Abstract
Gliomas are primary brain tumours that are thought to develop from neural stem or progenitor cells that carry tumour-initiating genetic alterations. Based on microscopic appearance and molecular characteristics, they are classified according to the WHO classification of central nervous system (CNS) tumours and graded into CNS WHO grades 1–4 from a low to high grade of malignancy. Diffusely infiltrating gliomas in adults comprise three tumour types with distinct natural course of disease, response to treatment and outcome: isocitrate dehydrogenase (IDH)-mutant and 1p/19q-codeleted oligodendrogliomas with the best prognosis; IDH-mutant astrocytomas with intermediate outcome; and IDH-wild-type glioblastomas with poor prognosis. Pilocytic astrocytoma is the most common glioma in children and is characterized by circumscribed growth, frequent BRAF alterations and favourable prognosis. Diffuse gliomas in children are divided into clinically indolent low-grade tumours and high-grade tumours with aggressive behaviour, with histone 3 K27-altered diffuse midline glioma being the leading cause of glioma-related death in children. Ependymal tumours are subdivided into biologically and prognostically distinct types on the basis of histology, molecular biomarkers and location. Although surgery, radiotherapy and alkylating agent chemotherapy are the mainstay of glioma treatment, individually tailored strategies based on tumour-intrinsic dominant signalling pathways have improved outcome in subsets of patients.
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References
Lamba, N., Wen, P. Y. & Aizer, A. A. Epidemiology of brain metastases and leptomeningeal disease. Neuro Oncol. 23, 1447–1456 (2021).
Ostrom, Q. T. et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2016–2020. Neuro Oncol. 25, iv1–iv99 (2023). This article provides the most recent update on the epidemiology of primary brain tumours in the USA.
Louis, D. N. et al. The 2021 WHO classification of tumors of the central nervous system: a summary. Neuro Oncol. 23, 1231–1251 (2021). This review article summarizes the key principles and novel concepts of the 2021 WHO classification.
Iorgulescu, J. B. et al. Molecular biomarker-defined brain tumors: epidemiology, validity, and completeness in the United States. Neuro Oncol. 24, 1989–2000 (2022).
Leece, R. et al. Global incidence of malignant brain and other central nervous system tumors by histology, 2003–2007. Neuro Oncol. 19, 1553–1564 (2017).
Girardi, F. et al. Global survival trends for brain tumors, by histology: analysis of individual records for 556,237 adults diagnosed in 59 countries during 2000–2014 (CONCORD-3). Neuro Oncol. 25, 580–592 (2023).
Girardi, F. et al. Global survival trends for brain tumors, by histology: Analysis of individual records for 67,776 children diagnosed in 61 countries during 2000–2014 (CONCORD-3). Neuro Oncol. 25, 593–606 (2023).
Barnholtz-Sloan, J. S., Ostrom, Q. T. & Cote, D. Epidemiology of brain tumors. Neurol. Clin. 36, 395–419 (2018).
Taylor, A. J. et al. Population-based risks of CNS tumors in survivors of childhood cancer: the British Childhood Cancer Survivor Study. J. Clin. Oncol. 28, 5287–5293 (2010).
Leary, J. B., Anderson-Mellies, A. & Green, A. L. Population-based analysis of radiation-induced gliomas after cranial radiotherapy for childhood cancers. Neurooncol Adv. 4, vdac159 (2022).
Sadetzki, S. et al. Long-term follow-up for brain tumor development after childhood exposure to ionizing radiation for tinea capitis. Radiat. Res. 163, 424–432 (2005).
Hauptmann, M. et al. Brain cancer after radiation exposure from CT examinations of children and young adults: results from the EPI-CT cohort study. Lancet Oncol. 24, 45–53 (2023). This study reports a dose–response relationship between CT-related radiation exposure before the age of 22 years and the development of primary brain tumours, strongly suggesting careful use of CT in children.
Deng, M. Y. et al. Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B. Nat. Commun. 12, 5530 (2021).
DeSisto, J. et al. Comprehensive molecular characterization of pediatric radiation-induced high-grade glioma. Nat. Commun. 12, 5531 (2021). Refs. 13 and 14 provide novel information on the molecular landscape of irradiation-induced gliomas.
Castaño-Vinyals, G. et al. Wireless phone use in childhood and adolescence and neuroepithelial brain tumours: results from the international MOBI-Kids study. Env. Int. 160, 107069 (2022).
Schüz, J. et al. Cellular telephone use and the risk of brain tumors: update of the UK Million Women Study. J. Natl Cancer Inst. 114, 704–711 (2022).
Claus, E. B., Cannataro, V. L., Gaffney, S. G. & Townsend, J. P. Environmental and sex-specific molecular signatures of glioma causation. Neuro Oncol. 24, 29–36 (2022).
Linos, E., Raine, T., Alonso, A. & Michaud, D. Atopy and risk of brain tumors: a meta-analysis. J. Natl Cancer Inst. 99, 1544–1550 (2007).
Disney-Hogg, L. et al. Impact of atopy on risk of glioma: a Mendelian randomisation study. BMC Med. 16, 42 (2018).
Sun, G. et al. Association between polymorphisms in interleukin-4Rα and interleukin-13 and glioma risk: a meta-analysis. Cancer Epidemiol. 37, 306–310 (2013).
Schwartzbaum, J. A. et al. Inherited variation in immune genes and pathways and glioblastoma risk. Carcinogenesis 31, 1770–1777 (2010).
Gutmann, D. H. et al. Neurofibromatosis type 1. Nat. Rev. Dis. Primers 3, 17004 (2017).
Coy, S., Rashid, R., Stemmer-Rachamimov, A. & Santagata, S. An update on the CNS manifestations of neurofibromatosis type 2. Acta Neuropathol. 139, 643–665 (2020).
Northrup, H. et al. Updated international tuberous sclerosis complex diagnostic criteria and surveillance and management recommendations. Pediatr. Neurol. 123, 50–66 (2021).
Sloan, E. A. et al. Gliomas arising in the setting of Li-Fraumeni syndrome stratify into two molecular subgroups with divergent clinicopathologic features. Acta Neuropathol. 139, 953–957 (2020).
Guerrini-Rousseau, L. et al. Constitutional mismatch repair deficiency-associated brain tumors: report from the European C4CMMRD consortium. Neurooncol Adv. 1, vdz033 (2019).
Suwala, A. K. et al. Primary mismatch repair deficient IDH-mutant astrocytoma (PMMRDIA) is a distinct type with a poor prognosis. Acta Neuropathol. 141, 85–100 (2021).
Bahuau, M. et al. Germ-line deletion involving the INK4 locus in familial proneness to melanoma and nervous system tumors. Cancer Res. 58, 2298–2303 (1998).
