External ventricular drainage in the management of pediatric patients with posterior fossa tumors and hydrocephalus: a retrospective cohort study.

PURPOSE: To determine whether intraoperative adjunctive EVD placement in patients with a posterior fossa tumor (PFT) led to improved surgical, radiographic, and clinical outcomes compared to those who did not receive an EVD. METHODS: Patients were grouped as those who underwent routine intraoperative adjunctive EVD insertion and those who did not at time of PFT resection. Patients who pre-operatively required a clinically indicated EVD insertion were excluded. Comparative analyses between both groups were conducted to evaluate clinical, radiological, and pathological outcomes. Odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were computed for post-operative outcomes. RESULTS: Fifty-five selected patients were included, 15 who had an EVD placed at the time of PFT resection surgery, and 40 who did not. Children without an EVD did not experience a higher rate of complications or poorer post-operative outcomes compared to those with an EVD placed during resection surgery. There was no significant difference in the degree of gross total resection (p = 0.129), post-operative CSF leak (p = 1.000), and post-operative hemorrhage (p = 0.554) between those with an EVD and those without. The frequency of new cranial nerve deficits post-operatively was higher in those with an EVD (40%) compared to those without (3%, p = 0.001). There was a trend towards more frequently observed post-operative hydrocephalus in the EVD group (p = 0.057). CONCLUSION: The routine use of EVD as an intraoperative adjunct in clinically stable pediatric patients with posterior fossa tumors and hydrocephalus may not be associated with improved radiological or clinical outcomes.

Prevalence and Perception of Intimate Partner Violence-Related Traumatic Brain Injury.

BACKGROUND: Traumatic brain injury (TBI) is a serious and often undiagnosed consequence of intimate partner violence (IPV). Data on prevalence of TBI among IPV survivors are emerging, but prevalence of IPV among patients presenting to TBI clinics is unknown. Identification of IPV is important to ensure patients with TBI receive appropriate intervention and referrals. OBJECTIVE: To determine the proportion of women 18 years and older presenting to an acquired brain injury (ABI) clinic with confirmed or suspected concussion who reported experiencing IPV in the last 12 months or their lifetime. METHODS: Single-center cross-sectional cohort study. Proportion of IPV-related TBI or head, neck, or facial) injuries were determined using a modified HELPS Brain Injury Screening Tool and the Neurobehavioral Symptom Inventory. RESULTS: Of the 97 women approached, 50 were enrolled in the study. The average age was 46.1 years and 32 women (64.0%) reported a relationship history with a violent partner; 12-month prevalence of IPV was 26.5% and lifetime prevalence was 44.0%. Within their lifetime, all (44.0%) who reported an IPV history reported emotional abuse, 24.0% reported physical abuse, and 18.0% sexual abuse. HELPS responses indicated a high potential of lifetime IPV-related TBI for 29.2%, most commonly from being hit in the face or head (20.8%). CONCLUSION: Implementation of IPV screening in community-based ABI clinics is a pivotal step toward understanding the potential scope of TBI and addressing the wide range of somatic, cognitive, and affective symptoms experienced by IPV survivors. IPV screening also will lead to timely referral and follow-up and increase patient safety after discharge from rehabilitation.

Analysis of factors that influence neurosurgical length of hospital stay among newly diagnosed pediatric brain tumor patients.

BACKGROUND: Postoperative length of stay (LOS) carries a high burden of healthcare costs. In resource-intense specialties such as neurosurgery, it is imperative to identify factors that influence LOS to improve care. The current study investigates the potential for variables that affect clinical presentation, tumor characteristics, treatment modalities, and postoperative complications to impact overall LOS in pediatric brain tumor patients. METHODS: A retrospective cohort study design was used with patients enrolled in the McMaster Pediatric Brain Tumor Study Group database. All patients up to 18 years of age, presenting with a newly diagnosed brain tumor admitted to and discharged from neurosurgery, were included. Patients were sorted into three cohorts: short LOS (≤3 days), extended LOS (≥20 days), and control LOS (4-19 days). RESULTS: Of the 124 patients included, 20 (65% male; median age: 9.1 years; range, 0.8-17.4 years) were considered short LOS, 28 (61% male; median age: 4.7 years; range, 0.4-14.7 years) were considered extended LOS, and 76 (57% male; median age: 8.5 years; range, 0.3-17.9 years) were considered control LOS. Variables that prolonged LOS were emesis at presentation (P < 0.001), developmental delay (P = 0.02), multiple surgeries (P = 0.004), tumor location (P < 0.05), subtotal resection (P = 0.02), feeding tube (P < 0.001), adjuvant chemoradiotherapy (P < 0.001), and posterior fossa syndrome (P = 0.004). CONCLUSIONS: This study identifies variables related to clinical presentation, tumor characteristics, treatment modalities, and postoperative complications associated with extended LOS. These findings uncover novel predictors of LOS that can be used to guide future research and improve health resource management.

