Association of preoperative seizures with reduced expression of soluble CD163, an M2 macrophage marker, in the cerebrospinal fluid in isocitrate dehydrogenase wild-type glioblastoma.

PURPOSE: To investigate the relationship between the tumor microenvironment (TME), tumor-related seizures (TRS), and cerebrospinal fluid (CSF) markers that predict preoperative seizures in patients with glioblastoma. METHODS: In total, 47 patients with isocitrate dehydrogenase (IDH) wild-type glioblastoma who underwent preoperative CSF examination, 3-T magnetic resonance spectroscopy (MRS), and neurological surgery between January 2017 and December 2023 were included. We measured the concentrations of soluble CD163 (sCD163), a soluble form of the M2 macrophage marker, in the CSF, the metabolite concentration on MRS, and the number of CD163-positive M2 macrophages in the tumor tissue. Factors associated with preoperative seizures were examined. RESULTS: Twelve patients (25.5%) had preoperative seizures. sCD163 levels in the CSF were positively correlated with the number of CD163-positive M2 macrophages in the tumor tissue, and both were significantly lower in the preoperative seizure group than in the non-preoperative seizure group (p = 0.0124 and p < 0.0001, respectively). MRS indicated that only glutathione (GSH) concentrations were higher in the preoperative seizure group than in the non-preoperative seizure group (2.55 mM and 1.87 mM, respectively; p = 0.0171). CD163-positive M2 macrophages were inversely correlated with GSH levels. sCD163 in the CSF had a high predictive accuracy (sensitivity, 91.7%; specificity, 54.3%; and area under the receiver operator curve, 0.745) for preoperative seizures. CONCLUSIONS: The CSF level of sCD163 is useful for predicting the TME and preoperative seizures in IDH wild-type glioblastoma.

Targeted therapies for myelodysplastic Syndromes/Neoplasms (MDS): current landscape and future directions.

INTRODUCTION: Myelodysplastic syndromes/neoplasms (MDS) are a heterogeneous group of hematologic malignancies that are stratified into high-risk (HR-MDS) and low-risk (LR-MDS) categories. Until recently LR-MDS has been typically managed by supportive measures and erythropoiesis-stimulating agents (ESAs); whereas, management of HR-MDS, typically included hypomethylating agents and allogeneic hematopoietic stem cell transplant. However, the limited rates and duration of response observed with these interventions prompted the search for targeted therapies to improve the outcomes among patients with MDS. AREAS COVERED: Here we review the current landscape of targeted therapies in MDS. These include pyruvate kinase and hypoxia-inducible factor (HIF) activators; TGF-beta, telomerase, BCL2 and isocitrate dehydrogenase (IDH) inhibitors; as well as novel approaches targeting inflammation, pyroptosis, immune evasion and RNA splicing machinery. EXPERT OPINION: This review highlights the progress and challenges in MDS treatment. Despite some promising results, many therapies remain in early development or have faced setbacks, emphasizing the need for a more comprehensive understanding of the disease's pathobiology. Continued research into targeted therapies, homogenous clinical trial designs, as well as increased incorporation of molecular prognostic tools and artificial intelligence into trial design are essential for developing effective treatments for MDS and improving patient outcomes.

Clinicopathological and radiological characteristics of false-positive and false-negative results in T2-FLAIR mismatch sign of IDH-mutated gliomas.

PURPOSE: To explore the clinicopathological and radiological characteristics associated with false-positive and false-negative results in the identification of isocitrate dehydrogenase (IDH) mutations in gliomas using the T2-fluid-attenuated inversion recovery (FLAIR) mismatch sign. METHODS: In 1515 patients with cerebral gliomas, tumor location, restricted diffusion using diffusion-weighted imaging, and the T2-FLAIR mismatch sign were retrospectively analyzed using preoperative magnetic resonance imaging. Moreover, both the false-positive and false-negative results of the T2-FLAIR mismatch sign were obtained. Univariate and multivariate logistic analyses were performed to evaluate the risk factors associated with false-positive and false-negative results. RESULTS: The overall false-positive rate was 3.5 % (53/1515), and its independent risk factors were the patient's age (adjusted odds ratio [OR], 0.977; 95 % confidence interval [CI], 0.957, 0.997; P = 0.027) and non-restricted diffusion (adjusted OR, 1.968; 95 % CI, 1.060, 3.652; P = 0.032). The overall false-negative rate was 39.7 % (602/1515); its independent risk factors were the patient's age (adjusted OR, 1.022; 95 % CI, 1.005, 1.038; P = 0.008), 1p/19q co-deletion (adjusted OR, 3.334; 95 % CI, 1.913, 5.810; P < 0.001), and telomerase reverse transcriptase promoter mutation (adjusted OR, 2.004; 95 % CI, 1.181, 3.402; P = 0.010). For the mismatch sign in idiopathic IDH, the area under the receiver operating characteristic curve (AUC) was 0.602. The combined AUC for the T2-FLAIR mismatch sign and risk factors was 0.871. CONCLUSIONS: Clinicopathological and radiological characteristics can lead to the misinterpretation of IDH status in gliomas based on the T2-FLAIR mismatch sign. However, this can be avoided if careful attention is paid.