Choi, D.-J. et al. The genomic landscape of familial glioma. Sci. Adv. 9, eade2675 (2023).
Bainbridge, M. N. et al. Germline mutations in shelterin complex genes are associated with familial glioma. J. Natl Cancer Inst. 107, 384 (2015).
Melin, B. S. et al. Genome-wide association study of glioma subtypes identifies specific differences in genetic susceptibility to glioblastoma and non-glioblastoma tumors. Nat. Genet. 49, 789–794 (2017).
Eckel-Passow, J. E. et al. Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C. Neuro Oncol. 22, 1602–1613 (2020).
Yanchus, C. et al. A noncoding single-nucleotide polymorphism at 8q24 drives IDH1-mutant glioma formation. Science 378, 68–78 (2022).
Parsons, D. W. et al. An integrated genomic analysis of human glioblastoma multiforme. Science 321, 1807–1812 (2008).
Yan, H. et al. IDH1 and IDH2 mutations in gliomas. N. Engl. J. Med. 360, 765–773 (2009).
Reitman, Z. J. et al. Profiling the effects of isocitrate dehydrogenase 1 and 2 mutations on the cellular metabolome. Proc. Natl Acad. Sci. USA 108, 3270–3275 (2011).
Xu, W. et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of α-ketoglutarate-dependent dioxygenases. Cancer Cell 19, 17–30 (2011).
Malta, T. M. et al. Glioma CpG island methylator phenotype (G-CIMP): biological and clinical implications. Neuro Oncol. 20, 608–620 (2018).
Bunse, L. et al. Suppression of antitumor T cell immunity by the oncometabolite (R)-2-hydroxyglutarate. Nat. Med. 24, 1192–1203 (2018). This study provides evidence for a paracrine, immunosuppressive effect of mutant IDH in the pathogenesis of gliomas.
Mortazavi, A. et al. IDH-mutated gliomas promote epileptogenesis through d-2-hydroxyglutarate-dependent mTOR hyperactivation. Neuro Oncol. 24, 1423–1435 (2022).
Bardella, C. et al. Expression of Idh1R132H in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell 30, 578–594 (2016).
Pirozzi, C. J. et al. Mutant IDH1 disrupts the mouse subventricular zone and alters brain tumor progression. Mol. Cancer Res. 15, 507–520 (2017).
Núñez, F. J. et al. IDH1-R132H acts as a tumor suppressor in glioma via epigenetic up-regulation of the DNA damage response. Sci. Transl. Med. 11, eaaq1427 (2019).
Banan, R. et al. Infratentorial IDH-mutant astrocytoma is a distinct subtype. Acta Neuropathol. 140, 569–581 (2020).
Tesileanu, C. M. S., Vallentgoed, W. R., French, P. J. & van den Bent, M. J. Molecular markers related to patient outcome in patients with IDH-mutant astrocytomas grade 2 to 4: a systematic review. Eur. J. Cancer 175, 214–223 (2022).
Shirahata, M. et al. Novel, improved grading system(s) for IDH-mutant astrocytic gliomas. Acta Neuropathol. 136, 153–166 (2018).
Bettegowda, C. et al. Mutations in CIC and FUBP1 contribute to human oligodendroglioma. Science 333, 1453–1455 (2011).
Sahm, F. et al. CIC and FUBP1 mutations in oligodendrogliomas, oligoastrocytomas and astrocytomas. Acta Neuropathol. 123, 853–860 (2012).
Appay, R. et al. CDKN2A homozygous deletion is a strong adverse prognosis factor in diffuse malignant IDH-mutant gliomas. Neuro Oncol. 21, 1519–1528 (2019).
Suwala, A. K. et al. Oligosarcomas, IDH-mutant are distinct and aggressive. Acta Neuropathol. 143, 263–281 (2022).
Brennan, C. W. et al. The somatic genomic landscape of glioblastoma. Cell 155, 462–477 (2013).
An, Z., Aksoy, O., Zheng, T., Fan, Q.-W. & Weiss, W. A. Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene 37, 1561–1575 (2018).
Lim, M., Xia, Y., Bettegowda, C. & Weller, M. Current state of immunotherapy for glioblastoma. Nat. Rev. Clin. Oncol. 15, 422–442 (2018).
Capper, D. et al. DNA methylation-based classification of central nervous system tumours. Nature 555, 469–474 (2018). This study established the central new role of DNA methylation profiling as a diagnostic tool in neuro-oncology.
Verhaak, R. G. W. et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17, 98–110 (2010).
Ryall, S. et al. Integrated molecular and clinical analysis of 1,000 pediatric low-grade gliomas. Cancer Cell 37, 569–583.e5 (2020).
Qaddoumi, I. et al. Genetic alterations in uncommon low-grade neuroepithelial tumors: BRAF, FGFR1, and MYB mutations occur at high frequency and align with morphology. Acta Neuropathol. 131, 833–845 (2016).
Huse, J. T. et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): an epileptogenic neoplasm with oligodendroglioma-like components, aberrant CD34 expression, and genetic alterations involving the MAP kinase pathway. Acta Neuropathol. 133, 417–429 (2017).
Ida, C. M. et al. Polymorphous low-grade neuroepithelial tumor of the young (PLNTY): molecular profiling confirms frequent MAPK pathway activation. J. Neuropathol. Exp. Neurol. 80, 821–829 (2021).
Mackay, A. et al. Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma. Cancer Cell 32, 520–537.e5 (2017).
Castel, D. et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol. 130, 815–827 (2015).
Castel, D. et al. Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation. Acta Neuropathol. 139, 1109–1113 (2020).
Mondal, G. et al. Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition. Acta Neuropathol. 139, 1071–1088 (2020).
Sievers, P. et al. A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR. Neuro Oncol. 23, 34–43 (2021).
Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat. Genet. 46, 444–450 (2014).
Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425–437 (2012).
Harutyunyan, A. S. et al. H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis. Nat. Commun. 10, 1262 (2019).
Crowell, C. et al. Systematic review of diffuse hemispheric glioma, H3 G34-mutant: outcomes and associated clinical factors. Neurooncol Adv. 4, vdac133 (2022).
Lucas, C.-H. G. et al. Diffuse hemispheric glioma, H3 G34-mutant: genomic landscape of a new tumor entity and prospects for targeted therapy. Neuro Oncol. 23, 1974–1976 (2021).
Clarke, M. et al. Infant high-grade gliomas comprise multiple subgroups characterized by novel targetable gene fusions and favorable outcomes. Cancer Discov. 10, 942–963 (2020).
Guerreiro Stucklin, A. S. et al. Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas. Nat. Commun. 10, 4343 (2019).
