Modeling epigenetic lesions that cause gliomas.

Epigenetic lesions that disrupt regulatory elements represent potential cancer drivers. However, we lack experimental models for validating their tumorigenic impact. Here, we model aberrations arising in isocitrate dehydrogenase-mutant gliomas, which exhibit DNA hypermethylation. We focus on a CTCF insulator near the PDGFRA oncogene that is recurrently disrupted by methylation in these tumors. We demonstrate that disruption of the syntenic insulator in mouse oligodendrocyte progenitor cells (OPCs) allows an OPC-specific enhancer to contact and induce Pdgfra, thereby increasing proliferation. We show that a second lesion, methylation-dependent silencing of the Cdkn2a tumor suppressor, cooperates with insulator loss in OPCs. Coordinate inactivation of the Pdgfra insulator and Cdkn2a drives gliomagenesis in vivo. Despite locus synteny, the insulator is CpG-rich only in humans, a feature that may confer human glioma risk but complicates mouse modeling. Our study demonstrates the capacity of recurrent epigenetic lesions to drive OPC proliferation in vitro and gliomagenesis in vivo.

R-2HG Exhibits Anti-tumor Activity by Targeting FTO/m6A/MYC/CEBPA Signaling.

R-2-hydroxyglutarate (R-2HG), produced at high levels by mutant isocitrate dehydrogenase 1/2 (IDH1/2) enzymes, was reported as an oncometabolite. We show here that R-2HG also exerts a broad anti-leukemic activity in vitro and in vivo by inhibiting leukemia cell proliferation/viability and by promoting cell-cycle arrest and apoptosis. Mechanistically, R-2HG inhibits fat mass and obesity-associated protein (FTO) activity, thereby increasing global N6-methyladenosine (m6A) RNA modification in R-2HG-sensitive leukemia cells, which in turn decreases the stability of MYC/CEBPA transcripts, leading to the suppression of relevant pathways. Ectopically expressed mutant IDH1 and S-2HG recapitulate the effects of R-2HG. High levels of FTO sensitize leukemic cells to R-2HG, whereas hyperactivation of MYC signaling confers resistance that can be reversed by the inhibition of MYC signaling. R-2HG also displays anti-tumor activity in glioma. Collectively, while R-2HG accumulated in IDH1/2 mutant cancers contributes to cancer initiation, our work demonstrates anti-tumor effects of 2HG in inhibiting proliferation/survival of FTO-high cancer cells via targeting FTO/m6A/MYC/CEBPA signaling.

Metabolic partitioning in the brain and its hijacking by glioblastoma.

The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.

Mutant IDH1 regulates the tumor-associated immune system in gliomas.

Gliomas harboring mutations in isocitrate dehydrogenase 1/2 (IDH1/2) have the CpG island methylator phenotype (CIMP) and significantly longer patient survival time than wild-type IDH1/2 (wtIDH1/2) tumors. Although there are many factors underlying the differences in survival between these two tumor types, immune-related differences in cell content are potentially important contributors. In order to investigate the role of IDH mutations in immune response, we created a syngeneic pair mouse model for mutant IDH1 (muIDH1) and wtIDH1 gliomas and demonstrated that muIDH1 mice showed many molecular and clinical similarities to muIDH1 human gliomas, including a 100-fold higher concentration of 2-hydroxygluratate (2-HG), longer survival time, and higher CpG methylation compared with wtIDH1. Also, we showed that IDH1 mutations caused down-regulation of leukocyte chemotaxis, resulting in repression of the tumor-associated immune system. Given that significant infiltration of immune cells such as macrophages, microglia, monocytes, and neutrophils is linked to poor prognosis in many cancer types, these reduced immune infiltrates in muIDH1 glioma tumors may contribute in part to the differences in aggressiveness of the two glioma types.

Enhancing predictability of IDH mutation status in glioma patients at initial diagnosis: a comparative analysis of radiomics from MRI, [18F]FET PET, and TSPO PET.

