IDH-mutant Gliomas Research Articles

THE MOLECULAR HISTORY OF IDH-MUTANT ASTROCYTOMAS WITHOUT ADJUVANT TREATMENT

Abstract AIMS Hypermutation and malignant transformation are potential complications arising from temozolomide treatment of IDH-mutant gliomas. However, the natural history of IDH-mutant low-grade gliomas without temozolomide treatment is relatively un-studied. We set out to study the molecular history of paired IDH-mutant astrocytomas without adjuvant treatment in the interim. METHOD We retrieved retrospectively from our hospitals paired tumors from 19 patients with IDH-mutant, 1p19q noncodeleted Grade 2 astrocytomas where no interim adjuvant treatment with either temozolomide or radiotherapy was given between primary and first recurrences. Two patients had multiple resected recurrences and radiotherapy but not temozolomide was given before the last specimens were resected. We studied the natural molecular history of these low-grade IDH-mutant astrocytomas without pressure of temozolomide with methylation profiling and copy number variation (CNV) analyses, target DNA sequencing, TERTp sequencing, FISH for ALT and selected biomarkers. RESULTS Recurrences were mostly higher grades (15/19 patients) and characterized by new CNVs not present in the primary tumors (17/19 cases). Few novel mutations were identified in recurrences. Tumors from 17/19 (89.5%) patients showed either CDKN2A homozygous deletion, MYC or PDGFRA amplification at recurrences. There was no case of hypermutation. Phylogenetic trees constructed for tumors for the two patients with multiple recurrences showed a conserved evolution pattern. CONCLUSION In summary, our studies demonstrated in contrast to the phenomenon of temozolomide-induced hypermutation, IDH-mutant, 1p19q non-codeleted Grade 2 astrocytomas which were not treated by temozolomide instead acquired new CNVs at tumor recurrences. These findings improve our understanding of the molecular life history of IDH-mutant 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.

Sex differences in the molecular profile of adult diffuse glioma are shaped by IDH status and tumor microenvironment.

Sex differences in adult diffuse glioma (ADG) are well-established clinically, yet the underlying molecular mechanisms remain inadequately understood. Here, we aim to reveal molecular features and cellular compositions unique to each sex in ADG to comprehend the role of sex in disease etiology. We quantified sex differences in transcriptome of ADG using multiple independent glioma patient datasets. Next, we delved into the single-cell landscape to examine sex differences in gene expression and cellular composition. To explore how sex influences disease progression, we analyzed paired samples from primary and recurrent ADG cases, aiming to identify sex-specific differences in molecular and cellular features. Our analysis revealed that mutations in isocitrate dehydrogenase (IDH) genes and the tumor microenvironment emerged as primary influencers of sex-differential molecular enrichments. In IDHwt tumors, genes in neuronal signaling pathway are found to be enriched in male tumors, while genes in hypoxia and inflammatory response pathways are enriched in female tumors. This pattern was reversed in IDHmut gliomas. We hypothesized that these distinctions could be attributed to heterogeneous cellular composition between sexes. Using single-cell data, we observed distinctive patterns of sex differences in cell states, cell composition and cell-cell interaction in IDHwt and IDHmut tumors separately. Further, by comparing molecular changes in paired primary and recurrent ADG samples, we identified sex-specific differences in molecular characteristics and cellular compositions of recurrent tumors. Our results provide a comprehensive multi-level characterization of sex differences in ADG, such findings provide novel insights into glioma disease progression in each sex.

Fractal dimension and lacunarity measures of glioma subcomponents are discriminative of the grade of gliomas and IDH status.

