Glioblastoma is the most common and malignant primary brain tumour in adults. Maximum feasible surgical resection, radiotherapy and temozolomide chemotherapy at initial diagnosis have improved prognosis but rapid recurrence is typical and survival remains brief. There is an urgent need for effective new treatments and approval of the antiangiogenic agent bevacizumab for recurrent glioblastoma by Health Canada in 2009 has been the most notable recent therapeutic advance for this disease. This review with illustrative case studies highlights how bevacizumab has been incorporated into the treatment of glioblastoma in Canada and describes the ongoing controversies surrounding its clinical application.

This manuscript served as a companion piece for the original article “Pregabalin for the Management of Cervicogenic Headache; A Double Blind Study” by Guy P. Boudreau and Luc Marchand, which was published in the September 2014 issue of The Canadian Journal of Neurological Sciences.1

Introduction: Our goal was to perform a systematic review of the literature on the use of intravenous lidocaine in pediatrics for status epilepticus (SE) and refractory status epilepticus (RSE) to determine its impact on seizure control. Methods: All articles from MEDLINE, BIOSIS, EMBASE, Global Health, HealthStar, Scopus, Cochrane Library, the International Clinical Trials Registry Platform (inception to November 2014), and gray literature were searched. The strength of evidence was adjudicated using both the Oxford and GRADE methodology by two independent reviewers. Results: Overall, 20 original studies were identified, with 19 manuscripts and 1 meeting abstracts. Two hundred and thirty-five pediatric patients were treated for 252 episodes of SE/RSE. Patients had varying numbers of anti-epileptic drugs (AEDs), 2 to 8, on board prior to lidocaine therapy. During 20 of the 252 (7.9%) episodes of SE/RSE, phenytoin was on board. The dose regimen of lidocaine varied, with some utilizing bolus dosing alone; others utilizing a combination of bolus and infusion therapy. Overall, 60.0% of seizures responded to lidocaine, with complete cessation and greater than 50% reduction seen in 57.6% and 12.3% respectively. Patient outcomes were sparingly reported. Conclusions: There currently exists level 2b, GRADE C evidence to support the consideration of lidocaine for SE and RSE in the pediatric population.

The role of fludeoxyglucose F 18 positron emission tomography (PET) in the presurgical evaluation of patients with medically intractable epilepsy continues to be refined. The purpose of this study was to systematically review the literature to assess the diagnostic accuracy and utility of PET in this setting. Thirty-nine studies were identified through MEDLINE and EMBASE databases that met the inclusion criteria. In adult patients, PET hypometabolism showed a 56 to 90% agreement with seizure onset localized by intracranial electroencephalogram (pediatric: 21 to 86%). In temporal lobe epilepsy patients with good surgical outcome, PET displayed moderate to high sensitivity in localizing the seizure focus (range: 71 to 89%). The sensitivity increased by 8 to 23% when PET results were combined with magnetic resonance imaging or electroencephalogram. PET has been shown to affect patient management by improving the guidance of intracranial electrodes placement, altering the decision to perform surgery, or excluding patients from further evaluation.

Background: Debate persists in Canada about the cost and benefit of vagal nerve stimulation in patients with refractory epilepsy. The aim of our study was to evaluate the impact of a vagal nerve stimulator on the seizure frequency and the admission rate of children with refractory epilepsies over five years of follow-up. Methods: 52 patients were implanted between 2000-2013. Of these, 37 were followed at CHU Sainte-Justine and 21 kept seizure diaries. Seizure frequency was compared to the baseline at 6 months, 12 months, 24 months and 60 months of follow up using a multivariate ANOVA analysis. The hospitalization rate was calculated as the mean difference between the number of hospitalizations prior to and after the implantation. Results: Seizure frequency decreased by 58% at 6 months, by 61% at 12 months, by 53% at 24 months and by 63% at 60 months of follow up respectively compared to the baseline (p<0.001). The hospitalization rate decreased by 50.87% after surgery (p<0.001). Conclusion: In our population, vagal nerve stimulation has a sustained impact on seizure frequency and hospitalization rates. This supports previous data from our group and others on cost-effectiveness of the technique in children with refractory epilepsy.

Early locomotor exercise after stroke has attracted a great deal of attention in clinical and animal research in recent years. A series of animal studies showed that early locomotor exercise poststroke could protect against ischemic brain injury and improve functional outcomes through the promotion of angiogenesis, inhibition of acute inflammatory response and neuron apoptosis, and protection of the blood-brain barrier. However, to date, the clinical application of early locomotor exercise poststroke was limited because some clinicians have little confidence in its effectiveness. Here we review the current progress of early locomotor exercise poststroke in animal models. We hope that a comprehensive awareness of the early locomotor exercise poststroke may help to implement early locomotor exercise more appropriately in treatment for ischemic stroke.

The Ki-67 proliferative index has become a useful, objective, immunohistochemical tool that can aid in grading and prognostication for patients with oligodendrogliomas. Previous studies have described the prognostic significance of the Ki-67 index for such patients.

According to the WHO classification of tumors of the central nervous system (2007) ”mitotic activity is low in WHO grade II oligodendroglioma, and labeling indices for proliferation markers are accordingly low, usually below 5%”. Furthermore, the predictive value of the Ki-67 index appears to be independent of age, tumor site, and histological grade. What is less well described is the relative accuracy of traditional vs. semi-automated methods of enumeration for a test where small differences can influence grading, prognosis and treatment. Tang et al. (2012), studying gastroenteropancreatic neuroendocrine tumours, found high concordance between two semi-automated methods for Ki-67 quantitation whereas “eyeballed estimates” were far less reliable. We will compare the reported proliferative index estimates to those calculated by digital image analysis of 35 recent oligodendrogliomas from the LHSC Pathology archives.

The current concept in the cell cycle stipulates that constant synthesis without coupled ubiquitin- mediated proteolysis maintains the levels of cyclin-dependent kinase proteins through the cell cycle. CDK proteins are elevated in glioblastoma, which has long been thought due to gene amplifications, although the amplifications occur only in a small set of the tumors according to the genome.

In this study, we show that the G1 phase CDK6 is a substrate of both ubiquitin and small ubiquitin-like modifier-1 (SUMO1), and that CDK6 is sumoylated due to the elevated activity of SUMO1 conjugation in glioblastoma. CDK6 sumoylation at Lys 216 structurally blocks the access of ubiquitination molecules to the Lys 147 ubiquitination site; thus, CDK6 sumoylation stabilize the protein, maintains the kinase activity and drives the cell cycle through G1/S transition. Inhibition of SUMO1 conjugation causes G1 arrest and abolishes the self-renewal and tumorigenic property of glioblastoma initiating or stem cells. In conclusion, SUMO1-CDK6 conjugation constitutes a new mechanism of cell cycle control and selective inhibition of SUMO1 conjugation may provide a novel strategy for the development of the cancer stem cells-targeted treatment.