Spectrum of Findings Seen in Patients With IDH1/2-Mutant Cholangiocarcinoma.

BACKGROUND: Cholangiocarcinoma-with a growing incidence rate and poor prognosis-is not an aggressive tumor that is not uncommon. Molecular profiling can reveal actionable aberrations in at least a third of the tumors. This is especially so in the case of intrahepatic cholangiocarcinoma (ICC), where mutations in the isocitrate dehydrogenase 1 and 2 genes (IDH1/2) make up 15%-20% of these tumors. IDH1/2 mutant ICC is a rare disease that has not been adequately reported. To expand the spectrum of findings seen in these patients, we present a single institution case series. METHODS AND RESULTS: We descriptively characterize the clinical, radiological, and histopathological findings of 12 such patients. IDH1/2 mutant ICC was found in elderly women, with two-thirds of patients having additional co-mutations. Anecdotally, patients who did receive systemic and/or locoregional therapies had long-term durable outcomes. CONCLUSION: Our findings indicate an increasing need to personalize an approach for these patients with specific molecular alterations. With the advent of the IDH1 inhibitor ivosidenib and other inhibitors in this space, IDH1/2 mutation has both prognostic and predictive value. Our series builds upon the patterns and findings seen in these patients.

Advancements in Phytosomal Therapies for Liver Cancer: A Comprehensive Review.

Phytosomes, innovative lipid-compatible complexes formed by combining natural phospholipids with water-soluble phytoconstituents, represent a groundbreaking technology in herbal medicine. This review examines the novel applications of phytosomes in liver cancer treatment. Phytosome technology overcomes traditional obstacles in utilizing herbal potential for modern medicine, such as issues with potency, solubility, permeability, and stability, which has led to increased interest in herbal drug sources. By enhancing the bioavailability and bioefficacy of polyphenolic phytoconstituents, particularly those with anti-angiogenic properties critical for tumor growth and embryonic nourishment, phytosome technology addresses these challenges. The complexity of liver cancer, including both cholangiocarcinoma and hepatocellular carcinoma, demands comprehensive medical management. Although natural compounds like resveratrol, curcumin, and silymarin show promise with their anticancer effects, their full efficacy in human trials is not yet confirmed. Phytosomal preparations, which incorporate these compounds into lipid complexes, offer a potential solution for improved bioavailability and absorption. This review thoroughly explores the application of phytosome technology in herbal medicine, highlighting its potential role in tackling the complexities of liver cancer treatment. As research advances, phytosomes are expected to be a valuable addition to the evolving field of natural product-based therapeutic formulations.

IDH2 regulates macrophage polarization and tumorigenesis by modulating mitochondrial metabolism in macrophages.

BACKGROUND: Targeting the tumor microenvironment represents an emerging therapeutic strategy for cancer. Macrophages are an essential part of the tumor microenvironment. Macrophage polarization is modulated by mitochondrial metabolism, including oxidative phosphorylation (OXPHOS), the tricarboxylic acid (TCA) cycle, and reactive oxygen species content. Isocitrate dehydrogenase 2 (IDH2), an enzyme involved in the TCA cycle, reportedly promotes cancer progression. However, the mechanisms through which IDH2 influences macrophage polarization and modulates tumor growth remain unknown. METHODS: In this study, IDH2-deficient knockout (KO) mice and primary cultured bone marrow-derived macrophages (BMDMs) were used. Both in vivo subcutaneous tumor experiments and in vitro co-culture experiments were performed, and samples were collected for analysis. Western blotting, RNA quantitative analysis, immunohistochemistry, and flow cytometry were employed to confirm changes in mitochondrial function and the resulting polarization of macrophages exposed to the tumor microenvironment. To analyze the effect on tumor cells, subcutaneous tumor size was measured, and growth and metastasis markers were identified. RESULTS: IDH2-deficient macrophages co-cultured with cancer cells were found to possess increased mitochondrial dysfunction and fission than wild-type BMDM. Additionally, the levels of M2-associated markers decreased, whereas M1-associated factor levels increased in IDH2-deficient macrophages. IDH2-deficient macrophages were predominantly M1. Tumor sizes in the IDH2-deficient mouse group were significantly smaller than in the wild-type mouse group. IDH2 deficiency in macrophages was associated with inhibited tumor growth and epithelial-mesenchymal transition. CONCLUSIONS: Our findings suggest that IDH2 deficiency inhibits M2 macrophage polarization and suppresses tumorigenesis. This study underlines the potential contribution of IDH2 expression in macrophages and tumor microenvironment remodeling, which could be useful in clinical cancer research.

