Add-On Deep Brain Stimulation versus Continued Vagus Nerve Stimulation for Childhood Epilepsy (ADVANCE): A Partially Randomized Patient Preference Trial.

Outcomes following vagus nerve stimulation (VNS) improve over years after implantation in children with drug-resistant epilepsy. The added value of deep brain stimulation (DBS) instead of continued VNS optimization is unknown. In a prospective, non-blinded, randomized patient preference trial of 18 children (aged 8-17 years) who did not respond to VNS after at least 1 year, add-on DBS resulted in greater seizure reduction compared with an additional year of VNS optimization (51.9% vs. 12.3%, p = 0.047). Add-on DBS also resulted in less bothersome seizures (p = 0.03), but no change in quality of life. DBS may be considered earlier for childhood epilepsy after non-response to VNS. ANN NEUROL 2024;96:405-411.

Lipidomic-Based Approach to 10 s Classification of Major Pediatric Brain Cancer Types with Picosecond Infrared Laser Mass Spectrometry.

Picosecond infrared laser mass spectrometry (PIRL-MS) is shown, through a retrospective patient tissue study, to differentiate medulloblastoma cancers from pilocytic astrocytoma and two molecular subtypes of ependymoma (PF-EPN-A, ST-EPN-RELA) using laser-extracted lipids profiled with PIRL-MS in 10 s of sampling and analysis time. The average sensitivity and specificity values for this classification, taking genomic profiling data as standard, were 96.41 and 99.54%, and this classification used many molecular features resolvable in 10 s PIRL-MS spectra. Data analysis and liquid chromatography coupled with tandem high-resolution mass spectrometry (LC-MS/MS) further allowed us to reduce the molecular feature list to only 18 metabolic lipid markers most strongly involved in this classification. The identified 'metabolite array' was comprised of a variety of phosphatidic and fatty acids, ceramides, and phosphatidylcholine/ethanolamine and could mediate the above-mentioned classification with average sensitivity and specificity values of 94.39 and 98.78%, respectively, at a 95% confidence in prediction probability threshold. Therefore, a rapid and accurate pathology classification of select pediatric brain cancer types from 10 s PIRL-MS analysis using known metabolic biomarkers can now be available to the neurosurgeon. Based on retrospective mining of 'survival' versus 'extent-of-resection' data, we further identified pediatric cancer types that may benefit from actionable 10 s PIRL-MS pathology feedback. In such cases, aggressiveness of the surgical resection can be optimized in a manner that is expected to benefit the patient's overall or progression-free survival. PIRL-MS is a promising tool to drive such personalized decision-making in the operating theater.

Treatment of Orthotopic U251 Human Glioblastoma Multiforme Tumors in NRG Mice by Convection-Enhanced Delivery of Gold Nanoparticles Labeled with the ß-Particle-Emitting Radionuclide, 177Lu.

