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Background: Dihydroxy‐6‐[18F]fluoro‐L‐phenylalanine (18F‐FDOPA) positron emission tomography (PET) is a valuable tool for managing high‐grade gliomas (HGGs), but there is a lack of literature on its relationship with glioma subtypes since the 2021 reclassification of brain tumors. There is also debate surrounding the mechanism of 18F‐FDOPA uptake, particularly after chemoradiation therapy. This study aimed to investigate the correlation between 18F‐FDOPA uptake and histomolecular characteristics, particularly L‐amino acid transporter 1 (LAT1) expression, in recurrent gliomas, and examine their impact on survival in HGGs. Methods: Thirty‐nine patients with recurrent HGGs (14 isocitrate dehydrogenase [IDH]‐mutant, 25 IDH‐wildtype) who underwent a brain 18F‐FDOPA PET/computed tomography (CT) or PET/magnetic resonance imaging (MRI) followed by surgical resection of the 18F‐FDOPA‐avid lesion within 6 months, were retrospectively reviewed. PET results were compared with histological examination and for SCL7A5/LAT1 immunostaining. The study also examined the relationship between PET parameters, LAT1 expression, and survival outcomes. Results: Astrocytoma IDH‐mutant G4 had higher 18F‐FDOPA uptake than glioblastoma IDH‐wildtype G4 (maximum tumor‐to‐normal brain ratio [TBRmax] 5 [3.4–9] vs. 3.8 [2.8–5.9], p = 0.02). IDH‐mutant gliomas had higher LAT1 expression than IDH‐wildtype gliomas (100 [14–273] vs. 15.5 [0–137], p < 0.05) as well as higher TBRmax (5 [2.4–9] vs. 3.8 [2.8–6], p < 0.05). In survival analysis, LAT1 score >100 was a predictor for longer progression‐free survival in IDH‐mutant HGGs. Conclusions: To our knowledge, our study is the first to suggest a link between LAT1 expression and IDH mutation status. We showed that higher TBRmax was associated with higher LAT1 expression and IDH mutation status. Further studies are needed to better understand the mechanisms underlying amino acid PET tracers uptake, especially in the post‐radiation and chemotherapy settings. [ABSTRACT FROM AUTHOR]

Purpose of Review: Isocitrate dehydrogenase (IDH) mutation is a defining molecular driver of WHO grade 2-4 astrocytomas and oligodendrogliomas. In this article, we review the recent therapeutic approaches specifically targeting IDH-mutant gliomas and summarize ongoing clinical trials in this population., Recent Findings: The IDH inhibitor vorasidenib recently demonstrated its efficacy after surgical resection in grade 2 IDH-mutated gliomas. Several studies in patients with IDH-mutant gliomas are currently exploring various strategies to target IDH mutations, including the use of small-molecule inhibitors, immunotherapies, peptide vaccines and agents targeting metabolic and epigenomic vulnerabilities., Summary: Mutant-IDH targeting holds significant promise in treating progressive or recurrent IDH-mutant gliomas. Recent results with IDH inhibitors will change practice and influence the existing guidelines in a near future., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: With the significant shift in the classification, risk stratification, and standards of care for gliomas, we sought to understand how the overall survival of patients with these tumors is impacted by molecular features, clinical metrics, and treatment received., Methods: We assembled a cohort of patients with a histopathologically diagnosed glioma from The Cancer Genome Atlas, Project Genomics Evidence Neoplasia Information Exchange, and Dana-Farber Cancer Institute/Brigham and Women's Hospital. This incorporated retrospective clinical, histological, and molecular data alongside prospective assessment of patient survival., Results: 4,400 gliomas were identified: 2,195 glioblastoma, 1,198 IDH1/2-mutant astrocytoma, 531 oligodendroglioma, 271 other IDH1/2-wildtype glioma, and 205 pediatric-type glioma. Molecular classification updated 27.2% of gliomas from their original histopathologic diagnosis. Examining the distribution of molecular alterations across glioma subtypes revealed mutually exclusive alterations within tumorigenic pathways. Non-TCGA patients had significantly improved overall survival compared to TCGA patients, with 26.7%, 55.6%, and 127.8% longer survival for glioblastoma, IDH1/2-mutant astrocytoma, and oligodendroglioma respectively (all p<0.01). Several prognostic features were characterized, including NF1 alteration and 21q loss in glioblastoma, and EGFR amplification and 22q loss in IDH1/2-mutant astrocytoma. Leveraging the size of this cohort, nomograms were generated to assess the probability of overall survival based on patient age, the molecular features of a tumor, and the treatment received., Conclusions: By applying modern molecular criteria, we characterize the genomic diversity across glioma subtypes, identify clinically applicable prognostic features, and provide a contemporary update on patient survival to serve as a reference for ongoing investigations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)

Background: Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels., Results: Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer., Conclusions: Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis., (© 2024. The Author(s).)