Since the overall glioma mass and its subcomponents-enhancing region (malignant part of the tumor), non-enhancing (less aggressive tumor cells), necrotic core (dead cells), and edema (water deposition)-are complex and irregular structures, non-Euclidean geometric measures such as fractal dimension (FD or "fractality") and lacunarity are needed to quantify their structural complexity. Fractality measures the extent of structural irregularity, while lacunarity measures the spatial distribution or gaps. The complex geometric patterns of the glioma subcomponents may be closely associated with the grade and molecular landscape. Therefore, we measured FD and lacunarity in the glioma subcomponents and developed machine learning models to discriminate between tumor grades and isocitrate dehydrogenase (IDH) gene status. 3D fractal dimension (FD3D) and lacunarity (Lac3D) were measured for the enhancing, non-enhancing plus necrotic core, and edema-subcomponents using preoperative structural-MRI obtained from the The Cancer Genome Atlas (TCGA) and University of California San Francisco Preoperative Diffuse Glioma MRI (UCSF-PDGM) glioma cohorts. The FD3D and Lac3D measures of the tumor-subcomponents were then compared across glioma grades (HGGs: high-grade gliomas vs. LGGs: low-grade gliomas) and IDH status (mutant vs. wild type). Using these measures, machine learning platforms discriminative of glioma grade and IDH status were developed. Kaplan-Meier survival analysis was used to assess the prognostic significance of FD3D and Lac3D measurements. HGG exhibited significantly higher fractality and lower lacunarity in the enhancing subcomponent, along with lower fractality in the non-enhancing subcomponent compared to LGG. This suggests that a highly irregular and complex geometry in the enhancing-subcomponent is a characteristic feature of HGGs. A comparison of FD3D and Lac3D between IDH-wild type and IDH-mutant gliomas revealed that mutant gliomas had ~2.5-fold lower FD3D in the enhancing-subcomponent and higher FD3D with lower Lac3D in the non-enhancing subcomponent, indicating a less complex and smooth enhancing subcomponent, and a more continuous non-enhancing subcomponent as features of IDH-mutant gliomas. Supervised ML models using FD3D from both the enhancing and non-enhancing subcomponents together demonstrated high-sensitivity in discriminating glioma grades (~97.9%) and IDH status (~94.4%). A combined fractal estimation of the enhancing and non-enhancing subcomponents using MR images could serve as a non-invasive, precise, and quantitative measure for discriminating glioma grade and IDH status. The combination of 2-hydroxyglutarate-magnetic resonance spectroscopy (2HG-MRS) with FD3D and Lac3D quantification may be established as a robust imaging signature for glioma subtyping.

Patterns of intersectional tumor volumes in T2-weighted MRI and [18F]FET PET in adult glioma: a prospective, observational study

Brain tumor volumes as assessed by magnetic resonance imaging (MRI) do not always spatially overlap with biological tumor volumes (BTV) measured by [18F]Fluoroethyltyrosine positron emission tomography ([18F]FET PET). We prospectively investigated volumetric patterns based on the extent of tumor volume overlap between the two modalities. Eighty-six patients with newly diagnosed glioma who had undergone MRI and [18F]FET PET between 2007 and 2009 were included in this prospective study and (re-)classified according to CNS WHO 2021 (Classification of Tumors of the Central Nervous System by the World Health Organization). Four different patterns of volume overlap were defined mathematically according to the extent of overlap between MRI-based T2 tumor volume (non-enhancing tumor volume, nCEV) and BTVs. Progression-free (PFS) and overall survival (OS) were determined. Seventy patients were diagnosed with isocitrate dehydrogenase wildtype (IDHwt) glioblastoma and 16 with IDH-mutant glioma, respectively. The most common pattern was characterized by a larger non-contrast-enhancing tumor volume (nCEV) that enclosed all or most of the BTV and was observed in 46 patients (54%) (pattern 1). This pattern was more frequent in IDH-mutant gliomas than in IDH-wildtype glioblastoma (81% versus 47%, p = 0.02). In multivariate analyses, pattern 1 was associated with prolonged PFS (HR 0.59; 95 CI 0.34-1.0; p = 0.05), but not OS (HR 0.66; 95 CI 0.4–1.08; p = 0.1). For OS, presence of an IDH mutation (p = 0.05) and lower age (p = 0.03) were associated with prolonged OS. The spatial relation between nCEV and BTV varies within and between glioma entities. Most frequently, a larger nCEV encases the BTV. Some patients show spatially dissociated nCEVs and BTVs. Not accounting for this phenomenon in surgery or radiotherapy planning might lead to undertreatment.

Enhancing Clinical Decision-Making: An Externally Validated Machine Learning Model for Predicting IDH Mutation in Gliomas using Radiomics from Pre-Surgical MRI

Enhancing Clinical Decision-Making: An Externally Validated Machine Learning Model for Predicting IDH Mutation in Gliomas using Radiomics from Pre-Surgical MRI

Vorasidenib: First Approval.

