Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

doi:10.1093/neuonc/noaa106

Review

. 2020 Aug 17;22(8):1073-1113.

doi: 10.1093/neuonc/noaa106.

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

Patrick Y Wen¹, Michael Weller², Eudocia Quant Lee¹, Brian M Alexander¹, Jill S Barnholtz-Sloan³, Floris P Barthel⁴, Tracy T Batchelor⁵, Ranjit S Bindra⁶, Susan M Chang⁷, E Antonio Chiocca⁸, Timothy F Cloughesy⁹, John F DeGroot¹⁰, Evanthia Galanis¹¹, Mark R Gilbert¹², Monika E Hegi¹³, Craig Horbinski¹⁴, Raymond Y Huang¹⁵, Andrew B Lassman¹⁶, Emilie Le Rhun¹⁷, Michael Lim¹⁸, Minesh P Mehta¹⁹, Ingo K Mellinghoff²⁰, Giuseppe Minniti²¹, David Nathanson²², Michael Platten²³, Matthias Preusser²⁴, Patrick Roth², Marc Sanson²⁵, David Schiff²⁶, Susan C Short²⁷, Martin J B Taphoorn²⁸, Joerg-Christian Tonn²⁹, Jonathan Tsang²², Roel G W Verhaak⁴, Andreas von Deimling³⁰, Wolfgang Wick³¹, Gelareh Zadeh³², David A Reardon¹, Kenneth D Aldape³³, Martin J van den Bent³⁴

Affiliations

¹ Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
² Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
³ Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.
⁴ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
⁵ Department of Neurology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School.
⁶ Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, USA.
⁷ University of California San Francisco, San Francisco, California, USA.
⁸ Department of Neurosurgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
⁹ David Geffen School of Medicine, Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹¹ Mayo Clinic, Rochester, Minnesota, USA.
¹² Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹³ Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
¹⁵ Division of Neuroradiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Department of Neurology and Herbert Irving Comprehensive Cancer Center, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.
¹⁷ University of Lille, Inserm, Neuro-oncology, General and Stereotaxic Neurosurgery service, University Hospital of Lille, Lille, France; Breast Cancer Department, Oscar Lambret Center, Lille, France and Department of Neurology & Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
¹⁸ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Miami Cancer Institute, Miami, Florida, USA.
²⁰ Department of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
²¹ Radiation Oncology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
²² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, USA.
²³ Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Heidelberg, Germany.
²⁴ Division of Oncology, Department of Medicine, Medical University of Vienna, Vienna, Austria.
²⁵ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
²⁶ University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
²⁷ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
²⁸ Department of Neurology, Medical Center Haaglanden, The Hague and Department of Neurology, Leiden University Medical Center, the Netherlands.
²⁹ Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.
³⁰ Neuropathology and Clinical Cooperation Unit Neuropathology, University Heidelberg and German Cancer Center, Heidelberg, Germany.
³¹ Department of Neurology and Neuro-oncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
³² MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Canada.
³³ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
³⁴ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

PMID: 32328653
PMCID: PMC7594557
DOI: 10.1093/neuonc/noaa106

Review

Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

Patrick Y Wen et al. Neuro Oncol. 2020.

. 2020 Aug 17;22(8):1073-1113.

doi: 10.1093/neuonc/noaa106.

Authors

Affiliations

¹ Dana-Farber Cancer Institute, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
² Department of Neurology and Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
³ Case Western Reserve University School of Medicine and University Hospitals of Cleveland, Cleveland, Ohio, USA.
⁴ The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut, USA.
⁵ Department of Neurology, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School.
⁶ Department of Therapeutic Radiology, Yale School of Medicine, New Haven, Connecticut, USA.
⁷ University of California San Francisco, San Francisco, California, USA.
⁸ Department of Neurosurgery, Brigham and Women's Hospital, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
⁹ David Geffen School of Medicine, Department of Neurology, University of California Los Angeles, Los Angeles, California, USA.
¹⁰ Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
¹¹ Mayo Clinic, Rochester, Minnesota, USA.
¹² Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
¹³ Lausanne University Hospital and University of Lausanne, Lausanne, Switzerland.
¹⁴ Department of Pathology, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA.
¹⁵ Division of Neuroradiology, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
¹⁶ Department of Neurology and Herbert Irving Comprehensive Cancer Center, NewYork-Presbyterian Hospital/Columbia University Irving Medical Center, New York, New York, USA.
¹⁷ University of Lille, Inserm, Neuro-oncology, General and Stereotaxic Neurosurgery service, University Hospital of Lille, Lille, France; Breast Cancer Department, Oscar Lambret Center, Lille, France and Department of Neurology & Brain Tumor Center, University Hospital and University of Zurich, Zurich, Switzerland.
¹⁸ Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
¹⁹ Miami Cancer Institute, Miami, Florida, USA.
²⁰ Department of Neurology and Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
²¹ Radiation Oncology Unit, Department of Medicine, Surgery and Neuroscience, University of Siena, Siena, Italy.
²² Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, University of California Los Angeles, Los Angeles, California, USA.
²³ Department of Neurology, Medical Faculty Mannheim, MCTN, Heidelberg University, Heidelberg, Germany.
²⁴ Division of Oncology, Department of Medicine, Medical University of Vienna, Vienna, Austria.
²⁵ Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, Paris, France.
²⁶ University of Virginia School of Medicine, Division of Neuro-Oncology, Department of Neurology, University of Virginia, Charlottesville, Virginia, USA.
²⁷ Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK.
²⁸ Department of Neurology, Medical Center Haaglanden, The Hague and Department of Neurology, Leiden University Medical Center, the Netherlands.
²⁹ Department of Neurosurgery, University Hospital, LMU Munich, Munich, Germany.
³⁰ Neuropathology and Clinical Cooperation Unit Neuropathology, University Heidelberg and German Cancer Center, Heidelberg, Germany.
³¹ Department of Neurology and Neuro-oncology Program, National Center for Tumor Diseases, Heidelberg University Hospital, Heidelberg, Germany.
³² MacFeeters Hamilton Centre for Neuro-Oncology Research, Princess Margaret Cancer Centre, Toronto, Canada.
³³ Laboratory of Pathology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
³⁴ Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.

