Faculty Bibliography

OBJECTIVE:The purpose of this study was to identify factors associated with fusion success among pediatric patients undergoing occiput-C2 rigid instrumentation and fusion. METHODS:The Pediatric Spine Study Group registry was queried to identify patients ≤ 21 years of age who underwent occiput-C2 posterior spinal rigid instrumentation and fusion and had a 2-year minimum clinical and radiographic (postoperative lateral cervical radiograph or CT scan) follow-up. Fusion failure was defined clinically if a patient underwent hardware revision surgery > 30 days after the index procedure or radiographically by the presence of hardware failure or screw haloing on the most recent follow-up imaging study. Univariate comparisons and multivariable logistic regression analyses were subsequently performed. RESULTS:Seventy-six patients met inclusion criteria. The median age at surgery was 9 years (range 1.5-17.2 years), and 51% of the cohort was male. Overall, 75% of patients had syndromic (n = 41) or congenital (n = 15) etiologies, with the most frequent diagnoses of Down syndrome (28%), Chiari malformation (13%), and Klippel-Feil syndrome (12%). Data were available to determine if there was a fusion failure in 97% (74/76) of patients. Overall, 38% (28/74) of patients had fusion failure (95% CI 27%-50%). Univariate analysis demonstrated that use of a rigid cervical collar postoperatively (p = 0.04) and structural rib autograft (p = 0.02) were associated with successful fusion. Multivariable logistic regression analysis determined that patients who had rib autograft used in surgery had a 73% decrease in the odds of fusion failure (OR 0.27, 95% CI 0.09-0.82; p = 0.02). Age, etiology including Down syndrome, instrumentation type, unilateral instrumentation, use of recombinant human bone morphogenetic protein, and other variables did not influence the risk for fusion failure. CONCLUSIONS:In this multicenter, multidisciplinary, international registry of children undergoing occiput-C2 instrumentation and fusion, fusion failure was seen in 38% of patients, a higher rate than previously reported in the literature. The authors' data suggest that postoperative immobilization in a rigid cervical collar may be beneficial, and the use of structural rib autograft should be considered, as rib autograft was associated with a 75% higher chance of successful fusion.

OBJECTIVE:Pediatric data regarding treatment via an auditory brainstem implant (ABI) remains sparse. The authors aimed to describe their experience at their institution and to delineate associated demographic data, audiometric outcomes, and surgical parameters. METHODS:An IRB-approved, retrospective chart review was conducted among the authors' pediatric patients who had undergone auditory brainstem implantation between 2012 and 2021. Demographic information including sex, age, race, coexisting syndrome(s), history of cochlear implant placement, average duration of implant use, and follow-up outcomes were collected. Surgical parameters collected included approach, intraoperative findings, number of electrodes activated, and complications. RESULTS:A total of 19 pediatric patients had an ABI placed at the authors' institution, with a mean age at surgery of 4.7 years (range 1.5-17.8 years). A total of 17 patients (89.5%) had bilateral cochlear nerve aplasia/dysplasia, 1 (5.3%) had unilateral cochlear nerve aplasia/dysplasia, and 1 (5.3%) had a hypoplastic cochlea with ossification. A total of 11 patients (57.9%) had a history of cochlear implants that were ineffective and required removal. The mean length of implant use was 5.31 years (0.25-10 years). Two patients (10.5%) experienced CSF-related complications requiring further surgical intervention. The most recent audiometric outcomes demonstrated that 15 patients (78.9%) showed improvement in their hearing ability: 5 with sound/speech awareness, 5 able to discriminate among speech and environmental sounds, and 5 able to understand common phrases/conversation without lip reading. Nine patients (47.4%) are in a school for the deaf and 7 (36.8%) are in a mainstream school with support. CONCLUSIONS:The authors' surgical experience with a multidisciplinary team demonstrates that the retrosigmoid approach for ABI placement in children with inner ear pathologies and severe sensorineural hearing loss is a safe and effective treatment modality. Audiometric outcome data showed that nearly 79% of these patients had an improvement in their environmental and speech awareness. Further multicenter collaborations are necessary to improve these outcomes and potentially standardize/enhance electrode placement.