Vorasidenib (VORANIGO®; Servier) is an orally administered, first-in-class, highly brain-penetrant dual inhibitor of mutant isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes being developed for use in IDH-mutant diffuse glioma. Vorasidenib received its first approval on 6 August 2024, in the USA, for the treatment of adult and pediatric patients aged 12 years and older with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation following surgery, including biopsy, sub-total resection, or gross total resection. Approval was based on results from the multinational phase III INDIGO trial, in which vorasidenib significantly improved progression-free survival and time to the next anticancer intervention relative to placebo. In the EU and other countries worldwide, regulatory review of vorasidenib in IDH-mutant glioma is currently underway. This article summarizes the milestones in the development of vorasidenib leading to this first approval for glioma.

Association of immunoglobulin E levels with glioma risk and survival.

Previous epidemiologic studies have reported an association of serum immunoglobulin E (IgE) levels with reduced glioma risk, but the association between IgE and glioma prognosis has not been characterized. This study aimed to examine how sex, tumor subtype, and IgE class modulate the association of serum IgE levels with glioma risk and survival. We conducted a case-control study using participants from the University of California, San Francisco Adult Glioma Study (1997-2010). Serum IgE levels for total, respiratory and food allergy were measured in adults diagnosed with glioma (n=1319) and cancer-free controls (n=1139) matched based on age, sex, and race and ethnicity. Logistic regression was adjusted for patient demographics to assess the association between IgE levels and glioma risk. Multivariable Cox regression adjusted for patient-specific and tumor-specific factors compared survival between the elevated and normal IgE groups. All statistical tests were 2-sided. Elevated total IgE was associated with reduced risk of IDH-wildtype (RR=0.78, 95% CI: 0.71-0.86) and IDH-mutant glioma (RR=0.73, 95% CI: 0.63-0.85). In multivariable Cox regression, positive respiratory IgE was associated with improved survival for IDH-wildtype glioma (RR=0.79, 95% CI: 0.67-0.93). The reduction in mortality risk was significant in females only (RR=0.75, 95% CI: 0.57-0.98) with an improvement in median survival of 6.9 months (P<.001). Elevated serum IgE was associated with improved prognosis for IDH-wildtype glioma, with a more pronounced protective effect in females than males, which has implications for the future study of IgE-based immunotherapies for glioma.

Vorasidenib- A Paradigm Shift in IDH1- or IDH2-Mutant Low-Grade Glioma Treatment.

Low-grade gliomas (LGGs) pose significant challenges in cancer research and treatment due to their infiltrative nature and tendency for recurrence, making them the most common brain tumour in adults. Most of the LGGs have the propensity to cause notable alterations in the microenvironment of the tumour thus making them difficult to treat. These alterations can be attributed to the prevalent mutations in the genes that produce isocitrate dehydrogenase (IDH) enzymes, especially in grade 2 diffuse gliomas. [1] Despite its inability to provide a complete cure, chemoradiation has been adopted as the standard therapy in grade 3 gliomas since it can lead to long-lasting remission. Chemoradiotherapy, when administered promptly, can help prevent tumour progression, and recurrence after surgery and improve long-term outcomes. Nevertheless, immediate adjuvant chemoradiotherapy is not administered in patients afflicted with tumours containing IDH mutant grade 2 gliomas. This decision is often made to circumvent potential harm such as radiation-induced cognitive problems, chemotherapy-related DNA mutations, and other negative effects on their health. [2] Due to the intricacies associated with the treatment decisions and the inclination to delay aggressive therapies to avoid adverse events, creates a necessity for a novel therapeutic strategy that is both effective and well tolerated. Vorasidenib, an oral medication specifically designed to deal with IDH mutations has displayed promise despite existing challenges. By aiming to specifically target aberrant metabolic pathways triggered by mutant IDH enzymes, Vorasidenib offers a potential treatment capable of interrupting tumour growth and could subsequently result in better patient outcomes. Among the many reasons that make Vorasadenib an appealing option are its capability to penetrate the blood-brain barrier and its promising safety profile, resulting in effective treatment while alleviating potential side effects. [3] Vorasidenib’s efficacy is derived from its ability to halt the metabolic cascades driven by mutant IDH enzymes thus leading to decreased progression of the gliomas. Clinical studies elicit the substantial value Vorasadenib has to offer by enhancing progression-free survival and postponing the advancement of the illness in patients with grade 2 IDH-mutant gliomas. This offers an optimistic prospect for delaying the need for more aggressive treatments in these patients. [2,4] Hence, to conclude Vorasadenib can transform treatment norms and enhance outcomes for those suffering from IDH-mutant LGG. Furthermore, it is crucial to investigate different treatment combinations, finding markers that would help assess clinical response to treatment, which in turn would be an important milestone in the treatment journey.