Friebel, E. et al. Single-cell mapping of human brain cancer reveals tumor-specific instruction of tissue-invading leukocytes. Cell 181, 1626–1642.e20 (2020).
Klemm, F. et al. Interrogation of the microenvironmental landscape in brain tumors reveals disease-specific alterations of immune cells. Cell 181, 1643–1660.e17 (2020). Refs. 72 and 73 identify major differences in the tumour microenvironment of primary versus metastatic brain tumours.
Thorsson, V. et al. The immune landscape of cancer. Immunity 48, 812–830.e14 (2018).
Venkatesh, H. S. et al. Neuronal activity promotes glioma growth through neuroligin-3 secretion. Cell 161, 803–816 (2015).
Pan, Y. et al. NF1 mutation drives neuronal activity-dependent initiation of optic glioma. Nature 594, 277–282 (2021).
Venkatesh, H. S. et al. Electrical and synaptic integration of glioma into neural circuits. Nature 573, 539–545 (2019).
Venkataramani, V. et al. Glutamatergic synaptic input to glioma cells drives brain tumour progression. Nature 573, 532–538 (2019).
Venkataramani, V. et al. Glioblastoma hijacks neuronal mechanisms for brain invasion. Cell 185, 2899–2917.e31 (2022).
Taylor, K. R. et al. Glioma synapses recruit mechanisms of adaptive plasticity. Nature 623, 366–374 (2023). Here, BDNF–TRKB signalling is identified as a pathway that may promote the activity of neuron glioma synaptic plasticity and augment tumour progression.
Hausmann, D. et al. Autonomous rhythmic activity in glioma networks drives brain tumour growth. Nature 613, 179–186 (2023). Glioblastoma cell networks include a small, plastic population of highly active glioblastoma cells that display rhythmic Ca2+ oscillations and thereby activate frequency-dependent MAPK and NF-κB signalling.
Mathur, R. et al. Glioblastoma evolution and heterogeneity from a 3D whole-tumor perspective. Cell 187, 446–463.e16 (2024).
Jones, D. T. W. et al. Tandem duplication producing a novel oncogenic BRAF fusion gene defines the majority of pilocytic astrocytomas. Cancer Res. 68, 8673–8677 (2008).
Jones, D. T. W. et al. Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma. Nat. Genet. 45, 927–932 (2013).
Sievers, P. et al. Posterior fossa pilocytic astrocytomas with oligodendroglial features show frequent FGFR1 activation via fusion or mutation. Acta Neuropathol. 139, 403–406 (2020).
Gronych, J. et al. An activated mutant BRAF kinase domain is sufficient to induce pilocytic astrocytoma in mice. J. Clin. Invest. 121, 1344–1348 (2011).
Reinhardt, A. et al. Anaplastic astrocytoma with piloid features, a novel molecular class of IDH wildtype glioma with recurrent MAPK pathway, CDKN2A/B and ATRX alterations. Acta Neuropathol. 136, 273–291 (2018).
Cimino, P. J. et al. Expanded analysis of high-grade astrocytoma with piloid features identifies an epigenetically and clinically distinct subtype associated with neurofibromatosis type 1. Acta Neuropathol. 145, 71–82 (2023).
Vaubel, R. et al. Biology and grading of pleomorphic xanthoastrocytoma-what have we learned about it? Brain Pathol. 31, 20–32 (2021).
Alexandrescu, S. et al. Epithelioid glioblastomas and anaplastic epithelioid pleomorphic xanthoastrocytomas-same entity or first cousins? Brain Pathol. 26, 215–223 (2016).
Robinson, J. P. et al. Activated BRAF induces gliomas in mice when combined with Ink4a/Arf loss or Akt activation. Oncogene 29, 335–344 (2010).
Ebrahimi, A. et al. Pleomorphic xanthoastrocytoma is a heterogeneous entity with pTERT mutations prognosticating shorter survival. Acta Neuropathol. Commun. 10, 5 (2022).
Zhou, J. et al. Tsc1 mutant neural stem/progenitor cells exhibit migration deficits and give rise to subependymal lesions in the lateral ventricle. Genes Dev. 25, 1595–1600 (2011).
Chan, J. A. et al. Pathogenesis of tuberous sclerosis subependymal giant cell astrocytomas: biallelic inactivation of TSC1 or TSC2 leads to mTOR activation. J. Neuropathol. Exp. Neurol. 63, 1236–1242 (2004).
Franz, D. N. et al. Everolimus for subependymal giant cell astrocytoma: 5-year final analysis. Ann. Neurol. 78, 929–938 (2015).
Rosenberg, S. et al. A recurrent point mutation in PRKCA is a hallmark of chordoid gliomas. Nat. Commun. 9, 2371 (2018).
Goode, B. et al. A recurrent kinase domain mutation in PRKCA defines chordoid glioma of the third ventricle. Nat. Commun. 9, 810 (2018).
Lucas, C.-H. G. et al. EWSR1-BEND2 fusion defines an epigenetically distinct subtype of astroblastoma. Acta Neuropathol. 143, 109–113 (2022).
Rossi, S. et al. Paediatric astroblastoma-like neuroepithelial tumour of the spinal cord with a MAMLD1–BEND2 rearrangement. Neuropathol. Appl. Neurobiol. 48, e12814 (2022).
Rudà, R. et al. EANO guidelines for the diagnosis and treatment of ependymal tumors. Neuro Oncol. 20, 445–456 (2018).
Pajtler, K. W. et al. Molecular classification of ependymal tumors across all CNS compartments, histopathological grades, and age groups. Cancer Cell 27, 728–743 (2015).
Thomas, C. et al. TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma. Acta Neuropathol. 141, 959–970 (2021).
Parker, M. et al. C11orf95–RELA fusions drive oncogenic NF-κB signalling in ependymoma. Nature 506, 451–455 (2014).
Kupp, R. et al. ZFTA translocations constitute ependymoma chromatin remodeling and transcription factors. Cancer Discov. 11, 2216–2229 (2021).
Zheng, T. et al. Cross-species genomics reveals oncogenic dependencies in ZFTA/C11orf95 fusion-positive supratentorial ependymomas. Cancer Discov. 11, 2230–2247 (2021).
Arabzade, A. et al. ZFTA–RELA dictates oncogenic transcriptional programs to drive aggressive supratentorial ependymoma. Cancer Discov. 11, 2200–2215 (2021).
Jünger, S. T. et al. CDKN2A deletion in supratentorial ependymoma with RELA alteration indicates a dismal prognosis: a retrospective analysis of the HIT ependymoma trial cohort. Acta Neuropathol. 140, 405–407 (2020).
Pajtler, K. W. et al. YAP1 subgroup supratentorial ependymoma requires TEAD and nuclear factor I-mediated transcriptional programmes for tumorigenesis. Nat. Commun. 10, 3914 (2019).
