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Abstract Background Cerebrospinal fluid (CSF) shunts allow children with hydrocephalus to survive and avoid brain injury (J Neurosurg 107:345-57, 2007; Childs Nerv Syst 12:192-9, 1996). The Hydrocephalus Clinical Research Network implemented non-randomized quality improvement protocols that were shown to decrease infection rates compared to pre-operative prophylactic intravenous antibiotics alone (standard care): initially with intrathecal (IT) antibiotics between 2007–2009 (J Neurosurg Pediatr 8:22-9, 2011), followed by antibiotic impregnated catheters (AIC) in 2012–2013 (J Neurosurg Pediatr 17:391-6, 2016). No large scale studies have compared infection prevention between the techniques in children. Our objectives were to compare the risk of infection following the use of IT antibiotics, AIC, and standard care during low-risk CSF shunt surgery (i.e., initial CSF shunt placement and revisions) in children. Methods A retrospective observational cohort study at 6 tertiary care children’s hospitals was conducted using Pediatric Health Information System + (PHIS +) data augmented with manual chart review. The study population included children ≤ 18 years who underwent initial shunt placement between 01/2007 and 12/2012. Infection and subsequent CSF shunt surgery data were collected through 12/2015. Propensity score adjustment for regression analysis was developed based on site, procedure type, and year; surgeon was treated as a random effect. Results A total of 1723 children underwent initial shunt placement between 2007–2012, with 1371 subsequent shunt revisions and 138 shunt infections. Propensity adjusted regression demonstrated no statistically significant difference in odds of shunt infection between IT antibiotics (OR 1.22, 95% CI 0.82–1.81, p = 0.3) and AICs (OR 0.91, 95% CI 0.56–1.49, p = 0.7) compared to standard care. Conclusion In a large, observational multicenter cohort, IT antibiotics and AICs do not confer a statistically significant risk reduction compared to standard care for pediatric patients undergoing low-risk (i.e., initial or revision) shunt surgeries.

Objective: To elucidate the current academic, demographic, and professional factors influencing the career trajectories of the American Association of Neurological Surgeons (AANS) William P. Van Wagenen (VW) fellows while also identifying trends that may influence future fellow selection. Methods: Fifty-five VW fellows were identified from 1968 to 2022 from the AANS website, along with corresponding institutions, countries, and continents of study. Additional variables such as age at selection, accruing additional degrees, neurosurgical subspecialty, the number of publications at the time of selection, funding, and h-index were collected from various publicly available sources. Results: Eighty-five percent of VW fellows were male and had a mean age of 34 ± 2.4 years. Ninety-one percent of fellows chose to study in Europe, and 40% had earned additional degrees. Univariate linear regression demonstrated a positive relationship between the year of selection and both age at selection (p = 0.0094) and the number of publications at hire (p

Abstract Low‐grade epilepsy‐associated tumors (LEATs) are a common cause of drug‐resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18‐year‐old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri‐tumoral sEEG electrodes for peri‐operative language mapping and demarcation of the peri‐tumoral ictal zone prior to DNET resection. Using electrodes that passed through tumor tissue, we show successful isolation of tumor DNA and subsequent analysis using standard methods for tumor classification by DNA, including Glioseq targeted sequencing and DNA methylation array analysis. This study provides preliminary evidence for the feasibility of molecular diagnosis of LEATs or other lesions using a minimally invasive method with microscopic tissue volumes. The implications of sEEG electrodes in tumor characterization are broad but would aid in diagnosis and subsequent targeted therapeutic strategies.

