Long-Term Tumor Stability After First-Line Treatment With Larotrectinib in an Infant With NTRK2 Fusion-Positive High-Grade Glioma.

Tissue-agnostic, molecularly targeted therapies are becoming increasingly common in cancer treatment. The molecular drivers of some classes and subclasses of tumors are rapidly being uncovered in an era of deep tumor sequencing occurring at the time of diagnosis. When and how targeted therapies should fit within up-front cytotoxic chemotherapy and radiation paradigms is yet to be determined, because many of them have been studied in single-arm studies in patients with relapsed or refractory cancer. Infant high-grade gliomas (HGGs) are biologically and clinically distinct from older child and adult HGGs, and are divided into 3 molecular subgroups. Group 1 infant HGGs are driven by receptor tyrosine kinase fusions, most commonly harboring an ALK, ROS1, NTRK, or MET fusion. Both larotrectinib and entrectinib are tropomyosin receptor kinase inhibitors with tissue-agnostic approvals for the treatment of patients with solid tumors harboring an NTRK fusion. This report discusses an 11-month-old female who presented with infantile spasms, found to have an unresectable, NTRK fusion-positive infant HGG. Larotrectinib was prescribed when the NTRK fusion was identified at diagnosis, and without additional intervention to date, the patient has continued with stable disease for >3 years. The only adverse event experienced was grade 1 aspartate transaminase and alanine transaminase elevations. The patient has a normal neurologic examination, is developing age-appropriately in all domains (gross motor, fine motor, cognitive, language, and social-emotional). She is no longer on antiseizure medications. To our knowledge, this is the first report of a patient with an infantile HGG receiving targeted therapy as first-line treatment with prolonged stable disease. A prospective study of larotrectinib in patients with newly diagnosed infant HGG is ongoing, and will hopefully help answer questions about durability of response, the need for additional therapies, and long-term toxicities seen with TRK inhibitors.

Influence of socioeconomic status on clinical outcomes of diffuse midline glioma and diffuse intrinsic pontine glioma.

OBJECTIVE: Given the lack of a definitive treatment and the poor prognosis of patients with diffuse midline glioma (DMG) and diffuse intrinsic pontine glioma (DIPG), socioeconomic status (SES) may affect treatment access and therefore survival. Therefore, this study aimed to examine the relationship between SES and treatment modalities, progression-free survival (PFS), and overall survival (OS) in children with DMG/DIPG. METHODS: A retrospective, single-institution review was conducted of medical records of patients ≤ 18 years of age who had DMG or DIPG that was diagnosed between 2000 and 2022. Patient demographics, surgical interventions, chemotherapy, radiation therapy, clinical trial enrollment, and medical care-related travel were extracted. SES variables (education and mean income) for associated patient census tracts were collected and stratified. Statistical analysis using unpaired t-tests, chi-square analysis, and log-rank tests was conducted. RESULTS: Of the 96 patients who met the inclusion criteria, the majority were female (59%) and non-Hispanic White (57%). The median PFS, median OS, and time from diagnosis to treatment did not differ between races/ethnicities or sex. Ninety-one of 96 patients had census tract data available. Patients from higher-income census tracts (> 50% of families with annual household income greater than $50,000) had a longer median OS (480 vs 235 days, p < 0.001) and traveled significantly longer distances for medical care (1550 vs 1114 miles, p = 0.048) than families from lower-income census tracts. Patients from the highest education quartile traveled significantly farther for treatment than the lowest education quartile (mean 2964 vs 478 miles, p = 0.047). Patients who received both oral and intravenous chemotherapy were more likely to be from higher-income census tracts than those who received intravenous or no chemotherapy. Duration of PFS, rates of clinical trial enrollment, biopsy rates, H3K27 mutation status, ventriculoperitoneal shunt placement rates, and radiotherapy rates were not associated with SES variables. CONCLUSIONS: Patients from families from higher-income census tracts experienced longer OS and traveled farther for treatment. Patients from families from higher-education-level census tracts traveled more often for treatment. The authors' findings suggest that SES influences DMG and DIPG OS. More studies should be done to understand the role of SES in the outcomes of children with DMG/DIPG.

A road map for the treatment of pediatric diffuse midline glioma.

