Heather J. McCrea

Juvenile xanthogranuloma (JXG) of the central nervous system (CNS) is a rare non‐Langerhans cell histiocytosis . CSF1R mutations have been reported for peripheral JXG, but not in CNS JXG. A 3‐month‐old male presented with fever, lymphadenopathy, and macrocephaly with bulging fontanelles. Imaging demonstrated multiple dural‐based masses causing obstructive hydrocephalus. The patient underwent right frontal endoscopic third ventriculostomy, choroid plexus cauterization, and craniotomy for resection and tissue diagnosis. Pathology was consistent with JXG, and NGS identified a somatic CSF1R mutation. Liquid imatinib monotherapy led to resolution of lesions and continued treatment response after 3 years without adverse events or drug interruptions.

Background Vitamin K is a vital component of prophylactic treatment in newborns, as deficiency leads to inadequate synthesis of coagulation factors. Vitamin K deficiency bleeding (VKDB) can lead to gastrointestinal, mucocutaneous, or intracranial hemorrhage. Unfortunately, the rise in vaccine hesitancy has been paralleled by a rise in refusal of vitamin K prophylaxis at birth. Case report Here, we present the case of a 2-month-old who presented to the emergency department with a large ICH due to a lack of vitamin K prophylaxis. The patient presented to the emergency room (ER) unresponsive with a blown pupil. Computed tomography (CT) scan showed a large intraparenchymal hemorrhage with substantial midline shift. The patient’s coagulation studies resulted with INR > 15, PTT > 200, and TEG > 69; he had not received vitamin K prophylaxis at birth. Vitamin K was given, and aggressive transfusion protocol was started in the ER. He was closely monitored in the pediatric intensive care unit (PICU) and safely taken for decompressive hemicraniectomy once coagulopathy was reversed. Post-operatively, he remained paralyzed on the oscillator for ventilatory support due to transfusion-related acute lung injury (TRALI). He was eventually able to be weaned from paralysis, sedation, and respiratory support and was discharged to home with outpatient follow-up and rehabilitation. He has since undergone cranioplasty, and at 6 months follow-up, he continues to progress, is appropriately alert, and moves all extremities grossly symmetrically. Conclusion Newborns who do not receive vitamin K at birth remain at risk for intracranial hemorrhage. In this case, it was vital to reverse coagulopathy before taking the patient for decompressive surgery. Teamwork amongst the emergency room, critical care, anesthesia, and neurosurgical teams was crucial to safely manage this patient’s large intracranial hemorrhage.

Pediatric hydrocephalus results from the overproduction, obstruction, or inability to resorb cerebrospinal fluid (CSF), which may lead to ventricular enlargement. Hydrocephalus may be secondary to other pathologies, including intraventricular hemorrhage (IVH). Surgical intervention may include a ventricular access device or a ventriculosubgaleal shunt in premature infants who are too small for permanent CSF diversion. Hydrocephalus, an inflammatory pathology, involves activation of the inflammasome. Elevation in pro-inflammatory proteins is often associated with worsening clinical outcomes in pediatric pathologies. Whether inflammasome proteins are reliable biomarkers for pediatric hydrocephalus has not been established. We analyzed CSF samples via an ELLA assay from pediatric hydrocephalic patients with IVH of prematurity vs. controls and compared changes in inflammasome protein concentrations post-reservoir surgery at different time points. The area under the curve was calculated using receiver operator characteristic curves. The levels of apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), caspase-1, and interleukin-18 were significantly elevated in pediatric hydrocephalic patients with IVH vs. controls. Thus, these proteins are reliable biomarkers of the inflammatory response in pediatric hydrocephalus following ROC analysis, with an AUC of 1.0 and high sensitivity and specificity at the corresponding cut-off points. Ongoing work seeks to validate these findings in a larger cohort of pediatric hydrocephalic patients with varying etiologies.