Sievers, P. et al. Recurrent fusions in PLAGL1 define a distinct subset of pediatric-type supratentorial neuroepithelial tumors. Acta Neuropathol. 142, 827–839 (2021).
Pajtler, K. W. et al. Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas. Acta Neuropathol. 136, 211–226 (2018).
Michealraj, K. A. et al. Metabolic regulation of the epigenome drives lethal infantile ependymoma. Cell 181, 1329–1345.e24 (2020).
Baroni, L. V. et al. Ultra high-risk PFA ependymoma is characterized by loss of chromosome 6q. Neuro Oncol. 23, 1360–1370 (2021).
Donson, A. M. et al. Significant increase of high-risk chromosome 1q gain and 6q loss at recurrence in posterior fossa group A ependymoma: a multicenter study. Neuro Oncol. 25, 1854–1967 (2023).
Witt, H. et al. DNA methylation-based classification of ependymomas in adulthood: implications for diagnosis and treatment. Neuro Oncol. 20, 1616–1624 (2018).
Cavalli, F. M. G. et al. Heterogeneity within the PF-EPN-B ependymoma subgroup. Acta Neuropathol. 136, 227–237 (2018).
Ebert, C. et al. Molecular genetic analysis of ependymal tumors. NF2 mutations and chromosome 22q loss occur preferentially in intramedullary spinal ependymomas. Am. J. Pathol. 155, 627–632 (1999).
Ghasemi, D. R. et al. MYCN amplification drives an aggressive form of spinal ependymoma. Acta Neuropathol. 138, 1075–1089 (2019).
Bockmayr, M. et al. Comprehensive profiling of myxopapillary ependymomas identifies a distinct molecular subtype with relapsing disease. Neuro Oncol. 24, 1689–1699 (2022).
Avila, E. K. et al. Brain tumor-related epilepsy management: a Society for Neuro-oncology (SNO) consensus review on current management. Neuro Oncol. 26, 7–24 (2024).
Suh, C. H., Kim, H. S., Jung, S. C., Choi, C. G. & Kim, S. J. 2-Hydroxyglutarate MR spectroscopy for prediction of isocitrate dehydrogenase mutant glioma: a systemic review and meta-analysis using individual patient data. Neuro Oncol. 20, 1573–1583 (2018).
Galldiks, N. et al. Investigational PET tracers in neuro-oncology—what’s on the horizon? A report of the PET/RANO group. Neuro Oncol. 24, 1815–1826 (2022).
Albert, N. L. et al. PET-based response assessment criteria for diffuse gliomas (PET RANO 1.0): a report of the RANO group. Lancet Oncol. 25, e29–e41 (2024).
Brat, D. J. et al. Molecular biomarker testing for the diagnosis of diffuse gliomas. Arch. Pathol. Lab. Med. 146, 547–574 (2022).
Sahm, F. et al. Molecular diagnostic tools for the World Health Organization (WHO) 2021 classification of gliomas, glioneuronal and neuronal tumors; an EANO guideline. Neuro Oncol. 25, 1731–1749 (2023).
Capper, D., Zentgraf, H., Balss, J., Hartmann, C. & von Deimling, A. Monoclonal antibody specific for IDH1 R132H mutation. Acta Neuropathol. 118, 599–601 (2009).
Ellison, D. W. et al. cIMPACT-NOW update 4: diffuse gliomas characterized by MYB, MYBL1, or FGFR1 alterations or BRAFV600E mutation. Acta Neuropathol. 137, 683–687 (2019).
Bandopadhayay, P. et al. MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism. Nat. Genet. 48, 273–282 (2016).
Hegi, M. E. et al. MGMT promoter methylation cutoff with safety margin for selecting glioblastoma patients into trials omitting temozolomide: a pooled analysis of four clinical trials. Clin. Cancer Res. 25, 1809–1816 (2019).
Bady, P., Delorenzi, M. & Hegi, M. E. Sensitivity analysis of the MGMT-STP27 model and impact of genetic and epigenetic context to predict the MGMT methylation status in gliomas and other tumors. J. Mol. Diagn. 18, 350–361 (2016).
Wen, P. Y. et al. Dabrafenib plus trametinib in patients with BRAFV600E-mutant low-grade and high-grade glioma (ROAR): a multicentre, open-label, single-arm, phase 2, basket trial. Lancet Oncol. 23, 53–64 (2022).
Panwalkar, P. et al. Immunohistochemical analysis of H3K27me3 demonstrates global reduction in group-A childhood posterior fossa ependymoma and is a powerful predictor of outcome. Acta Neuropathol. 134, 705–714 (2017).
Molinaro, A. M., Taylor, J. W., Wiencke, J. K. & Wrensch, M. R. Genetic and molecular epidemiology of adult diffuse glioma. Nat. Rev. Neurol. 15, 405–417 (2019).
Wang, Y. et al. Detection of tumor-derived DNA in cerebrospinal fluid of patients with primary tumors of the brain and spinal cord. Proc. Natl Acad. Sci. USA 112, 9704–9709 (2015).
Pitter, K. L. et al. Corticosteroids compromise survival in glioblastoma. Brain 139, 1458–1471 (2016).
Walbert, T. et al. SNO and EANO practice guideline update: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors. Neuro Oncol. 23, 1835–1844 (2021).
Happold, C. et al. Does valproic acid or levetiracetam improve survival in glioblastoma? A pooled analysis of prospective clinical trials in newly diagnosed glioblastoma. J. Clin. Oncol. 34, 731–739 (2016).
Roth, P. et al. Neurological and vascular complications of primary and secondary brain tumours: EANO–ESMO Clinical Practice Guidelines for prophylaxis, diagnosis, treatment and follow-up. Ann. Oncol. 32, 171–182 (2021).
Jo, J. et al. Epidemiology, biology, and management of venous thromboembolism in gliomas: an interdisciplinary review. Neuro Oncol. 25, 1381–1394 (2023).
Eigenbrod, S. et al. Molecular stereotactic biopsy technique improves diagnostic accuracy and enables personalized treatment strategies in glioma patients. Acta Neurochir. 156, 1427–1440 (2014).
Stummer, W. et al. Intraoperative fluorescence diagnosis in the brain: a systematic review and suggestions for future standards on reporting diagnostic accuracy and clinical utility. Acta Neurochir. 161, 2083–2098 (2019).
Stummer, W. et al. Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial. Lancet Oncol. 7, 392–401 (2006).
Horbinski, C. et al. NCCN Guidelines® insights: central nervous system cancers, version 2.2022. J. Natl Compr. Canc. Netw. 21, 12–20 (2023).
Weller, M. et al. EANO guidelines on the diagnosis and treatment of diffuse gliomas of adulthood. Nat. Rev. Clin. Oncol. 18, 170–186 (2021).
