Assessment of Ventricular Size and Neurocognitive Outcomes in Children with Post-natal Closure of Myelomeningocele.

OBJECTIVE: To assess if ventricular size prior to shunting is correlated with neurodevelopmental outcomes in children with post-natal myelomeningocele closure. STUDY DESIGN: This was a retrospective review of children with post-natal surgical closure of myelomeningocele and neuropsychological testing between 2018 through 2023 at UCSF. Frontal-occipital horn ratio (FOHR) was measured immediately prior to shunt placement, or on the first study that reported ventricular stability for non-shunted patients. The primary outcome was full scale IQ (FSIQ) on the Weschler Intelligence Scale. Secondary outcomes included indices of the Weschler scale, the Global Executive Composite from the Behavior Rating Inventory of Executive Function, and the General Adaptive Composite from the Adaptive Behavior Assessment Scale. Uni- and multi-variable regression was used to determine if FOHR was correlated with neuropsychological scores. RESULTS: Forty patients met inclusion criteria; 26 (65%) had shunted hydrocephalus. Age at neuropsychological testing was 10.9+/-0.6 years. FOHR was greater in the shunted group (0.64 vs 0.51, p<0.001). There were no differences in neuropsychological results between shunted and non-shunted groups. On univariable analysis, greater FOHR was associated with lower FSIQ (p=0.025) and lower Visual Spatial Index scores (p=0.013), which remained significant on multivariable analysis after adjusting for gestational age at birth, lesion level, shunt status, and shunt revision status (p=0.049 and p=0.006, respectively). Separate analyses by shunt status revealed that these effects were driven by the shunted group. CONCLUSION: Greater FOHR prior to shunting was correlated with lower FSIQ and the VSI scores on the Weschler Intelligence Scales. Larger studies will be needed to explore further the relationship between ventricle size, hydrocephalus, and neurodevelopmental outcomes.

Risk factors associated with in-hospital complications for pediatric sickle-cell disease-associated moyamoya syndrome: a nationwide cross-sectional study.

PURPOSE: Sickle-cell disease-associated moyamoya syndrome (SCD-MMS) carries a high risk for recurrent strokes and cerebrovascular morbidity in children. However, few data are available about complications that occur in children hospitalized with SCD-MMS. The purpose of this analysis was to determine the risk factors for in-hospital complications in pediatric SCD-MMS admissions, and thus aid physicians in optimizing future treatment plans. METHODS: A national database of pediatric hospital admissions was examined across the years 2003-2019. ICD-9 and ICD-10 diagnosis codes were analyzed to identify discharges with a primary diagnosis of SCD-MMS and identify in-hospital complications, defined as complication-associated diagnostic codes logged during the same admission. Patient demographics, comorbidities, and hospital characteristics were examined using univariate and multivariate logistic regression analyses to determine associations with in-hospital complications. RESULTS: In total, 274 admissions with a primary diagnosis of SCD-MMS were identified. During 64 (23.4%) admissions, transfusion therapy was given, and in 86 admissions (31.4%), surgical revascularization was performed. In 10 admissions (3.6%), a total of 11 in-hospital complications were identified. After multivariate regression, both comorbid chronic lung disease (adjusted OR 5.3 [1.1, 26.9], P = 0.04) and surgical revascularization (adjusted OR 10.2 [2.0, 52.4], P = 0.006) were associated with development of complications. CONCLUSIONS: In this nationwide database of pediatric SCD-MMS hospitalizations, comorbid chronic lung disease and surgical revascularization were associated with development of in-hospital complications. Patients with comorbid chronic lung disease or who are admitted for revascularization may warrant closer monitoring and greater medical optimization during the hospitalization.

Pediatric Moyamoya Revascularization Perioperative Care: A Modified Delphi Study.