PMID: 32328653
PMCID: PMC7594557
DOI: 10.1093/neuonc/noaa106

Abstract

Glioblastomas are the most common form of malignant primary brain tumor and an important cause of morbidity and mortality. In recent years there have been important advances in understanding the molecular pathogenesis and biology of these tumors, but this has not translated into significantly improved outcomes for patients. In this consensus review from the Society for Neuro-Oncology (SNO) and the European Association of Neuro-Oncology (EANO), the current management of isocitrate dehydrogenase wildtype (IDHwt) glioblastomas will be discussed. In addition, novel therapies such as targeted molecular therapies, agents targeting DNA damage response and metabolism, immunotherapies, and viral therapies will be reviewed, as well as the current challenges and future directions for research.

Keywords: clinical trials; diagnosis; glioblastoma; therapy.

PubMed Disclaimer

Figures

**Fig. 1**
Glioblastoma. (A) Incidence rate per 100 000 persons by age at diagnosis and sex, Central Brain Tumor Registry of the United States (CBTRUS) 2012–1016 (50 US states and Puerto Rico included) and (B) 5-year relative survival probability (with 95% confidence intervals) by age at diagnosis and sex, National Program of Cancer Registries (NPCR) 2012–2016 (43 US states included). **Glioblastoma defined by International Classification of Disease-Oncology (ICD-O) version 3 codes 9440/3, 9441/3, 9442/3.

**Fig. 2**
Glioblastomas are characterized by somatic molecular defects in 3 major processes: initiating tumor growth, evading senescence and enabling immortal growth. Genomic abnormalities in each of the 3 processes appear required for gliomagenesis. The 3 processes are shown here, as are some of the most frequently altered genes and pathways.

**Fig. 3**
The many forms of GBM. (A) Classic GBM, with pseudopalisading necrosis and microvascular proliferation. (B) Giant cell GBM. (C) Epithelioid GBM with BRAF V600E. (D) Gliosarcoma. (E) Granular cell GBM. (F) Small cell GBM. All images are from the UPMC Neuropathology Virtual Slide Database, 200x magnification.

**Fig. 4**
Sixty-four-year-old with a glioblastoma who presented with word finding difficulty. FLAIR (A) and contrast-enhanced T1W (B) images show a large, necrotic-appearing, enhancing mass with surrounding T2/FLAIR signal abnormality in the periventricular regions. There is evidence of hypercellularity on ADC map (black arrow in C) and elevated blood volume on CBV map (white arrow in D)

**Fig. 5**
Contrast-enhanced MRI T1W (left) and ¹⁸FET-PET (right) of a 42-year-old patient showing much larger extent of a glioblastoma on the PET images compared with the enhancing tumor evident by MRI. The tumor extent on the PET image was confirmed by histology.

**Fig. 6**
Standard of care treatment paradigm for newly diagnosed glioblastoma.

**Fig. 7**
Standard of care treatment paradigm for recurrent glioblastoma.

**Fig. 8**
Microsurgical resection of a right-sided recurrent IDHwt glioblastoma WHO grade IV using intraoperative neuronavigation, neuromonitoring and 5-ALA fluorescence techniques. (A) T1 contrast enhanced axial, sagittal and coronal planes including DTI fiber tracking (blue fibers). The green trajectories/red points represent the pointer for intraoperative neuronavigation. (B) Upper image: corresponding intraoperative 5-ALA fluorescence image taken from the area as depicted by neuronavigation. Lower image: opening of the right ventricle due to critical involvement by tumor formation. (C) Postoperative MRI confirms gross total resection without residual contrast enhancement, no perilesional ischemia (diffusion-weighted image upper right).

