, Marquardt, Viktoria, additional, Sander, Felix, additional, Stefanski, Anja, additional, Steltgens, Sascha, additional, Hassiepen, Christina, additional, Kaufhold, Anna, additional, Meyer, Frauke-Dorothee, additional, Seibt, Annette, additional, Kleinesudeik, Lara, additional, Hain, Anika, additional, Münk, Carsten, additional, Knobbe-Thomsen, Christiane Brigitte, additional, Schramm, Alexander, additional, Fischer, Ute, additional, Leprivier, Gabriel, additional, Stühler, Kai, additional, Fulda, Simone, additional, Siveke, Jens T., additional, Distelmaier, Felix, additional, Borkhardt, Arndt, additional, Weller, Michael, additional, Roth, Patrick, additional, Reifenberger, Guido, additional, and Remke, Marc, additional

Published
2021
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229. GOPC:ROS1 and other ROS1 fusions represent a rare but recurrent drug target in a variety of glioma types

Author

Sievers, Philipp, primary, Stichel, Damian, additional, Sill, Martin, additional, Schrimpf, Daniel, additional, Sturm, Dominik, additional, Selt, Florian, additional, Ecker, Jonas, additional, Kazdal, Daniel, additional, Miele, Evelina, additional, Kranendonk, Mariëtte E. G., additional, Tops, Bastiaan B. J., additional, Kohlhof-Meinecke, Patricia, additional, Beschorner, Rudi, additional, Kramm, Christof M., additional, Hasselblatt, Martin, additional, Reifenberger, Guido, additional, Capper, David, additional, Wesseling, Pieter, additional, Stenzinger, Albrecht, additional, Milde, Till, additional, Korshunov, Andrey, additional, Witt, Olaf, additional, Pfister, Stefan M., additional, Wick, Wolfgang, additional, von Deimling, Andreas, additional, Jones, David T. W., additional, and Sahm, Felix, additional

Published
2021
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231. DNA methylation-based classification of central nervous system tumours

Author

Capper, David, Jones, David T. W., Sill, Martin, Hovestadt, Volker, Schrimpf, Daniel, Sturm, Dominik, Koelsche, Christian, Sahm, Felix, Chavez, Lukas, Reuss, David E., Kratz, Annekathrin, Wefers, Annika K., Huang, Kristin, Pajtler, Kristian W., Schweizer, Leonille, Stichel, Damian, Olar, Adriana, Engel, Nils W., Lindenberg, Kerstin, Harter, Patrick N., Braczynski, Anne K., Plate, Karl H., Dohmen, Hildegard, Garvalov, Boyan K., Coras, Roland, Hlsken, Annett, Hewer, Ekkehard, Bewerunge-Hudler, Melanie, Schick, Matthias, Fischer, Roger, Beschorner, Rudi, Schittenhelm, Jens, Staszewski, Ori, Wani, Khalida, Varlet, Pascale, Pages, Melanie, Temming, Petra, Lohmann, Dietmar, Selt, Florian, Witt, Hendrik, Milde, Till, Witt, Olaf, Aronica, Eleonora, Giangaspero, Felice, Rushing, Elisabeth, Scheurlen, Wolfram, Geisenberger, Christoph, Rodriguez, Fausto J., Becker, Albert, Preusser, Matthias, Haberler, Christine, Bjerkvig, Rolf, Cryan, Jane, Farrell, Michael, Deckert, Martina, Hench, Jrgen, Frank, Stephan, Serrano, Jonathan, Kannan, Kasthuri, Tsirigos, Aristotelis, Brck, Wolfgang, Hofer, Silvia, Brehmer, Stefanie, Seiz-Rosenhagen, Marcel, Hnggi, Daniel, Hans, Volkmar, Rozsnoki, Stephanie, Hansford, Jordan R., Kohlhof, Patricia, Kristensen, Bjarne W., Lechner, Matt, Lopes, Beatriz, Mawrin, Christian, Ketter, Ralf, Kulozik, Andreas, Khatib, Ziad, Heppner, Frank, Koch, Arend, Jouvet, Anne, Keohane, Catherine, Mhleisen, Helmut, Mueller, Wolf, Pohl, Ute, Prinz, Marco, Benner, Axel, Zapatka, Marc, Gottardo, Nicholas G., Driever, Pablo Herniz, Kramm, Christof M., Mller, Hermann L., Rutkowski, Stefan, von Hoff, Katja, Frhwald, Michael C., Gnekow, Astrid, Fleischhack, Gudrun, Tippelt, Stephan, Calaminus, Gabriele, Monoranu, Camelia-Maria, Perry, Arie, Jones, Chris, Jacques, Thomas S., Radlwimmer, Bernhard, Gessi, Marco, Pietsch, Torsten, Schramm, Johannes, Schackert, Gabriele, Westphal, Manfred, Reifenberger, Guido, Wesseling, Pieter, Weller, Michael, Collins, Vincent Peter, Blmcke, Ingmar, Bendszus, Martin, Debus, Jrgen, Huang, Annie, Jabado, Nada, Northcott, Paul A., Paulus, Werner, Gajjar, Amar, Robinson, Giles W., Taylor, Michael D., Jaunmuktane, Zane, Ryzhova, Marina, Platten, Michael, Unterberg, Andreas, Wick, Wolfgang, Karajannis, Matthias A., Mittelbronn, Michel, Acker, Till, Hartmann, Christian, Aldape, Kenneth, Schller, Ulrich, Buslei, Rolf, Lichter, Peter, Kool, Marcel, Herold-Mende, Christel, Ellison, David W., Hasselblatt, Martin, Snuderl, Matija, Brandner, Sebastian, Korshunov, Andrey, von Deimling, Andreas, and Pfister, Stefan M.