Deciphering the multifaceted roles and clinical implications of 2-hydroxyglutarate in cancer.

Increasing evidence indicates that 2-hydroxyglutarate (2HG) is an oncometabolite that drives tumour formation and progression. Due to mutations in isocitrate dehydrogenase (IDH) and the dysregulation of other enzymes, 2HG accumulates significantly in tumour cells. Due to its structural similarity to α-ketoglutarate (αKG), accumulated 2HG leads to the competitive inhibition of αKG-dependent dioxygenases (αKGDs), such as KDMs, TETs, and EGLNs. This inhibition results in epigenetic alterations in both tumour cells and the tumour microenvironment. This review comprehensively discusses the metabolic pathways of 2HG and the subsequent pathways influenced by elevated 2HG levels. We will delve into the molecular mechanisms by which 2HG exerts its oncogenic effects, particularly focusing on epigenetic modifications. This review will also explore the various methods available for the detection of 2HG, emphasising both current techniques and emerging technologies. Furthermore, 2HG shows promise as a biomarker for clinical diagnosis and treatment. By integrating these perspectives, this review aims to provide a comprehensive overview of the current understanding of 2HG in cancer biology, highlight the importance of ongoing research, and discuss future directions for translating these findings into clinical applications.

AB019. Detailed analysis of DNA hydroxymethylation observed with the malignant progression of IDH-mutant gliomas.

BACKGROUND: Gliomas vary in prognosis with World Health Organization (WHO) grade. Low-grade gliomas can undergo malignant progression (MP), becoming aggressive high-grade tumors, worsening prognosis. This is prevalent in isocitrate dehydrogenase-mutant (IDH-mt) gliomas like astrocytoma and oligodendroglioma, but the mechanism of MP is still not fully understood. High-grade IDH-mt gliomas have been reported to exhibit TET-mediated DNA hydroxymethylation, which is suggested to potentially influence gene expression. We hypothesized that hydroxymethylation in specific regions could be implicated in triggering MP. METHODS: We collected glioma tumor samples over a decade, using WHO 2021 classification to study IDH-mt astrocytoma grade 2 progression to grades 3 or 4, indicating MP. Samples from five patients, demonstrating MP, were analyzed for DNA hydroxymethylation status across more than 850,000 genomic locations using the oxidative bisulfite process and Infinium EPIC methylation array. This was complemented by RNA sequencing for gene expression analysis and its correlation with hydroxymethylation, and motif-enrichment analysis to infer transcription factor involvement in hydroxymethylation-based gene regulation. Additionally, to delve into the fundamental causes of hydroxymethylation, we exposed an IDH-mt glioma cell line to hypoxic conditions and systematically explored the genomic locations where hydroxymethylation occurred. RESULTS: Our comprehensive analysis identified a significant overlap of hydroxymethylated genomic regions across samples during MP, with a notable enrichment in open sea and intergenic regions (P<0.001). These regions were significantly associated with cancer-related signalling pathways. Integration with RNA sequencing data revealed 91 genes with significant correlations between hydroxymethylation and gene expression, implying roles in cell cycle regulation and antineoplastic functions. Furthermore, motif-enrichment analysis suggested the potential regulatory role of KLF4 in these processes. The cell culture results revealed that a certain similarity exists between the hydroxymethylation patterns observed during MP and those in glioma cells cultured under hypoxic conditions. CONCLUSIONS: This study elucidates the importance of region-specific DNA hydroxymethylation in the MP of IDH-mt astrocytomas, suggesting its potential impact on gene expression relevant to cancer malignancy. Our findings propose a complex interplay between hydroxymethylation and gene regulation, which may offer new insights into the mechanisms driving glioma progression and highlight potential targets for therapeutic intervention.