Recent clinical trials for H3K27-altered diffuse midline gliomas (DMGs) have shown much promise. We present a consensus roadmap and identify three major barriers: (1) refinement of experimental models to include immune and brain-specific components; (2) collaboration among researchers, clinicians, and industry to integrate patient-derived data through sharing, transparency, and regulatory considerations; and (3) streamlining clinical efforts including biopsy, CNS-drug delivery, endpoint determination, and response monitoring. We highlight the importance of comprehensive collaboration to advance the understanding, diagnostics, and therapeutics for DMGs.

Attenuation of ventriculomegaly and iron overload after intraventricular hemorrhage by membrane attack complex inhibition.

OBJECTIVE: The pathophysiology of posthemorrhagic hydrocephalus (PHH) is not well understood, but recent data suggest blood components play a significant role. This study aimed to understand the timing of membrane attack complex (MAC) activation after intraventricular hemorrhage (IVH) and the effect of MAC inhibition on PHH development. METHODS: This study was composed of four parts. First, 24 young adult male rats underwent stereotactic intraventricular injection of autologous blood or saline and MRI on day 1, 3, or 7 after hemorrhage. Second, 18 rats underwent intraventricular injection of saline, autologous blood with aurin tricarboxylic acid (ATA) in vehicle, or autologous blood with vehicle and underwent serial MRI studies on days 1 and 3 after hemorrhage. Third, 12 rats underwent intraventricular injections as above and MRI 2 hours after hemorrhage. Finally, 24 rats underwent the intraventricular injections as above, as well as serial MRI studies on days 1, 7, 14, and 28 after hemorrhage. The MR images were used to calculate ventricular volume and iron deposition. Open field testing was performed to assess functional outcomes. Outcomes on day 28 were reported as a ratio to the animal's baseline values and normalized via log-transformation. Statistical analysis included the Shapiro-Wilk tests for normality and t-tests and 1-way analysis of variance for 2 and 3 groups of continuous variables, respectively. RESULTS: MAC was found within the hematoma 1 day after hemorrhage and persisted until day 7. Administration of ATA resulted in similar intraventricular hematoma volumes compared to vehicle 2 hours after hemorrhage. At 1 and 3 days after hemorrhage, ATA administration resulted in significantly smaller ventricular volumes and less hemolysis within the hematoma than in the vehicle animals. Administration of ATA also resulted in significantly smaller ventriculomegaly and less iron deposition in the periventricular area than in the vehicle rats 28 days after hemorrhage. Functionally, ATA rats were significantly faster, traveled longer distances, and spent less time resting than vehicle rats at 28 days. CONCLUSIONS: MAC was activated early and persisted within the hematoma until day 7 after IVH. MAC inhibition attenuated hemolysis in the clot and ventriculomegaly acutely after IVH. One month after hemorrhage, MAC inhibition attenuated ventriculomegaly and iron accumulation and improved functional outcomes.

Clinical Efficacy of ONC201 in H3K27M-Mutant Diffuse Midline Gliomas Is Driven by Disruption of Integrated Metabolic and Epigenetic Pathways.

Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

Ventriculoatrial and ventriculoperitoneal shunt malfunction and infection in infants with necrotizing enterocolitis.

OBJECTIVE: Necrotizing enterocolitis (NEC) and posthemorrhagic hydrocephalus are both conditions that can affect preterm infants. The peritoneum is the preferred terminus for shunt placement, but another terminus is sometimes used due to subjective concerns about infection and complications related to NEC. The aim of this study was to examine the rates of ventriculoatrial (VA) and ventriculoperitoneal (VP) shunt infection and failure in pediatric patients with a history of NEC. METHODS: A single-center retrospective review of medical records from 2009 to 2021 was performed to identify pediatric patients with NEC who underwent shunt placement before 2 years of age. Patients were excluded if shunt placement preceded NEC diagnosis. Patient demographic characteristics, timing of shunt placement, type of shunt, shunt infections or revisions, and timing and management of NEC were extracted. The Student t-test and Fisher exact test were used to calculate significance. Kaplan-Meier curves were calculated. RESULTS: Twenty-two patients met the inclusion criteria. Most patients underwent VP shunt placement (16 [71.4%]). Patients who underwent surgical management of NEC compared with those who underwent medical management were more likely to have a VA shunt placed (p = 0.02). One VA shunt and 3 VP shunts became infected during follow-up (p = 0.7). The mean time until infection was not significantly different between VA and VP shunts (p = 0.73). Significantly more VA shunts required revision (83% vs 31%, p = 0.04), and VA shunts had a significantly shorter time until failure (3.0 ± 0.8 vs 46.3 ± 7.55 months, p = 0.03). CONCLUSIONS: VP shunts had a significantly longer time until failure than VA shunts; these shunts had similar infection rates in infants with prior NEC. When feasible, neurosurgeons and pediatric general surgeons can consider placing a VP shunt even if the patient has a history of NEC.

