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Brain Pathology (Zurich, Switzerland) Jul 2022The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous... (Review)
Review
The 2021 5th edition of the WHO Classification of Tumors of the Central Nervous System reflects the discovery of genetic alterations underlying many central nervous system (CNS) neoplasms. Insights gained from technologic advances and novel applications in molecular diagnostics, including next-generation sequencing and DNA methylation-based profiling, coupled with the recognition of clinicopathologic correlates, have prompted substantial changes to CNS tumor classification; this is particularly true for pediatric low-grade gliomas and glioneuronal tumors (pLGG/GNTs). The 2021 WHO now classifies gliomas, glioneuronal tumors and neuronal tumors into 6 families, three of which encompass pLGG/LGNTs: "Pediatric type diffuse low-grade gliomas," "circumscribed astrocytic gliomas," and "glioneuronal and neuronal tumors." Among these are six newly recognized tumor types: "diffuse astrocytoma, MYB or MYBL1-altered"; "polymorphous low grade neuroepithelial tumor of the young (PLNTY)"; "diffuse low-grade glioma-MAPK altered"; "Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)"; "myxoid glioneuronal tumor (MGT)"; and "multinodular and vacuolating neuronal tumor (MVNT)." We review these newly recognized entities in the context of general changes to the WHO schema, discuss implications of the new classification for treatment of pLGG/LGNT, and consider strategies for molecular testing and interpretation.
Topics: Astrocytoma; Brain Neoplasms; Central Nervous System; Central Nervous System Neoplasms; Child; Glioma; Humans; Neoplasms, Neuroepithelial; World Health Organization
PubMed: 35218102
DOI: 10.1111/bpa.13060 -
Nature Mar 2022Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system....
Diffuse intrinsic pontine glioma (DIPG) and other H3K27M-mutated diffuse midline gliomas (DMGs) are universally lethal paediatric tumours of the central nervous system. We have previously shown that the disialoganglioside GD2 is highly expressed on H3K27M-mutated glioma cells and have demonstrated promising preclinical efficacy of GD2-directed chimeric antigen receptor (CAR) T cells, providing the rationale for a first-in-human phase I clinical trial (NCT04196413). Because CAR T cell-induced brainstem inflammation can result in obstructive hydrocephalus, increased intracranial pressure and dangerous tissue shifts, neurocritical care precautions were incorporated. Here we present the clinical experience from the first four patients with H3K27M-mutated DIPG or spinal cord DMG treated with GD2-CAR T cells at dose level 1 (1 × 10 GD2-CAR T cells per kg administered intravenously). Patients who exhibited clinical benefit were eligible for subsequent GD2-CAR T cell infusions administered intracerebroventricularly. Toxicity was largely related to the location of the tumour and was reversible with intensive supportive care. On-target, off-tumour toxicity was not observed. Three of four patients exhibited clinical and radiographic improvement. Pro-inflammatory cytokine levels were increased in the plasma and cerebrospinal fluid. Transcriptomic analyses of 65,598 single cells from CAR T cell products and cerebrospinal fluid elucidate heterogeneity in response between participants and administration routes. These early results underscore the promise of this therapeutic approach for patients with H3K27M-mutated DIPG or spinal cord DMG.
