Early experience with targeted therapy as a first-line adjuvant treatment for pediatric low-grade glioma.

OBJECTIVE: Pediatric low-grade gliomas (pLGGs) frequently exhibit dysregulation of the mitogen-activated protein kinase (MAPK) pathway. Targeted therapies, including mutant BRAF inhibitors (dabrafenib) and MEK inhibitors (trametinib), have shown promise in patients in whom conventional chemotherapy has failed. However, few studies have investigated the use of targeted therapy as a first-line treatment for pLGG. Here, the authors reviewed their institutional experience with using a personalized medicine approach to patients with newly diagnosed pLGGs. METHODS: All pediatric patients at the authors' institution who had been treated with dabrafenib or trametinib for pLGG without first receiving conventional chemotherapy or radiation were retrospectively reviewed. Demographic, clinical, and radiological data were collected. RESULTS: Eight patients underwent targeted therapy as a first-line treatment for pLGG. Five patients had a BRAF alteration (1 with a BRAFV600E mutation, 4 with a KIAA1549:BRAF fusion), and 3 patients had an NF1 mutation. One of the 8 patients was initially treated with dabrafenib, and trametinib was added later. Seven patients were initially treated with trametinib; of these, 2 later transitioned to dual therapy, whereas 5 continued with trametinib monotherapy. Six patients (75%) demonstrated a partial response to therapy during their treatment course, whereas stable disease was identified in the remaining 2 patients (25%). One patient experienced mild disease progression after completing a course of trametinib monotherapy, but ultimately stabilized after a period of close observation. Another patient experienced tumor progression while on dabrafenib, but subsequently responded to dual therapy with dabrafenib and trametinib. The most common adverse reactions to targeted therapy were cutaneous toxicity (100%) and diarrhea (50%). CONCLUSIONS: Targeted therapies have the potential to become a standard treatment option for pLGG due to their favorable toxicity profile and oral route of administration. This case series provides preliminary evidence that targeted therapies can induce an early disease response as a first-line adjuvant treatment; however, large-scale studies are required to assess long-term durability and safety.

Rate of craniometric change following suture release in patients with metopic and sagittal craniosynostosis.

OBJECTIVE: Craniosynostosis is a congenital disorder resulting from the premature fusion of cranial sutures in the infant skull. This condition results in significant cosmetic deformity and can impede neurodevelopment, if left untreated. Currently, rates of craniometric change following minimally invasive surgery have only been examined for sagittal craniosynostosis. A better understanding of postoperative skull adaptations in other craniosynostosis subtypes is needed to objectively categorize surgical outcomes and guide length of cranial orthosis therapy. METHODS: Eleven patients with sagittal and 8 with metopic craniosynostosis treated using endoscopic strip craniectomy and postoperative helmet orthoses were retrospectively reviewed. Using semiautomated image analysis of top-down orthogonal 2D photographs, the following craniometrics were recorded before surgery and at postoperative visits: cephalic index (CI), cranial vault asymmetry index (CVAI), anterior arc angle (AAA), posterior arc angle (PAA), anterior-middle width ratio (AMWR), anterior-posterior width ratio (APWR), left-right height ratio (LRHR), sagittal Hu moment (Sag-Hu), and brachycephaly Hu moment (Brachy-Hu). These craniometrics were then normalized to photograph-based measurements of normocephalic patients and the rates of change between metopic and sagittal craniosynostoses were compared. RESULTS: Patients with sagittal craniosynostosis exhibited significantly lower CI, lower PAA, higher AMWR, higher APWR, lower Sag-Hu, and higher Brachy-Hu preoperatively compared to patients with normocephalic craniosynostosis. Patients with metopic craniosynostosis exhibited lower AAA and AMWR preoperatively compared to normocephalic subjects. Sagittal and metopic patients had a rapid initial change in normalized CI or AAA, respectively. Craniometric rates of change that significantly differed between metopic and sagittal patients were found in AAA (p < 0.001), AMWR (p < 0.001), and APWR (p < 0.0001). Metopic patients had a prolonged AAA change with a significantly different rate of change up to 6 months postoperatively (median at 3 months = 0.027 normalized units/day, median at 6 months = 0.017 normalized units/day, and median at > 6 months = 0.007 normalized units/day), while sagittal CI rate of change at these time points was not significantly different. CONCLUSIONS: Patients with metopic craniosynostosis have a prolonged rate of change compared to patients with sagittal craniosynostosis and may benefit from longer helmet use and extended postoperative follow-up. Categorizing craniometric changes for other craniosynostosis subtypes will be important for evaluating current treatment guidelines.

