General Child Neurology
Acute cerebellar ataxia in children
Oct. 29, 2024
Worddefinition
At vero eos et accusamus et iusto odio dignissimos ducimus qui blanditiis praesentium voluptatum deleniti atque corrupti quos dolores et quas.
Pediatric and adult histone altered tumors …
- Updated 04.02.2024
- Released 10.24.2021
- Expires For CME 04.02.2027
Pediatric and adult histone altered tumors
Introduction
Overview
Pediatric and adult diffuse gliomas harboring histone alterations potentially comprise a variety of subtypes of gliomas. A subgroup of diffuse midline gliomas harboring the H3 K27M mutation was previously classified as brainstem gliomas or diffuse intrinsic pontine gliomas. The proposed cell of origin for these tumors is the neural precursor-like cell in the ventral pons expressing nestin and OLIG-2 (30). There are other high-grade tumors baring the same, as well as other, histone alterations. The majority of these involve the brainstem, thalamus, and spinal cord (28). Patient age and specific histone alterations are associated with neuroanatomic location.
In the 2007 World Health Organization classification of central nervous system tumors, diffuse intrinsic pontine glioma was not defined as a separate entity. It was classified and graded according to the definition criteria of supratentorial diffuse gliomas (29). The 2016 WHO classification of CNS tumors identified H3 K27M-mutant diffuse midline glioma as a unique entity with distinct clinical behavior and molecular features. This CNS tumor is a diffuse (infiltrating) glioma with predominantly astrocytic differentiation and a K27M mutation in either the H3F3A or HIST1H3B/C genes (30). The 2021 WHO classification of CNS tumors further modified the classification of gliomas (31). Adult and pediatric gliomas were independently categorized. Pediatric diffuse gliomas were then separated into prognostically and biologically distinct groups (pediatric high- and low-grade glioma). High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes (Table 1). The histone-altered tumors were placed into two categories (diffuse midline glioma H3 K27-altered, diffuse hemispheric glioma H3 G34-mutant) in the Pediatric-type diffuse high-grade glioma group, although they occur in adults as well.
Table 1. 2021 WHO Classification of Pediatric Diffuse High-Grade Glioma and Key Diagnostic Genes, Molecules, Pathways, or Combinations
|
Pediatric-type diffuse high-grade gliomas |
Genes/Molecular Profiles Characteristically Altered |
|
Diffuse midline glioma, H3 K27 altered |
H3 K27, TP53, ACVR1, PDGFRA, EGFR, EZHIP overexpression |
|
Diffuse hemispheric glioma, H3 G34-mutant |
H3 G34, TP53, ATRX |
|
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype |
IDH-wildtype, H3-wildtype, PDGFRA, MYCN, EGFR (methylome)* |
|
Infant-type hemispheric glioma |
NTRK family, ALK, ROS, MET |
|
| |
Key points
|
• Pediatric diffuse gliomas are separated into prognostically and biologically distinct groups. | |
|
• High-grade pediatric gliomas were further classified into biologically distinct groups, largely based on alteration in the histone genes. | |
|
• Tumors with these histone aberrancies occur in adults as well and have some unique features in that patient population |
Clinical manifestations
Presentation and course
|
• Neurologic symptoms vary based on the involvement of midline structures. | |
|
• H3 K27M mutant diffuse midline gliomas are more common in children than adults. | |
|
• There is no gender preponderance. |
Symptoms vary based on involvement of different midline structures and generally develop over 1 to 2 months (30; 15; 45). Cranial neuropathies can cause expected symptomatology: diplopia, ptosis, facial pain or numbness, facial palsy, tinnitus, hearing loss, vertigo, dysarthria, and dysphagia. Involvement of motor and sensory pathways causes weakness, hypoesthesia, hyperesthesia, and gait abnormalities. High CSF pressure causes headache, nausea, and vomiting. Other CNS symptoms include seizures and persistent hiccups.
H3 K27M mutant diffuse midline gliomas have an incidence rate of 0.06 per 100,000 population and a median diagnosis age of 14 years (42). H3K27M mutant diffuse midline gliomas have been extensively described in children and are less frequently seen in adults (58). In children, H3 K27M-mutant gliomas occur frequently within the brainstem, particularly the pons, whereas in adults they occur more frequently within the thalamus and spinal cord.
In a retrospective study of adult midline gliomas, the H3 K27M mutation was identified in 15% of cases (55). In this series, the most common midline locations for H3 K27M-mutated tumors were midbrain, pons, and cerebellum. In the pediatric population, this mutation is identified in approximately 27% of gliomas (35).
H3 G34-mutant diffuse hemispheric gliomas are reported to occur in less than 1% of all gliomas and in 15% of high-grade gliomas. The median age at diagnosis is 15.8 years, with a male to female ratio of 1.46:1 (11). These tumors are commonly seen in the frontal lobe.
Prognosis and complications
H3 K27M-mutant midline gliomas are associated with poor prognosis and are designated as a grade 4 entity in the 2016 WHO Classification (30). However, there is heterogeneity in the behavior of gliomas with H3 K27M mutation. Prognosis for circumscribed gliomas, thalamic, or diffuse non-midline gliomas with H3 K27M mutation remains uncertain (16; 39; 41; 43).