PURPOSE: According to the World Health Organization classification for tumors of the central nervous system, mutation status of the isocitrate dehydrogenase (IDH) genes has become a major diagnostic discriminator for gliomas. Therefore, imaging-based prediction of IDH mutation status is of high interest for individual patient management. We compared and evaluated the diagnostic value of radiomics derived from dual positron emission tomography (PET) and magnetic resonance imaging (MRI) data to predict the IDH mutation status non-invasively. METHODS: Eighty-seven glioma patients at initial diagnosis who underwent PET targeting the translocator protein (TSPO) using [18F]GE-180, dynamic amino acid PET using [18F]FET, and T1-/T2-weighted MRI scans were examined. In addition to calculating tumor-to-background ratio (TBR) images for all modalities, parametric images quantifying dynamic [18F]FET PET information were generated. Radiomic features were extracted from TBR and parametric images. The area under the receiver operating characteristic curve (AUC) was employed to assess the performance of logistic regression (LR) classifiers. To report robust estimates, nested cross-validation with five folds and 50 repeats was applied. RESULTS: TBRGE-180 features extracted from TSPO-positive volumes had the highest predictive power among TBR images (AUC 0.88, with age as co-factor 0.94). Dynamic [18F]FET PET reached a similarly high performance (0.94, with age 0.96). The highest LR coefficients in multimodal analyses included TBRGE-180 features, parameters from kinetic and early static [18F]FET PET images, age, and the features from TBRT2 images such as the kurtosis (0.97). CONCLUSION: The findings suggest that incorporating TBRGE-180 features along with kinetic information from dynamic [18F]FET PET, kurtosis from TBRT2, and age can yield very high predictability of IDH mutation status, thus potentially improving early patient management.

Radiosynthesis and biological evaluation of [18F]AG-120 for PET imaging of the mutant isocitrate dehydrogenase 1 in glioma.

Glioma are clinically challenging tumors due to their location and invasiveness nature, which often hinder complete surgical resection. The evaluation of the isocitrate dehydrogenase mutation status has become crucial for effective patient stratification. Through a transdisciplinary approach, we have developed an 18F-labeled ligand for non-invasive assessment of the IDH1R132H variant by using positron emission tomography (PET) imaging. In this study, we have successfully prepared diastereomerically pure [18F]AG-120 by copper-mediated radiofluorination of the stannyl precursor 6 on a TRACERlab FX2 N radiosynthesis module. In vitro internalization studies demonstrated significantly higher uptake of [18F]AG-120 in U251 human high-grade glioma cells with stable overexpression of mutant IDH1 (IDH1R132H) compared to their wild-type IDH1 counterpart (0.4 vs. 0.013% applied dose/µg protein at 120 min). In vivo studies conducted in mice, exhibited the excellent metabolic stability of [18F]AG-120, with parent fractions of 85% and 91% in plasma and brain at 30 min p.i., respectively. Dynamic PET studies with [18F]AG-120 in naïve mice and orthotopic glioma rat model reveal limited blood-brain barrier permeation along with a low uptake in the brain tumor. Interestingly, there was no significant difference in uptake between mutant IDH1R132H and wild-type IDH1 tumors (tumor-to-blood ratio[40-60 min]: ~1.7 vs. ~1.3). In conclusion, our preclinical evaluation demonstrated a target-specific internalization of [18F]AG-120 in vitro, a high metabolic stability in vivo in mice, and a slightly higher accumulation of activity in IDH1R132H-glioma compared to IDH1-glioma. Overall, our findings contribute to advancing the field of molecular imaging and encourage the evaluation of [18F]AG-120 to improve diagnosis and management of glioma and other IDH1R132H-related tumors.

Distinguishing IDH mutation status in gliomas using FTIR-ATR spectra of peripheral blood plasma indicating clear traces of protein amyloid aggregation.

