VGLL-fusions define a new class of intraparenchymal CNS schwannoma.

Background: Intracerebral schwannomas are rare tumors resembling their peripheral nerve sheath counterparts but localized in the CNS. They are not classified as a separate tumor type in the 2021 WHO classification. This study aimed to compile and characterize these rare neoplasms morphologically and molecularly.

Dominant stop-loss HNRNPA1 variants in juvenile-onset myopathy.

Introduction/aims: Heterogeneous nuclear ribonucleoprotein A1 is involved in nucleic acid homeostatic functions. The encoding gene HNRNPA1 has been associated with several neuromuscular disorders including an amyotrophic lateral sclerosis-like phenotype, distal hereditary motor neuropathy, multisystem proteinopathy, and various myopathies. We report two unrelated individuals with monoallelic stop loss variants affecting the same codon of HNRNPA1.

Multi-omic approach identifies hypoxic tumor-associated myeloid cells that drive immunobiology of high-risk pediatric ependymoma.

Ependymoma (EPN) is a devastating childhood brain tumor. Single-cell analyses have illustrated the cellular heterogeneity of EPN tumors, identifying multiple neoplastic cell states including a mesenchymal-differentiated subpopulation which characterizes the PFA1 subtype. Here, we characterize the EPN immune environment, in the context of both tumor subtypes and tumor cell subpopulations using single-cell sequencing (scRNAseq, n = 27), deconvolution of bulk tumor gene expression (n = 299), spatial proteomics (n = 54), and single-cell cytokine release assays (n = 12).

Spatially resolved transcriptomic profiles reveal unique defining molecular features of infiltrative 5ALA-metabolizing cells associated with glioblastoma recurrence.

Background: Spatiotemporal heterogeneity originating from genomic and transcriptional variation was found to contribute to subtype switching in isocitrate dehydrogenase-1 wild-type glioblastoma (GBM) prior to and upon recurrence. Fluorescence-guided neurosurgical resection utilizing 5-aminolevulinic acid (5ALA) enables intraoperative visualization of infiltrative tumors outside the magnetic resonance imaging contrast-enhanced regions. The cell population and functional status of tumor responsible for enhancing 5ALA-metabolism to fluorescence-active PpIX remain elusive.

Disproportionate Expression of ATM in Cerebellar Cortex During Human Neurodevelopment.

Cerebellar neurodegeneration is a classical feature of ataxia telangiectasia (A-T), an autosomal recessive condition caused by loss-of-function mutation of the ATM gene, a gene with multiple regulatory functions. The increased vulnerability of cerebellar neurones to degeneration compared to cerebral neuronal populations in individuals with ataxia telangiectasia implies a specific importance of intact ATM function in the cerebellum. We hypothesised that there would be elevated transcription of ATM in the cerebellar cortex relative to ATM expression in other grey matter regions during neurodevelopment in individuals without A-T.

Untargeted Metabolomic Characterization of Glioblastoma Intra-Tumor Heterogeneity Using OrbiSIMS.

Glioblastoma (GBM) is an incurable brain cancer with a median survival of less than two years from diagnosis. The standard treatment of GBM is multimodality therapy comprising surgical resection, radiation, and chemotherapy. However, prognosis remains poor, and there is an urgent need for effective anticancer drugs.

Optimizing biomarkers for accurate ependymoma diagnosis, prognostication, and stratification within International Clinical Trials: A BIOMECA study.

Background: Accurate identification of brain tumor molecular subgroups is increasingly important. We aimed to establish the most accurate and reproducible ependymoma subgroup biomarker detection techniques, across 147 cases from International Society of Pediatric Oncology (SIOP) Ependymoma II trial participants, enrolled in the pan-European "Biomarkers of Ependymoma in Children and Adolescents (BIOMECA)" study.

Methods: Across 6 European BIOMECA laboratories, we evaluated epigenetic profiling (DNA methylation array); immunohistochemistry (IHC) for nuclear p65-RELA, H3K27me3, and Tenascin-C; copy number analysis via fluorescent in situ hybridization (FISH) and MLPA (1q, CDKN2A), and MIP and DNA methylation array (genome-wide copy number evaluation); analysis of ZFTA- and YAP1-fusions by RT-PCR and sequencing, Nanostring and break-apart FISH.

Characterisation of Expression the Arginine Pathway Enzymes in Childhood Brain Tumours to Determine Susceptibility to Therapeutic Arginine Depletion.

Despite significant improvements in treatment and survival in paediatric cancers, outcomes for children with brain tumours remain poor. Novel therapeutic approaches are needed to improve survival and quality of survival. Extracellular arginine dependency (auxotrophy) has been recognised in several tumours as a potential therapeutic target.

Olfactory neuroblastoma limited to sphenoid sinus.

Olfactory neuroblastoma (ONB) is a rare tumour of the skull base, typically originating from the nasal cavity and around the cribriform plate. We present the rare case of ONB originating from and limited to the sphenoid sinus in a 42-year old lady. Pre-operatively the lesion was thought to be a sinonasal polyp and underwent functional endoscopic sinus surgery (FESS) and total excision of the polypoid lesion.

Glioblastoma in Beckwith-Wiedemann syndrome: first case report and review of potential pathomechanisms.