However, prognosis for H3 K27M-mutant midline gliomas remains dismal even with timely and optimal treatment; overall survival is typically 7 to 11 months in children and 8 to 28 months in adults (24; 52; 58; 68). Overall survival with standard care is slightly longer compared to patients with IDH wildtype glioblastoma but shorter compared to patients with WHO grade 4 IDH-mutant astrocytomas (32). K27M mutation is a significant independent prognostic marker for poor outcome among pediatric glioblastomas (26). Furthermore, as compared to H3.1K27M mutation, H3.3K27M mutation is associated with shorter survival, higher metastatic relapses, and poorer response to radiotherapy (65; 07).
Patients with H3 G34-mutant gliomas have a better prognosis than H3K27M mutant tumors. Median time to progression is approximately 10 months, median overall survival is approximately 17 months, and median time from progression to death is approximately 5 months (11). The 1-, 2-, and 3-year survival estimates are 70%, 39%, and 21%. Survival was better in patients over 18 years old who underwent near or gross-total resection. G34V-mutant tumors had significantly worse overall survival when compared to G34R-mutant tumors (11; 63). Many patients were noted to have distant recurrence (26%).
A retrospective study of H3 K27-altered diffuse midline gliomas or H3 G34-mutant diffuse hemispheric glioma found a higher risk of developing leptomeningeal disease in each of these subgroups (14). In this study, median time from tumor diagnosis to leptomeningeal disease was 12.9 months for H3 K27 patients and 5.6 months for H3 G34 patients.
Biological basis
|
• Frequency of isocitrate dehydrogenase (IDH) mutation in the midline region has been reported to be low. | |
|
• Supratentorial high-grade gliomas have mutations in H3F3A (located on chromosome 1q) encoding histone H3.3 | |
|
•Specific mutations are seen in different brain locations (G34R/V restricted to hemispheric tumors and K27M occurring in the midline). |
Etiology and pathogenesis
Frequency of IDH mutation in the midline region has been reported to be low (60).
H3 K27M-mutant gliomas are IDH-wildtype, lack 1p/19q co-deletion, and are defined by the presence of K27M mutation in the H3F3A or HIST1H3B/C genes, which encode the histone H3 variants H3.3 and H3.1 in both children and adults (66; 58). These histone mutations are mutually exclusive from the other common mutations that define distinct infiltrating glioma types.
Histones are basic nuclear proteins responsible for the nucleosome structure within eukaryotic cells. Among the five classes of histones, some are expressed only during the S phase, whereas others are replacement histones that are replication-independent and expressed in quiescent or terminally differentiated cells.
Supratentorial high-grade gliomas have mutations in H3F3A (located on chromosome 1q) encoding histone H3.3. H3.3 is a replacement histone subclass that is encoded by two distinct genes, H3.3A (H3F3A) and H3.3B. This leads to the creation of oncohistones.
Oncohistones in high-grade gliomas have specific associated mutations and brain locations. G34R/V is restricted to hemispheric tumors, while K27M occurs in the midline (24; 60; 65; 10). K27M mutations occur in two main histone variants H3.3 and H3.1 and result in lysine to methionine exchange at position 27 of H3F3A or HIST1H3B/C genes. G34 mutations of H3.3 result in glycine to arginine exchange at codon 34 of H3F3A (57; 65).
The H3 K27M-mutated midline gliomas are further divided into two subgroups, H3.1 K27M and H3.3 K27M (07).
H3.3 K27M mutation. H3.3 K27M mutation occurs at the median age of 7.5 years. Patients with this mutation have a poor prognosis and frequent leptomeningeal dissemination; they are likelier to have an oligodendroglial histologic phenotype, poor response to radiation, and median survival of 9 months (10). H3.3 K27M mutant pediatric high-grade glioma are enriched for PDGFRA amplification (60). These tumors are seen all over the midline structures (66; 07). Approximately 20% of tumors previously categorized as pediatric glioblastomas harbor this mutation (18).
H3.1 K27M mutation. H3.1 K27M mutation occurs at the median age of 5.5 years. Patients with this mutation are likelier to have an astroglial differentiation, a good response to radiation, and a median survival of 15 months (10). H3.1 K27M tumors are associated with ACVR1 mutations (01). These tumors are almost exclusive to the pons (66; 07).
H3 K27M-mutant diffuse midline gliomas frequently share genetic alterations, including tumor protein 53 (TP53) overexpression, alpha-thalassemia/mental retardation X-linked (ATRX) loss, monosomy 10, activin A receptor type 1 (ACVR) mutation, poly ADP-ribose polymerase (PARP1) overexpression, cyclin D1-3(CCND1-3), and cyclin-dependent kinase (CDK4/CDK6) mutations (58; 15). TP53 mutations occur in about 40% of diffuse intrinsic pontine gliomas and represent the second most frequent mutation, correlated with worse overall survival (05).
H3 K27M mutation is mutually exclusive or rarely co-occurs with IDH1 mutation, telomerase reverse transcriptase (TERT) promoter mutation, epidermal growth factor receptor (EGFR) amplification, and BRAF-V600E mutation (58; 34; 15). Prototypic alterations of adult primary glioblastoma IDHwt (eg, EGFR amplification, CDKN2A/B homozygous deletions, PTEN mutations) are infrequent in childhood (47; 60; 48; 26). O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is found in 75% of G34-mutant subtype tumors and in 3% of K27 mutant tumors (26; 34).
