Preclinical models of glioblastoma: limitations of current models and the promise of new developments.

Glioblastoma (GBM) is the most common and aggressive primary brain tumour, yet little progress has been made towards providing better treatment options for patients diagnosed with this devastating condition over the last few decades. The complex nature of the disease, heterogeneity, highly invasive potential of GBM tumours and until recently, reduced investment in research funding compared with other cancer types, are contributing factors to few advancements in disease management. Survival rates remain low with less than 5% of patients surviving 5 years. Another important contributing factor is the use of preclinical models that fail to fully recapitulate GBM pathophysiology, preventing efficient translation from the lab into successful therapies in the clinic. This review critically evaluates current preclinical GBM models, highlighting advantages and disadvantages of using such models, and outlines several emerging techniques in GBM modelling using animal-free approaches. These novel approaches to a highly complex disease such as GBM show evidence of a more truthful recapitulation of GBM pathobiology with high reproducibility. The resulting advancements in this field will offer new biological insights into GBM and its aetiology with potential to contribute towards the development of much needed improved treatments for GBM in future.

Iatrogenic pseudoaneurysm rupture of the anterior cerebral artery after placement of an external ventricular drain, treated with clip-wrapping: a case report and review of the literature.

External ventricular drains (EVDs) are often placed emergently for patients with hydrocephalus, which carries a risk of hemorrhage. Rarely, rupture of a pseudoaneurysm originating from an EVD placement precipitates such a hemorrhage. An EVD was placed in a patient with a ruptured left posterior communicating artery aneurysm who later underwent endovascular coil embolization. On post-bleed day 20, a distal right anterior cerebral artery pseudoaneurysm along the EVD tract ruptured, which was successfully treated via clip-wrapping. Although EVD-associated pseudoaneurysms are rare, they have a high propensity for rupture. Early treatment of these lesions should be considered to prevent neurologic deterioration.

Theory and evidence-base for a digital platform for the delivery of language tests during awake craniotomy and collaborative brain mapping.

Objectives: Build the theoretical and evidence-base for a digital platform (map-OR) which delivers intraoperative language tests during awake craniotomy and facilitates collaborative sharing of brain mapping data. Design: Mixed methodology study including two scoping reviews, international survey, synthesis of development guiding principles and a risk assessment using failure modes and effects analysis. Setting: The two scoping reviews examined the literature published in the English language. International survey was completed by members of awake craniotomy teams from 14 countries. Main outcome measures: Scoping review 1: number of technologies described for language mapping during awake craniotomy. Scoping review 2: barriers and facilitators to adopting novel technology in surgery. International survey: degree of language mapping technology penetration into clinical practice. Results: A total of 12 research articles describing 6 technologies were included. The technologies required a range of hardware components including portable devices, virtual reality headsets and large integrated multiscreen stacks. The facilitators and barriers of technology adoption in surgery were extracted from 11 studies and mapped onto the 4 Unified Theory of Acceptance and Use of Technology constructs. A total of 37 awake craniotomy teams from 14 countries completed the survey. Of the responses, 20 (54.1%) delivered their language tests digitally, 10 (27.0%) delivered tests using cards and 7 (18.9%) used a combination of both. The most commonly used devices were tablet computers (67.7%; n=21) and the most common software used was Microsoft PowerPoint (60.6%; n=20). Four key risks for the proposed digital platform were identified, the highest risk being a software and internet connectivity failure during surgery. Conclusions: This work represents a rigorous and structured approach to the development of a digital platform for standardized intraoperative language testing during awake craniotomy and for collaborative sharing of brain mapping data. Trial registration number: Scoping review protocol registrations in OSF registries (scoping review 1: osf.io/su9xm; scoping review 2: osf.io/x4wsc).

Impact of remoteness and rurality on the treatment and survival of patients with glioblastoma in the north of Scotland.

