Search Results (937)

Acute myeloid leukemia (AML) is a molecularly heterogeneous neoplasm of hematopoietic stem and progenitor cells. The advent of high-resolution genomic sequencing has uncovered several genetic drivers of AML which spurred a surge of therapies that target the disease at a mutational, clonal, or epigenetic level. Currently, the molecular profiling of AML patients before treatment is commonplace and crucial for ensuring that patients receive the most optimal therapy for any driver mutations they may have. Here, we detail the current targeted therapies available for AML: specifically, those targeting the BCL2 family (venetoclax), FLT3 (midostaurin, gilteritinib, quizartinib), IDH1/2 (enasidenib, ivosidenib), and MENIN (revumenib, ziftomenib). In addition, we outline potential mechanisms of resistance against these therapies, as well as efforts being taken to prevent or bypass them. Full article

Glial brain tumours, including astrocytoma IDH (Isocitrate Dehydrogenase) mutant and glioblastoma IDH wild-type, are highly malignant brain tumours with poor clinical outcomes. Genomic instability, encompassing microsatellite (MIN) and chromosomal instability (CIN), drives tumour heterogeneity and evolution. In this study, genomic instability was analysed in 85 patients using AP-PCR (Arbitrarily Primed Polymerase Chain Reaction) by comparing tumour and normal tissue (blood) DNA profiles of the same patient. Both types of alterations were present in all analysed samples, contributing almost equally to the total level of genomic instability. The dominant pattern of genomic instability in our cohort was low overall instability, predominantly manifesting as low-degree microsatellite instability. A general decrease in genomic instability was observed with increasing tumour grade. Glioblastoma IDH wild-type was more prevalent in older patients, whereas astrocytoma IDH mutant predominated in younger individuals. Notably, low genomic instability (both MIN and CIN) was associated with poorer survival in patients over 50 years of age. Females, compared to males, exhibited higher MIN in grade 2 tumours and elevated CIN in grade 4 tumours. Our results confirm that genomic instability contributes to tumour progression, MIN being the pivotal factor, and could serve as a prognostic biomarker in malignant gliomas. Full article

Background/Objectives: Diffuse midline glioma (DMG), H3 K27M-altered, represents a rare group of gliomas arising in midline structures of the central nervous system. Historically regarded as a pediatric entity, it is now increasingly recognized in adults. Although its relative prevalence among all midline diffuse gliomas and its clinical-radiological characteristics are well defined in children, these tumors remain less characterized in adults, and comparative evaluations with H3 K27 wildtype midline diffuse gliomas are limited. Methods: Consecutive adult patients with histopathologically confirmed diffuse glioma (WHO grade ≥ 2) diagnosed between 2016 and 2025 were retrospectively screened for midline tumor location, with systematic revision of imaging and pathology. For identified midline diffuse gliomas, comprehensive clinical, imaging, and immunohistochemical data were collected, and a detailed morphometric analysis was performed. H3 K27 alteration status was established immunohistochemically, with supplementary immunostaining when necessary. Descriptive and comparative analyses were conducted. Results: A total of 5% of the 541 adult diffuse gliomas were midline, and 23% of IDH wildtype midline gliomas were consistent with DMG, H3 K27-altered (all H3 K27M-mutant). The affected patients were significantly younger, and these tumors predominantly involved the thalamus and mesencephalon. Morphometric analyses revealed trends toward fewer high-grade features in H3 K27-altered tumors, with composite scores demonstrating significant discriminatory ability. The overall survival was not significantly different between groups but showed associations with ring-like enhancement as well as adjuvant and salvage therapies in the overall midline cohort. Conclusions: This study provides population-based prevalence estimates for DMG, H3 K27M-altered, and complements the limited literature with comparative clinical-radiological and morphometric data of potential prognostic relevance. Full article