Molecular profiling has revealed differences between adult and pediatric H3 K27M-mutant diffuse midline gliomas. Higher frequencies of ATRX loss and H3.3 mutation are found in adult than in pediatric H3 K27M-mt diffuse midline gliomas (68). TERT promoter mutations and O6-methylguanine DNA methyltransferase promoter methylation were not detected in pediatric patients but are present in a few adult patients.
H3 K27 wild type occurs at a median age of 6 years, with a median survival of 9 months (10).
Diffuse glioma, H3.3 G34-mutant are a distinct grade 4 entity described in the WHO 2021 classification (31). H3 G34-mutant diffuse hemispheric glioma was first described in 2012. Point mutations in the H3F3A gene, encoding for the histone variant H3.3, result in amino acid substitution at codon 34 from either glycine-to-arginine (G34R) or, more rarely, glycine-to-valine (G34V) (11). Co-occurring molecular alterations include ATRX mutation in 93%, TP53 mutation in 88%, PDGFA point mutation in 45%, PDGFRA amplification in 11%, and MGMT promoter methylation in 70% (63).
Diagnostic workup
Diagnosis is made with both imaging and histologic confirmation. Radiographic criteria alone are used for tumors with midline locations associated with serious procedural complications (22). Imaging primarily includes a brain MRI with and without gadolinium. MRI abnormalities include diffuse, T2 expansile signal changes in the midline structures.
In most cases, little or no enhancement is noted after the administration of gadolinium at initial diagnosis. Occasionally, areas of necrosis with surrounding serpiginous contrast enhancement can be present. A retrospective study to characterize imaging features of 24 diffuse midline gliomas found distinguishing features in H3K27-mutant midline gliomas as compared to their H3wild-type counterparts (01). In H3K27-mutant gliomas, there was an absence of perilesional edema at low frequency of strong contrast enhancement. Contrast enhancement of intermediate or higher and rim enhancement was associated with microscopically detected microvascular proliferation. Necrosis on MRI is less frequently seen than in the H3wt high-grade midline gliomas (01). H3G34 tumors demonstrate contrast enhancement and diffusion restriction on MRI.
PET imaging with amino acid tracers, such as 18-F-dihydroxy-phenylalanine (F-DOPA) is able to discriminate H3 K27M-mutant from wild-type diffuse midline gliomas and has demonstrated correlation of higher tracer uptake with worse prognosis (69; 49).
Traditional WHO grading for diffuse intrinsic pontine gliomas was not prognostic. Outcomes for grade 2, 3, and 4 tumors are equally poor (05). Next-generation sequencing can help accurately classify these tumors, improve understanding of unique tumor biology, and provide important insights into prognosis and management. Reports have shown that biopsy of these tumors is safe (22). Modern neuronavigation tools allow accurate 3D localization of deep structures in the brain and identification of major vessels prior to surgery, which greatly minimizes surgical complications (22).
Once tissue is obtained, both the macroscopic and microscopic evaluation can provide insight into the underlying disease. Macroscopically, these tumors cause enlargement and distortion of anatomical structures by diffuse infiltration. Microscopically, they typically have an astrocytic morphology or an oligodendroglial pattern. Mitotic activity is present in most cases but is not necessary for diagnosis (30). Features such as microvascular proliferation and necrosis may be seen. Immunohistochemistry reveals expression of neural cell adhesion molecule 1 (NCAM1), S100, oligodendrocyte transcription factor 2 (OLIG2) on tumor cells (30). Microtubule-associated protein 2 (MAP2) expression is common. Immunoreactivity of glial fibrillary acidic protein (GFAP) is variable, and synaptophysin can be focal. Chromogranin A and neuronal nuclei (NeuN) are not typically expressed (30).
Biopsy carries the risk of neurologic injury due to anatomical location of midline glioma. Minimally invasive techniques like liquid biopsy to detect biomarkers of H3 K27M in CSF, blood, and urine for diagnosis and monitoring treatment response are under investigation (25; 46). Two secreted proteins, cyclophilin A (CypA) and dimethylarginase 1 (DDAH1), are upregulated in CSF samples from patients with diffuse intrinsic pontine gliomas (54). Detecting tumor-derived circulating tumor DNA (ctDNA) from CSF samples can help with analysis of the tumor’s mutational profile.
Management
Anatomic location of the tumor severely limits any opportunity for meaningful surgical resection. Treatment usually consists of standard fractionated radiation to a dose of 54-59Gy (over 30 fractions) (10).
