Comprehensive Analysis of Hypermutation in Human Cancer.

We present an extensive assessment of mutation burden through sequencing analysis of >81,000 tumors from pediatric and adult patients, including tumors with hypermutation caused by chemotherapy, carcinogens, or germline alterations. Hypermutation was detected in tumor types not previously associated with high mutation burden. Replication repair deficiency was a major contributing factor. We uncovered new driver mutations in the replication-repair-associated DNA polymerases and a distinct impact of microsatellite instability and replication repair deficiency on the scale of mutation load. Unbiased clustering, based on mutational context, revealed clinically relevant subgroups regardless of the tumors' tissue of origin, highlighting similarities in evolutionary dynamics leading to hypermutation. Mutagens, such as UV light, were implicated in unexpected cancers, including sarcomas and lung tumors. The order of mutational signatures identified previous treatment and germline replication repair deficiency, which improved management of patients and families. These data will inform tumor classification, genetic testing, and clinical trial design.

AutoGVP: a dockerized workflow integrating ClinVar and InterVar germline sequence variant classification.

SUMMARY: With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically focused classification of germline sequence variants in a research setting. AVAILABILITY AND IMPLEMENTATION: AutoGVP is an open source dockerized workflow implemented in R and freely available on GitHub at https://github.com/diskin-lab-chop/AutoGVP.

Systematic review and cumulative analysis of clinical properties of BRAF V600E mutations in PLNTY histological samples.

PURPOSE: Polymorphous low-grade neuroepithelial tumors of the young (PLNTY) represent a rare pediatric-type tumor that most commonly presents as medically refractory epilepsy. PLNTY has only recently been recognized as a distinct clinical entity, having been first described in 2016 and added to the World Health Organization classification of CNS tumors in 2021. Molecular studies have determined that PLNTY is uniformly driven by aberrant MAPK pathway activation, with most tumors carrying either a BRAF V600E mutation or activating FGFR2 or FGFR3 fusion protein. Although it is known that these driver mutations are mutually exclusive, little is known about differences in clinical presentation or treatment outcomes between PLNTY cases driven by these distinct mutations. METHODS: We performed a systematic review and cumulative analysis of PLNTY cases to assess whether or not PLNTY tumors carrying the BRAF V600E mutation exhibit different clinical behaviors. By searching the literature for all cases of PLNTY wherein BRAF V600E status was characterized, we compiled a dataset of 62 unique patient instances. Using a logistic regression-based approach, we assessed a primary outcome of what factors of a clinical presentation were associated with BRAF V600E mutations and a secondary outcome of what factors predicted total seizure freedom post-surgical resection. RESULTS: PLNTY cases carrying BRAF V600E mutations in the literature were strongly positively associated with adult patients (p = 0.0055, OR = 6.556; 95% Conf. Int. = 1.737-24.742). BRAF V600E status was also positively associated with tumor involvement of the temporal lobe (p = 0.0046, OR = 11.036; 95% Conf. Int. = 2.100-58.006). Male sex was also positively associated with BRAF V600E status, but the result did not quite achieve statistical significance (p = 0.0731). BRAF V600E status was not found to be associated with post-operative seizure freedom. CONCLUSIONS: These findings indicate that BRAF V600E-positive PLNTY exhibit characteristic clinical presentations but are not necessarily different in treatment responsiveness. Non-BRAF V600E tumors are more commonly associated with young patients.

Imaging of pediatric brain tumors: A COG Diagnostic Imaging Committee/SPR Oncology Committee/ASPNR White Paper.

Tumors of the central nervous system are the most common solid malignancies in children and the most common cause of pediatric cancer-related mortality. Imaging plays a central role in diagnosis, staging, treatment planning, and response assessment of pediatric brain tumors. However, the substantial variability in brain tumor imaging protocols across institutions leads to variability in patient risk stratification and treatment decisions, and complicates comparisons of clinical trial results. This White Paper provides consensus-based imaging recommendations for evaluating pediatric patients with primary brain tumors. The proposed brain magnetic resonance imaging protocol recommendations balance advancements in imaging techniques with the practicality of deployment across most imaging centers.

Large scalp venous malformation in a pediatric patient managed with sclerotherapy and surgery: a case report and review of literature.

