Discovery of clinically relevant fusions in pediatric cancer.

BACKGROUND: Pediatric cancers typically have a distinct genomic landscape when compared to adult cancers and frequently carry somatic gene fusion events that alter gene expression and drive tumorigenesis. Sensitive and specific detection of gene fusions through the analysis of next-generation-based RNA sequencing (RNA-Seq) data is computationally challenging and may be confounded by low tumor cellularity or underlying genomic complexity. Furthermore, numerous computational tools are available to identify fusions from supporting RNA-Seq reads, yet each algorithm demonstrates unique variability in sensitivity and precision, and no clearly superior approach currently exists. To overcome these challenges, we have developed an ensemble fusion calling approach to increase the accuracy of identifying fusions. RESULTS: Our Ensemble Fusion (EnFusion) approach utilizes seven fusion calling algorithms: Arriba, CICERO, FusionMap, FusionCatcher, JAFFA, MapSplice, and STAR-Fusion, which are packaged as a fully automated pipeline using Docker and Amazon Web Services (AWS) serverless technology. This method uses paired end RNA-Seq sequence reads as input, and the output from each algorithm is examined to identify fusions detected by a consensus of at least three algorithms. These consensus fusion results are filtered by comparison to an internal database to remove likely artifactual fusions occurring at high frequencies in our internal cohort, while a "known fusion list" prevents failure to report known pathogenic events. We have employed the EnFusion pipeline on RNA-Seq data from 229 patients with pediatric cancer or blood disorders studied under an IRB-approved protocol. The samples consist of 138 central nervous system tumors, 73 solid tumors, and 18 hematologic malignancies or disorders. The combination of an ensemble fusion-calling pipeline and a knowledge-based filtering strategy identified 67 clinically relevant fusions among our cohort (diagnostic yield of 29.3%), including RBPMS-MET, BCAN-NTRK1, and TRIM22-BRAF fusions. Following clinical confirmation and reporting in the patient's medical record, both known and novel fusions provided medically meaningful information. CONCLUSIONS: The EnFusion pipeline offers a streamlined approach to discover fusions in cancer, at higher levels of sensitivity and accuracy than single algorithm methods. Furthermore, this method accurately identifies driver fusions in pediatric cancer, providing clinical impact by contributing evidence to diagnosis and, when appropriate, indicating targeted therapies.

Predictors of intracranial hypertension in children undergoing ICP monitoring after severe traumatic brain injury.

PURPOSE: Intracranial hypertension (ICH) is a common and treatable complication after severe traumatic brain injury (sTBI) in children. Describing the incidence and risk factors for developing ICH after sTBI could impact clinical practice. METHODS: Retrospective cohort study from 2006 to 2015 at two university-affiliated level I pediatric trauma centers of children admitted with accidental or abusive TBI, a post-resuscitation Glasgow Coma Score (GCS) of 8 or less, and an invasive intracranial pressure (ICP) monitor. Bivariate and multivariable logistic regression analysis were performed to identify demographic, injury, and imaging characteristics in patients who received ICP directed therapies for ICH (ICP > 20 mmHg). RESULTS: Eight to 5% (271/321) of monitored patients received ICP directed therapy for ICH during their PICU stay. Ninety-seven percent of patients had an abnormality on CT scan by either the Marshall or the Rotterdam score. Of the analyzed clinical and radiologic variables, only presence of hypoxia prior to PICU arrival, female sex, and a higher Injury Severity Score (ISS) were associated with increased risk of ICH (p < 0.05). CONCLUSIONS: In this retrospective study of clinical practice of ICP monitoring in children after sTBI, the vast majority of children had an abnormal CT scan and experienced ICH requiring clinical intervention. Commonly measured clinical variables and radiologic classification scores did not significantly add to the prediction for developing of ICH and further efforts are needed to define low-risk populations that would not develop ICH.

Postoperative Pain Protocol in Children after Selective Dorsal Rhizotomy.

