Publications by authors named "James Rutka"

412 Publications

Childhood head trauma and the risk of childhood brain tumours: a case-control study in Ontario, Canada.

Int J Cancer 2021 Sep 14. Epub 2021 Sep 14.

Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health, Toronto, ON, Canada.

Head trauma in early childhood has been hypothesized as a potential risk factor for childhood brain tumours (CBTs). However, head trauma has not been extensively studied in the context of CBTs and existing studies have yielded conflicting results. A population- and hospital-based case-control study of children 0-15 years with newly diagnosed CBTs from 1997-2003 recruited across Ontario through pediatric oncology centres was conducted. Controls were frequency-matched with cases by age, sex and geographical region. The association was assessed based on multivariable logistic regressions, accounting for child's age, sex, ethnicity, highest level of maternal education, and maternal pack-years of smoking during the pregnancy. Analyses were conducted separately based on age of first head trauma, sex and histology. A latency period analysis was conducted. Overall, based on 280 cases and 919 controls, CBTs were not significantly associated with previous history of head trauma (OR 1.34, 95% CI 0.96, 1.86), head trauma severity, number of head injuries, nor head or neck X-rays or computed tomography (CT) examinations. Results were consistent across sexes and histological subtypes. However, head trauma within the first year of life was significantly associated with CBTs (OR 2.00, 95% CI 1.01, 3.98), but the association diminished when adjusted for X-ray or CT occurring during the same time period (OR 1.62, 95% CI 0.75, 3.49), albeit limited sample size. Overall, no association was observed between head trauma and CBTs among all children, while head trauma occurring within first year of life may warrant further investigation in future research. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33805DOI Listing
September 2021

Improving long-term outcomes in pediatric torcular dural sinus malformations with embolization and anticoagulation: a retrospective review of The Hospital for Sick Children experience.

J Neurosurg Pediatr 2021 Jul 30:1-7. Epub 2021 Jul 30.

1Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto.

Objective: Torcular dural sinus malformations (tDSMs) are rare pediatric cerebrovascular malformations characterized by giant venous lakes localized to the midline confluence of sinuses. Historical clinical outcomes of patients with these lesions were poor, though better prognoses have been reported in the more recent literature. Long-term outcomes in children with tDSMs are uncertain and require further characterization. The goal of this study was to review a cohort of tDSM patients with an emphasis on long-term outcomes and to describe the treatment strategy.

Methods: This study is a single-center retrospective review of a prospectively maintained data bank including patients referred to and cared for at The Hospital for Sick Children for tDSM from January 1996 to March 2019. Each patient's clinical, radiological, and demographic information, as well as their mother's demographic information, was collected for review.

Results: Ten patients with tDSM, with a mean follow-up of 58 months, were included in the study. Diagnoses were made antenatally in 8 patients, and among those cases, 4 families opted for either elective termination (n = 1) or no further care following delivery (n = 3). Of the 6 patients treated, 5 had a favorable long-term neurological outcome, and follow-up imaging demonstrated a decrease or stability in the size of the tDSM over time. Staged embolization was performed in 3 patients, and anticoagulation was utilized in 5 treated patients.

Conclusions: The authors add to a growing body of literature indicating that clinical outcomes in tDSM may not be as poor as initially perceived. Greater awareness of the lesion's natural history and pathophysiology, advancing endovascular techniques, and individualized anticoagulation regimens may lead to continued improvement in outcomes.
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http://dx.doi.org/10.3171/2021.3.PEDS20921DOI Listing
July 2021

Guidelines for optimal utilization of social media for brain tumor stakeholders.

J Neurosurg 2021 Jul 23:1-8. Epub 2021 Jul 23.

7Department of Neurosurgery, Penn State University, Hershey; and.

Objective: Effective use of social media (SM) by medical professionals is vital for better connections with patients and dissemination of evidence-based information. A study of SM utilization by different stakeholders in the brain tumor community may help determine guidelines for optimal use.

Methods: Facebook, Twitter, and YouTube were searched by using the term "Brain Tumor." Platform-specific metrics were determined, including audience size, as a measure of popularity, and mean annual increase in audience size, as a measure of performance on SM. Accounts were categorized on the basis of apparent ownership and content, with as many as two qualitative themes assigned to each account. Correlations of content themes and posting behavior with popularity and performance metrics were assessed by using the Pearson's test.