Neurosurgical management of conus lipoma in Canada: a multi-center survey.

OBJECT: Lipomyelomeningocele (LMM) is a congenital spinal cord anomaly. While patients with LMM may initially be asymptomatic, neurological sequelae secondary to LMM may become apparent as the patient ages. Consequently, some pediatric neurosurgeons have advocated for upfront neurosurgical interventions irrespective of the presence of symptoms at diagnosis. By contrast, others pursue a conservative approach when overt neurological symptoms are not yet evident. In light of the various practice styles to the heterogeneous anatomical locations, symptoms, and ages associated with LMM, we have conducted a multi-center survey of Canadian pediatric neurosurgeons using clinical vignettes representative of LMM patients. METHODS: An online survey of the opinions of Canadian pediatric neurosurgeons was conducted using 5 separate cases with magnetic resonance imaging (MRI) scans of the lumbar spine. Each case was accompanied with the same three clinical vignettes, which varied in severity at time of presentation: asymptomatic, progressive somatic motor deficit, or longstanding overflow incontinence. Participants were asked the question, "Would you offer surgical management?" after each clinical vignette. After the five cases and their corresponding 3 clinical vignettes, participants were asked, "If you answered yes to any of the preceding questions, what type of surgery would you perform?". Options for surgical goals and techniques included complete removal, near-total removal, debulking, detethering, and expansile duroplasty. Surgical adjuncts included CUSA, LASER, and neurophysiologic monitoring. RESULTS: Twenty-three responses were received from the 38 questionnaires sent out to all staff pediatric neurosurgeons across academic medical centers in Canada. This represented a response rate of 61%. Canadian pediatric neurosurgeons generally maintain a conservative approach to the surgical management of LMM as only 13% (n = 3) of surgeons indicated that they would operate in all scenarios. By contrast, 43% (n = 10) indicated surgical management in only those cases presenting with symptoms, and another 43% (n = 10) displayed a variable surgical approach. Nine percent (n = 2) of participants would not perform surgery for incontinence. The greatest level of disagreement among participants pertained to the management of asymptomatic sacral LMM where 43% of participants favored prophylactic surgery, while 57% of participants preferred conservative management. CONCLUSIONS: The current study highlights the differences in management of LMM among Canadian pediatric neurosurgeons and provides further support for future prospective cohort studies to develop appropriate expert opinions and guidelines such that the care of LMM patients may be according to evidence-based best practice. This is especially true for the treatment of asymptomatic patients, a patient group that would benefit from a randomized controlled trial to assess the long-term outcomes of conservative and surgical management.

RNAi screen identifies essential regulators of human brain metastasis-initiating cells.

Brain metastases (BM) are the most common brain tumor in adults and are a leading cause of cancer mortality. Metastatic lesions contain subclones derived from their primary lesion, yet their functional characterization is limited by a paucity of preclinical models accurately recapitulating the metastatic cascade, emphasizing the need for a novel approach to BM and their treatment. We identified a unique subset of stem-like cells from primary human patient brain metastases, termed brain metastasis-initiating cells (BMICs). We now establish a BMIC patient-derived xenotransplantation (PDXT) model as an investigative tool to comprehensively interrogate human BM. Using both in vitro and in vivo RNA interference screens of these BMIC models, we identified SPOCK1 and TWIST2 as essential BMIC regulators. SPOCK1 in particular is a novel regulator of BMIC self-renewal, modulating tumor initiation and metastasis from the lung to the brain. A prospective cohort of primary lung cancer specimens showed that SPOCK1 was overexpressed only in patients who ultimately developed BM. Protein-protein interaction network mapping between SPOCK1 and TWIST2 identified novel pathway interactors with significant prognostic value in lung cancer patients. Of these genes, INHBA, a TGF-ß ligand found mutated in lung adenocarcinoma, showed reduced expression in BMICs with knockdown of SPOCK1. In conclusion, we have developed a useful preclinical model of BM, which has served to identify novel putative BMIC regulators, presenting potential therapeutic targets that block the metastatic process, and transform a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

Analysis of surgical and MRI factors associated with cerebellar mutism.