Energy metabolism-related GLUD1 contributes to favorable clinical outcomes of IDH-mutant glioma

BackgroundGlioma is the most common brain tumor. IDH mutations occur frequently in glioma, indicating a more favorable prognosis. We aimed to explore energy metabolism-related genes in glioma to promote the research and treatment.MethodsDatasets were obtained from TCGA and GEO databases. Candidate genes were screened by differential gene expression analysis, then functional enrichment analysis was conducted on the candidate genes. PPI was also carried out to help determine the target gene. GSEA and DO analysis were conducted in the different expression level groups of the target gene. Survival analysis and immune cell infiltrating analysis were performed as well.ResultsWe screened 34 candidate genes and selected GLUD1 as the target gene. All candidate genes were significantly enriched in 10 KEGG pathways and 330 GO terms. GLUD1 expression was higher in IDH-mutant samples than IDH-wildtype samples, and higher in normal samples than tumor samples. Low GLUD1 expression was related to poor prognosis according to survival analysis. Most types of immune cells were negatively related to GLUD1 expression, but monocytes and activated mast cells exhibited significantly positive correlation with GLUD1 expression. GLUD1 expression was significantly related to 119 drugs and 6 immune checkpoint genes. GLUD1 was able to serve as an independent prognostic indicator of IDH-mutant glioma.ConclusionIn this study, we identified an energy metabolism-related gene GLUD1 potentially contributing to favorable clinical outcomes of IDH-mutant glioma. In glioma, GLUD1 related clinical outcomes and immune landscape were clearer, and more valuable information was provided for immunotherapy.

A - 141 The Relationship of Tumor Location and Treatment on Cognition in Long-Term IDH-Mutant Glioma Survivors

Abstract Objective Isocitrate dehydrogenase 1 mutation (IDH-M) denotes a distinct subtype of glioma which has a relatively favorable prognosis but nevertheless requires treatment including surgery, radiation and/or chemotherapy and the tumors inevitably recur. Factors influencing cognition in long-term survivors (LTS) of IDH-M have not been well characterized. We investigated factors affecting cognition in a cohort of well characterized of IDH-M LTS. Method Patients (N = 65; 98.5% Caucasian; 47.7% female; Mage = 47.51; Medu = 16.06) who were at least 3 years post-IDH-M diagnosis who completed neuropsychological assessment in the Neuro-oncology division at Massachusetts General Hospital were included. Tests of processing speed, working memory, episodic memory, and executive function were analyzed along with tumor, treatment, and individual difference factors relevant to cognition. Exploratory analyses were conducted to generate hypotheses regarding factors of interest. Results Tumor hemisphere affected delayed recall of word list learning Z-score (F = 4.00; p = 0.024; left = −1.41; right = −0.59). Tumor lobe affected visual learning (F = 3.11; p = 0.054; frontal = −0.594; temporal = −0.807; parietal = −1.983). There were no effects of treatment type (photon vs proton radiation; single vs multi-agent chemotherapy), presence of seizures, psychiatric diagnosis, tumor subtype (oligodendroglioma/astrocytoma), grade (2,3,4) or disease duration (Mean = 9.5y; min = 3y; max = 28.8y) on cognition. Conclusions In this heavily treated group of IDH-M glioma LTS referred for neuropsychological evaluation, typical lateralizing/localizing cognitive deficits were revealed. However, simple dichotomies may fail to capture relevant contributors to cognitive impairment. Integration with individual factors including premorbid cognition, radiation dosimetry and brain network connectivity may be necessary to predict cognitive trajectories and outcomes.

Advances in the treatment of IDH-mutant gliomas.