BACKGROUND: Surgical revascularization decreases the long-term risk of stroke in children with moyamoya arteriopathy but can be associated with an increased risk of stroke during the perioperative period. Evidence-based approaches to optimize perioperative management are limited and practice varies widely. Using a modified Delphi process, we sought to establish expert consensus on key components of the perioperative care of children with moyamoya undergoing indirect revascularization surgery and identify areas of equipoise to define future research priorities. METHODS: Thirty neurologists, neurosurgeons, and intensivists practicing in North America with expertise in the management of pediatric moyamoya were invited to participate in a three-round, modified Delphi process consisting of a 138-item practice patterns survey, anonymous electronic evaluation of 88 consensus statements on a 5-point Likert scale, and a virtual group meeting during which statements were discussed, revised, and reassessed. Consensus was defined as ≥ 80% agreement or disagreement. RESULTS: Thirty-nine statements regarding perioperative pediatric moyamoya care for indirect revascularization surgery reached consensus. Salient areas of consensus included the following: (1) children at a high risk for stroke and those with sickle cell disease should be preadmitted prior to indirect revascularization; (2) intravenous isotonic fluids should be administered in all patients for at least 4 h before and 24 h after surgery; (3) aspirin should not be discontinued in the immediate preoperative and postoperative periods; (4) arterial lines for blood pressure monitoring should be continued for at least 24 h after surgery and until active interventions to achieve blood pressure goals are not needed; (5) postoperative care should include hourly vital signs for at least 24 h, hourly neurologic assessments for at least 12 h, adequate pain control, maintaining normoxia and normothermia, and avoiding hypotension; and (6) intravenous fluid bolus administration should be considered the first-line intervention for new focal neurologic deficits following indirect revascularization surgery. CONCLUSIONS: In the absence of data supporting specific care practices before and after indirect revascularization surgery in children with moyamoya, this Delphi process defined areas of consensus among neurosurgeons, neurologists, and intensivists with moyamoya expertise. Research priorities identified include determining the role of continuous electroencephalography in postoperative moyamoya care, optimal perioperative blood pressure and hemoglobin targets, and the role of supplemental oxygen for treatment of suspected postoperative ischemia.

EML4::ALK fusions in complex lymphatic malformations.

Gorham-Stout disease (GSD) and generalized lymphatic anomaly (GLA) are subtypes of complex lymphatic malformations (CLMs) with osseous involvement that cause significant complications, including pain and pathologic fractures. As with other vascular anomalies, somatic mosaic mutations in oncogenes are often present, and the mTOR inhibitor sirolimus alleviates symptoms in some, but not all, patients. We describe two patients, one with GSD and one with GLA, found to have EML4::ALK fusions. This report of a targetable, oncogenic fusion in vascular malformations expands our understanding of the genetic basis for CLMs and suggests additional targeted therapies could be effective.

Advances and Clinical Trials Update in the Treatment of Diffuse Intrinsic Pontine Gliomas.

BACKGROUND: Diffuse intrinsic pontine gliomas (DIPGs) are high-grade gliomas (HGGs) that occur primarily in children, and represent a leading cause of death in pediatric patients with brain tumors with a median overall survival of only 8-11 months. SUMMARY: While these lesions were previously thought to behave similarly to adult HGG, emerging data have demonstrated that DIPG is a biologically distinct entity from adult HGG frequently driven by mutations in the histone genes H3.3 and H3.1 not found in adult glioma. While biopsy of DIPG was historically felt to confer unacceptable risk of morbidity and mortality, multiple studies have demonstrated that stereotactic biopsy of DIPG is safe, allowing not only for improved understanding of DIPG but also forming the basis for protocols for personalized medicine in DIPG. However, current options for personalized medicine in DIPG are limited by the lack of efficacious targeted therapies for the mutations commonly found in DIPG. Multiple treatment modalities including targeted therapies, immunotherapy, convection-enhanced delivery, and focused ultrasound are in various stages of investigation. KEY MESSAGE: Increasing frequency of biopsy for DIPG has identified distinct driving mutations that may serve as therapeutic targets. Novel treatment modalities are under investigation.

Multiplatform molecular analyses refine classification of gliomas arising in patients with neurofibromatosis type 1.

Gliomas arising in the setting of neurofibromatosis type 1 (NF1) are heterogeneous, occurring from childhood through adulthood, can be histologically low-grade or high-grade, and follow an indolent or aggressive clinical course. Comprehensive profiling of genetic alterations beyond NF1 inactivation and epigenetic classification of these tumors remain limited. Through next-generation sequencing, copy number analysis, and DNA methylation profiling of gliomas from 47 NF1 patients, we identified 2 molecular subgroups of NF1-associated gliomas. The first harbored biallelic NF1 inactivation only, occurred primarily during childhood, followed a more indolent clinical course, and had a unique epigenetic signature for which we propose the terminology "pilocytic astrocytoma, arising in the setting of NF1". The second subgroup harbored additional oncogenic alterations including CDKN2A homozygous deletion and ATRX mutation, occurred primarily during adulthood, followed a more aggressive clinical course, and was epigenetically diverse, with most tumors aligning with either high-grade astrocytoma with piloid features or various subclasses of IDH-wildtype glioblastoma. Several patients were treated with small molecule MEK inhibitors that resulted in stable disease or tumor regression when used as a single agent, but only in the context of those tumors with NF1 inactivation lacking additional oncogenic alterations. Together, these findings highlight recurrently altered pathways in NF1-associated gliomas and help inform targeted therapeutic strategies for this patient population.

