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Simple Summary: Immune checkpoint blockade has shown remarkable efficacy across various cancers but has failed to improve outcomes in patients with relapsed medulloblastoma (MB). While it is thought that the cold, immunosuppressive tumor microenvironment of MB accounts for this poor efficacy, the precise mechanisms contributing to immune suppression in this context remain unclear. In this study, we explore the immune landscape of MB using a previously unexplored syngeneic mouse model. Our study demonstrates that this model faithfully recapitulates the cold, immunosuppressive tumor microenvironment observed in human disease. Importantly, our research uncovers mechanisms employed by myeloid cells and tumor cells to evade immune detection while highlighting the therapeutic potential of targeting V-domain Ig Suppressor of T-cell Activation (VISTA), a novel inhibitory immune checkpoint, to enhance anti-tumor immunity. Background: Relapsed medulloblastoma (MB) poses a significant therapeutic challenge due to its highly immunosuppressive tumor microenvironment. Immune checkpoint inhibitors (ICIs) have struggled to mitigate this challenge, largely due to low T-cell infiltration and minimal PD-L1 expression. Identifying the mechanisms driving low T-cell infiltration is crucial for developing more effective immunotherapies. Methods: We utilize a syngeneic mouse model to investigate the tumor immune microenvironment of MB and compare our findings to transcriptomic and proteomic data from human MB. Results: Flow cytometry reveals a notable presence of CD45hi/CD11bhi macrophage-like and CD45int/CD11bint microglia-like tumor-associated macrophages (TAMs), alongside regulatory T-cells (Tregs), expressing high levels of the inhibitory checkpoint molecule VISTA. Compared to sham control mice, the CD45hi/CD11bhi compartment significantly expands in tumor-bearing mice and exhibits a myeloid-specific signature composed of VISTA, CD80, PD-L1, CTLA-4, MHCII, CD40, and CD68. These findings are corroborated by proteomic and transcriptomic analyses of human MB samples. Immunohistochemistry highlights an abundance of VISTA-expressing myeloid cells clustering at the tumor–cerebellar border, while T-cells are scarce and express FOXP3. Additionally, tumor cells exhibit immunosuppressive properties, inhibiting CD4 T-cell proliferation in vitro. Identification of VISTA's binding partner, VSIG8, on tumor cells, and its correlation with increased VISTA expression in human transcriptomic analyses suggests a potential therapeutic target. Conclusions: This study underscores the multifaceted mechanisms of immune evasion in MB and highlights the therapeutic potential of targeting the VISTA–VSIG axis to enhance anti-tumor responses. [ABSTRACT FROM AUTHOR]

From the existing millions of fungal species, only a few cause disease. In this study, we investigated invasive fungal infections in the head and neck (H&N) over a 19-year period (2005 to 2024) at a large academic healthcare system. Among the 413 documented fungal H&N infections, 336 were noninvasive, and 77 were invasive. The highest incidence of invasive infections occurred in the sinonasal cavities, with a 15-fold difference compared to other sites. Most infections affected adults over 40 years old. The most common organisms were Mucorales (51%), hyaline molds (29%), and Candida (11%). Risk factors included malignancy, transplant, diabetes, and illicit drug use. Mortality was high in patients with malignancy and/or transplant. Infections affecting the mandible were usually a complication of osteoradionecrosis and were associated with the coinfection of Candida and Actinomyces. At other sites, infections were rare and were usually the result of penetrating injuries or immunosuppression. Treatment typically involved a combination of antifungals and surgical procedures. [ABSTRACT FROM AUTHOR]

