Isocitrate Dehydrogenase Mutation Research Articles

Genetic predisposition to altered blood cell homeostasis is associated with glioma risk and survival

Glioma is a highly fatal and heterogeneous brain tumor with few known risk factors. Our study examines genetically predicted variability in blood cell indices in relation to glioma risk and survival in 3418 cases and 8156 controls. We find that increased platelet to lymphocyte ratio (PLR) confers an increased risk of glioma (odds ratio (OR) = 1.25, p = 0.005), especially tumors with isocitrate dehydrogenase (IDH) mutations (OR = 1.38, p = 0.007) and IDHmut 1p/19q intact (IDHmut-intact OR = 1.53, p = 0.004) tumors. Genetically inferred increased counts of lymphocytes (IDHmut-intact OR = 0.70, p = 0.004) and neutrophils (IDHmut OR = 0.69, p = 0.019; IDHmut-intact OR = 0.60, p = 0.009) show inverse associations with risk, which may reflect enhanced immune-surveillance. Considering survival, we observe higher mortality risk in patients with IDHmut 1p/19q with genetically predicted increased counts of lymphocytes (hazard ratio (HR) = 1.65, 95% CI: 1.24–2.20), neutrophils (HR = 1.49, 1.13–1.97), and eosinophils (HR = 1.59, 1.18–2.14). Polygenic scores for blood cell traits are also differentially associated with 17 tumor immune microenvironment features in a subtype-specific manner, including signatures related to interferon signaling, PD-1 expression, and T-cell/Cytotoxic responses. Our findings highlight immune-mediated susceptibility mechanisms with potential disease management implications.

The Impact of Metabolic Rewiring in Glioblastoma: The Immune Landscape and Therapeutic Strategies

Glioblastoma (GBM) is an aggressive brain tumor characterized by extensive metabolic reprogramming that drives tumor growth and therapeutic resistance. Key metabolic pathways, including glycolysis, lactate production, and lipid metabolism, are upregulated to sustain tumor survival in the hypoxic and nutrient-deprived tumor microenvironment (TME), while glutamine and tryptophan metabolism further contribute to the aggressive phenotype of GBM. These metabolic alterations impair immune cell function, leading to exhaustion and stress in CD8+ and CD4+ T cells while favoring immunosuppressive populations such as regulatory T cells (Tregs) and M2-like macrophages. Recent studies emphasize the role of slow-cycling GBM cells (SCCs), lipid-laden macrophages, and tumor-associated astrocytes (TAAs) in reshaping GBM’s metabolic landscape and reinforcing immune evasion. Genetic mutations, including Isocitrate Dehydrogenase (IDH) mutations, Epidermal Growth Factor Receptor (EGFR) amplification, and Phosphotase and Tensin Homolog (PTEN) loss, further drive metabolic reprogramming and offer potential targets for therapy. Understanding the relationship between GBM metabolism and immune suppression is critical for overcoming therapeutic resistance. This review focuses on the role of metabolic rewiring in GBM, its impact on the immune microenvironment, and the potential of combining metabolic targeting with immunotherapy to improve clinical outcomes for GBM patients.

Presence of Fragmented Intratumoral Thrombosed Microvasculature in the Necrotic and Peri-Necrotic Regions on SWI Differentiates IDH Wild-Type Glioblastoma From IDH Mutant Grade 4 Astrocytoma.