BACKGROUND: Glioma is a primary brain tumor and the assessment of its molecular profile in a minimally invasive manner is important in determining treatment strategies. Among the molecular abnormalities of gliomas, mutations in the isocitrate dehydrogenase (IDH) gene are strong predictors of treatment sensitivity and prognosis. In this study, we attempted to non-invasively diagnose glioma development and the presence of IDH mutations using multivariate analysis of the plasma mid-infrared absorption spectra for a comprehensive and sensitive view of changes in blood components associated with the disease and genetic mutations. These component changes are discussed in terms of absorption wavenumbers that contribute to differentiation. METHODS: Plasma samples were collected at our institutes from 84 patients with glioma (13 oligodendrogliomas, 17 IDH-mutant astrocytoma, 7 IDH wild-type diffuse glioma, and 47 glioblastomas) before treatment initiation and 72 healthy participants. FTIR-ATR spectra were obtained for each plasma sample, and PLS discriminant analysis was performed using the absorbance of each wavenumber in the fingerprint region of biomolecules as the explanatory variable. This data was used to distinguish patients with glioma from healthy participants and diagnose the presence of IDH mutations. RESULTS: The derived classification algorithm distinguished the patients with glioma from healthy participants with 83% accuracy (area under the curve (AUC) in receiver operating characteristic (ROC) = 0.908) and diagnosed the presence of IDH mutation with 75% accuracy (AUC = 0.752 in ROC) in cross-validation using 30% of the total test data. The characteristic changes in the absorption spectra suggest an increase in the ratio of ß-sheet structures in the conformational composition of blood proteins of patients with glioma. Furthermore, these changes were more pronounced in patients with IDH-mutant gliomas. CONCLUSIONS: The plasma infrared absorption spectra could be used to diagnose gliomas and the presence of IDH mutations in gliomas with a high degree of accuracy. The spectral shape of the protein absorption band showed that the ratio of ß-sheet structures in blood proteins was significantly higher in patients with glioma than in healthy participants, and protein aggregation was a distinct feature in patients with glioma with IDH mutations.

IDH1 mutation is associated with improved resection rates, progression-free survival and overall survival in patients with anaplastic astrocytomas.

PURPOSE: The introduction of molecular markers in to the diagnosis of gliomas has changed the therapeutic approach to this tumors. The aim of this study was to examine the impact of surgery on anaplastic astrocytomas (AA), which has not previously been fully elucidated. METHODS: This was a retrospective study involving a total of 143 patients who underwent surgery for primary AA in our department between 1995 and 2020. RESULTS: Total tumor resection was achieved more often in patients with IDH-mutant tumors (41.09%) than in patients with IDH-wildtype tumors (30.76%). The median PFS was 1876 days for patients with IDH1 mutations and 238 days for patients with IDH-wildtype tumors. The 1-, 3-, 5- and 10-year PFS were longer in patients with total tumor resection and IDH-mutant AA (86.2%, 69%, 65.5% and 44.8%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (83.3%, 55.6%, 41.7% and 25%, respectively) and even longer compared to all IDH-wildtype tumors. The median OS was 2472 days for patients with IDH1 mutations and 434 days for patients with IDH-wildtype tumors. The 3-, 5- and 10-year OS times were longer in patients with total tumor resection and IDH-mutant AA (89.2%, 85.2% and 72.6%, respectively) than in patients with subtotal tumor resection and IDH-mutant AA (85.9%, 73.7% and 52.6%, respectively) and were even longer compared to all IDH-wildtype tumors. CONCLUSION: Total tumor resection is more common with IDH-mutant AA than with IDH-wildtype tumors. Patients with IDH-mutant AA had significantly better PFS and OS after total tumor resection than after subtotal tumor resection and biopsy.

Amino acid metabolism in glioma: in vivo MR-spectroscopic detection of alanine as a potential biomarker of poor survival in glioma patients.

PURPOSE: Reprogramming of amino acid metabolism is relevant for initiating and fueling tumor formation and growth. Therefore, there has been growing interest in anticancer therapies targeting amino acid metabolism. While developing personalized therapeutic approaches to glioma, in vivo proton magnetic resonance spectroscopy (MRS) is a valuable tool for non-invasive monitoring of tumor metabolism. Here, we evaluated MRS-detected brain amino acids and myo-inositol as potential diagnostic and prognostic biomarkers in glioma. METHOD: We measured alanine, glycine, glutamate, glutamine, and myo-inositol in 38 patients with MRI-suspected glioma using short and long echo-time single-voxel PRESS MRS sequences. The detectability of alanine, glycine, and myo-inositol and the (glutamate + glutamine)/total creatine ratio were evaluated against the patients' IDH mutation status, CNS WHO grade, and overall survival. RESULTS: While the detection of alanine and non-detection of myo-inositol significantly correlated with IDH wildtype (p = 0.0008, p = 0.007, respectively) and WHO grade 4 (p = 0.01, p = 0.04, respectively), glycine detection was not significantly associated with either. The ratio of (glutamate + glutamine)/total creatine was significantly higher in WHO grade 4 than in 2 and 3. We found that the overall survival was significantly shorter in glioma patients with alanine detection (p = 0.00002). CONCLUSION: Focusing on amino acids in MRS can improve its diagnostic and prognostic value in glioma. Alanine, which is visible at long TE even in the presence of lipids, could be a relevant indicator for overall survival.

