Newborns are more susceptible to severe disease from infection than adults, with maturation of immune responses implicated as a major factor. The type I interferon response delays mortality and ...limits viral replication in adult mice in a model of herpes simplex virus (HSV) encephalitis. We found that intact type I interferon signaling did not control HSV disease in the neonatal brain. However, the multifunctional HSV protein γ34.5 involved in countering type I interferon responses was important for virulence in the brain in both age groups. To investigate this observation further, we studied a specific function of γ34.5 which contributes to HSV pathogenesis in the adult brain, inhibition of the cellular process of autophagy. Surprisingly, we found that the beclin binding domain of γ34.5 responsible for inhibiting autophagy was dispensable for HSV disease in the neonatal brain, as infection of newborns with the deletion mutant decreased time to mortality compared to the rescue virus. Additionally, a functional beclin binding domain in HSV γ34.5 did not effectively inhibit autophagy in the neonate, unlike in the adult. Type I IFN responses promote autophagy in adult, a finding we confirmed in the adult brain after HSV infection; however, in the newborn brain we observed that autophagy was activated through a type I IFN-independent mechanism. Furthermore, autophagy in the wild-type neonatal mouse was associated with increased apoptosis in infected regions of the brain. Observations in the mouse model were consistent with those in a human case of neonatal HSV encephalitis. Our findings reveal age-dependent differences in autophagy for protection from HSV encephalitis, indicating developmental differences in induction and regulation of this innate defense mechanism after HSV infection in the neonatal brain.
Paediatric high-grade gliomas (HGGs) account for the most brain tumour-related deaths in children and have a median survival of 12-15 months. One promising avenue of research is the development of ...novel therapies targeting the properties of non-neoplastic cell-types within the tumour such as tumour associated macrophages (TAMs). TAMs are immunosuppressive and promote tumour malignancy in adult HGG; however, in paediatric medulloblastoma, TAMs exhibit anti-tumour properties. Much is known about TAMs in adult HGG, yet little is known about them in the paediatric setting. This raises the question of whether paediatric HGGs possess a distinct constituency of TAMs because of their unique genetic landscapes. Using human paediatric HGG tissue samples and murine models of paediatric HGG, we demonstrate diffuse midline gliomas possess a greater inflammatory gene expression profile compared to hemispheric paediatric HGGs. We also show despite possessing sparse T-cell infiltration, human paediatric HGGs possess high infiltration of IBA1+ TAMs. CD31, PDGFRβ, and PDGFB all strongly correlate with IBA1+ TAM infiltration. To investigate the TAM population, we used the RCAS/tv-a system to recapitulate paediatric HGG in newborn immunocompetent mice. Tumours are induced in Nestin-positive brain cells by PDGFA or PDGFB overexpression with Cdkn2a or Tp53 co-mutations. Tumours driven by PDGFB have a significantly lower median survival compared to PDGFA-driven tumours and have increased TAM infiltration. NanoString and quantitative PCR analysis indicates PDGFB-driven tumours have a highly inflammatory microenvironment characterized by high chemokine expression. In vitro bone marrow-derived monocyte and microglial cultures demonstrate bone marrow-derived monocytes are most responsible for the production of inflammatory signals in the tumour microenvironment in response to PDGFB stimulation. Lastly, using knockout mice deficient for individual chemokines, we demonstrate the feasibility of reducing TAM infiltration and prolonging survival in both PDGFA and PDGFB-driven tumours. We identify CCL3 as a potential key chemokine in these processes in both humans and mice. Together, these studies provide evidence for the potent inflammatory effects PDGFB has in paediatric HGGs.
Radiotherapy (RT) has long been and remains the only treatment option for diffuse intrinsic pontine glioma (DIPG). However, all patients show evidence of disease progression within months of ...completing RT. No further clinical benefit has been achieved using alternative radiation strategies. Here, we tested the hypothesis that histone demethylase inhibition by GSK-J4 enhances radiation-induced DNA damage, making it a potential radiosensitizer in the treatment of DIPG.
We evaluated the effects of GSK-J4 on genes associated with DNA double-strand break (DSB) repair in DIPG cells by RNA sequence, ATAC sequence, and quantitative real-time PCR. Radiation-induced DNA DSB repair was analyzed by immunocytochemistry of DSB markers γH2AX and 53BP1, DNA-repair assay, and cell-cycle distribution. Clonogenic survival assay was used to determine the effect of GSK-J4 on radiation response of DIPG cells.
response to radiation monotherapy and combination therapy of RT and GSK-J4 was evaluated in patient-derived DIPG xenografts.
GSK-J4 significantly reduced the expression of DNA DSB repair genes and DNA accessibility in DIPG cells. GSK-J4 sustained high levels of γH2AX and 53BP1 in irradiated DIPG cells, thereby inhibiting DNA DSB repair through homologous recombination pathway. GSK-J4 reduced clonogenic survival and enhanced radiation effect in DIPG cells.
studies revealed increased survival of animals treated with combination therapy of RT and GSK-J4 compared with either monotherapy.
Together, these results highlight GSK-J4 as a potential radiosensitizer and provide a rationale for developing combination therapy with radiation in the treatment of DIPG.