Isocitrate dehydrogenase (IDH) wild-type (IDHwt) glioblastomas (GB) are more aggressive and have a poorer prognosis than IDH mutant (IDHmt) tumors, emphasizing the need for accurate preoperative differentiation. However, a distinct imaging biomarker for differentiation mostly lacking. Intratumoral thrombosis has been reported as a histopathological biomarker for GB. To evaluate the fragmented intratumoral thrombosed microvasculature (FTV) signs on susceptibility-weighted imaging (SWI) for distinguishing IDHwt and IDHmt tumors. Retrospective. Ninety-seven treatment-naïve patients with histopathologically confirmed IDHwt GB (54 males, 26 females) and IDHmt grade 4 astrocytoma (13 males, 4 females). 3-T, SWI, fluid-attenuated-inversion-recovery (FLAIR), T1-weighted, T2-weighted, PD-weighted, post-contrast T1-weighted and dynamic-contrast-enhanced (DCE)-MRI. SWI data were evaluated by three experienced neuroradiologists (S.S., 11 years; J.S., 15 years; R.K.G., 40 years of experience), who assessed FTV presence in necrotic and peri-necrotic regions. FTV was identified as intratumoral susceptibility signal having minimal or no interslice connections. Quantitative DCE-MRI parameters were derived using first-pass-analysis and extended Tofts model. FLAIR abnormal, contrast-enhancing, and necrotic regions were segmented using in-house developed U-Net architecture. Fleiss' Kappa, Cohen's Kappa, Shapiro-Wilk test, t tests or Mann-Whitney U test, receiver-operating characteristic (ROC) analysis, confusion matrix. A P-value <0.05 was considered statistically significant. Fleiss' kappa test provided 91% inter-rater agreement, and Cohen's kappa provided intrarater agreement ranged from 81% to 97%. The raters' accuracy in distinguishing IDHwt from IDHmt ranged from 92% to 94%. Some of the quantitative DCE-MRI parameters (CBV, Ve, and Ktrans) provided statistically significant differences in differentiating IDHwt and IDHmt. Ktrans demonstrated 80.3% sensitivity and 81.2% specificity, with ROC analysis showing an AUC of 0.77. FTV signs in necrotic and peri-necrotic regions on SWI demonstrated a high accuracy in distinguishing IDHwt from IDHmt. Qualitative assessment of FTV signs showed almost perfect inter-rater and intrarater agreement. Quantitative DCE-MRI metrics also showed statistically significant differentiation of IDHwt and IDHmt. This study demonstrates that preoperative imaging, particularly the visualization of the fragmented thrombosed vasculature (FTV) sign on susceptibility-weighted imaging (SWI), effectively differentiates isocitrate dehydrogenase (IDH) wild-type (IDHwt) glioblastoma (GB) from IDH mutant (IDHmt) grade 4 astrocytomas. Over 90% of IDHwt GB patients displayed the FTV sign, a specific imaging biomarker absent in IDHmt cases. Perfusion parameters such as cerebral blood volume, Ve, and Ktrans were elevated in IDHwt gliomas, reflecting distinct vascular profiles. SWI offers a noninvasive and accurate diagnostic method, overcoming limitations of histopathology. Despite limitations like unequal sample sizes and retrospective analysis, this study underscores the clinical potential of SWI in improving glioma characterization and aiding treatment planning. 4 TECHNICAL EFFICACY: Stage 2.

RNF7-Mediated ROS Targets Malignant Phenotype and Radiotherapy Sensitivity in Glioma With Different IDH1 Genotypes.

RNF7 (Ring Finger Protein 7) is a key component of CRLs (Cullin-RING-type E3 ubiquitin ligases) and has been found to possess intrinsic anti-ROS capabilities. Aberrant expression of RNF7 has been observed in various tumor types and is known to significantly influence tumor initiation and progression. However, the specific role of RNF7 in glioblastoma remains unclear. IDH (isocitrate dehydrogenase) mutations, which induce metabolic reprogramming and result in notable heterogeneity among glioma with different IDH genotypes. Through analysis of public glioma databases, we identified a high expression of RNF7 in glioma and its correlation with patient prognosis. Moreover, we observed variations in RNF7 expression and its association with patient outcomes under different treatment modalities among different IDH genotypes. In this study, we demonstrated the critical role of RNF7 in the malignant phenotype of IDH1-mutant glioma and its contribution to radiation resistance. Subsequent functional enrichment analysis of RNF7 in glioma, coupled with validation through cellular experiments, confirmed its significant involvement in maintaining redox balance. Our findings suggest that RNF7 exerts a buffering effect against radiation-induced oxidative stress and counterbalances the redox stress induced by IDH1 mutation through its anti-ROS activity. Additionally, our follow-up investigations revealed that the upregulation of RNF7 after radiation exposure and in IDH1-mutant glioma cells is induced by ROS. Collectively, our study underscores the potential of RNF7 as a molecular biomarker in glioma. Elevated RNF7 expression often indicates a heightened metabolic resilience in glioma, leading to resistance against radiotherapy.