Background: The frequency and significance of IDH mutations in glioma across age groups is incompletely understood. We performed a multi-center retrospective age-stratified comparison of patients with IDH-mutant gliomas to identify age-specific differences in clinico-genomic features, treatments, and outcomes., Methods: Clinical, histologic, and sequencing data from patients with IDH-mutant, grade 2-4 gliomas, were collected from collaborating institutions between 2013-2019. Patients were categorized as pediatric (<19y), YA (19-39y) or older adult (≥40y). Clinical presentation, treatment, histologic, and molecular features were compared across age categories using Fisher's exact test or analysis-of-variance. Cox proportional-hazards regression was used to determine association of age and other covariates with overall (OS) and progression-free survival (PFS)., Results: We identified a cohort of 379 patients (204 YA) with IDH-mutant glioma with clinical data. There were 155 (41%) oligodendrogliomas and 224 (59%) astrocytomas. YA showed significantly shorter PFS and shorter median time-to-malignant transformation (MT) compared to pediatric and adult groups, but no significant OS difference. Adjusting for pathology type, extent of resection, and upfront therapy in multivariable analysis, the YA group was independently prognostic of shorter PFS than pediatric and adult groups. Among astrocytomas, CDK4/6 copy number amplifications were associated with both shorter PFS and shorter OS. Among oligodendrogliomas, PIK3CA and CDKN2A/2B alterations were associated with shorter OS., Conclusions: IDH-mutant glioma YA patients had significantly shorter PFS and time to MT but did not differ in OS compared to pediatric and adult groups. Treatment approach varied significantly by patient age and warrant further study as addressable age-associated outcome drivers., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background and Purpose: Isocitrate dehydrogenase ( IDH ) mutation and 1p/19q codeletion classify adult-type diffuse gliomas into three tumor subtypes with distinct prognosis. We aimed to evaluate the performance of edited magnetic resonance spectroscopy (MRS) for glioma subtyping in a clinical setting, via the quantification of D-2-hydroxyglutarate (2HG) and cystathionine. The delay between this noninvasive classification and the integrated histomolecular analysis was also quantified., Materials and Methods: Subjects with presumed low-grade glioma, eligible for surgery ( cohort 1 ), and subjects with IDH-mutant glioma, previously treated and with progressive disease ( cohort 2 ) were prospectively examined with a singlevoxel Mescher-Garwood point-resolved spectroscopy sequence at 3 T. Spectra were quantified using LCModel. The Cramér-Rao lower bounds (CRLB) threshold was set to 20%. Integrated histomolecular analysis according to the 2021 WHO classification was considered as a ground truth., Results: Thirty-four consecutive subjects were enrolled. Due to poor spectra quality and lack of histological specimen, data from 26 subjects was analyzed. Twenty-one belonged to cohort 1 [11 females; median age: 42 years] and 5 to cohort 2 [3 females; median age: 48 years]. Edited MRS showed 100% specificity for detection of IDH mutation and 91% specificity for prediction of 1p/19q codeletion status. Sensitivities for prediction of IDH and 1p/19q codeletion were 62% and 33%, respectively. The median CRLB values were 14% (13 - 32) for IDH -mutant and 572% (554 - 999) for IDH -wild-type tumors. The time between MRS and surgery was longer for low-grade than high-grade gliomas (p = .03), yet the time between MRS and WHO diagnosis did not differ between grades (p = .07), possibly reflecting molecular analyses induced delays in high-grade gliomas., Conclusions: Our results, acquired in a clinic setting, confirmed that edited MRS is highly specific for both IDH mutation and 1p/19q codeletion predictions and can provide a faster prognosis stratification. In the upcoming IDH-inhibitor treatment era, incorporation of edited MRS into clinical workflow is desirable., Abbreviations: 2HG = D-2-hydroxyglutarate; Cth = cystathionine. CRLB: Cramér-Rao lower bound; IDH: isocitrate dehydrogenase., Competing Interests: The other authors declare no conflict of interest., (© 2024 by American Journal of Neuroradiology.)

The 2016 and 2021 World Health Organization (WHO) 2021 Classification of Central Nervous System (CNS) tumors have resulted in a major improvement of the classification of IDH-mutant gliomas. With more effective treatments many patients experience prolonged survival . However, treatment guidelines are often still based on information from historical series comprising both patients with IDHwt and IDH mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological and molecular factors associated with outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with an IDH-mutant grade 2 and grade 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.)