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. 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. 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.

A patient-derived cell model for malignant transformation in IDH-mutant glioma

Malignant transformation (MT) is commonly seen in IDH-mutant gliomas. There has been a growing research interest in revealing its underlying mechanisms and intervening prior to MT at the early stages of the transforming process. Here we established a unique pair of matched 3D cell models: 403L, derived from a low-grade glioma (LGG), and 403H, derived from a high-grade glioma (HGG), by utilizing IDH-mutant astrocytoma samples from the same patient when the tumor was diagnosed as WHO grade 2 (tumor mutational burden (TMB) of 3.96/Mb) and later as grade 4 (TMB of 70.07/Mb), respectively. Both cell models were authenticated to a patient’s sample retaining endogenous expression of IDH1 R132H. DNA methylation profiles of the parental tumors referred to LGG and HGG IDH-mutant glioma clusters. The immunopositivity of SOX2, NESTIN, GFAP, OLIG2, and beta 3-Tubulin suggested the multilineage potential of both models. 403H was more prompt to cell invasion and developed infiltrative HGG in vivo. The differentially expressed genes (DEGs) from the RNA sequencing analysis revealed the tumor invasion and aggressiveness related genes exclusively upregulated in the 403H model. Pathway analysis showcased an enrichment of genes associated with epithelial-mesenchymal transition (EMT) and Notch signaling pathways in 403H and 403L, respectively. Mass spectrometry-based targeted metabolomics and hyperpolarized (HP) 1-13C pyruvate in-cell NMR analyses demonstrated significant alterations in the TCA cycle and fatty acid metabolism. Citrate, glutamine, and 2-HG levels were significantly higher in 403H. To our knowledge, this is the first report describing the development of a matched pair of 3D patient-derived cell models representative of MT and temozolomide (TMZ)-induced hypermutator phenotype (HMP) in IDH-mutant glioma, providing insights into genetic and metabolic changes during MT/HMP. This novel in vitro model allows further investigation of the mechanisms of MT at the cellular level.Graphic

Cognitive phenotypes: Unraveling the heterogeneity in cognitive dysfunction among patients with primary brain tumors receiving radiotherapy.

Patients with primary brain tumors demonstrate heterogeneous patterns of cognitive dysfunction, which we explore using latent profile analysis (LPA) to identify cognitive phenotypes and their trajectories in patients receiving radiotherapy (RT). Ninety-six patients completed neuropsychological testing before and post-RT (3, 6, 12-months) on a prospective longitudinal trial, including measures of processing speed, executive function, language, and verbal and visual memory. Models with 2-4 classes were examined. Demographic and clinical data were examined across phenotypes and post-RT cognitive change was evaluated. The optimal model identified three unique cognitive phenotypes including a group of patients with generalized impairments (11.5%), a group with isolated verbal memory impairments (21.9%), and a group with minimal impairments (66.7%). The Verbal Memory phenotype had fewer years of education (p=.007) and a greater proportion of males (p<.001); the Generalized group had a greater proportion of patients with IDH-wild type gliomas and showed greater symptoms of anxiety and poorer quality of life (p-values<.05); and the Minimal Impairment phenotype had higher rates of IDH-Mutant gliomas. Approximately 50% of patients declined on at least one cognitive domain with memory the most vulnerable. Patients that declined reported greater symptoms of depression (p=.007) and poorer quality of life (p=.025). We identified three distinct cognitive phenotypes in patients with primary brain tumors receiving RT, each associated with unique demographic and clinical (e.g., IDH mutational status) profiles, with mood symptoms associated with late cognitive decline. This patient-centered approach enhances our understanding of clinical profiles associated with cognitive dysfunction and treatment-related neurotoxicity.

Multi-pool chemical exchange saturation transfer MRI in glioma grading, molecular subtyping and evaluating tumor proliferation.