The surgical risk factors and neuro-imaging characteristics associated with cerebellar mutism (CM) remain unclear and require further investigation. Therefore, we aimed to examine surgical and MRI findings associated with CM in children following posterior fossa tumor resection. Using our data registry, we retrospectively collected data from pediatric patients who acquired CM and were matched based on age and pathology type with individuals who did not acquire CM after posterior fossa surgery. The strength of association between surgical and MRI variables and CM were examined using odds ratios (ORs) and corresponding 95% confidence intervals (CIs). A total of 22 patients (11 with and 11 without CM) were included. Medulloblastoma was the most common pathology among CM patients (91%); the remaining 9% were diagnosed with a pilocytic astrocytoma. Tumor attachment to the floor of the fourth ventricle (OR 6; 95% CI 0.7-276), calcification/hemosiderin deposition (OR 7; 95% CI 0.9-315.5), and post-operative peri-ventricular ischemia on MRI (OR 5; 95% CI 0.5-236.5) were found to have the highest measures of association with CM. Our results may suggest that tumor attachment to the floor of the fourth ventricle, pathological calcification, and post-operative ischemia have a relatively higher prevalence in patients with CM. Collectively, our work calls for a larger multi-institutional cohort study of CM patients to encourage further investigation of the determinants and management of CM in order to potentially minimize its development and predict onset.

Aneurysmal Subarachnoid Hemorrhage and Neuroinflammation: A Comprehensive Review.

Aneurysmal subarachnoid hemorrhage (SAH) can lead to devastating outcomes including vasospasm, cognitive decline, and even death. Currently, treatment options are limited for this potentially life threatening injury. Recent evidence suggests that neuroinflammation plays a critical role in injury expansion and brain damage. Red blood cell breakdown products can lead to the release of inflammatory cytokines that trigger vasospasm and tissue injury. Preclinical models have been used successfully to improve understanding about neuroinflammation following aneurysmal rupture. The focus of this review is to provide an overview of how neuroinflammation relates to secondary outcomes such as vasospasm after aneurysmal rupture and to critically discuss pharmaceutical agents that warrant further investigation for the treatment of subarachnoid hemorrhage. We provide a concise overview of the neuroinflammatory pathways that are upregulated following aneurysmal rupture and how these pathways correlate to long-term outcomes. Treatment of aneurysm rupture is limited and few pharmaceutical drugs are available. Through improved understanding of biochemical mechanisms of injury, novel treatment solutions are being developed that target neuroinflammation. In the final sections of this review, we highlight a few of these novel treatment approaches and emphasize why targeting neuroinflammation following aneurysmal subarachnoid hemorrhage may improve patient care. We encourage ongoing research into the pathophysiology of aneurysmal subarachnoid hemorrhage, especially in regards to neuroinflammatory cascades and the translation to randomized clinical trials.

The role of stem cells in pediatric central nervous system malignancies.

Representing the leading cause of childhood cancer mortality, pediatric brain tumors are comprised of diverse histological features, genetic perturbations, cellular populations, treatment protocols, and clinical outcomes. In this chapter we discuss recent and emerging data that implicate cancer stem cells (also known as brain tumor-initiating cells) in initiating and maintaining the growth of a number of pediatric brain tumors including: medulloblastoma, supratentorial primitive neuroectodermal tumor, atypical teratoid/rhabdoid tumor, ependymoma, low-grade glioma, glioblastoma, diffuse intrinsic pontine glioma, germ cell tumor, and craniopharyngioma. The development of a stem cell framework for the study and treatment of these tumors will enable future clinical approaches to harness the heterogeneous cellular and genomic landscape of these solid tumors as an avenue for developing targeted patient-oriented therapies, thereby improving the overall survivorship for the most lethal childhood cancer.

Chronic subdural hematoma management: a systematic review and meta-analysis of 34,829 patients.