Glymphatic System and Post-hemorrhagic Hydrocephalus.

The glymphatic system is a recently identified route for exchanging parenchyma interstitial fluid and cerebrospinal fluid along perivascular space, facilitating brain waste clearance. Glymphatic system dysfunction has been reported in many neurological diseases. Here we discussed the possible role of glymphatic system in posthemorrhagic brain injury, especially posthemorrhagic hydrocephalus.

Sports Participation and Sports-Related Neurologic Injuries in Pediatric Patients With Arachnoid Cysts.

BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with arachnoid cysts (ACs). OBJECTIVE: To prospectively survey patients with ACs to define the risk of sports-associated neurologic injury in untreated and treated patients. METHODS: A prospectively administered survey was given to all patients diagnosed with an AC who presented to a single pediatric neurosurgery clinic between December 2010 and December 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurologic injury. The type and date of surgery for the AC were noted if surgery was performed. RESULTS: Of the 303 patients with completed surveys, 189 patients participated in sports, and 94 patients had prospective data available. There was no significant difference in cyst location or Galassi score between patients who did and did not participate in contact vs noncontact sports and those who did and did not experience a concussion. A cumulative total of 2700.5 seasons of sports were played (2499.7 in untreated and 200.8 in treated patients). There were 44 sports-related concussions among 34 patients: 43 in untreated patients and 1 in a treated patient. For all participants, the concussion rate was 16.3 per 1000 seasons of all sports and 14.8 per 1000 seasons of contact sports. The concussion rate after AC treatment was 4.9 per 1000 seasons of all sports. Three patients experienced sports-related AC rupture or hemorrhage, none of which required surgery or resulted in lasting neurologic symptoms or deficits. CONCLUSION: The rates of sports-related concussion and cyst rupture in patients with AC in both treated and untreated populations were low. We advocate for a generally permissive posture toward sports participation in this population.

Characteristics of activation of monocyte-derived macrophages versus microglia after mouse experimental intracerebral hemorrhage.

Both monocyte-derived macrophages (MDMs) and brain resident microglia participate in hematoma resolution after intracerebral hemorrhage (ICH). Here, we utilized a transgenic mouse line with enhanced green fluorescent protein (EGFP) labeled microglia (Tmem119-EGFP mice) combined with a F4/80 immunohistochemistry (a pan-macrophage marker) to visualize changes in MDMs and microglia after ICH. A murine model of ICH was used in which autologous blood was stereotactically injected into the right basal ganglia. The autologous blood was co-injected with CD47 blocking antibodies to enhance phagocytosis or clodronate liposomes for phagocyte depletion. In addition, Tmem119-EGFP mice were injected with the blood components peroxiredoxin 2 (Prx2) or thrombin. MDMs entered the brain and formed a peri-hematoma cell layer by day 3 after ICH and giant phagocytes engulfed red blood cells were found. CD47 blocking antibody increased the number of MDMs around and inside the hematoma and extended MDM phagocytic activity to day 7. Both MDMs and microglia could be diminished by clodronate liposomes. Intracerebral injection of Prx2 but not thrombin attracted MDMs into brain parenchyma. In conclusion, MDMs play an important role in phagocytosis after ICH which can be enhanced by CD47 blocking antibody, suggesting the modulation of MDMs after ICH could be a future therapeutic target.

Sports Participation and Neurological Injuries in Pediatric Patients With Chiari I Malformation.