Background: The geographical catchment area served by the Neurosurgical Unit in Aberdeen, Scotland is the largest in the United Kingdom. We examined whether a distance-decay effect on survival exists for patients diagnosed with glioblastoma, who have to travel substantial distances for neurosurgical and oncological treatment in the north of Scotland. Methods: Electronic medical records of adult patients with glioblastoma, referred for treatment between 2007 and 2018, who underwent surgical resection were reviewed. Travel time by car (as a measure of distance travelled) was calculated from the patients' home to their general practice (GP) and to their main neuro-oncological centre. Results: There were 122 patients; 71 (58.2%) were male and the mean age was 57.8 years. The urban-rural split was 61.5% and 38.5%, respectively. Median driving time to the neuro-oncological centre was 36 min and to the GP this was 6 min. Most patients underwent either sub-total (49.6%) or gross total (46.3%) surgical resection. Post-operative treatments included: radiotherapy only (15.6%), chemotherapy only (6.6%), and chemotherapy with radiotherapy (63.1%). Temozolomide was used in 70.5% of patients. Seventeen patients did not receive any post-operative chemo-radiotherapy. The median survival time was 345 days. There was no statistically significant association between distance travelled and survival time in days. MGMT methylation status, extent of resection, Charlson co-morbidity index and treatment received significantly affected survival. Conclusions: There was no evidence of disadvantage on survival time for patients living further from their neuro-oncological centre compared to those who live nearer.

Burden of motorcyclists without helmets in a state without a universal helmet law: a propensity score analysis.

BACKGROUND: Although helmets are associated with reduction in mortality from motorcycle collisions, many states have failed to adopt universal helmet laws for motorcyclists, in part on the grounds that prior research is limited by study design (historical controls) and confounding variables. The goal of this study was to evaluate the association of helmet use in motorcycle collisions with hospital charges and mortality in trauma patients with propensity score analysis in a state without a universal helmet law. METHODS: Motorcycle collision data from the Arizona State Trauma Registry from 2014 to 2017 were propensity score matched by regressing helmet use on patient age, sex, race/ethnicity, alcohol intoxication, illicit drug use, and comorbidities. Linear and logistic regression models were used to evaluate the impact of helmet use. RESULTS: Our sample consisted of 6849 cases, of which 3699 (54.0%) were helmeted and 3150 (46.0%) without helmets. The cohort was 88.1% male with an average age of 40.9±16.0 years. Helmeted patients were less likely to be admitted to the intensive care unit (20.3% vs. 23.7%, OR 0.82 (0.72-0.93)) and ventilated (7.8% vs. 12.0%, OR 0.62 (0.52-0.75)). Propensity-matched analyses consisted of 2541 pairs and demonstrated helmet use to be associated with an 8% decrease in hospital charges (B -0.075 (0.034)) and a 56% decrease in mortality (OR 0.44 (0.31-0.58)). DISCUSSION: In a state without mandated helmet use for all motorcyclists, the burden of the unhelmeted rider is significant with respect to lives lost and healthcare charges incurred. Although the helmet law debate with respect to civil liberties is complex and unsettled, it appears clear that helmet use is strongly associated with both survival and less economic encumbrance on the state. LEVEL OF EVIDENCE: Level III, prognostic and epidemiological.