Results: Facebook (67 pages and 304,581 likes) was predominantly used by organizations (64% of pages). Top themes on Facebook, Twitter, and YouTube were charity and fundraising (67% of pages), education and research (72% of accounts), and experience sharing and support seeking (48% of videos, 60% of views, and 82% of user engagement), respectively. On Facebook, only the presence of other concurrent platforms influenced a page's performance (rho = 0.59) and popularity (rho = 0.61) (p < 0.05). On Twitter, the number of monthly tweets (rho = 0.66) and media utilization (rho = 0.78) were significantly correlated with increased popularity and performance (both p < 0.05). Personal YouTube videos (30% of videos and 61% of views) with the theme of experience sharing and support seeking had the highest level of engagement (60% of views, 70% of comments, and 87% of likes).

Conclusions: Popularity and prevalence of qualitative themes differ among SM platforms. Thus, optimal audience engagement on each platform can be achieved with thematic considerations. Such considerations, along with optimal SM behavior such as media utilization and multiplatform presence, may help increase content popularity and thus increase community access to neurooncology content provided by medical professionals.
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http://dx.doi.org/10.3171/2020.11.JNS203226DOI Listing
July 2021

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

Neurosurg Rev 2021 Jul 7. Epub 2021 Jul 7.

Department of Surgery, University of Toronto, Toronto, Canada.

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.
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http://dx.doi.org/10.1007/s10143-021-01597-zDOI Listing
July 2021

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

Epilepsia 2021 Aug 14;62(8):1897-1906. Epub 2021 Jun 14.

Department of Neurosurgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

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.
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http://dx.doi.org/10.1111/epi.16959DOI Listing
August 2021

tissue pathology from spatially encoded mass spectrometry classifiers visualized in real time through augmented reality.

Chem Sci 2020 Jul 23;11(33):8723-8735. Epub 2020 Jul 23.

Techna Institute for the Advancement of Technology for Health, University Health Network 100 College Street, Room 7-207, MaRS Building, Princess Margaret Cancer Research Tower, 7th floor (STTARR) Toronto ON M5G 1P5 Canada +1-416-581-8473.

Integration between a hand-held mass spectrometry desorption probe based on picosecond infrared laser technology (PIRL-MS) and an optical surgical tracking system demonstrates tissue pathology from point-sampled mass spectrometry data. Spatially encoded pathology classifications are displayed at the site of laser sampling as color-coded pixels in an augmented reality video feed of the surgical field of view. This is enabled by two-way communication between surgical navigation and mass spectrometry data analysis platforms through a custom-built interface. Performance of the system was evaluated using murine models of human cancers sampled in the presence of body fluids with a technical pixel error of 1.0 ± 0.2 mm, suggesting a 84% or 92% (excluding one outlier) cancer type classification rate across different molecular models that distinguish cell-lines of each class of breast, brain, head and neck murine models. Further, through end-point immunohistochemical staining for DNA damage, cell death and neuronal viability, spatially encoded PIRL-MS sampling is shown to produce classifiable mass spectral data from living murine brain tissue, with levels of neuronal damage that are comparable to those induced by a surgical scalpel. This highlights the potential of spatially encoded PIRL-MS analysis for use during neurosurgical applications of cancer type determination or point-sampling tissue during tumor bed examination to assess cancer removal. The interface developed herein for the analysis and the display of spatially encoded PIRL-MS data can be adapted to other hand-held mass spectrometry analysis probes currently available.
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http://dx.doi.org/10.1039/d0sc02241aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8163395PMC
July 2020

Noncoding RNAs in Glioblastoma: Emerging Biological Concepts and Potential Therapeutic Implications.

Cancers (Basel) 2021 Mar 28;13(7). Epub 2021 Mar 28.

Institute of Medical Science, Faculty of Medicine, University of Toronto, 1 King's College Circle, Medical Sciences Building, Toronto, ON M5S 1A8, Canada.

Noncoding RNAs (ncRNAs) have emerged as a novel class of genomic regulators, ushering in a new era in molecular biology. With the advent of advanced genetic sequencing technology, several different classes of ncRNAs have been uncovered, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs), circular RNAs (circRNAs), and piwi-interacting RNAs (piRNAs), which have been linked to many important developmental and disease processes and are being pursued as clinical and therapeutic targets. Molecular phenotyping studies of glioblastoma (GBM), the most common and lethal cancer of the adult brain, revealed that several ncRNAs are frequently dysregulated in its pathogenesis. Additionally, ncRNAs regulate many important aspects of glioma biology including tumour cell proliferation, migration, invasion, apoptosis, angiogenesis, and self-renewal. Here, we present an overview of the biogenesis of the different classes of ncRNAs, discuss their biological roles, as well as their relevance to gliomagenesis. We conclude by discussing potential approaches to therapeutically target the ncRNAs in clinic.
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http://dx.doi.org/10.3390/cancers13071555DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8037102PMC
March 2021

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

Neurosurg Focus 2021 03;50(3):E13

4Department of Surgery (Neurosurgery), Université Laval, Québec City, Québec, Canada.