Wen, P. Y. et al. RANO 2.0: proposal for an update to the Response Assessment in Neuro-Oncology (RANO) criteria for high- and low-grade gliomas in adults. J. Clin. Oncol. 41, 2017–2017 (2023).
Ellingson, B. M. et al. Consensus recommendations for a standardized Brain Tumor Imaging Protocol in clinical trials. Neuro-Oncol. 17, 1188–1198 (2015).
Albert, N. L. et al. Response Assessment in Neuro-Oncology working group and European Association for Neuro-Oncology recommendations for the clinical use of PET imaging in gliomas. Neuro-Oncol. 18, 1199–1208 (2016).
Kros, J. M. et al. Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033. Neuro Oncol. 25, 1443–1449 (2023).
Weller, M. et al. Improved prognostic stratification of patients with isocitrate dehydrogenase-mutant astrocytoma. Acta Neuropathol. 147, 11 (2024).
Jakola, A. S. et al. Comparison of a strategy favoring early surgical resection vs a strategy favoring watchful waiting in low-grade gliomas. JAMA 308, 1881 (2012).
Chang, E. F. et al. Seizure characteristics and control following resection in 332 patients with low-grade gliomas. J. Neurosurg. 108, 227–235 (2008).
Pallud, J. et al. Epileptic seizures in diffuse low-grade gliomas in adults. Brain 137, 449–462 (2014).
Hervey-Jumper, S. L. et al. Interactive effects of molecular, therapeutic, and patient factors on outcome of diffuse low-grade glioma. J. Clin. Oncol. 41, 2029–2042 (2023).
Pignatti, F. et al. Prognostic factors for survival in adult patients with cerebral low-grade glioma. J. Clin. Oncol. 20, 2076–2084 (2002).
Daniels, T. B. et al. Validation of EORTC prognostic factors for adults with low-grade glioma: a report using Intergroup 86-72-51. Int. J. Radiat. Oncol. Biol. Phys. 81, 218–224 (2011).
Miller, J. J. et al. Isocitrate dehydrogenase (IDH) mutant gliomas: a Society for Neuro-Oncology (SNO) consensus review on diagnosis, management, and future directions. Neuro-Oncol. 25, 4–25 (2023).
Buckner, J. C. et al. Radiation plus procarbazine, CCNU, and vincristine in low-grade glioma. N. Engl. J. Med. 374, 1344–1355 (2016).
Lassman, A. B. et al. Joint final report of EORTC 26951 and RTOG 9402: phase III trials with procarbazine, lomustine, and vincristine chemotherapy for anaplastic oligodendroglial tumors. J. Clin.Oncol. 40, 2539–2545 (2022). Long-term follow-up confirms PCV polychemotherapy as standard of care for oligodendroglioma, IDH mutant, CNS WHO grade 3.
van den Bent, M. J. et al. Adjuvant and concurrent temozolomide for 1p/19q non-co-deleted anaplastic glioma (CATNON; EORTC study 26053-22054): second interim analysis of a randomised, open-label, phase 3 study. Lancet Oncol. 22, 813–823 (2021). Updated results of the CATNON trial confirm maintenance temozolomide after radiotherapy as standard of care for astrocytoma, IDH mutant, CNS WHO grade 3.
Jaeckle, K. A. et al. CODEL: phase III study of RT, RT + TMZ, or TMZ for newly diagnosed 1p/19q codeleted oligodendroglioma. Analysis from the initial study design. Neuro-Oncol. 23, 457–467 (2021).
Mohile, N. A. et al. Therapy for diffuse astrocytic and oligodendroglial tumors in adults: ASCO–SNO guideline. J. Clin. Oncol. 40, 403–426 (2022).
van den Bent, M. J. et al. Long-term efficacy of early versus delayed radiotherapy for low-grade astrocytoma and oligodendroglioma in adults: the EORTC 22845 randomised trial. Lancet 366, 985–990 (2005).
Shaw, E. et al. Prospective randomized trial of low- versus high-dose radiation therapy in adults with supratentorial low-grade glioma: initial report of a North Central Cancer Treatment Group/Radiation Therapy Oncology Group/Eastern Cooperative Oncology Group study. J. Clin. Oncol. 20, 2267–2276 (2002).
Bell, E. H. et al. Comprehensive genomic analysis in NRG Oncology/RTOG 9802: a phase III trial of radiation versus radiation plus procarbazine, lomustine (CCNU), and vincristine in high-risk low-grade glioma. J. Clin. Oncol. 38, 3407–3417 (2020).
Tabrizi, S. et al. Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma. Radiother. Oncol. 137, 95–101 (2019).
van den Bent, M. J. et al. Interim results from the CATNON trial (EORTC study 26053-22054) of treatment with concurrent and adjuvant temozolomide for 1p/19q non-co-deleted anaplastic glioma: a phase 3, randomised, open-label intergroup study. Lancet 390, 1645–1653 (2017).
Cairncross, G. et al. Phase III trial of chemoradiotherapy for anaplastic oligodendroglioma: long-term results of RTOG 9402. J. Clin. Oncol. 31, 337–343 (2013).
van den Bent, M. J. et al. Adjuvant procarbazine, lomustine, and vincristine chemotherapy in newly diagnosed anaplastic oligodendroglioma: long-term follow-up of EORTC brain tumor group study 26951. J. Clin. Oncol. 31, 344–350 (2013).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/search?term=NCT00887146 (2024).
Rohle, D. et al. An inhibitor of mutant IDH1 delays growth and promotes differentiation of glioma cells. Science 340, 626–630 (2013).
Kadiyala, P. et al. Inhibition of 2-hydroxyglutarate elicits metabolic reprogramming and mutant IDH1 glioma immunity in mice. J. Clin. Invest. 131, e139542 (2021).
Mellinghoff, I. K. et al. Ivosidenib in isocitrate dehydrogenase 1-mutated advanced glioma. J. Clin. Oncol. 38, 3398–3406 (2020).
Mellinghoff, I. K. et al. Vorasidenib, a dual inhibitor of mutant IDH1/2, in recurrent or progressive glioma; results of a first-in-human phase I trial. Clin. Cancer Res. 27, 4491–4499 (2021).
de la Fuente, M. I. et al. Olutasidenib (FT-2102) in patients with relapsed or refractory IDH1-mutant glioma: a multicenter, open-label, phase Ib/II trial. Neuro Oncol. 25, 146–156 (2023).
Natsume, A. et al. The first-in-human phase I study of a brain-penetrant mutant IDH1 inhibitor DS-1001 in patients with recurrent or progressive IDH1-mutant gliomas. Neuro Oncol. 25, 326–336 (2023).