Standardized Ventriculostomy Protocol without an Occlusive Dressing: Results of an Observational Study in Patients with Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Catheter-related infections are a potentially life-threatening complication of having an external ventricular drain (EVD). Patients with aneurysmal subarachnoid hemorrhage (aSAH) are at increased risk of infection associated with prolonged ventricular drainage, with a reported mean infection rate of 6%. We report the EVD-associated infection rate among patients with aSAH managed with a unique standardized treatment protocol without an occlusive EVD dressing. METHODS: Patients with aSAH admitted from August 2015 through August 2017 were retrospectively analyzed for EVD placement. Cerebrospinal fluid (CSF) samples were obtained twice weekly for culture and routine studies. EVD-associated infection was defined as growth of CSF cultures. RESULTS: During the 2-year study period, 122 patients presented with an aSAH, with 91 (74.6%) having EVD placement. In patients with EVDs, the mean age was 57.9 years (68% women); 88% of aSAHs were Fisher grade III or IV. Mean duration of EVD was 14 days, and 13% of patients required EVD replacement. Endovascular coiling and surgical clipping were performed in 34 (37%) and 53 (58%) patients with EVD, respectively. A total of 347 CSF studies were performed with no EVD-associated infections. There were 3 CSF samples with false-positive Gram stain results but no growth on concurrent or multiple repeat cultures. CONCLUSIONS: Using a standardized protocol for placement and management of EVDs in patients with aSAH is associated with low risk of CSF infection. Our study demonstrates that occlusive EVD dressings are not necessary and that routine CSF sampling in patients with EVD may lead to false-positive findings and unnecessary antibiotic administration.

Do medical students studying in the United Kingdom have an adequate factual knowledge of basic life support?

BACKGROUND: Healthcare professionals have a duty to maintain basic life support (BLS) skills. This study aims to evaluate medical students' factual knowledge of BLS and the training they receive. METHODS: A cross-sectional, closed-response questionnaire was distributed to the first- and fourth-year students studying at institutions in the United Kingdom. The paper questionnaire sought to quantify respondent's previous BLS training, factual knowledge of the BLS algorithm using five multiple choice questions (MCQs), and valuate their desire for further BLS training. Students received 1 point for each correctly identified answer to the 5 MCQ's. RESULTS: A total of 3,732 complete responses were received from 21 medical schools. Eighty percent (n=2,999) of students completed a BLS course as part of their undergraduate medical studies. There was a significant difference (P<0.001) in the percentage of the fourth-year students selecting the correct answer in all the MCQ's compared to the first-year students except in identifying the correct depth of compressions required during CPR (P=0.095). Overall 10.3% (95% CI 9.9% to 10.7%) of respondents correctly identified the answer to 5 MCQ's on BLS 9% of the first-year students (n=194) and 12% of the fourth-year students (n=190). On an institutional level the proportion of students answering all MCQ's correctly ranged from 2% to 54% at different universities. Eighty-one percent of students (n=3,031) wished for more BLS training in their curriculum. CONCLUSION: Factual knowledge of BLS is poor among medical students in the UK. There is a disparity in standards of knowledge across institutions and respondents indicating that they would like more training.

Pork Belly: A Simulation Training Model for Intramuscular Perforator Dissection.

BACKGROUND: Free tissue transfer has evolved from muscle flaps to fasciocutaneous flaps. Dissection of the intramuscular course of feeding vessels is technically challenging. Simulation-based microsurgery skills acquisition is moving toward nonliving training models. Living porcine model or human cadavers are currently cost-ineffective methods for the early learning curve in teaching intramuscular dissection. The aim of this study was to validate an inexpensive ex vivo porcine model simulating harvest of the deep inferior epigastric artery perforator (DIEAP) flap, specifically including perforator intramuscular dissection. METHODS: An initial needs analysis and anatomical dissections (characteristics of vascular anatomy) established the necessity and surgical design (step-by-step) of the ex vivo DIEAP flap harvesting model. A pilot study utilizing objective assessment methodology (time to complete flap raising and hand motion analysis) demonstrated the surgeons' performance. A detailed feedback questionnaire was used to assess the participants' perception of this model. RESULTS: Fifty-seven participants completed the initial needs analysis. Fifteen pork bellies were dissected and the vascular anatomical characteristics of the inferior epigastric vessels are presented. Eight surgeons performed the step-by-step flap design demonstrating construct validity in flap raising and intramuscular dissection. All surgeons completed the ex vivo DIEAP harvesting and they recommend this model as the first step in training for intramuscular dissection. CONCLUSIONS: The pork belly simulation is a cheap, easy, ethically considerate, and high-fidelity simulation model for intramuscular dissection for the DIEAP free flap. This study guides future validation trials to explore if the absence of physiological blood flow affects skills acquisition in the intramuscular dissection learning curve. The pork belly could be the first step in perforators dissection before progressing to the in vivo porcine model.