INTRODUCTION: Selective dorsal rhizotomy (SDR) provides lasting relief of spasticity for children suffering from cerebral palsy, although controlling postoperative pain is challenging. Postoperatively, escalation of therapies to include a patient-controlled analgesia (PCA) pump and intensive care unit (ICU) admission is common. OBJECTIVES: We developed a multimodal pain management protocol that included intraoperative placement of an epidural catheter with continuous opioid administration. We present the 3-year results of protocol implementation. METHODS: With institutional review board approval, all patients who were subjected to SDR at our institution were identified for review. Hourly pain scores were recorded. Adverse effects of medication, including desaturation, nausea/vomiting, and pruritus, were also noted. Comparisons were made between patients treated with PCA and those treated with multimodal pain control using t and χ2 tests as appropriate. RESULTS: Thirty-nine patients undergoing the procedure with protocolized pain control (average age 6.8 years, 57% male) were compared to 7 PCA-treated controls (average age 6.6 years, 54% male). Pain control was satisfactory in both groups, with average pain scores of 1.5 in both groups on postoperative day 0, decreasing by postoperative day 3 to 1.1 in the PCA group and 0.5 in the protocol group. No patients under the protocol required ICU admission; all patients with PCA spent at least 1 day in the ICU. Desaturations were seen in 16 patients in the protocol group (41%), but none required ICU transfer. Treatment for pruritis was given to 57% of PCA patients and 15% of protocol patients. Treatment for nausea and vomiting was given to 100% of PCA patients and 51% of protocol patients. Medication requirements for the hospitalization were decreased from 1.1 to 0.28 doses per patient for pruritis, and from 3 to 1.1 doses per patient for nausea. CONCLUSIONS: Multimodal analgesia is an excellent alternative to PCA for postoperative pain after SDR. Actual analgesia is comparative to that of controls without the need for intensive care monitoring. Side effects of high-dose opiates were less frequent and required less medication. With the protocol, patients were safely treated outside the ICU.

Remifentanil for Sedation of Children With Traumatic Brain Injury.

OBJECTIVE: To determine whether remifentanil would provide adequate sedation while allowing frequent and reproducible neurologic assessments in children admitted to the pediatric intensive care unit (PICU) with traumatic brain injury (TBI) during mechanical ventilation. DESIGN: Retrospective review. SETTING: Tertiary care PICU. PATIENTS: Thirty-eight patients over a 30-month period. MEASUREMENTS AND MAIN RESULTS: Median age was 9 years (interquartile range [IQR] 2.25-12 years). The median Glasgow Coma Scale (GCS) was 9 (IQR: 8-10). All patients were tracheally intubated and receiving mechanical ventilation. A continuous infusion of remifentanil was started at 0.1 µg/kg/min, and bolus doses of 0.25 to 1 µg/kg were administered every 3 to 5 minutes as needed to reach the desired sedation level. Infusions were stopped at least hourly to perform neurologic examinations. The median remifentanil dose was 0.25 µg/kg/min with an IQR of 0.1 and 0.6 µg/kg/min. The maximum dose for any patient in the cohort was 2 µg/kg/min. Median duration of therapy with remifentanil was 20 hours (IQR: 8-44 hours). Adequate sedation was achieved with sedation scores (State Behavioral Scale) meeting target levels with a median value of 100% of the time (IQR: 79%-100%). Neurologic examinations were able to be performed within a median of 9 minutes (IQR: 5-14 minutes) of pausing the infusion. No serious safety events occurred. In 68% of the patients, neurologic examinations remained reassuring during remifentanil infusion, and patients were extubated. The remaining patients were transitioned to traditional sedative agents for long-term management of their traumatic injuries once the neurologic status was deemed stable. CONCLUSION: This data suggest that remifentanil is a suitable sedative agent for use in children with TBI. It provides a rapid onset of sedation with recovery that permits reliable and reproducible clinical examination.

Cerebellopontine angle tumors in young children, displaying cranial nerve deficits, and restricted diffusion on diffusion-weighted imaging: a new clinical triad for atypical teratoid/rhabdoid tumors.

Atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS) are rare, highly malignant neoplasms that carry a poor prognosis. Even with prompt diagnosis, gross total resection and early initiation of intensive adjuvant therapy, the majority of patients will succumb within 9-12 months of diagnosis. The CPA location in children harbors lesions along a wide spectrum varying from benign to highly malignant. Imaging features of lesions within the CPA that aid the diagnostic process will help to initiate early treatment in higher-grade lesions. We report three cases, in very young children, all with cranial nerve deficits, who displayed CPA lesions with restricted diffusion on diffusion-weighted imaging (DWI) with pathology confirming AT/RT. We propose that in young children with a CPA tumor diffusion-weighted imaging should be routinely evaluated to aid in prompt management. In addition, the diagnosis of AT/RT should be highly suggestive in infants presenting with cranial nerve findings as well as DWI restricted diffusion within the CPA.

Atlantoaxial Rotatory Subluxation in Children.

OBJECTIVES: Pediatric cervical injuries are uncommon. This study was to describe injury circumstances, clinical findings, and management among children diagnosed with atlantoaxial rotatory subluxation (AARS) to aid in its recognition and management. METHODS: Subanalysis of a large case-control study from January 2000 to December 2004 in 17 hospitals in the Pediatric Emergency Care Applied Research Network was performed. Cases were children younger than 16 years with AARS after blunt trauma (n = 55); controls were (a) children with other cervical spine injuries (other CSI, n = 485) and (b) those with normal imaging of the cervical spine (non-CSI, n = 1060). RESULTS: Children with AARS were younger (mean [SD] age, 7.7 [3.8] vs 10.7 [4.6]; Wilcoxon P < 0.01). Falls accounted for 36% of injuries; there were no diving mechanisms (vs other CSI, falls 19%, Fisher exact P < 0.01, and diving 7%, P = 0.04). Children with AARS sought medical care more than 24 hours after the injury event (21% vs 1% for non-CSI controls, P < 0.01). Clinical findings associated with AARS included neck pain (67%) and torticollis (57%) versus other CSI, pain (47%) and torticollis (5%, P < 0.01) for each, and versus non-CSI controls, pain (33%) and torticollis (6%, P < 0.01) for each. Management of AARS included no intervention (n = 6, 11%), soft or rigid collar only (n = 24, 44%), traction (n = 14, 25%), halo (n = 9, 16%), internal fixation (n = 2, 4%), and varied across institutions (P = 0.02). CONCLUSIONS: Children with AARS often have a delayed presentation with neck pain and torticollis; falls are a common injury mechanism. Treatment varied across institutions. Further work is needed to identify optimal management.

Somatic neurofibromatosis type 1 (NF1) inactivation characterizes NF1-associated pilocytic astrocytoma.

Low-grade brain tumors (pilocytic astrocytomas) arising in the neurofibromatosis type 1 (NF1) inherited cancer predisposition syndrome are hypothesized to result from a combination of germline and acquired somatic NF1 tumor suppressor gene mutations. However, genetically engineered mice (GEM) in which mono-allelic germline Nf1 gene loss is coupled with bi-allelic somatic (glial progenitor cell) Nf1 gene inactivation develop brain tumors that do not fully recapitulate the neuropathological features of the human condition. These observations raise the intriguing possibility that, while loss of neurofibromin function is necessary for NF1-associated low-grade astrocytoma development, additional genetic changes may be required for full penetrance of the human brain tumor phenotype. To identify these potential cooperating genetic mutations, we performed whole-genome sequencing (WGS) analysis of three NF1-associated pilocytic astrocytoma (PA) tumors. We found that the mechanism of somatic NF1 loss was different in each tumor (frameshift mutation, loss of heterozygosity, and methylation). In addition, tumor purity analysis revealed that these tumors had a high proportion of stromal cells, such that only 50%-60% of cells in the tumor mass exhibited somatic NF1 loss. Importantly, we identified no additional recurrent pathogenic somatic mutations, supporting a model in which neuroglial progenitor cell NF1 loss is likely sufficient for PA formation in cooperation with a proper stromal environment.

Fentanyl and Midazolam Are Ineffective in Reducing Episodic Intracranial Hypertension in Severe Pediatric Traumatic Brain Injury.