To evaluate the performance of multi-pool Chemical exchange saturation transfer (CEST) MRI in prediction of glioma grade, isocitrate dehydrogenase (IDH) mutation, alpha-thalassemia/mental retardation syndrome X-linked (ATRX) loss and Ki-67 labeling index (LI), based on the fifth edition of the World Health Organization classification of central nervous system tumors (WHO CNS5). 95 patients with adult-type diffuse gliomas were analyzed. The amide, direct water saturation (DS), nuclear Overhauser enhancement (NOE), semi-solid magnetization transfer (MT) and amine signals were derived using Lorentzian fitting, and asymmetry-based amide proton transfer-weighted (APTwasym) signal was calculated. The mean value of tumor region was measured and intergroup differences were estimated using student-t test. The receiver operating curve (ROC) and area under the curve (AUC) analysis were used to evaluate the diagnostic performance of signals and their combinations. Spearman correlation analysis was performed to evaluate tumor proliferation. The amide and DS signals were significantly higher in high-grade gliomas compared to low-grade gliomas, as well as in IDH-wildtype gliomas compared to IDH-mutant gliomas (all p < 0.001). The DS, MT and amine signals showed significantly differences between ATRX loss and retention in grade 2/3 IDH-mutant gliomas (all p < 0.05). The combination of signals showed the highest AUC in prediction of grade (0.857), IDH mutation (0.814) and ATRX loss (0.769). Additionally, the amide and DS signals were positively correlated with Ki-67 LI (both p < 0.001). Multi-pool CEST MRI demonstrated good potential to predict glioma grade, IDH mutation, ATRX loss and Ki-67 LI.

456P Real-world data of IDH mutant gliomas in Spain, a RETSINE: GEINO study

456P Real-world data of IDH mutant gliomas in Spain, a RETSINE: GEINO study

Absolute Metabolite Quantification in Individuals with Glioma and Healthy Individuals Using Whole-Brain Three-dimensional MR Spectroscopic and Echo-planar Time-resolved Imaging.

MR spectroscopic imaging (MRSI) can be used to quantify an extended brain metabolic profile but is confounded by changes in tissue water levels due to disease. To develop a fast absolute quantification method for metabolite concentrations combining whole-brain MRSI with echo-planar time-resolved imaging (EPTI) relaxometry in individuals with glioma and healthy individuals. In this prospective study performed from August 2022 to August 2023, using internal water as concentration reference, the MRSI-EPTI quantification method was compared with the conventional method using population-average literature relaxation values. Healthy participants and participants with mutant IDH1 gliomas underwent imaging at 3 T with a 32-channel coil. Real-time navigated adiabatic spiral three-dimensional MRSI scans were acquired in approximately 8 minutes and reconstructed with a super-resolution pipeline to obtain brain metabolic images at 2.4-mm isotropic resolution. High-spatial-resolution multiparametric EPTI was performed in 3 minutes, with 1-mm isotropic resolution, to correct the relaxation and proton density of the water reference signal. Bland-Altman analysis and the Wilcoxon signed rank test were used to compare absolute quantifications from the proposed and conventional methods. Six healthy participants (four male; mean age, 37 years ± 11 [SD]) and nine participants with glioma (six male; mean age, 41 years ± 15; one with wild-type IDH1 and eight with mutant IDH1) were included. In healthy participants, there was good agreement (+4% bias) between metabolic concentrations derived using the two methods, with a CI of plus or minus 26%. In participants with glioma, there was large disagreement between the two methods (+39% bias) and a CI of plus or minus 55%. The proposed quantification method improved tumor contrast-to-noise ratio (median values) for total N-acetyl-aspartate (EPTI: 0.541 [95% CI: 0.217, 0.910]; conventional: 0.484 [95% CI: 0.199, 0.823]), total choline (EPTI: 1.053 [95% CI: 0.681, 1.713]; conventional: 0.940 [95% CI: 0.617, 1.295]), and total creatine (EPTI: 0.745 [95% CI: 0.628, 0.909]; conventional: 0.553 [95% CI: 0.444, 0.828]) (P = .03 for all). The whole-brain MRSI-EPTI method provided fast absolute quantification of metabolic concentrations with individual-specific corrections at 2.4-mm isotropic resolution, yielding concentrations closer to the true value in disease than the conventional literature-based corrections. © RSNA, 2024 Supplemental material is available for this article.

A perioperative study of Safusidenib in patients with IDH1-mutated glioma.