BACKGROUND: Currently, there is no consensus recommendation regarding the safety of sports participation for pediatric patients with Chiari I malformation (CM-I). OBJECTIVE: To prospectively survey the treated and untreated patients with CM-I to define the risk of sports-associated neurological injury. METHODS: A prospective survey was administered to 744 pediatric patients at one neurosurgery clinic between 2010 and 2021. Data were recorded on demographic information, imaging characteristics, treatment, sports participation, and presence of sports-related neurological injury. Patients with incomplete data were called. Two hundred seven patients completed at least 1 subsequent survey and were prospectively followed (mean 1.6 years). RESULTS: Of 744 patients with completed surveys, 462 participated in sports. Sports participants were more likely to be older at presentation ( P < .001) and have rounded cerebellar tonsil morphology ( P < .001). Seasons of sports played before and after CM-I decompression (CMD) totaled 5918.7 and 936, respectively. There were 84 sports-related concussions among 55 patients; 79 in untreated patients and 5 after CMD. For all sports participants, the concussion rate was 12.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 13.8/1000 of contact sports. The concussion rate after CMD was 5.3/1000 seasons of all sports, 9.2/1000 seasons of limited-contact sports, and 7.1/1000 seasons of contact sports. There were no reports of long-lasting neurological issues postconcussion or of permanent spinal cord injury. CONCLUSION: No permanent or catastrophic sports-associated neurological injuries were reported. The concussion rates in treated and untreated patients with CM-I were low. Therefore, sports participation in this population should be permitted in most cases.

Conservative management of intraventricular migration of a gelatin sponge: illustrative case.

BACKGROUND: Gelatin sponges, such as Gelfoam, are used as hemostatic agents during surgery and are generally absorbed over the course of 4-6 weeks in most body cavities. The time course of the dissolution of Gelfoam sponges within the cerebral ventricles has not been described. OBSERVATIONS: The authors present a case of intraventricular migration of Gelfoam after ventriculoperitoneal shunt placement in a 6-week-old infant. The infant was imaged regularly after ventriculoperitoneal shunt placement, and the Gelfoam sponge persisted within the ventricles on all images until 11 months after surgery. At no time during follow-up did the patient have any symptoms of hydrocephalus requiring retrieval of the sponge or shunt revision. LESSONS: This is the first case describing time until absorption of a gelatin sponge within the ventricle and successful conservative management.

Syrinx regression after correction of iatrogenic kyphotic deformity: illustrative case.

BACKGROUND: Syringomyelia has a long-established association with pediatric scoliosis, but few data exist on the relationship of syringomyelia to pediatric kyphotic deformities. OBSERVATIONS: This report reviewed a unique case of rapid and sustained regression of syringomyelia in a 13-year-old girl after surgical correction of iatrogenic kyphotic deformity. LESSONS: In cases of syringomyelia associated with acquired spinal deformity, treatment of deformity to resolve an associated subarachnoid block should be considered because it may obviate the need for direct treatment of syrinx.

Serial H3K27M cell-free tumor DNA (cf-tDNA) tracking predicts ONC201 treatment response and progression in diffuse midline glioma.

BACKGROUND: Diffuse Midline Glioma (DMG) with the H3K27M mutation is a lethal childhood brain cancer, with patients rarely surviving 2 years from diagnosis. METHODS: We conducted a multi-site Phase 1 trial of the imipridone ONC201 for children with H3K27M-mutant glioma (NCT03416530). Patients enrolled on Arm D of the trial (n = 24) underwent serial lumbar puncture for cell-free tumor DNA (cf-tDNA) analysis and patients on all arms at the University of Michigan underwent serial plasma collection. We performed digital droplet polymerase chain reaction (ddPCR) analysis of cf-tDNA samples and compared variant allele fraction (VAF) to radiographic change (maximal 2D tumor area on MRI). RESULTS: Change in H3.3K27M VAF over time ("VAF delta") correlated with prolonged PFS in both CSF and plasma samples. Nonrecurrent patients that had a decrease in CSF VAF displayed a longer progression free survival (P = .0042). Decrease in plasma VAF displayed a similar trend (P = .085). VAF "spikes" (increase of at least 25%) preceded tumor progression in 8/16 cases (50%) in plasma and 5/11 cases (45.4%) in CSF. In individual cases, early reduction in H3K27M VAF predicted long-term clinical response (>1 year) to ONC201, and did not increase in cases of later-defined pseudo-progression. CONCLUSION: Our work demonstrates the feasibility and potential utility of serial cf-tDNA in both plasma and CSF of DMG patients to supplement radiographic monitoring. Patterns of change in H3K27M VAF over time demonstrate clinical utility in terms of predicting progression and sustained response and possible differentiation of pseudo-progression and pseudo-response.