The Hybrid Operative Suite with Intraoperative Biplane Rotational Angiography in Pediatric Cerebrovascular Neurosurgery: Utility and Lessons Learned.

INTRODUCTION: The benefits of performing open and endovascular procedures in a hybrid neuroangiography surgical suite include confirmation of treatment results and reduction in number of procedures, leading to improved efficiency of care. Combined procedural suites are infrequently used in pediatric facilities due to technical and logistical limitations. We report the safety, utility, and lessons learned from a single-institution experience using a hybrid suite equipped with biplane rotational digital subtraction angiography and pan-surgical capabilities. METHODS: We conducted a retrospective review of consecutive cases performed at our institution that utilized the hybrid neuroangiography surgical suite from February 2020 to August 2021. Demographics, surgical metrics, and imaging results were collected from the electronic medical record. Outcomes, interventions, and nuances for optimizing preoperative/intraoperative setup and postoperative care were presented. RESULTS: Eighteen procedures were performed in 17 patients (mean age 13.4 years, range 6-19). Cases included 14 arteriovenous malformations (AVM; 85.7% ruptured), one dural arteriovenous fistula, one mycotic aneurysm, and one hemangioblastoma. The average operative time was 416 min (range 321-745). There were no intraoperative or postoperative complications. All patients were alive at follow-up (range 0.1-14.7 months). Five patients had anticipated postoperative deficits arising from their hemorrhage, and 12 returned to baseline neurological status. Four illustrative cases demonstrating specific, unique applications of the hybrid angiography suite are presented. CONCLUSION: The hybrid neuroangiography surgical suite is a safe option for pediatric cerebrovascular pathologies requiring combined surgical and endovascular intervention. Hybrid cases can be completed within the same anesthesia session and reduce the need for return to the operating room for resection or surveillance angiography. High-quality intraoperative angiography enables diagnostic confirmation under a single procedure, mitigating risk of morbidity and accelerating recovery. Effective multidisciplinary planning enables preoperative angiograms to be completed to inform the operative plan immediately prior to definitive resection.

Functional role of brain-engrafted macrophages against brain injuries.

BACKGROUND: Brain-resident microglia have a distinct origin compared to macrophages in other organs. Under physiological conditions, microglia are maintained by self-renewal from the local pool, independent of hematopoietic progenitors. Pharmacological depletion of microglia during whole-brain radiotherapy prevents synaptic loss and long-term recognition memory deficits. However, the origin or repopulated cells and the mechanisms behind these protective effects are unknown. METHODS: CD45low/int/CD11b+ cells from naïve brains, irradiated brains, PLX5622-treated brains and PLX5622 + whole-brain radiotherapy-treated brains were FACS sorted and sequenced for transcriptomic comparisons. Bone marrow chimeras were used to trace the origin and long-term morphology of repopulated cells after PLX5622 and whole-brain radiotherapy. FACS analyses of intrinsic and exotic synaptic compartments were used to measure phagocytic activities of microglia and repopulated cells. In addition, concussive brain injuries were given to PLX5622 and brain-irradiated mice to study the potential protective functions of repopulated cells after PLX5622 + whole-brain radiotherapy. RESULTS: After a combination of whole-brain radiotherapy and microglia depletion, repopulated cells are brain-engrafted macrophages that originate from circulating monocytes. Comparisons of transcriptomes reveal that brain-engrafted macrophages have an intermediate phenotype that resembles both monocytes and embryonic microglia. In addition, brain-engrafted macrophages display reduced phagocytic activity for synaptic compartments compared to microglia from normal brains in response to a secondary concussive brain injury. Importantly, replacement of microglia by brain-engrafted macrophages spare mice from whole-brain radiotherapy-induced long-term cognitive deficits, and prevent concussive injury-induced memory loss. CONCLUSIONS: Brain-engrafted macrophages prevent radiation- and concussion-induced brain injuries and cognitive deficits.