AB066. From imaging to molecular diagnosis: VASARI magnetic resonance imaging features to predict isocitrate dehydrogenase mutation status in glioma.

BACKGROUND: Glioma, the most common brain tumor, poses significant challenges in patient care and economic burden. Clinicians often struggle with management strategies, especially under the 2021 World Health Organization (WHO) central nervous system (CNS) classification emphasizing molecular diagnosis. Isocitrate dehydrogenase (IDH) mutation status is crucial in glioma management. However, many facilities lack the capability for comprehensive molecular tests, and not all patients are candidates for invasive biopsies. MRI offers a non-invasive method to evaluate glioma characteristics. The Visually Accessible Rembrandt Images (VASARI) MRI feature set provides a systematic approach to analyzing brain glioma. This study examines the association of VASARI features with IDH mutation status and their predictive capability. METHODS: This study included 105 glioma patients treated between 2017 and 2022 who had not undergone surgery, chemotherapy, or radiotherapy. Brain MRIs were assessed using VASARI MRI features by two blinded radiologists. Pathological and molecular examinations were conducted per the 2021 WHO CNS tumor classification. IDH mutations were assessed using polymerase chain reaction (PCR) followed by DNA sequencing. Chi-squared analysis identified VASARI features significantly associated with IDH mutation status. A random forest model predicted IDH mutation status using these features. RESULTS: Brain MRI assessments using VASARI terminology showed good inter-observer agreement (kappa =0.714-0.831) and excellent intra-observer agreement (kappa =0.910). Thirteen VASARI features were significantly associated with IDH mutation status. The prediction model based on VASARI MRI features achieved an area under the curve (AUC) of 0.97, with 93.75% sensitivity, 75% specificity, and 84.38% accuracy on test data. CONCLUSIONS: The VASARI MRI feature set is a reliable method for evaluating glioma patients and is feasible for routine radiological practice. Several VASARI features significantly associate with IDH mutation status, aiding glioma patient management. The IDH mutation prediction model based on VASARI features performs excellently and warrants further validation before routine implementation.

Therapeutic inhibition of isocitrate dehydrogenase mutations in glioma and cholangiocarcinoma: new insights and promises-a narrative review.

BACKGROUND AND OBJECTIVE: The identification of mutation hot spots in the isocitrate dehydrogenase (IDH) genes is one of the most important cancer genome-wide sequencing discoveries with relevant impact in the treatment of some orphan tumors. These genes were mostly found mutated in lower-grade gliomas (LGGs), acute myeloid leukaemia (AML), myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPNs) and in cholangiocarcinoma. This aberrant genomic condition represents a therapeutic target of great interest in cancer research, especially in AML, given the limitations of currently approved therapies in this field. In this review, we investigate the role of IDH mutation and the mutant IDH (mIDH)- targeted therapies for cholangiocarcinoma and glioma. METHODS: Here, we provide an overview of the IDH mutation role and discuss its role in tumorigenesis and progression of some solid cancers, in which the therapeutic strategy can be completely changed thanks to these brand-new therapeutic options. KEY CONTENT AND FINDINGS: The encouraging early clinical data demonstrated to be a proof of concept for investigational mIDH1/2 inhibitors in tumors with a paucity of therapeutic possibilities. CONCLUSIONS: Moreover, we list the most important randomised clinical trials still active with their preliminary results.

Contrast-Enhanced Computed Tomography-Based Machine Learning Radiomics Predicts IDH1 Expression and Clinical Prognosis in Head and Neck Squamous Cell Carcinoma.