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.
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http://dx.doi.org/10.3171/2020.12.FOCUS20959DOI Listing
March 2021

Developing a professionalism and harassment policy for organized neurosurgery.

J Neurosurg 2021 Mar 23;134(5):1355-1356. Epub 2021 Mar 23.

9Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.

Annual conferences, educational courses, and other meetings draw a diverse community of individuals, yet also create a unique environment without the traditional guard rails. Unlike events held at one's home institution, clear rules and jurisdiction have not been universally established. To promote the open exchange of ideas, as well as an environment conducive to professional growth of all participants, the leading neurosurgical professional organizations joined to delineate the expectations for anyone who participates in sponsored events. The One Neurosurgery Summit Taskforce on Professionalism and Harassment developed a foundational policy that establishes common expectations for behavior and a unified roadmap for the prompt response to untoward events. We hope that publishing this policy will inspire other medical organizations to establish their own meeting and conference policies. More importantly, we wish to bring greater attention to everyone's responsibility for ensuring a safe and respectful space for education, scientific debate, and networking during organized events.
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http://dx.doi.org/10.3171/2021.1.JNS218000DOI Listing
March 2021

Developing a Professionalism and Harassment Policy for Organized Neurosurgery.

Neurosurgery 2021 04;88(5):1038-1039

Department of Neurosurgery, University of Michigan, Ann Arbor, Michigan, USA.

Annual conferences, educational courses, and other meetings draw a diverse community of individuals, yet also create a unique environment without the traditional guard rails. Unlike events held at one's home institution, clear rules and jurisdiction have not been universally established. To promote the open exchange of ideas, as well as an environment conducive to professional growth of all participants, the leading neurosurgical professional organizations joined forces to delineate the expectations for anyone who participates in sponsored events. The One Neurosurgery Summit Taskforce on Professionalism and Harassment developed a foundational policy that establishes common expectations for behavior and a unified roadmap for the prompt response to untoward events. We hope that publishing this policy will inspire other medical organizations to establish their own meeting and conference policies. More importantly, we wish to bring greater attention to everyone's responsibility for ensuring a safe and respectful space for education, scientific debate, and networking during organized events.
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http://dx.doi.org/10.1093/neuros/nyab051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046587PMC
April 2021

Epileptogenic modulation index and synchronization in hypsarrhythmia of West syndrome secondary to perinatal arterial ischemic stroke.

Clin Neurophysiol 2021 05 5;132(5):1185-1193. Epub 2021 Feb 5.

Division of Neurology, Department of Pediatrics, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada; Children's Stroke Program, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8, Canada. Electronic address:

Objective: Perinatal arterial ischemic stroke (PAIS) is associated with epileptic spasms of West syndrome (WS) and long term Focal epilepsy (FE). The mechanism of epileptogenic network generation causing hypsarrhythmia of WS is unknown. We hypothesized that Modulation index (MI) [strength of phase-amplitude coupling] and Synchronization likelihood (SL) [degree of connectivity] could interrogate the epileptogenic network in hypsarrhythmia of WS secondary to PAIS.

Methods: We analyzed interictal scalp electroencephalography (EEG) in 10 WS and 11 FE patients with unilateral PAIS. MI between gamma (30-70 Hz) and slow waves (3-4 Hz) was calculated to measure phase-amplitude coupling. SL between electrode pairs was analyzed in 9-frequency bands (5-delta, theta, alpha, beta, gamma) to examine inter- and intra-hemispheric connectivity.

Results: MI was higher in affected hemispheres in WS (p = 0.006); no differences observed in FE. Inter-hemispheric SL of 3-delta, theta, alpha, beta, gamma bands was significantly higher in WS (p < 0.001). In WS, modified Z-Score of intra-hemispheric SL values in 3-delta, theta, alpha, beta and gamma in the affected hemispheres were significantly higher than those in the unaffected hemispheres (p < 0.001) as well as 0.5-4 Hz (p = 0.004).

Conclusions: The significantly higher modulation in affected hemisphere and stronger inter- and intra-hemispheric connectivity generate hypsarrhythmia of WS secondary to PAIS.