In this study, we investigated convection-enhanced delivery (CED) of 23 ± 3 nm gold nanoparticles (AuNPs) labeled with the ß-particle-emitting radionuclide 177Lu (177Lu-AuNPs) for treatment of orthotopic U251-Luc human glioblastoma multiforme (GBM) tumors in NRG mice. The cytotoxicity in vitro of 177Lu-AuNPs (0.0-2.0 MBq, 4 × 1011 AuNPs) on U251-Luc cells was also studied by a clonogenic survival assay, and DNA double-strand breaks (DSBs) caused by ß-particle emissions of 177Lu were measured by confocal immunofluorescence microscopy for γH2AX. NRG mice with U251-Luc tumors in the right cerebral hemisphere of the brain were treated by CED of 1.1 ± 0.2 MBq of 177Lu-AuNPs (4 × 1011 AuNPs). Control mice received unlabeled AuNPs or normal saline. Tumor retention of 177Lu-AuNPs was assessed by single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Radiation doses were estimated for the tumor, brain, and other organs. The effectiveness for treating GBM tumors was determined by bioluminescence imaging (BLI) and T2-weighted magnetic resonance imaging (MRI) and by Kaplan-Meier median survival. Normal tissue toxicity was assessed by monitoring body weight and hematology and blood biochemistry analyses at 14 d post-treatment. 177Lu-AuNPs (2.0 MBq, 4 × 1011 AuNPs) decreased the clonogenic survival of U251-Luc cells to 0.005 ± 0.002 and increased DNA DSBs by 14.3-fold compared to cells treated with unlabeled AuNPs or normal saline. A high proportion of 177Lu-AuNPs was retained in the U251-Luc tumor in NRG mice up to 21 d with minimal re-distribution to the brain or other organs. The radiation dose in the tumor was high (599 Gy). The dose in the normal right cerebral hemisphere of the brain excluding the tumor was 93-fold lower (6.4 Gy), and 2000-3000-fold lower doses were calculated for the contralateral left cerebral hemisphere (0.3 Gy) or cerebellum (0.2 Gy). The doses in peripheral organs were <0.1 Gy. BLI revealed almost complete tumor growth arrest in mice treated with 177Lu-AuNPs, while tumors grew rapidly in control mice. MRI at 28 d post-treatment and histological staining showed no visible tumor in mice treated with 177Lu-AuNPs but large GBM tumors in control mice. All control mice reached a humane endpoint requiring sacrifice within 39 d (normal saline) or 45 d post-treatment (unlabeled AuNPs), while 5/8 mice treated with 177Lu-AuNPs survived up to 150 d. No normal tissue toxicity was observed in mice treated with 177Lu-AuNPs. We conclude that CED of 177Lu-AuNPs was highly effective for treating U251-Luc human GBM tumors in the brain in NRG mice at amounts that were non-toxic to normal tissues. These 177Lu-AuNPs administered by CED hold promise for treating patients with GBM to prevent recurrence and improve long-term outcome.

Outcomes following management of relapsed pediatric posterior fossa ependymoma in the molecular era.

PURPOSE: The overall survival and prognostic factors for children with multiply recurrent posterior fossa ependymoma are not well understood. We aimed to assess prognostic factors associated with survival for relapsed pediatric posterior fossa ependymoma. METHODS: An institutional database was queried for children with a primary diagnosis of posterior fossa ependymoma from 2000 to 2019. Kaplan-Meier survival analysis and Cox-proportional hazard regression were used to assess the relationship between treatment factors and overall survival. RESULTS: There were 60 patients identified; molecular subtype was available for 56, of which 49 (87.5%) were PF-A and 7 (12.5%) were PF-B. Relapse occurred in 29 patients (48%) at a mean time of 24 months following primary resection. Median 50% survival was 12.3 years for all patients and 3.3 years following diagnosis of first relapsed disease. GTR was associated with significantly improved survival following primary resection (HR 0.373, 95% CI 0.14-0.96). Presence of recurrent disease was significantly associated with worse survival (p < 0.0001). At recurrent disease diagnosis, disseminated disease was a negative prognostic factor (HR 11.0 95% CI 2.7-44) while GTR at first relapse was associated with improved survival HR 0.215 (95% CI: 0.048-0.96, p = 0.044). Beyond first relapse, the impact of GTR was not significant on survival, though surgery compared to no surgery was favorable with HR 0.155 (95% CI: 0.04-0.59). CONCLUSIONS: Disseminated disease at recurrence and extent of resection for first relapsed disease were important prognostic factors. Surgery compared to no surgery was associated with improved survival for the multiply recurrent ependymoma cohort.

Vagus Nerve Stimulation Modulates Phase-Amplitude Coupling in Thalamic Local Field Potentials.

OBJECTIVE: The antiseizure effects of vagus nerve stimulation (VNS) are thought to be mediated by the modulation of afferent thalamocortical circuitry. Cross-frequency phase-amplitude coupling (PAC) is a mechanism of hierarchical network coordination across multiple spatiotemporal scales. In this study, we leverage local field potential (LFP) recordings from the centromedian (CM) (n = 3) and anterior (ATN) (n = 2) nuclei in five patients with tandem thalamic deep brain stimulation and VNS to study neurophysiological changes in the thalamus in response to VNS. MATERIALS AND METHODS: Bipolar LFP data were recorded from contact pairs spanning target nuclei in VNS "on" and "off" states. RESULTS: Active VNS was associated with increased PAC between theta, alpha, and beta phase and gamma amplitude in CM (q < 0.05). Within the ATN, PAC changes also were observed, although these were less robust. In both nuclei, active VNS also modulated interhemispheric bithalamic functional connectivity. CONCLUSIONS: We report that VNS is associated with enhanced PAC and coordinated interhemispheric interactions within and between thalamic nuclei, respectively. These findings advance understanding of putative neurophysiological effects of acute VNS and contextualize previous animal and human studies showing distributed cortical synchronization after VNS.