Subjects
Cancer diagnosis -- Methods, Methylation -- Observations, DNA sequencing -- Methods, Tumors -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challengingwith substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology., Author(s): David Capper [1, 2, 3, 4]; David T. W. Jones [5, 6]; Martin Sill [5, 6, 7]; Volker Hovestadt [8]; Daniel Schrimpf [1, 2]; Dominik Sturm [5, 6, 9]; [...]

Published
2018
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232. The landscape of genomic alterations across childhood cancers

Author

Grbner, Susanne N., Worst, Barbara C., Weischenfeldt, Joachim, Buchhalter, Ivo, Kleinheinz, Kortine, Rudneva, Vasilisa A., Johann, Pascal D., Balasubramanian, Gnana Prakash, Segura-Wang, Maia, Brabetz, Sebastian, Bender, Sebastian, Hutter, Barbara, Sturm, Dominik, Pfaff, Elke, Hbschmann, Daniel, Zipprich, Gideon, Heinold, Michael, Eils, Jrgen, Lawerenz, Christian, Erkek, Serap, Lambo, Sander, Waszak, Sebastian, Blattmann, Claudia, Borkhardt, Arndt, Kuhlen, Michaela, Eggert, Angelika, Fulda, Simone, Gessler, Manfred, Wegert, Jenny, Kappler, Roland, Baumhoer, Daniel, Burdach, Stefan, Kirschner-Schwabe, Renate, Kontny, Udo, Kulozik, Andreas E., Lohmann, Dietmar, Hettmer, Simone, Eckert, Cornelia, Bielack, Stefan, Nathrath, Michaela, Niemeyer, Charlotte, Richter, Gnther H., Schulte, Johannes, Siebert, Reiner, Westermann, Frank, Molenaar, Jan J., Vassal, Gilles, Witt, Hendrik, Lichter, Peter, Weber, Ursula, Eils, Roland, Korshunov, Andrey, Witt, Olaf, Pfister, Stefan, Reifenberger, Guido, Felsberg, Jrg, von Kalle, Christof, Schmidt, Manfred, Bartholom, Cynthia, Taylor, Michael, Jones, David, Jger, Natalie, Korbel, Jan, Sttz, Adrian, Rausch, Tobias, Radlwimmer, Bernhard, Yaspo, Marie-Laure, Lehrach, Hans, Warnatz, Hans-Jrg, Landgraf, Pablo, Brors, Benedikt, Zapatka, Marc, Wagner, Susanne, Haake, Andrea, Richter, Julia, Richter, Gesine, Lawerenz, Chris, Kerssemakers, Jules, Jaeger-Schmidt, Christina, Scholz, Ingrid, Bergmann, Anke K., Borst, Christoph, Burkhardt, Birgit, Claviez, Alexander, Dreyling, Martin, Eberth, Sonja, Einsele, Hermann, Frickhofen, Norbert, Haas, Siegfried, Hansmann, Martin-Leo, Karsch, Dennis, Kneba, Michael, Lisfeld, Jasmin, Mantovani-Lffler, Luisa, Rohde, Marius, Ott, German, Stadler, Christina, Staib, Peter, Stilgenbauer, Stephan, Trmper, Lorenz, Zenz, Thorsten, Kube, Dieter, Kppers, Ralf, Weniger, Marc, Hummel, Michael, Klapper, Wolfram, Kostezka, Ulrike, Lenze, Dido, Mller, Peter, Rosenwald, Andreas, Szczepanowski, Monika, Ammerpohl, Ole, Aukema, Sietse M., Binder, Vera, Hoell, Jessica I., Leich, Ellen, Lpez, Cristina, Nagel, Inga, Pischimariov, Jordan, Rosenstiel, Philip, Schilhabel, Markus, Schreiber, Stefan, Vater, Inga, Wagener, Rabea, Bernhart, Stephan H., Binder, Hans, Doose, Gero, Hoffmann, Steve, Hopp, Lydia, Kretzmer, Helene, Kreuz, Markus, Langenberger, David, Loeffler, Markus, Rosolowski, Maciej, Schlesner, Matthias, Stadler, Peter F., Sungalee, Stephanie, Kratz, Christian P., van Tilburg, Cornelis M., Kramm, Christof M., Fleischhack, Gudrun, Dirksen, Uta, Rutkowski, Stefan, Frhwald, Michael, von Hoff, Katja, Wolf, Stephan, Klingebiel, Thomas, Koscielniak, Ewa, Koster, Jan, Resnick, Adam C., Zhang, Jinghui, Liu, Yanling, Zhou, Xin, Waanders, Angela J., Zwijnenburg, Danny A., Raman, Pichai, Weber, Ursula D., Northcott, Paul A., Pajtler, Kristian W., Kool, Marcel, Piro, Rosario M., Korbel, Jan O., Jones, David T. W., Chavez, Lukas, and Pfister, Stefan M.