In previous studies, we demonstrated that panobinostat, a histone deacetylase inhibitor, and bortezomib, a proteasomal inhibitor, displayed synergistic therapeutic activity against pediatric and adult high‐grade gliomas. Despite the remarkable initial response to this combination, resistance emerged. Here, in this study, we aimed to investigate the molecular mechanisms underlying the anticancer effects of panobinostat and marizomib, a brain‐penetrant proteasomal inhibitor, and the potential for exploitable vulnerabilities associated with acquired resistance. RNA sequencing followed by gene set enrichment analysis (GSEA) was employed to compare the molecular signatures enriched in resistant compared with drug‐naïve cells. The levels of adenosine 5′‐triphosphate (ATP), nicotinamide adenine dinucleotide (NAD)+ content, hexokinase activity, and tricarboxylic acid (TCA) cycle metabolites required for oxidative phosphorylation to meet their bioenergetic needs were analyzed. Here, we report that panobinostat and marizomib significantly depleted ATP and NAD+ content, increased mitochondrial permeability and reactive oxygen species generation, and promoted apoptosis in pediatric and adult glioma cell lines at initial treatment. However, resistant cells exhibited increased levels of TCA cycle metabolites, which required for oxidative phosphorylation to meet their bioenergetic needs. Therefore, we targeted glycolysis and the electron transport chain (ETC) with small molecule inhibitors, which displayed substantial efficacy, suggesting that resistant cell survival is dependent on glycolytic and ETC complexes. To verify these observations in vivo, lonidamine, an inhibitor of glycolysis and mitochondrial function, was chosen. We produced two diffuse intrinsic pontine glioma (DIPG) models, and lonidamine treatment significantly increased median survival in both models, with particularly dramatic effects in panobinostat‐ and marizomib‐resistant cells. These data provide new insights into mechanisms of treatment resistance in gliomas.

Summary: Metabolic reprogramming in pediatric diffuse midline glioma is driven by gene expression changes induced by the hallmark histone mutation H3K27M, which results in aberrantly permissive activation of oncogenic signaling pathways. Previous studies of diffuse midline glioma with altered H3K27 (DMG-H3K27a) have shown that the RAS pathway, specifically through its downstream kinase, extracellular-signal-related kinase 5 (ERK5), is critical for tumor growth. Further downstream effectors of ERK5 and their role in DMG-H3K27a metabolic reprogramming have not been explored. We establish that ERK5 is a critical regulator of cell proliferation and glycolysis in DMG-H3K27a. We demonstrate that ERK5 mediates glycolysis through activation of transcription factor MEF2A, which subsequently modulates expression of glycolytic enzyme PFKFB3. We show that in vitro and mouse models of DMG-H3K27a are sensitive to the loss of PFKFB3. Multi-targeted drug therapy against the ERK5-PFKFB3 axis, such as with small-molecule inhibitors, may represent a promising therapeutic approach in patients with pediatric diffuse midline glioma.

Acquired resistance to conventional chemotherapeutic agents limits their effectiveness and can cause cancer treatment to fail. Because enzymes in the aurora kinase family are vital regulators of several mitotic events, we reasoned that targeting these kinases with tozasertib, a pan‐aurora kinase inhibitor, would not only cause cytokinesis defects, but also induce cell death in high‐grade pediatric and adult glioma cell lines. We found that tozasertib induced cell cycle arrest, increased mitochondrial permeability and reactive oxygen species generation, inhibited cell growth and migration, and promoted cellular senescence and pro‐apoptotic activity. However, sustained exposure to tozasertib at clinically relevant concentrations conferred resistance, which led us to examine the mechanistic basis for the emergence of drug resistance. RNA‐sequence analysis revealed a significant upregulation of the gene encoding pyruvate dehydrogenase kinase isoenzyme 4 (PDK4), a pyruvate dehydrogenase (PDH) inhibitory kinase that plays a crucial role in the control of metabolic flexibility under various physiological conditions. Upregulation of PDK1, PDK2, PDK3, or PDK4 protein levels was positively correlated with tozasertib‐induced resistance through inhibition of PDH activity. Tozasertib‐resistant cells exhibited increased mitochondrial mass as measured by 10‐N‐nonyl‐Acridine Orange. Inhibition of PDK with dichloroacetate resulted in increased mitochondrial permeability and cell death in tozasertib‐resistant glioma cell lines. Based on these results, we believe that PDK is a selective target for the tozasertib resistance phenotype and should be considered for further preclinical evaluations.

