Faculty Bibliography

OBJECTIVEThe choice of treatment modality for optic pathway gliomas (OPGs) is controversial. Chemotherapy is widely regarded as first-line therapy; however, subtotal resections have been reported for decompression or salvage therapy as first- and second-line treatment. The goal of this study was to further investigate the role and efficacy of resection for OPGs.METHODSA retrospective chart review was performed on 83 children who underwent surgical treatment for OPGs between 1986 and 2014. Pathology was reviewed by a neuropathologist. Clinical outcomes, including progression-free survival (PFS), overall survival (OS), and complications, were analyzed.RESULTSThe 5- and 10-year PFS rates were 55% and 46%, respectively. The 5- and 10-year OS rates were 87% and 78%, respectively. The median extent of resection was 80% (range 30%-98%). Age less than 2 years at surgery and pilomyxoid features of the tumor were found to be associated with significantly lower 5-year OS. No difference was seen in PFS or OS of children treated with surgery as a first-line treatment compared with children with surgery as a second- or third-line treatment. Severe complications included new disabling visual deficit in 5%, focal neurological deficit in 8%, and infection in 2%. New hormone deficiency occurred in 22% of the children.CONCLUSIONSApproximately half of all children experience a long-term benefit from resection both as primary treatment and as a second-line therapy after failure of primary treatment. Primary surgery does not appear to have a significant benefit for children younger than 2 years or tumors with pilomyxoid features. Given the risks associated with surgery, an interdisciplinary approach is needed to tailor the treatment plan to the individual characteristics of each child.

OBJECTIVE:Incomplete resection of neocortical epileptogenic foci correlates with failed epilepsy surgery in children. We often treat patients with neocortical epilepsy with a staged approach using invasive monitoring to localize the focus, resect the seizure onset zone, and, in select cases, post-resection invasive monitoring (PRM). We report the technique and the outcomes of children treated with staged surgery including PRM. METHODS:We retrospectively reviewed the charts of pediatric patients with neocortical epilepsy who underwent resective surgery with PRM. RESULTS:We identified 71 patients, 5 patients with MRI-negative epilepsy and 66 patients with MRI-identified neocortical lesions; 64/66 (97%) patients had complete lesionectomy. In 61/71 (86%) patients PRM was associated with positive outcomes. Those findings were: 1) clinical seizures with electrographic involvement at resection margins (47%); 2) subclinical seizures and interictal discharges at resection margins (29%); and 3) clinical and subclinical seizures revealing a new epileptogenic focus (20%). In 55/71 (77%) patients, PRM data led to additional resection (re-resection; RR). Six additional patients had no further resection due to overlap with eloquent cortex. Histopathology showed tuberous sclerosis complex (TSC; n = 46), focal cortical dysplasia (FCD; n = 16)), gliosis (n = 4), tumors (n = 4), and Sturge-Weber syndrome (n = 1). There were no major complications. Seizure-free outcome in children with TSC was 63% at 1-year follow-up and 56% at 2-year follow-up. In FCD, seizure freedom after 1 and 2 years was 85%. SIGNIFICANCE/CONCLUSIONS:Post-resection monitoring may provide additional information about the extent of the epileptogenic zone, such as residual epileptogenic activity at the margins of the resection cavity, and may unmask additional seizure foci. This method may be especially useful in achieving long-term stable seizure-free outcome.

PURPOSE/OBJECTIVE:Molecular subgroups of pediatric brain tumors associated with divergent biological, clinical, and prognostic features have been identified. However, data regarding the impact of subgroup affiliation on the outcome of children with malignant brain tumors treated with radiation-sparing protocol is limited. We report long-term clinical outcomes and the molecular subgroups of malignant brain tumors in young children whose first-line treatment was high-dose chemotherapy without irradiation. METHODS:Tumor subclassification was performed using the Illumina HumanMethylation450 BeadChip (450k) genome-wide methylation array profiling platform. Clinical information was obtained from chart review. RESULTS:Methylation array profiling yielded information on molecular subgroups in 22 children. Median age at surgery was 26 months (range 1-119 months). Among medulloblastomas (MB), all 6 children in the infant sonic hedgehog (SHH) subgroup were long-term survivors, whereas all 4 children in subgroup 3 MB died. There was one long-term survivor in subgroup 4 MB. One out of five children with ependymoma was a long-term survivor (RELPOS). Both children with primitive neuroectodermal tumors died. One child with ATRT TYR and one child with choroid plexus carcinoma were long-term survivors. CONCLUSIONS:The efficacy of high-dose chemotherapy radiation-sparing treatment appears to be confined to favorable molecular subgroups of pediatric brain tumors, such as infant SHH MB. Identification of molecular subgroups that benefit from radiation-sparing therapy will aid in the design of prospective, "precision medicine"-driven clinical trials.

