Comment on, "T2-FLAIR mismatch sign, an imaging biomarker for CDKN2A-intact in non-enhancing astrocytoma, IDH-mutant".

The study by Onishi et al. (2024) investigates the correlation between the T2-FLAIR mismatch sign and CDKN2A status in non-enhancing astrocytoma, IDH-mutant. Through the use of radiological and molecular pathological analyses, the research explores the potential of T2-FLAIR mismatch as an imaging biomarker for predicting CDKN2A-intact astrocytomas. Immunohistochemical staining and next-generation sequencing were employed to confirm molecular diagnosis, enhancing the study's robustness. While the findings contribute significantly to preoperative diagnostics and treatment planning, limitations exist. The relatively small sample size (31 patients) and exclusion of gadolinium-enhancing astrocytomas may restrict the generalizability of the results. Additionally, variation in imaging protocols and the retrospective nature of the study limit the overall impact. Future research with a larger cohort, standardized imaging protocols, and a prospective design is recommended to validate the clinical utility of T2-FLAIR mismatch in differentiating CDKN2A status in astrocytomas.

Epigenetic landscape reorganisation and reactivation of embryonic development genes are associated with malignancy in IDH-mutant astrocytoma.

Accurate grading of IDH-mutant gliomas defines patient prognosis and guides the treatment path. Histological grading is challenging, and aside from CDKN2A/B homozygous deletions in IDH-mutant astrocytomas, there are no other objective molecular markers used for grading. RNA-sequencing was conducted on primary IDH-mutant astrocytomas (n = 138) included in the prospective CATNON trial, which was performed to assess the prognostic effect of adjuvant and concurrent temozolomide. We integrated the RNA-sequencing data with matched DNA-methylation and NGS data. We also used multi-omics data from IDH-mutant astrocytomas included in the TCGA dataset and validated results on matched primary and recurrent samples from the GLASS-NL study. Since discrete classes do not adequately capture grading of these tumours, we utilised DNA-methylation profiles to generate a Continuous Grading Coefficient (CGC) based on classification scores from a CNS-tumour classifier. CGC was an independent predictor of survival outperforming current WHO-CNS5 and methylation-based classification. Our RNA-sequencing analysis revealed four distinct transcription clusters that were associated with (i) upregulation of cell cycling genes; (ii) downregulation of glial differentiation genes; (iii) upregulation of embryonic development genes (e.g. HOX, PAX, and TBX) and (iv) upregulation of extracellular matrix genes. The upregulation of embryonic development genes was associated with a specific increase of CpG island methylation near these genes. Higher grade IDH-mutant astrocytomas have DNA-methylation signatures that, on the RNA level, are associated with increased cell cycling, tumour cell de-differentiation and extracellular matrix remodelling. These combined molecular signatures can serve as an objective marker for grading of IDH-mutant astrocytomas.

IGFBP7+ subpopulation and IGFBP7 risk score in astrocytoma: insights from scRNA-Seq and bulk RNA-Seq.

Background: Glioma is the predominant malignant brain tumor that lacks effective treatment options due to its shielding by the blood-brain barrier (BBB). Astrocytes play a role in the development of glioma, yet the diverse cellular composition of astrocytoma has not been thoroughly researched. Methods: We examined the internal diversity of seven distinct astrocytoma subgroups through single-cell RNA sequencing (scRNA-seq), pinpointed crucial subgroups using CytoTRACE, monocle2 pseudotime analysis, and slingshot pseudotime analysis, employed various techniques to identify critical subgroups, and delved into cellular communication analysis. Then, we combined the clinical information of GBM patients and used bulk RNA sequencing (bulk RNA-seq) to analyze the prognostic impact of the relevant molecules on GBM patients, and we performed in vitro experiments for validation. Results: The analysis of the current study revealed that C0 IGFBP7+ Glioma cells were a noteworthy subpopulation of astrocytoma, influencing the differentiation and progression of astrocytoma. A predictive model was developed to categorize patients into high- and low-scoring groups based on the IGFBP7 Risk Score (IGRS), with survival analysis revealing a poorer prognosis for the high-IGRS group. Analysis of immune cell infiltration, identification of genes with differential expression, various enrichment analyses, assessment of copy number variations, and evaluation of drug susceptibility were conducted, all of which highlighted their significant influence on the prognosis of astrocytoma. Conclusion: This research enhances comprehension of the diverse cell composition of astrocytoma, delves into the various factors impacting the prognosis of astrocytoma, and offers fresh perspectives on treating glioma.