Inhibition of TRPM7 with carvacrol suppresses glioblastoma functions in vivo.

Glioblastoma (GBM) is the most prevalent and aggressive type of primary human brain tumours originating in the central nervous system. Despite the fact that current treatments involve surgery, chemotherapy (Temozolomide), and radiation therapy, the prognosis for patients diagnosed with GBM remains extremely poor. The standard treatment is not only unable to completely eradicate the tumour cells, but also tumour recurrence after surgical resection presents a major challenge. Furthermore, adjuvant therapies including radiation and chemotherapy have high cytotoxicity which causes extensive damage to surrounding healthy tissues and treatment is usually halted before GBM is fully eradicated. Finally, most GBM cases demonstrate temozolomide resistance, a common reason for GBM treatment failure. Therefore, there is an urgent need to develop a suitable alternative therapy that targets GBM specifically and has low cytotoxicity for healthy cells. We previously reported that transient receptor potential melastatin 7 (TRPM7) channels are aberrantly upregulated in GBM, and inhibition of TRPM7 reduced GBM cellular functions including proliferation, migration, and invasion. This suggests TRPM7 is a potential therapeutic target for GBM treatment. In this study, we investigated the effects of the TRPM7 inhibitor, carvacrol, on human GBM cell lines U87 and U251 in vivo. With the use of a flank xenograft GBM mouse model, we demonstrated that carvacrol significantly reduced the tumour size in both mice injected with U87 and U251 cells, decreased p-Akt protein level and increased p-GSK3ß protein levels. Therefore, these results suggest that carvacrol may have therapeutic potential for GBM treatment.

Preservation of endocrine function after Ommaya reservoir insertion in children with cystic craniopharyngioma.

INTRODUCTION: Children with craniopharyngiomas (CP) can experience significant morbidities caused by extensive surgery and/or radiation. Ommaya reservoir insertion (ORI) into cystic CP represents a minimally invasive approach allowing immediate decompression and aims to avoid additional injuries. The purpose of this study was to determine the surgical outcome and relevance of upfront ORI (± intracystic treatment) for preservation of endocrine function. METHODS: We performed a retrospective chart review of children with CP treated at the Hospital for Sick Children between 01/01/2000 and 15/01/2020. Endocrine function was reviewed at the time of initial surgery and throughout follow-up. New endocrinological deficits related to the index procedure were defined as immediate failure (IF), whereas postoperative duration of endocrinological stability (ES) was analyzed using the Kaplan-Meier method. The rate of IF and ES was compared between the treatment groups. RESULTS: Seventy-nine patients were included and had a median age of 8.3 years (range 2.1-18.0 years); 31 were males. Fifty-three patients with upfront surgical treatment, including 29 ORI and 24 gross total or partial resections had sufficient endocrinological follow-up data. Endocrine dysfunction occurring immediately after the index procedure (IF) was observed in 15 patients (62.5%) in the resection group compared to two patients (6.8%) in the ORI group, odds ratio: 0.05 (CI: 0.01-0.26, p < 0.0001). Excluding those with immediate endocrinological deficits, mean ES after ORI was 19.4 months (CI: 11.6-34.2), compared to 13.4 months (CI:10.6-NA) after surgical resection. CONCLUSIONS: Endocrine function was preserved in patients with upfront ORI (± intracystic treatment), which was confirmed as a minimally invasive procedure with an overall low morbidity profile.

Evolution of microneurosurgical anatomy with special reference to the history of anatomy, surgical anatomy, and microsurgery: historical overview.