IDH-mutant gliomas in children and adolescents - from biology to clinical trials

Gliomas account for nearly 30% of all primary central nervous system (CNS) tumors in children and adolescents and young adults (AYA), contributing to significant morbidity and mortality. The updated molecular classification of gliomas defines molecularly diverse subtypes with a spectrum of tumors associated with age-distinct incidence. In adults, gliomas are characterized by the presence or absence of mutations in isocitrate dehydrogenase (IDH), with mutated IDH (mIDH) gliomas providing favorable outcomes and avenues for targeted therapy with the emergence of mIDH inhibitors. Despite their rarity, IDH mutations have been reported in 5-15% of pediatric glioma cases. Those with primary mismatch-repair deficient mIDH astrocytomas (PMMRDIA) have a particularly poor prognosis. Here, we describe the biology of mIDH gliomas and review the literature regarding the emergence of mIDH inhibitors, including clinical trials in adults. Given the paucity of clinical trial data from pediatric patients with mIDH glioma, we propose guidelines for the inclusion of pediatric and AYA patients with gliomas onto prospective trials and expanded access programs as well as the potential of combined mIDH inhibition and immunotherapy in the treatment of patients with PMMRDIA at high risk of progression.

Identification of a ceRNA Network Regulating Malignant Transformation of Isocitrate Dehydrogenase Mutant Astrocytoma: An Integrated Bioinformatics Study.

Astrocytoma is the most common glioma, accounting for about 65% of glioblastoma. Its malignant transformation is also one of the important causes of patient mortality, making it the most prevalent and difficult to treat in primary brain tumours. However, little is known about the underlying mechanisms of this transformation. In this study, we established a ceRNA network to screen out the potential regulatory pathways involved in the malignant transformation of IDH-mutant astrocytomas. Firstly, the Chinese Glioma Genome Atlas (CGGA) was employed to compare the expression levels of the differential expressed genes (DEGs) in astrocytomas. Then, the ceRNA-regulated network was constructed based on the interaction of lncRNA-miRNA-mRNA. The Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore the main functions of the differentially expressed genes. COX regression analysis and log-rank test were combined to screen the ceRNA network further. In addition, quantitative real-time PCR (qRT-PCR) was conducted to identify the potential regulatory mechanisms of malignant transformation in IDH-mutant astrocytoma. We constructed a ceRNA network with 34 lncRNAs, 29 miRNAs, and 71 mRNAs. GO and KEGG analyses results suggested that DEGs were associated with tumor-associated molecular functions and pathways. In addition, we screened two ceRNA regulatory networks using Cox regression analysis and log-rank test. QRT-PCR assay identified the NAA11/hsa- miR-142-3p/GS1-39E22.2 regulatory axis of the ceRNA network to be associated with the malignant transformation of IDH-mutant astrocytoma. The discovery of this mechanism deepens our understanding of the molecular mechanisms of malignant transformation in astrocytomas and provides new perspectives for exploring glioma progression and targeted therapies.

Comprehensive exploration of isocitrate dehydrogenase (IDH) mutations: Tumorigenesis, drug discovery, and covalent inhibitor advances.

Isocitrate dehydrogenase (IDH) is an enzyme that catalyses the oxidative decarboxylation of isocitrate, producing α-ketoglutarate (α-KG) relative to the hydroxylation of substrates. However, IDH mutants can further reduce α-KG to 2-hydroxyglutarate (2-HG) which competitively inhibits α-KG dependent enzymes, leading to the downregulation of normal hydroxylation pathways. Good IDH mutant inhibitors can effectively reduce the level of 2-HG and therefore disturb cellular malignant transformation. In this review, we introduce the biological functions of IDH, describe the tumorigenesis mechanisms of IDH variants, and review the structure-based drug discovery of clinical inhibitors during 2012-2024. We also find successful applications of covalent strategy in the development of irreversible IDH inhibitors. Biological screening methods are also collected in this paper, which may help researchers to rapidly construct workflows for drug discovery and development.

