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In this patient-focused review, we present a 34-year-old previously healthy man admitted for fever and headache two weeks after a motor vehicle accident. On admission, his workup was concerning for meningoencephalitis based on elevated cerebrospinal fluid (CSF) white blood cell count and elevated CSF protein. He was admitted for management of meningoencephalitis. During his course, no causative infectious agent was identified despite an extensive workup. He additionally underwent an autoimmune and paraneoplastic workup that was negative. During his hospitalization, he developed acute transverse myelitis manifested by bilateral lower extremity paralysis. After four weeks marked by persistent clinical deterioration, brain biopsy was performed. Pathologic examination was consistent with neuromyelitis optica spectrum disorder (NMOSD). In this case report and literature review, we explore the presentations of NMOSD that mimic an infection. Clinicians should be aware of the possibility of NMOSD masquerading as infectious meningoencephalitis or acute transverse myelitis.

GD2-targeting immunotherapies have improved survival in children with neuroblastoma, yet on-target, off-tumor toxicities can occur and a subset of patients cease to respond. The majority of neuroblastoma patients who receive immunotherapy have been previously treated with cytotoxic chemotherapy, making it paramount to identify neuroblastoma-specific antigens that remain stable throughout standard treatment. Cell surface glycoproteomics performed on human-derived neuroblastoma tumors in mice following chemotherapy treatment identified protein tyrosine kinase 7 (PTK7) to be abundantly expressed. Furthermore, PTK7 shows minimal expression on pediatric-specific normal tissues. We developed an anti-PTK7 chimeric antigen receptor (CAR) and find PTK7 CAR T cells specifically target and kill PTK7-expressing neuroblastoma in vitro. In vivo, human/murine binding PTK7 CAR T cells regress aggressive neuroblastoma metastatic mouse models and prolong survival with no toxicity. Together, these data demonstrate preclinical efficacy and tolerability for targeting PTK7 and support ongoing investigations to optimize PTK7-targeting CAR T cells for neuroblastoma.

Brain subependymal giant cell astrocytomas (SEGAs) in patients with tuberous sclerosis have been reported to respond to everolimus.

Metastatic disease in the brain is difficult to control and predicts poor prognosis. Here, we analyze human brain metastases and demonstrate their robust infiltration by CD8+T cell subsets with distinct antigen specificities, phenotypic states, and spatial localization within the tumor microenvironment. Brain metastases are densely infiltrated by T cells; the majority of infiltrating CD8+T cells express PD-1. Single-cell RNA sequencing shows significant clonal overlap between proliferating and exhausted CD8+T cells, but these subsets have minimal clonal overlap with circulating and other tumor-infiltrating CD8+T cells, including bystander CD8+T cells specific for microbial antigens. Using spatial transcriptomics and spatial T cell receptor (TCR) sequencing, we show these clonally unrelated, phenotypically distinct CD8+T cell populations occupy discrete niches within the brain metastasis tumor microenvironment. Together, our work identifies signaling pathways within CD8+T cells and in their surrounding environment that may be targeted for immunotherapy of brain metastases.

Leptomeningeal dissemination in children is typical of high-grade, and occasionally low-grade, neoplasms. Rare cases of widely disseminated oligodendroglia-like leptomeningeal tumors, sometimes with associated spinal cord lesions, have been described that respond to treatment and follow an indolent course. Whether these lesions represent an established tumor category or are a unique entity remains to be established. We present 9 pediatric cases of such diffuse leptomeningeal neuroepithelial tumors (DLNT), 8 with assessment of 2 common genetic alterations seen in oligodendrogliomas, 1p and 19q chromosomal deletions and isocitrate dehydrogenase-1 (IDH1) R132H mutations. Four patients were male and 5 female, with a mean age at presentation of 4 years (range, 2 to 7 y). All presented with signs of increased intracranial pressure and diffuse contrast enhancement of the leptomeninges by magnetic resonance imaging. Three had a cervical or upper thoracic spinal cord tumor, and another had a small cerebellar lesion. Leptomeningeal biopsies showed a thickened and fibrotic arachnoid infiltrated by monotonous cells with round nuclei and prominent perinuclear clearing. All cases were strongly immunoreactive for S100 protein, and most showed faint granular synaptophysin reactivity. Six of 8 cases showed deletions of chromosome arm 1p by fluorescence in situ hybridization, 2 of which also had loss of 19q. None of the lesions reacted with IDH1-R132H antibodies. Although the clinicopathologic features show overlap of these DLNT lesions with oligodendroglioma and extraventricular neurocytoma, they do not exactly match either one, suggesting that DLNTs are a distinct tumor entity.

Cytokines play critical roles during T cell development; however, it is unclear to what extent development is altered by the high levels of cytokines produced during immune responses. A potential mechanism to shield developing cells from cytokine influence is attenuation of cytokine signaling. Using intracellular staining and flow cytometry to detect cytokine-induced Stat phosphorylation, we analyzed the cytokine responsiveness of developmentally defined mouse T cells. We assessed CD4–CD8– (DN), CD4+CD8+ (DP), CD4+CD8– (SP4), and CD4–CD8+ (SP8) in the thymus, and CD4+CD44lo (naive), CD4+CD44hi (memory), CD8+CD44lo (naive), and CD8+CD44hi (memory) in the periphery for responsiveness to interleukin-2 (IL-2), IL-4, IL-6, IL-7, IL- 10, IL-15, interferon-α (IFN-α), and IFN-γ. SP thymocytes responded to a wider range of cytokines than did the less mature DN and DP subpopulations. DP thymocytes were nonresponsive to all cytokines tested except for modest responses to IL-4 and IFN-α. Peripheral naive and memory T cells also displayed differential cytokine sensitivity. Memory T cells were less responsive to the proinflammatory cytokines IL-6 and IFN-γ when compared with naive T cells, and the memory CD4+ subset was less responsive to IL-4. In summary, developing thymocytes and memory T cells appear to be resistant to the influences of numerous cytokines produced during immune responses.

We describe a case of a 5-year-old girl with onchocerciasis. The patient was recently adopted from Ethiopia and presented with a firm, raised nodule on the midportion of the forehead. Initially, Langerhans cell histiocytosis with bone involvement was suspected; however, histopathologic analysis of the excised nodule revealed the presence of a young-adult, female Onchocerca volvulusworm. This case exemplifies the importance of recognizing the key morphologic characteristics of adult O. volvulusworms isolated from pediatric patients in nonendemic areas to ensure adroit clinical management.