Radiation is the mainstay of treatment. Photon-based radiotherapy to a range of 54 to 59.4 Gy given in 30 to 33 fractions of 1.8 Gy daily for 6 weeks, as well as hypo-fractionated radiation (39 to 45 Grays given in 13 fractions of 3.0 Grays over 3 to 4 weeks), has been utilized with similar survival rates (37; 23; 67). Monotherapy and combination chemotherapy have been trialed, with uniformly poor results (21; 62). Temozolomide has limited value in treating pediatric H3 K27M-mutant gliomas, likely due to a higher likelihood of unmethylated MGMT (09; 53). It is still often used in the treatment of adult tumors. It is likely that the pivotal trials that established the standard of care for adult high-grade gliomas included histone mutated tumors, although this was not specifically evaluated. Pre-radiation chemotherapy has shown improvement in overall survival and progression-free survival in a small series of patients (64; 19), although how to best interpret these data in the current WHO 2021 era is uncertain. In a series of adult patients, surgery was followed by concurrent radiation and temozolomide and, subsequently, maintenance temozolomide (56). At recurrence, a combination of re-radiation, bevacizumab, and lomustine were utilized, similar to what is typically used in recurrent glioblastoma IDHwt.
Future directions
Novel ongoing treatment trials include convection-enhanced therapies, targeted therapies, and immunotherapy (vaccine therapies, CAR-T cells).
Convection-enhanced delivery. Convection-enhanced delivery is a therapeutic delivery strategy that allows for targeted treatment of a specific region via a cannula that can be placed in difficult-to-access areas and allows for direct intraparenchymal infusion of drugs at a steady rate over a prolonged period of time. This approach is not limited to a single group of therapeutic agents. Studies have shown safe placement of convection-enhanced delivery catheters into the brainstem in humans (02; 59).
Immunotherapy.
Peptide-based vaccine therapy. Glioma-associated antigens interleukin-13 receptor alpha 2 (IL-13Rα2), EphA2, and survivin are commonly overexpressed in pediatric gliomas (40). A pilot study of subcutaneous vaccination with glioma-associated antigen epitope peptides in HLA-A2-positive children with newly diagnosed brainstem and high-grade gliomas was well tolerated and has preliminary evidence of immunologic and clinical responses (51).
Dendritic cell vaccines reactivate tumor-specific T cells in both clinical and preclinical settings. Autologous dendritic cell vaccine administered intradermally is safe and able to generate a diffuse intrinsic pontine glioma-specific immune response detected in peripheral blood mononuclear cells and CSF (04).
The disialoganglioside GD2 is highly expressed in H3 K27M-mutant glioma cells. Preclinical studies have demonstrated GD2 as a novel immunotherapy target in H3 K27M mutant diffuse midline gliomas, and antitumor efficacy of GD2-CAR T-cells delivered systemically (36). The first-in-human phase I clinical trial included four patients with H3 K27M-mutant diffuse intrinsic pontine glioma or diffuse midline glioma treated with GD2-CAR T cells administered intravenously, with subsequent intraventricular infusions (33). GD2-CAR T therapy produced toxicities that were largely related to tumor location and reversible with intensive supportive care. Radiographic response was seen in three patients but was not durable. Proinflammatory cytokines were increased in plasma and CSF. These preliminary cases suggest that GD2-CAR T-cell therapy holds significant promise for H3K27M+ diffuse intrinsic pontine gliomas or diffuse midline gliomas.
A single-center trial of newly diagnosed pediatric patients with diffuse intrinsic pontine glioma who underwent oncolytic viral therapy (DNX-2401, an oncolytic adenovirus that selectively replicates in tumor cells) followed by radiation revealed changes in T-cell activity and stabilization to the reduction of tumor size (17). Adverse events related to virotherapy were largely grade 1 or grade 2, with only one event of grade 3 and no grade 4 or 5 events (17).
Targeted therapies. K27M mutation drives gliomagenesis by alteration of an important site of posttranslational modification in the histone H3 variants and leads to altered DNA methylation and gene expression profiles (60; 03). Ongoing efforts aim to study the efficacy of therapeutics targeting histone-modifying enzymes for midline gliomas with histone H3 mutations.
Panobinostat. Panobinostat is a general histone deacetylase inhibitor that has shown good in vitro efficacy against diffuse intrinsic pontine gliomas (20; 50). Panobinostat synergizes with histone demethylase inhibitor GSKJ4 in H3.3K27M mutant diffuse intrinsic pontine gliomas cells (20). Together, these data suggest a promising therapeutic strategy for diffuse intrinsic pontine gliomas. Compassionate use of panobinostat in four adult patients with H3 K27M-mutant glioma revealed good tolerability without any serious adverse effects (38).
ONC201. ONC201 is a small-molecule selective antagonist of dopamine receptor D2/3 (DRD2/3) that crosses the blood-brain barrier and exhibits P53 independent anticancer efficacy. DRD2 expression within the central nervous system is highest in midline structures of the brain. DRD2 is a G protein-coupled receptor that promotes tumor growth and has emerged as a therapeutic target for gliomas that overexpress this receptor (27; 06). H3 K27M-mutant diffuse midline gliomas have been reported to exhibit elevated expression and dependency on DRD2 as a downstream epigenetic consequence of the mutation (08). It has an exceptional safety profile and has been reported to have clinical and radiographic responses in both recurrent and frontline settings (08). ONC206 is another drug in the same class actively undergoing investigation. An international phase 3 randomized, double-blind, placebo-controlled study (ACTION study) is currently evaluating the benefit of ONC201 after frontline radiation on overall survival and progression-free survival.