Significance: Epileptogenic cortical-subcortical transcallosal networks from affected hemisphere post-PAIS provokes infantile spasms.
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http://dx.doi.org/10.1016/j.clinph.2020.12.028DOI Listing
May 2021

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

Anal Chem 2021 03 2;93(10):4408-4416. Epub 2021 Mar 2.

Techna Institute for the Advancement of Technology for Health, University Health Network, 100 College Street, Toronto, Ontario M5G 1P5, Canada.

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.
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http://dx.doi.org/10.1021/acs.analchem.0c04129DOI Listing
March 2021

Diffuse intrinsic pontine glioma: current insights and future directions.

Chin Neurosurg J 2021 Jan 11;7(1). Epub 2021 Jan 11.

Cell Biology Program, The Hospital for Sick Children, 686 Bay St, Toronto, ON, M5G 0A4, Canada.

Diffuse intrinsic pontine glioma (DIPG) is a lethal pediatric brain tumor and the leading cause of brain tumor-related death in children. As several clinical trials over the past few decades have led to no significant improvements in outcome, the current standard of care remains fractionated focal radiation. Due to the recent increase in stereotactic biopsies, tumor tissue availabilities have enabled our advancement of the genomic and molecular characterization of this lethal cancer. Several groups have identified key histone gene mutations, genetic drivers, and methylation changes in DIPG, providing us with new insights into DIPG tumorigenesis. Subsequently, there has been increased development of in vitro and in vivo models of DIPG which have the capacity to unveil novel therapies and strategies for drug delivery. This review outlines the clinical characteristics, genetic landscape, models, and current treatments and hopes to shed light on novel therapeutic avenues and challenges that remain.
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http://dx.doi.org/10.1186/s41016-020-00218-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798267PMC
January 2021

Modeling human brain tumors in flies, worms, and zebrafish: From proof of principle to novel therapeutic targets.

Neuro Oncol 2021 05;23(5):718-731

Institute of Medical Science, Faculty of Medicine, University of Toronto, Toronto, Canada.

For decades, cell biologists and cancer researchers have taken advantage of non-murine species to increase our understanding of the molecular processes that drive normal cell and tissue development, and when perturbed, cause cancer. The advent of whole-genome sequencing has revealed the high genetic homology of these organisms to humans. Seminal studies in non-murine organisms such as Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio identified many of the signaling pathways involved in cancer. Studies in these organisms offer distinct advantages over mammalian cell or murine systems. Compared to murine models, these three species have shorter lifespans, are less resource intense, and are amenable to high-throughput drug and RNA interference screening to test a myriad of promising drugs against novel targets. In this review, we introduce species-specific breeding strategies, highlight the advantages of modeling brain tumors in each non-mammalian species, and underscore the successes attributed to scientific investigation using these models. We conclude with an optimistic proposal that discoveries in the fields of cancer research, and in particular neuro-oncology, may be expedited using these powerful screening tools and strategies.
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http://dx.doi.org/10.1093/neuonc/noaa306DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8099479PMC
May 2021

MRI-guided focused ultrasound enhances drug delivery in experimental diffuse intrinsic pontine glioma.

J Control Release 2021 02 11;330:1034-1045. Epub 2020 Nov 11.

Cell Biology Research Program, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, The Hospital for Sick Children, Toronto, ON, Canada; Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada; Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, ON, Canada. Electronic address:

Diffuse intrinsic pontine glioma (DIPG) is a surgically unresectable and devasting tumour in children. To date, there are no effective chemotherapeutics despite a myriad of clinical trials. The intact blood-brain barrier (BBB) is likely responsible for the limited clinical response to chemotherapy. MRI-guided focused ultrasound (MRgFUS) is a promising non-invasive method for treating CNS tumours. Moreover, MRgFUS allows for the temporary and repeated disruption of the BBB. Our group previously reported the feasibility of temporary BBB opening within the normal murine brainstem using MRgFUS following intravenous (IV) administration of microbubbles. In the current study, we set out to test the effectiveness of targeted chemotherapy when paired with MRgFUS in murine models of DIPG. Doxorubicin was selected from a drug screen consisting of conventional chemotherapeutics tested on patient-derived cell lines. We studied the RCAS/Tv-a model where RCAS-Cre, RCAS-PDGFB, and RCAS-H3.3K27M were used to drive tumourigenesis upon injection in the pons. We also used orthotopically injected SU-DIPG-6 and SU-DIPG-17 xenografts which demonstrated a diffusely infiltrative tumour growth pattern similar to human DIPG. In our study, SU-DIPG-17 xenografts were more representative of human DIPG with an intact BBB. Following IV administration of doxorubicin, MRgFUS-treated animals exhibited a 4-fold higher concentration of drug within the SU-DIPG-17 brainstem tumours compared to controls. Moreover, the volumetric tumour growth rate was significantly suppressed in MRgFUS-treated animals whose tumours also exhibited decreased Ki-67 expression. Herein, we provide evidence for the ability of MRgFUS to enhance drug delivery in a mouse model of DIPG. These data provide critical support for clinical trials investigating MRgFUS-mediated BBB opening, which may ameliorate DIPG chemotherapeutic approaches in children.
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http://dx.doi.org/10.1016/j.jconrel.2020.11.010DOI Listing
February 2021