OBJECTIVE: To evaluate the clinical effectiveness of bolus-dose fentanyl and midazolam to treat episodic intracranial hypertension in children with severe traumatic brain injury. DESIGN: Retrospective cohort. SETTING: PICU in a university-affiliated children's hospital level I trauma center. PATIENTS: Thirty-one children 0-18 years of age with severe traumatic brain injury (Glasgow Coma Scale score of ≤ 8) who received bolus doses of fentanyl and/or midazolam for treatment of episodic intracranial hypertension. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The area under the curve from high-resolution intracranial pressure-time plots was calculated to represent cumulative intracranial hypertension exposure: area under the curve for intracranial pressure above 20 mm Hg (area under the curve-intracranial hypertension) was calculated in 15-minute epochs before and after administration of fentanyl and/or midazolam for the treatment of episodic intracranial hypertension. Our primary outcome measure, the difference between predrug and postdrug administration epochs (Δarea under the curve-intracranial hypertension), was calculated for all occurrences. We examined potential covariates including age, injury severity, mechanism, and time after injury; time after injury correlated with Δarea under the curve-intracranial hypertension. In a mixed-effects model, with patient as a random effect, drug/dose combination as a fixed effect, and time after injury as a covariate, intracranial hypertension increased after administration of fentanyl and/or midazolam (overall aggregate mean Δarea under the curve-intracranial hypertension = +17 mm Hg × min, 95% CI, 0-34 mm Hg × min; p = 0.04). The mean Δarea under the curve-intracranial hypertension increased significantly after administration of high-dose fentanyl (p = 0.02), low-dose midazolam (p = 0.006), and high-dose fentanyl plus low-dose midazolam (0.007). Secondary analysis using age-dependent thresholds showed no significant impact on cerebral perfusion pressure deficit (mean Δarea under the curve-cerebral perfusion pressure). CONCLUSIONS: Bolus dosing of fentanyl and midazolam fails to reduce the intracranial hypertension burden when administered for episodic intracranial hypertension. Paradoxically, we observed an overall increase in intracranial hypertension burden following drug administration, even after accounting for within-subject effects and time after injury. Future work is needed to confirm these findings in a prospective study design.

Radiation-Induced Moyamoya Syndrome after Proton Beam Therapy in the Pediatric Patient: A Case Series.

Minimizing normal-tissue radiation exposure is especially important in the pediatric population as children appear to be particularly sensitive to postradiation vasculopathies after conventional photon radiotherapy. Given the limited scattering effect and low-dose radiation delivery to the surrounding tissues with proton beam radiotherapy, this modality is considered to be an effective treatment for pediatric skull-base tumors compared to conventional radiotherapy, and to have fewer adverse side effects. We report 2 cases of radiation-induced moyamoya syndrome following proton beam therapy in pediatric patients. To our knowledge, only a few other reported cases of radiation-induced moyamoya syndrome following proton beam therapy exist in the current literature. While rare, radiation-induced moyamoya syndrome can occur in the pediatric population with newer techniques like proton beam radiotherapy. Accordingly, patients and their families should be informed about this potential complication prior to all forms of radiation treatment.

Posterior fossa tumor with distinct choroid plexus papilloma and ependymoma components.

Synchronous occurrence of multiple primary central nervous system (CNS) tumors of different histological types is uncommon in patients without radiation history or genetic syndrome association. We herein report a sporadic case of posterior fossa tumor with synchronous choroid plexus papilloma (CPP) and ependymoma (EP) components. A 7-year-old girl with no significant past or familial medical history presented with 2 years of migraine type headaches. Brain magnetic resonance imaging showed a cystic mass with a mural enhancing nodule centered within the cerebellar vermis. The patient underwent gross total resection of the tumor. Histologic examination showed a tumor with two distinct components. The predominant component demonstrated classic morphological and immunohistochemical characteristics of choroid plexus papilloma CPP, WHO grade I. However, there were a few discrete foci, where tumor cells showed architectural, cytological, and immunohistochemical features characteristic of an ependymoma, WHO grade II. In addition, there was exuberant piloid gliosis secondary to infiltration of the CPP component into the adjacent brain parenchyma. Followup brain imaging at 14 months after surgery showed no evidence of residual or recurrent tumor. To the best of our knowledge, this is the first reported case of synchronous CPP and EP in the posterior fossa.