BACKGROUND: Venous malformations (VMs) are slow-flow vascular anomalies present at birth that enlarge during adolescence, subsequently causing thrombosis, hemorrhage, and pain. CASE PRESENTATION: We describe a case of an adolescent male presenting with a large scalp venous malformation. Given the size and location of the lesion, a hybrid approach employing both sclerotherapy and surgical resection was utilized. The VM was successfully removed without complication. CONCLUSION: A hybrid approach is a safe and effective treatment consideration for immediate management of large venous malformation in higher-risk locations.

Co-administration of Ketamine in Pediatric Patients with Neurologic Conditions at Risk for Intracranial Hypertension.

BACKGROUND: Ketamine has traditionally been avoided as an induction agent for tracheal intubation in patients with neurologic conditions at risk for intracranial hypertension due to conflicting data in the literature. The objective of this study was to evaluate and compare the effects of ketamine versus other medications as the primary induction agent on peri-intubation neurologic, hemodynamic and respiratory associated events in pediatric patients with neurologic conditions at risk for intracranial hypertension. METHODS: This retrospective observational study enrolled patients < 18 years of age at risk for intracranial hypertension who were admitted to a quaternary children's hospital between 2015 and 2020. Associated events included neurologic, hemodynamic and respiratory outcomes comparing primary induction agents of ketamine versus non-ketamine for tracheal intubation. RESULTS: Of 143 children, 70 received ketamine as the primary induction agent prior to tracheal intubation. Subsequently after tracheal intubation, all the patients received adjunct analgesic and sedative medications (fentanyl, midazolam, and/or propofol) at doses that were inadequate to induce general anesthesia but would keep them comfortable for further diagnostic workup. There were no significant differences between associated neurologic events in the ketamine versus non-ketamine groups (p = 0.42). This included obtaining an emergent computed tomography scan (p = 0.28), an emergent trip to the operating room within 5 h of tracheal intubation (p = 0.6), and the need for hypertonic saline administration within 15 min of induction drug administration for tracheal intubation (p = 0.51). There were two patients who had clinical and imaging evidence of herniation, which was not more adversely affected by ketamine compared with other medications (p = 0.49). Of the 143 patients, 23 had pre-intubation and post-intubation intracranial pressure values recorded; 11 received ketamine, and 3 of these patients had intracranial hypertension that resolved or improved, whereas the remaining 8 children had intracranial pressure within the normal range that was not exacerbated by ketamine. There were no significant differences in overall associated hemodynamic or respiratory events during tracheal intubation and no 24-h mortality in either group. CONCLUSIONS: The administration of ketamine as the primary induction agent prior to tracheal intubation in combination with other agents after tracheal intubation in children at risk for intracranial hypertension was not associated with an increased risk of peri-intubation associated neurologic, hemodynamic or respiratory events compared with those who received other induction agents.

Separation of Craniopagus Twins by a Multidisciplinary Team.

Conjoined twins who are classified as craniopagus (joined at the cranium) have a rare congenital anomaly. Despite advances in surgical techniques and critical care, the rate of complications and death is still high among twins with total fusion in which the superior sagittal sinus is shared. Here, we describe total-fusion craniopagus twins who at 10 months of age underwent successful surgical separation performed by a multidisciplinary team. Computer-aided design and modeling with a three-dimensional printer, custom-designed cranial distraction and constriction devices, and intraoperative navigation techniques were used. These techniques allowed for separation of the twins at an early age and harnessed the regenerative capacity of their young brains.

Pediatric Central Nervous System Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Central nervous system (CNS) cancers account for approximately one quarter of all pediatric tumors and are the leading cause of cancer-related death in children. More than 4,000 brain and CNS tumors are diagnosed each year in children and teens, and the incidence rate has remained stagnant in recent years. The most common malignant pediatric CNS tumors are gliomas, embryonal tumors consisting of predominately medulloblastomas, and germ cell tumors. The inaugural version of the NCCN Guidelines for Pediatric Central Nervous System Cancers focuses on the diagnosis and management of patients with pediatric diffuse high-grade gliomas. The information contained in the NCCN Guidelines is designed to help clinicians navigate the complex management of pediatric patients with diffuse high-grade gliomas. The prognosis for these highly aggressive tumors is generally poor, with 5-year survival rates of <20% despite the use of combined modality therapies of surgery, radiation therapy and systemic therapy. Recent advances in molecular profiling has expanded the use of targeted therapies in patients whose tumors harbor certain alterations. However, enrollment in a clinical trial is the preferred treatment for eligible patients.

Hemicraniectomy and externalized ventricular drain placement in a pediatric patient with myelin oligodendrocyte glycoprotein-associated tumefactive demyelinating disease.

