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JAMA Feb 2023Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7... (Review)
Review
IMPORTANCE
Malignant primary brain tumors cause more than 15 000 deaths per year in the United States. The annual incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals and increases with age. Five-year survival is approximately 36%.
OBSERVATIONS
Approximately 49% of malignant brain tumors are glioblastomas, and 30% are diffusely infiltrating lower-grade gliomas. Other malignant brain tumors include primary central nervous system (CNS) lymphoma (7%) and malignant forms of ependymomas (3%) and meningiomas (2%). Symptoms of malignant brain tumors include headache (50%), seizures (20%-50%), neurocognitive impairment (30%-40%), and focal neurologic deficits (10%-40%). Magnetic resonance imaging before and after a gadolinium-based contrast agent is the preferred imaging modality for evaluating brain tumors. Diagnosis requires tumor biopsy with consideration of histopathological and molecular characteristics. Treatment varies by tumor type and often includes a combination of surgery, chemotherapy, and radiation. For patients with glioblastoma, the combination of temozolomide with radiotherapy improved survival when compared with radiotherapy alone (2-year survival, 27.2% vs 10.9%; 5-year survival, 9.8% vs 1.9%; hazard ratio [HR], 0.6 [95% CI, 0.5-0.7]; P < .001). In patients with anaplastic oligodendroglial tumors with 1p/19q codeletion, probable 20-year overall survival following radiotherapy without vs with the combination of procarbazine, lomustine, and vincristine was 13.6% vs 37.1% (80 patients; HR, 0.60 [95% CI, 0.35-1.03]; P = .06) in the EORTC 26951 trial and 14.9% vs 37% in the RTOG 9402 trial (125 patients; HR, 0.61 [95% CI, 0.40-0.94]; P = .02). Treatment of primary CNS lymphoma includes high-dose methotrexate-containing regimens, followed by consolidation therapy with myeloablative chemotherapy and autologous stem cell rescue, nonmyeloablative chemotherapy regimens, or whole brain radiation.
CONCLUSIONS AND RELEVANCE
The incidence of primary malignant brain tumors is approximately 7 per 100 000 individuals, and approximately 49% of primary malignant brain tumors are glioblastomas. Most patients die from progressive disease. First-line therapy for glioblastoma is surgery followed by radiation and the alkylating chemotherapeutic agent temozolomide.
Topics: Adult; Humans; Antineoplastic Combined Chemotherapy Protocols; Brain; Brain Neoplasms; Glioblastoma; Glioma; Lymphoma; Temozolomide
PubMed: 36809318
DOI: 10.1001/jama.2023.0023 -
Cell Dec 2020Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental...
Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.
Topics: Animals; Astrocytes; Brain Neoplasms; Carcinogenesis; Cell Lineage; Cellular Reprogramming; Chromatin; Embryo, Mammalian; Epigenesis, Genetic; Gene Expression Regulation, Neoplastic; Gene Silencing; Glioma; Histones; Interneurons; Lysine; Mice, Inbred C57BL; Models, Biological; Mutation; Neoplasm Grading; Neural Stem Cells; Oligodendroglia; Promoter Regions, Genetic; Prosencephalon; Receptor, Platelet-Derived Growth Factor alpha; Transcription, Genetic; Transcriptome
PubMed: 33259802
DOI: 10.1016/j.cell.2020.11.012 -
The Lancet. Oncology Jun 2021The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q... (Randomized Controlled Trial)
Randomized Controlled Trial
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.
BACKGROUND
The CATNON trial investigated the addition of concurrent, adjuvant, and both current and adjuvant temozolomide to radiotherapy in adults with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas. The benefit of concurrent temozolomide chemotherapy and relevance of mutations in the IDH1 and IDH2 genes remain unclear.
METHODS
This randomised, open-label, phase 3 study done in 137 institutions across Australia, Europe, and North America included patients aged 18 years or older with newly diagnosed 1p/19q non-co-deleted anaplastic gliomas and a WHO performance status of 0-2. Patients were randomly assigned (1:1:1:1) centrally using a minimisation technique to radiotherapy alone (59·4 Gy in 33 fractions; three-dimensional conformal radiotherapy or intensity-modulated radiotherapy), radiotherapy with concurrent oral temozolomide (75 mg/m per day), radiotherapy with adjuvant oral temozolomide (12 4-week cycles of 150-200 mg/m temozolomide given on days 1-5), or radiotherapy with both concurrent and adjuvant temozolomide. Patients were stratified by institution, WHO performance status score, age, 1p loss of heterozygosity, the presence of oligodendroglial elements on microscopy, and MGMT promoter methylation status. The primary endpoint was overall survival adjusted by stratification factors at randomisation in the intention-to-treat population. A second interim analysis requested by the independent data monitoring committee was planned when two-thirds of total required events were observed to test superiority or futility of concurrent temozolomide. This study is registered with ClinicalTrials.gov, NCT00626990.
