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Radiologie (Heidelberg, Germany) Aug 2023Pediatric spinal tumors are rare and manifest frequently with unspecific symptoms, frequently resulting in delayed diagnosis. Many spinal tumor entities in children and... (Review)
Review
Pediatric spinal tumors are rare and manifest frequently with unspecific symptoms, frequently resulting in delayed diagnosis. Many spinal tumor entities in children and adults are similar, but the lesions demonstrate a different prevalence and sometimes a different molecular genetic profile in children. For radiological evaluation of spinal tumor lesions, it is helpful to define the affected anatomical compartment. Important intradural pediatric tumor entities are astrocytomas, ependymomas, nerve sheath tumors, and liquorgenic metastases of intracranial neoplasms. Extradural masses are mostly primary tumors originating from osseous elements of the spine. Bone metastases are rare in children and can occur, for example, in neuroblastoma. Magnetic resonance imaging (MRI) is the most important noninvasive method for radiological spinal tumor evaluation.
Topics: Adult; Humans; Child; Spinal Neoplasms; Spinal Cord Neoplasms; Spine; Magnetic Resonance Imaging; Astrocytoma
PubMed: 37407746
DOI: 10.1007/s00117-023-01178-9 -
Continuum (Minneapolis, Minn.) Dec 2023This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily...
OBJECTIVE
This article highlights key aspects of the diagnosis and management of adult-type diffuse gliomas, including glioblastomas and IDH-mutant gliomas relevant to the daily practice of the general neurologist.
LATEST DEVELOPMENTS
The advances in molecular characterization of gliomas have translated into more accurate prognostication and tumor classification. Gliomas previously categorized by histological appearance solely as astrocytomas or oligodendrogliomas are now also defined by molecular features. Furthermore, ongoing clinical trials have incorporated these advances to tailor more effective treatments for specific glioma subtypes.
ESSENTIAL POINTS
Despite recent insights into the molecular aspects of gliomas, these tumors remain incurable. Care for patients with these complex tumors requires a multidisciplinary team in which the general neurologist has an important role. Efforts focus on translating the latest data into more effective therapies that can prolong survival.
Topics: Adult; Humans; Brain Neoplasms; Glioma; Oligodendroglioma; Astrocytoma; Prognosis; Mutation; Isocitrate Dehydrogenase
PubMed: 38085893
DOI: 10.1212/CON.0000000000001352 -
Genes & Development Jun 2024Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic... (Review)
Review
Glioblastoma (GBM) is the most aggressive primary brain cancer. These tumors exhibit high intertumoral and intratumoral heterogeneity in neoplastic and nonneoplastic compartments, low lymphocyte infiltration, and high abundance of myeloid subsets that together create a highly protumorigenic immunosuppressive microenvironment. Moreover, heterogeneous GBM cells infiltrate adjacent brain tissue, remodeling the neural microenvironment to foster tumor electrochemical coupling with neurons and metabolic coupling with nonneoplastic astrocytes, thereby driving growth. Here, we review heterogeneity in the GBM microenvironment and its role in low-to-high-grade glioma transition, concluding with a discussion of the challenges of therapeutically targeting the tumor microenvironment and outlining future research opportunities.