Traumatic brain injury (TBI) is one of the leading causes of death and neurological disability worldwide. The search for biomarkers that indicate TBI severity and prognosis with greater accuracy is ongoing. This study aimed to evaluate the significance of several neuroinflammatory cytokines and chemokines, assessing their potential as biomarkers in pediatric TBI (pTBI). This was an exploratory analysis of inflammatory cytokines and chemokines measured in a subset of 26 children aged 0–18 years with TBI and 21 controls. TBI severity was determined by GCS. The functional outcome was measured via the GOS-E score at 6 weeks and 3, 6, 9, and 12 months post-injury. Serum samples were analyzed for ICAM-1, VCAM-1, SAA, CRP, IFN-g, IL-10, IL-12p70, IL-13, IL-1b, IL-2, IL-4, IL-6, IL-8, TNF-a, TNF-b, eotaxin, eotaxin-3, IP-10, MCP-1, MCP-4, MDC, MIP-1a, MIP-1b and TARC. Levels of IL-6, IL-10, IL-13, IL-16, MDC, and GM-CSF were increased, and IFN-γ, IL-5, IL-8, and eotaxin-3 were decreased at enrollment when compared with controls. Elevated IL-6 and IL-10 at enrollment were associated with severe TBI (AUC of 1, p = 0.0002 and p = 0.8, suggesting biomarker potential. Our data indicate that several cytokines and chemokines measured after TBI may aid in the assessment of pTBI severity and prognosis. IL-6, IL-10, and IL-16 may show potential as biomarkers for pTBI severity and outcomes.

Most children with medulloblastoma (MB) achieve remission, but some face very aggressive metastatic tumors. Their dismal outcome highlights the critical need to advance therapeutic approaches that benefit such high-risk patients. Minnelide, a clinically relevant analog of the natural product triptolide, has oncostatic activity in both preclinical and early clinical settings. Despite its efficacy and tolerable toxicity, this compound has not been evaluated in MB. Utilizing a bioinformatic data set that integrates cellular drug response data with gene expression, we predicted that Group 3 (G3) MB, which has a poor 5-year survival, would be sensitive to triptolide/Minnelide. We subsequently showed that both triptolide and Minnelide attenuate the viability of G3 MB cells ex vivo. Transcriptomic analyses identified MYC signaling, a pathologically relevant driver of G3 MB, as a downstream target of this class of drugs. We validated this MYC dependency in G3 MB cells and showed that triptolide exerts its efficacy by reducing both MYC transcription and MYC protein stability. Importantly, Minnelide acted on MYC to reduce tumor growth and leptomeningeal spread, which resulted in improved survival of G3 MB animal models. Moreover, Minnelide improved the efficacy of adjuvant chemotherapy, further highlighting its potential for the treatment of MYC-driven G3 MB.

Introduction To evaluate the outcomes and demographics of encephalocele patients who were born and received treatment in our neonatal ICU and conduct a PRISMA literature review. Methods An Institutional Review Board (IRB)-approved retrospective cohort study was undertaken to investigate the results of treating encephalocele patients at Jackson Memorial Hospital (JMH) from 1998 to 2022. The study focused on assessing outcomes and the impact of maternal socioeconomic factors, such as religion, age, and education, along with the timing of diagnosis, in connection with a systematic review. Results A total of 20 encephalocele patients were identified (13 females and 7 males), with 15 having available medical records for review. Most of these cases involved occipital encephaloceles (73.3%). Maternal ages at the time of delivery ranged from 15 to 42 years, with a mean age of 27.3 years. The average gestational age at birth was 37 weeks. Ten cases had a prenatal diagnosis documented, occurring between 12 and 24.5 weeks of gestation. Three of the surviving patients had records of prenatal counseling that included discussions about termination. No infections were reported. Among the 15 cases, 11 patients (73.3%) were alive at the last follow-up, with a mean age at follow-up of 4.12 years, ranging from 6 weeks to 15 years post-birth. Hydrocephalus was noted in 26.7%. Only 1 mother had completed high school. Most mothers were either on Medicaid (9 patients) or uninsured (3 patients), with only 3 having commercial insurance. Religious affiliations varied among the mothers, with 14 out of 15 identifying with a particular religion. The systematic review identified 22 articles from various countries, with 11 articles meeting the inclusion criteria for qualitative analysis. These articles revealed potential maternal risk factors for encephaloceles, including low-nutrient diets, inadequate folic acid intake, young maternal age, advanced maternal age, low socioeconomic status, and limited educational attainment. Conclusions In the twenty-first century, there is a positive trend in the survival rates of children born with encephalocele. However, maternal factors such as low socioeconomic status and limited educational attainment remain prominent, affecting their ability to access timely prenatal care and impacting follow-up medical care for these children.