Subdural hematoma prevalence and long-term developmental outcomes in patients with benign expansion of the subarachnoid spaces.

OBJECTIVE: Benign expansion of the subarachnoid spaces (BESS) is a condition seen in macrocephalic infants. BESS is associated with mild developmental delays which tend to resolve within a few years. It is accepted that patients with BESS are at increased risk of spontaneous subdural hematomas (SDHs), although the exact pathophysiology is not well understood. The prevalence of spontaneous SDH in BESS patients is poorly defined, with only a few large single-center series published. In this study the authors aimed to better define BESS prevalence and developmental outcomes through the longitudinal review of a large cohort of BESS patients. METHODS: A large retrospective review was performed at a single institution from 1995 to 2020 for patients 2 years of age or younger with a diagnosis of BESS by neurology or neurosurgery and head circumference > 85th percentile. Demographic data, head circumference, presence of developmental delay, occurrence of SDH, and need for surgery were extracted from patient charts. The subarachnoid space (SAS) size was measured from the available MR images, and the sizes of those who did and did not develop SDH were compared. RESULTS: Free text search revealed BESS mentioned within the medical records of 1410 of 2.6 million patients. After exclusion criteria, 480 patients remained eligible for the study. Thirty-two percent (n = 154) of patients were diagnosed with developmental delay, most commonly gross motor delay (53%). Gross motor delay resolved in 86% of patients at a mean age of 22.2 months. The prevalence of spontaneous SDH in this BESS population over a period of 25 years was 8.1%. There was no significant association between SAS size and SDH formation. CONCLUSIONS: This study represents results for one of the largest cohorts of patients with BESS at a single institution. Gross motor delay was the most common developmental delay diagnosed, and a majority of patients had resolution of their delay. These data support that children with BESS have a higher prevalence of SDH than the general pediatric population, although SAS size was not significantly associated with SDH development.

Superficial abdominal reflex in syringomyelia: Associations with Chiari I malformation.

An abnormal or absent superficial abdominal reflex (SAR) may be associated with an underlying spinal cord syrinx. The sensitivity of an abnormal or absent SAR and the relationship to Chiari malformation type I (CM-I) or syrinx morphology has not been studied. We aimed to describe the relationship between SAR abnormalities and syrinx size, location, and etiology. Children who underwent brain or c-spine MRI over 11 years were reviewed in this retrospective cohort study. Patients with idiopathic and CM-I-associated syringes (axial diameter ≥ 3 mm) were included. Clinical examination findings (including SAR) and imaging characteristics were analyzed. Of 271 patients with spinal cord syrinx, 200 had either CM-I-associated or idiopathic syrinx, and 128 of these patients had SAR-evaluation documentation. Forty-eight percent (62/128) had an abnormal or absent reflex. Abnormal/absent SAR was more common in patients with CM-I-associated syrinx (61%) compared with idiopathic syrinx (22%) (P < 0.0001). Abnormal/absent SAR was associated with wider syringes (P < 0.001), longer syringes (P < 0.05), and a more cranial location of the syrinx (P < 0.0001). Controlling for CM-I, scoliosis, age, sex, cranial extent of syrinx, and syrinx dimensions, CM-I was independently associated with abnormal or absent SAR (OR 4.2, 95% CI 1.4-14, P < 0.01). Finally, the sensitivity of SAR for identifying a patient with syrinx was 48.1%. An abnormal/absent SAR was present in most patients with CM-I-associated syrinx but in a minority of patients with idiopathic syrinx. This has implications for pathophysiology of CM-I-associated syrinx and in guiding clinical care of patients presenting with syrinx.

Delayed Minocycline Treatment Ameliorates Hydrocephalus Development and Choroid Plexus Inflammation in Spontaneously Hypertensive Rats.