Topics: Humans; Tumor Microenvironment; Glioblastoma; Brain Neoplasms; Animals
PubMed: 38811170
DOI: 10.1101/gad.351427.123 -
Genes Apr 2024Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical... (Review)
Review
Glioblastoma, the most aggressive and common malignant primary brain tumour, is characterized by infiltrative growth, abundant vascularization, and aggressive clinical evolution. Patients with glioblastoma often face poor prognoses, with a median survival of approximately 15 months. Technological progress and the subsequent improvement in understanding the pathophysiology of these tumours have not translated into significant achievements in therapies or survival outcomes for patients. Progress in molecular profiling has yielded new omics data for a more refined classification of glioblastoma. Several typical genetic and epigenetic alterations in glioblastoma include mutations in genes regulating receptor tyrosine kinase (RTK)/rat sarcoma (RAS)/phosphoinositide 3-kinase (PI3K), p53, and retinoblastoma protein (RB) signalling, as well as mutation of isocitrate dehydrogenase (), methylation of O-methylguanine-DNA methyltransferase (), amplification of epidermal growth factor receptor vIII, and codeletion of 1p/19q. Certain microRNAs, such as miR-10b and miR-21, have also been identified as prognostic biomarkers. Effective treatment options for glioblastoma are limited. Surgery, radiotherapy, and alkylating agent chemotherapy remain the primary pillars of treatment. Only promoter methylation of the gene predicts the benefit from alkylating chemotherapy with temozolomide and it guides the choice of first-line treatment in elderly patients. Several targeted strategies based on tumour-intrinsic dominant signalling pathways and antigenic tumour profiles are under investigation in clinical trials. This review explores the potential genetic and epigenetic biomarkers that could be deployed as analytical tools in the diagnosis and prognostication of glioblastoma. Recent clinical advancements in treating glioblastoma are also discussed, along with the potential of liquid biopsies to advance personalized medicine in the field of glioblastoma, highlighting the challenges and promises for the future.
Topics: Glioblastoma; Humans; Brain Neoplasms; Biomarkers, Tumor
PubMed: 38674436
DOI: 10.3390/genes15040501 -
Genes & Development Aug 2023The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of... (Review)
Review
The different cell types in the brain have highly specialized roles with unique metabolic requirements. Normal brain function requires the coordinated partitioning of metabolic pathways between these cells, such as in the neuron-astrocyte glutamate-glutamine cycle. An emerging theme in glioblastoma (GBM) biology is that malignant cells integrate into or "hijack" brain metabolism, co-opting neurons and glia for the supply of nutrients and recycling of waste products. Moreover, GBM cells communicate via signaling metabolites in the tumor microenvironment to promote tumor growth and induce immune suppression. Recent findings in this field point toward new therapeutic strategies to target the metabolic exchange processes that fuel tumorigenesis and suppress the anticancer immune response in GBM. Here, we provide an overview of the intercellular division of metabolic labor that occurs in both the normal brain and the GBM tumor microenvironment and then discuss the implications of these interactions for GBM therapy.
Topics: Humans; Glioblastoma; Brain; Neuroglia; Astrocytes; Neurons; Tumor Microenvironment
PubMed: 37648371
DOI: 10.1101/gad.350693.123 -
Advanced Science (Weinheim,... Apr 2024Organoids are becoming increasingly relevant in biology and medicine for their physiological complexity and accuracy in modeling human disease. To fully assess their...
Organoids are becoming increasingly relevant in biology and medicine for their physiological complexity and accuracy in modeling human disease. To fully assess their biological profile while preserving their spatial information, spatiotemporal imaging tools are warranted. While previously developed imaging techniques, such as four-dimensional (4D) live imaging and light-sheet imaging have yielded important clinical insights, these technologies lack the combination of cyclic and multiplexed analysis. To address these challenges, bioorthogonal click chemistry is applied to display the first demonstration of multiplexed cyclic imaging of live and fixed patient-derived glioblastoma tumor organoids. This technology exploits bioorthogonal click chemistry to quench fluorescent signals from the surface and intracellular of labeled cells across multiple cycles, allowing for more accurate and efficient molecular profiling of their complex phenotypes. Herein, the versatility of this technology is demonstrated for the screening of glioblastoma markers in patient-derived human glioblastoma organoids while conserving their viability. It is anticipated that the findings and applications of this work can be broadly translated into investigating physiological developments in other organoid systems.
Topics: Humans; Glioblastoma; Diagnostic Imaging; Organoids
PubMed: 38326078
DOI: 10.1002/advs.202309289 -
Cells Aug 2023Glioblastoma is the most aggressive intracranial tumor [...].