Cdk4/6 inhibitors. CDK alterations are described in about 30% to 40% of diffuse midline gliomas. Cdk4/6 inhibitors (palbociclib, ribociclib, and abemaciclib), tyrosine kinase inhibitors, and other agents that more specifically target these mutations are being explored in patients with diffuse midline gliomas (13; 61; 44). Other potential therapeutic targets tested with in vivo studies include BET bromodomain inhibitors (50).
mTOR inhibitors. PI3K/AKT/mTOR pathway is dysregulated in more than 50% of diffuse midline gliomas. A single-center study from Italy reported significant benefit in overall survival with utilization of personalized treatment based on tumor molecular alterations. mTOR inhibition with everolimus was associated with the best overall survival (12).
Multiple phase I and II trials are currently ongoing to test novel agents to treat midline gliomas with histone mutation in a frontline and recurrent setting (Table 2). An understanding of molecular pathology and ongoing efforts to improve diagnostic tools and therapy holds promise for future advances in prognosis.
Table 2. Ongoing Trials to Test Novel Agents for Diffuse Midline Glioma in a Frontline and Recurrent Setting
ClinicalTrials.gov Identifier | Trial Design |
NCT04771897 | Phase 1 nonrandomized, multi-center study to evaluate the safety and tolerability of BXQ-350 (intravenous anti-neoplastic therapeutic agent) in children with newly diagnosed diffuse midline glioma |
NCT05544526 | Phase 1 study to assess safety and tolerability of the GD2CAR T-cell therapy for patients with diffuse midline glioma |
NCT04264143 | Phase I study examining the feasibility of intermittent convection-enhanced delivery of MTX110 (a water-soluble panobinostat nanoparticle formulation) for the treatment of children with newly diagnosed diffuse midline glioma |
NCT05478837 | Phase 1 clinical trial of genetically modified cells (KIND T cells) for the treatment of HLA-A*0201-positive patients with H3.3K27M-mutated diffuse midline glioma |
NCT04943848 | Phase I clinical trial of neo-antigen heat shock protein vaccine (rHSC-DIPGVax) in combination with checkpoint blockade for treatment of diffuse midline glioma |
NCT05009992 | Phase 2 trial to determine the combination of ONC201 with different drugs, panobinostat or paxalisib (enzyme inhibitors) for treating patients with diffuse midline gliomas |
NCT04185038 | Phase 1 study of B7-H3-Specific CAR T cell locoregional immunotherapy for diffuse midline glioma |
NCT04732065 | Phase 1 and target validation study of ONC206 (DRD2 antagonist/ClpP agonist) in children and young adults with newly diagnosed or recurrent diffuse midline glioma |
NCT02960230 | Phase 1 trail of H3.3K27M peptide vaccine with nivolumab for children with newly diagnosed diffuse intrinsic pontine gliomas and other gliomas |
NCT04804709 | Phase 1 trial of oral panobinostat in combination with focused ultrasound with microbubbles and neuro-navigator-controlled sonication to temporarily open up the blood brain barrier and allow for a greater concentration of drug to reach the tumor. |
NCT05580562 | International phase 3 randomized, double-blind, placebo-controlled study (ACTION study) evaluating the benefit of ONC201 after frontline radiation on overall survival and progression-free survival. |
Abbreviations: CED, convection-enhanced delivery; DMG, diffuse midline glioma; FUS, focused ultrasound | |
Media
References
- 01
- Banan R, Akbarian A, Samii M, et al. Diffuse midline gliomas, H3 K27M-mutant are associated with less peritumoral edema and contrast enhancement in comparison to glioblastomas, H3 K27M-wildtype of midline structures. PLoS One 2021;16(8):e0249647. PMID 34347774
- 02
- Barua NU, Lowis SP, Woolley M, O'Sullivan S, Harrison R, Gill SS. Robot-guided convection-enhanced delivery of carboplatin for advanced brainstem glioma. Acta Neurochir (Wien) 2013;155(8):1459-65. PMID 23595829
- 03
- Bender S, Tang Y, Lindroth AM, et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 2013;24(5):660-72. PMID 24183680
- 04
- Benitez-Ribas D, Cabezon R, Florez-Grau G, et al. Immune response generated with the administration of autologous dendritic cells pulsed with an allogenic tumoral cell-lines lysate in patients with newly diagnosed diffuse intrinsic pontine glioma. Front Oncol 2018;8:127. PMID 29755954
- 05
- Buczkowicz P, Bartels U, Bouffet E, Becher O, Hawkins C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 2014;128(4):573-81. PMID 25047029
- 06
- Caragher SP, Hall RR, Ahsan R, Ahmed AU. Monoamines in glioblastoma: complex biology with therapeutic potential. Neuro Oncol 2018;20(8):1014-25. PMID 29126252