Hydrocephalus is a complicated disorder that affects both adult and pediatric populations. The mechanism of hydrocephalus development, especially when there is no mass lesion present causing an obstructive, is poorly understood. Prior studies have demonstrated that spontaneously hypertensive rats (SHRs) develop hydrocephalus by week 7, which was attenuated with minocycline. The aim of this study was to determine sex differences in hydrocephalus development and to examine the effect of minocycline administration after hydrocephalus onset. Male and female Wistar-Kyoto rats (WKYs) and SHRs underwent magnetic resonance imaging at weeks 7 and 9 to determine ventricular volume. Choroid plexus epiplexus cell activation, cognitive deficits, white matter atrophy, and hippocampal neuronal loss were examined at week 9. In the second phase of the experiment, male SHRs (7 weeks old) were treated with either saline or minocycline (20 mg/kg) for 14 days, and similar radiologic, histologic, and behavior tests were performed. Hydrocephalus was present at week 7 and increased at week 9 in both male and female SHRs, which was associated with greater epiplexus cell activation than WKYs. Male SHRs had greater ventricular volume and epiplexus cell activation compared to female SHRs. Minocycline administration improved cognitive function, white matter atrophy, and hippocampal neuronal cell loss. In conclusion, while both male and female SHRs developed hydrocephalus and epiplexus cell activation by week 9, it was more severe in males. Delayed minocycline treatment alleviated hydrocephalus, epiplexus macrophage activation, brain pathology, and cognitive impairment in male SHRs.

Levetiracetam Prophylaxis for Children Admitted With Traumatic Brain Injury.

BACKGROUND: Prophylactic antiseizure medications (ASMs) for pediatric traumatic brain injury (TBI) are understudied. We evaluated clinical and radiographic features that inform prescription of ASMs for pediatric TBI. We hypothesized that despite a lack of evidence, levetiracetam is the preferred prophylactic ASM but that prophylaxis is inconsistently prescribed. METHODS: This retrospective study assessed children admitted with TBI from January 1, 2017, to December 31, 2019. TBI severity was defined using Glasgow Coma Scale (GCS) scores. Two independent neuroradiologists reviewed initial head computed tomography and brain magnetic resonance imaging. Fisher exact tests and descriptive and regression analyses were conducted. RESULTS: Among 167 children with TBI, 44 (26%) received ASM prophylaxis. All 44 (100%) received levetiracetam. Prophylaxis was more commonly prescribed for younger children, those with neurosurgical intervention, and abnormal neuroimaging (particularly intraparenchymal hematoma) (odds ratio = 10.3, confidence interval 1.8 to 58.9), or GCS ≤12. Six children (13.6%), all on ASM, developed early posttraumatic seizures (EPTSs). Of children with GCS ≤12, four of 17 (23.5%) on levetiracetam prophylaxis developed EPTSs, higher than the reported rate for phenytoin. CONCLUSIONS: Although some studies suggest it may be inferior to phenytoin, levetiracetam was exclusively used for EPTS prophylaxis. Intraparenchymal hematoma >1 cm was the single neuroimaging feature associated with ASM prophylaxis regardless of the GCS score. Yet these trends are not equivalent to optimal evidence-based management. We still observed important variability in neuroimaging characteristics and TBI severity for children on prophylaxis. Thus, further study of ASM prophylaxis and prevention of pediatric EPTSs is warranted.

Targeting integrated epigenetic and metabolic pathways in lethal childhood PFA ependymomas.