BACKGROUND: Acquired demyelination of the central nervous system in children can manifest as multiple sclerosis, neuromyelitis optica, myelin oligodendrocyte glycoprotein (MOG)-associated demyelination, or as an acute monophasic illness without serum antibodies. Rarely do patients with demyelinating disease need surgical intervention for fulminant crises. CASE: We report a case of anti-MOG antibody-related tumefactive demyelination in a 10-year-old female who required urgent hemicraniectomy and external ventricular drain placement for progressive white matter edema with obstructive hydrocephalus, subfalcine, and transtentorial herniation.

Surgical management and outcomes of intracranial metastatic Wilms' tumor in the pediatric population: a case series.

PURPOSE: Approximately 1 to 2% of patients with Wilms' tumor (WT), or nephroblastoma, will have metastasis to the brain. Due to the rarity of intracranial metastasis, the clinical characteristics, prognosis, and a standardized treatment approach to this occurrence remain poorly understood. Here we review the surgical management and treatment outcome of WT patients with intracranial metastasis at our institution. METHODS: A retrospective chart review of patients with WT at the Children's Hospital of Philadelphia was performed from 2007 to 2021. Clinical characteristics, operative details, radiographic studies, pathology, and patient outcomes were collected and analyzed. RESULTS: A total of 3 patients with histologically confirmed intracranial metastatic disease from WT were identified with a mean age of 5.7 years (range 3-10 years). 2 of the 3 patients were male. The mean time from diagnosis of primary WT to development of central nervous system metastasis was 15.3 months. Both supratentorial (n = 3) and infratentorial (n = 1) sites of metastasis were observed. Surgical resection was performed, and gross total resection was achieved in all 3 patients. All cases had favorable histology with no anaplasia and received whole-brain irradiation and chemotherapy. Two of 3 patients had a good neurologic function at postoperative follow-up. One patient died from their disease 4 months after resection of the brain metastasis. CONCLUSION: In WT patients with limited systemic disease burden, the combination of surgery, chemotherapy, and radiotherapy may play a role in enhancing survival when intracranial metastasis is present, despite the perioperative risk associated with surgery.

Optical Detection of Intracranial Pressure and Perfusion Changes in Neonates With Hydrocephalus.

OBJECTIVE: To demonstrate that a novel noninvasive index of intracranial pressure (ICP) derived from diffuse optics-based techniques is associated with intracranial hypertension. STUDY DESIGN: We compared noninvasive and invasive ICP measurements in infants with hydrocephalus. Infants born term and preterm were eligible for inclusion if clinically determined to require cerebrospinal fluid (CSF) diversion. Ventricular size was assessed preoperatively via ultrasound measurement of the fronto-occipital (FOR) and frontotemporal (FTHR) horn ratios. Invasive ICP was obtained at the time of surgical intervention with a manometer. Intracranial hypertension was defined as invasive ICP ≥15 mmHg. Diffuse optical measurements of cerebral perfusion, oxygen extraction, and noninvasive ICP were performed preoperatively, intraoperatively, and postoperatively. Optical and ultrasound measures were compared with invasive ICP measurements, and their change in values after CSF diversion were obtained. RESULTS: We included 39 infants, 23 with intracranial hypertension. No group difference in ventricular size was found by FOR (P = .93) or FTHR (P = .76). Infants with intracranial hypertension had significantly higher noninvasive ICP (P = .02) and oxygen extraction fraction (OEF) (P = .01) compared with infants without intracranial hypertension. Increased cerebral blood flow (P = .005) and improved OEF (P < .001) after CSF diversion were observed only in infants with intracranial hypertension. CONCLUSIONS: Noninvasive diffuse optical measures (including a noninvasive ICP index) were associated with intracranial hypertension. The findings suggest that impaired perfusion from intracranial hypertension was independent of ventricular size. Hemodynamic evidence of the benefits of CSF diversion was seen in infants with intracranial hypertension. Noninvasive optical techniques hold promise for aiding the assessment of CSF diversion timing.

A transcriptome-based classifier to determine molecular subtypes in medulloblastoma.