Anatomical and subcortical invasiveness in diffuse low-grade astrocytomas differ between IDH status and provide prognostic information.

Background: Diffuse astrocytomas preferentially infiltrate eloquent areas affecting the outcome. A preoperative understanding of isocitrate dehydrogenase (IDH) status may offer opportunities for specific targeted therapies impacting treatment management. The aim of this study was to analyze clinical, topographical, radiological in WHO 2 astrocytomas with different IDH status and the long-term patient's outcome. Methods: A series of confirmed WHO 2 astrocytoma patients (between 2005 and 2015) were retrospectively analyzed. MRI sequences (FLAIR) were used for tumor volume segmentation and to create a frequency map of their locations into the Montreal Neurological Institute (MNI) space. The Brain-Grid (BG) system (standardized radiological tool of intersected lines according to anatomical landmarks) was used as an overlay for infiltration analysis of each tumor. Long-term follow-up was used to perform a survival analysis. Results: Forty patients with confirmed IDH status (26 IDH-mutant, IDHm/14 IDH-wild type, IDHwt) according to WHO 2021 classification were included with a mean follow-up of 7.8 years. IDHm astrocytomas displayed a lower number of BG-voxels (P < 0.05) and were preferentially located in the anterior insular region. IDHwt group displayed a posterior insular and peritrigonal location. IDHwt group displayed a shorter OS compared with IDHm (P < 0.05), with the infiltration of 7 or more BG-voxels as an independent factor predicting a shorter OS. Conclusions: IDHm and IDHwt astrocytomas differed in preferential location, number of BG-voxels and OS at long follow-up time. The number of BG-voxels affected the OS in IDHwt was possibly reflecting higher tumor invasiveness. We encourage the systematic use of alternative observational tools, such as gradient maps and the Brain-Grid analysis, to better detect differences of tumor invasiveness in diffuse low-grade gliomas subtypes.

[Clinicopathological and molecular characteristics of pediatric gliomas: analysis of 111 cases].

Objective: To summarize the clinical, pathological and molecular characteristics of various types of pediatric glioma, and to explore the differences in the morphology and clinical significance among various types of pediatric glioma. Methods: Based on the fifth edition of the World Health Organization classification of central nervous system tumors, this study classified or reclassified 111 pediatric gliomas that were diagnosed at Guangzhou Medical University Affiliated Women and Children's Medical Center from January 2020 to June 2023. The clinical manifestations, imaging findings, histopathology, and molecular characteristics of these tumors were analyzed. Relevant literature was also reviewed. Results: The 111 patients with pediatric glioma included 56 males and 55 females, with the age ranging from 10 days to 13 years (average age, 5.5 years). Clinically, manifestations presented from 5 days to 8 years before the diagnosis, including epilepsy in 16 cases, increased intracranial pressure in 48 cases and neurological impairment in 66 cases. MRI examinations revealed tumor locations as supratentorial in 43 cases, infratentorial in 65 cases, and spinal cord in 3 cases. There were 73 cases presented with a solid mass and 38 cases with cystic-solid lesions. The largest tumor diameter ranged from 1.4 to 10.6 cm. Among the 111 pediatric gliomas, there were 6 cases of pediatric diffuse low-grade glioma (pDLGG), 63 cases of circumscribed astrocytoma glioma (CAG), and 42 cases of pediatric diffuse high-grade glioma (pDHGG). Patients with pDLGG and CAG were younger than those with pDHGG. The incidence of pDLGG and CAG was significantly lower in the midline of the infratentorial region compared to that of pDHGG. They were more likely to be completely resected surgically. The pDLGG and CAG group included 4 cases of pleomorphic xanthoastrocytoma, showing histological features of high-grade gliomas. Among the high-grade gliomas, 13 cases were diffuse midline gliomas and also showed histological features of low-grade glioma. Immunohistochemical studies of H3K27M, H3K27ME3, p53, ATRX, BRAF V600E, and Ki-67 showed significant differences between the pDLGG and CAG group versus the pDHGG group (P<0.01). Molecular testing revealed that common molecular variations in the pDLGG and CAG group were KIAA1549-BRAF fusion and BRAF V600E mutation, while the pDHGG group frequently exhibited mutations in HIST1H3B and H3F3A genes, 1q amplification, and TP53 gene mutations. With integrated molecular testing, 2 pathological diagnoses were revised, and the pathological subtypes of 35.3% (12/34) of the pediatric gliomas that could not be reliably classified by histology were successfully classified. Conclusions: There are significant differences in clinical manifestations, pathological characteristics, molecular variations, and prognosis between the pDLGG, CAG and pDHGG groups. The integrated diagnosis combining histology and molecular features is of great importance for the accurate diagnosis and treatment of pediatric gliomas.