FINDINGS
Between Dec 4, 2007, and Sept 11, 2015, 751 patients were randomly assigned (189 to radiotherapy alone, 188 to radiotherapy with concurrent temozolomide, 186 to radiotherapy and adjuvant temozolomide, and 188 to radiotherapy with concurrent and adjuvant temozolomide). Median follow-up was 55·7 months (IQR 41·0-77·3). The second interim analysis declared futility of concurrent temozolomide (median overall survival was 66·9 months [95% CI 45·7-82·3] with concurrent temozolomide vs 60·4 months [45·7-71·5] without concurrent temozolomide; hazard ratio [HR] 0·97 [99·1% CI 0·73-1·28], p=0·76). By contrast, adjuvant temozolomide improved overall survival compared with no adjuvant temozolomide (median overall survival 82·3 months [95% CI 67·2-116·6] vs 46·9 months [37·9-56·9]; HR 0·64 [95% CI 0·52-0·79], p<0·0001). The most frequent grade 3 and 4 toxicities were haematological, occurring in no patients in the radiotherapy only group, 16 (9%) of 185 patients in the concurrent temozolomide group, and 55 (15%) of 368 patients in both groups with adjuvant temozolomide. No treatment-related deaths were reported.
INTERPRETATION
Adjuvant temozolomide chemotherapy, but not concurrent temozolomide chemotherapy, was associated with a survival benefit in patients with 1p/19q non-co-deleted anaplastic glioma. Clinical benefit was dependent on IDH1 and IDH2 mutational status.
FUNDING
Merck Sharpe & Dohme.
Topics: Adolescent; Adult; Aged; Australia; Chemotherapy, Adjuvant; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Combined Modality Therapy; Dacarbazine; Europe; Female; Glioma; Humans; Isocitrate Dehydrogenase; Loss of Heterozygosity; Male; Middle Aged; North America; Radiotherapy, Conformal; Temozolomide; Young Adult
PubMed: 34000245
DOI: 10.1016/S1470-2045(21)00090-5 -
Nature Reviews. Neuroscience Dec 2023Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of... (Review)
Review
Experience sculpts brain structure and function. Activity-dependent modulation of the myelinated infrastructure of the nervous system has emerged as a dimension of adaptive change during childhood development and in adulthood. Myelination is a richly dynamic process, with neuronal activity regulating oligodendrocyte precursor cell proliferation, oligodendrogenesis and myelin structural changes in some axonal subtypes and in some regions of the nervous system. This myelin plasticity and consequent changes to conduction velocity and circuit dynamics can powerfully influence neurological functions, including learning and memory. Conversely, disruption of the mechanisms mediating adaptive myelination can contribute to cognitive impairment. The robust effects of neuronal activity on normal oligodendroglial precursor cells, a putative cellular origin for many forms of glioma, indicates that dysregulated or 'hijacked' mechanisms of myelin plasticity could similarly promote growth in this devastating group of brain cancers. Indeed, neuronal activity promotes the pathogenesis of many forms of glioma in preclinical models through activity-regulated paracrine factors and direct neuron-to-glioma synapses. This synaptic integration of glioma into neural circuits is central to tumour growth and invasion. Thus, not only do neuron-oligodendroglial interactions modulate neural circuit structure and function in the healthy brain, but neuron-glioma interactions also have important roles in the pathogenesis of glial malignancies.
Topics: Humans; Neurons; Oligodendroglia; Myelin Sheath; Neuroglia; Glioma
PubMed: 37857838
DOI: 10.1038/s41583-023-00744-3 -
Journal of Clinical Oncology : Official... Feb 2022To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults.
PURPOSE
To provide guidance to clinicians regarding therapy for diffuse astrocytic and oligodendroglial tumors in adults.