Antiepileptic Strategies for Patients with Primary and Metastatic Brain Tumors.

OPINION STATEMENT: Seizure activity is common in patients with primary and metastatic brain tumors, affecting more than 50% of cases over the course of their disease. Several mechanisms contribute to brain tumor-related epilepsy (BTRE), including a pro-inflammatory environment, excessive secretion of glutamate and an increase in neuronal excitatory tone, reduction of GABAergic inhibitory activity, and an increase in 2-hydroxygluturate production in isocitrate dehydrogenase mutant tumors. After a verified seizure in a brain tumor patient, the consensus is that BTRE has developed, and it is necessary to initiate an antiepileptic drug (AED). It is not recommended to initiate AED prophylaxis. Second- and third-generation AEDs are the preferred options for initiation, due to a lack of hepatic enzyme induction and reduced likelihood for drug-drug interactions, especially in regard to neoplastic treatment. The efficacy of appropriate AEDs for patients with BTRE is fairly equivalent, although some data suggests that levetiracetam may be slightly more active in suppressing seizures than other AEDs. The consensus among most Neuro-Oncology providers is to initiate levetiracetam monotherapy after a first seizure in a brain tumor patient, as long as the patient does not have any psychiatric co-morbidities. If levetiracetam is not tolerated well or is ineffective, other appropriate initial AED options for monotherapy or as an add-on anticonvulsant include lacosamide, valproic acid, briviracetam, lamotrigine, and perampanel.

The curious case of IDH mutant acute myeloid leukaemia: biochemistry and therapeutic approaches.

Of the many genetic alterations that occur in cancer, relatively few have proven to be suitable for the development of targeted therapies. Mutations in isocitrate dehydrogenase (IDH) 1 and -2 increase the capacity of cancer cells to produce a normally scarce metabolite, D-2-hydroxyglutarate (2-HG), by several orders of magnitude. The discovery of the unusual biochemistry of IDH mutations spurred a flurry of activity that revealed 2-HG as an 'oncometabolite' with pleiotropic effects in malignant cells and consequences for anti-tumour immunity. Over the next decade, we learned that 2-HG dysregulates a wide array of molecular pathways, among them a large family of dioxygenases that utilise the closely related metabolite α-ketoglutarate (α-KG) as an essential co-substrate. 2-HG not only contributes to malignant transformation, but some cancer cells become addicted to it and sensitive to inhibitors that block its synthesis. Moreover, high 2-HG levels and loss of wild-type IDH1 or IDH2 activity gives rise to synthetic lethal vulnerabilities. Herein, we review the biology of IDH mutations with a particular focus on acute myeloid leukaemia (AML), an aggressive disease where selective targeting of IDH-mutant cells is showing significant promise.

Vascular differences between IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 at imaging and transcriptomic levels.

Global agreement in central nervous system (CNS) tumor classification is essential for predicting patient prognosis and determining the correct course of treatment, as well as for stratifying patients for clinical trials at international level. The last update by the World Health Organization of CNS tumor classification and grading in 2021 considered, for the first time, IDH-wildtype glioblastoma and astrocytoma IDH-mutant grade 4 as different tumors. Mutations in the genes isocitrate dehydrogenase (IDH) 1 and 2 occur early and, importantly, contribute to gliomagenesis. IDH mutation produces a metabolic reprogramming of tumor cells, thus affecting the processes of hypoxia and vascularity, resulting in a clear advantage for those patients who present with IDH-mutated astrocytomas. Despite the clinical relevance of IDH mutation, current protocols do not include full sequencing for every patient. Alternative biomarkers could be useful and complementary to obtain a more reliable classification. In this sense, magnetic resonance imaging (MRI)-perfusion biomarkers, such as relative cerebral blood volume and flow, could be useful from the moment of presurgery, without incurring additional financial costs or requiring extra effort. The main purpose of this work is to analyze the vascular and hemodynamic differences between IDH-wildtype glioblastoma and IDH-mutant astrocytoma. To achieve this, we evaluate and validate the association between dynamic susceptibility contrast-MRI perfusion biomarkers and IDH mutation status. In addition, to gain a deeper understanding of the vascular differences in astrocytomas depending on the IDH mutation, we analyze the transcriptomic bases of the vascular differences.