Pediatric glioma immune profiling identifies TIM3 as a therapeutic target in BRAF fusion pilocytic astrocytoma.

Despite being the leading cause of cancer-related childhood mortality, pediatric gliomas have been relatively understudied, and the repurposing of immunotherapies has not been successful. Whole-transcriptome sequencing, single-cell sequencing, and sequential multiplex immunofluorescence were used to identify an immunotherapeutic strategy that could be applied to multiple preclinical glioma models. MAPK-driven pediatric gliomas have a higher IFN signature relative to other molecular subgroups. Single-cell sequencing identified an activated and cytotoxic microglia (MG) population designated MG-Act in BRAF-fused, MAPK-activated pilocytic astrocytoma (PA), but not in high-grade gliomas or normal brain. T cell immunoglobulin and mucin domain 3 (TIM3) was expressed on MG-Act and on the myeloid cells lining the tumor vasculature but not normal brain vasculature. TIM3 expression became upregulated on immune cells in the PA microenvironment, and anti-TIM3 reprogrammed ex vivo immune cells from human PAs to a proinflammatory cytotoxic phenotype. In a genetically engineered murine model of MAPK-driven, low-grade gliomas, anti-TIM3 treatment increased median survival over IgG- and anti-PD-1-treated mice. Single-cell RNA-Seq data during the therapeutic window of anti-TIM3 revealed enrichment of the MG-Act population. The therapeutic activity of anti-TIM3 was abrogated in mice on the CX3CR1 MG-KO background. These data support the use of anti-TIM3 in clinical trials of pediatric low-grade, MAPK-driven gliomas.

Noninvasive prediction of BRAF V600E mutation status of pleomorphic xanthoastrocytomas with MRI morphologic features and diffusion-weighted imaging.

OBJECTIVES: Seeking a noninvasive predictor for BRAF V600E mutation status of pleomorphic xanthoastrocytomas (PXAs) is essential for their prognoses and therapeutic use of BRAF inhibitors. We aimed to noninvasively diagnose BRAF V600E-mutated PXAs using MRI morphologic, DWI and clinical parameters. METHODS: The clinical findings, anatomical MRI characteristics, and diffusion parameters of 36 pathologically confirmed PXAs were retrospectively analyzed, and BRAF V600E-mutated (n = 16) and wild-type (n = 20) groups were compared. A binary logistic-regression analysis was performed, and a ROC curve was calculated to determine the independent predictors of BRAF V600E mutation status, diagnostic accuracy, and optimal cut-off value. RESULTS: A comparison of findings between groups showed that BRAF V600E-mutated PXAs were more frequent in children and young adults (≤ 35 years; P = 0.042) who often had histories of seizures (P = 0.004). Furthermore, BRAF V600E-mutated PXAs generally presented as solitary masses (P = 0.024), superficial locations with meningeal attachment (P < 0.001), predominantly cystic with mural nodules (P = 0.005), and had greater minimal ADC ratio (ADCratio) values of the tumor and peritumoral edema (P < 0.001). Binary logistic regression showed that age ≤ 35 years, solitary mass, superficial locations with meningeal attachment, and a greater minimal ADCratio of the tumor were independent predictors of BRAF V600E-mutated PXAs. The combination of all four independent predictors resulted in the highest sensitivity (100%) and specificity (90%), with AUC = 0.984. CONCLUSION: The BRAF V600E mutation status of PXAs could be noninvasively predicted using clinical and MRI characteristics. CRITICAL RELEVANCE STATEMENT: The noninvasive diagnostic criteria for BRAF V600E-mutated PXAs could offer guidance for the administration of BRAF V600E mutation inhibitors in the future.