Subjects
Childhood cancer -- Genetic aspects, Cancer research, Gene mutation -- Health aspects, Genomics -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 78% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials., Author(s): Susanne N. Grbner [1, 2, 3]; Barbara C. Worst [1, 2, 3, 4]; Joachim Weischenfeldt [5, 6]; Ivo Buchhalter [7]; Kortine Kleinheinz [7]; Vasilisa A. Rudneva [5, 8]; Pascal [...]

Published
2018
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233. Correction to: DNA methylation-based reclassification of olfactory neuroblastoma

Author

Capper, David, Engel, Nils W., Stichel, Damian, Lechner, Matt, Glöss, Stefanie, Schmid, Simone, Kölsche, Christian, Schrimpf, Daniel, Niesen, Judith, Wefers, Annika K., Jones, David T. W., Sill, Martin, Weigert, Oliver, Ligon, Keith L., Olar, Adriana, Koch, Arend, Forster, Martin, Moran, Sebastian, Tirado, Oscar M., Sáinz-Jaspeado, Miguel, Mora, Jaume, Esteller, Manel, Alonso, Javier, del Muro, Xavier Garcia, Paulus, Werner, Felsberg, Jörg, Reifenberger, Guido, Glatzel, Markus, Frank, Stephan, Monoranu, Camelia M., Lund, Valerie J., von Deimling, Andreas, Pfister, Stefan, Buslei, Rolf, Ribbat-Idel, Julika, Perner, Sven, Gudziol, Volker, Meinhardt, Matthias, and Schüller, Ulrich

Published
2018
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236. BCAT1 promotes cell proliferation through amino acid catabolism in gliomas carrying wild-type IDH1

Author

Tonjes, Martje, Barbus, Sebastian, Park, Yoon Jung, Wang, Wei, Schlotter, Magdalena, Lindroth, Anders M., Pleier, Sabrina V., Bai, Alfa H.C., Karra, Daniela, Piro, Rosario M., Felsberg, Jorg, Addington, Adele, Lemke, Dieter, Weibrecht, Irene, Hovestadt, Volker, Rolli, Claudio G., Campos, Benito, Turcan, Sevin, Sturm, Dominik, Witt, Hendrik, Chan, Timothy A., Herold-Mende, Christel, Kemkemer, Ralf, Konig, Rainer, Schmidt, Kathrin, Hull, William-Edmund, Pfister, Stefan M., Jugold, Manfred, Hutson, Susan M., Plass, Christoph, Okun, Jurgen G., Reifenberger, Guido, Lichter, Peter, and Radlwimmer, Bernhard

Subjects
Cell proliferation -- Physiological aspects -- Genetic aspects -- Research, Methylation -- Physiological aspects -- Genetic aspects -- Research, Amino acid metabolism -- Research, Gliomas -- Genetic aspects -- Care and treatment -- Research, Biological sciences, Health
Abstract

Here we show that glioblastoma express high levels of branched-chain amino acid transaminase 1 (BCAT1), the enzyme that initiates the catabolism of branched-chain amino acids (BCAAs). Expression of BCAT1 was [...]

Published
2013
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237. Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays

Author

Hovestadt, Volker, Remke, Marc, Kool, Marcel, Pietsch, Torsten, Northcott, Paul A., Fischer, Roger, Cavalli, Florence M. G., Ramaswamy, Vijay, Zapatka, Marc, Reifenberger, Guido, Rutkowski, Stefan, Schick, Matthias, Bewerunge-Hudler, Melanie, Korshunov, Andrey, Lichter, Peter, Taylor, Michael D., Pfister, Stefan M., and Jones, David T. W.