- 07
- Castel D, Philippe C, Calmon R, et al. Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes. Acta Neuropathol 2015;130(6):815-27. PMID 26399631
- 08
- Chi AS, Tarapore RS, Hall MD, et al. Pediatric and adult H3 K27M-mutant diffuse midline glioma treated with the selective DRD2 antagonist ONC201. J Neurooncol 2019;145(1):97-105. PMID 31456142
- 09
- Cohen KJ, Heideman RL, Zhou T, et al. Temozolomide in the treatment of children with newly diagnosed diffuse intrinsic pontine gliomas: a report from the Children's Oncology Group. Neuro Oncol 2011;13(4):410-6. PMID 21345842
- 10
- Cohen KJ, Jabado N, Grill J. Diffuse intrinsic pontine gliomas-current management and new biologic insights. Is there a glimmer of hope? Neuro Oncol 2017;19(8):1025-34. PMID 28371920
- 11
- Crowell C, Mata-Mbemba D, Bennet, J, et al. Systematic review of diffuse hemispheric glioma, H3 G34-mutant: outcomes and associated clinical factors. Neurooncol Adv 2022;4(1):vdac133. PMID 36105387
- 12
- Del Baldo G, Carai A, Abbas R, et al. Targeted therapy for pediatric diffuse intrinsic pontine glioma: a single-center experience. Ther Adv Med Oncol 2022;14:17588359221113693. PMID 36090803
- 13
- DeWire M, Fuller C, Hummel TR, et al. A phase I/II study of ribociclib following radiation therapy in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). J Neurooncol 2020;149(3):511-22. PMID 33034839
- 14
- Diaz M, Rana S, Correia CES, et al. Leptomeningeal disease in histone-mutant gliomas. Neurooncol Adv 2023;5(1):vdad068. PMID 37346983
- 15
- Dono A, Takayasu T, Ballester LY, Esquenazi Y. Adult diffuse midline gliomas: clinical, radiological, and genetic characteristics. J Clin Neurosci 2020;82(Pt A):1-8. PMID 33317715
- 16
- Feng J, Hao S, Pan C, et al. The H3.3 K27M mutation results in a poorer prognosis in brainstem gliomas than thalamic gliomas in adults. Hum Pathol 2015;46(11):1626-32. PMID 26297251
- 17
- Gallego Perez-Larraya J, Garcia-Moure M, Labiano S, et al. Oncolytic DNX-2401 virus for pediatric diffuse intrinsic pontine glioma. N Engl J Med 2022;386(26):2471-81. PMID 35767439
- 18
- Gielen GH, Gessi M, Hammes J, Kramm CM, Waha A, Pietsch T. H3F3A K27M mutation in pediatric CNS tumors: a marker for diffuse high-grade astrocytomas. Am J Clin Pathol 2013;139(3):345-9. PMID 23429371
- 19
- Gokce-Samar Z, Beuriat PA, Faure-Conter C, et al. Pre-radiation chemotherapy improves survival in pediatric diffuse intrinsic pontine gliomas. Childs Nerv Syst 2016;32(8):1415-23. PMID 27379495
- 20
- Grasso CS, Tang Y, Truffaux N, et al. Functionally defined therapeutic targets in diffuse intrinsic pontine glioma. Nat Med 2015;21(6):555-9. PMID 25939062
- 21
- Grimm SA, Chamberlain MC. Brainstem glioma: a review. Curr Neurol Neurosci Rep 2013;13(5):346. PMID 23512689
- 22
- Gupta N, Goumnerova LC, Manley P, et al. Prospective feasibility and safety assessment of surgical biopsy for patients with newly diagnosed diffuse intrinsic pontine glioma. Neuro Oncol 2018;20(11):1547-55. PMID 29741745
- 23
- Janssens GO, Jansen MH, Lauwers SJ, et al. Hypofractionation vs conventional radiation therapy for newly diagnosed diffuse intrinsic pontine glioma: a matched-cohort analysis. Int J Radiat Oncol Biol Phys 2013;85(2):315-20. PMID 22682807
- 24
- Khuong-Quang DA, Buczkowicz P, Rakopoulos P, et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 2012;124(3):439-47. PMID 22661320
- 25
- Kilgour E, Rothwell DG, Brady G, Dive C. Liquid biopsy-based biomarkers of treatment response and resistance. Cancer Cell 2020;37(4):485-95. PMID 32289272
- 26
- Korshunov A, Ryzhova M, Hovestadt V, et al. Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers. Acta Neuropathol 2015;129(5):669-78. PMID 25752754
- 27
- Li J, Zhu S, Kozono D, et al. Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma. Oncotarget 2014;5(4):882-93. PMID 24658464
- 28
- Louis DN, Giannini C, Capper D, et al. cIMPACT-NOW update 2: diagnostic clarifications for diffuse midline glioma, H3 K27M-mutant and diffuse astrocytoma/anaplastic astrocytoma, IDH-mutant. Acta Neuropathol 2018;135(4):639-42. PMID 29497819
- 29
- Louis DN, Ohgaki H, Wiestler OD, et al. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 2007;114(2):97-109. PMID 17618441
- 30
- 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):803-20. PMID 27157931
- 31
- Louis DN, Perry A, Wesseling P, et al. The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. Neuro Oncol 2021;23(8):1231-51. PMID 34185076
- 32
- Louis DN, Wesseling P, Aldape K, et al. cIMPACT-NOW update 6: new entity and diagnostic principle recommendations of the cIMPACT-Utrecht meeting on future CNS tumor classification and grading. Brain Pathol 2020;30(4):844-56. PMID 32307792