T2-FLAIR mismatch sign, an imaging biomarker for CDKN2A-intact in non-enhancing astrocytoma, IDH-mutant.

INTRODUCTION: The WHO classification of central nervous system tumors (5th edition) classified astrocytoma, IDH-mutant accompanied with CDKN2A/B homozygous deletion as WHO grade 4. Loss of immunohistochemical (IHC) staining for methylthioadenosine phosphorylase (MTAP) was developed as a surrogate marker for CDKN2A-HD. Identification of imaging biomarkers for CDKN2A status is of immense clinical relevance. In this study, we explored the association between radiological characteristics of non-enhancing astrocytoma, IDH-mutant to the CDKN2A/B status. METHODS: Thirty-one cases of astrocytoma, IDH-mutant with MTAP results by IHC were included in this study. The status of CDKN2A was diagnosed by IHC staining for MTAP in all cases, which was further confirmed by comprehensive genomic analysis in 12 cases. The T2-FLAIR mismatch sign, cystic component, calcification, and intratumoral microbleeding were evaluated. The relationship between the radiological features and molecular pathological diagnosis was analyzed. RESULTS: Twenty-six cases were identified as CDKN2A-intact while 5 cases were CDKN2A-HD. The presence of > 33% and > 50% T2-FLAIR mismatch was observed in 23 cases (74.2%) and 14 cases (45.2%), respectively, and was associated with CDKN2A-intact astrocytoma (p = 0.0001, 0.0482). None of the astrocytoma, IDH-mutant with CDKN2A-HD showed T2-FLAIR mismatch sign. Cystic component, calcification, and intratumoral microbleeding were not associated with CDKN2A status. CONCLUSION: In patients with non-enhancing astrocytoma, IDH-mutant, the T2-FLAIR mismatch sign is a potential imaging biomarker for the CDKN2A-intact subtype. This imaging biomarker may enable preoperative prediction of CDKN2A status among astrocytoma, IDH-mutant.

Enhancing glioma care with advanced imaging: T2-FLAIR mismatch as a predictive biomarker in IDH-mutant astrocytoma.

The study highlights that diffuse glioma, a prevalent type of brain tumor, affect approximately 100,000 individuals worldwide each year. IDH-mutant astrocytoma and oligodendrogliomas typically have a more favorable prognosis compared to IDH-wildtype glioblastomas. However, many IDH-mutant astrocytoma has the potential to progress to grade 4 glioblastomas, leading to a less favorable prognosis. In a recent investigation, Shumpei Onishi et al. examined the T2-FLAIR mismatch sign as a possible imaging biomarker for assessing CDKN2A status in non-enhancing IDH-mutant astrocytoma. The findings indicate that the T2-FLAIR mismatch sign is linked to CDKN2A-intact astrocytoma, providing a valuable tool for diagnostic and prognostic purposes. Additionally, the use of Indocyanine Green (ICG) for real-time visualization during neurosurgical procedures demonstrates potential, though it may have limitations in specificity. While these advancements offer promise in glioma management, there remains a critical need for larger, standardized studies to validate these findings and further improve treatment outcomes.

Unveiling hierarchy and spatial distribution of O6-methylguanine-DNA methyltransferase promoter methylation in World Health Organization grade 2-3 gliomas.

This study investigated the role of O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation hierarchy and heterogeneity in grade 2-3 gliomas, focusing on variations in chemotherapy benefits and resection dependency. A cohort of 668 newly diagnosed grade 2-3 gliomas, with comprehensive clinical, radiological, and molecular data, formed the basis of this analysis. The extent of resection was categorized into gross total resection (GTR ≥100%), subtotal resection (STR >90%), and partial resection (PR ≤90%). MGMTp methylation levels were examined using quantitative pyrosequencing. Our findings highlighted the critical role of GTR in improving the prognosis for astrocytomas (IDH1/2-mutant and 1p/19q non-codeleted), contrasting with its lesser significance for oligodendrogliomas (IDH1/2 mutation and 1p/19q codeletion). Oligodendrogliomas demonstrated the highest average MGMTp methylation levels (median: 28%), with a predominant percentage of methylated cases (average methylation levels >20%). Astrocytomas were more common in the low-methylated group (10%-20%), while IDH wild-type gliomas were mostly unmethylated (<10%). Spatial distribution analysis revealed a decrement in frontal lobe involvement from methylated, low-methylated to unmethylated cases (72.8%, 59.3%, and 47.8%, respectively). In contrast, low-methylated and unmethylated cases were more likely to invade the temporal-insular region (19.7%, 34.3%, and 40.4%, respectively). Astrocytomas with intermediate MGMTp methylation were notably associated with temporal-insular involvement, potentially indicating a moderate response to temozolomide and underscoring the importance of aggressive resection strategies. In conclusion, our study elucidates the complex interplay of MGMTp methylation hierarchy and heterogeneity among grade 2-3 gliomas, providing insights into why astrocytomas and IDH wild-type lower-grade glioma might derive less benefit from chemotherapy.