This article reviews the evolution of microneurosurgical anatomy (MNA) with special reference to the development of anatomy, surgical anatomy, and microsurgery. Anatomy can be said to have started in the ancient Greek era with the work of Hippocrates, Galen, and others as part of the pursuit of natural science. In the sixteenth century, Vesalius made a great contribution in reviving Galenian knowledge while adding new knowledge of human anatomy. Also in the sixteenth century, Ambroise Paré can be said to have started modern surgery. As surgery developed, more detailed anatomical knowledge became necessary for treating complicated diseases. Many noted surgeons at the time were also anatomists eager to spread anatomical knowledge in order to enhance surgical practice. Thus, surgery and anatomy developed together, with advances in each benefiting the other. The concept of surgical anatomy evolved in the eighteenth century and became especially popular in the nineteenth century. In the twentieth century, microsurgery was introduced in various surgical fields, starting with Carl O. Nylen in otology. It flourished and became popularized in the second half of the century, especially in the field of neurosurgery, following Jacobson and Suarez's success in microvascular anastomosis in animals and subsequent clinical application as developed by M.G. Yasargil and others. Knowledge of surgical anatomy as seen under the operating microscope became important for surgeons to perform microneurosurgical procedures accurately and safely, which led to the fuller development of MNA as conducted by many neurosurgeons, among whom A.L. Rhoton, Jr. might be mentioned as representative.

History of the Department of Surgery at the University of Toronto: celebrating a centennial of progress and innovation.

Now in its centennial year since inauguration, the Department of Surgery at the University of Toronto lays claim to more than 500 faculty, 270 residents, and 250 clinical fellows. There are 7 direct entry residency training programs, and 4 subspecialty programs accredited by the Royal College of Physicians and Surgeons of Canada. There have been 10 chairs of the department since 1921. This article chronicles the life and times of the previous chairs in sequence; the success of the department originates from its many talented and luminary surgeons who have innovated and shaped their fields of surgery. In recent years, the department's academic productivity has been characterized by more than 1400 peer-reviewed publications per year, and annual research grant capture in excess of $90 million. Since the time of William Gallie, surgical trainees have been enabled to develop careers in surgery and science through the Gallie Program and, more recently, the Surgeon Scientist Training Program (SSTP) to attain higher graduate degrees. Providing quaternary surgical care at multiple hospital sites in Toronto, the Department of Surgery takes great pride in its robust clinical fellowship programs across all specialties that continue to attract trainees from around the world.

Mass Spectrometry Imaging Reveals a Gradient of Cancer-like Metabolic States in the Vicinity of Cancer Not Seen in Morphometric Margins from Microscopy.

Spatially resolved ambient mass spectrometry imaging methods have gained popularity to characterize cancer sites and their borders using molecular changes in the lipidome. This utility, however, is predicated on metabolic homogeneity at the border, which would create a sharp molecular transition at the morphometric borders. We subjected murine models of human medulloblastoma brain cancer to mass spectrometry imaging, a technique that provides a direct readout of tissue molecular content in a spatially resolved manner. We discovered a distance-dependent gradient of cancer-like lipid molecule profiles in the brain tissue within 1.2 mm of the cancer border, suggesting that a cancer-like state progresses beyond the histologic border, into the healthy tissue. The results were further corroborated using orthogonal liquid chromatography and mass spectrometry (LC-MS) analysis of selected tissue regions subjected to laser capture microdissection. LC-MS/MS analysis for robust identification of the affected molecules implied changes in a number of different lipid classes, some of which are metabolized from the essential docosahexaenoic fatty acid (DHA) present in the interstitial fluid. Metabolic molecular borders are thus not as sharp as morphometric borders, and mass spectrometry imaging can reveal molecular nuances not observed with microscopy. Caution must be exercised in interpreting multimodal imaging results stipulated on a coincidental relationship between metabolic and morphometric borders of cancer, at least within animal models used in preclinical research.

Epilepsy surgery in infants up to 3 months of age: Safety, feasibility, and outcomes: A multicenter, multinational study.