From an epidemiological perspective, polymorphous low-grade neuroepithelial tumor (PLNTY) represents a small proportion of brain tumors encountered in epilepsy surgery series. Their rarity and relatively recent recognition likely contribute to underdiagnosis and poor prognosis. In terms of histopathological features, they are similar to oligodendrogliomas. Molecular analyses can be used to show the fusion between fibroblast growth factor receptor (FGFR3) and transforming acidic coiled coil (TACC) proteins, which most commonly results in progression towards glioblastoma (GBM). We report a case of a 62-year-old man who underwent left frontal craniotomy to remove a frontal mass. Histologically, the glial lesion consisted of elements associated with oligodendroglia-like features. Immunohistochemistry was positive for glial fibrillary acidic protein (GFAP), oligodendrocyte transcription factor 2 (OLIG2), and α-thalassemia X-linked mental retardation syndrome (ATRX) nuclear expression, but negative for isocitrate dehydrogenase 1 (IDH1) and BRAF-V600E. Next-generation sequencing showed the FGFR-TACC3 fusion, and taken together, these findings supported the final diagnosis of PLNTY. During follow-up, the patient underwent a second neurosurgery, where histological evaluation indicated a GMB. This article presents clinical and radiological data, morphology, immunohistochemistry, molecular features, and treatment to enhance the clinical and pathological understanding of PLNTY with FGFR3-TACC3 fusion for all professionals involved in medical decisions. Full article

The development of targeted treatments, including inhibitors of BCL-2, FLT3, IDH1/2, and menin, has significantly expanded the therapeutic landscape of acute myeloid leukemia (AML), offering more personalized and molecularly driven treatment approaches. Despite these advances, achieving durable responses represents a major challenge, limited by the emergence of intrinsic and acquired resistance to targeted agents. This review summarizes the current understanding of the cellular and molecular mechanisms underlying resistance to targeted therapies in AML. Key mechanisms include acquired mutations that alter the drug target, other co-occurring genetic and epigenetic alterations, activation of bypass signaling pathways, and metabolic reprogramming. Furthermore, the role of clonal heterogeneity and the bone marrow microenvironment in the development of resistance is increasingly recognized. In addition, we discuss emerging strategies aiming at overcoming resistance, such as combination treatments and novel inhibitors designed to target resistant clones. Finally, this review highlights the critical need for mechanism-driven therapeutic design in order to achieve sustained responses and improve long-term outcomes in patients with AML. Full article

Background: Local delivery after resection of high-grade glioma, particularly glioblastoma (GBM), aims to increase intratumoral drug exposure while limiting systemic toxicity. The only U.S. Food and Drug Administration (FDA)-approved implantable intracranial chemotherapy is the carmustine (1,3-bis[2-chloroethyl]-1-nitrosourea; BCNU)-impregnated polyanhydride wafer (Gliadel wafer), indicated for newly diagnosed high-grade glioma and recurrent GBM. More than two decades of clinical use and randomized data show that intracavitary chemotherapy is feasible and confers a modest survival benefit in carefully selected patients. Nevertheless, Gliadel wafer has not altered the overall poor prognosis of GBM because of biological resistance to nitrosoureas, constrained brain-parenchymal pharmacokinetics, and device-related adverse effects. Objective: The aim is to synthesize clinical and preclinical evidence defining the current limitations of Gliadel wafer and to outline strategies for next-generation local delivery systems, with emphasis on GBM within the broader high-grade glioma setting. Methods: A narrative review of randomized and observational clinical studies, pharmacokinetic studies, and preclinical investigations evaluating Gliadel wafer and potential next-generation local delivery systems in GBM and other high-grade gliomas was performed. Results: The literature delineates key limitations of Gliadel wafer: short diffusion distances and burst-weighted carmustine release, high tumor cell resistance to carmustine due to heterogeneity, and device-related side effects. Emerging approaches to address these limitations include (i) multidrug systems with synergistic effects against GBM cells; (ii) advanced biomaterials that enable controlled and sustained release; and (iii) targeted agents with minimal off-target effects. Testing newer generations of local drug-delivery systems in more predictive translational models, such as patient-derived organoids and spontaneous large-animal glioma models, is essential to maximize the translatability of preclinical studies to human studies. However, broader adoption of spontaneous large-animal glioma models is constrained by ethical oversight, animal-welfare considerations, cost, and limited availability compared with rodent platforms. Conclusions: Next-generation local drug-delivery systems should include multiple synergistic tumor-selective drugs that can be released in a controlled, sustained manner deep into the residual tumor. Preclinical testing of these systems should be conducted in clinically relevant animal models that are more translatable than those used in early Gliadel wafer studies. Full article