OBJECTIVE: To compare the efficacy and safety of multiple treatment modalities for the management of chronic subdural hematoma (CSDH) patients. BACKGROUND: Current management strategies of CSDHs remain widely controversial. Treatment options vary from medical therapy and bedside procedures to major operative techniques. METHODS: We searched MEDLINE (PubMed and Ovid), EMBASE, CINAHL, Google scholar, and the Cochrane library from January 1970 through February 2013 for randomized and observational studies reporting one or more outcome following the management of symptomatic patients with CSDH. Independent reviewers evaluated the quality of studies and abstracted the data on the safety and efficacy of percutaneous bedside twist-drill drainage, single or multiple operating room burr holes, craniotomy, corticosteroids as a main or adjuvant therapy, use of drains, irrigation of the hematoma cavity, bed rest, and treatment of recurrences following CSDH management. Mortality, morbidity, cure, and recurrence rates were examined for each management option. Randomized, prospective, retrospective, and overall observational studies were analyzed separately. Pooled estimates, confidence intervals (CIs), and relative risks (RRs) were calculated for all outcomes using a random-effects model. RESULTS: A total of 34,829 patients from 250 studies met our eligibility criteria. Sixteen trials were randomized, and the remaining 234 were observational. We included our unpublished single center series of 834 patients. When comparing percutaneous bedside drainage to operating room burr hole evacuation, there was no significant difference in mortality (RR, 0.69; 95% CI, 0.46-1.05; P = 0.09), morbidity (RR, 0.45; 95% CI, 0.2-1.01; P = 0.05), cure (RR, 1.05; 95% CI, 0.98-1.11; P = 0.15), and recurrence rates (RR, 1; 95% CI, 0.66-1.52; P = 0.99). Higher morbidity was associated with the adjuvant use of corticosteroids (RR, 1.97; 95% CI, 1.54-2.45; P = 0.005), with no significant improvement in recurrence and cure rates. The use of drains following CSDH drainage resulted in a significant decrease in recurrences (RR, 0.46; 95% CI, 0.27-0.76; P = 0.002). Craniotomy was associated with higher complication rates if considered initially (RR, 1.39; 95% CI, 1.04-1.74; P = 0.01); however, craniotomy was superior to minimally invasive procedures in the management of recurrences (RR, 0.22; 95% CI, 0.05-0.85; P = 0.003). CONCLUSIONS: Percutaneous bedside twist-drill drainage is a relatively safe and effective first-line management option. These findings may result in potential health cost savings and eliminate perioperative risks related to general anesthetic.

FoxG1 interacts with Bmi1 to regulate self-renewal and tumorigenicity of medulloblastoma stem cells.

Brain tumors represent the leading cause of childhood cancer mortality, of which medulloblastoma (MB) is the most frequent malignant tumor. Recent studies have demonstrated the presence of several MB molecular subgroups, each distinct in terms of prognosis and predicted therapeutic response. Groups 1 and 2 are characterized by relatively good clinical outcomes and activation of the Wnt and Shh pathways, respectively. In contrast, groups 3 and 4 ("non-Shh/Wnt MBs") are distinguished by metastatic disease, poor patient outcome, and lack a molecular pathway phenotype. Current gene expression platforms have not detected brain tumor-initiating cell (BTIC) self-renewal genes in groups 3 and 4 MBs as BTICs typically comprise a minority of tumor cells and may therefore go undetected on bulk tumor analyses. Since increasing BTIC frequency has been associated with increasing tumor aggressiveness and poor patient outcome, we investigated the subgroup-specific gene expression profile of candidate stem cell genes within 251 primary human MBs from four nonoverlapping MB transcriptional databases (Amsterdam, Memphis, Toronto, Boston) and 74 NanoString-subgrouped MBs (Vancouver). We assessed the functional relevance of two genes, FoxG1 and Bmi1, which were significantly enriched in non-Shh/Wnt MBs and showed these genes to mediate MB stem cell self-renewal and tumor initiation in mice. We also identified their transcriptional regulation through reciprocal promoter occupancy in CD15+ MB stem cells. Our work demonstrates the application of stem cell data gathered from genomic platforms to guide functional BTIC assays, which may then be used to develop novel BTIC self-renewal mechanisms amenable to therapeutic targeting.

Brain metastasis-initiating cells: survival of the fittest.