Topics: Astrocytoma; Brain Stem Neoplasms; Child; Gangliosides; Gene Expression Profiling; Glioma; Histones; Humans; Immunotherapy, Adoptive; Mutation; Receptors, Chimeric Antigen; Spinal Cord Neoplasms
PubMed: 35130560
DOI: 10.1038/s41586-022-04489-4 -
International Journal of Molecular... Nov 2022Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the... (Review)
Review
Glioma is the most common type of primary CNS tumor, composed of cells that resemble normal glial cells. Recent genetic studies have provided insight into the inter-tumoral heterogeneity of gliomas, resulting in the updated 2021 WHO classification of gliomas. Thorough understanding of inter-tumoral heterogeneity has already improved the prognosis and treatment outcomes of some types of gliomas. Currently, the challenge for researchers is to study the intratumoral cell heterogeneity of newly defined glioma subtypes. Cancer stem cells (CSCs) present in gliomas and many other tumors are an example of intratumoral heterogeneity of great importance. In this review, we discuss the modern concept of glioma stem cells and recent single-cell sequencing-driven progress in the research of intratumoral glioma cell heterogeneity. The particular emphasis was placed on the recently revealed variations of the cell composition of the subtypes of the adult-type diffuse gliomas, including astrocytoma, oligodendroglioma and glioblastoma. The novel data explain the inconsistencies in earlier glioma stem cell research and also provide insight into the development of more effective targeted therapy and the cell-based immunotherapy of gliomas. Separate sections are devoted to the description of single-cell sequencing approach and its role in the development of cell-based immunotherapies for glioma.
Topics: Humans; Glioma; Oligodendroglioma; Glioblastoma; Astrocytoma; Neoplastic Stem Cells
PubMed: 36430704
DOI: 10.3390/ijms232214224 -
Acta Neuropathologica Jul 2018According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade...
According to the 2016 World Health Organization Classification of Tumors of the Central Nervous System (2016 CNS WHO), IDH-mutant astrocytic gliomas comprised WHO grade II diffuse astrocytoma, IDH-mutant (AII), WHO grade III anaplastic astrocytoma, IDH-mutant (AAIII), and WHO grade IV glioblastoma, IDH-mutant (GBM). Notably, IDH gene status has been made the major criterion for classification while the manner of grading has remained unchanged: it is based on histological criteria that arose from studies which antedated knowledge of the importance of IDH status in diffuse astrocytic tumor prognostic assessment. Several studies have now demonstrated that the anticipated differences in survival between the newly defined AII and AAIII have lost their significance. In contrast, GBM still exhibits a significantly worse outcome than its lower grade IDH-mutant counterparts. To address the problem of establishing prognostically significant grading for IDH-mutant astrocytic gliomas in the IDH era, we undertook a comprehensive study that included assessment of histological and genetic approaches to prognosis in these tumors. A discovery cohort of 211 IDH-mutant astrocytic gliomas with an extended observation was subjected to histological review, image analysis, and DNA methylation studies. Tumor group-specific methylation profiles and copy number variation (CNV) profiles were established for all gliomas. Algorithms for automated CNV analysis were developed. All tumors exhibiting 1p/19q codeletion were excluded from the series. We developed algorithms for grading, based on molecular, morphological and clinical data. Performance of these algorithms was compared with that of WHO grading. Three independent cohorts of 108, 154 and 224 IDH-mutant astrocytic gliomas were used to validate this approach. In the discovery cohort several molecular and clinical parameters were of prognostic relevance. Most relevant for overall survival (OS) was CDKN2A/B homozygous deletion. Other parameters with major influence were necrosis and the total number of CNV. Proliferation as assessed by mitotic count, which is a key parameter in 2016 CNS WHO grading, was of only minor influence. Employing the parameters most relevant for OS in our discovery set, we developed two models for grading these tumors. These models performed significantly better than WHO grading in both the discovery and the validation sets. Our novel algorithms for grading IDH-mutant astrocytic gliomas overcome the challenges caused by introduction of IDH status into the WHO classification of diffuse astrocytic tumors. We propose that these revised approaches be used for grading of these tumors and incorporated into future WHO criteria.
Topics: Adolescent; Adult; Aged; Algorithms; Astrocytoma; Brain Neoplasms; Cyclin-Dependent Kinase Inhibitor p16; Female; Gene Expression Regulation, Neoplastic; Humans; Isocitrate Dehydrogenase; Ki-67 Antigen; Male; Middle Aged; Models, Biological; Mutation; Neoplasm Grading; Neoplasm Proteins; World Health Organization; Young Adult
PubMed: 29687258
DOI: 10.1007/s00401-018-1849-4 -
Advanced Science (Weinheim,... Jul 2022Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor...