OBJECTIVE: Drug-resistant epilepsy (DRE) during the first few months of life is challenging and necessitates aggressive treatment, including surgery. Because the most common causes of DRE in infancy are related to extensive developmental anomalies, surgery often entails extensive tissue resections or disconnection. The literature on "ultra-early" epilepsy surgery is sparse, with limited data concerning efficacy controlling the seizures, and safety. The current study's goal is to review the safety and efficacy of ultra-early epilepsy surgery performed before the age of 3 months. METHODS: To achieve a large sample size and external validity, a multinational, multicenter retrospective study was performed, focusing on epilepsy surgery for infants younger than 3 months of age. Collected data included epilepsy characteristics, surgical details, epilepsy outcome, and complications. RESULTS: Sixty-four patients underwent 69 surgeries before the age of 3 months. The most common pathologies were cortical dysplasia (28), hemimegalencephaly (17), and tubers (5). The most common procedures were hemispheric surgeries (48 procedures). Two cases were intentionally staged, and one was unexpectedly aborted. Nearly all patients received blood products. There were no perioperative deaths and no major unexpected permanent morbidities. Twenty-five percent of patients undergoing hemispheric surgeries developed hydrocephalus. Excellent epilepsy outcome (International League Against Epilepsy [ILAE] grade I) was achieved in 66% of cases over a median follow-up of 41 months (19-104 interquartile range [IQR]). The number of antiseizure medications was significantly reduced (median 2 drugs, 1-3 IQR, p < .0001). Outcome was not significantly associated with the type of surgery (hemispheric or more limited resections). SIGNIFICANCE: Epilepsy surgery during the first few months of life is associated with excellent seizure control, and when performed by highly experienced teams, is not associated with more permanent morbidity than surgery in older infants. Thus surgical treatment should not be postponed to treat DRE in very young infants based on their age.

Cross-sectional analysis of women in neurosurgery: a Canadian perspective.

OBJECTIVE: Although the past decades have seen a steady increase of women in medicine in general, women continue to represent a minority of the physician-training staff and workforce in neurosurgery in Canada and worldwide. As such, the aim of this study was to analyze the experiences of women faculty practicing neurosurgery across Canada to better understand and address the factors contributing to this disparity. METHODS: A historical, cross-sectional, and mixed-method analysis of survey responses was performed using survey results obtained from women attending neurosurgeons across Canada. A web-based survey platform was utilized to collect responses. Quantitative analyses were performed on the responses from the study questionnaire, including summary and comparative statistics. Qualitative analyses of free-text responses were performed using axial and open coding. RESULTS: A total of 19 of 31 respondents (61.3%) completed the survey. Positive enabling factors for career success included supportive colleagues and work environment (52.6%); academic accomplishments, including publications and advanced degrees (36.8%); and advanced fellowship training (47.4%). Perceived barriers reported included inequalities with regard to career advancement opportunities (57.8%), conflicting professional and personal interests (57.8%), and lack of mentorship (36.8%). Quantitative analyses demonstrated emerging themes of an increased need for women mentors as well as support and recognition of the contributions to career advancement of personal and family-related factors. CONCLUSIONS: This study represents, to the authors' knowledge, the first analysis of factors influencing career success and satisfaction in women neurosurgeons across Canada. This study highlights several key factors contributing to the low representation of women in neurosurgery and identifies specific actionable items that can be addressed by training programs and institutions. In particular, female mentorship, opportunities for career advancement, and increased recognition and integration of personal and professional roles were highlighted as areas for future intervention. These findings will provide a framework for addressing these factors and improving the recruitment and retention of females in this specialty.

Connectomic Profiling Identifies Responders to Vagus Nerve Stimulation.