Pediatric brain tumors are the leading cause of cancer-related death in children in the United States and contribute a disproportionate number of potential years of life lost compared to adult cancers. Moreover, survivors frequently suffer long-term side effects, including secondary cancers. The Children's Brain Tumor Network (CBTN) is a multi-institutional international clinical research consortium created to advance therapeutic development through the collection and rapid distribution of biospecimens and data via open-science research platforms for real-time access and use by the global research community. The CBTN's 32 member institutions utilize a shared regulatory governance architecture at the Children's Hospital of Philadelphia to accelerate and maximize the use of biospecimens and data. As of August 2022, CBTN has enrolled over 4700 subjects, over 1500 parents, and collected over 65,000 biospecimen aliquots for research. Additionally, over 80 preclinical models have been developed from collected tumors. Multi-omic data for over 1000 tumors and germline material are currently available with data generation for > 5000 samples underway. To our knowledge, CBTN provides the largest open-access pediatric brain tumor multi-omic dataset annotated with longitudinal clinical and outcome data, imaging, associated biospecimens, child-parent genomic pedigrees, and in vivo and in vitro preclinical models. Empowered by NIH-supported platforms such as the Kids First Data Resource and the Childhood Cancer Data Initiative, the CBTN continues to expand the resources needed for scientists to accelerate translational impact for improved outcomes and quality of life for children with brain and spinal cord tumors.

Sonic Hedgehog medulloblastoma (Shh-MB) comprises four subtypes each with distinct clinical traits. Here the authors characterize the genome, transcriptome, and methylome of Shh-MB subtypes, revealing a complex fusion landscape and the molecular convergence of MYCN and cAMP signaling pathways.

Background: Malignant gliomas are deadly tumours with few therapeutic options. Although immunotherapy may be a promising therapeutic strategy for treating gliomas, a significant barrier is the CD11b+ tumour-associated myeloid cells (TAMCs), a heterogeneous glioma infiltrate comprising up to 40% of a glioma's cellular mass that inhibits anti-tumour T-cell function and promotes tumour progression. A theranostic approach uses a single molecule for targeted radiopharmaceutical therapy (TRT) and diagnostic imaging; however, there are few reports of theranostics targeting the tumour microenvironment. Methods: Utilizing a newly developed bifunctional chelator, Lumi804, an anti-CD11b antibody (αCD11b) was readily labelled with either Zr-89 or Lu-177, yielding functional radiolabelled conjugates for PET, SPECT, and TRT. Findings: 89Zr/177Lu-labeled Lumi804-αCD11b enabled non-invasive imaging of TAMCs in murine gliomas. Additionally, 177Lu-Lumi804-αCD11b treatment reduced TAMC populations in the spleen and tumour and improved the efficacy of checkpoint immunotherapy. Interpretation: 89Zr- and 177Lu-labeled Lumi804-αCD11b may be a promising theranostic pair for monitoring and reducing TAMCs in gliomas to improve immunotherapy responses. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.

Glioblastoma (GBM) remains an aggressive brain tumor with a high rate of mortality. Immune checkpoint (IC) molecules are expressed on tumor infiltrating lymphocytes (TILs) and promote T cell exhaustion upon binding to IC ligands expressed by the tumor cells. Interfering with IC pathways with immunotherapy has promoted reactivation of anti-tumor immunity and led to success in several malignancies. However, IC inhibitors have achieved limited success in GBM patients, suggesting that other checkpoint molecules may be involved with suppressing TIL responses. Numerous IC pathways have been described, with current testing of inhibitors underway in multiple clinical trials. Identification of the most promising checkpoint pathways may be useful to guide the future trials for GBM. Here, we analyzed the The Cancer Genome Atlas (TCGA) transcriptomic database and identified PD1 and TIGIT as top putative targets for GBM immunotherapy. Additionally, dual blockade of PD1 and TIGIT improved survival and augmented CD8+ TIL accumulation and functions in a murine GBM model compared with either single agent alone. Furthermore, we demonstrated that this combination immunotherapy affected granulocytic/polymorphonuclear (PMN) myeloid derived suppressor cells (MDSCs) but not monocytic (Mo) MDSCs in in our murine gliomas. Importantly, we showed that suppressive myeloid cells express PD1, PD-L1, and TIGIT-ligands in human GBM tissue, and demonstrated that antigen specific T cell proliferation that is inhibited by immunosuppressive myeloid cells can be restored by TIGIT/PD1 blockade. Our data provide new insights into mechanisms of GBM αPD1/αTIGIT immunotherapy.