Published
2013
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238. Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Author

Sievers, Philipp, primary, Henneken, Sophie C., additional, Blume, Christina, additional, Sill, Martin, additional, Schrimpf, Daniel, additional, Stichel, Damian, additional, Okonechnikov, Konstantin, additional, Reuss, David E., additional, Benzel, Julia, additional, Maaß, Kendra K., additional, Kool, Marcel, additional, Sturm, Dominik, additional, Zheng, Tuyu, additional, Ghasemi, David R., additional, Kohlhof-Meinecke, Patricia, additional, Cruz, Ofelia, additional, Suñol, Mariona, additional, Lavarino, Cinzia, additional, Ruf, Viktoria, additional, Boldt, Henning B., additional, Pagès, Mélanie, additional, Pouget, Celso, additional, Schweizer, Leonille, additional, Kranendonk, Mariëtte E. G., additional, Akhtar, Noreen, additional, Bunkowski, Stephanie, additional, Stadelmann, Christine, additional, Schüller, Ulrich, additional, Mueller, Wolf C., additional, Dohmen, Hildegard, additional, Acker, Till, additional, Harter, Patrick N., additional, Mawrin, Christian, additional, Beschorner, Rudi, additional, Brandner, Sebastian, additional, Snuderl, Matija, additional, Abdullaev, Zied, additional, Aldape, Kenneth, additional, Gilbert, Mark R., additional, Armstrong, Terri S., additional, Ellison, David W., additional, Capper, David, additional, Ichimura, Koichi, additional, Reifenberger, Guido, additional, Grundy, Richard G., additional, Jabado, Nada, additional, Krskova, Lenka, additional, Zapotocky, Michal, additional, Vicha, Ales, additional, Varlet, Pascale, additional, Wesseling, Pieter, additional, Rutkowski, Stefan, additional, Korshunov, Andrey, additional, Wick, Wolfgang, additional, Pfister, Stefan M., additional, Jones, David T. W., additional, von Deimling, Andreas, additional, Pajtler, Kristian W., additional, and Sahm, Felix, additional

Published
2021
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239. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary

Author

Louis, David N, primary, Perry, Arie, additional, Wesseling, Pieter, additional, Brat, Daniel J, additional, Cree, Ian A, additional, Figarella-Branger, Dominique, additional, Hawkins, Cynthia, additional, Ng, H K, additional, Pfister, Stefan M, additional, Reifenberger, Guido, additional, Soffietti, Riccardo, additional, von Deimling, Andreas, additional, and Ellison, David W, additional

Published
2021
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241. EMBR-13. NOVEL SYNERGISTIC APPROACHES FOR TARGETED THERAPY OF MYC-DRIVEN MEDULLOBLASTOMA USING CRISPR/CAS9 GENE EDITING

Author

Qin, Nan, primary, Picard, Daniel, additional, Rickert, Daniel, additional, Meyer, Frauke-Dorothee, additional, Blümel, Lena, additional, Göbbels, Sarah, additional, Bartl, Jasmin, additional, Pauck, David, additional, Fischer, Ute, additional, Borkhardt, Arndt, additional, Reifenberger, Guido, additional, and Remke, Marc, additional

Published
2021
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243. Clear cell meningiomas are defined by a highly distinct DNA methylation profile and mutations in SMARCE1

Author

Sievers, Philipp, Sill, Martin, Blume, Christina, Tauziede-Espariat, Arnault, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Dogan, Helin, Hartmann, Christian, Mawrin, Christian, Hasselblatt, Martin, Stummer, Walter, Schick, Uta, Hench, Jürgen, Frank, Stephan, Ketter, Ralf, Schweizer, Leonille, Schittenhelm, Jens, Puget, Stéphanie, Brandner, Sebastian, Jaunmuktane, Zane, Küsters, Benno, Abdullaev, Zied, Pekmezci, Melike, Snuderl, Matija, Ratliff, Miriam, Herold-Mende, Christel, Unterberg, Andreas, Aldape, Kenneth, Ellison, David W, Wesseling, Pieter, Reifenberger, Guido, Wick, Wolfgang, Perry, Arie, Varlet, Pascale, Pfister, Stefan M, Jones, David TW, von Deimling, Andreas, Sahm, Felix, and German Consortium 'Aggressive Meningiomas'

Subjects
Male, German Consortium “Aggressive Meningiomas”, DNA Mutational Analysis, Clinical Sciences, DNA methylation profile, Cohort Studies, Young Adult, Rare Diseases, Genetic, otorhinolaryngologic diseases, Genetics, Humans, 2.1 Biological and endogenous factors, Aetiology, Child, neoplasms, Clear cell, Cancer, Pediatric, Neurology & Neurosurgery, Brain Neoplasms, Human Genome, Neurosciences, Non-Histone, DNA, DNA Methylation, SMARCE1, Immunohistochemistry, nervous system diseases, Brain Disorders, Brain tumor, Chromosomal Proteins, DNA-Binding Proteins, Brain Cancer, Neoplasm Recurrence, Treatment Outcome, Local, Mutation, Disease Progression, Neoplasm, Female, Meningioma, Epigenesis, Genome-Wide Association Study
Abstract