Toxoplasmosis is a zoonotic disease with limited therapeutic options, which are further hampered by significant toxicity and suboptimal efficacy. Effective interventions for chronic infection remain insufficient, and thus, natural product-derived drug screening remains a key focus in anti-Toxoplasma research. Licochalcone A (Lico A), a major bioactive compound isolated from Glycyrrhiza uralensis, exhibits potent activity against Toxoplasma tachyzoites. However, systematic studies of its targets, pharmacokinetics, and efficacy are lacking, hindering its development as an anti-Toxoplasma candidate drug. In this study, we used SPR-MS to identify 33 high-affinity target proteins (affinity score > 1000). Furthermore, an AI-driven multidimensional analysis identified a cluster of five proteins (TgMORN1, D3XD37, ABCB2, MIC15, and IDH), with TgMORN1 yielding the highest composite score. RNAi experiments confirmed TgMORN1 as a key target, as its silencing attenuated the anti-proliferative effect of Lico A. Western blotting, NanoDSF, and SPR supported direct binding between Lico A and TgMORN1, suggesting that Lico A modulates TgMORN1 thermal stability through residues S168 and D203, with high species specificity. Pharmacokinetic evaluation revealed that Lico A had favorable absorption and blood–brain barrier permeability, supporting its potential utility in treating brain disease. In vitro assays showed that Lico A effectively inhibited Toxoplasma gondii brain cyst formation. Collectively, these findings support Lico A as a promising candidate for the treatment of toxoplasmosis. Full article

Colitis-associated carcinoma (CAC) represents ~1% of colorectal carcinomas and has important differences from sporadic colorectal carcinoma (sCRC). The precursors and carcinomas that arise in the setting of IBD are uniquely challenging to visualize by endoscopy and diagnose via histology, and the rising prevalence of IBD amplifies the challenges of surveillance to informed management. Although in broad strokes, CAC and sCRC share molecular features (~85% chromosomal instability pathway 15% microsatellite instability high (MSI-H)), CAC has a distinct distribution of molecular abnormalities, including lower frequencies of APC and KRAS mutations, greater prevalence of IDH1R132H, and more frequent copy number alterations (e.g., MYC amplifications), and functional data indicate that most CACs show far less dependence on Wnt signaling than sCRC, suggesting a distinct pathogenesis from the earliest stages. Although there are significant gaps in our knowledge of the pathogenesis of CAC, our understanding is growing. This review summarizes how chronic colitis reshapes epithelial homeostasis and somatic evolution, resulting in the distinctive pathogenesis of CAC, and highlights knowledge gaps that could be addressed by applying multimodal technologies to well-annotated clinical material. The review is structured in two sections, the first introducing the IBDs and the homeostatic mechanisms that preserve integrity and prevent colorectal neoplasia. The second section compares failure modes in sporadic and colitic settings and describes the differences in the resulting neoplasms. Full article

