Search Results (1,020)

Background/Objectives: Oligodendroglioma-like morphology may generate diagnostic uncertainty in central nervous system tumors, although oligodendroglioma is defined by the integrated presence of IDH mutation and whole-arm 1p/19q codeletion. This study aimed to evaluate the diagnostic pitfalls of oligodendroglioma-like morphology by comparing initial microscopic impressions with final integrated diagnoses. Methods: We retrospectively reviewed 23 non-oligodendroglial central nervous system tumors showing focal or predominant oligodendroglioma-like morphology but not fulfilling the integrated diagnostic criteria for oligodendroglioma. Clinical, radiological, histopathological, immunohistochemical, molecular/cytogenetic, initial microscopic impression, final integrated diagnosis, and follow-up data were analyzed descriptively. Results: Initial microscopic impressions included low-grade glial tumor, high-grade glial tumor, dysembryoplastic neuroepithelial tumor, ependymoma, astroblastoma, oligodendroglioma, dysplasia, central neurocytoma, metastatic epithelial tumor, and pilocytic astrocytoma/low-grade glial tumor. Final integrated diagnoses were astrocytoma, IDH-mutant, CNS WHO grade 2–4 (n = 9); dysembryoplastic neuroepithelial tumor (n = 3); central neurocytoma (n = 3); metastatic renal cell carcinoma (n = 2); low-grade glioneuronal tumor (n = 2); and PLNTY, glioblastoma IDH-wildtype, supratentorial ependymoma, and pilocytic astrocytoma (n = 1 each). Conclusions: Oligodendroglioma-like morphology should be interpreted as a diagnostic pitfall pattern rather than a specific diagnosis. Structured integrated reappraisal using targeted immunohistochemical and molecular/cytogenetic testing helps refine differential diagnosis in routine neuropathology practice. Full article

Glioblastoma and diffuse gliomas pose major therapeutic challenges due to marked intratumoral heterogeneity, limited tissue accessibility, and the blood–brain barrier. Tissue-based next-generation sequencing (NGS) remains essential for WHO CNS5 molecular classification, yet it is invasive and poorly suited to serial monitoring. Two complementary non- or minimally invasive approaches have advanced rapidly: radiogenomics, which correlates multiparametric MRI features with genomic alterations, and cerebrospinal fluid (CSF) liquid biopsy sequencing, which detects circulating tumor DNA with high tissue concordance. This review examines the independent progress and synergistic integration of radiogenomics and CSF-NGS. Imaging signatures can non-invasively predict key drivers (IDH1/2, EGFR, TERT, PTEN, TP53) and molecular subtypes, while CSF-ctDNA sequencing enables real-time assessment of clonal evolution, therapy resistance (including post-temozolomide hypermutation), and residual disease. We discuss technical considerations, performance metrics, multimodal artificial-intelligence fusion, and emerging clinical applications for diagnosis, prognosis, treatment selection, and longitudinal surveillance. Critical challenges, standardization, prospective validation, and workflow integration are highlighted. By combining the spatial phenotypic information of radiogenomics with the temporal genomic resolution of CSF sequencing, this multimodal strategy offers a promising path toward precision neuro-oncology and reduced reliance on repeated invasive sampling. Full article