Surgical management of complex multiloculated hydrocephalus in infants and children.

OBJECTIVE: Multiloculated hydrocephalus may occur as a consequence of intraventricular hemorrhage or infection and is characterized by enlargement of multiple noncommunicating intraventricular and/or periventricular cysts. In this study, we report the outcomes of open and endoscopic fenestration for multiloculated hydrocephalus at our institution. METHODS: Records of children who underwent endoscopic or open fenestration at St. Louis Children's Hospital from 1999 to 2011 were analyzed. The cause of MLH, operative parameters, length of hospital stay, and subsequent shunt intervention rate were recorded. RESULTS: Twenty-five subjects were identified for study. Twelve subjects underwent open craniotomy and 13 underwent endoscopic fenestration. Endoscopic fenestration was associated with decreased blood loss, operative time, and length of stay (p = 0.003, 0.002, 0.02, respectively). Subjects undergoing craniotomy had an average of 5.1 ± 4.5 subsequent shunt-related interventions versus 3.1 ± 4.0 in the endoscopy group (p = 0.25). The craniotomy group's median subsequent shunt revision rate was 0.74 interventions per year versus 0.50 interventions per year in the endoscopy group (p = 0.51). Fifty percent of subjects in the open fenestration group required additional fenestration surgery compared to 38.5% in the endoscopic group (p = 0.70). CONCLUSION: Both open and endoscopic fenestration appeared effective at improving shunt management. The endoscopic technique may offer advantages in operative time, blood loss, and length of hospital stay. These data suggest that endoscopic fenestration may be used as the initial approach for treatment of multiloculated hydrocephalus, with craniotomy and open fenestration used for more severe or refractory cases.

PECARN prediction rule for cervical spine imaging of children presenting to the emergency department with blunt trauma: a multicentre prospective observational study.

BACKGROUND: Cervical spine injuries in children are uncommon but potentially devastating; however, indiscriminate neck imaging after trauma unnecessarily exposes children to ionising radiation. The aim of this study was to derive and validate a paediatric clinical prediction rule that can be incorporated into an algorithm to guide radiographic screening for cervical spine injury among children in the emergency department. METHODS: In this prospective observational cohort study, we screened children aged 0-17 years presenting with known or suspected blunt trauma at 18 specialised children's emergency departments in hospitals in the USA affiliated with the Pediatric Emergency Care Applied Research Network (PECARN). Injured children were eligible for enrolment into derivation or validation cohorts by fulfilling one of the following criteria: transported from the scene of injury to the emergency department by emergency medical services; evaluated by a trauma team; and undergone neck imaging for concern for cervical spine injury either at or before arriving at the PECARN-affiliated emergency department. Children presenting with solely penetrating trauma were excluded. Before viewing an enrolled child's neck imaging results, the attending emergency department clinician completed a clinical examination and prospectively documented cervical spine injury risk factors in an electronic questionnaire. Cervical spine injuries were determined by imaging reports and telephone follow-up with guardians within 21-28 days of the emergency room encounter, and cervical spine injury was confirmed by a paediatric neurosurgeon. Factors associated with a high risk of cervical spine injury (>10%) were identified by bivariable Poisson regression with robust error estimates, and factors associated with non-negligible risk were identified by classification and regression tree (CART) analysis. Variables were combined in the cervical spine injury prediction rule. The primary outcome of interest was cervical spine injury within 28 days of initial trauma warranting inpatient observation or surgical intervention. Rule performance measures were calculated for both derivation and validation cohorts. A clinical care algorithm for determining which risk factors warrant radiographic screening for cervical spine injury after blunt trauma was applied to the study population to estimate the potential effect on reducing CT and x-ray use in the paediatric emergency department. This study is registered with ClinicalTrials.gov, NCT05049330. FINDINGS: Nine emergency departments participated in the derivation cohort, and nine participated in the validation cohort. In total, 22 430 children presenting with known or suspected blunt trauma were enrolled (11 857 children in the derivation cohort; 10 573 in the validation cohort). 433 (1·9%) of the total population had confirmed cervical spine injuries. The following factors were associated with a high risk of cervical spine injury: altered mental status (Glasgow Coma Scale [GCS] score of 3-8 or unresponsive on the Alert, Verbal, Pain, Unresponsive scale [AVPU] of consciousness); abnormal airway, breathing, or circulation findings; and focal neurological deficits including paresthesia, numbness, or weakness. Of 928 in the derivation cohort presenting with at least one of these risk factors, 118 (12·7%) had cervical spine injury (risk ratio 8·9 [95% CI 7·1-11·2]). The following factors were associated with non-negligible risk of cervical spine injury by CART analysis: neck pain; altered mental status (GCS score of 9-14; verbal or pain on the AVPU; or other signs of altered mental status); substantial head injury; substantial torso injury; and midline neck tenderness. The high-risk and CART-derived factors combined and applied to the validation cohort performed with 94·3% (95% CI 90·7-97·9) sensitivity, 60·4% (59·4-61·3) specificity, and 99·9% (99·8-100·0) negative predictive value. Had the algorithm been applied to all participants to guide the use of imaging, we estimated the number of children having CT might have decreased from 3856 (17·2%) to 1549 (6·9%) of 22 430 children without increasing the number of children getting plain x-rays. INTERPRETATION: Incorporated into a clinical algorithm, the cervical spine injury prediction rule showed strong potential for aiding clinicians in determining which children arriving in the emergency department after blunt trauma should undergo radiographic neck imaging for potential cervical spine injury. Implementation of the clinical algorithm could decrease use of unnecessary radiographic testing in the emergency department and eliminate high-risk radiation exposure. Future work should validate the prediction rule and care algorithm in more general settings such as community emergency departments. FUNDING: The Eunice Kennedy Shriver National Institute of Child Health and Human Development and the Health Resources and Services Administration of the US Department of Health and Human Services in the Maternal and Child Health Bureau under the Emergency Medical Services for Children programme.