METHODS
ASCO and the Society for Neuro-Oncology convened an Expert Panel and conducted a systematic review of the literature.
RESULTS
Fifty-nine randomized trials focusing on therapeutic management were identified.
RECOMMENDATIONS
Adults with newly diagnosed oligodendroglioma, isocitrate dehydrogenase (IDH)-mutant, 1p19q codeleted CNS WHO grade 2 and 3 should be offered radiation therapy (RT) and procarbazine, lomustine, and vincristine (PCV). Temozolomide (TMZ) is a reasonable alternative for patients who may not tolerate PCV, but no high-level evidence supports upfront TMZ in this setting. People with newly diagnosed astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 2 should be offered RT with adjuvant chemotherapy (TMZ or PCV). People with astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 should be offered RT and adjuvant TMZ. People with astrocytoma, IDH-mutant, CNS WHO grade 4 may follow recommendations for either astrocytoma, IDH-mutant, 1p19q non-codeleted CNS WHO grade 3 or glioblastoma, IDH-wildtype, CNS WHO grade 4. Concurrent TMZ and RT should be offered to patients with newly diagnosed glioblastoma, IDH-wildtype, CNS WHO grade 4 followed by 6 months of adjuvant TMZ. Alternating electric field therapy, approved by the US Food and Drug Administration, should be considered for these patients. Bevacizumab is not recommended. In situations in which the benefits of 6-week RT plus TMZ may not outweigh the harms, hypofractionated RT plus TMZ is reasonable. In patients age ≥ 60 to ≥ 70 years, with poor performance status or for whom toxicity or prognosis are concerns, best supportive care alone, RT alone (for promoter unmethylated tumors), or TMZ alone (for promoter methylated tumors) are reasonable treatment options. Additional information is available at www.asco.org/neurooncology-guidelines.
Topics: Astrocytoma; Brain Neoplasms; Clinical Decision-Making; Consensus; Evidence-Based Medicine; Humans; Medical Oncology; Oligodendroglioma; Predictive Value of Tests; Randomized Controlled Trials as Topic; Time Factors; Treatment Outcome
PubMed: 34898238
DOI: 10.1200/JCO.21.02036 -
Neuro-oncology Apr 2022Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network...
BACKGROUND
Microtubes (MTs), cytoplasmic extensions of glioma cells, are important cell communication structures promoting invasion and treatment resistance through network formation. MTs are abundant in chemoresistant gliomas, in particular, glioblastomas (GBMs), while they are uncommon in chemosensitive IDH-mutant and 1p/19q co-deleted oligodendrogliomas. The aim of this study was to identify potential signaling pathways involved in MT formation.
METHODS
Bioinformatics analysis of TCGA was performed to analyze differences between GBM and oligodendroglioma. Patient-derived GBM stem cell lines were used to investigate MT formation under transforming growth factor-beta (TGF-β) stimulation and inhibition in vitro and in vivo in an orthotopic xenograft model. RNA sequencing and proteomics were performed to detect commonalities and differences between GBM cell lines stimulated with TGF-β.
RESULTS
Analysis of TCGA data showed that the TGF-β pathway is highly activated in GBMs compared to oligodendroglial tumors. We demonstrated that TGF-β1 stimulation of GBM cell lines promotes enhanced MT formation and communication via calcium signaling. Inhibition of the TGF-β pathway significantly reduced MT formation and its associated invasion in vitro and in vivo. Downstream of TGF-β, we identified thrombospondin 1 (TSP1) as a potential mediator of MT formation in GBM through SMAD activation. TSP1 was upregulated upon TGF-β stimulation and enhanced MT formation, which was inhibited by TSP1 shRNAs in vitro and in vivo.
CONCLUSION
TGF-β and its downstream mediator TSP1 are important mediators of the MT network in GBM and blocking this pathway could potentially help to break the complex MT-driven invasion/resistance network.
Topics: Glioblastoma; Glioma; Humans; Oligodendroglioma; Thrombospondin 1; Transforming Growth Factor beta
PubMed: 34543427
DOI: 10.1093/neuonc/noab212 -
Nature Genetics Dec 2022Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized...