This is a single arm, open label perioperative trial to assess the feasibility, pharmacokinetics and pharmacodynamics of treatment with safusidenib following biopsy, and prior to surgical resection in patients with IDH1 mutated glioma who have not received radiation therapy or chemotherapy. Fifteen participants will receive treatment in two parts. First, biopsy followed by one cycle (28days) of safusidenib, an orally available, small molecular inhibitor of mutated IDH1, then maximal safe resection of the tumor (Part A). Second, after recovery from surgery, safusidenib until disease progression or unacceptable toxicity (Part B). This research will enable objective measurement of biological activity of safusidenib in patients with IDH1 mutated glioma. Anti-tumor activity will be assessed by progression free survival and time to next intervention.Clinical Trial Registration: NCT05577416 (ClinicalTrials.gov).

Valproic acid targets IDH1 mutants through alteration of lipid metabolism

Histone deacetylases (HDACs) have a wide range of targets and can rewire both the chromatin and lipidome of cancer cells. In this study, we show that valproic acid (VPA), a brain penetrant anti-seizure medication and histone deacetylase inhibitor, inhibits the growth of IDH1 mutant tumors in vivo and in vitro, with at least some selectivity over IDH1 wild-type tumors. Surprisingly, genes upregulated by VPA showed no enhanced chromatin accessibility at the promoter, but there was a correlation between VPA-downregulated genes and diminished promoter chromatin accessibility. VPA inhibited the transcription of lipogenic genes and these lipogenic genes showed significant decreases in promoter chromatin accessibility only in the IDH1 MT glioma cell lines tested. VPA inhibited the mTOR pathway and a key lipogenic gene, fatty acid synthase (FASN). Both VPA and a selective FASN inhibitor TVB-2640 rewired the lipidome and promoted apoptosis in an IDH1 MT but not in an IDH1 WT glioma cell line. We further find that HDACs are involved in the regulation of lipogenic genes and HDAC6 is particularly important for the regulation of FASN in IDH1 MT glioma. Finally, we show that FASN knockdown alone and VPA in combination with FASN knockdown significantly improved the survival of mice in an IDH1 MT primary orthotopic xenograft model in vivo. We conclude that targeting fatty acid metabolism through HDAC inhibition and/or FASN inhibition may be a novel therapeutic opportunity in IDH1 mutant gliomas.

Usefulness of synthetic MRI for differentiation of IDH-mutant diffuse gliomas and its comparison with the T2-FLAIR mismatch sign.

The T2-FLAIR mismatch sign is a characteristic imaging biomarker for astrocytoma, isocitrate dehydrogenase (IDH)-mutant. However, investigators have provided varying interpretations of the positivity/negativity of this sign given for individual cases the nature of qualitative visual assessment. Moreover, MR sequence parameters also influence the appearance of the T2-FLAIR mismatch sign. To resolve these issues, we used synthetic MR technique to quantitatively evaluate and differentiate astrocytoma from oligodendroglioma. This study included 20 patients with newly diagnosed non-enhanced IDH-mutant diffuse glioma who underwent preoperative synthetic MRI using the Quantification of Relaxation Times and Proton Density by Multiecho acquisition of a saturation-recovery using Turbo spin-Echo Readout (QRAPMASTER) sequence at our institution. Two independent reviewers evaluated preoperative conventional MR images to determine the presence or absence of the T2-FLAIR mismatch sign. Synthetic MRI was used to measure T1, T2 and proton density (PD) values in the tumor lesion. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance. The pathological diagnoses included astrocytoma, IDH-mutant (n = 12) and oligodendroglioma, IDH-mutant and 1p/19q-codeleted (n = 8). The sensitivity and specificity of T2-FLAIR mismatch sign for astrocytoma were 66.7% and 100% [area under the ROC curve (AUC) = 0.833], respectively. Astrocytoma had significantly higher T1, T2, and PD values than did oligodendroglioma (p < 0.0001, < 0.0001, and 0.0154, respectively). A cutoff lesion T1 value of 1580 ms completely differentiated astrocytoma from oligodendroglioma (AUC = 1.00). Quantitative evaluation of non-enhanced IDH-mutant diffuse glioma using synthetic MRI allowed for better differentiation between astrocytoma and oligodendroglioma than did conventional T2-FLAIR mismatch sign. Measurement of T1 and T2 value by synthetic MRI could improve the differentiation of IDH-mutant diffuse gliomas.