Traumatic brain injury (TBI) remains a major cause of morbidity and death among the pediatric population. Timely diagnosis, however, remains a complex task because of the lack of standardized methods that permit its accurate identification. The aim of this study was to determine whether serum levels of brain injury biomarkers can be used as a diagnostic and prognostic tool in this pathology. This prospective, observational study collected and analyzed the serum concentration of neuronal injury biomarkers at enrollment, 24h and 48h post-injury, in 34 children ages 0–18 with pTBI and 19 healthy controls (HC). Biomarkers included glial fibrillary acidic protein (GFAP), neurofilament protein L (NfL), ubiquitin-C-terminal hydrolase (UCH-L1), S-100B, tau and tau phosphorylated at threonine 181 (p-tau181). Subjects were stratified by admission Glasgow Coma Scale score into two categories: a combined mild/moderate (GCS 9–15) and severe (GCS 3–8). Glasgow Outcome Scale-Extended (GOS-E) Peds was dichotomized into favorable (≤4) and unfavorable (≥5) and outcomes. Data were analyzed utilizing Prism 9 and R statistical software. The findings were as follows: 15 patients were stratified as severe TBI and 19 as mild/moderate per GCS. All biomarkers measured at enrollment were elevated compared with HC. Serum levels for all biomarkers were significantly higher in the severe TBI group compared with HC at 0, 24, and 48h. The GFAP, tau S100B, and p-tau181 had the ability to differentiate TBI severity in the mild/moderate group when measured at 0h post-injury. Tau serum levels were increased in the mild/moderate group at 24h. In addition, NfL and p-tau181 showed increased serum levels at 48h in the aforementioned GCS category. Individual biomarker performance on predicting unfavorable outcomes was measured at 0, 24, and 48h across different GOS-E Peds time points, which was significant for p-tau181 at 0h at all time points, UCH-L1 at 0h at 6–9 months and 12 months, GFAP at 48h at 12 months, NfL at 0h at 12 months, tau at 0h at 12 months and S100B at 0h at 12 months. We concluded that TBI leads to increased serum neuronal injury biomarkers during the first 0–48h post-injury. A biomarker panel measuring these proteins could aid in the early diagnosis of mild to moderate pTBI and may predict neurological outcomes across the injury spectrum.

Dysregulation of Sonic hedgehog (SHH) signaling drives the growth of distinct cancer subtypes, including medulloblastoma (MB). Such cancers have been treated in the clinic with a number of clinically relevant SHH inhibitors, the majority of which target the upstream SHH regulator, Smoothened (SMO). Despite considerable efficacy, many of these patients develop resistance to these drugs, primarily due to mutations in SMO. Therefore, it is essential to identify druggable, signaling components downstream of SMO to target in SMO inhibitor resistant cancers. We utilized an integrated functional genomics approach to identify epigenetic regulators of SHH signaling and identified a novel complex of Ubiquitin-like with PHD and RING finger domains 1 (UHRF1), DNA methyltransferase 1 (DNMT1), and GLI proteins. We show that this complex is distinct from previously described UHRF1/DNMT1 complexes, suggesting that it works in concert to regulate GLI activity in SHH driven tumors. Importantly, we show that UHRF1/DNMT1/GLI complex stability is targeted by a repurposed FDA-approved therapy, with a subsequent reduction in the growth of SHH-dependent MB ex vivo and in vivo.Implications:This work describes a novel, druggable UHRF1/DNMT1/GLI complex that regulates SHH-dependent tumor growth, and highlights an FDA-approved drug capable of disrupting this complex to attenuate tumor growth.