Identification and validation of miRNA-target genes network in pediatric brain tumors.

Alterations in miRNA levels have been observed in various types of cancer, impacting numerous cellular processes and increasing their potential usefulness in combination therapies also in brain tumors. Recent advances in understanding the genetics and epigenetics of brain tumours point to new aberrations and associations, making it essential to continually update knowledge and classification. Here we conducted molecular analysis of 123 samples of childhood brain tumors (pilocytic astrocytoma, medulloblastoma, ependymoma), focusing on identification of genes that could potentially be regulated by crucial representatives of OncomiR-1: miR-17-5p and miR-20a-5p. On the basis of microarray gene expression analysis and qRTPCR profiling, we selected six (WEE1, CCND1, VEGFA, PTPRO, TP53INP1, BCL2L11) the most promising target genes for further experiments. The WEE1, CCND1, PTPRO, TP53INP1 genes showed increased expression levels in all tested entities with the lowest increase in the pilocytic astrocytoma compared to the ependymoma and medulloblastoma. The obtained results indicate a correlation between gene expression and the WHO grade and subtype. Furthermore, our analysis showed that the integration between genomic and epigenetic pathways should now point the way to further molecular research.

The Clinicopathological Features of the Solitary Subependymal Giant Cell Astrocytoma: A Systematic Review.

Subependymal giant cell astrocytoma (SEGA), a circumscribed grade I glioma, is typically associated with tuberous sclerosis complex (TSC). However, "solitary SEGA" has been described. We performed a systematic review of available case reports and case series of solitary SEGA. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement was used with the following MeSH terms: "Subependymal giant cell astrocytoma," "Sporadic," "Absence," "Non-associated," "Solitary," and "Tuberous Sclerosis." Data sources included PubMed, Google Scholar, Web of Science, and Cochrane from 1979 to June 29, 2023. Of the 546 studies, 20 met the inclusion criteria. Fifty-nine cases were analyzed. The mean age was 19 years (range 4-75), with 29 women (49.1%). Tumor ranged in size from 0.8 to 5.8 cm. Headache was the most frequent initial symptom (75.6%). The lateral ventricles near the foramen of Monro were the most common location (66.10%). Tumors expressed neuroglial (n = 19) or only glial (n = 20) markers. In nine of 59 cases, genetic studies ruled out germinal TSC1/2 mutations; in 13 cases (22.03%), somatic mutations in those genes were identified. "Solitary SEGAs" included tumors with neuroglial profile and classic morphological pattern, and tumors with only glial markers. It is necessary to confirm in SEGA-like tumors, the dual nature with at least glial fibrillary acidic protein (GFAP), neurofilaments, and synaptophysin antibodies. Screening for TSC1/2 mutations, and probably of the NF type 1 gene, is recommended for both germline and somatic mutations. Long-term clinical follow-up is necessary to analyze biological behavior and compare it with genetic and molecular profiles.

Understanding spinal cord astrocytoma: Molecular mechanism, therapy, and comprehensive management.

Spinal cord astrocytoma is a rare and highly debilitating tumor, yet our knowledge of its clinical characteristics, molecular features, and pathogenesis remains limited compared to that of its counterparts in the brain. Current diagnostic and therapeutic approaches for spinal cord astrocytomas are primarily based on established guidelines for brain astrocytomas. However, recent studies have revealed unique clinical and pathological attributes that distinguish spinal cord astrocytomas from their corresponding brain counterparts. These findings underscore the inadequacy of directly applying the clinical guidelines developed for brain astrocytomas to spinal astrocytomas. In this review, we provided an up-to-date overview of the advancements in understanding spinal cord astrocytomas. We also discussed the challenges and future research prospects in this field with the aim of improving the precision of diagnosis and therapy for these tumors. Specifically, we emphasized the importance of enhancing our understanding of the molecular heterogeneity, immune characteristics, and clinical trials of spinal cord astrocytomas.