- 33
- Majzner RG, Ramakrishna S, Yeom KW, et al. GD2-CAR T cell therapy for H3K27M-mutated diffuse midline gliomas. Nature 2022;603(7903):934-41. PMID 35130560
- 34
- Meyronet D, Esteban-Mader M, Bonnet C, et al. Characteristics of H3 K27M-mutant gliomas in adults. Neuro Oncol 2017;19(8):1127-34. PMID 28201752
- 35
- Mosaab A, El-Ayadi M, Khorshed EN, et al. Histone H3K27M mutation overrides histological grading in pediatric gliomas. Sci Rep 2020;10(1):8368. PMID 32433577
- 36
- Mount CW, Majzner RG, Sundaresh S, et al. Potent antitumor efficacy of anti-GD2 CAR T cells in H3-K27M(+) diffuse midline gliomas. Nat Med 2018;24(5):572-9. PMID 29662203
- 37
- Negretti L, Bouchireb K, Levy-Piedbois C, et al. Hypofractionated radiotherapy in the treatment of diffuse intrinsic pontine glioma in children: a single institution's experience. J Neurooncol 2011;104(3):773-7. PMID 21327862
- 38
- Neth BJ, Balakrishnan SN, Carabenciov ID, et al. Panobinostat in adults with H3 K27M-mutant diffuse midline glioma: a single center experience. J Neurooncol 2022;157(1):91-100. PMID 35076860
- 39
- Nguyen AT, Colin C, Nanni-Metellus I, et al. Evidence for BRAF V600E and H3F3A K27M double mutations in paediatric glial and glioneuronal tumours. Neuropathol Appl Neurobiol 2015;41(3):403-8. PMID 25389051
- 40
- Okada H, Low KL, Kohanbash G, et al. Expression of glioma-associated antigens in pediatric brain stem and non-brain stem gliomas. J Neurooncol 2008;88(3):245-50. PMID 18324354
- 41
- Orillac C, Thomas C, Dastagirzada Y, et al. Pilocytic astrocytoma and glioneuronal tumor with histone H3 K27M mutation. Acta Neuropathol Commun 2016;4(1):84. PMID 27519587
- 42
- Ostrom QT, Price M, Neff C, et al. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2015-2019. Neuro Oncol 2022;24(Suppl 5):v1-95. PMID 36196752
- 43
- Pages M, Beccaria K, Boddaert N, et al. Co-occurrence of histone H3 K27M and BRAF V600E mutations in paediatric midline grade I ganglioglioma. Brain Pathol 2018;28(1):103-11. PMID 27984673
- 44
- Parenrengi MA, Suryaningtyas W, Al Fauzi A, et al. Nimotuzumab as additional therapy for GLIOMA in pediatric and adolescent: a systematic review. Cancer Control 2022;29:10732748211053927. PMID 35191733
- 45
- Park C, Kim TM, Bae JM, et al. Clinical and genomic characteristics of adult diffuse midline glioma. Cancer Res Treat 2021;53(2):389-98. PMID 33171023
- 46
- Patel J, Aittaleb R, Doherty R, et al. Liquid biopsy in H3K27M diffuse midline glioma. Neuro Oncol 2024;26(Supplement_2):S101-9. PMID 38096156
- 47
- Paugh BS, Qu C, Jones C, et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 2010;28(18):3061-8. PMID 20479398
- 48
- Phillips JJ, Aranda D, Ellison DW, et al. PDGFRA amplification is common in pediatric and adult high-grade astrocytomas and identifies a poor prognostic group in IDH1 mutant glioblastoma. Brain Pathol 2013;23(5):565-73. PMID 23438035
- 49
- Piccardo A, Tortora D, Mascelli S, et al. Advanced MR imaging and (18)F-DOPA PET characteristics of H3K27M-mutant and wild-type pediatric diffuse midline gliomas. Eur J Nucl Med Mol Imaging 2019;46(8):1685-94. PMID 31030232
- 50
- Piunti A, Hashizume R, Morgan MA, et al. Therapeutic targeting of polycomb and BET bromodomain proteins in diffuse intrinsic pontine gliomas. Nat Med 2017;23(4):493-500. PMID 28263307
- 51
- Pollack IF, Jakacki RI, Butterfield LH, et al. Antigen-specific immune responses and clinical outcome after vaccination with glioma-associated antigen peptides and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in children with newly diagnosed malignant brainstem and nonbrainstem gliomas. J Clin Oncol 2014;32(19):2050-8. PMID 24888813
- 52
- Reyes-Botero G, Giry M, Mokhtari K, et al. Molecular analysis of diffuse intrinsic brainstem gliomas in adults. J Neurooncol 2014;116(2):405-11. PMID 24242757
- 53
- Rizzo D, Scalzone M, Ruggiero A, et al. Temozolomide in the treatment of newly diagnosed diffuse brainstem glioma in children: a broken promise? J Chemother 2015;27(2):106-10. PMID 25466729
- 54
- Saratis AM, Yadavilli S, Magge S, et al. Insights into pediatric diffuse intrinsic pontine glioma through proteomic analysis of cerebrospinal fluid. Neuro Oncol 2012;14(5):547-60. PMID 22492959
- 55
- Schreck KC, Ranjan S, Skorupan N, et al. Incidence and clinicopathologic features of H3 K27M mutations in adults with radiographically-determined midline gliomas. J Neurooncol 2019;143(1):87-93. PMID 30864101
- 56