**Fig. 9**
This figure shows, from left to right, how the transition from 2D RT to 3D RT to intensity modulated radiotherapy to intensity modulated proton therapy harnesses the potential for sparing normal, uninvolved brain substructures from unnecessary RT dose; whether this produces meaningful patient clinical benefit is a subject of current clinical trial testing.

**Fig. 10**
Selected recently completed or ongoing trials with targeted molecular therapies. CDK = cyclin-dependent kinase; EGF = epidermal growth factor; EGFR = epidermal growth factor receptor; FGFR = fibroblast growth factor receptor; GF = growth factor; HDAC = histone deacetylase; HSP = heat shock protein; MDM2 = murine double minute 2; mTOR = mammalian target of rapamycin; PARP = poly(ADP-ribose) polymerase; PDGFR = platelet derived growth factor receptor; PKC = protein kinase C; RTK = receptor tyrosine kinase; TGF-β = transforming growth factor beta; TGFβR = transforming growth factor beta receptor; TrK = tropomyosin receptor kinase; VEGF = vascular endothelial growth factor; VEGFR = vascular endothelial growth factor receptor; XPO1 = exportin 1.

**Fig. 11**
A simplified overview of signaling from common types of DNA damage to the DDR and cell cycle checkpoint pathways. Initial damage is sensed by proteins including the histone γ -H2AX, which is rapidly phosphorylated by ATM at a specific serine residue in response to chromatin structure alteration at DBS sites, activating recruitment of repair proteins including BRCA1 and the MRN complex (MRE11, Rad51, NBS1). DSB repair is undertaken by the end-joining pathway involving the kinase DNA-PK and Ku protein binding partners and the homologous recombination pathway involving Rad51 and associated proteins. Single strand breaks (SSB) and replication stress leading to stalled replication forks activate PARP which in turn recruits repair factors including XRCC1 and promotes chromatin remodeling at the break site and base excision repair. ATR and ATM function both in the initial signaling cascade and as transducers to downstream activation of the cell cycle checkpoints inhibitors, Chk1 and Chk2 producing cell cycle delay to facilitate repair. Points in the pathway at which specific inhibitors are available are indicated. As predicted from their roles in the DDR pathway, ATM and ATR inhibitors sensitize to a broad range of DNA damaging agents causing single or double strand breaks. PARPi and cell cycle checkpoint inhibitors including Wee1 inhibitors are specifically effective in cells undergoing rapid replication. DSB = Double Strand Break; SSB = Single Strand Break.

**Fig. 12**
An expanded pharmacopoeia of metabolic drug targets in glioblastoma (Adapted with permission from Bi et al. Nature Rev Cancer 2020;20:57–70.) The extensive focus on altered glioma metabolism has led to a considerable expansion in the list of potential drug targets. Receptor tyrosine kinase (RTK)-driven metabolic dependencies have also been identified. For example, epidermal growth factor receptor (EGFR) amplification produces major changes in metabolic enzyme dependencies, including in glucose uptake, glycolysis, fatty acid (FA) synthesis, membrane lipid remodeling, cholesterol uptake, NAD+ production and epigenetic remodeling. Targeting lysophosphatidylcholine (LysoPC) acyltransferase 1 (LPCAT1) decreases the level of saturated phosphatidylcholines (PCs) and disrupts plasma membrane localization of EGFR variant III (EGFRvIII), which blocks EGFRvIII- driven oncogenic signaling and suppresses glioblastoma (GBM) tumor growth. LXR-623, a brain- penetrant liver X receptor (LXR) agonist, targets the cholesterol homeostasis of GBM cells by promoting ATP- binding cassette subfamily A member 1 (ABCA1)-mediated cholesterol efflux and inhibiting low- density lipoprotein receptor (LDLR)-mediated cholesterol uptake. Isocitrate dehydrogenase (IDH) mutants in glioma cells generate the oncometabolite d-2-hydroxyglutarate (D2HG), which defines the dependencies of NAD+ and glutathione (GSH) production and impacts epigenetic events in glioma cells. The oxidative phosphorylation (OXPHOS) inhibitors, including metformin, Gboxin and IACS-010759, target glioma cells by inhibiting transmembrane protein complexes in the mitochondrial inner membrane, known as the electron transport chain (ETC). 2DG, 2-deoxy-d-glucose; 2PG, 2-phosphoglyceric acid; αKG, α-ketoglutarate; ACBP, acyl-CoA-binding protein; ACLY, ATP citrate lyase; ACSS2, acetyl-CoA synthetase; AMPK, AMP-activated protein kinase; BCAA, branched-chain amino acid; BCAT1, branched- chain amino acid transaminase 1; BCKA, branched-chain keto acid; BRD4, bromodomain containing 4; DCA, dichloroacetate; ELOVL2, ELOVL FA elongase 2; FASN, FA synthase; GDH1, glutamate dehydrogenase 1; GLS, glutaminase; GLUT1, glucose transporter 1; HSPD1, heat shock protein family D (Hsp60) member 1; IDH1, isocitrate dehydrogenase 1; LDHA, lactate dehydrogenase A; MCT1, monocarboxylate transporter 1; NA, nicotinic acid; NAMPT, nicotinamide phosphoribosyl-transferase; NAPRT1, nicotinate phosphoribosyltransferase domain containing 1; NM, nicotinamide; PDK, pyruvate dehydrogenase kinase; PEP, 2-phosphoenolpyruvate; PKM2, pyruvate kinase muscle isozyme M2; SHMT1, serine hydroxymethyltransferase 1; TCA, tricarboxylic acid; xCT, cystine/glutamate transporter. Reproduced with permission from Bi J, et al.

