Acta Neuropathologica Communications最新文献

Currently there are no therapeutic agents that are effective against both vestibular schwannoma and meningioma, the two most common tumour types affecting patients with the rare tumour predisposition syndrome NF2-related schwannomatosis. This study aimed to characterise the similarities and differences in the tumour immune microenvironments of meningioma and vestibular schwannoma to identify potential therapeutic targets viable for both tumour types. Publicly available bulk Affymetrix expression data for both meningioma (n = 22) and vestibular schwannoma (n = 31) were used to compare gene expression and signalling pathways, and deconvolved to predict the abundance of the immune cell types present. Publicly available single cell RNA sequencing data for both meningioma (n = 6) and vestibular schwannoma (n = 15) was used to further investigate specific T cell and macrophage subtypes for their signalling pathways, gene expression, and drug targets for predicted drug repurposing in both tumour types. Immune cells comprised a larger proportion of the vestibular schwannoma tumour microenvironment compared to meningioma and included a significantly higher abundance of alternatively activated macrophages. However, these alternatively activated macrophages, alongside other immune cell subtypes such as CD8 + T cells and classically activated macrophages, were predicted to be more active in meningioma than vestibular schwannoma. Despite these differences, T cells and tumour associated macrophages of both vestibular schwannoma and meningioma shared drug-target kinases amenable to drug repurposing with Food and Drug Administration (FDA) drugs approved for other conditions. These include bosutinib, sorafenib, mitoxantrone, and nintedanib which are yet to be clinically investigated for vestibular schwannoma or meningioma. Drug repurposing may offer an expedited route to the clinical translation of approved drugs effective for treating both meningioma and vestibular schwannoma to benefit NF2-related schwannomatosis patients.

Embryonal tumors with multilayered rosettes (ETMR) are rare embryonal tumors that usually affect children under two years old. They are characterized histologically by the presence of multilayered rosettes and by the immunohistochemical expression of LIN28A. Their genetic hallmarks include C19MC amplification, which is most common, followed by DICER1 mutation. Each of these alterations correlates with a specific methylation class in the Heidelberg central nervous system tumor classifier and the National Institutes of Health brain tumor classifier. Meanwhile, 2.5 percent of LIN28A-positive embryonal tumors lack the previously mentioned genetic alterations associated with ETMR. Here, we present and discuss a case of this type. A posterior fossa tumor was found in a five-month-old infant. Histologically, the lesion appeared as an embryonal tumor, lacking multilayered rosettes but showing focal positivity for LIN28A. It did not show C19MC amplification or DICER1 mutation, yet it clustered within the ETMR non-C19MC-altered methylation class of the Heidelberg classifier (V12.5) and the ETMR-DICER class of the NIH classifier. Additionally, a YAP1::MAML2 fusion was identified, a finding not yet associated with these methylation classes.

Introduction: Dedifferentiated (DC) and poorly differentiated chordomas (PDC) are rare, aggressive chordomas with a significantly worse prognosis than conventional chordomas (CC). The molecular mechanisms driving them remain poorly understood.

Methods: Matched primary CC and recurrent DC cryopreserved samples from one patient were analyzed with whole-exome sequencing (WES). Samples from three additional DCs and one PDC underwent targeted sequencing of cancer-related genes. Furthermore, 102 CC cases - 32 novel and 70 from literature, were analyzed. Functional and survival analysis was performed.

Results: WES revealed striking genomic changes during progression from CC to DC, with the number of somatic mutations increasing from 211 in primary to 430 in the recurrent DC; recurrence acquired TP53 and BRCA1 deleterious mutations, along with copy-number alterations, including loss of 6q containing the TBXT locus. Targeted sequencing identified TP53 mutations in 4/5 DC&PDC cases compared to 1/102 cases in combined CC cohorts (p = 2.7×10^-5, OR=162.9). In 3 recurrent DC samples with TP53 variant, presence of the mutation was assessed in primary CC sample and in neither, this variant was found. Literature review revealed TP53 mutations in 9/23 (39%) DC&PDC cases versus 5/445 (1.24%) CC cases. Survival analysis demonstrated that TP53 mutations confer a significantly worse prognosis in DC patients (p = 0.03).

Conclusion: TP53 mutations are acquired during chordoma progression and are associated with an aggressive phenotype; TP53 sequencing could serve as a prognostic and potentially predictive biomarker in aggressive chordomas.

Vincristine is an essential chemotherapy agent administered for various pediatric cancers including acute lymphoblastic leukemia (ALL). While multi-agent chemotherapy for pediatric ALL is highly curative, with survival approaching 95%, it carries the risk of irreversible neurocognitive late effects. Vincristine is known to cause peripheral neuropathy, but its relationship to brain toxicity remains understudied. We investigated vincristine-mediated brain toxicity in young mice lacking Sarm1, a gene whose deletion protects against vincristine-induced peripheral neuropathy. Littermate wildtype and knockout mice were randomly assigned to saline or vincristine groups. In vivo MRI was performed from childhood to early adulthood to measure brain structure volumes, followed by ex vivo diffusion tensor imaging (DTI) to assess microstructural changes. In a separate cohort, electron microscopy (EM) quantified axon morphology in the sciatic nerve and corpus callosum. Vincristine induced significant volume reduction across the brain, while Sarm1 knockout reduced loss in both grey and white matter. Several regions, including the amygdala and dentate gyrus, showed near-complete recovery in knockouts. DTI revealed limited changes with no genotype differences. EM demonstrated vincristine-induced axon morphology alterations in wildtype mice in both the sciatic nerve and corpus callosum. Sarm1 knockout rescued sciatic nerve morphology but not corpus callosum axons. These findings suggest that SARM1-mediated peripheral axon damage may contribute to vincristine-induced brain volume deficits, whereas brain axons may be affected through distinct, SARM1-independent mechanisms. These results suggest a link between vincristine-induced peripheral axon damage and alterations in brain development, with implications for neurocognitive deficits experienced by ALL survivors. Our results suggest that mitigating vincristine-induced peripheral neuropathy may also help reduce neurocognitive deficits in pediatric patients undergoing vincristine treatment.