RATIONALE AND OBJECTIVES: Isocitrate dehydrogenase 1 (IDH1) is a potential therapeutic target across various tumor types. Here, we aimed to devise a radiomic model capable of predicting the IDH1 expression levels in patients with head and neck squamous cell carcinoma (HNSCC) and examined its prognostic significance. MATERIALS AND METHODS: We utilized genomic data, clinicopathological features, and contrast-enhanced computed tomography (CECT) images from The Cancer Genome Atlas and the Cancer Imaging Archive for prognosis analysis and radiomic model construction. The selection of optimal features was conducted using the intraclass correlation coefficient, minimum redundancy maximum relevance, and recursive feature elimination algorithms. A radiomic model for IDH1 prediction and radiomic score (RS) were established using a gradient-boosting machine. Associations between IDH1 expression, RS, clinicopathological variables, and overall survival (OS) were determined using univariate and multivariate Cox proportional hazards regression analyses and Kaplan-Meier curves. RESULTS: IDH1 emerged as a distinct predictive factor in patients with HNSCC (hazard ratio [HR] 1.535, 95% confidence interval [CI]: 1.117-2.11, P = 0.008). The radiomic model, built on eight optimal features, demonstrated area under the curve values of 0.848 and 0.779 in the training and validation sets, respectively, for predicting IDH1 expression levels. Calibration and decision curve analyses validated the model's suitability and clinical utility. RS was significantly associated with OS (HR=2.22, 95% CI: 1.026-4.805, P = 0.043). CONCLUSION: IDH1 expression is a significant prognostic marker. The developed radiomic model, derived from CECT features, offers a promising approach for diagnosing and prognosticating HNSCC.

Predictive machine learning models based on VASARI features for WHO grading, isocitrate dehydrogenase mutation, and 1p19q co-deletion status: a multicenter study.

The objective of our study was to develop predictive models using Visually Accessible Rembrandt Images (VASARI) magnetic resonance imaging (MRI) features combined with machine learning techniques to predict the World Health Organization (WHO) grade, isocitrate dehydrogenase (IDH) mutation status, and 1p19q co-deletion status of high-grade gliomas. To achieve this, we retrospectively included 485 patients with high-grade glioma from the First Affiliated Hospital of Xinjiang Medical University, of which 312 patients were randomly divided into a training set (n=218) and a test set (n=94) in a 7:3 ratio. Twenty-five VASARI MRI features were selected from an initial set of 30, and three machine learning models - Multilayer Perceptron (MP), Bernoulli Naive Bayes (BNB), and Logistic Regression (LR) - were trained using the training set. The most informative features were identified using recursive feature elimination. Model performance was assessed using the test set and an independent validation set of 173 patients from Beijing Tiantan Hospital. The results indicated that the MP model exhibited the highest predictive accuracy on the training set, achieving an area under the curve (AUC) close to 1, indicating perfect discrimination. However, its performance decreased in the test and validation sets; particularly for predicting the 1p19q co-deletion status, the AUC was only 0.703, suggesting potential overfitting. On the other hand, the BNB model demonstrated robust generalization on the test and validation sets, with AUC values of 0.8292 and 0.8106, respectively, for predicting IDH mutation status and 1p19q co-deletion status, indicating high accuracy, sensitivity, and specificity. The LR model also showed good performance with AUCs of 0.7845 and 0.8674 on the test and validation sets, respectively, for predicting IDH mutation status, although it was slightly inferior to the BNB model for the 1p19q co-deletion status. In conclusion, integrating VASARI MRI features with machine learning techniques shows promise for the non-invasive prediction of glioma molecular markers, which could guide treatment strategies and improve prognosis in glioma patients. Nonetheless, further model optimization and validation are necessary to enhance its clinical utility.

Evaluation of glial tumors: correlation between magnetic resonance imaging and histopathological analysis.

Objective: To determine the correlation of conventional and diffusion-weighted imaging findings on magnetic resonance imaging (MRI) of the brain, based on Visually AcceSAble Rembrandt Images (VASARI) criteria, with the histopathological grading of gliomas: low-grade or high-grade. Materials and Methods: Preoperative MRI scans of 178 patients with brain gliomas and pathological confirmation were rated by two neuroradiologists for tumor size, location, and tumor morphology, using a standardized imaging feature set based on the VASARI criteria. Results: In the univariate analysis, more than half of the MRI characteristics evaluated showed a significant association with the tumor grade. The characteristics most significantly associated with the tumor grade were hemorrhage; restricted diffusion; pial invasion; enhancement; and a non-contrast-enhancing tumor crossing the midline. In a multivariable regression model, the presence of enhancement and hemorrhage maintained a significant association with high tumor grade. The absence of contrast enhancement and restricted diffusion were associated with the presence of an isocitrate dehydrogenase gene mutation. Conclusion: Our data illustrate that VASARI MRI features, especially intratumoral hemorrhage, contrast enhancement, and multicentricity, correlate strongly with glial tumor grade.