The role of occipital condyle and atlas anomalies on occipital cervical fusion outcomes in Chiari malformation type I with syringomyelia: a study from the Park-Reeves Syringomyelia Research Consortium.

OBJECTIVE: Congenital anomalies of the atlanto-occipital articulation may be present in patients with Chiari malformation type I (CM-I). However, it is unclear how these anomalies affect the biomechanical stability of the craniovertebral junction (CVJ) and whether they are associated with an increased incidence of occipitocervical fusion (OCF) following posterior fossa decompression (PFD). The objective of this study was to determine the prevalence of condylar hypoplasia and atlas anomalies in children with CM-I and syringomyelia. The authors also investigated the predictive contribution of these anomalies to the occurrence of OCF following PFD (PFD+OCF). METHODS: The authors analyzed the prevalence of condylar hypoplasia and atlas arch anomalies for patients in the Park-Reeves Syringomyelia Research Consortium database who underwent PFD+OCF. Condylar hypoplasia was defined by an atlanto-occipital joint axis angle (AOJAA) ≥ 130°. Atlas assimilation and arch anomalies were identified on presurgical radiographic imaging. This PFD+OCF cohort was compared with a control cohort of patients who underwent PFD alone. The control group was matched to the PFD+OCF cohort according to age, sex, and duration of symptoms at a 2:1 ratio. RESULTS: Clinical features and radiographic atlanto-occipital joint parameters were compared between 19 patients in the PFD+OCF cohort and 38 patients in the PFD-only cohort. Demographic data were not significantly different between cohorts (p > 0.05). The mean AOJAA was significantly higher in the PFD+OCF group than in the PFD group (144° ± 12° vs 127° ± 6°, p < 0.0001). In the PFD+OCF group, atlas assimilation and atlas arch anomalies were identified in 10 (53%) and 5 (26%) patients, respectively. These anomalies were absent (n = 0) in the PFD group (p < 0.001). Multivariate regression analysis identified the following 3 CVJ radiographic variables that were predictive of OCF occurrence after PFD: AOJAA ≥ 130° (p = 0.01), clivoaxial angle < 125° (p = 0.02), and occipital condyle-C2 sagittal vertical alignment (C-C2SVA) ≥ 5 mm (p = 0.01). A predictive model based on these 3 factors accurately predicted OCF following PFD (C-statistic 0.95). CONCLUSIONS: The authors' results indicate that the occipital condyle-atlas joint complex might affect the biomechanical integrity of the CVJ in children with CM-I and syringomyelia. They describe the role of the AOJAA metric as an independent predictive factor for occurrence of OCF following PFD. Preoperative identification of these skeletal abnormalities may be used to guide surgical planning and treatment of patients with complex CM-I and coexistent osseous pathology.