OBJECTIVE: Vagus nerve stimulation (VNS) is a common treatment for medically intractable epilepsy, but response rates are highly variable, with no preoperative means of identifying good candidates. This study aimed to predict VNS response using structural and functional connectomic profiling. METHODS: Fifty-six children, comprising discovery (n = 38) and validation (n = 18) cohorts, were recruited from 3 separate institutions. Diffusion tensor imaging was used to identify group differences in white matter microstructure, which in turn informed beamforming of resting-state magnetoencephalography recordings. The results were used to generate a support vector machine learning classifier, which was independently validated. This algorithm was compared to a second classifier generated using 31 clinical covariates. RESULTS: Treatment responders demonstrated greater fractional anisotropy in left thalamocortical, limbic, and association fibers, as well as greater connectivity in a functional network encompassing left thalamic, insular, and temporal nodes (p < 0.05). The resulting classifier demonstrated 89.5% accuracy and area under the receiver operating characteristic (ROC) curve of 0.93 on 10-fold cross-validation. In the external validation cohort, this model demonstrated an accuracy of 83.3%, with a sensitivity of 85.7% and specificity of 75.0%. This was significantly superior to predictions using clinical covariates alone, which exhibited an area under the ROC curve of 0.57 (p < 0.008). INTERPRETATION: This study provides the first multi-institutional, multimodal connectomic prediction algorithm for VNS, and provides new insights into its mechanism of action. Reliable identification of VNS responders is critical to mitigate surgical risks for children who may not benefit, and to ensure cost-effective allocation of health care resources. ANN NEUROL 2019;86:743-753.

Navigating the Postgraduate Research Fellowship: A Roadmap for Surgical Residents.

BACKGROUND: To preserve the future of surgical innovation, opportunities for surgical residents to receive structured research training are paramount. The objective of this article is to help surgical residents navigate a research fellowship by overviewing key topics such as choosing an area of focus and supervisor, applying for external funding, transitioning away from clinical duties, managing intellectual property, integrating family planning, and incorporating research experience into independent career development. MATERIALS AND METHODS: Using the framework of the University of Toronto's graduate degree-awarding Surgeon-Scientist Training Program, the authors outline key considerations, decisions, and pearls for surgical residents considering or currently enrolled in a full-time research fellowship training program. RESULTS: Full-time research fellowships offer a unique opportunity for residents interested in an academic career. Such full-time research fellowships away from clinical duties allow surgical trainees to focus on developing key research competencies, including how to generate hypotheses, apply research methodology, gain experience presenting and publishing manuscripts, and ultimately apply these skills as independent investigators to improve patient and population health. Research fellowships may also be an opportunity to develop intellectual property or facilitate family planning. Practical tips are provided for the transition back into clinical training and how to effectively market one's research skills for career advancement. CONCLUSIONS: The authors outline key considerations, decisions, and pearls for surgical residents considering or currently enrolled in a full-time research fellowship training program. By adhering to the principles highlighted in this article, residents will be able to successfully navigate a full-time research fellowship to optimize their intellectual development, maximize their academic productivity, and facilitate their transition into an independent investigator.

Online Impact and Presence of a Specialized Social Media Team for the Journal of Neurosurgery: Descriptive Analysis.

BACKGROUND: Social media use continues to gain momentum in academic neurosurgery. To increase journal impact and broaden engagement, many scholarly publications have turned to social media to disseminate research. The Journal of Neurosurgery Publishing Group (JNSPG) established a dedicated, specialized social media team (SMT) in November 2016 to provide targeted improvement in digital outreach. OBJECTIVE: The goal of this study was to examine the impact of the JNSPG SMT as measured by increased engagement. METHODS: We analyzed various metrics, including impressions, engagements, retweets, likes, profile clicks, and URL clicks, from consecutive social media posts from the JNSPG's Twitter and Facebook platforms between February 1, 2015 and February 28, 2019. Standard descriptive statistics were utilized. RESULTS: Between February 2015 and October 2016, when a specialized SMT was created, 170 tweets (8.1 tweets/month) were posted compared to 3220 tweets (115.0 tweets/month) between November 2016 and February 2019. All metrics significantly increased, including the impressions per tweet (mean 1646.3, SD 934.9 vs mean 4605.6, SD 65,546.5; P=.01), engagements per tweet (mean 35.2, SD 40.6 vs mean 198.2, SD 1037.2; P<.001), retweets (mean 2.5, SD 2.8 vs mean 10.5, SD 15.3; P<.001), likes (mean 2.5, SD 4.0 vs mean 18.0, SD 37.9; P<.001), profile clicks (mean 1.5, SD 2.0 vs mean 5.2, SD 43.3; P<.001), and URL clicks (mean 13.1, SD 14.9 vs mean 38.3, SD 67.9; P<.001). Tweets that were posted on the weekend compared to weekdays had significantly more retweets (mean 9.2, SD 9.8 vs mean 13.4, SD 25.6; P<.001), likes (mean 15.3, SD 17.9 vs mean 23.7, SD 70.4; P=.001), and URL clicks (mean 33.4, SD 40.5 vs mean 49.5, SD 117.3; P<.001). Between November 2015 and October 2016, 49 Facebook posts (2.3 posts/month) were sent compared to 2282 posts (81.5 posts/month) sent between November 2016 and February 2019. All Facebook metrics significantly increased, including impressions (mean 5475.9, SD 5483.0 vs mean 8506.1, SD 13,113.9; P<.001), engagements (mean 119.3, SD 194.8 vs mean 283.8, SD 733.8; P<.001), and reach (mean 2266.6, SD 2388.3 vs mean 5344.1, SD 8399.2; P<.001). Weekend Facebook posts had significantly more impressions per post (mean 7967.9, SD 9901.0 vs mean 9737.8, SD 19,013.4; P=.03) and a higher total reach (mean 4975.8, SD 6309.8 vs mean 6108.2, SD 12,219.7; P=.03) than weekday posts. CONCLUSIONS: Social media has been established as a crucial tool for the propagation of neurosurgical research and education. Implementation of the JNSPG specialized SMT had a demonstrable impact on increasing the online visibility of social media content.