Applications of chemical exchange saturation transfer magnetic resonance imaging in identifying genetic markers in gliomas.

Chemical exchange saturation transfer (CEST) imaging is an important molecular magnetic resonance imaging technique that can image numerous low-concentration biomolecules with water-exchangeable protons (such as cellular proteins) and tissue pH. CEST, or more specially amide proton transfer-weighted imaging, has been widely used for the detection, diagnosis, and response assessment of brain tumors, and its feasibility in identifying molecular markers in gliomas has also been explored in recent years. In this paper, after briefing on the basic principles and quantification methods of CEST imaging, we review its early applications in identifying isocitrate dehydrogenase mutation status, MGMT methylation status, 1p/19q deletion status, and H3K27M mutation status in gliomas. Finally, we discuss the limitations or weaknesses in these studies.

IDH mutations in G2-3 conventional central bone chondrosarcoma: a mono institutional experience.

BACKGROUND: Heterozygous isocitrate dehydrogenase (IDH) mutations occur in about half of conventional central bone chondrosarcomas (CCBC). Aim of this study was to assess the frequency and prognostic impact of IDH mutations in high grade CCBC patients. METHODS: 64 patients with G2 and G3 CCBC were included. DNA extraction, PCR amplification of IDH1/2 exon 4s, and sequencing analysis with Sanger were performed. RESULTS: IDH mutations were detected in 24/54 patients (44%): IDH1 in 18, IDH2 in 4, and both IDH1/2 in 2 patients. The frequency of mutations was 37% in G2 vs. 69% in G3 (p = 0.039), and 100% in three Ollier disease associated chondrosarcoma. 5-year overall survival (OS) at 124 months (range 1-166) was 51%, with no significant difference based on the IDH mutational status: 61% in IDHmut vs. 44% in IDH wild type (IDHwt). The 5-year relapse free survival (RFS) was 33% (95% CI:10-57) for IDHmut vs. 57% (95%CI: 30-77) for IDHwt. Progression free survival (PFS) was 25% (95%CI:1-65) IDHmut vs. 16% (95%CI: 0.7-52) IDHwt. 55% (5/9) of IDHmut G2 became higher grade at the recurrence, as compared with 25% (3/12) of G2 IDHwt. CONCLUSIONS: This study shows a higher frequency of IDH mutations in G3 CCBC as compared with G2. No significant differences in OS, RFS, and PFS by mutational status were detected. After relapse, a higher rate of G3 for IDH mutated CCBC was observed.

Long-term follow up of patients with WHO grade 2 oligodendroglioma.

PURPOSE: Since the introduction of the molecular definition of oligodendrogliomas based on isocitrate dehydrogenase (IDH)-status and the 1p19q-codeletion, it has become increasingly evident how this glioma entity differs much from other diffuse lower grade gliomas and stands out with longer survival and often better responsiveness to adjuvant therapy. Therefore, apart from using a molecular oligodendroglioma definition, an extended follow-up time is necessary to understand the nature of this slow growing, yet malignant condition. The aim of this study was to describe the long-term course of the oligodendroglioma disease in a population-based setting and to determine which factors affect outcome in terms of survival. METHODS: All adults with WHO-grade 2 oligodendrogliomas with known 1p19q-codeletion from five Scandinavian neurosurgical centers and with a follow-up time exceeding 5 years, were analyzed regarding survival and factors potentially affecting survival. RESULTS: 126 patients diagnosed between 1998 and 2016 were identified. The median follow-up was 12.0 years, and the median survival was 17.8 years (95% CI 16.0-19.6). Factors associated with shorter survival in multivariable analysis were age (HR 1.05 per year; CI 1.02-1.08, p < 0.001), tumor diameter (HR 1.05 per millimeter; CI 1.02-1.08, p < 0.001) and poor preoperative functional status (KPS < 80) (HR 4.47; CI 1.70-11.78, p = 0.002). In our material, surgical strategy was not associated with survival. CONCLUSION: Individuals with molecularly defined oligodendrogliomas demonstrate long survival, also in a population-based setting. This is important to consider for optimal timing of therapies that may cause long-term side effects. Advanced age, large tumors and poor function before surgery are predictors of shorter survival.