Toward an understanding of sexual harassment in neurosurgery.

J Neurosurg 2020 Nov 10:1-10. Epub 2020 Nov 10.

5Department of Neurosurgery, The Hospital for Sick Children, University of Toronto, Ontario, Canada.

Objective: The goal of this study was the creation and administration of a survey to assess the depth and breadth of sexual harassment across neurosurgery.

Methods: A survey was created to 1) assess perceived attitudes toward systemic issues that might be permissive of sexual harassment; 2) measure the reported prevalence and severity of sexual harassment; and 3) determine the populations at highest risk and those most likely to perpetrate sexual harassment. Demographic information was also included to facilitate further analysis. The SurveyMonkey platform was used, and a request to complete the survey was sent to all Society of Neurological Surgeons and Congress of Neurological Surgeons (CNS) active and resident members as well as CNS transitional, emeritus, and inactive members. Data were analyzed using RStudio version 1.2.5019.

Results: Nearly two-thirds of responders indicated having witnessed sexual harassment in some form (62%, n = 382). Males were overwhelmingly identified as the offenders in allegations of sexual harassment (72%), with individuals in a "superior position" identified as offenders in 86%. Less than one-third of responders addressed the incidents of sexual harassment when they happened (yes 31%, no 62%, unsure 7%). Of those who did report, most felt there was either no impact or a negative one (negative: 34%, no impact: 38%). Almost all (85%) cited barriers to taking action about sexual harassment, including retaliation/retribution (87%), impact on future career (85%), reputation concerns (72%), and associated stress (50%). Female neurosurgeons were statistically more likely than male neurosurgeons to report witnessing or experiencing sexual harassment, as well as assessing it as a problem.

Conclusions: This study demonstrates that neurosurgeons report significant sexual harassment across all ages and practice settings. Sexual harassment impacts both men and women, with more than half personally subjected to this behavior and two-thirds having witnessed it. Male dominance, a hierarchical environment, and a permissive environment remain prevalent within the neurosurgical community. This is not just a historical problem, but it continues today. A change of culture will be required for neurosurgery to shed this mantle, which must include zero tolerance of this behavior, new policies, awareness of unconscious bias, and commitment to best practices to enhance diversity. Above all, it will require that all neurosurgeons and neurosurgical leaders develop an awareness of sexual harassment in the workplace and establish consistent mechanisms to mitigate against its highly deleterious effects in the specialty.
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http://dx.doi.org/10.3171/2020.6.JNS201649DOI Listing
November 2020

Surgical management of pediatric rolandic arteriovenous malformations: a single-center case series.

J Neurosurg Pediatr 2020 Oct 30:1-7. Epub 2020 Oct 30.

1The Hospital for Sick Children, Toronto.

Objective: Pediatric rolandic arteriovenous malformations (AVMs) present a treatment challenge given the lifetime risk of hemorrhage, rehemorrhage, and associated long-term morbidity. Microsurgical resection has been recommended as the optimal treatment for AVMs in general, but there is no dedicated literature on the outcomes of resection of pediatric rolandic AVMs. Here, the study objective was to review the outcomes of microsurgical resection of pediatric rolandic AVMs in the modern era, together with the utilization of surgical adjuncts including navigation, intraoperative angiography, and neurophysiological monitoring.

Methods: The authors performed a retrospective review of patients 18 years of age and younger with cerebral AVMs microsurgically treated between January 2000 and May 2016 at The Hospital for Sick Children. Only those patients with an AVM whose nidus was located within the rolandic region were analyzed. A descriptive analysis was performed to identify patient demographics, preoperative AVM characteristics, and postoperative obliteration rates and neurological complications.