Mellinhoff, I. K. et al. Vorasidenib in IDH1- or IDH2-mutant low-grade glioma. N. Engl. J. Med. 389, 589–601 (2023).
Turcan, S. et al. Efficient induction of differentiation and growth inhibition in IDH1 mutant glioma cells by the DNMT inhibitor decitabine. Oncotarget 4, 1729–1736 (2013).
Sulkowski, P. L. et al. 2-Hydroxyglutarate produced by neomorphic IDH mutations suppresses homologous recombination and induces PARP inhibitor sensitivity. Sci. Transl. Med. 9, eaal2463 (2017).
McBrayer, S. K. et al. Transaminase inhibition by 2-hydroxyglutarate impairs glutamate biosynthesis and redox homeostasis in glioma. Cell 175, 101–116.e25 (2018).
Shi, D. D. et al. De novo pyrimidine synthesis is a targetable vulnerability in IDH mutant glioma. Cancer Cell 40, 939–956.e16 (2022).
Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).
Schumacher, T. et al. A vaccine targeting mutant IDH1 induces antitumour immunity. Nature 512, 324–327 (2014).
Platten, M. et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature 592, 463–468 (2021).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/search?term=NCT03893903 (2022).
Molinaro, A. M. et al. Association of maximal extent of resection of contrast-enhanced and non-contrast-enhanced tumor with survival within molecular subgroups of patients with newly diagnosed glioblastoma. JAMA Oncol. 6, 495–503 (2020).
Karschnia, P. et al. Prognostic validation of a new classification system for extent of resection in glioblastoma: a report of the RANO resect group. Neuro Oncol 25, 940–954 (2023).
Stupp, R. et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N. Engl. J. Med. 352, 987–996 (2005).
Hegi, M. E. et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N. Engl. J. Med. 352, 997–1003 (2005).
Stupp, R. et al. Effect of tumor-treating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318, 2306–2316 (2017).
Malmström, A. et al. Temozolomide versus standard 6-week radiotherapy versus hypofractionated radiotherapy in patients older than 60 years with glioblastoma: the Nordic randomised, phase 3 trial. Lancet Oncol. 13, 916–926 (2012).
Wick, W. et al. Temozolomide chemotherapy alone versus radiotherapy alone for malignant astrocytoma in the elderly: the NOA-08 randomised, phase 3 trial. Lancet Oncol. 13, 707–715 (2012).
Perry, J. R. et al. Short-course radiation plus temozolomide in elderly patients with glioblastoma. N. Engl. J. Med. 376, 1027–1037 (2017).
Gilbert, M. R. et al. Dose-dense temozolomide for newly diagnosed glioblastoma: a randomized phase III clinical trial. J. Clin. Oncol. 31, 4085–4091 (2013).
Gilbert, M. R. et al. A randomized trial of bevacizumab for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 699–708 (2014).
Chinot, O. L. et al. Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma. N. Engl. J. Med. 370, 709–722 (2014).
Wick, W. et al. Lomustine and bevacizumab in progressive glioblastoma. N. Engl. J. Med. 377, 1954–1963 (2017).
Sonabend, A. M. et al. Repeated blood-brain barrier opening with an implantable ultrasound device for delivery of albumin-bound paclitaxel in patients with recurrent glioblastoma: a phase 1 trial. Lancet Oncol. 24, 509–522 (2023).
Neftel, C. et al. An integrative model of cellular states, plasticity, and genetics for glioblastoma. Cell 178, 835–849.e21 (2019).
Barthel, F. P. et al. Longitudinal molecular trajectories of diffuse glioma in adults. Nature 576, 112–120 (2019).
Doz, F. et al. Efficacy and safety of larotrectinib in TRK fusion-positive primary central nervous system tumors. Neuro Oncol. 24, 997–1007 (2022).
Loriot, Y. et al. Tumor agnostic efficacy and safety of erdafitinib in patients (pts) with advanced solid tumors with prespecified fibroblast growth factor receptor alterations (FGFRalt) in RAGNAR: interim analysis (IA) results. J. Clin.Oncol. 40 (suppl. 16), Abstr. 3007 (2022).
Wen, P. Y. et al. Glioblastoma in adults: a Society for Neuro-Oncology (SNO) and European Society of Neuro-Oncology (EANO) consensus review on current management and future directions. Neuro Oncol. 22, 1073–1113 (2020).
Weller, M. et al. Rindopepimut with temozolomide for patients with newly diagnosed, EGFRvIII-expressing glioblastoma (ACT IV): a randomised, double-blind, international phase 3 trial. Lancet Oncol. 18, 1373–1385 (2017).
Ahluwalia, M. S. et al. Phase IIa study of SurVaxM plus adjuvant temozolomide for newly diagnosed glioblastoma. J. Clin. Oncol. 41, 1453–1465 (2023).
Wen, P. Y. et al. A randomized double-blind placebo-controlled phase II trial of dendritic cell vaccine ICT-107 in newly diagnosed patients with glioblastoma. Clin. Cancer Res. 25, 5799–5807 (2019).
Liau, L. M. et al. Association of autologous tumor lysate-loaded dendritic cell vaccination with extension of survival among patients with newly diagnosed and recurrent glioblastoma: a phase 3 prospective externally controlled cohort trial. JAMA Oncol. 9, 112 (2023).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
Lim, M. et al. Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter. Neuro Oncol. 24, 1935–1949 (2022).
Omuro, A. et al. Radiotherapy combined with nivolumab or temozolomide for newly diagnosed glioblastoma with unmethylated MGMT promoter: an international randomized phase 3 trial. Neuro Oncol. 25, 123–134 (2023).
Reardon, D. A. et al. Effect of nivolumab vs bevacizumab in patients with recurrent glioblastoma: the CheckMate 143 phase 3 randomized clinical trial. JAMA Oncol. 6, 1003–1010 (2020).
Jackson, C. M., Choi, J. & Lim, M. Mechanisms of immunotherapy resistance: lessons from glioblastoma. Nat. Immunol. 20, 1100–1109 (2019).
Weiss, T. et al. Immunocytokines are a promising immunotherapeutic approach against glioblastoma. Sci. Transl. Med. 12, eabb2311 (2020).
Look, T. et al. Targeted delivery of tumor necrosis factor in combination with CCNU induces a T cell-dependent regression of glioblastoma. Sci. Transl. Med. 15, eadf2281 (2023).
Desjardins, A. et al. Recurrent glioblastoma treated with recombinant poliovirus. N. Engl. J. Med. 379, 150–161 (2018).
Chiocca, E. A. et al. Combined immunotherapy with controlled interleukin-12 gene therapy and immune checkpoint blockade in recurrent glioblastoma: an open-label, multi-institutional phase I trial. Neuro Oncol. 24, 951–963 (2022).