Objetivo: Determinar a correlação dos achados de imagem convencional e de difusão na ressonância magnética (RM) do encéfalo, com base nos critérios Visually AcceSAble Rembrandt Images (VASARI), com a classificação histopatológica de gliomas: gliomas de baixo grau e gliomas de alto grau. Materiais e Métodos: Imagens de RM pré-cirúrgicas de 178 pacientes com gliomas cerebrais e confirmação patológica foram avaliadas por dois neurorradiologistas quanto ao tamanho, localização e morfologia do tumor usando um padrão de imagem baseado nos critérios VASARI. Resultados: Na análise univariada, mais da metade das características avaliadas apresentou associação significativa com o grau do tumor. Hemorragia, restrição à difusão, invasão pial, realce e tumor sem realce cruzando a linha média foram as características com associação mais significativa. No modelo de regressão multivariada, a presença de realce e hemorragia manteve associação significativa com tumores de alto grau. A ausência de realce pelo meio de contraste e a restrição da difusão foram associados à presença da mutação do gene isocitrato desidrogenase. Conclusão: Nossos dados ilustram que as características de RM do VASARI, especialmente hemorragia intratumoral, presença de realce de contraste e multicentricidade, forneceram uma correlação importante com o grau da neoplasia glial.

Clinical utility of plasma cell-free DNA (cfDNA) in diffuse gliomas for the detection of IDH1 R132H mutation.

Liquid biopsy for CNS tumors is in its nascent phase, hindered by the low levels of circulating tumor DNA (ctDNA). Overcoming this challenge requires highly sensitive molecular techniques. DD-PCR emerges as a standout technique due to its ability to identify rare mutations, copy number variations, and circulating nucleic acids, making it one of the best methods for identifying somatic mutations in cell-free DNA (cfDNA). Despite promising results from various studies demonstrating the feasibility of obtaining informative ctDNA profiles from liquid biopsy samples, challenges persist, including the need to standardize sample collection, storage, and processing methods, define clear assay positivity thresholds, and address the overall low assay sensitivity. Our two-phase study began by assessing DD-PCR efficacy in FFPE tissues, revealing robust concordance with immunohistochemistry. In Phase 1 (85 cases), DD-PCR on FFPE tissues demonstrated 100 % sensitivity and specificity for IDH1 R132H mutations. In Phase 2 (100 cases), analysis extended to cfDNA, maintaining high specificity (100 %) with moderate sensitivity (44.2 %). Overall concordance with immunohistochemistry was 61 %, highlighting liquid biopsy's potential in glioma management. The findings emphasized DD-PCR's clinical utility in both tissue and liquid biopsy, underscoring its role in early detection, diagnosis, and therapeutic monitoring of diffuse gliomas.

Tricarboxylic Acid Cycle Relationships with Non-Metabolic Processes: A Short Story with DNA Repair and Its Consequences on Cancer Therapy Resistance.

Metabolic changes involving the tricarboxylic acid (TCA) cycle have been linked to different non-metabolic cell processes. Among them, apart from cancer and immunity, emerges the DNA damage response (DDR) and specifically DNA damage repair. The oncometabolites succinate, fumarate and 2-hydroxyglutarate (2HG) increase reactive oxygen species levels and create pseudohypoxia conditions that induce DNA damage and/or inhibit DNA repair. Additionally, by influencing DDR modulation, they establish direct relationships with DNA repair on at least four different pathways. The AlkB pathway deals with the removal of N-alkylation DNA and RNA damage that is inhibited by fumarate and 2HG. The MGMT pathway acts in the removal of O-alkylation DNA damage, and it is inhibited by the silencing of the MGMT gene promoter by 2HG and succinate. The other two pathways deal with the repair of double-strand breaks (DSBs) but with opposite effects: the FH pathway, which uses fumarate to help with the repair of this damage, and the chromatin remodeling pathway, in which oncometabolites inhibit its repair by impairing the homologous recombination repair (HRR) system. Since oncometabolites inhibit DNA repair, their removal from tumor cells will not always generate a positive response in cancer therapy. In fact, their presence contributes to longer survival and/or sensitization against tumor therapy in some cancer patients.

The effects of BMP2 and the mechanisms involved in the invasion and angiogenesis of IDH1 mutant glioma cells.