Predictors of Telemedicine Utilization in a Pediatric Neurosurgical Population During the COVID-19 Pandemic.

OBJECTIVE: In the wake of the COVID-19 pandemic, telemedicine has become rapidly adopted by the neurosurgical community; however, few studies have examined predictors of telemedicine utilization. Here, we analyze patient variables associated with the acceptance of a telemedicine encounter by a pediatric neurosurgical population during the early phases of the COVID-19 pandemic. METHODS: All patients seen in a single institution's outpatient pediatric neurosurgery clinic between April 1, 2020 and July 31, 2020 were retrospectively reviewed. Demographic variables were collected for each patient's first completed encounter. Patients participating in telemedicine were compared with those seen in person. Univariate analysis was performed using the Wilcoxon rank sum test for continuous variables and Fischer exact test for categorical variables. A logistic regression multivariable analysis was then performed. RESULTS: We included 682 patients (374 telemedicine and 308 in person). Univariate analysis demonstrated that telemedicine visits were more likely to occur at earlier study dates (P < 0.001) and that patients participating in telemedicine visits were more likely to be established rather than new patients (P < 0.001), White or Caucasian (P < 0.001), not Hispanic or Latino (P < 0.001), English-speaking (P < 0.001), non-Medicare/Medicaid recipients (P < 0.001), have lower no-show rates (P = 0.006), and live farther from the hospital (P = 0.005). Multivariable analysis demonstrated older age (P = 0.031), earlier appointment date (P < 0.01), established patient status (P < 0.001), English-speaking (P < 0.02), and non-Medicare/Medicaid insurance (P < 0.05) were significant predictors of telemedicine utilization. CONCLUSIONS: Significant demographic differences exist among pediatric patients who participated in telemedicine versus those who requested an in-person visit at our institution. Addressing barriers to access will be crucial for promoting health equity in continued utilization of telemedicine.

Neurosurgical Operative Videos: An Analysis of an Increasingly Popular Educational Resource.

OBJECTIVE: Surgical education has increasingly relied on electronic learning. In particular, online operative videos have become a core resource within neurosurgery. We analyze the forums for neurosurgical operative videos. METHODS: Operative videos from 5 sources were reviewed: 1) the NEUROSURGERY Journal YouTube channel; 2) the American Association of Neurological Surgeons Neurosurgery YouTube channel; 3) The Neurosurgical Atlas Operative Video Cases; 4) Operative Neurosurgery; and 5) Neurosurgical Focus: Video. Title, year of publication, senior author, institution, country, and subspecialty were documented for each video. RESULTS: A total of 1233 videos showing 1247 surgeries were identified. Ten videos included >1 surgery; of those, there was a median of 2 surgeries (interquartile range, 2.0-2.5) per video. The most frequently represented subspecialties included vascular (48.3%), tumor (35.2%), and skull base surgery (27.5%), with almost 40% of videos showing >1 category. Videos were submitted by investigators from 28 countries, but 82.1% of the videos originated in the United States. CONCLUSIONS: Neurosurgical operative videos have become increasingly common through a variety of online platforms. Future efforts may benefit from collecting videos from underrepresented regions and subspecialties, providing long-term follow-up data and showing techniques for managing complications.

Effect of Loading Method on a Peptide Substrate Reporter in Intact Cells.