Clear cell meningioma represents an uncommon variant of meningioma that typically affects children and young adults. Although an enrichment of loss-of-function mutations in the SMARCE1 gene has been reported for this subtype, comprehensive molecular investigations are lacking. Here we describe a molecularly distinct subset of tumors (n = 31), initially identified through genome-wide DNA methylation screening among a cohort of 3093 meningiomas, of which most were diagnosed histologically as clear cell meningioma. This cohort was further supplemented by an additional 11 histologically diagnosed clear cell meningiomas for analysis (n = 42). Targeted DNA sequencing revealed SMARCE1 mutations in 33/34 analyzed samples, accompanied by a nuclear loss of expression determined via immunohistochemistry and a decreased SMARCE1 transcript expression in the tumor cells. Analysis of time to progression or recurrence of patients within the clear cell meningioma group (n = 14) in comparison to those with meningioma WHO grade 2 (n = 220) revealed a similar outcome and support the assignment of WHO grade 2 to these tumors. Our findings indicate the existence of a highly distinct epigenetic signature of clear cell meningiomas, separate from all other variants of meningiomas, with recurrent mutations in the SMARCE1 gene. This suggests that these tumors may arise from a different precursor cell population than the broad spectrum of the other meningioma subtypes.

Published
2021

244. Integrative Genomic Analyses of Patient-Matched Intracranial and Extracranial Metastases Reveal a Novel Brain-Specific Landscape of Genetic Variants in Driver Genes of Malignant Melanoma

Author

Váraljai, Renáta, Horn, Susanne, Sucker, Antje, Pierscianek, Daniela, Schmitt, Verena, Carpinteiro, Alexander, Becker, Katrin Anne, Reifenberger, Julia, Roesch, Alexander, Felsberg, Joerg, Reifenberger, Guido, Sure, Ulrich, Schadendorf, Dirk, and Helfrich, Iris

Subjects
oncogenes, Medizin, Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Dermatologie, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Anatomie, melanoma brain metastases, matched-pair analyses, single nucleotide polymorphism, mutational load, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, lcsh:RC254-282, Article, Medizinische Fakultät » Universitätsklinikum Essen » Institut für Molekularbiologie (Tumorforschung), Medizinische Fakultät » Universitätsklinikum Essen » Klinik für Neurochirurgie Wirbelsäulenchirurgie, ddc:610
Abstract

Background: Development of brain metastases in advanced melanoma patients is a frequent event that limits patients’ quality of life and survival. Despite recent insights into melanoma genetics, systematic analyses of genetic alterations in melanoma brain metastasis formation are lacking. Moreover, whether brain metastases harbor distinct genetic alterations beyond those observed at different anatomic sites of the same patient remains unknown. Experimental Design and Results: In our study, 54 intracranial and 18 corresponding extracranial melanoma metastases were analyzed for mutations using targeted next generation sequencing of 29 recurrently mutated driver genes in melanoma. In 11 of 16 paired samples, we detected nucleotide modifications in brain metastases that were absent in matched metastases at extracranial sites. Moreover, we identified novel genetic variants in ARID1A, ARID2, SMARCA4 and BAP1, genes that have not been linked to brain metastases before, albeit most frequent mutations were found in ARID1A, ARID2 and BRAF. Conclusion: Our data provide new insights into the genetic landscape of intracranial melanoma metastases supporting a branched evolution model of metastasis formation.

Published
2021

245. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.

Author

Sievers, Philipp, Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Sturm, Dominik, Hench, Jürgen, Frank, Stephan, Krskova, Lenka, Vicha, Ales, Zapotocky, Michal, Bison, Brigitte, Castel, David, Grill, Jacques, Debily, Marie-Anne, Harter, Patrick N, Snuderl, Matija, Kramm, Christof M, Reifenberger, Guido, Korshunov, Andrey, Jabado, Nada, Wesseling, Pieter, Wick, Wolfgang, Solomon, David A, Perry, Arie, Jacques, Thomas S, Jones, Chris, Witt, Olaf, Pfister, Stefan M, von Deimling, Andreas, Jones, David TW, Sahm, Felix, Sievers, Philipp, Sievers, Philipp, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Reuss, David E, Sturm, Dominik, Hench, Jürgen, Frank, Stephan, Krskova, Lenka, Vicha, Ales, Zapotocky, Michal, Bison, Brigitte, Castel, David, Grill, Jacques, Debily, Marie-Anne, Harter, Patrick N, Snuderl, Matija, Kramm, Christof M, Reifenberger, Guido, Korshunov, Andrey, Jabado, Nada, Wesseling, Pieter, Wick, Wolfgang, Solomon, David A, Perry, Arie, Jacques, Thomas S, Jones, Chris, Witt, Olaf, Pfister, Stefan M, von Deimling, Andreas, Jones, David TW, and Sahm, Felix