ObjectiveEfforts directed at mitigating neurological disability in preterm infants with intraventricular hemorrhage (IVH) and post hemorrhagic hydrocephalus (PHH) are limited by a dearth of quantifiable metrics capable of predicting long-term outcome. The objective of this study was to examine the relationships between candidate cerebrospinal fluid (CSF) biomarkers of PHH and neurodevelopmental outcomes in infants undergoing neurosurgical treatment for PHH.Study designPreterm infants with PHH were enrolled across the Hydrocephalus Clinical Research Network. CSF samples were collected at the time of temporizing neurosurgical procedure (n = 98). Amyloid precursor protein (APP), L1CAM, NCAM-1, and total protein (TP) were compared in PHH versus control CSF. Fifty-four of these PHH subjects underwent Bayley Scales of Infant Development-III (Bayley-III) testing at 15-30 months corrected age. Controlling for false discovery rate (FDR) and adjusting for post-menstrual age (PMA) and IVH grade, Pearson's partial correlation coefficients were used to examine relationships between CSF proteins and Bayley-III composite cognitive, language, and motor scores.ResultsCSF APP, L1CAM, NCAM-1, and TP were elevated in PHH over control at temporizing surgery. CSF NCAM-1 was associated with Bayley-III motor score (R = -0.422, p = 0.007, FDR Q = 0.089), with modest relationships noted with cognition (R = -0.335, p = 0.030, FDR Q = 0.182) and language (R = -0.314, p = 0.048, FDR Q = 0.194) scores. No relationships were observed between CSF APP, L1CAM, or TP and Bayley-III scores. FOHR at the time of temporization did not correlate with Bayley-III scores, though trends were observed with Bayley-III motor (p = 0.0647 and R = -0.2912) and cognitive scores (p = 0.0506 and R = -0.2966).ConclusionCSF NCAM-1 was associated with neurodevelopment in this multi-institutional PHH cohort. This is the first report relating a specific CSF protein, NCAM-1, to neurodevelopment in PHH. Future work will further investigate a possible role for NCAM-1 as a biomarker of PHH-associated neurological disability.

Background: 23Na MRI correlates with tumor proliferation, and studies in pediatric patients are lacking. The purpose of the study: (1) to compare total sodium concentration (TSC) between pediatric glioma and non-neoplastic brain tissue using 23Na MRI; (2) compare tissue conspicuity of bound sodium concentration (BSC) using 23Na MRI dual echo relative to TSC imaging. Methods: TSC was measured in: (1) non-neoplastic brain tissues and (2) three types of manually segmented gliomas (diffuse intrinsic brainstem glioma (DIPG), recurrent supratentorial low-grade glioma (LGG), and high-grade glioma (HGG)). In a subset of patients, serial changes in both TSC and BSC (dual echo 23Na MRI) were assessed. Results: Twenty-six pediatric patients with gliomas (median age of 12.0 years, range 4.9–23.3 years) were scanned with 23Na MRI. DIPG treated with RT demonstrated higher TSC values than the uninvolved infratentorial tissues (p < 0.001). Recurrent supratentorial LGG and HGG exhibited higher TSC values than the uninvolved white matter (WM) and gray matter (GM) (p < 0.002 for LGG, and p < 0.02 for HGG). The dual echo 23Na MRI suppressed the sodium signal within both CSF and necrotic foci. Conclusion: Quantitative 23Na MRI of pediatric gliomas demonstrates a range of values that are higher than non-neoplastic tissues. Dual echo 23Na MRI of BCS improves tissue conspicuity relative to TSC imaging.