Subgroup and subtype-specific outcomes in adult medulloblastoma.

Medulloblastoma, a common pediatric malignant central nervous system tumour, represent a small proportion of brain tumours in adults. Previously it has been shown that in adults, Sonic Hedgehog (SHH)-activated tumours predominate, with Wingless-type (WNT) and Group 4 being less common, but molecular risk stratification remains a challenge. We performed an integrated analysis consisting of genome-wide methylation profiling, copy number profiling, somatic nucleotide variants and correlation of clinical variables across a cohort of 191 adult medulloblastoma cases identified through the Medulloblastoma Advanced Genomics International Consortium. We identified 30 WNT, 112 SHH, 6 Group 3, and 41 Group 4 tumours. Patients with SHH tumours were significantly older at diagnosis compared to other subgroups (p < 0.0001). Five-year progression-free survival (PFS) for WNT, SHH, Group 3, and Group 4 tumours was 64.4 (48.0-86.5), 61.9% (51.6-74.2), 80.0% (95% CI 51.6-100.0), and 44.9% (95% CI 28.6-70.7), respectively (p = 0.06). None of the clinical variables (age, sex, metastatic status, extent of resection, chemotherapy, radiotherapy) were associated with subgroup-specific PFS. Survival among patients with SHH tumours was significantly worse for cases with chromosome 3p loss (HR 2.9, 95% CI 1.1-7.6; p = 0.02), chromosome 10q loss (HR 4.6, 95% CI 2.3-9.4; p < 0.0001), chromosome 17p loss (HR 2.3, 95% CI 1.1-4.8; p = 0.02), and PTCH1 mutations (HR 2.6, 95% CI 1.1-6.2; p = 0.04). The prognostic significance of 3p loss and 10q loss persisted in multivariable regression models. For Group 4 tumours, chromosome 8 loss was strongly associated with improved survival, which was validated in a non-overlapping cohort (combined cohort HR 0.2, 95% CI 0.1-0.7; p = 0.007). Unlike in pediatric medulloblastoma, whole chromosome 11 loss in Group 4 and chromosome 14q loss in SHH was not associated with improved survival, where MYCN, GLI2 and MYC amplification were rare. In sum, we report unique subgroup-specific cytogenetic features of adult medulloblastoma, which are distinct from those in younger patients, and correlate with survival disparities. Our findings suggest that clinical trials that incorporate new strategies tailored to high-risk adult medulloblastoma patients are urgently needed.

Pediatric moyamoya MRI score: an imaging-based scale to predict outcomes in surgically treated pediatric patients with moyamoya.

OBJECTIVE: Moyamoya is a progressive arteriopathy that predisposes patients to stroke due to stenosis of the intracranial internal carotid arteries and their proximal branches. Despite the morbidity caused by this condition, the ability to accurately predict prognosis for individual patients remains challenging. The goal of this study was to develop a systematic scoring method based on parenchymal findings on preoperative brain MRI to predict long-term outcomes for surgically treated pediatric patients with moyamoya. METHODS: A retrospective surgical cohort of pediatric patients (≤ 18 years of age at the time of the initial surgery) with moyamoya from a single center were studied. Radiological variables with existing correlations between outcomes in moyamoya or other vascular diseases were chosen to score preoperative MRI based on easily defined parenchymal findings that could be rapidly assessed and used to make a numeric score. Calculated scores were correlated with clinical outcome measures using the Pearson correlation coefficient and area under the receiver operating characteristic curve (AUROC). RESULTS: A total of 35 children with moyamoya disease or moyamoya syndrome were included in the study, with a median follow-up time of 2.6 years from the time of surgery. The pediatric moyamoya MRI score (PMMS) consists of ischemic changes (0-2; 0 = none, 1 = focal, 2 = diffuse), encephalomalacia (0-2; 0 = none, 1 = focal, 2 = diffuse), and hemorrhage (0-1; 0 = not present, 1 = present). PMMSs were highly correlated with pediatric modified Rankin Scale scores at the last follow-up (r = 0.7, 95% CI 0.44-0.84; p < 0.001) as a six-point scale, and when dichotomized (AUROC = 0.85). CONCLUSIONS: The PMMS was found to be a simple tool based on preoperative MRI data that could be quickly and easily calculated and correlated with disability. This scoring method may aid future development of predictive models of outcomes for children with moyamoya disease and moyamoya syndrome.