Background/Objectives: Pediatric solid tumors (PST) are a biologically distinct group of malignancies whose developmental origins and molecular drivers differ substantially from those of adult cancers, with direct implications for therapeutic strategy and clinical outcome. This review synthesizes current evidence on molecular pathogenesis, tumor microenvironment biology, and the structural conditions that shape access to care across select PST. Methods: A narrative review of peer-reviewed literature was conducted primarily using PubMed, supplemented by Google Scholar, covering publications from 2000 to 2025. Tumor types were selected based on their prevalence in the pediatric population and the availability of evidence addressing both molecular features and health disparities. Body: Across eight tumor types (neuroblastoma, Ewing sarcoma, pediatric brain tumors, rhabdomyosarcoma, Wilms tumor, retinoblastoma, osteosarcoma, and chondrosarcoma), recurrent molecular alterations including MYCN amplification, EWS-FLI1 fusions, PAX-FOXO1 rearrangements and IDH 1/2 mutations emerge as central determinants of disease behavior and eligibility for treatment. The tumor microenvironment manifests as a shared mediator of immune exclusion and therapeutic resistance across tumor types, with, but not limited to, tumor-associated macrophages, myeloid-derived suppressor cells, and checkpoint molecule expression, identified as recurrent features influencing treatment response. Immunotherapeutic strategies have shown variable efficacy across PST, with the most consistent clinical benefit established in neuroblastoma. A critical and underappreciated pattern stands out across tumor types: children carrying the most aggressive molecular subtypes are disproportionately those with the least access to therapies those subtypes demand, emphasizing an overlap of biological and structural disadvantage that is also amplified in low- and middle-income countries, where late-stage presentation, treatment abandonment and limited access to molecular diagnostics compound the biological disadvantage. Conclusions: Within the eight PST reviewed, the most aggressive molecular subtypes and the greatest structural disadvantages converge in the same children; those carrying MYCN amplification, PAX-FOXO1 fusions, or EWS-FLI1 fusions are disproportionately those with the least access to the therapies their biology demands. Genomic and immunologic advances will only reach their full clinical potential when paired with inclusive trial data, diversified genomic databases, and most importantly, equitable access to biomarker-specialized therapies across all populations. Full article

Clinical decision making in Acute Myeloid Leukemia (AML) critically relies on rapid genomic characterization. To better understand the AML diagnostic landscape in Canada, the Canadian Leukemia Study Group (CLSG) conducted a survey of laboratory hematology leadership (n = 18) at 16 laboratories across 10 provinces, administered using Google Forms in September 2024. Nearly all surveyed sites were equipped to deliver a full suite of testing platforms through existing on-site infrastructure or laboratory partnerships. Reporting practices varied in terms of genomic integration into bone marrow results and the use of AML classification systems. Turn-around-time (TAT) targets were predominantly determined through internal institutional consensus (62%) or recommendations by provincial cancer agencies/international groups (44%). TAT reduction was a top priority for 56% of laboratories, suggesting timely biomarker results to be an active area for improvement. Various treatment-determining biomarkers were frequently assessed as rapid-tests (defined as a 5-day TAT), including FLT3-ITD (69%), FLT3-TKD (56%), and NPM1 (56%), while others such as IDH1 and TP53 were rapid at a limited number of laboratories. Respondents demonstrated a strong shared interest in joint projects such as the validation of AML measurable residual disease (MRD) assays (56%). There was also unanimous support for establishing CLSG AML laboratory consensus guidelines. This survey documents the current state of Canadian AML laboratories and provides a foundation for future shared development projects. Full article

High carbonate alkalinity (CA) is a major constraint on shrimp culture in saline–alkaline waters. The hepatopancreas is central to shrimp immunity and metabolic regulation. Litopenaeus vannamei underwent a 7-day exposure period to 5 mmol/L CA, followed by a subsequent 7-day recovery phase after removal of the stressor. The physiological regulatory mechanism of the hepatopancreas during CA stress and recovery was investigated by integrating multiple biological levels including histomorphology, antioxidant and immune indices, energy metabolism, and metabolite profiles. Results showed that CA stress induced structural changes in the hepatopancreas and triggered stress responses. Specifically, a significant upregulation was observed in genes involved in antioxidation (romo1, nrf2, gpx, hsp70), apoptosis (casp-9, casp-3), endoplasmic reticulum (ER) stress (ire1, xbp1), immune defense (alf, crus, pen-3, lys, propo), and detoxification (cyp450). CA stress also increased osmoregulatory genes (ccp, nhe, ca, aqp, vatp, nka-β, nka-α), whereas clc and tip4 were suppressed. CA stress reduced the levels of energy-metabolism-related biochemical indicators, including glucose (GLU), pyruvic acid (PYR), lactic acid (LAC) and triglycerides (TG), while markedly inducing the expression of genes involved in carbohydrate metabolism (ldh, pdh, hk, pk), lipid metabolism (ampk, srebp, fas), the tricarboxylic acid (TCA) cycle (mdh, cs, idh, odh, sdh, fh), and the electron transport chain (ETC) (ndh, cytc, coi, cco, atph). Moreover, the hepatopancreatic metabolic profile was remodeled, especially “phenylalanine, tyrosine and tryptophan biosynthesis” and the metabolism of β-alanine, arachidonic acid, linoleic acid, and sphingolipids being substantially altered during both the stress and recovery phases. Several functional metabolites linked to stress responses were further pinpointed. Following stress relief, some physiological parameters partially recovered, yet overall function failed to return to normal. Collectively, CA stress compromised hepatopancreatic homeostasis by damaging morphological integrity, eliciting stress and immune responses, and perturbing energy metabolism and metabolite homeostasis; these adverse effects were not readily reversible in the short term. Full article