Iron promotes isocitrate dehydrogenase mutant glioma cell motility

Enriched iron metabolic features such as high transferrin receptor (TfR) expression and high iron content are commonly observed in aggressive gliomas and can be associated with poor clinical responses. However, the underlying question of how iron contributes to tumor aggression remains elusive. Gliomas harboring isocitrate dehydrogenase (IDH) mutations account for a high percentage (> 70 %) of recurrent tumors and cells with an acquired IDH mutation have been reported to have increased motility and invasion. This study aims to investigate how an acquired IDH mutation modulates iron metabolism and the implication(s) of iron on tumor cell growth. IDH mutant cells (U87R132H) grow significantly faster which is accompanied with increased TfR expression and iron uptake in vitro compared to wild-type U87 cells. This phenotype is retained in vivo. Biomechanically, U87R132H cells are significantly less stiff and supplementation with ferrous ammonium sulfate (Fe2+) augments membrane fluidity to drive U87R132H cells into a super motile state. These findings provide insight into how an acquired IDH mutation may be able to modulate iron metabolism, allowing iron to serve as a biomechanical driver of tumor progression.

Correlation of microRNAs-10b/21/34a expression levels with IDH1-mutation status in patients with glioblastoma

Introduction/Objective. Isocitrate dehydrogenase mutations play a significant role in gliomagenesis. Specific microRNAs such as miR-10b/21 act as oncogenic microRNAs, while miR-34a acts as tumor suppressors in glioblastoma. Our study aimed to investigate the mutation status of IDH correlate with microRNAs-10b/21/34a expression levels in patients with glioblastoma. Methods. The study included 43 patients diagnosed with glioblastoma. We examined microRNA-10b, microRNA-21 and microRNA-34a expression levels in peripheral blood mononuclear cells after surgery and prior to concurrent radiotherapy with temozolomide, at the 15th and 30th fractions of radiotherapy with temozolomide. The data on IDH1 mutation status were gathered from medical history and histopathology. Results. Two groups were created to assess the association of microRNAs-10b/21/34a expression levels: glio-blastoma IDH1-wild type and glioblastoma IDH1-mutant + Not Other Specified (NOS). The median microRNA-10b expression level before the initiation of concurrent radiotherapy with temozolomide was 130.44 (52.20 - 622.53) in the IDH1-wildtype glioblastoma group and 94.61 (2.13 - 816.89) in the IDH1-mutant + glioblastoma NOS group. The median microRNA-21 expression level was 57.16 (2.68 - 278.98) in the IDH1-wildtype glioblastoma group and 69.74 (4.60 - 825.43) in the IDH1-mutant + glioblastoma NOS group. The median microRNA-34a expression level was 13.52 (3.16 - 105.20) in the IDH1-wildtype glioblastoma group and 10.11 (1.00 - 210.55) in the IDH1-mutant + glioblastoma NOS group. The results showed no statistically significant difference in the expression levels of miR-10b/21/34a between the two groups (p &gt; 0.05). Conclusion. Our results suggest that the IDH1 mutation status may not be a critical factor for altered expression of microRNAs-10b/21/34a in glioblastoma patients.

Oncogenic IDH1mut drives robust loss of histone acetylation and increases chromatin heterogeneity