Beckwith-Wiedemann syndrome (BWS) is a rare congenital overgrowth syndrome associated with certain childhood tumours. We present the case of a 36-year-old lady with BWS who developed a left frontoinsular secondary glioblastoma. This is the first case report in the literature of glioblastoma associated with BWS.

Improved survival outcomes despite older age at diagnosis: an era-by-era analysis of patients with primary central nervous system lymphoma treated at a single referral centre in the United Kingdom.

Observational studies with long-term follow-up of patients with primary central nervous system lymphoma (PCNSL) are scarce. Patient data over a period of four decades were retrospectively analysed from databases at Nottingham University Hospitals Trust, UK. The cohort was delineated by two distinct therapeutic eras; the first from 01/01/1982 to 31/12/2010 (n = 147) and the second 01/01/2011 to 31/07/2020 (n = 125).

Identifying cellular signalling molecules in developmental disorders of the brain: Evidence from focal cortical dysplasia and tuberous sclerosis.

Aims: We understand little of the pathogenesis of developmental cortical lesions, because we understand little of the diversity of the cell types that contribute to the diseases or how those cells interact. We tested the hypothesis that cellular diversity and cell-cell interactions play an important role in these disorders by investigating the signalling molecules in the commonest cortical malformations that lead to childhood epilepsy, focal cortical dysplasia (FCD) and tuberous sclerosis (TS).

Methods: Transcriptional profiling clustered cases into molecularly distinct groups.

A case series of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

In this study, we report three paediatric cases of Diffuse Glioneuronal Tumours with Oligodendroglioma-like features and Nuclear Clusters (DGONC).

Usefulness of PAX8 Immunohistochemistry in Adult Intraocular Tumor Diagnosis.

Purpose: To evaluate the distribution of the PAX8 transcription factor protein in ocular tissues and to investigate if immunohistochemical stains for this biomarker are useful in the diagnosis of intraocular tumors.

Design: Observational case series.

Participants: Excision and cytologic analysis specimens of 6 ciliary body epithelial neoplasms, 2 iris epithelial neoplasms, 3 retinal pigment epithelial neoplasms, 3 intraocular medulloepitheliomas, 15 uveal melanomas, and 5 uveal melanocytomas.

A retrospective analysis of recurrent pediatric ependymoma reveals extremely poor survival and ineffectiveness of current treatments across central nervous system locations and molecular subgroups.

Background: Relapse occurs in 50% of pediatric ependymoma cases and has poor prognosis. Few studies have investigated the clinical progress of relapsed disease, and treatment lacks a standardized approach.

Methods And Materials: We analyzed 302 pediatric ependymoma cases.

Thioredoxin System Protein Expression Is Associated with Poor Clinical Outcome in Adult and Paediatric Gliomas and Medulloblastomas.

The thioredoxin (Trx) system is an important enzyme family that regulates cellular redox homeostasis. Protein expression of Trx system family members has been assessed in various cancers and linked to various clinicopathological variables, disease progression, treatment response and survival outcomes but information is lacking in brain tumours. Expression of the system was therefore examined, by immunohistochemistry in different brain tumour types, adult and paediatric cases, to determine if expression was of importance to clinical outcome.

Tissue metabolite profiles for the characterisation of paediatric cerebellar tumours.

Paediatric brain tumors are becoming well characterized due to large genomic and epigenomic studies. Metabolomics is a powerful analytical approach aiding in the characterization of tumors. This study shows that common cerebellar tumors have metabolite profiles sufficiently different to build accurate, robust diagnostic classifiers, and that the metabolite profiles can be used to assess differences in metabolism between the tumors.

Continued 26S proteasome dysfunction in mouse brain cortical neurons impairs autophagy and the Keap1-Nrf2 oxidative defence pathway.

The ubiquitin-proteasome system (UPS) and macroautophagy (autophagy) are central to normal proteostasis and interdependent in that autophagy is known to compensate for the UPS to alleviate ensuing proteotoxic stress that impairs cell function. UPS and autophagy dysfunctions are believed to have a major role in the pathomechanisms of neurodegenerative disease. Here we show that continued 26S proteasome dysfunction in mouse brain cortical neurons causes paranuclear accumulation of fragmented dysfunctional mitochondria, associated with earlier recruitment of Parkin and lysine 48-linked ubiquitination of mitochondrial outer membrane (MOM) proteins, including Mitofusin-2.

Deep sequencing reveals persistence of cell-associated mumps vaccine virus in chronic encephalitis.

Routine childhood vaccination against measles, mumps and rubella has virtually abolished virus-related morbidity and mortality. Notwithstanding this, we describe here devastating neurological complications associated with the detection of live-attenuated mumps virus Jeryl Lynn (MuV) in the brain of a child who had undergone successful allogeneic transplantation for severe combined immunodeficiency (SCID). This is the first confirmed report of MuV associated with chronic encephalitis and highlights the need to exclude immunodeficient individuals from immunisation with live-attenuated vaccines.

Brain weight in sudden unexpected death in infancy: experience from a large single-centre cohort.

Aims: Published reports of brain weight in sudden infant death syndrome (SIDS) are contradictory, although several have concluded that brain weight is increased in SIDS compared with controls or reference data. This is important as, if brain weight is significantly different, it may be of diagnostic use or provide insights into the aetiology of SIDS. The aim of this study was to use a large series of well-characterized sudden unexpected infant deaths from a single centre to provide definitive data regarding this issue.