The liver is an immunologically distinctive organ. Portal blood continuously delivers gut-derived antigens and microbial products, requiring hepatic immunity to balance surveillance with restraint. In hepatocellular carcinoma (HCC), this physiology is commonly overlaid by chronic injury, inflammation, and fibrosis, so the background liver forms part of the disease context in which the tumor microenvironment (TME) develops. This review synthesizes how cellular architecture, tumor-intrinsic programs, and structural, metabolic, and microbial conditions interact to shape immune evasion and heterogeneity. HCC provides the principal evidence base, with intrahepatic cholangiocarcinoma (iCCA) used as a structured, biologically distinct comparator. We organize therapies by the microenvironmental barriers they are intended to modify and distinguish established clinical efficacy from evidence that the proposed mechanisms mediate treatment benefit. Single-cell and spatial studies have resolved cellular states and spatial arrangements, including onco-fetal endothelial–myeloid neighborhoods and a macrophage–fibroblast boundary band separating lymphocyte-rich stroma from malignant tissue. These patterns operate within fibrotic and metabolically altered tissue and vary by etiology, spatial context, and tumor type. Vascular endothelial growth factor blockade with immune checkpoint inhibition and dual checkpoint blockade are established first-line options in advanced HCC. Chemo-immunotherapy is established in biliary tract cancer, and IDH1 inhibition has established efficacy in IDH1-mutant cholangiocarcinoma. Myeloid- and stroma-directed strategies, natural-product approaches, and engineered-cell therapies remain preclinical or early clinical. None of the pivotal trials tested whether the proposed microenvironmental mechanism mediated treatment benefit. The liver TME informs treatment selection without yet determining it. Full article

(1) Background: Modifications to tumor classifications could fundamentally alter the foundation of research approaches. A concrete illustration of this issue is the actual WHO classification of tumors of the central nervous system, published in 2021. According to the WHO classification, GBM is an IDH wild-type tumor. However, some multi-omics databases retain the classification from the time the samples for the datasets were collected, prior to the WHO 2021 classification, including IDH mutant GBMs. We were interested in assessing the number of papers published in the biomedical literature from 2022 to 2025 that are based on these databases, to ensure the correct implementation of the WHO 2021 classification of GBM. (2) Methods: We systematically reviewed publications in the biomedical literature from 2022 to 2025 that utilized the two most widely used multi-omics databases in the glioma research field, the CGGA and TCGA databases, to assess the correct application of the classification of GBM. (3) Results: We identified 269 publications, but only 45 (14%) correctly included only IDH wild-type GBM; 83 (33%) also contained IDH mutant tumors; and 141 (53%) provided no information about the IDH status of their research material. (4) Conclusions: Using a systematic search strategy, we found that 1/3 of published papers used IDH mutant tumors, and 1/2 of the studies did not report the IDH status of the tumors. Full article