Diffuse intrinsic pontine glioma (DIPG) is a rare and fatal pediatric brain tumor. Mutation of p53-induced protein phosphatase 1 (PPM1D) in DIPG cells promotes tumor cell proliferation, and inhibition of PPM1D expression in DIPG cells with PPM1D mutation effectively reduces the proliferation activity of tumor cells. Panobinostat effectively kills DIPG tumor cells, but its systemic toxicity and low blood-brain barrier (BBB) permeability limits its application. In this paper, a nano drug delivery system based on functionalized macrophage exosomes with panobinostat and PPM1D-siRNA for targeted therapy of DIPG with PPM1D mutation is prepared. The nano drug delivery system has higher drug delivery efficiency and better therapeutic effect than free drugs. In vivo and in vitro experimental results show that the nano drug delivery system can deliver panobinostat and siRNA across the BBB and achieve a targeted killing effect of DIPG tumor cells, resulting in the prolonged survival of orthotopic DIPG mice. This study provides new ideas for the delivery of small molecule drugs and gene drugs for DIPG therapy.
Topics: Animals; Astrocytoma; Brain Stem Neoplasms; Diffuse Intrinsic Pontine Glioma; Exosomes; Glioma; Humans; Macrophages; Mice; Panobinostat; Protein Phosphatase 2C; RNA, Small Interfering
PubMed: 35585670
DOI: 10.1002/advs.202200353 -
Acta Neuropathologica Nov 2018EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations...
Distribution of EGFR amplification, combined chromosome 7 gain and chromosome 10 loss, and TERT promoter mutation in brain tumors and their potential for the reclassification of IDHwt astrocytoma to glioblastoma.
EGFR amplification (EGFRamp), the combination of gain of chromosome 7 and loss of chromosome 10 (7+/10-), and TERT promoter mutation (pTERTmut) are alterations frequently observed in adult IDH-wild-type (IDHwt) glioblastoma (GBM). In the absence of endothelial proliferation and/or necrosis, these alterations currently are considered to serve as a surrogate for upgrading IDHwt diffuse or anaplastic astrocytoma to GBM. Here, we set out to determine the distribution of EGFRamp, 7+/10-, and pTERTmut by analyzing high-resolution copy-number profiles and next-generation sequencing data of primary brain tumors. In addition, we addressed the question whether combinations of partial gains on chromosome 7 and partial losses on chromosome 10 exhibited a diagnostic and prognostic value similar to that of complete 7+/10-. Several such combinations proved relevant and were combined as the 7/10 signature. Our results demonstrate that EGFRamp and the 7/10 signature are closely associated with IDHwt GBM. In contrast, pTERTmut is less specific for IDHwt GBM. We conclude that, in the absence of endothelial proliferation and/or necrosis, the detection of EGFRamp is a very strong surrogate marker for the diagnosis of GBM in IDHwt diffuse astrocytic tumors. The 7/10 signature is also a strong surrogate marker. However, care should be taken to exclude pleomorphic xanthoastrocytoma. pTERTmut is less restricted to this entity and needs companion analysis by other molecular markers to serve as a surrogate for diagnosing IDHwt GBM. A combination of any two of EGFRamp, the 7/10 signature and pTERTmut, is highly specific for IDHwt GBM and the combination of all three alterations is frequent and exclusively seen in IDHwt GBM.
Topics: Adult; Aged; Astrocytoma; Brain; Brain Neoplasms; Chromosomes, Human, Pair 10; Chromosomes, Human, Pair 7; Cohort Studies; ErbB Receptors; Female; Glioblastoma; Humans; Isocitrate Dehydrogenase; Male; Middle Aged; Mutation
PubMed: 30187121
DOI: 10.1007/s00401-018-1905-0 -
Cells Jun 2022Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive...
Glioblastoma (GBM, grade IV astrocytoma), the most frequently occurring primary brain tumor, presents unique challenges to therapy due to its location, aggressive biological behavior, and diffuse infiltrative growth, thus contributing to having disproportionately high morbidity and mortality [...].