Glioblastoma is the most aggressive intracranial tumor [...].
Topics: Glioblastoma; Humans; Brain Neoplasms; Drug Resistance, Neoplasm
PubMed: 37626873
DOI: 10.3390/cells12162063 -
Redox Biology Aug 2023Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (HS)...
PURPOSE
Glioblastoma (GBM) is the most common type of adult brain tumor with extremely poor survival. Cystathionine-gamma lyase (CTH) is one of the main Hydrogen Sulfide (HS) producing enzymes and its expression contributes to tumorigenesis and angiogenesis but its role in glioblastoma development remains poorly understood.
METHODS
and Principal Results: An established allogenic immunocompetent in vivo GBM model was used in C57BL/6J WT and CTH KO mice where the tumor volume and tumor microvessel density were blindly measured by stereological analysis. Tumor macrophage and stemness markers were measured by blinded immunohistochemistry. Mouse and human GBM cell lines were used for cell-based analyses. In human gliomas, the CTH expression was analyzed by bioinformatic analysis on different databases. In vivo, the genetic ablation of CTH in the host led to a significant reduction of the tumor volume and the protumorigenic and stemness transcription factor sex determining region Y-box 2 (SOX2). The tumor microvessel density (indicative of angiogenesis) and the expression levels of peritumoral macrophages showed no significant changes between the two genotypes. Bioinformatic analysis in human glioma tumors revealed that higher CTH expression is positively correlated to SOX2 expression and associated with worse overall survival in all grades of gliomas. Patients not responding to temozolomide have also higher CTH expression. In mouse or human GBM cells, pharmacological inhibition (PAG) or CTH knockdown (siRNA) attenuates GBM cell proliferation, migration and stem cell formation frequency.
MAJOR CONCLUSIONS
Inhibition of CTH could be a new promising target against glioblastoma formation.
Topics: Mice; Humans; Animals; Glioblastoma; Cystathionine gamma-Lyase; Mice, Inbred C57BL; Temozolomide; Cell Line; Cell Line, Tumor
PubMed: 37300955
DOI: 10.1016/j.redox.2023.102773 -
Brain Pathology (Zurich, Switzerland) Sep 2023Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and...
Fusions involving CRAF (RAF1) are infrequent oncogenic drivers in pediatric low-grade gliomas, rarely identified in tumors bearing features of pilocytic astrocytoma, and involving a limited number of known fusion partners. We describe recurrent TRAK1::RAF1 fusions, previously unreported in brain tumors, in three pediatric patients with low-grade glial-glioneuronal tumors. We present the associated clinical, histopathologic and molecular features. Patients were all female, aged 8 years, 15 months, and 10 months at diagnosis. All tumors were located in the cerebral hemispheres and predominantly cortical, with leptomeningeal involvement in 2/3 patients. Similar to previously described activating RAF1 fusions, the breakpoints in RAF1 all occurred 5' of the kinase domain, while the breakpoints in the 3' partner preserved the N-terminal kinesin-interacting domain and coiled-coil motifs of TRAK1. Two of the three cases demonstrated methylation profiles (v12.5) compatible with desmoplastic infantile ganglioglioma (DIG)/desmoplastic infantile astrocytoma (DIA) and have remained clinically stable and without disease progression/recurrence after resection. The remaining tumor was non-classifiable; with focal recurrence 14 months after initial resection; the patient remains symptom free and without further recurrence/progression (5 months post re-resection and 19 months from initial diagnosis). Our report expands the landscape of oncogenic RAF1 fusions in pediatric gliomas, which will help to further refine tumor classification and guide management of patients with these alterations.
Topics: Child; Female; Humans; Adaptor Proteins, Vesicular Transport; Astrocytoma; Brain Neoplasms; Ganglioglioma; Glioma; Oncogene Fusion
PubMed: 37399073
DOI: 10.1111/bpa.13185