Results: A total of 279 AVMs were evaluated in the study period. Twenty-three of these AVMs were rolandic, and the median age in the 11 microsurgically treated cases was 11 years (range 1-17 years). AVM hemorrhage was the most common presentation, occurring in 8 patients (73%). Lesions were either Spetzler-Martin grade II (n = 8, 73%) or grade III (n = 3, 27%). The postoperative obliteration rate of AVMs was 100%. The mean imaging follow-up duration was 33 months (range 5-164 months). There was no documented recurrence of an AVM during follow-up. One patient developed a transient postoperative hemiparesis, while another patient developed right fingertip hyperesthesia.

Conclusions: Microsurgical resection of rolandic pediatric AVMs yields excellent AVM obliteration with minimal neurological morbidity in selected patients. The incorporation of surgical adjuncts, including neurophysiological monitoring and neuronavigation, allows accurate demarcation of functional cortex and enables effective resection.
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http://dx.doi.org/10.3171/2020.6.PEDS18547DOI Listing
October 2020

Inhibition of TRPM7 with waixenicin A reduces glioblastoma cellular functions.

Cell Calcium 2020 12 14;92:102307. Epub 2020 Oct 14.

Departments of Surgery, Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada; Department of Pharmacology, Faculty of Medicine, University of Toronto, Toronto, Canada; Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, Canada. Electronic address:

Glioblastoma (GBM) is the most common malignant primary brain tumour originating in the CNS. Median patient survival is <15 months with standard treatment which consists of surgery alongside radiation therapy and temozolomide chemotherapy. However, because of the aggressive nature of GBM, and the significant toxicity of these adjuvant therapies, long-term therapeutic effects are unsatisfactory. Thus, there is urgency to identify new drug targets for GBM. Recent evidence shows that the transient receptor potential melastatin 7 (TRPM7) cation channel is aberrantly upregulated in GBM and its inhibition leads to reduction of GBM cellular functions. This suggests that TRPM7 may be a potential drug target for GBM treatment. In this study, we assessed the effects of the specific TRPM7 antagonist waixenicin A on human GBM cell lines U87 or U251 both in vitro and in vivo. First, we demonstrated in vitro that application of waixenicin A reduced TRPM7 protein expression and inhibited the TRPM7-like currents in GBM cells. We also observed reduction of GBM cell viability, migration, and invasion. Using an intracranial xenograft GBM mouse model, we showed that with treatment of waixenicin A, there was increased cleaved caspase 3 activity, alongside reduction in Ki-67, cofilin, and Akt activity in vivo. Together, these data demonstrate higher GBM cell apoptosis, and lower proliferation, migration, invasion and survivability following treatment with waixenicin A.
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http://dx.doi.org/10.1016/j.ceca.2020.102307DOI Listing
December 2020

Utility of invasive electroencephalography in children 3 years old and younger with refractory epilepsy.

J Neurosurg Pediatr 2020 Sep 18:1-6. Epub 2020 Sep 18.

1Department of Neurological Surgery, NewYork-Presbyterian Hospital/Weill Cornell Medical Center, New York.

Objective: Early surgical intervention for pediatric refractory epilepsy is increasingly advocated as surgery has become safer and data have demonstrated improved outcomes with early seizure control. There is concern that the risks associated with staged invasive electroencephalography (EEG) in very young children outweigh the potential benefits. Here, the authors present a cohort of children with refractory epilepsy who were referred for invasive monitoring, and they evaluate the role and safety of staged invasive EEG in those 3 years old and younger.

Methods: The authors conducted a retrospective review of children 3 years and younger with epilepsy, who had been managed surgically at two institutions between 2001 and 2015. A cohort of pediatric patients older than 3 years of age was used for comparison. Demographics, seizure etiology, surgical management, surgical complications, and adverse events were recorded. Statistical analysis was completed using Stata version 13. A p < 0.05 was considered statistically significant. Fisher's exact test was used to compare proportions.

Results: Ninety-four patients (45 patients aged ≤ 3 [47.9%]) and 208 procedures were included for analysis. Eighty-six procedures (41.3%) were performed in children younger than 3 years versus 122 in the older cohort (58.7%). Forty-two patients underwent grid placement (14 patients aged ≤ 3 [33.3%]); 3 of them developed complications associated with the implant (3/42 [7.14%]), none of whom were among the younger cohort. Across all procedures, 11 complications occurred in the younger cohort versus 5 in the older patients (11/86 [12.8%] vs 5/122 [4.1%], p = 0.032). Two adverse events occurred in the younger group versus 1 in the older group (2/86 [2.32%] vs 1/122 [0.82%], p = 0.571). Following grid placement, 13/14 younger patients underwent guided resections compared to 20/28 older patients (92.9% vs 71.4%, p = 0.23).