Topics: Astrocytoma; Brain Neoplasms; Glioblastoma; Humans; Molecular Biology
PubMed: 35681545
DOI: 10.3390/cells11111850 -
Journal of Clinical Oncology : Official... Apr 2023In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with... (Randomized Controlled Trial)
Randomized Controlled Trial
PURPOSE
In patients with diffuse low-grade glioma (LGG), the extent of surgical tumor resection (EOR) has a controversial role, in part because a randomized clinical trial with different levels of EOR is not feasible.
METHODS
In a 20-year retrospective cohort of 392 patients with IDH-mutant grade 2 glioma, we analyzed the combined effects of volumetric EOR and molecular and clinical factors on overall survival (OS) and progression-free survival by recursive partitioning analysis. The OS results were validated in two external cohorts (n = 365). Propensity score analysis of the combined cohorts (n = 757) was used to mimic a randomized clinical trial with varying levels of EOR.
RESULTS
Recursive partitioning analysis identified three survival risk groups. Median OS was shortest in two subsets of patients with astrocytoma: those with postoperative tumor volume (TV) > 4.6 mL and those with preoperative TV > 43.1 mL and postoperative TV ≤ 4.6 mL. Intermediate OS was seen in patients with astrocytoma who had chemotherapy with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL in addition to oligodendroglioma patients with either preoperative TV > 43.1 mL and residual TV ≤ 4.6 mL or postoperative residual volume > 4.6 mL. Longest OS was seen in astrocytoma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL who received no chemotherapy and oligodendroglioma patients with preoperative TV ≤ 43.1 mL and postoperative TV ≤ 4.6 mL. EOR ≥ 75% improved survival outcomes, as shown by propensity score analysis.
CONCLUSION
Across both subtypes of LGG, EOR beginning at 75% improves OS while beginning at 80% improves progression-free survival. Nonetheless, maximal resection with preservation of neurological function remains the treatment goal. Our findings have implications for surgical strategies for LGGs, particularly oligodendroglioma.
Topics: Humans; Oligodendroglioma; Retrospective Studies; Brain Neoplasms; Neurosurgical Procedures; Glioma; Astrocytoma; Treatment Outcome
PubMed: 36599113
DOI: 10.1200/JCO.21.02929 -
Acta Neuropathologica Mar 2020
Topics: Astrocytoma; Brain Neoplasms; Humans; Isocitrate Dehydrogenase; Mutation; Neoplasm Grading; Terminology as Topic; World Health Organization
PubMed: 31996992
DOI: 10.1007/s00401-020-02127-9 -
Child's Nervous System : ChNS :... Nov 2016The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and... (Review)
Review
INTRODUCTION
The purpose of this review is to document the various types of astrocytoma that occur in the fetus and neonate, their locations, initial findings, pathology, and outcome. Data are presented that show which patients are likely to survive or benefit from treatment compared with those who are unlikely to respond.
MATERIALS AND METHODS
One hundred one fetal and neonatal tumors were collected from the literature for study.
RESULTS
Macrocephaly and an intracranial mass were the most common initial findings. Overall, hydrocephalus and intracranial hemorrhage were next. Glioblastoma (GBM) was the most common neoplasm followed in order by subependymal giant cell astrocytoma (SEGA), low-grade astrocytoma, anaplastic astrocytoma, and desmoplastic infantile astrocytoma (DIA). Tumors were detected most often toward the end of the third trimester of pregnancy.
CONCLUSION
A number of patients were considered inoperable since their tumor occupied much of the intracranial cavity involving large areas of the brain. High-grade astrocytomas were more common than low-grade ones in this review. Fetuses and neonates with astrocytoma have a mixed prognosis ranging from as low as 20 % (GBM) to a high of 90 %. The overall survival was 47/101 or 46 %.
Topics: Astrocytoma; Brain Neoplasms; Female; Fetus; Humans; Infant, Newborn; Pregnancy
PubMed: 27568373
DOI: 10.1007/s00381-016-3215-y