PURPOSE: This study investigated the effect of an isocitrate dehydrogenase 1 (IDH1) mutation (mutIDH1) on the invasion and angiogenesis of human glioma cells. METHODS: Doxycycline was used to induce the expression of mutIDH1 in glioma cells. Transwell and wound healing assays were conducted to assess glioma cell migration and invasion. Western blotting and cell immunofluorescence were used to measure the expression levels of various proteins. The influence of bone morphogenetic protein 2 (BMP2) on invasion, angiogenesis-related factors, BMP2-related receptor expression, and changes in Smad signaling pathway-related proteins were evaluated after treatment with BMP2. Differential gene expression and reference transcription analysis were performed. RESULTS: Successful infection with recombinant lentivirus expressing mutIDH1 was demonstrated. The IDH1 mutation promoted glioma cell migration and invasion while positively regulating the expression of vascularization-related factors and BMP2-related receptors. BMP2 exhibited a positive regulatory effect on the migration, invasion, and angiogenesis of mutIDH1-glioma cells, possibly mediated by BMP2-induced alterations in Smad signaling pathway-related factors.After BMP2 treatment, the differential genes of MutIDH1-glioma cells are closely related to the regulation of cell migration and cell adhesion, especially the regulation of Smad-related proteins. KEGG analysis confirmed that it was related to BMP signaling pathway and TGF-ß signaling pathway and cell adhesion. Enrichment analysis of gene ontology and genome encyclopedia further confirmed the correlation of these pathways. CONCLUSION: Mutation of isocitrate dehydrogenase 1 promotes the migration, invasion, and angiogenesis of glioma cells, through its effects on the BMP2-driven Smad signaling pathway. In addition, BMP2 altered the transcriptional patterns of mutIDH1 glioma cells, enriching different gene loci in pathways associated with invasion, migration, and angiogenesis.

Current challenges in the treatment of gliomas: The molecular era.

Gliomas originate from glial cells in the central nervous system. Approximately 80%-85% of malignant brain tumors in adults are gliomas. The most common central nervous system tumor in children is low-grade pediatric glioma. Diagnosis was determined by histological features until 2016 when the World Health Organization classification integrated molecular data with anatomopathological information to achieve a more integral diagnosis. Molecular characterization has led to better diagnostic and prognostic staging, which in turn has increased the precision of treatment. Current efforts are focused on more effective therapies to prolong survival and improve the quality of life of adult and pediatric patients with glioma. However, improvements in survival have been modest. Currently, clinical guidelines, as well as the article by Mohamed et al accompanying this editorial piece, are adapting treatment recommendations (surgery, chemotherapy, and radiotherapy) according to diagnosis and prognosis guided by molecular biomarkers. Furthermore, this paves the way for the design of clinical trials with new therapies, which is especially important in pediatric gliomas.

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 (28 days) 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).

Adult low-grade gliomas (aLGG) are primary brain cancers, defined by mutations in IDH1 or IDH2. When the IDH gene becomes abnormal (mutated), production of a metabolite that causes cancer cells to grow is increased. These tumors grow slowly but invade the normal functioning brain, making them nearly impossible to cure. The current standard of care treatment includes surgery, followed by radiation therapy and chemotherapy, the timing of which depends on the risk of cancer regrowth. Some patients may be suitable for monitoring with MRI scans alone, however recurrences will inevitably occur. Recently developed targeted mutant IDH inhibitors for aLGG patients may be beneficial both at diagnosis and recurrence. Notably, early treatment prior to radiation therapy and chemotherapy delays growth of aLGG and the need for subsequent radiation therapy and chemotherapy. Nevertheless, most patients will eventually suffer further tumor growth and the optimal timing and sequencing of these therapies remains an area of active research. This research investigates the mutant IDH1 inhibitor safusidenib. The researchers are conducting an innovative clinical trial where patients with aLGG, who have not received radiation therapy or chemotherapy, are treated with safusidenib following a biopsy and prior to surgical removal of their tumor. In this study they investigate whether this trial design is safe and feasible, and how safusidenib works; with the goal to better understand the optimal use of IDH inhibitors for patients with aLGG.

Histopathological Spectrum of Gliomas and Its Immunohistochemical Correlation in a Tertiary Care Setup.