Malignant gliomas are heterogeneous tumors, mostly incurable, arising in the central nervous system (CNS) driven by genetic, epigenetic, and metabolic aberrations. Mutations in isocitrate dehydrogenase (IDH1/2mut) enzymes are predominantly found in low-grade gliomas and secondary high-grade gliomas, with IDH1 mutations being more prevalent. Mutant-IDH1/2 confers a gain-of-function activity that favors the conversion of a-ketoglutarate (α-KG) to the oncometabolite 2-hydroxyglutarate (2-HG), resulting in an aberrant hypermethylation phenotype. Yet, the complete depiction of the epigenetic alterations in IDHmut cells has not been thoroughly explored. Here, we applied an unbiased approach, leveraging epigenetic-focused cytometry by time-of-flight (CyTOF) analysis, to systematically profile the effect of mutant-IDH1 expression on a broad panel of histone modifications at single-cell resolution. This analysis revealed extensive remodeling of chromatin patterns by mutant-IDH1, with the most prominent being deregulation of histone acetylation marks. The loss of histone acetylation occurs rapidly following mutant-IDH1 induction and affects acetylation patterns over enhancers and intergenic regions. Notably, the changes in acetylation are not predominantly driven by 2-HG, can be rescued by pharmacological inhibition of mutant-IDH1, and reversed by acetate supplementations. Furthermore, cells expressing mutant-IDH1 show higher epigenetic and transcriptional heterogeneity and upregulation of oncogenes such as KRAS and MYC, highlighting its tumorigenic potential. Our study underscores the tight interaction between chromatin and metabolism dysregulation in glioma and highlights epigenetic and oncogenic pathways affected by mutant-IDH1-driven metabolic rewiring.

Non-enhancing margin and pial invasion in MRI can predict IDH status in glioma patients.

The presence of isocitrate dehydrogenase (IDH) mutations and 1p/19q codeletion significantly influences the diagnosis and prognosis of patients with lower-grade gliomas (LGGs). The ability to predict these molecular signatures preoperatively can inform surgical strategies. This study sought to establish an interpretable imaging feature set for predicting molecular signatures and overall survival in LGGs. A cohort of 113 patients with grade 2 or 3 glioma (66 with mutated IDH and 47 with wild-type IDH) was analyzed. The feature set, chief complaints, and onset symptoms were integrated into a logistic regression model to predict IDH mutation and 1p/19q codeletion statuses. Receiver operator characteristic (ROC) and area under the curve (AUC) analyses were performed. The predictive model was externally validated using a public database from The Cancer Genome Atlas (TCGA). Smooth non-enhancing margin and pial invasion were significant predictors of IDH mutation, with odds ratio (OR) values of 3.55 (P = 0.03) and 7.89 (P = 1.0 × 10-3), respectively. Using the Visually Accessible Rembrandt Images (VASARI) feature set alone to predict IDH mutation status yielded an AUC value of 0.83, which increased to 0.85 and 0.87 when incorporating clinical information and onset symptoms for predicting IDH mutation and 1p/19q codeletion, respectively. Gliomas with IDH mutations were more likely to exhibit smooth non-enhancing margins and pial invasion. In clinical practice, imaging prediction allows for the assessment of IDH mutation to shift from a postoperative outcome to a preoperative guidance indicator, facilitating more precise treatment for patients with LGGs.

VASARI 2.0: a new updated MRI VASARI lexicon to predict grading and IDH status in brain glioma