Brain metastases (BMs) are the most common brain tumor in adults, developing in about 10% of adult cancer patients. It is not the incidence of BM that is alarming, but the poor patient prognosis. Even with aggressive treatments, median patient survival is only months. Despite the high rate of BM-associated mortality, very little research is conducted in this area. Lack of research and staggeringly low patient survival is indicative that a novel approach to BMs and their treatment is needed. The ability of a small subset of primary tumor cells to produce macrometastases is reminiscent of brain tumor-initiating cells (BTICs) or cancer stem cells (CSCs) hypothesized to form primary brain tumors. BTICs are considered stem cell-like due to their self-renewal and differentiation properties. Similar to the subset of cells forming metastases, BTICs are most often a rare subpopulation. Based on the functional definition of a TIC, cells capable of forming a BM could be considered to be brain metastasis-initiating cells (BMICs). These putative BMICs would not only have the ability to initiate tumor growth in a secondary niche, but also the machinery to escape the primary tumor, migrate through the circulation, and invade the neural niche.

A single center experience in the management of progressive juvenile pilocytic astrocytoma.

BACKGROUND: Juvenile pilocytic astrocytoma (JPA) typically follows an indolent clinical course. The first-line treatment for most JPAs is surgical resection. However, a gross total resection may not be feasible for deep-seated lesions and/or infiltrative tumors, leading to multimodal treatment approaches that may be complicated by patient age and tumor location. Despite the prevalence of pediatric JPAs, there is no single approach to treating progressive disease. METHODS: We investigated the multifaceted management of progressive JPAs through a retrospective analysis of JPAs treated at a single center over an 18-year period (1998-2016). All cases were categorized according to location, whether supratentorial or infratentorial, and for each case we calculated the number of interventions and the time between interventions. RESULTS: We identified a total of 40 JPAs, (11 supratentorial, 29 infratentorial). Total number of interventions among all supratentorial JPA patients was 21 (average 2 interventions/patient). The total number of interventions among infratentorial JPAs was 40 (average 1.4 interventions/patient). CONCLUSIONS: Treatment of progressive JPA is variable and may require numerous surgeries and adjuvant therapies.

Medulloblastoma stem cells: where development and cancer cross pathways.

Brain tumors are the leading cause of childhood cancer mortality, with medulloblastoma (MB) representing the most frequent malignant tumor. The recent molecular classification of MB has reconceptualized the heterogeneity that exists within pathological subtypes by giving context to the role of key developmental signaling pathways in MB pathogenesis. The identification of cancer stem cell (CSC) populations, termed brain tumor-initiating cells (BTICs), in MB has provided novel cellular targets for the study of these aberrantly activated signaling pathways, namely, Sonic hedgehog (Shh) and Wingless (Wnt), along with the identification of novel BTIC self-renewal pathways. In this review, we discuss recent evidence for the presence of a MB stem cell that drives tumorigenesis in this malignant childhood tumor. We focus on evidence from cerebellar development, the recent identification of BTICs, the presence of activated developmental signaling pathways in MB, the role of epigenetic stem cell regulatory mechanisms, and how these developmental and epigenetic pathways may be targeted for novel therapeutic options.

GBM secretome induces transient transformation of human neural precursor cells.

Glioblastoma (GBM) is the most aggressive primary brain tumor in humans, with a uniformly poor prognosis. The tumor microenvironment is composed of both supportive cellular substrates and exogenous factors. We hypothesize that exogenous factors secreted by brain tumor initiating cells (BTICs) could predispose normal neural precursor cells (NPCs) to transformation. When NPCs are grown in GBM-conditioned media, and designated as "tumor-conditioned NPCs" (tcNPCs), they become highly proliferative and exhibit increased stem cell self-renewal, or the unique ability of stem cells to asymmetrically generate another stem cell and a daughter cell. tcNPCs also show an increased transcript level of stem cell markers such as CD133 and ALDH and growth factor receptors such as VEGFR1, VEGFR2, EGFR and PDGFRα. Media analysis by ELISA of GBM-conditioned media reveals an elevated secretion of growth factors such as EGF, VEGF and PDGF-AA when compared to normal neural stem cell-conditioned media. We also demonstrate that tcNPCs require prolonged or continuous exposure to the GBM secretome in vitro to retain GBM BTIC characteristics. Our in vivo studies reveal that tcNPCs are unable to form tumors, confirming that irreversible transformation events may require sustained or prolonged presence of the GBM secretome. Analysis of GBM-conditioned media by mass spectrometry reveals the presence of secreted proteins Chitinase-3-like 1 (CHI3L1) and H2A histone family member H2AX. Collectively, our data suggest that GBM-secreted factors are capable of transiently altering normal NPCs, although for retention of the transformed phenotype, sustained or prolonged secretome exposure or additional transformation events are likely necessary.