Pleomorphic xanthoastrocytoma (PXA) is a rare primary CNS tumor. Recent advances in the molecular characterization are helping to define subtypes of tumor. The discovery of
mutations within a ...substantial percentage of PXA fosters a clearer understanding of the pathophysiology of these tumors with clear prognostic and therapeutic implications. These findings are expected to provide insight into the spectrum of clinical behavior observed in PXA, ranging from cure with surgery to diffuse dissemination throughout the neuraxis. This review details the clinical presentation including radiographic appearance of PXA. Pathology, including molecular pathology is discussed. Therapeutic management including surgical resection, radiotherapy and systemic therapies are reviewed.
Purpose
Osteochondromyxomas (OMX) are rare congenital bone tumors that have only been described in the context of Carney complex syndrome (CNC). Data on OMX as a separate entity and in association ...with other disorders remain limited, making both diagnosis and treatment difficult.
Methods
A case report of a 17-year-old female diagnosed with sellar OMX is presented in the setting of spondyloepiphyseal dysplasia (SED). We discuss the radiographic and histopathological interpretations in addition to reviewing the current literature on OMX.
Results
A successful gross total resection of the tumor was achieved via an endonasal endoscopic transsphenoidal approach. A diagnosis was established radiographically and pathologically.
Conclusion
The diagnosis and treatment of OMX are best achieved via tissue biopsy. Following confirmed osteochondromyxoma cases long term for recurrence and outcomes will be essential in understanding its natural tumor history and in establishing standard treatments.
Implantable devices are increasingly more common for management of movement disorders, pain, and epilepsy. These devices are often complex and constructed of nonbiodegradable or hazardous materials. ...Therefore, proper postmortem handling of these devices is exceedingly important. Unfortunately, there is no consolidated resource available for postmortem neuromodulation device protocols. Thus, we surveyed and catalogued the protocols for implantable devices to summarize proper postmortem device protocols for implantable neurosurgical devices currently on the market.
We performed a cross-sectional study of companies producing commonly implanted neurosurgical devices. Using information from company websites, user manuals, and catalogs we categorized devices into 3 groups: A (formal recommendation for explantation), B (recommendation for explantation without formal company protocol), and C (explantation is not necessary). We then compiled the data into a stoplight diagram, providing a clear postmortem disposal algorithm for each device category.
Twelve companies were queried regarding 46 devices. Postmortem protocols were available for 50% (23/46) of devices; the remaining devices did not have formal recommendations. Overall, 50% of devices were classified as category A "red light" on the stoplight diagram based on recommendations, 10.9% as category B "yellow light," and the remaining 39.1% were classified as category C "green light" indicating they are safe to bury or cremate.
Evolution in therapies and growth in functional neurosurgery has expanded the range of implantable neurosurgical devices. We provide an educational document summarizing their postmortem protocols. This resource aims to aid health-care providers and encourage proper disposal practices during burial or cremation.
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Purpose
Benign triton tumors (BTTs) in the pediatric population are extremely rare occurrences. Paucity of data on BTTs poses both diagnostic and therapeutic challenges, particularly when found ...intracranially.
Methods
A case report of a 10-year-old male diagnosed with incidental maxillary trigeminal (V2) BTT is presented. We discuss radiographic and histopathological interpretations. Furthermore, we provide a brief review of current literature and historical background on pediatric trigeminal BTT diagnosis, histopathology, and management.
Results
Successful gross total resection of the tumor was achieved via Dolenc approach to the cavernous sinus. Management options with consideration of outcomes from the few prior cases reported in the literature are presented.
Conclusion
Treatment of trigeminal nerve tumors requires a broad differential diagnosis and understanding rare tumors is essential in the diagnosis and treatment algorithm.
DICER1 tumor predisposition syndrome is a rare genetic disorder that predisposes individuals to multiple benign and malignant neoplasms. The phenotype is vast and includes pleuropulmonary blastoma ...(PPB), thyroid nodules, cystic nephroma, Wilms tumor, ovarian Sertoli–Leydig cell tumor, and medulloepithelioma, among others. Herein, we describe a patient with a DICER1 germline pathogenic variant presenting with two neoplasms that are not commonly encountered in the context of DICER1 syndrome. The first tumor is a multiloculated cystic hepatic lesion with a biphasic pattern, composed of cysts lined by bland biliary type (CK19-positive) epithelium surrounded by a condensation of sarcomatous spindled cell proliferation in a myxoid stroma. This neoplasm resembled PPB or cystic nephroma with malignant transformation. The second tumor is a chest nodule consistent with low-grade hidradenocarcinoma. Although it is difficult to speculate with just a single case, these unusual neoplasms occurring in particular at a young age raises the possibility that they can be inherent to, and thus, be part of the DICER1 tumor predisposition syndrome phenotype.
Somatic malignancies arising in mature teratomas are exceedingly rare entities and even more so are those arising in immature teratomas. Here, we present a unique case of a 13-year-old who initially ...underwent ovarian sparing cystectomy for a 7.7 cm left ovarian mass with a pre-operative diagnosis of mature cystic teratoma. Histologically, all 3 germ cell layers were present and immature neuroepithelial tubules were also identified. Subsequent sections revealed a nodular lesion composed of neuropil, neuroblasts with a spectrum of maturation, and Schwannian-type stroma. The neuroblasts were diffusely positive for PHOX2B. Neuroblastoma arising in an immature teratoma has only been described in the literature once previously in an adult patient.
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