Astrocytomas are among the most common primary tumors of the central nervous system, arising from astrocytic glial cells and encompassing a wide spectrum of histopathological grades and clinical behaviors. Human immunodeficiency virus (HIV) infection is characterized by chronic immune dysregulation, neuroinflammation, and increased susceptibility to both opportunistic infections and malignancies. The management of astrocytomas in patients living with HIV presents unique clinical challenges but should, whenever feasible, follow standard neuro-oncological principles. We report the case of a 34-year-old man with well-controlled HIV infection who presented in February 2025 with progressive neurological symptoms. Brain imaging revealed a left temporo-insular lesion, and the diagnosis was confirmed by neuronavigation-guided biopsy performed on 31 March 2025. Histopathological and immunohistochemical evaluation established the diagnosis of an isocitrate dehydrogenase (IDH) wild-type astrocytoma, central nervous system (CNS) World Health Organization (WHO) grade 2, according to the 2021 classification of central nervous system tumors. Full article

The citric acid cycle disruptions are implicated in the pathogenesis of chronic diseases, including diabetes, obesity, cancer, and cardiovascular conditions. Numerous publications link TCA cycle disorders to oncological, neurodegenerative, and osteoporotic diseases, and specific single-nucleotide polymorphisms have been proposed as potential markers. Nevertheless, lifestyle and diet have been strongly linked to risk factors for mitochondrial dysfunction; thus, preventive measures that minimize these risks are a relevant field of research. This review summarizes 45 years of relevant publications on the TCA cycle, its genetics and epigenetics, and the restorative potential of certain nutrients. The review includes articles in English and Russian, registered in PubMed, Elsevier, eLIBRARY.RU. The genes encoding the TCA cycle enzymes have been collected and presented. Information is provided that a number of changes in the expression of these genes, for example, Arg18Trp, Ser87Leu, Ala252Thr, and Leu357Val of the ACO2 gene, leads to the development of neurodegenerative diseases; mutations rs121913499, rs121913500 in the IDH1, IDH2 genes, rs1270341616 and the DLST gene lead to the development of cancer. There is evidence that through epigenetic modifications, nutrition affects the activity of the TCA cycle. Niacin, α-lipoic acid, succinic acid, resveratrol, curcumin, arginine, leucine, quercetin, ursolic acid, and alternol affect the regulation of the TCA cycle at the genetic level. Further research into the effects of plant metabolites, vitamins, and bioactive supplements on the TCA cycle may improve the existing preventative and therapeutic diets. Full article

Background/Objectives: Chondrosarcoma, glioblastoma, acute myeloid leukemia, chronic lymphocytic leukemia, and cholangiocarcinoma cancers all contain mutations in the gene isocitrate dehydrogenase 2 (IDH2). The mutant IDH2 enzyme metabolizes alpha-ketoglutarate (αKG) into the potent oncometabolite D-2-hydroxyglutarate (D2HG) in the mitochondria of these cancers, leading to altered cellular metabolism. Emerging evidence suggests that mitochondrial transfer between cancer and recipient cells represents an important form of intercellular communication that may influence cellular metabolism. The presence of intercellular TNTs between IDH2-mutant chondrosarcoma cells motivated an investigation into mitochondria-associated physiological changes occurring during an intercellular exchange with immune cells. A mitochondrial transfer is a two-way process, and we hypothesized that mitochondria-associated material derived from IDH2-mutant chondrosarcoma cells is exchanged with normal cells through TNTs. We further hypothesized that disruption of the actin cytoskeleton will inhibit this transfer. Accordingly, our objectives were to (1) quantify the extent and directionality of the mitochondrial exchange between IDH2-mutant cells and wild-type cells and to modulate this process via cytoskeletal inhibitors, and (2) measure the metabolic changes associated with the coculture and mitochondrial exchange. Methods: IDH2-mutant chondrosarcoma cells were cocultured with immune cells in vitro to quantify the extent and directionality of the mitochondrial exchange, and cytochalasin B was used as a cytoskeletal inhibitor to disrupt actin-dependent transfer. Metabolic changes associated with coculture and mitochondrial exchange were assessed using Seahorse extracellular flux analysis. Results: The experimental data presented here demonstrate a bidirectional exchange of mitochondria-associated material between IDH2-mutant chondrosarcoma cells and immune cells in vitro, accompanied by metabolic alterations in both cell types. Conclusions: These findings advance our understanding of intercellular communication in the tumor microenvironment and provide a foundation for future studies examining the functional and therapeutic relevance of a mitochondrial exchange in IDH2-mutant cancers. Full article