Summary: Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763–0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

RASopathy is caused by dysfunction in the MAPK pathway, and include syndromes like Noonan syndrome (NS), NS with multiple lentigines (formerly known as Leopard syndrome), cardiofaciocutaneous (CFC), Legius syndrome, capillary malformation–arteriovenous malformation, neurofibromatosis type 1, and Costello syndrome. When counted together, RASopathies affect 1/1000 live births, and are characterized by cardiovascular manifestations, short stature, developmental delay, renal, urogenital, skin/skeletal abnormalities, and dysmorphic appearance. NS—one of the most common RASopathies—occurs in 1/1000 to 1/2500 live births. On the other hand, the frequency of CFC is unknown, but it is one of the rarest RASopathies, with estimates of only a few hundred cases worldwide. However, its phenotype overlaps with that of NS. In this case series, we describe 5 patients with a clinical and genetic diagnosis of RASopathy—either NS or CFC—all of whom were also diagnosed with isolated sagittal synostosis (ISS). Medical records from ophthalmology, cardiology, plastic surgery, medical genetics, cleft craniofacial, and neurosurgery were used to determine patient history. In our cohort, late presentation of ISS was the predominant form of ISS presentation. We hope this report further characterizes the burgeoning relationship between RASopathy and ISS. Furthermore, these findings support including sagittal synostosis among the presenting features in the clinical phenotype of RASopathies. Ethical approval was obtained from the university’s institutional review board.

Background:. We report the incidence of Chiari malformation I (CMI) in a cohort of 377 patients with isolated sagittal synostosis (ISS), which is to the best of our knowledge the largest such series reported to date. Methods:. A retrospective review of patients seen at a single institution from 2007 to 2017 was completed. ISS, Chiari malformations (CMI and CMII) and hydrocephalus were diagnosed by a senior neuroradiologist (G.Z.). Patients who met the inclusion criteria were divided into early (group A) and late (group B) presenting groups, as well as operated (group I) and unoperated (group II) groups. The patients were further subdivided into group AI (early operated), group AII (early unoperated), group BI (late operated), and group BII (late unoperated). Once identified, patient notes were examined for the following data sets: date of birth, age of presentation, age at last follow-up, other systemic conditions as well as molecular testing results. Surgical interventions, ophthalmological, and other relevant data were recorded. Statistical analysis was run in the form of a chi-square test to identify a significant difference between each subgroup. A literature review of the incidence of Chiari malformations in patients with ISS was conducted. Results:. Three hundred seventy-seven patients constitute the study’s total cohort (272 were males and 105 females). This cohort was divided into patients who underwent surgical repair of ISS (group 1: n = 200), and patients who did not (group 2: n = 177). The entire cohort was also divided into early (group A: n = 161) and late (group B: n = 216) presenting craniosynostosis. In the total cohort, 22/377 (5.8%) patients with CMI were identified. CMI was found in 14/200 (7.0%) patients in group I, and 8/177 (4.5%) patients in group II. CMI was found in 2/161 (1%) patients in group A, and 20/216 (9.2%) patients in group B. The incidence of CMI in group AI (early operated) was 2/151 (1.3%), in group AII (early unoperated) was 0/10, in group BI (late operated) was 11/49 (21%), and in group BII (late unoperated) was 9/167 (5.4%). Chi-square analysis revealed a significant difference between the incidence of CMI in the early-presenting (group A) and late-presenting (group B) groups (P = 0.001) and between the late-presenting operated (BI) and late-presenting unoperated (BII) groups (P = 0.001). The incidence of hydrocephalus was 1.6% (6/377) in the total cohort. However, all patients diagnosed with hydrocephalus came from group II (no surgical ISS correction). The incidence of hydrocephalus in group II was 3.3% (6/177). The incidence of hydrocephalus in group BII (late unoperated ISS) was 3.0% (5/167). The incidence of hydrocephalus in group AII (early unoperated ISS) was 9.0% (1/11). Conclusions:. We noted the highest incidence of CMI—21%—in group BI (late-presenting operated). We noted hydrocephalus in group II (nonoperated), with the highest incidence of hydrocephalus found in the group BII (late-presenting unoperated) subgroup. We therefore recommend patients with ISS receive funduscopic examination to screen for raised intracranial pressure (ICP) associated with CMI and hydrocephalus, especially patients with late-presenting ISS.