Individualized discrimination of tumor progression from treatment-related changes in different types of adult-type diffuse gliomas using [11C]methionine PET.

PURPOSE: This study aimed to assess the ability of [11C]methionine (MET) PET in distinguishing between tumor progression (TP) and treatment-related changes (TRCs) among different types of adult-type diffuse gliomas according to the 2021 World Health Organization classification and predict overall survival (OS). METHODS: We retrospectively selected 113 patients with adult-type diffuse gliomas with suspected TP who underwent MET PET imaging. Maximum and mean tumor-to-background ratios (TBRmax, TBRmean) and metabolic tumor volume (MTV) were calculated. Diagnoses were verified by histopathology (n = 50) or by clinical/radiological follow-up (n = 63). The diagnostic performance of MET PET parameters was evaluated through receiver operating characteristic (ROC) analysis and area under the curve (AUC) calculation. Survival analysis employed the Kaplan-Meier method and Cox proportional-hazards regression. RESULTS: TP and TRCs were diagnosed in 76 (67%) and 37 (33%) patients, respectively. ROC analysis revealed TBRmax had the best performance in differentiating TP from TRCs with a cut-off of 1.96 in IDH-mutant astrocytoma (AUC, 0.87; sensitivity, 93%; specificity 69%), 1.80 in IDH-mutant and 1p/19q-codeleted oligodendroglioma (AUC, 0.96; sensitivity, 100%; specificity, 89%), and 2.13 in IDH wild-type glioblastoma (AUC, 0.89; sensitivity, 89%; specificity, 78%), respectively. On multivariate analysis, higher TBRmean and MTV were significantly correlated with shorter OS in all IDH-mutant gliomas, as well as in IDH-mutant astrocytoma subgroup. CONCLUSION: This work confirms that MET PET has varying diagnostic performances in distinguishing TP from TRCs within three types of adult-type diffuse gliomas, and highlights its high diagnostic accuracy in IDH-mutant and 1p/19q-codeleted oligodendroglioma and potential prognostic value for IDH-mutant gliomas, particularly IDH-mutant astrocytoma.

Analysis of safety and efficacy of proton radiotherapy for IDH-mutated glioma WHO grade 2 and 3.

PURPOSE: Proton beam radiotherapy (PRT) has been demonstrated to improve neurocognitive sequelae particularly. Nevertheless, following PRT, increased rates of radiation-induced contrast enhancements (RICE) are feared. How safe and effective is PRT for IDH-mutated glioma WHO grade 2 and 3? METHODS: We analyzed 194 patients diagnosed with IDH-mutated WHO grade 2 (n = 128) and WHO grade 3 (n = 66) glioma who were treated with PRT from 2010 to 2020. Serial clinical and imaging follow-up was performed for a median of 5.1 years. RESULTS: For WHO grade 2, 61% were astrocytoma and 39% oligodendroglioma while for WHO grade 3, 55% were astrocytoma and 45% oligodendroglioma. Median dose for IDH-mutated glioma was 54 Gy(RBE) [range 50.4-60 Gy(RBE)] for WHO grade 2 and 60 Gy(RBE) [range 54-60 Gy(RBE)] for WHO grade 3. Five year overall survival was 85% in patients with WHO grade 2 and 67% in patients with WHO grade 3 tumors. Overall RICE risk was 25%, being higher in patients with WHO grade 2 (29%) versus in patients with WHO grade 3 (17%, p = 0.13). RICE risk increased independent of tumor characteristics with older age (p = 0.017). Overall RICE was symptomatic in 31% of patients with corresponding CTCAE grades as follows: 80% grade 1, 7% grade 2, 13% grade 3, and 0% grade 3 + . Overall need for RICE-directed therapy was 35%. CONCLUSION: These data demonstrate the effectiveness of PRT for IDH-mutated glioma WHO grade 2 and 3. The RICE risk differs with WHO grading and is higher in older patients with IDH-mutated Glioma WHO grade 2 and 3.