Occult Brain Arteriovenous Malformation Superimposed on a Pial Arteriovenous Fistula: Case Report.

INTRODUCTION: Pial arteriovenous fistulas are characterized by an abnormal connection between an intracranial artery and vein without an intervening nidus. Their predominant symptoms largely arise from mass effect, shunting, or hemorrhage. Most conservatively managed cases progress to death, but endovascular and/or surgical intervention is often successful. CASE PRESENTATION: We present the unique case of a 15-year-old girl with spontaneous intracranial hemorrhage from a single-vessel arteriovenous fistula. Although preoperative imaging failed to show a distinct nidus, intraoperative indocyanine green angiography performed after successful clipping of the primary fistulous site revealed residual shunting from a peri-lesional arteriovenous malformation. DISCUSSION/CONCLUSION: This case demonstrates the importance of intraoperative imaging and meticulous circumferential inspection of these lesions to detect residual vascular shunting.

The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression.

Recent studies have identified a Lys 27-to-methionine (K27M) mutation at one allele of H3F3A, one of the two genes encoding histone H3 variant H3.3, in 60% of high-grade pediatric glioma cases. The median survival of this group of patients after diagnosis is ∼1 yr. Here we show that the levels of H3K27 di- and trimethylation (H3K27me2 and H3K27me3) are reduced globally in H3.3K27M patient samples due to the expression of the H3.3K27M mutant allele. Remarkably, we also observed that H3K27me3 and Ezh2 (the catalytic subunit of H3K27 methyltransferase) at chromatin are dramatically increased locally at hundreds of gene loci in H3.3K27M patient cells. Moreover, the gain of H3K27me3 and Ezh2 at gene promoters alters the expression of genes that are associated with various cancer pathways. These results indicate that H3.3K27M mutation reprograms epigenetic landscape and gene expression, which may drive tumorigenesis.

Brain Arteriovenous Malformation Recurrence After Apparent Microsurgical Cure: Increased Risk in Children Who Present With Arteriovenous Malformation Rupture.

BACKGROUND AND PURPOSE: Do children have an increased risk for brain arteriovenous malformation (AVM) recurrence compared with adults and does this risk vary depending on initial presentation with AVM rupture? METHODS: We retrospectively studied 115 patients initially presenting with brain AVM under age 25 years who underwent complete surgical resection of the AVM as documented by digital subtraction angiography (DSA) and had delayed follow-up DSA to evaluate for AVM recurrence after apparent initial cure. RESULTS: The mean time from baseline DSA to follow-up DSA was 2.3 years, ranging from 0 to 15 years. Twelve patients (10.4% of the 115 patient cohort and 16.7% of 72 patients with hemorrhage at initial presentation) demonstrated AVM recurrence on follow-up DSA. All patients with recurrence initially presented with intracranial hemorrhage, and intracranial hemorrhage was a significant predictor of recurrence (log rank P=0.037). Among patients with initial hemorrhage, the 5-year recurrence rate was 17.8% (95% CI, 8.3%-35.7%). All recurrences occurred in patients who were children at the time of their initial presentation; the oldest was 15 years of age at the time of initial AVM surgery. The 5-year recurrence rate for children (0-18 years of age) with an initial presentation of hemorrhage was 21.4% (95% CI, 10.1%-41.9%). Using Cox regression, we found the risk of AVM recurrence decreased by 14% per each year increase in age at the time of initial surgical resection (hazard ratio=0.86 [95% CI, 0.75-0.99]; P=0.031). CONCLUSIONS: There is a high rate of recurrence of apparently cured brain AVMs in children who initially present with AVM rupture. Imaging follow-up is warranted to prevent re-rupture.

Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.

Brain tumors are the most common solid tumors of childhood, and the genetic drivers and optimal therapeutic strategies for many of the different subtypes remain unknown. Here, we identify that bithalamic gliomas harbor frequent mutations in the EGFR oncogene, only rare histone H3 mutation (in contrast to their unilateral counterparts), and a distinct genome-wide DNA methylation profile compared to all other glioma subtypes studied to date. These EGFR mutations are either small in-frame insertions within exon 20 (intracellular tyrosine kinase domain) or missense mutations within exon 7 (extracellular ligand-binding domain) that occur in the absence of accompanying gene amplification. We find these EGFR mutations are oncogenic in primary astrocyte models and confer sensitivity to specific tyrosine kinase inhibitors dependent on location within the kinase domain or extracellular domain. We initiated treatment with targeted kinase inhibitors in four children whose tumors harbor EGFR mutations with encouraging results. This study identifies a promising genomically-tailored therapeutic strategy for bithalamic gliomas, a lethal and genetically distinct brain tumor of childhood.