ß-Catenin marks proliferating endothelial cells in glioblastoma.

BACKGROUND: Angiogenesis is a key process in the growth and maintenance of tumors. The Wnt signaling pathway is required for angiogenesis of the central nervous system though development of the blood-brain barrier and subsequent proliferation of endothelial cells during tumor growth. However, the specificity of the Wnt pathway in regulating endothelial cells of different central nervous systems remains to be investigated. MATERIALS & METHODS: Patient-derived tissue samples from 35 paraffin-embedded tumors were used to assess ß-catenin immunoexpression. Tumor samples consisted of the following pathologies: grade II diffuse astrocytoma, glioblastoma, hemangioblastoma, and metastatic adenocarcinoma (lung or breast primary). Average percent reactivity was recorded as a mean observed in ten high-power fields. The following scale was used to grade immunoreactivity: 0 = immunonegative, 1 = 1-25% reactive, 2 = 26-50% reactive, 3 = 51-75% reactive, 4 = 76-100% reactive. RESULTS: While we did not observe nuclear expression of ß-catenin in any samples, there was uniform cytoplasmic expression of ß-catenin within glial tumor cells. There was a clear distinction in tumor endothelial cells whereby diffuse staining was noted in areas of microvascular hyperplasia in GBM and a less immunoreactive profile in low-grade astrocytomas. By contrast, non-glial tumors, contained very minimal cytoplasmic ß-catenin expression in tumor and stromal cells and were devoid of immunoreactivity in endothelial cells. CONCLUSION: ß-catenin is unique marker of proliferating endothelial cells in GBM. Therapies targeting the spatial and structural heterogeneity inherent to GBM may prove to be efficacious and result in an improved survivorship.

Intraventricular Masson tumor: case report and systematic review of primary intracranial intravascular papillary endothelial hyperplasia.

Intracranial Masson tumor (intravascular papillary endothelial hyperplasia, IPEH) is a benign lesion that is thought to originate from a reactionary process in response to compromised blood flow. IPEH may be classified into one of three subtypes based on etiology as it may result from the excessive proliferation of endothelial cells within a normal vessel (primary), vascular malformation (type II), or organized hematoma (type III). We report the case of a 79-year-old woman who presented with confusion, gait instability, and urinary incontinence. Neuroimaging revealed a hemorrhagic lesion within the right lateral ventricle, which was successfully resected. To our knowledge, this is the first reported case of an intraventricular IPEH and 33rd case of primary intracranial IPEH. We further performed a systematic review of the literature on all prior type I intracranial IPEH cases and discuss the importance of long-term follow-up in intracranial IPEH.

Clinical outcomes in pediatric hydrocephalus patients treated with endoscopic third ventriculostomy and choroid plexus cauterization: a systematic review and meta-analysis.