Abstract

BackgroundMalignant astrocytic gliomas in children show a remarkable biological and clinical diversity. Small in-frame insertions or missense mutations in the epidermal growth factor receptor gene (EGFR) have recently been identified in a distinct subset of pediatric-type bithalamic gliomas with a unique DNA methylation pattern.MethodsHere, we investigated an epigenetically homogeneous cohort of malignant gliomas (n = 58) distinct from other subtypes and enriched for pediatric cases and thalamic location, in comparison with this recently identified subtype of pediatric bithalamic gliomas.ResultsEGFR gene amplification was detected in 16/58 (27%) tumors, and missense mutations or small in-frame insertions in EGFR were found in 20/30 tumors with available sequencing data (67%; 5 of them co-occurring with EGFR amplification). Additionally, 8 of the 30 tumors (27%) harbored an H3.1 or H3.3 K27M mutation (6 of them with a concomitant EGFR alteration). All tumors tested showed loss of H3K27me3 staining, with evidence of overexpression of the EZH inhibitory protein (EZHIP) in the H3 wildtype cases. Although some tumors indeed showed a bithalamic growth pattern, a significant proportion of tumors occurred in the unilateral thalamus or in other (predominantly midline) locations.ConclusionsOur findings present a distinct molecular class of pediatric-type malignant gliomas largely overlapping with the recently reported bithalamic gliomas characterized by EGFR alteration, but additionally showing a broader spectrum of EGFR alterations and tumor localization. Global H3K27me3 loss in this group appears to be mediated by either H3 K27 mutation or EZHIP overexpression. EGFR inhibition may represent a potential therapeutic strategy in these highly aggressive gliomas.

Published
2021

246. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary.

Author

Louis, David N, Louis, David N, Perry, Arie, Wesseling, Pieter, Brat, Daniel J, Cree, Ian A, Figarella-Branger, Dominique, Hawkins, Cynthia, Ng, HK, Pfister, Stefan M, Reifenberger, Guido, Soffietti, Riccardo, von Deimling, Andreas, Ellison, David W, Louis, David N, Louis, David N, Perry, Arie, Wesseling, Pieter, Brat, Daniel J, Cree, Ian A, Figarella-Branger, Dominique, Hawkins, Cynthia, Ng, HK, Pfister, Stefan M, Reifenberger, Guido, Soffietti, Riccardo, von Deimling, Andreas, and Ellison, David W

Abstract

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

Published
2021

247. Sarcomatous Meningioma: Diagnostic Pitfalls and the Utility of Molecular Testing.

Author

Lucas, Calixto-Hope G, Lucas, Calixto-Hope G, Devine, Patrick, Solomon, David A, Giannini, Caterina, Reifenberger, Guido, Dahiya, Sonika, Caccamo, Dario, Perry, Arie, Lucas, Calixto-Hope G, Lucas, Calixto-Hope G, Devine, Patrick, Solomon, David A, Giannini, Caterina, Reifenberger, Guido, Dahiya, Sonika, Caccamo, Dario, and Perry, Arie

Abstract

Anaplastic meningiomas can have a sarcomatous appearance on histology but true sarcomatous (metaplastic) differentiation is rare. These tumors follow an aggressive clinical course with recurrence and poor clinical outcomes. Due to significant overlap in morphology and immunohistochemical profiles, distinguishing between sarcomatous transformation of a meningioma and a true sarcoma can be challenging. Here, we outline potential diagnostic pitfalls and the utility of ancillary molecular testing in 3 patients diagnosed with sarcomatous meningiomas. We report loss of typical meningothelial markers in sarcomatous meningiomas. Ancillary molecular testing can support the diagnosis of sarcomatous meningioma when a molecular signature consistent with meningioma is seen, such as inactivation of the NF2 gene. Recognition of this rare transformation in meningioma can prevent a misdiagnosis of a primary sarcoma, whether sporadic or radiation-induced from prior treatment of a more classic meningioma.