Background/Objectives: Isocitrate Dehydrogenase (IDH)1/2-mutant diffuse gliomas represent a biologically distinct subgroup of adult brain tumors in which eary metabolic reprogramming and accumulation of the oncometabolite D-2-hydroxyglutarate (D-2HG) drive epigenetic, immunologic, and clinical characteristics, including a high burden of glioma-associated epilepsy. This review summarizes the molecular and metabolic consequences of IDH mutations, their role in glioma-associated epilepsy, and the evolving impact of mutant IDH-targeted therapies in contemporary neuro-oncology. Methods: We conducted a narrative review of key molecular, translational, imaging, and clinical studies on IDH-mutant diffuse gliomas. The literature included the 2021 (World Health Organization) WHO Classification of Tumours of the Central Nervous System, studies investigating D-2HG biology and glioma-associated epilepsy, and prospective clinical trials and real-world evidence evaluating IDH-targeted therapies and contemporary antiseizure management. Particular emphasis was placed on vorasidenib, advanced metabolic imaging, and emerging liquid biopsy approaches. Results: IDH mutations are early driver events that promote D-2HG accumulation, resulting in widespread epigenetic reprogramming, metabolic dysregulation, and an immunosuppressive tumor microenvironment. D-2HG has also been implicated in the development of glioma-associated epilepsy, although the underlying mechanisms remain incompletely understood. Advances in integrated histomolecular diagnostics, magnetic resonance spectroscopy, amino acid positron emission tomography, and cerebrospinal fluid liquid biopsy have improved disease classification and treatment monitoring. Mutant IDH inhibitors, particularly vorasidenib, prolong progression-free survival, delay the need for subsequent treatment, and reduce intratumoral D-2HG concentrations, and have shown encouraging early signals of improved seizure control and preserved health-related quality of life in patients with grade 2 IDH-mutant gliomas, although this evidence remains preliminary and requires confirmation in larger prospective studies. Conclusions: IDH-mutant diffuse gliomas exemplify precision neuro-oncology, in which a single metabolic alteration informs diagnosis, disease monitoring, and targeted therapeutic approach. Additionally, ongoing studies are expected to further define the role of IDH inhibition across different disease stages and in combination with immunotherapy and standard treatments. Lastly, future clinical trials should systematically incorporate seizure outcomes, neurocognitive function, patient-reported outcomes, and immunologic endpoints to optimize both tumor control and quality of life. Full article

Short episodes of intradialytic hypoxemia (IDH) are a common but still under-recognized complication of hemodialysis with clinically significant consequences. The aim of the study was to analyze the effect of IDH on the secretion of hypoxia-inducible factors 1 and 2 and sirtuin 1. The study group consisted of 49 chronic hemodialysis patients, mean age 58.8 ± 15.3 years. Pulse oximetry was continuously recorded throughout hemodialysis. Blood was collected three times during a single mid-week hemodialysis session and at the start of the next mid-week session to assess levels of sirtuin 1 (SIRT1), hypoxia-inducible factor 1 (HIF-1), and hypoxia-inducible factor 2 (HIF-2). IDH, defined as a decrease in blood oxygen saturation below 90%, occurred in 22 (45%) patients. The mean time of hypoxemia during dialysis was 0.52% of the total hemodialysis session time. Plasma SIRT1 and HIF-2 concentrations did not change significantly during hemodialysis, whereas plasma HIF-1 levels decreased significantly. Multiple regression analysis showed that pre-dialysis plasma SIRT1 and HIF-1 explained a significant portion of the variability of blood oxygen saturation during hemodialysis. Pre-dialysis plasma levels of sirtuin 1 and HIF-1 could be considered predictors of the decline in blood oxygen saturation during hemodialysis sessions; they also determine the degree of variability of this parameter during the procedure. Full article

Background: Glioblastoma (GBM) carries a median survival of 15 months. Approximately 16–27% of patients die within six months despite standard therapy. Radiomic MRI features have been proposed as prognostic biomarkers, yet many published studies employ standard cross-validation (CV) with feature selection on the full dataset, introducing data leakage. Methods: Sixty patients with IDH-wildtype GBM from the publicly available UCSF-PDGM dataset (single-center, GE Discovery MR750, 3 T; 2015–2021) with BraTS 2021 segmentation masks were analyzed. One thousand two hundred eighty-four (1284) IBSI-compliant radiomic features (7 feature classes × 4 MRI sequences × 3 tumor subregions) were extracted using PyRadiomics. After preprocessing (variance filter, correlation filter |r| > 0.95), approximately 120 features remained per fold. Feature selection was performed strictly within each training fold of a nested 5-fold cross-validation framework (5-fold × 3 repeats = 15 outer folds). Results: For 1-year mortality, radiomics AUC dropped from 0.816 (standard CV) to 0.593 (nested CV; ΔAUC = −0.223, 27% inflation), while clinical models remained stable (0.708 vs. 0.705). For early mortality (≤180 days, n = 16 events), standard CV inflated radiomics AUC to 0.888, whereas nested CV yielded 0.815 (ΔAUC = −0.073, 8% inflation). In feature stability analysis, whole-tumor surface area (13/15 folds) and mesh volume (10/15 folds) showed the highest cross-endpoint stability; nine of 13 exploratory OS-associated features were never selected for early mortality classification. Extent of resection (HR = 0.44, p = 0.009) and age (HR = 1.03, p = 0.038) were independently associated with overall survival; tumor surface area remained independently associated with survival (HR = 1.38, p = 0.021). Conclusions: Nested cross-validation revealed substantial performance inflation in standard radiomics pipelines. These descriptive inflation estimates are specific to this dataset and pipeline configuration and should not be generalized as universal parameters for radiomics. Full article