**Figure 13.**
Challenges to effectively treat GBM include (top) the presence of the blood–brain barrier that precludes the delivery of many drugs into the brain coupled to (middle) an immunosuppressive microenvironment and (bottom) compensatory signaling networks that can render GBM therapies ineffective.

See this image and copyright information in PMC

Comment in

In the midst of crisis, a great opportunity.
Strowd RE. Strowd RE. Neuro Oncol. 2020 Aug 17;22(8):1056-1057. doi: 10.1093/neuonc/noaa143. Neuro Oncol. 2020. PMID: 32621488 Free PMC article. No abstract available.
Role of surgery for glioblastoma: response to letters from Dr. Gerritsen and his colleagues and Dr. Vargas Lopez.
Wen PY, Weller M, Chiocca EA, Lim M, Tonn JC, Zadeh G, Aldape K, van den Bent M. Wen PY, et al. Neuro Oncol. 2021 Mar 25;23(3):506-507. doi: 10.1093/neuonc/noaa305. Neuro Oncol. 2021. PMID: 33471080 Free PMC article. No abstract available.
Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions.
Vargas López AJ. Vargas López AJ. Neuro Oncol. 2021 Mar 25;23(3):502-503. doi: 10.1093/neuonc/noaa287. Neuro Oncol. 2021. PMID: 33471898 Free PMC article. No abstract available.
Maximizing extent of resection while minimizing the risk of neurological morbidity in glioma patients: a novel grading scale to translate these surgical goals into a merged onco-functional clinical outcome.
Gerritsen JKW, Vincent AJPE, De Vleeschouwer S. Gerritsen JKW, et al. Neuro Oncol. 2021 Mar 25;23(3):504-505. doi: 10.1093/neuonc/noaa288. Neuro Oncol. 2021. PMID: 33471906 Free PMC article. No abstract available.

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References

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1. Brat DJ, Aldape K, Colman H, et al. . cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020;139(3):603–608. - PMC - PubMed
1. Leece R, Xu J, Ostrom QT, Chen Y, Kruchko C, Barnholtz-Sloan JS. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 2017;19(11):1553–1564. - PMC - PubMed

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[1] Ostrom QT, Cioffi G, Gittleman H, et al. . CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21(Supplement_5):v1–v100. - PMC - PubMed

[2] Ostrom QT, Cioffi G, Gittleman H, et al. . CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. 2019;21(Supplement_5):v1–v100. - PMC - PubMed

[3] Louis DN, Perry A, Reifenberger G, et al. . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. - PubMed

[4] Louis DN, Perry A, Reifenberger G, et al. . The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol. 2016;131(6):803–820. - PubMed

[5] Yan H, Parsons DW, Jin G, et al. . IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. - PMC - PubMed

[6] Yan H, Parsons DW, Jin G, et al. . IDH1 and IDH2 mutations in gliomas. N Engl J Med. 2009;360(8):765–773. - PMC - PubMed

[7] Brat DJ, Aldape K, Colman H, et al. . cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020;139(3):603–608. - PMC - PubMed

[8] Brat DJ, Aldape K, Colman H, et al. . cIMPACT-NOW update 5: recommended grading criteria and terminologies for IDH-mutant astrocytomas. Acta Neuropathol. 2020;139(3):603–608. - PMC - PubMed

[9] Leece R, Xu J, Ostrom QT, Chen Y, Kruchko C, Barnholtz-Sloan JS. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 2017;19(11):1553–1564. - PMC - PubMed

[10] Leece R, Xu J, Ostrom QT, Chen Y, Kruchko C, Barnholtz-Sloan JS. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 2017;19(11):1553–1564. - PMC - PubMed

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Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

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Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions

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