IntroductionPrecision medicine refers to managing brain tumors according to each patient’s unique characteristics when it was realized that patients with the same type of tumor differ greatly in terms of survival, responsiveness to treatment, and toxicity of medication. Precision diagnostics can now be advanced through the establishment of imaging biomarkers, which necessitates quantitative image acquisition and processing. The VASARI (Visually AcceSAble Rembrandt Images) manual annotation methodology is an ideal and suitable way to determine the accurate association between genotype and imaging phenotype. Our work proposes an updated version of the VASARI score that is derived by changing the evaluation ranges of its components in an effort to increase the diagnostic accuracy of the VASARI manual annotation system and to find neuroimaging biomarkers in neuro-oncology with increasing reliability.Materials and methodsWe gathered the histological grade and molecular status of 126 patients with glioma (Men/Women = 75/51; mean age: 55.30) by a retrospective analysis. Two residents and three neuroradiologists blindedly examined each patient using all 25 VASARI characteristics, after having appropriately modified the reference ranges in order to implement an innovative VASARI lexicon (VASARI 2.0). It was determined how well the observers agreed. A box plot and a bar plot were used in a statistical analysis to assess the distribution of the observations. After that, we ran a Wald test and univariate and multivariate logistic regressions. To find cutoff values that are predictive of a diagnosis, we also computed the odds ratios, confidence intervals, and evaluation matrices using receiver operating characteristic curves for each variable. Finally, we performed a Pearson correlation test to evaluate whether the variable grades and IDH were correlated.ResultsAn excellent Intraclass Correlation Coefficient (ICC) estimate was obtained. In this study, five features were part of the predictive model for determining glioma grade: F4, enhancement quality [area under the curve (AUC): 0.87]; F5, tumor-enhancing proportion (AUC: 0.70); F6, tumor–non-enhancing proportion (AUC: 0.89); F7, necrosis proportion (AUC: 0.79); and F17, diffusion characteristics (AUC: 0.75). Furthermore, six features were found to predict IDH mutation status: F4, enhancement quality (AUC: 0.904); F5, tumor-enhancing proportion (AUC: 0.73); F6, tumor–non-enhancing proportion (AUC: 0.91); F7, necrosis proportion (AUC: 0.84); F14, proportion of edema (AUC: 0.75); and diffusion characteristics F17 (AUC: 0.79). VASARI 2.0 models showed good performances according to the AUC values, which are also compared with traditional VASARI scores.Discussion and conclusionGlioma grade and isocitrate dehydrogenase (IDH) status can be predicted using specific magnetic resonance imaging (MRI) features, which have significant prognostic consequences. The accuracy of texture-derived metrics from preoperative MRI gliomas and machine learning analysis for predicting grade, IDH status, and their correlation can be enhanced by the suggested new and updated VASARI manual annotation system. To help with therapy selection and enhance patient care, we intend to create prediction models that incorporate these MRI findings with additional clinical data.

Advancing the outcomes of AML out of antecedent MPN by targeting mutated IDH1.

Outcomes of myeloproliferative neoplasms (MPN)-associated acute leukaemias are dismal with conventional therapy. Approximately 20% of MPN-associated acute leukaemias have mutations in isocitrate dehydrogenase (IDH). Olutasidenib, and inhibitor of IDH1, demonstrates important clinical benefits in MPN-associated leukaemia with IDH1 mutation. Commentary on: Botton etal. Olutasidenib demonstrates significant clinical activity in mutated IDH1 acute myeloid leukemia arising from a prior myeloproliferative neoplasm. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19944.

A qBOLD-based clinical radiomics-integrated model for predicting isocitrate dehydrogenase-1 mutation in gliomas.

Quantitative blood oxygenation level-dependent (qBOLD) technique can be applied to detect tissue damage and changes in hemodynamic in gliomas. It is not known whether qBOLD-based radiomics approaches can improve the prediction of isocitrate dehydrogenase-1 (IDH-1) mutation. To establish a qBOLD-based clinical radiomics-integrated model for predicting IDH-1 mutation in gliomas. A total of 125 patients of grade II-IV glioma (IDH1 mutation: IDH1 wild-type=50:75) were divided into a training group (n=87) and a validation group (n=38). Contrast enhanced T1-weighted (CE-T1W), T2-weighted (T2W), and 3D multi-gradient-recalled-echo (MGRE) images were acquired. Radiomics features were extracted from the region of interests of each image. The feature selection and support vector machine radiomics models were established for each sequence. A clinical radiomics-integrated model was finally constructed combining the best radiomics model with age. The predictive effectiveness of the models was evaluated by area under the receiver operating characteristic curve (AUC). Brier score was used to assess overall predictive performance. Decision curve analysis and calibration curve were also conducted. The best radiomics model was CE-T1W + T2W + qBOLD with AUCs of 0.823 (95% confidence interval [CI]: 0.743-0.831) in the training group and 0.751 (95% CI: 0.655-0.794) in the validation group, respectively. The clinical radiomics-integrated model, incorporating the best radiomics model with age, showed the best predictive effectiveness with AUCs of 0.851 (95% CI 0.759-0.918) in the training group and 0.786 (95% CI 0.622-0.902) in the validation group. A clinical radiomics-integrated model that combined qBOLD parametric maps, CE-T1W, and T2W images with age achieved promising performance for predicting IDH1 mutation in glioma patients.

Oligoastrocytoma: The Vanishing Entity With True Dual Genotype, a Report, its Molecular Profiles and Review of Literature.