- Schulte JD, Buerki RA, Lapointe S, et al. Clinical, radiologic, and genetic characteristics of histone H3 K27M-mutant diffuse midline gliomas in adults. Neurooncol Adv 2020;2(1):vdaa142. PMID 33354667
- 57
- Schwartzentruber J, Korshunov A, Liu XY, et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 2012;482(7384):226-31. PMID 22286061
- 58
- Solomon DA, Wood MD, Tihan T, et al. Diffuse midline gliomas with histone H3-K27M mutation: a series of 47 cases assessing the spectrum of morphologic variation and associated genetic alterations. Brain Pathol 2016;26(5):569-80. PMID 26517431
- 59
- Souweidane MM, Kramer K, Pandit-Taskar N, et al. Convection-enhanced delivery for diffuse intrinsic pontine glioma: a single-centre, dose-escalation, phase 1 trial. Lancet Oncol 2018;19(8):1040-50. PMID 29914796
- 60
- Sturm D, Witt H, Hovestadt V, et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 2012;22(4):425-37. PMID 23079654
- 61
- Van Mater D, Gururangan S, Becher O, et al. A phase I trial of the CDK 4/6 inhibitor palbociclib in pediatric patients with progressive brain tumors: a Pediatric Brain Tumor Consortium study (PBTC-042). Pediatr Blood Cancer 2021;68(4):e28879. PMID 33405376
- 62
- Vanan MI, Eisenstat DD. DIPG in children - what can we learn from the past? Front Oncol 2015;5:237. PMID 26557503
- 63
- Vuong HG, Le HT, Dunn IF. The prognostic significance of further genotyping H3G34 diffuse hemispheric gliomas. Cancer 2022;128(10):1907-12. PMID 35195909
- 64
- Wagner S, Reinert C, Schmid HJ, et al. High-dose methotrexate prior to simultaneous radiochemotherapy in children with malignant high-grade gliomas. Anticancer Res 2005;25(3c):2583-7. PMID 16080497
- 65
- Wu G, Broniscer A, McEachron TA, et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 2012;44(3):251-3. PMID 22286216
- 66
- Wu G, Diaz AK, Paugh BS, et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 2014;46(5):444-50. PMID 24705251
- 67
- Zaghloul MS, Eldebawy E, Ahmed S, et al. Hypofractionated conformal radiotherapy for pediatric diffuse intrinsic pontine glioma (DIPG): a randomized controlled trial. Radiother Oncol 2014;111(1):35-40. PMID 24560760
- 68
- Zheng L, Gong J, Yu T, et al. Diffuse midline gliomas with histone H3 K27M mutation in adults and children: a retrospective series of 164 cases. Am J Surg Pathol 2022;46(6):863-71. PMID 35416795
- 69
- Zukotynski KA, Fahey FH, Kocak M, et al. Evaluation of 18F-FDG PET and MRI associations in pediatric diffuse intrinsic brain stem glioma: a report from the Pediatric Brain Tumor Consortium. J Nucl Med 2011;52(2):188-95. PMID 21233173
- 70
- References especially recommended by the author or editor for general reading.
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Jigisha Thakkar MD
Dr. Thakkar of Loyola University Medical School has no relevant financial relationships to disclose.
See Profile -
Diego D Luy MD
Dr. Luy of Loyola University has no relevant financial relationships to disclose.
See Profile -
Vikram C Prabhu MD
Dr. Prabhu of University of Nebraska Medical Center has no relevant financial relationships to disclose.
See Profile
Editor
-
Rimas V Lukas MD
Dr. Lukas of Northwestern University Feinberg School of Medicine received honorariums from Novartis and Novocure for speaking engagements, honorariums from Cardinal Health, Novocure, and Merck for advisory board membership, and research support from BMS as principal investigator.
See Profile
Former Authors
- Tamer Refaat Abdelrhman MD PhD
- Courtney Hentz MD
- Atul K Mallik MD PhD
- Yuchen Zheng MD
- Taylor Stevens MD
- Douglas Anderson MD
- Ewa Borys MD
- Anupama Chundury MD
This is an article preview.
Start a Free Account
to access the full version.
-
Nearly 3,000 illustrations, including video clips of neurologic disorders.
-
Every article is reviewed by our esteemed Editorial Board for accuracy and currency.
-
Full spectrum of neurology in 1,200 comprehensive articles.
-
Listen to MedLink on the go with Audio versions of each article.
Questions or Comment?
MedLink®, LLC
3525 Del Mar Heights Rd, Ste 304
San Diego, CA 92130-2122
Toll Free (U.S. + Canada): 800-452-2400
US Number: +1-619-640-4660
Support: service@medlink.com
Editor: editor@medlink.com
ISSN: 2831-9125
Also in This Category
-
-
Neuro-Oncology
Overview of neuropathology updates for infiltrating gliomas
Oct. 11, 2024
-
Infectious Disorders
Zika virus: neurologic complications
Oct. 08, 2024
-
Neuro-Oncology
Anti-LGI1 encephalitis
Oct. 03, 2024
-
General Child Neurology
Cerebral edema in childhood
Sep. 29, 2024
-
Neuro-Oncology
CNS germinoma
Sep. 25, 2024
-
Developmental Malformations
Vein of Galen malformations
Sep. 22, 2024
-
Neuro-Oncology
Vestibular schwannoma
Sep. 19, 2024