Comparative Morphological and Molecular Genetic Characteristics of Cell and Tissue Strains of Experimental Rat Glioma 10-17-2 (Astrid-17).

In order to obtain models of gliomas of varying degrees of malignancy, we performed morphological and molecular genetic study of a tissue strain of glioma 10-17-2 (Astrid-17) obtained by intracranial passaging of tumor fragments of chemically induced rat brain tumor, and a cell strain isolated from it. More or less pronounced changes in the expression levels of Mki67, Trp53, Vegfa, and Gfap genes in the tissue and cell strain of glioma 10-17-2 (Astrid-17) compared with intact brain tissue were shown. The tissue model of glioma 10-17-2 (Astrid-17) according to the studied characteristics shows features of grade 3-4 astrocytoma and the cellular model - grade 2-3 astrocytoma.

Advances in Molecular Pathology, Diagnosis and Treatment of Spinal Cord Astrocytomas.

Spinal cord astrocytoma (SCA) is a rare subtype of astrocytoma, posing challenges in diagnosis and treatment. Low-grade SCA can achieve long-term survival solely through surgery, while high-grade has a disappointing prognosis even with comprehensive treatment. Diagnostic criteria and standard treatment of intracranial astrocytoma have shown obvious limitations in SCA. Research on the molecular mechanism in SCA is lagging far behind that on intracranial astrocytoma. In recent years, huge breakthroughs have been made in molecular pathology of astrocytoma, and novel techniques have emerged, including DNA methylation analysis and radiomics. These advances are now making it possible to provide a precise diagnosis and develop corresponding treatment strategies in SCA. Our aim is to review the current status of diagnosis and treatment of SCA, and summarize the latest research advancement, including tumor subtype, molecular characteristics, diagnostic technology, and potential therapy strategies, thus deepening our understanding of this uncommon tumor type and providing guidance for accurate diagnosis and treatment.

Clinical features, MRI, molecular alternations, and prognosis of astrocytoma based on WHO 2021 classification of central nervous system tumors: A single-center retrospective study.

BACKGROUND: The diagnosis of glioma has advanced since the release of the WHO 2021 classification with more molecular alterations involved in the integrated diagnostic pathways. Our study aimed to present our experience with the clinical features and management of astrocytoma, IDH mutant based on the latest WHO classification. METHODS: Patients diagnosed with astrocytoma, IDH-mutant based on the WHO 5th edition classification of CNS tumors at our center from January 2009 to January 2022 were included. Patients were divided into WHO 2-3 grade group and WHO 4 grade group. Integrate diagnoses were retrospectively confirmed according to WHO 2016 and 2021 classification. Clinical and MRI characteristics were reviewed, and survival analysis was performed. RESULTS: A total of 60 patients were enrolled. 21.67% (13/60) of all patients changed tumor grade from WHO 4th edition classification to WHO 5th edition. Of these, 21.43% (6/28) of grade II astrocytoma and 58.33% (7/12) of grade III astrocytoma according to WHO 4th edition classification changed to grade 4 according to WHO 5th edition classification. Sex (p = 0.042), recurrent glioma (p = 0.006), and Ki-67 index (p < 0.001) of pathological examination were statistically different in the WHO grade 2-3 group (n = 27) and WHO grade 4 group (n = 33). CDK6 (p = 0.004), FGFR2 (p = 0.003), and MYC (p = 0.004) alterations showed an enrichment in the WHO grade 4 group. Patients with higher grade showed shorter mOS (mOS = 75.9 m, 53.6 m, 26.4 m for grade 2, 3, and 4, respectively, p = 0.01). CONCLUSIONS: Patients diagnosed as WHO grade 4 according to the 5th edition WHO classification based on molecular alterations are more likely to have poorer prognosis. Therefore, treatment should be tailored to their individual needs. Further research is needed for the management of IDH-mutant astrocytoma is needed in the future.