High-Flow Vascular Malformations in Children.

Children can have a variety of intracranial vascular anomalies ranging from small and incidental with no clinical consequences to complex lesions that can cause substantial neurologic deficits, heart failure, or profoundly affect development. In contrast to high-flow lesions with direct arterial-to-venous shunts, low-flow lesions such as cavernous malformations are associated with a lower likelihood of substantial hemorrhage, and a more benign course. Management of vascular anomalies in children has to incorporate an understanding of how treatment strategies may affect the normal development of the central nervous system. In this review, we discuss the etiologies, epidemiology, natural history, and genetic risk factors of three high-flow vascular malformations seen in children: brain arteriovenous malformations, intracranial dural arteriovenous fistulas, and vein of Galen malformations.

Embryology of Spinal Dysraphism and its Relationship to Surgical Treatment.

Spinal dysraphism is an umbrella term that encompasses a number of congenital malformations that affect the central nervous system. The etiology of these conditions can be traced back to a specific defect in embryological development, with the more disabling malformations occurring at an earlier gestational age. A thorough understanding of the relevant neuroembryology is imperative for clinicians to select the correct treatment and prevent complications associated with spinal dysraphism. This paper will review the neuroembryology associated with the various forms of spinal dysraphism and provide a clinical-pathological correlation for these congenital malformations.

A middle cerebral artery ischemic stroke occurring in a child with a large prolactinoma.

Pituitary adenomas are rare in children, and often present with symptoms of headache, nausea or emesis, visual disturbance, or hormonal hypersecretion. With large tumors, mass effect from the lesion can lead to severe endocrinopathy and compression of intracranial neurovascular structures. In this case report, we describe an unusual presentation of an ischemic stroke in the territory of the right middle cerebral artery resulting from a prolactin-secreting macroadenoma. The patient's primary symptoms were headache, left facial droop, and left hemibody weakness. She was successfully managed with cabergoline, a dopamine agonist, with a reduction in the size of the tumor and normalization of serum prolactin levels. She remained clinically stable throughout her hospitalization, and was safely discharged without surgical intervention. In her recent 2-year follow-up, her tumor and prolactin levels were stable and she had dramatic improvements in her left-sided muscle strength.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma-PNOC003: A report from the Pacific Pediatric Neuro-Oncology Consortium.

This clinical trial evaluated whether whole exome sequencing (WES) and RNA sequencing (RNAseq) of paired normal and tumor tissues could be incorporated into a personalized treatment plan for newly diagnosed patients (<25 years of age) with diffuse intrinsic pontine glioma (DIPG). Additionally, whole genome sequencing (WGS) was compared to WES to determine if WGS would further inform treatment decisions, and whether circulating tumor DNA (ctDNA) could detect the H3K27M mutation to allow assessment of therapy response. Patients were selected across three Pacific Pediatric Neuro-Oncology Consortium member institutions between September 2014 and January 2016. WES and RNAseq were performed at diagnosis and recurrence when possible in a CLIA-certified laboratory. Patient-derived cell line development was attempted for each subject. Collection of blood for ctDNA was done prior to treatment and with each MRI. A specialized tumor board generated a treatment recommendation including up to four FDA-approved agents based upon the genomic alterations detected. A treatment plan was successfully issued within 21 business days from tissue collection for all 15 subjects, with 14 of the 15 subjects fulfilling the feasibility criteria. WGS results did not significantly deviate from WES-based therapy recommendations; however, WGS data provided further insight into tumor evolution and fidelity of patient-derived cell models. Detection of the H3F3A or HIST1H3B K27M (H3K27M) mutation using ctDNA was successful in 92% of H3K27M mutant cases. A personalized treatment recommendation for DIPG can be rendered within a multicenter setting using comprehensive next-generation sequencing technology in a clinically relevant timeframe.

The genetic landscape of gliomas arising after therapeutic radiation.