Medulloblastoma is a highly heterogeneous pediatric brain tumor with five molecular subtypes, Sonic Hedgehog TP53-mutant, Sonic Hedgehog TP53-wildtype, WNT, Group 3, and Group 4, defined by the World Health Organization. The current mechanism for classification into these molecular subtypes is through the use of immunostaining, methylation, and/or genetics. We surveyed the literature and identified a number of RNA-Seq and microarray datasets in order to develop, train, test, and validate a robust classifier to identify medulloblastoma molecular subtypes through the use of transcriptomic profiling data. We have developed a GPL-3 licensed R package and a Shiny Application to enable users to quickly and robustly classify medulloblastoma samples using transcriptomic data. The classifier utilizes a large composite microarray dataset (15 individual datasets), an individual microarray study, and an RNA-Seq dataset, using gene ratios instead of gene expression measures as features for the model. Discriminating features were identified using the limma R package and samples were classified using an unweighted mean of normalized scores. We utilized two training datasets and applied the classifier in 15 separate datasets. We observed a minimum accuracy of 85.71% in the smallest dataset and a maximum of 100% accuracy in four datasets with an overall median accuracy of 97.8% across the 15 datasets, with the majority of misclassification occurring between the heterogeneous Group 3 and Group 4 subtypes. We anticipate this medulloblastoma transcriptomic subtype classifier will be broadly applicable to the cancer research and clinical communities.

BRAF fusions in pediatric histiocytic neoplasms define distinct therapeutic responsiveness to RAF paradox breakers.

Pediatric histiocytic neoplasms are hematopoietic disorders frequently driven by the BRAF-V600E mutation. Here, we identified two BRAF gene fusions (novel MTAP-BRAF and MS4A6A-BRAF) in two aggressive histiocytic neoplasms. In contrast to previously described BRAF fusions, MTAP-BRAF and MS4A6A-BRAF do not respond to the paradox breaker RAF inhibitor (RAFi) PLX8394 due to stable fusion dimerization mediated by the N-terminal fusion partners. This highlights a significant and clinically relevant shift from the current dogma that BRAF-fusions respond similarly to BRAF-inhibitors. As an alternative, we show suppression of fusion-driven oncogenic growth with the pan-RAFi LY3009120 and MEK inhibition.

A Retrospective Study of Neurological Complications in Pediatric Patients With Moyamoya Disease Undergoing General Anesthesia.

BACKGROUND: Moyamoya disease is a condition with potentially devastating and permanent neurological sequelae. Adequate volume status and blood pressure, tight control of carbon dioxide to achieve normocarbia, and providing postoperative analgesia to prevent hyperventilation are typical goals that are used during anesthetic care in these patients. The purpose of this study was to assess postanesthesia neurological complications in moyamoya patients undergoing general anesthesia for imaging studies and surgical procedures excluding neurosurgical revascularization. METHODS: We performed a retrospective cohort study examining moyamoya patients who received general anesthesia for imaging studies and nonneurosurgical-revascularization procedures between January 1, 2001 and December 1, 2016 at our quaternary care pediatric hospital. A general anesthetic encounter was excluded if it occurred within 30 days after a revascularization surgery. The electronic medical records of study patients were analyzed for perioperative management, and neurological outcomes within 30 days of an anesthetic were assessed. RESULTS: A total of 58 patients undergoing 351 anesthesia exposures were included in the study. Three patients experienced neurological complications, which included focal neurological weakness, seizure, and altered mental status. The incidence of complications during anesthesia encounters was 0.85% (3/351) with a 95% confidence interval of 0.28-2.62. CONCLUSIONS: Over a 16-year period at our hospital, 3 children with moyamoya disease who underwent anesthesia for nonneurosurgical-revascularization purposes demonstrated postanesthesia neurological symptoms. The symptoms were consistent with transient ischemic attacks and all resolved without long-term sequelae.

Decadron, Diamox, and Zantac: A Novel Combination for Ventricular Shunt Failure in Pediatric Neurosurgical Patients.