Isocitrate dehydrogenase (IDH) mutant gliomas are classified as astrocytoma or oligodendroglioma based on the recent application of ATRX mutation, TP53 mutation, and 1p/19q co-deletion. Astrocytomas classically show ATRX and TP53 mutations, whereas oligodendrogliomas are defined by 1p/19q co-deletion. However, there are reports of gliomas that harbor both astrocytoma and oligodendroglioma morphologically and molecularly. Here we present a patient of a 29-year-old woman who presented with a headache and underwent gross total excision. Magnetic resonance imaging showed a right frontal space-occupying lesion with T2 fluid-attenuated inversion recovery mismatch. Histology showed 2 distinct areas of morphology compatible with oligodendroglioma and astrocytoma. Immunohistochemistry showed both components being positive for IDH R132H. Alpha thalassemia/mental retardation syndrome X-linked (ATRX) showed loss of nuclear expression and p53 was strongly positive in the morphologic astrocytoma component, whereas ATRX was retained and p53 was negative in the morphologic oligodendroglioma component. Fluorescence in situ hybridization showed 1p/19q co-deletion in the oligodendroglioma component while co-deletion was absent in the astrocytoma component. TERT mutation was present in the oligodendroglioma component, whereas it was absent in the astrocytoma component. Although rare, gliomas harboring both oligodendroglioma and astrocytoma components in a single tumor exist and show genetically distinct areas.

Clinical Value of 18 F-(2S,4R)-4-Fluoroglutamine PET/CT in Glioma.

The aim of this study was to evaluate the clinical application value of 18 F-FGln PET/CT in glioma. Patients with suspected gliomas by MRI were included in this study. Static and/or dynamic brain 18 F-FGln PET/CT was performed. The PET parameters SUV max , SUV mean , MTV, and TLG were evaluated. Twenty-three patients were included in the analysis. Nineteen of 23 patients were positive for 18 F-FGln PET. The SUV max of high- and low-grade gliomas were 4.75 ± 2.21 and 1.00 ± 0.66 ( P < 0.001), respectively. FGln-PET SUV max , SUV mean , and TLG all showed statistically significant correlations with glioma grade, with correlation coefficients ( r ) of 0.667 ( P < 0.001), 0.693 ( P < 0.001), and 0.487 ( P = 0.021), respectively. Additionally, the SUV max , SUV mean , and TLG exhibited higher distinguishing performance for glioma grade by receiver operating characteristic curve analysis. The areas under the receiver operating characteristic curve of SUV max , SUV mean , and TLG were 0.976 (95% confidence interval [CI], 0.918-1) ( P = 0.002), 0.976 (95% CI, 0.918-1) ( P = 0.002), and 0.835 (95% CI, 0.628-1.000) ( P = 0.026), respectively. For glioma isocitrate dehydrogenase (IDH) mutation status, the SUV max of IDH wildtype and mutant glioma were 2.95 ± 1.99 and 6.13 ± 2.16 ( P = 0.005), respectively. The SUV mean and SUV max had good-to-satisfactory performance for IDH status with the area under the receiver operating characteristic curve of SUV max and SUV mean of 0.885 (95% CI, 0.734-1.000) ( P = 0.009) and 0.942 (95% CI, 0.828-1) ( P = 0.002). Although we do not assert that 18 F-FGln PET/CT imaging is satisfactory in the differential diagnosis of glioma, we revealed its potential for identifying the stage of gliomas and the IDH mutation status and propose that glutamine-based PET imaging enables the assessment of metabolic nutrient uptake of gliomas to assist clinical diagnosis and treatment of patients.

Epigenetic Therapies.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the "histone code" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.

Acute myeloid leukemia treatment outcomes with isocitrate dehydrogenase mutations: A systematic review and meta-analysis.