Background: Adult diffuse gliomas represent one of the most aggressive types of brain tumors. Proton therapy offers a minimally invasive treatment option whose biological effectiveness may be enhanced through nuclear reactions involving boron atoms, leading to the emission of high-LET α-particles. In this study, we investigated the potential enhancement of radiation-induced damage of a novel boron-conjugated, ATP-competitive SRC kinase inhibitor, in the U-87 MG glioma cell line and its isogenic cell line stably expressing the IDH1 R132H mutation. Methods: Glioma cells were exposed to either proton or X-ray irradiation to assess whether any enhancement associated with this boron-delivery strategy was specific to proton interactions. Cell survival assays and analyses of DNA damage responses were conducted in both cell lines. Results: While no significant synergistic effects were observed in survival endpoints, differences emerged at the level of early DNA damage effects, with IDH1-mutant glioma cells displaying an enhanced acute response following combined treatment with proton irradiation. Conclusions: These findings support further pharmacological development of boron-based SRC-targeted strategies and underscore the importance of tailoring therapeutic approaches to specific glioma molecular subtypes. Full article

Introduction: Significant studies have substantiated the evidence for complete resection of intrinsic brain tumours in recent years. However, achieving this through a single surgery is not always possible due to tumour localisation in eloquent areas. Therefore, the present analysis aimed to evaluate surgical outcomes in a cohort of patients undergoing planned two-stage glioma surgery. Methods: Patients who underwent surgery for diffusely infiltrating brain tumours between 2013 and 2023 at the Department of Neurosurgery at Düsseldorf University Hospital were screened for undergoing two-stage surgery, defined by a priori-considered surgical re-intervention up to 6 weeks after the initial surgery. Results: Of 1558 patients with glioma, 447 underwent multiple surgeries, of whom 36 underwent planned two-stage surgery during the course of their disease. Two-stage surgery was performed mostly as glioma surgery at first diagnosis (75%). The mean time between the first and second surgery was 11.67 days (±7.59). Two-stage surgery was performed due to various reasons, mostly in localisations that required multifocal approaches (47.2%), due to non-compliance during initial awake surgery (30.6%), or cases with primary debulking for subsequent awake-surgery approaches (22.2%). Tumours were mainly located in the left hemisphere (50%) (right hemisphere 25%, or bilateral 25%) and motor- or speech-eloquent in 61.11%. Tumours were 72.2% IDH-wildtype. An intended complete resection result was achieved in 58.88% after the second surgery, changing from 93.94% submaximal resection to 58.88% supramaximal and maximal resection after the second surgery. Second surgery significantly reduced residual tumour volume of both T1-CE (Wilcoxon signed-rank test, Z = −4.62, p < 0.001) and T2-nCE (Z = −4.62, p < 0.001). In contrast, functional (KPS: Z = −0.93, p = 0.350) and neurological status (NIHSS: Z = −0.89, p = 0.372) did not significantly change. Perioperative complications of the second surgery occurred in nine (25%) cases, requiring surgical intervention under general anaesthesia or ICU treatment (Clavien–Dindo grade IIIb/IV) in six (16.67%) cases. Conclusion: Planned two-stage surgery was mostly performed as a surgical strategy in eloquent locations to achieve supramaximal or maximal resection. A two-staged surgery significantly extended resection results without neurological and functional deterioration. Despite relevant complication rates, primary debulking followed by staged resection as well as two-staged multifocal approaches may yield a favourable risk–benefit profile. Full article