Conclusions: While overall complication rates were higher in the younger cohort, subdural grid placement was not associated with an increased risk of surgical complications in that population. Invasive electrocorticography informs management in very young children with refractory, localization-related epilepsy and should therefore be used when clinically indicated.
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http://dx.doi.org/10.3171/2020.6.PEDS19504DOI Listing
September 2020

Outcomes of BRAF V600E Pediatric Gliomas Treated With Targeted BRAF Inhibition.

JCO Precis Oncol 2020 20;4. Epub 2020 May 20.

Semmelweis University, Budapest, Hungary.

Purpose: Children with pediatric gliomas harboring a BRAF V600E mutation have poor outcomes with current chemoradiotherapy strategies. Our aim was to study the role of targeted BRAF inhibition in these tumors.

Patients And Methods: We collected clinical, imaging, molecular, and outcome information from patients with BRAF V600E-mutated glioma treated with BRAF inhibition across 29 centers from multiple countries.

Results: Sixty-seven patients were treated with BRAF inhibition (pediatric low-grade gliomas [PLGGs], n = 56; pediatric high-grade gliomas [PHGGs], n = 11) for up to 5.6 years. Objective responses were observed in 80% of PLGGs, compared with 28% observed with conventional chemotherapy ( < .001). These responses were rapid (median, 4 months) and sustained in 86% of tumors up to 5 years while receiving therapy. After discontinuation of BRAF inhibition, 76.5% (13 of 17) of patients with PLGG experienced rapid progression (median, 2.3 months). However, upon rechallenge with BRAF inhibition, 90% achieved an objective response. Poor prognostic factors in conventional therapies, such as concomitant homozygous deletion of , were not associated with lack of response to BRAF inhibition. In contrast, only 36% of those with PHGG responded to BRAF inhibition, with all but one tumor progressing within 18 months. In PLGG, responses translated to 3-year progression-free survival of 49.6% (95% CI, 35.3% to 69.5%) versus 29.8% (95% CI, 20% to 44.4%) for BRAF inhibition versus chemotherapy, respectively ( = .02).

Conclusion: Use of BRAF inhibition results in robust and durable responses in BRAF V600E-mutated PLGG. Prospective studies are required to determine long-term survival and functional outcomes with BRAF inhibitor therapy in childhood gliomas.
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http://dx.doi.org/10.1200/PO.19.00298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7446502PMC
May 2020

Editorial. The lessons of neurosurgery: a new publication for the Journal of Neurosurgery.

J Neurosurg 2020 Sep 4:1-2. Epub 2020 Sep 4.

2Editor-in-Chief, Journal of Neurosurgery Publishing Group, Charlottesville, Virginia.

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http://dx.doi.org/10.3171/2020.8.JNS203120DOI Listing
September 2020

Generator replacement with cardiac-based VNS device in children with drug-resistant epilepsy: An observational study.

Epilepsy Res 2020 11 16;167:106431. Epub 2020 Jul 16.

Epilepsy Program, Division of Neurology, Department of Pediatrics, The Hospital for Sick Children (University of Toronto), Toronto, Ontario, M5G 1X8, Canada. Electronic address:

Purpose: This study evaluated the seizure outcomes in children with drug-resistant epilepsy (DRE), having a pre-existing VNS device, after generator replacement with cardiac-based VNS device.

Methods: This retrospective study enrolled 30 children with DRE from 2 centers with an existing VNS device nearing end-of-service who underwent generator replacement with cardiac-based VNS device and had at least 1 year follow up. Seizure outcomes and adverse effects were studied.

Results: The mean age at insertion of cardiac-based VNS device was 15.03 years. 26.7 % patients showed at least one class improvement at last follow up (mean 2.08 years) and half of the patients maintained their McHugh seizure-outcome class. Thirty-six percent of patients had > 50 % seizure reduction at last follow up. Ten patients reported improvement in ictal severity. Most of the patients tolerated the replacement well.

Conclusions: Nearly one-third of patients with DRE showed additional improvement after replacement with cardiac based VNS device. Half of the patients maintained their seizure control.
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http://dx.doi.org/10.1016/j.eplepsyres.2020.106431DOI Listing
November 2020

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

J Surg Res 2020 12 23;256:282-289. Epub 2020 Jul 23.

Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Division of Genetics and Development, Krembil Research Institute, Toronto Western Hospital, Toronto, Ontario, Canada; Spinal Program, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada. Electronic address:

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.
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http://dx.doi.org/10.1016/j.jss.2020.06.054DOI Listing
December 2020

Editorial. Putting pen to paper during a pandemic: increased manuscript submissions to the JNS Publishing Group.