BRAF(V600E) mutation is a negative prognosticator in pediatric ganglioglioma.

Gangliogliomas are typically low-grade neuroepithelial tumors seen in the pediatric and young adult populations. Despite their often bland histologic appearance, these tumors recur with varying frequencies; however, little data exist that adequately predict ganglioglioma recurrence in children. To identify potential histopathologic features predictive of recurrence-free survival, a series of 53 patients with World Health Organization (WHO) grade I gangliogliomas were evaluated, representing the largest cohort of pediatric gangliogliomas with accompanying histopathologic and survival data. Fifteen patients (28 %) exhibited disease recurrence during the study period. BRAF(V600E) immunohistochemistry was performed on 47 of these tumors. Histopathologic features associated with shorter recurrence-free survival included an absence of oligodendroglial morphology, higher glial cell density, microvascular proliferation, and the presence of a high lymphoplasmacytic inflammatory infiltrate. Eighteen tumors (38.3 %) had positive BRAF(V600E) staining, which was associated with shorter recurrence-free survival. Collectively, the combined use of histopathologic and molecular features to stratify grade I gangliogliomas into low and high-risk groups provides important information relevant to the management of children and young adults with these rare tumors.

TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma.

Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association with increased patient age. The prognostic implications of these mutations were highly subgroup-specific. TERT mutations identified a subset with good and poor prognosis in SHH and Group 4 tumors, respectively. Monosomy 6 was mostly restricted to WNT tumors without TERT mutations. Hallmark SHH focal copy number aberrations and chromosome 10q deletion were mutually exclusive with TERT mutations within SHH tumors. TERT promoter mutations are the most common recurrent somatic point mutation in medulloblastoma, and are very highly enriched in adult SHH and WNT tumors. TERT mutations define a subset of SHH medulloblastoma with distinct demographics, cytogenetics, and outcomes.

Surgical management of symptomatic Chiari II malformation in infants and children.

PURPOSE: Variation exists in the surgical methods employed for decompression of Chiari II malformation (CIIM), yet an evaluation of these techniques has not been performed. The purpose of this study was to assess the efficacy of bony decompression (cervical laminectomy alone versus suboccipital craniectomy with laminectomy) with or without dural augmentation for the treatment of symptomatic CIIM. METHODS: Clinical records of children 0-18 years of age who underwent surgical repair of myelomeningocele or CIIM decompression at St. Louis Children's Hospital (SLCH) from 1990-2011 were reviewed. Signs/symptoms prompting decompression, surgical technique, operative parameters, and clinical outcomes were recorded for analysis. RESULTS: Thirty-three subjects were treated at SLCH for CIIM decompression. Twenty-six subjects underwent bony decompression only (21 cervical laminectomy alone, 5 suboccipital craniectomy + cervical laminectomy) while seven underwent bony decompression with upfront dural augmentation (three cervical laminectomy alone, four suboccipital craniectomy + cervical laminectomy). Median follow up was 5.0 years (range, 3 months-19 years). Symptomatic improvement was noted in 20/33 subjects (60.6%). Sixty-two (61.5%) percent of children who underwent bony decompression had symptomatic improvement, compared with 57.1% of those with upfront dural augmentation (p = 0.37). Estimated blood loss, operative time, and length of perioperative hospital stay appeared lower in the bony decompression group but were not statistically different in this limited cohort. CONCLUSIONS: The results from this series suggest that bony CIIM decompression via tailored cervical laminectomies alone, without suboccipital craniectomy or upfront dural augmentation, is a reasonable initial management approach for decompression of symptomatic CIIM.