Published
2021

248. The long non-coding RNA HOTAIRM1 promotes tumor aggressiveness and radiotherapy resistance in glioblastoma

Author

Ahmadov, Ulvi, Picard, Daniel, Bartl, Jasmin, Silginer, Manuela, Trajkovic-Arsic, Marija, Qin, Nan, Blümel, Lena, Wolter, Marietta, Lim, Jonathan K. M., Pauck, David, Winkelkotte, Alina M., Melcher, Marlen, Langini, Maike, Marquardt, Viktoria, Sander, Felix, Stefanski, Anja, Steltgens, Sascha, Hassiepen, Christina, Kaufhold, Anna, Meyer, Frauke-Dorothee, Seibt, Annette, Kleinesudeik, Lara, Hain, Anika, Münk, Carsten, Knobbe-Thomsen, Christiane Brigitte, Schramm, Alexander, Fischer, Ute, Leprivier, Gabriel, Stühler, Kai, Fulda, Simone, Siveke, Jens, Distelmaier, Felix, Borkhardt, Arndt, Weller, Michael, Roth, Patrick, Reifenberger, Guido, Remke, Marc, Ahmadov, Ulvi, Picard, Daniel, Bartl, Jasmin, Silginer, Manuela, Trajkovic-Arsic, Marija, Qin, Nan, Blümel, Lena, Wolter, Marietta, Lim, Jonathan K. M., Pauck, David, Winkelkotte, Alina M., Melcher, Marlen, Langini, Maike, Marquardt, Viktoria, Sander, Felix, Stefanski, Anja, Steltgens, Sascha, Hassiepen, Christina, Kaufhold, Anna, Meyer, Frauke-Dorothee, Seibt, Annette, Kleinesudeik, Lara, Hain, Anika, Münk, Carsten, Knobbe-Thomsen, Christiane Brigitte, Schramm, Alexander, Fischer, Ute, Leprivier, Gabriel, Stühler, Kai, Fulda, Simone, Siveke, Jens, Distelmaier, Felix, Borkhardt, Arndt, Weller, Michael, Roth, Patrick, Reifenberger, Guido, and Remke, Marc

Abstract

Glioblastoma is the most common malignant primary brain tumor. To date, clinically relevant biomarkers are restricted to isocitrate dehydrogenase (IDH) gene 1 or 2 mutations and O6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Long non-coding RNAs (lncRNAs) have been shown to contribute to glioblastoma pathogenesis and could potentially serve as novel biomarkers. The clinical significance of HOXA Transcript Antisense RNA, Myeloid-Specific 1 (HOTAIRM1) was determined by analyzing HOTAIRM1 in multiple glioblastoma gene expression data sets for associations with prognosis, as well as, IDH mutation and MGMT promoter methylation status. Finally, the role of HOTAIRM1 in glioblastoma biology and radiotherapy resistance was characterized in vitro and in vivo. We identified HOTAIRM1 as a candidate lncRNA whose up-regulation is significantly associated with shorter survival of glioblastoma patients, independent from IDH mutation and MGMT promoter methylation. Glioblastoma cell line models uniformly showed reduced cell viability, decreased invasive growth and diminished colony formation capacity upon HOTAIRM1 down-regulation. Integrated proteogenomic analyses revealed impaired mitochondrial function and determination of reactive oxygen species (ROS) levels confirmed increased ROS levels upon HOTAIRM1 knock-down. HOTAIRM1 knock-down decreased expression of transglutaminase 2 (TGM2), a candidate protein implicated in mitochondrial function, and knock-down of TGM2 mimicked the phenotype of HOTAIRM1 down-regulation in glioblastoma cells. Moreover, HOTAIRM1 modulates radiosensitivity of glioblastoma cells both in vitro and in vivo. Our data support a role for HOTAIRM1 as a driver of biological aggressiveness, radioresistance and poor outcome in glioblastoma. Targeting HOTAIRM1 may be a promising new therapeutic approach.

Published
2021

249. Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors

Author

Sievers, Philipp, Henneken, Sophie C., Blume, Christina, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Okonechnikov, Konstantin, Reuss, David, Benzel, Julia, Maaß, Kendra K., Kool, Marcel, Sturm, Dominik, Zheng, Tuyu, Ghasemi, David R., Kohlhof-Meinecke, Patricia, Cruz, Ofelia, Suñol, Mariona, Lavarino, Cinzia, Ruf, Viktoria, Boldt, Henning B., Pagès, Mélanie, Pouget, Celso, Schweizer, Leonille, Kranendonk, Mariëtte E. G., Akhtar, Noreen, Bunkowski, Stephanie, Stadelmann, Christine, Schüller, Ulrich, Müller, Wolf C., Dohmen, Hildegard, Acker, Till, Harter, Patrick Nikolaus, Mawrin, Christian, Beschorner, Rudi, Brandner, Sebastian, Snuderl, Matija, Abdullaev, Zied, Aldape, Kenneth, Gilbert, Mark R., Armstrong, Terri S., Ellison, David W., Capper, David, Ichimura, Koichi, Reifenberger, Guido, Grundy, Richard G., Jabado, Nada, Krskova, Lenka, Zapotocky, Michal, Vicha, Ales, Varlet, Pascale, Wesseling, Pieter, Rutkowski, Stefan, Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan, Jones, David T. W., Deimling, Andreas von, Pajtler, Kristian Wilfried, Sahm, Felix, Sievers, Philipp, Henneken, Sophie C., Blume, Christina, Sill, Martin, Schrimpf, Daniel, Stichel, Damian, Okonechnikov, Konstantin, Reuss, David, Benzel, Julia, Maaß, Kendra K., Kool, Marcel, Sturm, Dominik, Zheng, Tuyu, Ghasemi, David R., Kohlhof-Meinecke, Patricia, Cruz, Ofelia, Suñol, Mariona, Lavarino, Cinzia, Ruf, Viktoria, Boldt, Henning B., Pagès, Mélanie, Pouget, Celso, Schweizer, Leonille, Kranendonk, Mariëtte E. G., Akhtar, Noreen, Bunkowski, Stephanie, Stadelmann, Christine, Schüller, Ulrich, Müller, Wolf C., Dohmen, Hildegard, Acker, Till, Harter, Patrick Nikolaus, Mawrin, Christian, Beschorner, Rudi, Brandner, Sebastian, Snuderl, Matija, Abdullaev, Zied, Aldape, Kenneth, Gilbert, Mark R., Armstrong, Terri S., Ellison, David W., Capper, David, Ichimura, Koichi, Reifenberger, Guido, Grundy, Richard G., Jabado, Nada, Krskova, Lenka, Zapotocky, Michal, Vicha, Ales, Varlet, Pascale, Wesseling, Pieter, Rutkowski, Stefan, Korshunov, Andrey, Wick, Wolfgang, Pfister, Stefan, Jones, David T. W., Deimling, Andreas von, Pajtler, Kristian Wilfried, and Sahm, Felix