J Neurosurg 2020 Jul 24:1-3. Epub 2020 Jul 24.

3Editor-in-Chief, Journal of Neurosurgery Publishing Group, Charlottesville, Virginia.

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http://dx.doi.org/10.3171/2020.7.JNS202691DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393803PMC
July 2020

Editorial. Preprint servers and neurosurgical publications.

Authors:
James T Rutka

J Neurosurg 2020 Jul 24:1-3. Epub 2020 Jul 24.

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http://dx.doi.org/10.3171/2020.7.JNS202698DOI Listing
July 2020

Three-Dimensional Computed Tomography Reconstruction Unmasks Shunt Disconnection in a Child.

Can J Neurol Sci 2020 11 4;47(6):826-827. Epub 2020 Jun 4.

Division of Neurosurgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.

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http://dx.doi.org/10.1017/cjn.2020.110DOI Listing
November 2020

Integrated Molecular and Clinical Analysis of 1,000 Pediatric Low-Grade Gliomas.

Cancer Cell 2020 04;37(4):569-583.e5

Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada; Department of Neurosurgery, The Hospital for Sick Children, Toronto ON, Canada.

Pediatric low-grade gliomas (pLGG) are frequently driven by genetic alterations in the RAS-mitogen-activated protein kinase (RAS/MAPK) pathway yet show unexplained variability in their clinical outcome. To address this, we characterized a cohort of >1,000 clinically annotated pLGG. Eighty-four percent of cases harbored a driver alteration, while those without an identified alteration also often exhibited upregulation of the RAS/MAPK pathway. pLGG could be broadly classified based on their alteration type. Rearrangement-driven tumors were diagnosed at a younger age, enriched for WHO grade I histology, infrequently progressed, and rarely resulted in death as compared with SNV-driven tumors. Further sub-classification of clinical-molecular correlates stratified pLGG into risk categories. These data highlight the biological and clinical differences between pLGG subtypes and opens avenues for future treatment refinement.
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http://dx.doi.org/10.1016/j.ccell.2020.03.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7169997PMC
April 2020

Evolution of cerebellomedullary fissure opening: its effects on posterior fossa surgeries from the fourth ventricle to the brainstem.

Neurosurg Rev 2021 Apr 12;44(2):699-708. Epub 2020 Apr 12.

Department of Neurosurgery, Tokyo Medical University, Tokyo, Japan.

Surgical approaches to the fourth ventricle and its surrounding brainstem regions have changed significantly in the previous 30 years, after the establishment of cerebellomedullary fissure (CMF) opening. With the development of CMF opening techniques, CMF opening surgeries have become widely used for the treatment of various pathologies and have contributed to the improvement of surgical results in posterior fossa surgeries. We here review the historical progress of CMF opening surgeries to help the future progression of neurosurgical treatments. The authors studied the available literature to clarify how CMF opening surgeries have developed and progressed, and how much the idea and development of CMF opening techniques have affected the advancement of posterior fossa surgeries. With the establishment of angiography, anatomical studies on CMF in the 1960s were performed mainly to clarify vascular anatomy on radiological images. After reporting the microsurgical anatomy of CMF in a cadaveric study in 1982, one of the authors (T.M.) first proposed the clinical usefulness of CMF opening in 1992. This new method enabled wide exposure of the fourth ventricle without causing vermian splitting syndrome, and it took the place of the standard approach instead of the conventional transvermian approach. Several authors reported their experiences using this method from the end of the twentieth century to the early twenty-first century, and the naming of the approach, "telovelar approach" by Mussi and Rhoton in 2000 contributed to the global spread of CMF opening surgeries. The approach has become widely applied not only for tumors but also for vascular and brainstem lesions, and has assisted in the development of their surgical treatments, and brought up the idea of various fissure dissection in the posterior fossa. Studies of microsurgical anatomy of the fourth ventricle, including the CMF, has led to new surgical approaches represented by the transCMF/telovelar approach. The CMF opening method caused a revolution in posterior fossa surgeries. The idea was developed based on the experience gained while dissecting the CMF (the roof of the fourth ventricle) in the laboratory. Anatomical studies using cadaveric specimens, particularly their dissection by surgeons themselves, together with a deep understanding of brain anatomy are essential for further advancements in neurosurgical treatments.
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http://dx.doi.org/10.1007/s10143-020-01295-2DOI Listing
April 2021
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