Characterization of a Clival Chordoma Xenograft Model Reveals Tumor Genomic Instability.

Patient-derived xenografts retain the genotype of the parent tumors more readily than tumor cells maintained in culture. The two previously reported clival chordoma xenografts were derived from recurrent tumors after radiation. To study the genetics of clival chordoma in the absence of prior radiation exposure we established a patient-derived xenograft at primary resection of a clival chordoma. Epicranial grafting of clival chordoma collected during surgery was performed. Tumor growth was established in a nonobese diabetic/severe combined immunodeficiency mouse and tumors have been passaged serially for seven generations. Physaliferous cell architecture was shown in the regenerated tumors, which stained positive for Brachyury, cytokeratin, and S100 protein. The tumors showed bone invasion. Single-nucleotide polymorphism analysis of the tumor xenograft was compared with the parental tumor. Copy number gain of the T gene (brachyury) and heterozygous loss of cyclin dependent kinase inhibitor 2A (CDKN2A) was observed. Heterozygous loss of the tumor-suppressor fragile histidine triad (FHIT) gene also was observed, although protein expression was preserved. Accumulation of copy number losses and gains as well as increased growth rate was observed over three generations. The patient-derived xenograft reproduces the phenotype of clival chordoma. This model can be used in the future to study chordoma biology and to assess novel treatments.

Branches From the "SEAD": Sustained and Feasible Expansion of the Surgical Exploration and Discovery Program.

PROBLEM: A predicted shortage of surgeons and attrition among surgical residents has highlighted the need to attract well-suited medical students to surgical specialties. Literature suggests that early exposure may increase interest by addressing misconceptions and allowing students more time to make an informed career decision. APPROACH: The Surgical Exploration and Discovery (SEAD) program was created in 2012 with the goal of providing medical students with comprehensive and multifaceted exposure to surgical specialties to develop their knowledge and skills, and in turn positively influence their interest in pursuing a surgical career. The purpose of this innovation report is to describe the challenges, successes, and evolution of the SEAD program. OUTCOMES: Since its inception, SEAD has expanded to include 5 North American institutions and has educated nearly 400 participants in 5 y. Through a replication strategy, SEAD has maintained its basic curriculum, while accommodating the constraints and innovative approaches unique to each institution. Short-term results have demonstrated improved knowledge of curricular objectives, student perception of significant value of the program, and the generation of interest in a career in surgery. CONCLUSIONS: Future directions include the evaluation of long-term impact on pursuing a career in surgery and continuing further expansion using the current replication model, while maintaining a high-quality surgical education program.

Swelling-induced chloride current in glioblastoma proliferation, migration, and invasion.