Radiotherapy improves survival for common childhood cancers such as medulloblastoma, leukemia, and germ cell tumors. Unfortunately, long-term survivors suffer sequelae that can include secondary neoplasia. Gliomas are common secondary neoplasms after cranial or craniospinal radiation, most often manifesting as high-grade astrocytomas with poor clinical outcomes. Here, we performed genetic profiling on a cohort of 12 gliomas arising after therapeutic radiation to determine their molecular pathogenesis and assess for differences in genomic signature compared to their spontaneous counterparts. We identified a high frequency of TP53 mutations, CDK4 amplification or CDKN2A homozygous deletion, and amplifications or rearrangements involving receptor tyrosine kinase and Ras-Raf-MAP kinase pathway genes including PDGFRA, MET, BRAF, and RRAS2. Notably, all tumors lacked alterations in IDH1, IDH2, H3F3A, HIST1H3B, HIST1H3C, TERT (including promoter region), and PTEN, which genetically define the major subtypes of diffuse gliomas in children and adults. All gliomas in this cohort had very low somatic mutation burden (less than three somatic single nucleotide variants or small indels per Mb). The ten high-grade gliomas demonstrated markedly aneuploid genomes, with significantly increased quantity of intrachromosomal copy number breakpoints and focal amplifications/homozygous deletions compared to spontaneous high-grade gliomas, likely as a result of DNA double-strand breaks induced by gamma radiation. Together, these findings demonstrate a distinct molecular pathogenesis of secondary gliomas arising after radiation therapy and identify a genomic signature that may aid in differentiating these tumors from their spontaneous counterparts.

The Management of Myelomeningocele Study: full cohort 30-month pediatric outcomes.

BACKGROUND: Previous reports from the Management of Myelomeningocele Study demonstrated that prenatal repair of myelomeningocele reduces hindbrain herniation and the need for cerebrospinal fluid shunting, and improves motor function in children with myelomeningocele. The trial was stopped for efficacy after 183 patients were randomized, but 30-month outcomes were only available at the time of initial publication in 134 mother-child dyads. Data from the complete cohort for the 30-month outcomes are presented here. Maternal and 12-month neurodevelopmental outcomes for the full cohort were reported previously. OBJECTIVE: The purpose of this study is to report the 30-month outcomes for the full cohort of patients randomized to either prenatal or postnatal repair of myelomeningocele in the original Management of Myelomeningocele Study. STUDY DESIGN: Eligible women were randomly assigned to undergo standard postnatal repair or prenatal repair <26 weeks gestation. We evaluated a composite of mental development and motor function outcome at 30 months for all enrolled patients as well as independent ambulation and the Bayley Scales of Infant Development, Second Edition. We assessed whether there was a differential effect of prenatal surgery in subgroups defined by: fetal leg movements, ventricle size, presence of hindbrain herniation, gender, and location of the myelomeningocele lesion. Within the prenatal surgery group only, we evaluated these and other baseline parameters as predictors of 30-month motor and cognitive outcomes. We evaluated whether presence or absence of a shunt at 1 year was associated with 30-month motor outcomes. RESULTS: The data for the full cohort of 183 patients corroborate the original findings of Management of Myelomeningocele Study, confirming that prenatal repair improves the primary outcome composite score of mental development and motor function (199.4 ± 80.5 vs 166.7 ± 76.7, P = .004). Prenatal surgery also resulted in improvement in the secondary outcomes of independent ambulation (44.8% vs 23.9%, P = .004), WeeFIM self-care score (20.8 vs 19.0, P = .006), functional level at least 2 better than anatomic level (26.4% vs 11.4%, P = .02), and mean Bayley Scales of Infant Development, Second Edition, psychomotor development index (17.3% vs 15.1%, P = .03), but does not affect cognitive development at 30 months. On subgroup analysis, there was a nominally significant interaction between gender and surgery, with boys demonstrating better improvement in functional level and psychomotor development index. For patients receiving prenatal surgery, the presence of in utero ankle, knee, and hip movement, absence of a sac over the lesion and a myelomeningocele lesion of ≤L3 were significantly associated with independent ambulation. Postnatal motor function showed no correlation with either prenatal ventricular size or postnatal shunt placement. CONCLUSION: The full cohort data of 30-month cognitive development and motor function outcomes validate in utero surgical repair as an effective treatment for fetuses with myelomeningocele. Current data suggest that outcomes related to the need for shunting should be counseled separately from the outcomes related to distal neurologic functioning.