Studies of live cells often require loading of exogenous molecules through the cell membrane; however, effects of loading method on experimental results are poorly understood. Therefore, in this work, we compared three methods for loading a fluorescently labeled peptide into cells of the model organism Dictyostelium discoideum. We optimized loading by pinocytosis, electroporation, and myristoylation to maximize cell viability and characterized loading efficiency, localization, and uniformity. We also determined how the loading method affected measurements of enzyme activity on the peptide substrate reporter using capillary electrophoresis. Loading method had a strong effect on the stability and phosphorylation of the peptide. The half-life of the intact peptide in cells was 19 ± 2, 53 ± 15, and 12 ± 1 min, for pinocytosis, electroporation, and myristoylation, respectively. The peptide was phosphorylated only in cells loaded by electroporation. Fluorescence microscopy suggested that the differences between methods were likely due to differences in peptide localization.

TQuest, A Web-Based Platform to Enable Precision Medicine by Linking a Tumor's Genetic Defects to Therapeutic Options.

PURPOSE: Currently, there are only a few software tools designed to assist physicians to translate molecular abnormalities in the cancer genome into potential treatment options. There is a pressing need to develop software to reliably identify known targeted therapies and experimental treatments for patients on the basis of the results of tumor DNA sequencing. METHODS: The TQuest platform includes a data layer, data acquisition layer, search engine, and user interface. It identifies associations between one or more molecular targets and therapeutic options. The data layer consists of indexed interventional clinical trials and an expert-curated database of clinically or experimentally validated associations between mutations and drug response. The data acquisition layer includes an information-harvesting module that keeps an up-to-date full-text index of clinical trials by crawling clinicaltrials.gov and combining it with US Food and Drug Administration label data. The user interface is a Web-based module that allows users to upload genomic variants, tumor morphology, and diagnosis. The search results are qualified and ranked by a relevance score. RESULTS: We have manually curated information for 368 distinct genomic variants of 162 gene targets corresponding to 863 drug and target interactions. The platform currently contains a full-text index of approximately 80,000 interventional clinical trials. We applied TQuest to molecular data from 73 metastatic breast cancers. TQuest identified a total of 276 drugs as potential therapeutic options, ranging from one to 103 per patient. CONCLUSION: TQuest correctly identified all US Food and Drug Administration-approved drugs and routine indications for all cases and also identified many additional drugs that were used in the context of a given molecular abnormality in various clinical trials. The prototype Web application is available at www.tquest.us , and the source code is open and available on GitHub.

Synthetic Strategies Employed for the Construction of Fostriecin and Related Natural Products.

Fostriecin and related natural products present a significant challenge for synthetic chemists due to their structural complexity and chemical sensitivity. This review will chronicle the successful efforts of synthetic chemists in the construction of these biologically active molecules. Key carbon-carbon bond forming reactions will be highlighted, as well as the methods used to install the numerous stereocenters present in this class of compounds.

Mutation based treatment recommendations from next generation sequencing data: a comparison of web tools.

Interpretation of complex cancer genome data, generated by tumor target profiling platforms, is key for the success of personalized cancer therapy. How to draw therapeutic conclusions from tumor profiling results is not standardized and may vary among commercial and academically-affiliated recommendation tools. We performed targeted sequencing of 315 genes from 75 metastatic breast cancer biopsies using the FoundationOne assay. Results were run through 4 different web tools including the Drug-Gene Interaction Database (DGidb), My Cancer Genome (MCG), Personalized Cancer Therapy (PCT), and cBioPortal, for drug and clinical trial recommendations. These recommendations were compared amongst each other and to those provided by FoundationOne. The identification of a gene as targetable varied across the different recommendation sources. Only 33% of cases had 4 or more sources recommend the same drug for at least one of the usually several altered genes found in tumor biopsies. These results indicate further development and standardization of broadly applicable software tools that assist in our therapeutic interpretation of genomic data is needed. Existing algorithms for data acquisition, integration and interpretation will likely need to incorporate artificial intelligence tools to improve both content and real-time status.