Todo, T. et al. Intratumoral oncolytic herpes virus G47∆ for residual or recurrent glioblastoma: a phase 2 trial. Nat. Med. 28, 1630–1639 (2022).
O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl. Med. 9, eaaa0984 (2017).
Fisher, P. G. et al. Outcome analysis of childhood low-grade astrocytomas. Pediatr. Blood Cancer 51, 245–250 (2008).
Sievert, A. J. & Fisher, M. J. Pediatric low-grade gliomas. J. Child Neurol. 24, 1397–1408 (2009).
Packer, R. J. et al. Carboplatin and vincristine chemotherapy for children with newly diagnosed progressive low-grade gliomas. J. Neurosurg. 86, 747–754 (1997).
Hwang, E. I. et al. Long-term efficacy and toxicity of bevacizumab-based therapy in children with recurrent low-grade gliomas: bevacizumab-based treatment in pediatric LGG update. Pediatr. Blood Cancer 60, 776–782 (2013).
Bouffet, E. et al. Phase II study of weekly vinblastine in recurrent or refractory pediatric low-grade glioma. J. Clin. Oncol. 30, 1358–1363 (2012).
Fangusaro, J. et al. Selumetinib in paediatric patients with BRAF-aberrant or neurofibromatosis type 1-associated recurrent, refractory, or progressive low-grade glioma: a multicentre, phase 2 trial. Lancet Oncol. 20, 1011–1022 (2019).
Hargrave, D. R. et al. Efficacy and safety of dabrafenib in pediatric patients with BRAF V600 mutation-positive relapsed or refractory low-grade glioma: results from a phase I/IIa study. Clin. Cancer Res. 25, 7303–7311 (2019).
Lassaletta, A. et al. Reirradiation in patients with diffuse intrinsic pontine gliomas: the Canadian experience. Pediatr. Blood Cancer 65, e26988 (2018).
Amsbaugh, M. J. et al. A phase 1/2 trial of reirradiation for diffuse intrinsic pontine glioma. Int. J. Radiat. Oncol. Biol. Phys. 104, 144–148 (2019).
Grasso, C. S. et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat. Med. 21, 555–559 (2015).
Nagaraja, S. et al. Transcriptional dependencies in diffuse intrinsic pontine glioma. Cancer Cell 31, 635–652.e6 (2017).
Lin, G. L. et al. Therapeutic strategies for diffuse midline glioma from high-throughput combination drug screening. Sci. Transl. Med. 11, eaaw0064 (2019).
Przystal, J. M. et al. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 24, 1438–1451 (2022).
Chi, A. S. et al. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. J. Neurooncol. 145, 97–105 (2019).
Gardner, S. L. et al. Phase I dose escalation and expansion trial of single agent ONC201 in pediatric diffuse midline gliomas following radiotherapy. Neurooncol. Adv. 4, vdac143 (2022).
Mount, C. W. et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M+ diffuse midline gliomas. Nat. Med. 24, 572–579 (2018).
Majzner, R. G. et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 603, 934–941 (2022).
Vitanza, N. A. et al. Locoregional infusion of HER2-specific CAR T cells in children and young adults with recurrent or refractory CNS tumors: an interim analysis. Nat. Med. 27, 1544–1552 (2021).
Grassl, N. et al. A H3K27M-targeted vaccine in adults with diffuse midline glioma. Nat. Med. 29, 2586–2592 (2023).
Chen, C. C. L. et al. Histone H3.3G34-mutant interneuron progenitors co-opt PDGFRA for gliomagenesis. Cell 183, 1617–1633.e22 (2020).
Sweha, S. R. et al. Epigenetically defined therapeutic targeting in H3.3G34R/V high-grade gliomas. Sci. Transl. Med. 13, eabf7860 (2021).
Jakacki, R. I. et al. Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children’s Oncology Group ACNS0423 study. Neuro Oncol. 18, 1442–1450 (2016).
Das, A. et al. Efficacy of nivolumab in pediatric cancers with high mutation burden and mismatch repair deficiency. Clin. Cancer Res. 29, 4770–4783 (2023).
Rudà, R. et al. EANO-EURACAN-SNO guidelines on circumscribed astrocytic gliomas, glioneuronal, and neuronal tumors. Neuro Oncol. 24, 2015–2034 (2022).
Karajannis, M. A. et al. Phase II study of sorafenib in children with recurrent or progressive low-grade astrocytomas. Neuro Oncol. 16, 1408–1416 (2014).
Krueger, D. A. et al. Everolimus long-term safety and efficacy in subependymal giant cell astrocytoma. Neurology 80, 574–580 (2013).
Bouffet, E. et al. Efficacy and safety of trametinib monotherapy or in combination with dabrafenib in pediatric BRAF V600–mutant low-grade glioma. J. Clin. Oncol. 41, 664–674 (2023).
Kaley, T. et al. BRAF inhibition in BRAFV600-mutant gliomas: results from the VE-BASKET study. J. Clin. Oncol. 36, 3477–3484 (2018).
Rudà, R., Bruno, F., Pellerino, A. & Soffietti, R. Ependymoma: evaluation and management updates. Curr. Oncol. Rep. 24, 985–993 (2022).
Gomez, D. R. et al. High failure rate in spinal ependymomas with long-term follow-up. Neuro Oncol. 7, 254–259 (2005).
Merchant, T. E. et al. Preliminary results from a phase II trial of conformal radiation therapy and evaluation of radiation-related CNS effects for pediatric patients with localized ependymoma. J. Clin. Oncol. 22, 3156–3162 (2004).
Timmermann, B. et al. Combined postoperative irradiation and chemotherapy for anaplastic ependymomas in childhood: results of the German prospective trials HIT 88/89 and HIT 91. Int. J. Radiat. Oncol. Biol. Phys. 46, 287–295 (2000).
Gilbert, M. R. et al. A phase II study of dose-dense temozolomide and lapatinib for recurrent low-grade and anaplastic supratentorial, infratentorial, and spinal cord ependymoma. Neuro Oncol. 23, 468–477 (2021).
IJzerman-Korevaar, M., Snijders, T. J., de Graeff, A., Teunissen, S. C. C. M. & de Vos, F. Y. F. Prevalence of symptoms in glioma patients throughout the disease trajectory: a systematic review. J. Neurooncol. 140, 485–496 (2018).
Coomans, M. B. et al. Symptom clusters in newly diagnosed glioma patients: which symptom clusters are independently associated with functioning and global health status? Neuro Oncol. 21, 1447–1457 (2019).
Boele, F. W. et al. Health-related quality of life of significant others of patients with malignant CNS versus non-CNS tumors: a comparative study. J. Neurooncol. 115, 87–94 (2013).