Background/Objectives: Recurrent glioblastoma has a poor prognosis and no universally accepted standard of care. Regorafenib has been investigated in this setting, but its use may be limited by treatment-related toxicity. This study evaluated the feasibility, safety, and clinical outcomes of reduced-dose regorafenib in patients with recurrent IDH-wildtype glioblastoma. Methods: We retrospectively analyzed 21 patients with recurrent IDH-wildtype glioblastoma (WHO 2021) treated at a single center after progression according to the Stupp protocol. Regorafenib was started at 80 mg/day on the standard 3-weeks-on/1-week-off schedule. We assessed overall survival from diagnosis (OS1) and from first progression (OS2), progression-free survival from diagnosis (PFS1) and from first progression (PFS2), treatment exposure, dose modifications, and treatment-related adverse events (CTCAE v5.0). Results: Median PFS2 was 5 months (95% CI, 3–8), median OS2 was 6 months (95% CI, 5–10), and median OS1 was 21 months (95% CI, 15–27). No grade ≥ 3 adverse events occurred, and no patient discontinued treatment permanently because of toxicity. Conclusions: In this retrospective single-center cohort, reduced-dose regorafenib was feasible and well tolerated in selected patients. These descriptive, hypothesis-generating findings warrant prospective studies to define the role of individualized regorafenib dosing in recurrent glioblastoma. Full article

Glutamate dehydrogenase (GLUD1) links glutamine metabolism and redox regulation, yet its prognostic and functional relevance across different glioma subtypes warrants further study. Here, we show that GLUD1 expression was inversely associated with tumor grade and positively associated with survival across glioma subtypes, a relationship not fully recapitulated by broader glutaminolysis-related gene signatures. To investigate the consequences of GLUD1 inhibition, we treated endogenous IDH-mutant and IDH-wildtype glioma cell lines with the reported GLUD1 inhibitor R162. GLUD1 inhibition reduced viability in all cell lines tested. This effect was not rescued by α-ketoglutarate (α-KG) supplementation, indicating that impaired tricarboxylic acid (TCA) cycle anaplerosis was not the primary mechanism underlying GLUD1 dependency. Instead, GLUD1 inhibition caused intracellular glutamate accumulation, increased reactive oxygen species (ROS), γ-H2AX induction, and elevated intracellular calcium, while complementary in silico analyses predicted disruption of mitochondrial membrane potential following R162 exposure. Together, these findings indicate that GLUD1 inhibition induces metabolic and redox stress associated with disrupted glutamate and calcium homeostasis and DNA damage. Our findings distinguish the favorable prognostic value of GLUD1 expression from the cellular vulnerability revealed by its inhibition, supporting further investigations of GLUD1 as both a prognostic biomarker and potential therapeutic target in glioma. Full article

Gliomas are the most common malignant primary brain tumors. The 2021 WHO classification requires the integration of molecular biomarkers, including IDH mutation, MGMT promoter methylation, and 1p/19q codeletion, alongside histological criteria, yet their assessment still relies on invasive surgical biopsy. We present M²-YOLO (Multi-task Molecular YOLO), a unified deep learning framework that simultaneously performs glioma instance segmentation and non-invasive molecular biomarker prediction from preoperative multi-sequence MRI. The proposed approach was evaluated on the multi-site UTSW-Glioma dataset comprising 625 patients. M²-YOLO achieved Dice scores of 0.853 for edema and 0.697 for tumor core segmentation, together with AUC-ROC values of 0.849 for IDH mutation and 0.718 for 1p/19q codeletion prediction. MGMT prediction yielded an AUC of 0.520, consistent with the limited discriminative capacity of anatomical MRI for this biomarker. These results demonstrate the potential of a unified multi-task framework for combining tumor delineation and molecular characterization within a single non-invasive workflow, supporting future applications in precision neuro-oncology. Full article