PURPOSE/OBJECTIVE:Although ongoing studies are assessing the efficacy of new systemic therapies for patients with triple negative breast cancer (TNBC), the overwhelming majority have excluded patients with brain metastases (BM). Therefore, we aim to characterize systemic therapies and outcomes in a cohort of patients with TNBC and BM managed with stereotactic radiosurgery (SRS) and delineate predictors of increased survival. METHODS:We used our prospective patient registry to evaluate data from 2012 to 2023. We included patients who received SRS for TNBC-BM. A competing risk analysis was conducted to assess local and distant control. RESULTS:Forty-three patients with 262 tumors were included. The median overall survival (OS) was 16 months (95% CI 13-19 months). Predictors of increased OS after initial SRS include Breast GPA score > 1 (p < 0.001) and use of immunotherapy such as pembrolizumab (p = 0.011). The median time on immunotherapy was 8 months (IQR 4.4, 11.2). The median time to new CNS lesions after the first SRS treatment was 17 months (95% CI 12-22). The cumulative rate for development of new CNS metastases after initial SRS at 6 months, 1 year, and 2 years was 23%, 40%, and 70%, respectively. Thirty patients (70%) underwent multiple SRS treatments, with a median time of 5 months (95% CI 0.59-9.4 months) for the appearance of new CNS metastases after second SRS treatment. CONCLUSIONS:TNBC patients with BM can achieve longer survival than might have been previously anticipated with median survival now surpassing one year. The use of immunotherapy is associated with increased median OS of 23 months.

UNLABELLED:DNA methylation is an essential molecular assay for central nervous system (CNS) tumor diagnostics. While some fusions define specific brain tumors, others occur across many different diagnoses. We performed a retrospective analysis of 219 primary CNS tumors with whole genome DNA methylation and RNA next-generation sequencing. DNA methylation profiling results were compared with RNAseq detected gene fusions. We detected 105 rare fusions involving 31 driver genes, including 23 fusions previously not implicated in brain tumors. In addition, we identified 6 multi-fusion tumors. Rare fusions and multi-fusion events can impact the diagnostic accuracy of DNA methylation by decreasing confidence in the result, such as BRAF, RAF, or FGFR1 fusions, or result in a complete mismatch, such as NTRK, EWSR1, FGFR, and ALK fusions. IMPLICATIONS/UNASSIGNED:DNA methylation signatures need to be interpreted in the context of pathology and discordant results warrant testing for novel and rare gene fusions.

OBJECTIVE:The focus of this modified Delphi study was to investigate and build consensus regarding the medical management of children with moderate and severe acute spinal cord injury (SCI) during their initial inpatient hospitalization. This impetus for the study was based on the AANS/CNS guidelines for pediatric SCI published in 2013, which indicated that there was no consensus provided in the literature describing the medical management of pediatric patients with SCIs. METHODS:An international, multidisciplinary group of 19 physicians, including pediatric neurosurgeons, orthopedic surgeons, and intensivists, were asked to participate. The authors chose to include both complete and incomplete injuries with traumatic as well as iatrogenic etiologies (e.g., spinal deformity surgery, spinal traction, intradural spinal surgery, etc.) due to the overall low incidence of pediatric SCI, potentially similar pathophysiology, and scarce literature exploring whether different etiologies of SCI should be managed differently. An initial survey of current practices was administered, and based on the responses, a follow-up survey of potential consensus statements was distributed. Consensus was defined as ≥ 80% of participants reaching agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree). A final meeting was held virtually to generate final consensus statements. RESULTS:Following the final Delphi round, 35 statements reached consensus after modification and consolidation of previous statements. Statements were categorized into the following eight sections: inpatient care unit, spinal immobilization, pharmacological management, cardiopulmonary management, venous thromboembolism prophylaxis, genitourinary management, gastrointestinal/nutritional management, and pressure ulcer prophylaxis. All participants stated that they would be willing or somewhat willing to change their practices based on consensus guidelines. CONCLUSIONS:General management strategies were similar for both iatrogenic (e.g., spinal deformity, traction, etc.) and traumatic SCIs. Steroids were recommended only for injury after intradural surgery, not after acute traumatic or iatrogenic extradural surgery. Consensus was reached that mean arterial pressure ranges are preferred for blood pressure targets following SCI, with goals between 80 and 90 mm Hg for children at least 6 years of age. Further multicenter study of steroid use following acute neuromonitoring changes was recommended.