Abstract

Ependymomas encompass a heterogeneous group of central nervous system (CNS) neoplasms that occur along the entire neuroaxis. In recent years, extensive (epi-)genomic profiling efforts have identified several molecular groups of ependymoma that are characterized by distinct molecular alterations and/or patterns. Based on unsupervised visualization of a large cohort of genome-wide DNA methylation data, we identified a highly distinct group of pediatric-type tumors (n = 40) forming a cluster separate from all established CNS tumor types, of which a high proportion were histopathologically diagnosed as ependymoma. RNA sequencing revealed recurrent fusions involving the pleomorphic adenoma gene-like 1 (PLAGL1) gene in 19 of 20 of the samples analyzed, with the most common fusion being EWSR1:PLAGL1 (n = 13). Five tumors showed a PLAGL1:FOXO1 fusion and one a PLAGL1:EP300 fusion. High transcript levels of PLAGL1 were noted in these tumors, with concurrent overexpression of the imprinted genes H19 and IGF2, which are regulated by PLAGL1. Histopathological review of cases with sufficient material (n = 16) demonstrated a broad morphological spectrum of tumors with predominant ependymoma-like features. Immunohistochemically, tumors were GFAP positive and OLIG2- and SOX10 negative. In 3/16 of the cases, a dot-like positivity for EMA was detected. All tumors in our series were located in the supratentorial compartment. Median age of the patients at the time of diagnosis was 6.2 years. Median progression-free survival was 35 months (for 11 patients with data available). In summary, our findings suggest the existence of a novel group of supratentorial neuroepithelial tumors that are characterized by recurrent PLAGL1 fusions and enriched for pediatric patients.

Published
2021

250. Prognostic role of Ki-67 in glioblastomas excluding contribution from non-neoplastic cells

Author

Dahlrot, Rikke H., Bangsø, Julie A., Petersen, Jeanette K., Rosager, Ann Mari, Sørensen, Mia D., Reifenberger, Guido, Hansen, Steinbjørn, Kristensen, Bjarne W., Dahlrot, Rikke H., Bangsø, Julie A., Petersen, Jeanette K., Rosager, Ann Mari, Sørensen, Mia D., Reifenberger, Guido, Hansen, Steinbjørn, and Kristensen, Bjarne W.

Abstract

Survival of glioblastoma patients varies and prognostic markers are important in the clinical setting. With digital pathology and improved immunohistochemical multiplexing becoming a part of daily diagnostics, we investigated the prognostic value of the Ki-67 labelling index (LI) in glioblastomas more precisely than previously by excluding proliferation in non-tumor cells from the analysis. We investigated the Ki-67 LI in a well-annotated population-based glioblastoma patient cohort (178 IDH-wildtype, 3 IDH-mutated). Ki-67 was identified in full tumor sections with automated digital image analysis and the contribution from non-tumor cells was excluded using quantitative double-immunohistochemistry. For comparison of the Ki-67 LI between WHO grades (II-IV), 9 IDH-mutated diffuse astrocytomas and 9 IDH-mutated anaplastic astrocytomas were stained. Median Ki-67 LI increased with increasing WHO grade (median 2.7%, 6.4% and 27.5%). There was no difference in median Ki-67 LI between IDH-mutated and IDH-wildtype glioblastomas (p = 0.9) and Ki-67 LI was not associated with survival in glioblastomas in neither univariate (p = 0.9) nor multivariate analysis including MGMT promoter methylation status and excluding IDH-mutated glioblastomas (p = 0.2). Ki-67 may be of value in the differential diagnostic setting, but it must not be over-interpreted in the clinico-pathological context.

Published
2021

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