Glioblastoma (GBM) is an extremely aggressive and incurable primary tumor of the brain. GBM is characterized by interpatient and intratumoral heterogeneity, making this cancer particularly resistant to therapy and likely to recur. Mapping the complex dynamics that underpin the development and evolution of gliomas with human-based in vitro models is difficult. This study aimed to generate 3D glioma patient-derived tumor constructs (PTCs) using a clinically relevant, Matrigel-free, hyaluronic acid system, evaluate their suitability in drug screening assays, and determine the stability of their genetic profiles compared to originating tumors. In this study, we utilized a synthetically modified hyaluronic acid and gelatin hydrogel system to generate tumor constructs containing cells from clinical glioma biospecimens. PTCs were characterized phenotypically, after which they were deployed in chemotherapy drug screens using temozolomide (TMZ) and a P53 activator compound. Drug responses of these 3D cultures were compared with 2D cultures, as well as PTCs that were generated after passaging in 2D. RNA sequencing was used to evaluate genetic parity between PTCs or 2D cultures with originating tumor tissues, using The Cancer Genome Atlas (TCGA) GBM subpopulations for subcategorizing. PTCs were created successfully from five World Health Organization (WHO) grade 4, two grade 3, and two grade 2 gliomas. PTCs were maintained with high viability. Chemotherapy drug screens demonstrated that expected TMZ responses were observed for Isocitrate dehydrogenase (IDH) mutant diffuse gliomas while drug response was variable for IDH wildtype GBM PTCs. PTCs demonstrated stable drug response over time, while 2D passaging resulted in significant shifts in drug sensitivity. RNA sequencing revealed maintenance of subpopulation signatures for PTCs which clustered with their originating patient tumor tissue. In contrast, 2D cultures largely clustered together regardless of the patient. Our PTC approach utilizes a defined hydrogel biomaterial system that maintains the genotypic and drug response characteristics of patient tumors making this an ideal ex vivo model for translational applications. Full article

Background/Objectives: Isocitrate dehydrogenase (IDH) mutation is a key prognostic indicator in diffuse gliomas; however, it is clinically determined from invasive tissue sampling. Non-invasive preoperative identification of IDH mutation from routine anatomical MRI could support treatment decision making. This study evaluated deep learning models for IDH mutation detection using routine anatomical MRI (post-contrast T1-weighted (T1c), T2-weighted, and fluid attenuated inversion recovery (FLAIR) MRI) and quantified how tumor-focused image preprocessing and different training schemes, centralized learning (CL) versus federated learning (FL) with alternative aggregation strategies, affected model performance. Methods: Anatomical MRI from 501 diffuse glioma patients in the UCSF Preoperative Diffuse Glioma MRI (UCSF-PDGM) dataset was analyzed using a deep learning classifier built on a 2D U-Net encoder, with age and sex included as covariates. Two methods of tumor-focused image preprocessing, Naïve Soft Filtering (NSF) and Gradient-Based Soft Filtering (GBSF), were compared. Centralized learning (CL) was benchmarked against federated learning (FL) using Federated Averaging (FA) and Federated Trimmed Mean (FTM) aggregation strategies. Model performance was compared in terms of accuracy, precision, recall, F1 score, specificity, and the area under the receiver operating characteristic curve (ROC-AUC). Results: The CL model with NSF achieved the best test performance (accuracy = 0.949, F1 = 0.951, ROC-AUC = 0.971), with NSF consistently outperforming GBSF. FL’s performance decreased relative to CL’s, but the FA strategy outperformed FTM (FTM accuracy = 0.915 vs. FA accuracy = 0.949), which indicates that the FL aggregation strategy has an influence on model performance. Conclusions: Deep learning applied to routine anatomical MRI could classify IDH mutation status with high accuracy. Context-preserving image preprocessing with NSF substantially improved performance across training schemes. FL provides a privacy-preserving alternative to CL, but incurs a measurable performance degradation that is sensitive to the choice of aggregation strategy. Full article