We have identified a discrete, focal telomere DNA expansion phenotype in the photoreceptor cell layer of normal, non‐neoplastic human retinas. This phenotype is similar to that observed in a subset of human cancers, including a large fraction of tumors of the central nervous system, which maintain their telomeres via the non‐telomerase‐mediated alternative lengthening of telomeres (ALT) mechanism. We observed that these large, ultra‐bright telomere DNA foci are restricted to the rod photoreceptors and are not observed in other cell types. Additionally, focus‐positive rod cells are dispersed homogeneously throughout the posterior retinal photoreceptor cell layer and appear to be human‐specific. We examined 108 normal human retinas obtained at autopsy from a wide range of ages. These large, ultra‐bright telomere DNA foci were not observed in infants before 6 months of age; however, the prevalence of focus‐positive rod cells dramatically increased throughout life. To investigate associations between this phenotype and retinal pathology, we assessed adult glaucoma (N = 29) and diabetic retinopathy (N = 38) cases. Focus‐positive rod cells were prominent in these diseases. When compared to the normal group, after adjusting for age, logistic regression modeling revealed significantly increased odds of falling in the high category of focus‐positive rod cells for glaucoma and diabetic retinopathy. In summary, we have identified a dramatic telomere alteration associated with aging and diseases affecting the retina. [ABSTRACT FROM AUTHOR]

Objective : To determine imaging features that may separate adamantinomatous and papillary variants of craniopharyngiomas given that tumors with adamantinomatous signature features are associated with higher recurrence rates, morbidity, and mortality. We specifically reviewed calcification on CT, T1 bright signal intensity, and cystic change on T2 weighted images for differentiating these two types. Methods : We retrospectively reviewed the MRI and CT studies in 38 consecutive patients with pathologically proven craniopharyngiomas between January 2004 and February 2014 for the presence of calcification on CT scans, bright signal intensity on T1 weighted images, and cystic change on T2 weighted images. Results : Of the 38 craniopharyngiomas, 30 were adamantinomatous type and 8 were papillary type. On CT scans, calcification was present in 25 of 38 tumors. All calcified tumors were adamantinomatous type. Twenty four of 38 tumors had bright signal intensity on T1 weighted images. Of these 24 tumors, 22 (91.7%) were adamantinomatous and 2 were papillary type. Cystic change on T2 weighted images was noted in 37 of 38 tumors; only 1 tumor with papillary type did not show cystic change. Conclusion : T1 bright signal intensity and calcification on CT scans uniformly favor the adamantinomatous type over papillary type of craniopharyngioma in children. However, these findings are more variable in adults where calcification and T1 bright signal intensity occur in 70.6% and 58.8% respectively of adult adamantinomatous types of craniopharyngiomas. [ABSTRACT FROM AUTHOR]

Gliomas are among the most frequent adult primary brain tumors. Mutations in IDH1, a metabolic enzyme, strongly correlate with secondary glioblastomas and increased survival. cMYC is an oncogene also implicated in aberrant metabolism, but its prognostic impact remains unclear. Recent genotyping studies also showed SNP variants near the cMYC gene locus, associate with an increased risk for development of IDH1/2 mutant gliomas suggesting a possible interaction between cMYC and IDH1. We evaluated nuclear cMYC protein levels and IDH1 (R132H) by immunohistochemistry in patients with oligodendroglioma/oligoastrocytomas (n = 20), astrocytomas (grade II) (n = 19), anaplastic astrocytomas (n = 21) or glioblastomas (n = 111). Of 158 tumors with sufficient tissue, 110 (70 %) showed nuclear cMYC immunopositivity--most frequent (95 %, χ(2) p = 0.0248) and intense (mean 1.33, ANOVA p = 0.0179) in anaplastic astrocytomas versus glioblastomas (63 %) or low grade gliomas (74 %). cMYC expression associated with younger age as well as p53 immunopositivity (OR = 3.6, p = 0.0332) and mutant IDH1 (R132H) (OR = 7.4, p = 0.06) among malignant gliomas in our cohort. Independent analysis of the publically available TCGA glioblastoma dataset confirmed our strong association between cMYC and mutant IDH1 expression. Both IDH1 (R132H) and cMYC protein expression were associated with improved overall survival by univariate analysis. However, cMYC co-expression associated with shortened time to malignant transformation and overall survival among IDH1 (R132H) mutants in both univariate and multivariate analyses. In summary, our findings suggest that cMYC may be associated with a unique clinicopathologic and biologic group of infiltrating gliomas and help mediate the malignant transformation of IDH1 mutant gliomas.