Clinical Manifestations of Chiari I Malformation.

Chiari 1 malformation (CM1) includes a spectrum of clinical manifestations. These signs and symptoms result from compression at the cervicomedullary junction and alteration in cerebrospinal fluid dynamics thus affecting several structures above, at, and below the cervicomedullary junction. Differences in presentation exist among different age groups and high clinical suspicion should be present in younger children. Additionally, CM1 can be associated with other diagnoses and can have unusual acute presentations that should be recognized to ensure excellent outcomes..

Epileptic versus neuro-oncological focus of management in pediatric patients with concurrent primary brain lesion and seizures: a systematic review.

OBJECTIVE: Seizures can be a debilitating manifestation of underlying neoplastic intracranial pathology. Existing literature offers a paucity of scientific consensus regarding risk factors, seizure semiology, operative techniques, and tumor characteristics in pediatric patients with a concurrent diagnosis of primary intracranial neoplasm and seizures. To address the limited evidence in current literature, the authors systematically reviewed published literature on current clinical characteristics and management strategies for patients presenting concurrently with seizures and a newly diagnosed brain lesion, while aiming to synthesize a potential management protocol or set of recommendations for these patients. METHODS: An initial search revealed 792 papers, of which 196 studies were excluded, leaving 596 studies available for abstract review. After further stratification, 546 studies were eliminated, leaving 50 studies for eligibility assessment. Of the 50 studies, 12 met the criteria for outcome extraction. RESULTS: The results indicate that patients with a mean age of 9 years with a newly diagnosed brain tumor and presenting symptoms of seizure are likely to present with daily seizures of the complex partial subtype, with the most likely primary epileptogenic and neoplastic foci occurring in the temporal lobe. The most common tumor subtypes were low-grade gliomas, ganglioglioma, dysembryoplastic neuroepithelial tumor, or astrocytoma. With the aim of gross-total resection, 77.54% of patients are likely to achieve seizure freedom. CONCLUSIONS: This study highlights the demographic, clinical, seizure, tumor, and postoperative outcomes for pediatric patients presenting with a primary brain tumor and concurrent seizures. Further prospective multicenter studies are necessary to understand and compare varying treatment approaches and to develop standardized guidelines for these patients, with the goal of optimizing neuro-oncological and seizure-related outcomes.

Pediatric Endoscopic Endonasal Skull Base Surgery: A Retrospective Review Over 11 Years.

OBJECTIVE: To show the safety and efficacy of the endoscopic endonasal approach (EEA) for skull base surgery in pediatric patients through descriptive analysis of cases over an 11-year period. METHODS: The study comprised 94 patients undergoing EEA for skull base surgery, between January 2007 and June 2018, at 2 tertiary pediatric hospitals. Descriptive statistics are presented regarding the presentation, intraoperative details, and complications. RESULTS: Over the study period, 130 surgeries were performed in 94 patients: 94 primary surgeries and 36 reoperations. The mean patient age was 13.8 years and 48.9% of patients were female. Presenting signs/symptoms included endocrinopathies (56.4%), vision abnormalities (37.2%), and cranial nerve deficits (20.2%). EEA alone was used in 95.7% of primary surgeries and 91.7% of reoperations. Diseases treated included craniopharyngioma (18.1%), pituitary adenoma (17.0%), Rathke cleft cyst (13.8%), chordoma (9.6%), osteosarcoma (5.3%), juvenile nasopharyngeal angiofibroma (4.3%), skull base fracture (4.3%), and encephalocele (3.2%). A lumbar drain was used in 20.2% of primary surgeries and 25% of reoperations. A nasoseptal flap was used in 36.2% of primary surgeries and 25% of reoperations. Postoperative complications included cerebrospinal fluid leak (12.8%), sinusitis (7.4%), bacterial meningitis (3.2%), and carotid artery injury in 1 reoperation. CONCLUSIONS: EEA for anterior cranial base disease is safe and efficacious in pediatric patients and can be used to treat many of the rare and heterogenous diseases that arise in this anatomic location. Management strategies and rates of sinonasal and intracranial complications including cerebrospinal fluid leak rate are similar to those reported in adult cohorts.