Integrative multi-omic analysis reveals neurodevelopmental gene dysregulation in CIC-knockout and IDH1-mutant cells.

Capicua (CIC)'s transcriptional repressor function is implicated in neurodevelopment and in oligodendroglioma (ODG) aetiology. However, CIC's role in these contexts remains obscure, primarily from our currently limited knowledge regarding its biological functions. Moreover, CIC mutations in ODG invariably co-occur with a neomorphic IDH1/2 mutation, yet the functional relationship between these two genetic events is unknown. Here, we analysed models derived from an E6/E7/hTERT-immortalized (i.e. p53- and RB-deficient) normal human astrocyte cell line. To examine the consequences of CIC loss, we compared transcriptomic and epigenomic profiles between CIC wild-type and knockout cell lines, with and without mutant IDH1 expression. Our analyses revealed dysregulation of neurodevelopmental genes in association with CIC loss. CIC ChIP-seq was also performed to expand upon the currently limited ensemble of known CIC target genes. Among the newly identified direct CIC target genes were EPHA2 and ID1, whose functions are linked to neurodevelopment and the tumourigenicity of in vivo glioma tumour models. NFIA, a known mediator of gliogenesis, was discovered to be uniquely overexpressed in CIC-knockout cells expressing mutant IDH1-R132H protein. These results identify neurodevelopment and specific genes within this context as candidate targets through which CIC alterations may contribute to the progression of IDH-mutant gliomas. © 2021 The Authors. The Journal of Pathology published by John Wiley & Sons, Ltd on behalf of The Pathological Society of Great Britain and Ireland.

A Rare Co-Occurrence of Maffucci Syndrome and Astrocytoma with IDH1 R132H Mutation: A Case Report.

Background: Maffucci syndrome is a rare genetic disorder associated with the development of multiple enchondromas and soft tissue cavernous hemangiomas, as well as an increased risk of malignant tumors. Case Description: Here we report a case of Maffucci syndrome in a patient who presented with a giant left frontal lobe tumor. Molecular genetic analysis of the tumor revealed an isocitrate dehydrogenase (IDH) mutation p.R132H (c.395C>A) mutation in the IDH1 gene and a heterozygous duplication of the CDKN2A genes. Conclusions: The presence of an IDH1 mutation is notable because this mutation is frequently seen in glial tumors and other neoplasms, and its co-occurrence with Maffucci syndrome may represent a novel risk factor for the development of gliomas. This case underscores the importance of genetic testing in patients with Maffucci syndrome who present with central nervous system tumors, as well as the need for further research to understand the relationship between IDH1 mutations and the development of gliomas in this population.

[Prognosis of overall and disease-free survival in patients with grade 3 astrocytomas (anaplastic astrocytoma, WHO 2016)]. / Faktory, opredelyayushchie prognoz obshchei i bezretsidivnoi vyzhivaemosti u patsientov s astrotsitomami grade 3 (anaplasticheskimi astrotsitomami, WHO 2016).

Anaplastic astrocytoma (AA) is a rare intracerebral tumor. Therefore, the number of studies devoted to risk factors of overall and disease-free survival is small. This single-center clinical study is devoted to various factors influencing prognosis of treatment in this group of patients. MATERIAL AND METHODS: A retrospective study included 389 patients diagnosed with grade 3 astrocytoma. We analyzed dependence of overall and disease-free survival from the following factors: gender, age of onset of disease, tumor extent, surgery, neurological disorders before and after surgery (NANO grading system), Ki67 index, postoperative radio- and chemotherapy (number courses, treatment regimens). RESULTS: Significant risk factors for overall and disease-free survival were spread and volume of tumor, postoperative neurological aggravation, Ki67 index, IDH mutation, radio- and chemotherapy. Age, frontal lobe tumor and disease manifestation variant were significant only for overall, but not for disease-free survival. CONCLUSION: This study was based on material of one of the largest clinical series of patients with AA operated on in one center in «molecular¼ era. Our results are consistent with previous data. Analysis of tumor biology and risk factors for IDH-negative AA without molecular signs of glioblastoma may be perspective.