An outbreak of fungal infections has been identified in patients who received epidural injections of methylprednisolone acetate that was contaminated with environmental molds. In this report, we present the mycological and histopathological findings in an index case of Exserohilum meningitis and vasculitis in an immunocompetent patient, who received a cervical spine epidural steroid injection for chronic neck pain 1 week before the onset of fulminant meningitis with subsequent multiple brain and spinal cord infarcts. The fungus was recovered from two separate cerebrospinal fluid specimens collected before initiation of antifungal therapy and at autopsy on standard bacterial and fungal culture media. The mold was identified phenotypically as Exserohilum species. DNA sequencing targeting the internal transcribed spacer region and D1/D2 region of 28S ribosomal DNA enabled further speciation as E. rostratum. Gross examination at autopsy revealed moderate brain edema with bilateral uncal herniation and a ventriculostomy tract to the third ventricle. The brainstem, cerebellum, and right orbitofrontal cortex were soft and friable, along with hemorrhages in the cerebellar vermis and thalamus. Microscopic examination demonstrated numerous fungi with septate hyphae invading blood vessel walls and inducing acute necrotizing inflammation. The leptomeninges were diffusely infiltrated by mixed inflammatory cells along with scattered foci of fungal elements. This is the first report of iatrogenic E. rostratum meningitis in humans. This report describes the microbiological procedures and histopathological features for the identification of E. rostratum (a pigmented vascularly invasive fungi), the cause of a current nationwide outbreak of fatal fungal meningitis.

Purpose: A rare, familial early-onset form of Fuchs corneal dystrophy (FCD) is caused by mutation in the COL8A2 gene. This study describes the aberrant pattern of distribution of collagen type VIII and basement membrane components in Descemet's membrane (DM) and endothelium of three individuals with the same L450W mutation that represent different stages of early-onset FCD., Methods: Immunohistochemical studies with bright field, fluorescence, and confocal microscopy characterized the pathology of sectioned corneal buttons with antibodies against COL8A1, COL8A2, COL4, laminin, and fibronectin. A portion of each was processed for electron microscopy., Results: Histologic examination of pathologic changes in case 1 demonstrated relative preservation of the endothelium, whereas in case 2 much of this layer was atrophic and in case 3 there was complete loss of the endothelium. DM also increased in thickness to 25 mum for case 1, to 31 mum for case 2, and to 38 mum for case 3. Case 1 was the only specimen to reveal shallow warts along the posterior surface of DM, whereas the most advanced specimen, case 3, showed evidence of earlier nodularity that had been buried by the accretion of further extracellular matrix material. The posterior aspect of DM in this specimen had the unusual property of lighter staining relative to the anterior region of DM, laid down earlier in life. Immunocytochemistry revealed increased expression and complex, sharply defined patterns of deposition of collagen VIII, collagen IV, laminin, and fibronectin. Ultrastructurally, the posterior nonbanded layer of DM was intermixed with banded collagen, and the posterior region of DM showed a high density of foci of spindle-shaped structures with intense-staining bands, spaced at approximately 120 nm. Finally, ultrastructural studies of the endothelium in case 1 revealed unusual accumulation of swelling mitochondria. The endothelial cells also had large amounts of abnormal prominent rough endoplasmic reticulum. Type VIII collagen alpha 2 immunogold signal was associated with the highly granular ribosomes of the rough endoplasmic reticulum of these patients., Conclusions: Microscopic and electron microscopic examination revealed pathological changes in DM of L450W COL8A2 mutants that were consistent with several-fold increased growth of the extracellular matrix and progressive deposition and synthesis of extracellular material by endothelial cells. As with late-onset FCD, this is accompanied by attenuation and eventual loss of the endothelium itself. Whether the abnormal deposition of collagen, laminin, and fibronectin contributes to the dysfunction and death of the endothelium remains to be determined.