Childhood posterior fossa group A ependymomas (PFAs) have limited treatment options and bear dismal prognoses compared to group B ependymomas (PFBs). PFAs overexpress the oncohistone-like protein EZHIP (enhancer of Zeste homologs inhibitory protein), causing global reduction of repressive histone H3 lysine 27 trimethylation (H3K27me3), similar to the oncohistone H3K27M. Integrated metabolic analyses in patient-derived cells and tumors, single-cell RNA sequencing of tumors, and noninvasive metabolic imaging in patients demonstrated enhanced glycolysis and tricarboxylic acid (TCA) cycle metabolism in PFAs. Furthermore, high glycolytic gene expression in PFAs was associated with a poor outcome. PFAs demonstrated high EZHIP expression associated with poor prognosis and elevated activating mark histone H3 lysine 27 acetylation (H3K27ac). Genomic H3K27ac was enriched in PFAs at key glycolytic and TCA cycle­related genes including hexokinase-2 and pyruvate dehydrogenase. Similarly, mouse neuronal stem cells (NSCs) expressing wild-type EZHIP (EZHIP-WT) versus catalytically attenuated EZHIP-M406K demonstrated H3K27ac enrichment at hexokinase-2 and pyruvate dehydrogenase, accompanied by enhanced glycolysis and TCA cycle metabolism. AMPKα-2, a key component of the metabolic regulator AMP-activated protein kinase (AMPK), also showed H3K27ac enrichment in PFAs and EZHIP-WT NSCs. The AMPK activator metformin lowered EZHIP protein concentrations, increased H3K27me3, suppressed TCA cycle metabolism, and showed therapeutic efficacy in vitro and in vivo in patient-derived PFA xenografts in mice. Our data indicate that PFAs and EZHIP-WT­expressing NSCs are characterized by enhanced glycolysis and TCA cycle metabolism. Repurposing the antidiabetic drug metformin lowered pathogenic EZHIP, increased H3K27me3, and suppressed tumor growth, suggesting that targeting integrated metabolic/epigenetic pathways is a potential therapeutic strategy for treating childhood ependymomas.

Longitudinal scoliosis behavior in Chiari malformation with and without syringomyelia.

OBJECTIVE: The objective of this study was to understand the natural history of scoliosis in patients with Chiari malformation type I (CM-I) with and without syringomyelia. METHODS: A retrospective review of data was conducted. Patients with CM-I were identified from a cohort of 14,118 individuals age 18 years or younger who had undergone MRI over an 11-year period at the University of Michigan. Patients eligible for study inclusion had a coronal curve ≥ 10° on radiography, associated CM-I with or without syringomyelia, and at least 1 year of clinical follow-up prior to any surgery. Curve magnitude at initial diagnosis, prior to posterior fossa decompression (PFD; if applicable), and at the last follow-up (prior to any surgical correction of scoliosis) was recorded, and clinical and radiographic characteristics were noted. The change in curve magnitude by 10° was defined as curve progression (increase by 10°) or regression (decrease by 10°). RESULTS: Forty-three patients met the study inclusion criteria and were analyzed. About one-third (35%) of the patients presented with symptoms attributed to their CM-I. The mean degree of scoliosis at presentation was 32.6° ± 17.7°. Twenty-one patients (49%) had an associated syrinx. The mean tonsil position below the level of the foramen magnum was 9.8 ± 5.8 mm. Patients with a syrinx were more likely to have a curve > 20° (86% vs 41%, p = 0.002). Curve magnitude remained stable (≤ ±10°) in 77% of patients (33/43), progressed in 16% (7/43), and regressed in 7% (3/43). Mean age was higher (14.8 ± 0.59 years) among patients with regressed curves (p = 0.026). All regressed curves initially measured ≤ 20° (mean 14° ± 5.3°), and none of the patients with regressed curves had a syrinx. The change in curve magnitude was statistically similar in patients with (7.32° ± 17.7°) and without (5.32° ± 15.8°) a syrinx (p = 0.67). After a mean follow-up of 3.13 ± 2.04 years prior to surgery, 27 patients (63%) ultimately underwent posterior fossa or scoliosis correction surgery. For those who eventually underwent PFD only, the rate of change in curve magnitude prior to surgery was 0.054° ± 0.79°. The rate of change in curve magnitude was statistically similar before (0.054° ± 0.79°) and after (0.042° ± 0.33°) surgery (p = 0.45) for patients who underwent PFD surgery only. CONCLUSIONS: The natural history of scoliosis in the presence of CM-I is variable, though most curves remained stable. All curves that regressed were ≤ 20° at initial diagnosis, and most patients in such cases were older at scoliosis diagnosis. Patients who underwent no surgery or PFD only had similar profiles for the change in curve magnitude, which remained relatively stable overall, as compared to patients who underwent PFD and subsequent fusion, who demonstrated curve progression. Among the patients with a syrinx, no curves regressed, most remained stable, and some progressed. Understanding this variability is a first step toward building a prediction model for outcomes for these patients.