Histone 3 lysine27-to-methionine (H3-K27M) mutations most frequently occur in diffuse midline gliomas (DMGs) of the childhood pons but are also increasingly recognized in adults. Their potential heterogeneity at different ages and midline locations is vastly understudied. Here, through dissecting the single-cell transcriptomic, epigenomic and spatial architectures of a comprehensive cohort of patient H3-K27M DMGs, we delineate how age and anatomical location shape glioma cell-intrinsic and -extrinsic features in light of the shared driver mutation. We show that stem-like oligodendroglial precursor-like cells, present across all clinico-anatomical groups, display varying levels of maturation dependent on location. We reveal a previously underappreciated relationship between mesenchymal cancer cell states and age, linked to age-dependent differences in the immune microenvironment. Further, we resolve the spatial organization of H3-K27M DMG cell populations and identify a mitotic oligodendroglial-lineage niche. Collectively, our study provides a powerful framework for rational modeling and therapeutic interventions.
Topics: Humans; Child; Glioma; Histones; Methionine; Mutation; Racemethionine; Tumor Microenvironment
PubMed: 36471067
DOI: 10.1038/s41588-022-01236-3 -
Pediatric and Developmental Pathology :... 2022Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization...
Pediatric glial tumors are unique from their adult counterparts. This important distinction is recognized and incorporated into the World Health Organization classification of central nervous system tumors and applies to both high- and low-grade gliomas, incorporating their specific molecular profiles. Molecular alterations in pediatric high-grade gliomas provide important prognostic information, for example in H3 K27M-mutant tumors. The integration of molecular information is also important for pediatric low-grade gliomas due to their overlapping morphologies and the prognostic and therapeutic implications of these molecular alterations. In this paper, we cover a variety of glial tumors, encompassing neoplasms with predominantly glial histology, astrocytic tumors, oligodendroglial tumors, and mixed glioneuronal tumors. Considering the complexity of this evolving field, the purpose of this article is to offer a practical approach to the diagnosis of pediatric gliomas, including the selection of the most appropriate molecular surrogate immunohistochemical stains, basic molecular studies, and more sophisticated techniques if needed. The goal is to reach a rapid, sound diagnosis, helping guide clinical decision-making regarding prognosis and potential therapies.
Topics: Adult; Brain Neoplasms; Child; Glioma; Humans; Mutation; Neuroglia; Prognosis
PubMed: 33872106
DOI: 10.1177/10935266211009101 -
Practical Neurology Dec 2022Radiation therapy is widely used for benign and malignant brain tumours as it is effective and well tolerated. However, damage to the surrounding healthy nervous system... (Review)
Review
Radiation therapy is widely used for benign and malignant brain tumours as it is effective and well tolerated. However, damage to the surrounding healthy nervous system tissue leads to a variety of complications both in the short term and long term, ranging from mild and self-limiting to irreversible and fatal. Radiation neurotoxicity is due to a combination of early inflammation and oligodendroglial damage followed later by brain tissue necrosis, white matter damage, accelerated vascular disease and the development of secondary tumours. This article explains the basic principles of radiation physics, the different modalities used in clinical practice, how radiotherapy is planned and delivered and the scientific basis of radiation damage. The main body of the article focuses on the clinical features of radiation toxicity in the brain, spinal cord, cranial and peripheral nerves with an emphasis on the distinction between early and delayed complications.
Topics: Humans; Radiation Injuries; Brain; Brain Neoplasms; Spinal Cord; Neurotoxicity Syndromes
PubMed: 35995554
DOI: 10.1136/pn-2022-003343 -
Surgical Pathology Clinics Dec 2020Gliomas are a diverse group of primary central nervous system tumors with astrocytic, oligodendroglial, and/or ependymal features and are an important cause of... (Review)
Review
Gliomas are a diverse group of primary central nervous system tumors with astrocytic, oligodendroglial, and/or ependymal features and are an important cause of morbidity/mortality in pediatric patients. Glioma classification relies on integrating tumor histology with key molecular alterations. This approach can help establish a diagnosis, guide treatment, and determine prognosis. New categories of pediatric glioma have been recognized in recent years, due to increasing application of molecular profiling in brain tumors. The aim of this review is to alert pediatric pathologists to emerging diagnostic concepts in pediatric glioma neuropathology, emphasizing the incorporation of molecular features into diagnostic practice.
Topics: Biomarkers, Tumor; Brain Neoplasms; Child; Glioma; Humans; Mutation; Prognosis
PubMed: 33183734
DOI: 10.1016/j.path.2020.08.006