OBJECTIVE: Endoscopic third ventriculostomy and choroid plexus cauterization (ETV+CPC) is a novel procedure for infant hydrocephalus that was developed in sub-Saharan Africa to mitigate the risks associated with permanent implanted shunt hardware. This study summarizes the hydrocephalus literature surrounding the ETV+CPC intraoperative abandonment rate, perioperative mortality rate, cerebrospinal fluid infection rate, and failure rate. METHODS: This systematic review and meta-analysis followed a prespecified protocol and abides by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A comprehensive search strategy using MEDLINE, EMBASE, PsychInfo, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Scopus, and Web of Science was conducted from database inception to October 2019. Studies included controlled trials, cohort studies, and case-control studies of patients with hydrocephalus younger than 18 years of age treated with ETV+CPC. Pooled estimates were calculated using DerSimonian and Laird random-effects modeling, and the significance of subgroup analyses was tested using meta-regression. The quality of the pooled outcomes was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. RESULTS: After screening and reviewing 12,321 citations, the authors found 16 articles that met the inclusion criteria. The pooled estimate for the ETV+CPC failure rate was 0.44 (95% CI 0.37-0.51). Subgroup analysis by geographic income level showed statistical significance (p < 0.01), with lower-middle-income countries having a lower failure rate (0.32, 95% CI 0.28-0.36) than high-income countries (0.53, 95% CI 0.47-0.60). No difference in failure rate was found between hydrocephalus etiology (p = 0.09) or definition of failure (p = 0.24). The pooled estimate for perioperative mortality rate (n = 7 studies) was 0.001 (95% CI 0.00-0.004), the intraoperative abandonment rate (n = 5 studies) was 0.04 (95% CI 0.01-0.08), and the postoperative CSF infection rate (n = 5 studies) was 0.0004 (95% CI 0.00-0.003). All pooled outcomes were found to be low-quality evidence. CONCLUSIONS: This systematic review and meta-analysis provides the most comprehensive pooled estimate for the ETV+CPC failure rate to date and demonstrates, for the first time, a statistically significant difference in failure rate by geographic income level. It also provides the first reported pooled estimates for the risk of ETV+CPC perioperative mortality, intraoperative abandonment, and CSF infection. The low quality of this evidence highlights the need for further research to improve the understanding of these critical clinical outcomes and their relevant explanatory variables and thus to appreciate which patients may benefit most from an ETV+CPC. Systematic review registration no.: CRD42020160149 (https://www.crd.york.ac.uk/prospero/).

Desmoplastic myxoid tumor of pineal region, SMARCB1-mutant, in young adult.

We present a young adult woman who developed a myxoid tumor of the pineal region having a SMARCB1 mutation, which was phenotypically similar to the recently described desmoplastic myxoid, SMARCB1-mutant tumor of the pineal region (DMT-SMARCB1). The 24-year-old woman presented with headaches, nausea, and emesis. Neuroimaging identified a hypodense lesion in CT scans that was T1-hypointense, hyperintense in both T2-weighted and FLAIR MRI scans, and displayed gadolinium enhancement. The resected tumor had an abundant, Alcian-blue positive myxoid matrix with interspersed, non-neoplastic neuropil-glial-vascular elements. It immunoreacted with CD34 and individual cells for EMA. Immunohistochemistry revealed loss of nuclear INI1 expression by the myxoid component but its retention in the vascular elements. Molecular analyses identified a SMARCB1 deletion and DNA methylation studies showed that this tumor grouped together with the recently described DMT-SMARCB1. A cerebrospinal fluid cytologic preparation had several cells morphologically similar to those in routine and electron microscopy. We briefly discuss the correlation of the pathology with the radiology and how this tumor compares with other SMARCB1-mutant tumors of the nervous system.

Hemimegalencephaly: a fetal case with neuropathological confirmation and review of the literature.

Hemimegalencephaly (HME) is a developmental abnormality of the central nervous system, identified by an abnormal increase in the size of one cerebral hemisphere. HME may present as either a syndromic or isolated case. To date the literature on HME has focused primarily on non-fetal pediatric patients, largely related to surgical resection specimens of the HME hemisphere. We present the case of a male fetus at 22 weeks gestation with intracranial abnormalities identified on a follow-up ultrasound. Gross examination of the fetal brain confirmed the increased size of the right cerebral hemisphere. The ipsilateral brain stem and cerebellum were not involved. Light microscopy demonstrated the presence of accelerated cortical differentiation along with several migrational anomalies in the HME hemisphere. Based on the gross and microscopic findings, a diagnosis of fetal hemimegalencephaly was made. The periventricular proliferative zone of the abnormal hemisphere contained a normal population of neuroepithelial precursor cells. An exhaustive immunohistochemical study found immunoreactivity for calretinin and synaptophysin, while the Ki-67 proliferation labeling was not increased in the HME hemisphere. Our case is the first autopsied report on fetal hemimegalencephaly and confirms that the key pathogenic changes may present as early as 20-22 weeks gestation. The major pathological features of our case are in keeping with a disturbance in accelerated neuronal differentiation and migrational abnormalities.

WNT: an unexpected tumor suppressor in medulloblastoma.

Medulloblastoma (MB) represents the most common malignant pediatric brain tumor and is defined by four molecular subgroups with WNT MB having the most favorable prognosis. Our work provides a rational therapeutic option in which the protective effects of WNT-driven MBs may be augmented in Group 3 and 4 MB.