Glioblastoma (GBM) remains as the most common and aggressive brain tumor. The survival of GBM has been linked to the aberrant activation of swelling-induced chloride current ICl,swell . In this study, we investigated the effects of ICl,swell on cell viability, proliferation, and migration in the human GBM cell lines, U251 and U87, using a combination of patch clamp electrophysiology, MTT, colony formation, wound healing assays and Western immunoblotting. First, we showed that the specific inhibitor of ICl,swell , DCPIB, potently reduced the ICl,swell in U87 cells. Next, in both U87 and U251 cells, we found that DCPIB reduced GBM viability, proliferation, colony formation, migration, and invasion. In addition, our Western immunoblot assay showed that DCPIB-treated U251 cells had a reduction in JAK2, STAT3, and Akt phosphorylation, thus, suggesting that DCPIB potentially suppresses GBM functions through inhibition of the JAK2/STAT3 and PI3K/Akt signaling pathways. Therefore, the ICl,swell may be a potential drug target for GBM.

Strong coupling between slow oscillations and wide fast ripples in children with epileptic spasms: Investigation of modulation index and occurrence rate.

OBJECTIVE: Epileptic spasms (ES) often become drug-resistant. To reveal the electrophysiological difference between children with ES (ES+) and without ES (ES-), we compared the occurrence rate (OR) of high-frequency oscillations (HFOs) and the modulation index (MI) of coupling between slow and fast oscillations. In ES+, we hypothesized that (1) pathological HFOs are more widely distributed and (2) slow oscillations show stronger coupling with pathological HFOs than in ES-. METHODS: We retrospectively reviewed 24 children with drug-resistant multilobar onset epilepsy, who underwent intracranial video electroencephalography prior to multilobar resections. We measured the OR of HFOs and determined the electrodes with a high rate of HFOs by cluster analysis. We calculated MI, which reflects the degree of coupling between HFO (ripple/fast ripple [FR]) amplitude and 5 different frequency bands of delta and theta activities (0.5-1 Hz, 1-2 Hz, 2-3 Hz, 3-4 Hz, 4-8 Hz). RESULTS: In ES+ (n = 10), the OR(FRs) , the number of electrodes with high-rate FRs, and the MI(FRs & 3-4 Hz) in all electrodes were significantly higher than in ES- (n = 14). In both the ES+ and ES- groups, MI(ripples/FRs & 3-4 Hz) was the highest among the 5 frequency bands. Within the good seizure outcome group, the OR(FRs) and the MI(FRs & 3-4 Hz) in the resected area in ES+ were significantly higher than in ES- (OR[FRs] , P = .04; MI[FRs & 3-4 Hz] , P = .04). SIGNIFICANCE: In ES+, the larger number of high-rate FR electrodes indicates more widespread epileptogenicity than in ES-. High values of OR(FRs) and MI(FRs & 3-4 Hz) in ES+ compared to ES- are a signature of the severity of epileptogenicity. We proved that ES+ children who achieved seizure freedom following multilobar resections exhibited strong coupling between slow oscillations and FRs.

The role of surgery in refractory epilepsy secondary to polymicrogyria in the pediatric population.

OBJECTIVE: Polymicrogyria (PMG) is a common malformation of cortical development. Many patients with PMG will have medically refractory epilepsy but the role of epilepsy surgery is unclear. The objective of this study was to assess the efficacy of surgical resection/disconnection in achieving seizure control in pediatric patients with PMG. METHODS: A retrospective review of children undergoing epilepsy surgery for PMG between 2002 and 2017 at The Hospital for Sick Children in Toronto, Canada, was performed. RESULTS: A total of 12 children aged 6 months to 17.8 years (median 8.8 years) underwent resective surgery (7 children) or functional hemispherectomy (5 children). Gross total resection or complete disconnection of PMG was carried out in 7 of 12 children. Follow-up duration was between 1 and 9 years (median 2.1 years). Nine children remained seizure-free at last follow-up. Complete resection or disconnection of PMG led to seizure freedom in 6 of 7 patients (86%), whereas subtotal resection produced seizure freedom in 3 of 5 patients (60%). SIGNIFICANCE: We present one of the largest surgical series of pediatric PMG patients. Seizure outcomes were best with complete resection/disconnection of PMG. However, tailored resections based on electroclinical and neuroradiologic data can produce good outcomes and remain an appropriate strategy for patients with extensive PMG.