Li, Q. et al. Caregiver burden and influencing factors among family caregivers of patients with glioma: a cross-sectional survey. J. Clin. Neurosci. 96, 107–113 (2022).
Coomans, M. B. et al. Calculating the net clinical benefit in neuro-oncology clinical trials using two methods: quality-adjusted survival effect sizes and joint modeling. Neuro Oncol. Adv. 2, vdaa147 (2020).
Dirven, L. et al. Working plan for the use of patient-reported outcome measures in adults with brain tumours: a Response Assessment in Neuro-Oncology (RANO) initiative. Lancet Oncol. 19, e173–e180 (2018).
Armstrong, T. S. et al. Glioma patient-reported outcome assessment in clinical care and research: a Response Assessment in Neuro-Oncology collaborative report. Lancet Oncol. 21, e97–e103 (2020).
Peeters, M. et al. Glioma patient-reported outcomes: patients and clinicians. BMJ Support. Palliat. Care 13, e205–e212 (2023).
Pe, M. et al. Setting international standards in analyzing patient-reported outcomes and quality of life endpoints in cancer clinical trials-innovative medicines initiative (SISAQOL-IMI): stakeholder views, objectives, and procedures. Lancet Oncol. 24, e270–e283 (2023).
Taphoorn, M. J. B. et al. Health-related quality of life in a randomized phase III study of bevacizumab, temozolomide, and radiotherapy in newly diagnosed glioblastoma. J. Clin. Oncol. 33, 2166–2175 (2015).
Wefel, J. S. et al. Neurocognitive, symptom, and health-related quality of life outcomes of a randomized trial of bevacizumab for newly diagnosed glioblastoma (NRG/RTOG 0825). Neuro Oncol. 23, 1125–1138 (2021).
Wolter, M., Felsberg, J., Malzkorn, B., Kaulich, K. & Reifenberger, G. Droplet digital PCR-based analyses for robust, rapid, and sensitive molecular diagnostics of gliomas. Acta Neuropathol. Commun. 10, 42 (2022).
Euskirchen, P. et al. Same-day genomic and epigenomic diagnosis of brain tumors using real-time nanopore sequencing. Acta Neuropathol. 134, 691–703 (2017).
Patel, A. et al. Rapid-CNS2: rapid comprehensive adaptive nanopore-sequencing of CNS tumors, a proof-of-concept study. Acta Neuropathol. 143, 609–612 (2022).
Hollon, T. et al. Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging. Nat. Med. 29, 828–832 (2023).
Vermuelen, C. et al. Ultra-fast deep-learned CNS tumor classification during surgery. Nature 622, 842–849 (2023).
Berzero, G., Pieri, V., Mortini, P., Filippi, M. & Finocchiaro, G. The coming of age of liquid biopsy in neuro-oncology. Brain 146, 4015–4024 (2023).
Fares, J. et al. Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial. Lancet Oncol. 22, 1103–1114 (2021).
Friedman, G. K. et al. Oncolytic HSV-1 G207 immunovirotherapy for pediatric high-grade gliomas. N. Engl. J. Med. 384, 1613–1622 (2021).
Umemura, Y. et al. Combined cytotoxic and immune-stimulatory gene therapy for primary adult high-grade glioma: a phase 1, first-in-human trial. Lancet Oncol. 24, 1042–1052 (2023).
Nassiri, F. et al. Oncolytic DNX-2401 virotherapy plus pembrolizumab in recurrent glioblastoma: a phase 1/2 trial. Nat. Med. 29, 1370–1378 (2023).
Ling, A. L. et al. Clinical trial links oncolytic immunoactivation to survival in glioblastoma. Nature 623, 157–166 (2023).
Alexander, B. M. et al. Adaptive global innovative learning environment for glioblastoma: GBM AGILE. Clin. Cancer Res. 24, 737–743 (2018).
Rahman, R. et al. Inaugural results of the individualized screening trial of innovative glioblastoma therapy: a phase II platform trial for newly diagnosed glioblastoma using Bayesian adaptive randomization. J. Clin. Oncol. 41, 5524–5535 (2023).
US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/search?term=NCT01089101 (2024).
Nobre, L. et al. Outcomes of BRAF V600E pediatric gliomas treated with targeted BRAF inhibition. JCO Precis. Oncol. 4, PO.19.00298 (2020).
Lassaletta, A. et al. Therapeutic and prognostic implications of BRAF V600E in pediatric low-grade gliomas. J. Clin. Oncol. 35, 2934–2941 (2017).
Lassman, A. B. et al. Infigratinib in patients with recurrent gliomas and FGFR alterations: a multicenter phase II study. Clin. Cancer Res. 28, 2270–2277 (2022).
Stepien, N. et al. Feasibility and antitumour activity of the FGFR inhibitor erdafitnib in three paediatric CNS tumour patients. Pediatr. Blood Cancer 71, e30836 (2024).
Weller, M. et al. Glioma. Nat. Rev. Dis. Primers 1, 15017 (2015).
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Introduction (M.W.); Epidemiology (M.W. and S.M.C.); Mechanisms/pathophysiology (M.W., G.R. and M.M.); Diagnosis, screening and prevention (M.W., M.L. and G.R.); Management (M.W., M.L. and P.Y.W.); Quality of life (M.W. and L.D.); Outlook (M.W.); overview of Primer (M.W.).
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M.W. has received research grants from Novartis, Quercis and Versameb, and honoraria for lectures or advisory board participation or consulting from Bayer, Curevac, Medac, Merck (EMD), Novartis, Novocure, Orbus, Philogen and Servier. P.Y.W. has received research grants from Amgen, Angiochem, AstraZeneca, Exelixis, Genentech/Roche, GlaxoSmithKline, Merck, Novartis, Sanofi–Aventis and Vascular Biogenics and honoraria for lectures or advisory board participation from AbbVie, Celldex, Foundation Medicine, Genentech/Roche, Merck, Novartis, Vascular Biogenics, Midatech and Monteris. M.L. has received research support from Arbor, Accuray and Biohaven and honoraria from VBI, InCephalo Therapeutics, Merck, Pyramid Bio, Insightec, Biohaven, Sanianoia, Hemispherian, Novocure, Noxxon, InCando, Hoth, CraniUs, MediFlix and GCAR. He is a shareholder for Egret Therapeutics. M.M. holds equity in MapLight Therapeutics and is on the SAB for TippingPoint Biosciences. G.R., S.M.C. and L.D. declare no competing interests.
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Weller, M., Wen, P.Y., Chang, S.M. et al. Glioma. Nat Rev Dis Primers 10, 33 (2024). https://doi.org/10.1038/s41572-024-00516-y
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DOI: https://doi.org/10.1038/s41572-024-00516-y