Isocitrate dehydrogenase (IDH) gene alterations and acute myeloid leukemia (AML) treatment results remain controversial. This study reviews the literature on IDH mutations in AML to determine the foundation of individualized therapy and improve effectiveness, survival time, and recurrence rate. Seven English and 2 Chinese databases were searched for literature on IDH mutations and AML outcomes. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated. Twenty studies were included in this analysis. For the prognostic influence of IDH mutation on AML patients, the pooled HRs of overall survival in AML patients were 0.76 (95% CI, 0.63-0.93); the pooled HRs of event-free survival were 1.34 (95% CI, 1.15-1.57; heterogeneity: I2 = 52.2%, P = .027 < 0.05); the pooled HRs of recurrence free survival were 0.79 (95% CI, 0.61-1.02). The pooled HRs of overall survival in AML patients with mutant IDH1 were 1.62 (95% CI, 1.42-1.86) and of mutant IDH2 were 1.07 (95% CI, 0.89-1.29). The pooled HRs for event-free survival in AML patients with mutant IDH1 were 1.71 (95% CI, 1.40-2.08) and of mutant IDH2 were 0.93 (95% CI, 0.65-1.34). No evidence of publication bias was observed. Different subtypes of IDH mutations may lead to different AML prognoses, suggesting the feasibility of personalized treatment for AML patients.

Prevalence of SPOP and IDH Gene Mutations in Prostate Cancer in a Jordanian Population.

Speckle-type POZ (SPOP) is described as an essential tumor suppressor factor in gastric cancer, colorectal cancer, and prostate cancer (PCa). SPOP gene mutations were reported in primary human PCa. Isocitrate dehydrogenase-1 (IDH1) oncogene mutations were detected in gliomas, acute myeloid leukemia, some benign and malignant cartilaginous tumors, and only 1% of PCa. This study aimed to investigate the prevalence of mutations of SPOP and IDH1 genes in PCa in the Jordanian population. One hundred formalin-fixed paraffin-embedded tissue samples were collected from patients diagnosed with prostate adenocarcinoma. The obtained specimens were subjected to genomic DNA extraction, PCR amplification, and direct sequencing of exons 4, 5, 6, and 7 of the SPOP gene and exon 6 of the IDH1 gene. SPOP gene mutations were found in 17% of PCa cases, while no mutation was detected in the screened exon 6 of the IDH1 gene. Clinicopathological data demonstrated a strong correlation between prostate-specific antigen (PSA) levels and both Gleason score (GS) and the International Society of Urological Pathology (ISUP) grade group (GG). There was no significant correlation between PSA levels and age (p = 0.816) nor there were significant associations for SPOP mutational status with age (p = 0.659), PSA levels (p = 0.395), GS (p = 0.259), and ISUP GG (p = 0.424) in the tested population. The study found a strong correlation between PSA levels and both GS and ISUP GG. It also identified a high frequency (17%) of SPOP gene mutations in Jordanian Arab PCa patients, mainly in exon 7. No IDH1 mutations were detected in exon 6.

Role of the tumor board when prescribing mutant isocitrate dehydrogenase inhibitors to patients with isocitrate dehydrogenase-mutant glioma.

Isocitrate dehydrogenase (IDH)-mutant gliomas, comprising both astrocytomas and oligodendrogliomas, represent a distinct group of tumors that pose an interdisciplinary challenge. Addressing the needs of affected patients requires close collaboration among various disciplines, including neuropathology, neuroradiology, neurosurgery, radiation oncology, neurology, medical oncology, and other relevant specialties when necessary. Interdisciplinary tumor boards are central in determining the ideal diagnostic and therapeutic strategies for these patients. The key tasks of a tumor board include the evaluation of imaging findings, selecting the appropriate surgical approach, discussing additional treatment options, and identification/determination of tumor recurrence and progression. In addition to established treatments such as radiotherapy and alkylating chemotherapy, patients with an isocitrate dehydrogenase (IDH)-mutant glioma for whom additional treatment is indicated may now also have the option of receiving treatment with an mutant isocitrate dehydrogenase inhibitor such as vorasidenib or ivosidenib. In this regard, the collaborative nature of tumor boards becomes even more crucial for evaluating comprehensively the needs of these patients. Through interdisciplinary discussions, tumor boards aim to develop personalized treatment strategies that maximize therapeutic efficacy while minimizing potential side effects and preserving patients' quality of life.