Introduction Central nervous system (CNS) tumors pose significant diagnostic challenges due to their varied morphological and differentiating characteristics. Modern advancements in immunohistochemistry (IHC) and molecular pathology have greatly enhanced prognostication, screening, and therapeutic management. Gliomas, a type of tumor originating from glial cells in the CNS, can develop from astrocytes, oligodendrocytes, or ependymal cells. According to the 2021 update, the classification of diffuse gliomas is primarily based on the presence or absence of isocitrate dehydrogenase (IDH1/2) mutations. IDH-wildtype gliomas (glioblastomas) have a significantly poorer prognosis compared to IDH-mutant gliomas (astrocytomas and oligodendrogliomas). Gliomas are highly infiltrative and resistant to treatment, making them largely incurable regardless of their grade and prognosis. Objective This study aimed to determine the histopathological diversity of gliomas and its correlation with protein expressions of IDH, ATRX gene (α-thalassemia/mental retardation syndrome X-linked), Ki-67, and p53 mutations (tumor suppressor gene-53), according to the 2021 World Health Organization (WHO) Classification of CNS Tumors, Fifth Edition. Methods This descriptive cross-sectional study was carried out in the Department of Pathology at a tertiary care center, focusing on various types of gliomas received over a two-year period. A total of 54 specimens of gliomas received from the Department of Neurosurgery were subjected to histopathological examination. Sections were stained using hematoxylin and eosin (H&E), and IHC was performed using four markers (IDH, ATRX, p53, Ki-67) in each case. Results were analyzed according to the 2021 WHO Classification of CNS Tumors, Fifth Edition. Results The majority of individuals were between the age group of 40 and 60 years, showing a male predominance (65%). The most common site was the frontal lobe. Glioblastoma constituted the largest proportion (46.2%) of the total cases, followed by astrocytoma (20.3%), oligodendroglioma (18.5%), pilocytic astrocytoma (7.4%), and ependymoma (7.4%). All 11 cases of astrocytoma exhibited IDH mutation and ATRX loss, with p53 positive in the majority of cases. Strong nuclear p53 immunohistochemical positivity in >10% of tumor nuclei correlates with TP53 mutations. Among 25 cases of glioblastoma, IDH was negative, ATRX was retained in all cases, and 11 cases were positive for p53 mutation. For oligodendroglioma, out of 10 cases, IDH mutation was positive, and ATRX was retained in all cases. p53 mutation was not seen in any case. All cases of pilocytic astrocytoma were negative for IDH and p53 mutations, with ATRX retained in all cases. In all cases of ependymoma, IDH and p53 mutations were negative, and ATRX was retained in all cases. Glioblastomas exhibited the highest Ki-67 expression. Conclusion The 2021 WHO Classification of CNS Tumors, Fifth Edition, was updated, building on previously established concepts and continuing to evolve. The final diagnosis of gliomas relies on a comprehensive combination of clinical evaluation, neuroimaging, pathological examination, and molecular analysis. Nonetheless, histopathological examination, along with IHC, remains the cornerstone of diagnosis.

Nanographene Oxide Promotes Angiogenesis by Regulating Osteoclast Differentiation and Platelet-Derived Growth Factor Secretion.

An imbalanced system of angiogenesis-osteoblasts-osteoclasts is regarded as the main factor in bone remodeling dysfunction diseases or osseointegration loss. Osteoclast precursors are the key cells that accelerate bone-specific angiogenesis and maintain normal osteoblast and osteoclast function. Graphene oxide is an effective scaffold surface modification agent with broad application prospects in bone tissue engineering. However, the effect of graphene oxide on the interaction between osteoclasts and angiogenesis has not yet been elucidated. In this study, a rat calvarial defect model was established and treated with an electrochemically derived nanographene oxide (ENGO) hydrogel. Higher angiogenesis and platelet-derived growth factor (PDGF) B in preosteoclasts were observed in the ENGO group compared with that in the control group. Moreover, in vitro experiments demonstrate the efficacy of ENGO in substantially reducing the expression of the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast-associated markers and inhibiting bone resorption activity. Additionally, ENGO enhances the secretion of the osteoclast-derived coupling factor PDGF-BB and promotes angiogenesis. Our investigation revealed the crucial role of isocitrate dehydrogenase 1 (IDH1) in the ENGO-mediated regulation of osteoclast differentiation and PDGF-BB secretion. The decreased expression of IDH1 reduces the level of histone lysine demethylase 7A (KDM7A) and subsequently increases the H3K9me2 level in the cathepsin K promoter region. In summary, we found that ENGO promotes angiogenesis by inhibiting the maturity of RANKL-induced osteoclasts and enhancing PDGF-BB secretion. These results indicate that ENGO holds promise for the application in fostering osteoclast-endothelial cell crosstalk, providing an effective strategy for treating bone resorption and osteoclast-related bone loss diseases.