Brain tumors exhibit extensive metabolic reprogramming that supports proliferation, invasion, therapeutic resistance, and adaptation to dynamic microenvironmental conditions. These alterations provide opportunities for metabolic imaging approaches that extend beyond conventional anatomical neuroimaging. Hyperpolarized magnetic resonance imaging (hpMRI) has emerged as a novel metabolic imaging platform capable of non-invasively visualizing real-time cellular metabolism through dynamic nuclear polarization of carbon-13-labeled substrates. By dramatically enhancing magnetic resonance signal intensity, hpMRI enables interrogation of enzyme-specific metabolic pathways and provides unique insight into tumor energetics, metabolic heterogeneity, and treatment response. The distinct contribution of this review is an updated, brain tumor-specific, clinically oriented framework that integrates recent human evidence with longitudinal metabolic phenotyping, emerging pathway-specific probes, acquisition standardization, multimodal validation, and the remaining barriers to clinical implementation. Particular emphasis is placed on hyperpolarized [1-¹³C]pyruvate, which has demonstrated feasibility and safety in patients with gliomas and has enabled assessment of glycolytic metabolism, oxidative phosphorylation, tumor recurrence, and longitudinal treatment response. Serial changes in lactate and bicarbonate flux may also reflect evolution toward more glycolytic, heterogeneous, and treatment-resistant tumor phenotypes, supporting the potential prognostic value of hpMRI before conventional radiographic progression becomes evident. We also review emerging applications involving α-ketoglutarate metabolism, redox biology, glutathione cycling, perfusion imaging, and molecular characterization of clinically relevant alterations including IDH1, TERT, and c-MYC-associated metabolic programs. In addition, we discuss recent advances in acquisition methods, image standardization, and multimodal integration with conventional MRI and positron emission tomography. Although several technical and logistical challenges remain, hpMRI is an investigational, radiation-free metabolic imaging modality with potential applications in diagnosis, molecular stratification, and treatment monitoring; however, substantial technical, regulatory, logistical, and economic barriers currently limit routine clinical use, molecular stratification, therapeutic monitoring, and precision medicine approaches in neuro-oncology. Continued clinical translation and development of novel metabolic probes may further expand its role in brain tumors and other neurological diseases. Full article

Background/Objectives: Myeloproliferative neoplasms (MPNs) are chronic myeloid malignancies characterized by substantial genetic heterogeneity. Although routine molecular evaluation focuses on canonical driver alterations (BCR::ABL1, JAK2, CALR, and MPL), additional somatic mutations have important diagnostic and prognostic implications. Methods: We retrospectively analyzed 1209 consecutive patients who underwent peripheral blood next-generation sequencing (NGS) for suspected or established MPNs using a comprehensive 75-gene DNA/RNA panel. Results: Canonical driver alterations were identified in 141 patients, while 1068 were driver-negative. Retrospective analysis demonstrated that 251 patients (21%) harbored at least one additional pathogenic or likely pathogenic mutation that was not routinely reported. Among driver-positive patients, 57 of 141 (40%) carried clinically relevant co-mutations, including high-molecular-risk genes such as ASXL1, TP53, SRSF2, SF3B1, RUNX1, U2AF1, and IDH2. Furthermore, 194 of 1068 (18%) driver-negative patients harbored additional pathogenic mutations, several of which supported clonal hematopoiesis or alternative myeloid neoplasms. Peripheral blood and bone marrow molecular findings demonstrated high concordance (R² = 0.87). Conclusions: These findings indicate that comprehensive NGS performed at the time of initial evaluation provides clinically relevant genomic information beyond canonical driver mutations, improves disease classification and risk stratification, and may facilitate earlier diagnosis and personalized management of patients with suspected MPNs. Full article