OBJECTIVE:Cervical spine disorders in children are relatively uncommon; therefore, paradigms for surgical and nonsurgical clinical management are not well established. The purpose of this study was to bring together an international, multidisciplinary group of pediatric cervical spine experts to build consensus via a modified Delphi approach regarding the clinical management of children with cervical spine disorders and those undergoing cervical spine stabilization surgery. METHODS:A modified Delphi method was used to identify consensus statements for the management of children with cervical spine disorders requiring stabilization. A survey of current practices, supplemented by a literature review, was electronically distributed to 17 neurosurgeons and orthopedic surgeons experienced with the clinical management of pediatric cervical spine disorders. Subsequently, 52 summary statements were formulated and distributed to the group. Statements that reached near consensus or that were of particular interest were then discussed during an in-person meeting to attain further consensus. Consensus was defined as ≥ 80% agreement on a 4-point Likert scale (strongly agree, agree, disagree, strongly disagree). RESULTS:Forty-five consensus-driven statements were identified, with all participants willing to incorporate them into their practice. For children with cervical spine disorders and/or stabilization, consensus statements were divided into the following categories: A) preoperative planning (12 statements); B) radiographic thresholds of instability (4); C) intraoperative/perioperative management (15); D) postoperative care (11); and E) nonoperative management (3). Several important statements reaching consensus included the following recommendations: 1) to obtain pre-positioning baseline signals with intraoperative neuromonitoring; 2) to use rigid instrumentation when technically feasible; 3) to provide postoperative external immobilization for 6-12 weeks with a rigid cervical collar rather than halo vest immobilization; and 4) to continue clinical postoperative follow-up at least until anatomical cervical spine maturity was reached. In addition, preoperative radiographic thresholds for instability that reached consensus included the following: 1) translational motion ≥ 5 mm at C1-2 (excluding patients with Down syndrome) or ≥ 4 mm in the subaxial spine; 2) dynamic angulation in the subaxial spine ≥ 10°; and 3) abnormal motion and T2 signal change on MRI seen at the same level. CONCLUSIONS:In this study, the authors have demonstrated that a multidisciplinary, international group of pediatric cervical spine experts was able to reach consensus on 45 statements regarding the management of pediatric cervical spine disorders and stabilization. Further study is required to determine if implementation of these practices can lead to reduced complications and improved outcomes for children.

BACKGROUND/UNASSIGNED:Central nervous system (CNS) cancer is the 10th leading cause of cancer-associated deaths for adults, but the leading cause in pediatric patients and young adults. The variety and complexity of histologic subtypes can lead to diagnostic errors. DNA methylation is an epigenetic modification that provides a tumor type-specific signature that can be used for diagnosis. METHODS/UNASSIGNED:We performed a prospective study using DNA methylation analysis as a primary diagnostic method for 1921 brain tumors. All tumors received a pathology diagnosis and profiling by whole genome DNA methylation, followed by next-generation DNA and RNA sequencing. Results were stratified by concordance between DNA methylation and histopathology, establishing diagnostic utility. RESULTS/UNASSIGNED:Of the 1602 cases with a World Health Organization histologic diagnosis, DNA methylation identified a diagnostic mismatch in 225 cases (14%), 78 cases (5%) did not classify with any class, and in an additional 110 (7%) cases DNA methylation confirmed the diagnosis and provided prognostic information. Of 319 cases carrying 195 different descriptive histologic diagnoses, DNA methylation provided a definitive diagnosis in 273 (86%) cases, separated them into 55 methylation classes, and changed the grading in 58 (18%) cases. CONCLUSIONS/UNASSIGNED:DNA methylation analysis is a robust method to diagnose primary CNS tumors, improving diagnostic accuracy, decreasing diagnostic errors and inconclusive diagnoses, and providing prognostic subclassification. This study provides a framework for inclusion of DNA methylation profiling as a primary molecular diagnostic test into professional guidelines for CNS tumors. The benefits include increased diagnostic accuracy, improved patient management, and refinements in clinical trial design.

Diffuse spinal cord gliomas (SCGs) are rare tumors associated with a high morbidity and mortality that affect both pediatric and adult populations. In this retrospective study, we sought to characterize the clinical, pathological, and molecular features of diffuse SCG in 22 patients with histological and molecular analyses. The median age of our cohort was 23.64 years (range 1-82) and the overall median survival was 397 days. K27M mutation was significantly more prevalent in males compared to females. Gross total resection and chemotherapy were associated with improved survival, compared to biopsy and no chemotherapy. While there was no association between tumor grade, K27M status (p = 0.366) or radiation (p = 0.772), and survival, males showed a trend toward shorter survival. K27M mutant tumors showed increased chromosomal instability and a distinct DNA methylation signature.