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.

OBJECTIVES/OBJECTIVE:Although hemispheric surgeries are among the most effective procedures for drug-resistant epilepsy (DRE) in the pediatric population, a large variability in outcomes remains. Identifying ideal hemispherectomy candidates is imperative to maximize the potential for seizure freedom. The objective was to develop an online, freely-accesible tool that accurately predicts the probability of seizure freedom for any patient at 1-, 2-, and 5-years post-hemispherectomy to provide clinicians accessible and reliable prognostic information to complement clinical judgement. METHODS:Retrospective data of all pediatric patients with DRE and seizure outcome data from the original Hemispherectomy Outcome Prediction Scale (HOPS) study were included. The primary outcome of interest was time-to-seizure recurrence. A multivariate Cox proportional-hazards regression model was developed to predict the likelihood of post-hemispheric surgery seizure freedom duration based on a combination of variables identified by clinical judgement and inferential statistics as predictive of the primary outcome. The final model from this study was encoded in a publicly accessible online calculator on the (iNEST) website. RESULTS:The selected variables for inclusion in the final model included the 5 original HOPS variables (age at seizure onset, etiologic substrate, seizure semiology, prior non-hemispheric resective surgery, and contralateral FDG-PET hypometabolism) and 3 additional variables (age at surgery, history of infantile spasms, and magnetic resonance (MR) imaging lesion). Predictors of shorter time-to-seizure recurrence included younger age at seizure onset, older age at surgery, prior resective surgery, generalized seizure semiology, FDG-PET hypometabolism contralateral to side of surgery, contralateral MR imaging lesion, non-lesional MR imaging, non-stroke etiologies, and history of infantile spasms. The area under the curve (AUC) of the final model was 73.0%. SIGNIFICANCE/CONCLUSIONS:Online calculators are efficient, cost-free tools that can facilitate physicians in risk-estimation and inform joint decision-making with families, potentially leading to greater satisfaction. Although the HOPS data was previously validated in the first analysis, the authors encourage prospective external validation of this new tool.

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.

OBJECTIVE:This study was undertaken to determine whether the vertical parasagittal approach or the lateral peri-insular/peri-Sylvian approach to hemispheric surgery is the superior technique in achieving long-term seizure freedom. METHODS:We conducted a post hoc subgroup analysis of the HOPS (Hemispheric Surgery Outcome Prediction Scale) study, an international, multicenter, retrospective cohort study that identified predictors of seizure freedom through logistic regression modeling. Only patients undergoing vertical parasagittal, lateral peri-insular/peri-Sylvian, or lateral trans-Sylvian hemispherotomy were included in this post hoc analysis. Differences in seizure freedom rates were assessed using a time-to-event method and calculated using the Kaplan-Meier survival method. RESULTS:Data for 672 participants across 23 centers were collected on the specific hemispherotomy approach. Of these, 72 (10.7%) underwent vertical parasagittal hemispherotomy and 600 (89.3%) underwent lateral peri-insular/peri-Sylvian or trans-Sylvian hemispherotomy. Seizure freedom was obtained in 62.4% (95% confidence interval [CI] = 53.5%-70.2%) of the entire cohort at 10-year follow-up. Seizure freedom was 88.8% (95% CI = 78.9%-94.3%) at 1-year follow-up and persisted at 85.5% (95% CI = 74.7%-92.0%) across 5- and 10-year follow-up in the vertical subgroup. In contrast, seizure freedom decreased from 89.2% (95% CI = 86.3%-91.5%) at 1-year to 72.1% (95% CI = 66.9%-76.7%) at 5-year to 57.2% (95% CI = 46.6%-66.4%) at 10-year follow-up for the lateral subgroup. Log-rank test found that vertical hemispherotomy was associated with durable seizure-free progression compared to the lateral approach (p = .01). Patients undergoing the lateral hemispherotomy technique had a shorter time-to-seizure recurrence (hazard ratio = 2.56, 95% CI = 1.08-6.04, p = .03) and increased seizure recurrence odds (odds ratio = 3.67, 95% CI = 1.05-12.86, p = .04) compared to those undergoing the vertical hemispherotomy technique. SIGNIFICANCE/CONCLUSIONS:This pilot study demonstrated more durable seizure freedom of the vertical technique compared to lateral hemispherotomy techniques. Further studies, such as prospective expertise-based observational studies or a randomized clinical trial, are required to determine whether a vertical approach to hemispheric surgery provides superior long-term seizure outcomes.