OBJECTIVE: Cerebral ventricular shunt failure is common and presents with symptoms that range from headaches to death. The combination of Diamox (acetazolamide), Decadron (dexamethasone), and Zantac (ranitidine) (DDZ) is used at our institution to medically stabilize pediatric patients presenting with symptomatic shunt failure before shunt revision. We describe our experience of this drug combination as a temporizing measure to decrease symptoms associated with shunt failure. METHODS: We performed a single-center retrospective chart review of patients younger than 18 years with ventricular shunt failure who underwent a shunt revision between January 2015 to October 2017 and received DDZ before surgery. The outcome variables evaluated included pre-DDZ and post-DDZ clinical symptoms, pain scores, and vital signs. RESULTS: There were 112 cases that received DDZ before shunt revision. The 4 most commonly reported symptoms were analyzed. Headache was observed in 42 cases pre-DDZ, and post-DDZ there was a 71% reduction in headache (P < 0.0001); emesis was reported pre-DDZ in 76 cases, and post-DDZ there was an 83% reduction (P < 0.0001); irritability was noted pre-DDZ in 30 cases, and post-DDZ there was a 77% reduction (P = 0.0003); lethargy pre-DDZ was observed in 60 cases, and post-DDZ 73% demonstrated improvement (P < 0.0001). Maximum pain scores significantly decreased post-DDZ (P < 0.0001). Heart rate, systolic, and diastolic blood pressures significantly decreased post-DDZ (P < 0.0001, P < 0.0001, P = 0.0002, respectively). CONCLUSIONS: The combination of Decadron, Diamox, and Zantac is a novel treatment for ventricular shunt failure that may temporarily improve symptoms in patients awaiting shunt revision. Future studies could compare efficacy with other medical treatments.

annoFuse: an R Package to annotate, prioritize, and interactively explore putative oncogenic RNA fusions.

BACKGROUND: Gene fusion events are significant sources of somatic variation across adult and pediatric cancers and are some of the most clinically-effective therapeutic targets, yet low consensus of RNA-Seq fusion prediction algorithms makes therapeutic prioritization difficult. In addition, events such as polymerase read-throughs, mis-mapping due to gene homology, and fusions occurring in healthy normal tissue require informed filtering, making it difficult for researchers and clinicians to rapidly discern gene fusions that might be true underlying oncogenic drivers of a tumor and in some cases, appropriate targets for therapy. RESULTS: We developed annoFuse, an R package, and shinyFuse, a companion web application, to annotate, prioritize, and explore biologically-relevant expressed gene fusions, downstream of fusion calling. We validated annoFuse using a random cohort of TCGA RNA-Seq samples (N = 160) and achieved a 96% sensitivity for retention of high-confidence fusions (N = 603). annoFuse uses FusionAnnotator annotations to filter non-oncogenic and/or artifactual fusions. Then, fusions are prioritized if previously reported in TCGA and/or fusions containing gene partners that are known oncogenes, tumor suppressor genes, COSMIC genes, and/or transcription factors. We applied annoFuse to fusion calls from pediatric brain tumor RNA-Seq samples (N = 1028) provided as part of the Open Pediatric Brain Tumor Atlas (OpenPBTA) Project to determine recurrent fusions and recurrently-fused genes within different brain tumor histologies. annoFuse annotates protein domains using the PFAM database, assesses reciprocality, and annotates gene partners for kinase domain retention. As a standard function, reportFuse enables generation of a reproducible R Markdown report to summarize filtered fusions, visualize breakpoints and protein domains by transcript, and plot recurrent fusions within cohorts. Finally, we created shinyFuse for algorithm-agnostic interactive exploration and plotting of gene fusions. CONCLUSIONS: annoFuse provides standardized filtering and annotation for gene fusion calls from STAR-Fusion and Arriba by merging, filtering, and prioritizing putative oncogenic fusions across large cancer datasets, as demonstrated here with data from the OpenPBTA project. We are expanding the package to be widely-applicable to other fusion algorithms and expect annoFuse to provide researchers a method for rapidly evaluating, prioritizing, and translating fusion findings in patient tumors.

Low-grade astrocytoma in the setting of a developmental venous anomaly.

Developmental venous anomalies (DVAs) are the most common type of cerebrovascular malformation and are considered benign. There are a few literature studies associating DVA with brain tumors, suggesting a possible underlying predisposition in these patients for tumor neogenesis. We report a 7-year-old female with a complex DVA who developed a low-grade astrocytoma in the opposite hemisphere. With analysis of a comprehensive solid tumor panel and imaging, we describe the possible association of an underlying susceptibility to neoplastic growth in the presence of a vascular malformation.

Endoscopic third ventriculostomy prior to resection of posterior fossa tumors in children.

OBJECTIVE: Hydrocephalus is a common presenting symptom of pediatric posterior fossa tumors and often requires permanent cerebrospinal fluid diversion even after resection. Endoscopic third ventriculostomy (ETV) is a well-established treatment of obstructive hydrocephalus in children. The objective of this study is to demonstrate that ETV prior to posterior fossa tumor resection decreases the rate of postoperative ventriculoperitonal shunt (VPS) placement. METHODS: We performed a retrospective analysis of patients who presented with hydrocephalus and underwent posterior fossa tumor resection between 2005 and 2016 excluding pineal and tectal tumors. The rate of postoperative VPS placement was compared in patients who underwent resection and had a VPS placed perioperatively (historical controls) with patients who underwent ETV prior to resection. The two groups were matched for demographics, tumor histology, and tumor location. We also performed a literature review of prior studies that examined the role of ETV in pediatric posterior fossa tumors. RESULTS: Thirty-six patients in the control group were compared to 38 patients in our study. The patients were matched across all variables (age, gender, tumor histology, and tumor locations). The rate of postoperative VPS placement was 31% in the control group compared to 16% in the ETV group. No complications were encountered during ETV. CONCLUSIONS: Endoscopic third ventriculostomy prior to posterior fossa tumor resection in children appears to decrease the rate of postoperative VPS placement. Given its efficacy and safety, ETV should be considered prior to tumor resection in these patients.

Reduction of ventriculostomy-associated CSF infection with antibiotic-impregnated catheters in pediatric patients: a single-institution study.

OBJECTIVE: External ventricular drains (EVDs) are commonly used in the neurosurgical population. However, very few pediatric neurosurgery studies are available regarding EVD-associated infection rates with antibiotic-impregnated EVD catheters. The authors previously published a large pediatric cohort study analyzing nonantibiotic-impregnated EVD catheters and risk factors associated with infections. In this study, they aimed to analyze the EVD-associated infection rate after implementation of antibiotic-impregnated EVD catheters. METHODS: A retrospective observational cohort of pediatric patients (younger than 18 years of age) who underwent a burr hole for antibiotic-impregnated EVD placement and who were admitted to a quaternary care ICU between January 2011 and January 2019 were reviewed. The ventriculostomy-associated infection rate in patients with antibiotic-impregnated EVD catheters was compared to the authors' historical control of patients with nonantibiotic-impregnated EVD catheters. RESULTS: Two hundred twenty-nine patients with antibiotic-impregnated EVD catheters were identified. Neurological diagnostic categories included externalization of an existing shunt (externalized shunt) in 34 patients (14.9%); brain tumor (tumor) in 77 patients (33.6%); intracranial hemorrhage (ICH) in 27 patients (11.8%); traumatic brain injury (TBI) in 6 patients (2.6%); and 85 patients (37.1%) were captured in an "other" category. Two of 229 patients (0.9% of all patients) had CSF infections associated with EVD management, totaling an infection rate of 0.99 per 1000 catheter days. This is a significantly lower infection rate than was reported in the authors' previously published analysis of the use of nonantibiotic-impregnated EVD catheters (0.9% vs 6%, p = 0.00128). CONCLUSIONS: In their large pediatric cohort, the authors demonstrated a significant decline in ventriculostomy-associated CSF infection rate after implementation of antibiotic-impregnated EVD catheters at their institution.

External validity of the chiari severity index and outcomes among pediatric chiari I patients treated with intra- or extra-Dural decompression.

INTRODUCTION: Chiari malformation type-1 (CM-1) may be treated by intradural (ID) or extradural (ED) posterior fossa decompression, although the optimal approach is debated. The Chiari Severity Index (CSI) is a pre-operative metric to predict patient-defined improvement after CM-1 surgery. In this study, we evaluate the results of ID versus ED decompression and assess the external validity of the CSI. METHODS: We performed a retrospective cohort study of pediatric CM-1 patients undergoing decompression at a single academic children's hospital. Characteristics of headache, syrinx, and myelopathy were collected to derive CSI grade. The primary outcome measure was pre-operative symptom resolution. The proportion of patients with favorable outcome was tabulated for each of the three CSI grades and compared to previously published results. RESULTS: From 2004 to 2014, 189 patients underwent ID (48%) or ED (52%) decompression at the Children's Hospital of Philadelphia (CHOP). Follow-up ranged from 1 to 75 months. Rates of symptom resolution (58-64%) and reoperation (8%) were similar regardless of surgical approach. Although proportions of favorable outcomes differed between the CHOP and Washington University (WU) cohorts, the difference was not related to CSI grade (p = 0.63). Furthermore, there was no difference in the proportion of favorable outcomes between the two cohorts regardless of ID (p = 0.26) or ED approach (p = 0.11). CONCLUSIONS: Equivalent rates of symptom resolution and reoperation following ID and ED decompression support the ED approach as a first-line surgical option for pediatric CM-1 patients. In addition, our findings provide preliminary evidence supporting the generalizability of the CSI and its use in future comparative trials.