Evolution of an evidence-based supermicrosurgery simulation training curriculum: A systematic review.

BACKGROUND: Supermicrosurgery (SM) involves operating on vessels with calibers from 0.3-0.8 mm. SM requires skills beyond those of conventional microsurgery. Current microsurgery courses do not prepare a junior surgeon for such a challenge. Several models have been developed to assist in the early learning curve, but their true purpose, benefit, and validation have not been addressed. This systematic literature review summarizes the existing SM simulation models, and their likely impact on microsurgery training for small-caliber vessel-based procedures is assessed. METHODS: An electronic literature search was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. From the literature search, 90 potential articles from MEDLINE and 300 articles from other databases were identified and screened. Twenty-five studies were screened against the inclusion criteria by two independent reviewers for a final critical analysis. RESULTS: Thirty-six articles were included in the reviewing process, and 15 SM simulation training models were identified. The simulation models were classified as nonbiological or biological and as ex vivo or in vivo. None of these models demonstrated validity. However, critical analysis of the full-text articles established the clinical correlation of each model along with the specific skill demonstrated. A novel ladder-based curriculum was established. Further, an expert's questionnaire generated a Likert scale and the clinical impact of each SM simulation training model. CONCLUSION: This is the first review to highlight the clinical relevance of SM models and the need for validation. Currently, a variety of training models in SM appear to enable the acquisition of specific skills, and the clinical impact of a selection is recognized in a proposed SM simulation training curriculum.

Utilization of intraoperative confocal laser endomicroscopy in brain tumor surgery.

Precise identification of tumor margins is of the utmost importance in neuro-oncology. Confocal microscopy is capable of rapid imaging of fresh tissues at cellular resolution and has been miniaturized into handheld probe-based systems suitable for use in the operating room. We aimed to perform a literature review to provide an update on the current status of confocal laser endomicroscopy (CLE) technology for brain tumor surgery. Aside from benchtop confocal microscopes used in ex vivo fashion, there are four CLE systems that have been investigated for potential application in the workflow of brain tumor surgery. Preclinical studies on animal tumor models and clinical studies on human brain tumors have assessed in vivo and ex vivo imaging approaches, suggesting that confocal microscopy holds promise for rapid identification of the characteristic (diagnostic) histological features of tumor and normal brain tissues. However, there are few studies assessing diagnostic accuracy sufficient to provide a definitive determination of the clinical and economical value of CLE in brain tumor surgery. Intraoperative real-time, high-resolution tissue imaging has significant clinical potential in the field of neuro-oncology. CLE is an emerging imaging technology that shows promise for improving brain tumor surgery workflow in in vivo and ex vivo studies. Future clinical studies are necessary to demonstrate clinical and economic benefit of CLE.

Counting the Cost of Cervical Collars.

Veljanoski D , Grier G , Wilson MH . Counting the cost of cervical collars. Prehosp Disaster Med. 2017;32(6):701-702.

Intimal Surface Suture Line (End-Product) Assessment of End-to-Side Microvascular Anastomosis.

Microsurgery simulation courses increasingly use assessment methodologies to evaluate the quality of microvascular anastomosis and to provide constructive feedback in competency-based training. Assessment tools evaluating the "journey" of skill acquisition in anastomosis have evolved, including global rating scores, hand motion analysis, and evaluation of the final outcome, that is, "end-product" assessment. Anastomotic patency is the gold standard end-product in clinical microvascular surgery, and in vivo end-to-side anastomosis, which can be confirmed using the Acland-test. Microsurgery simulation training is moving to include nonliving models, where possible, according to the principles of the replacement, reduction, and refinement of the use of animals in research. While a standardized end-product assessment tool for nonliving end-to-end anastomosis exists, there is no similar tool for end-to-side anastomosis. Intimal surface suture line assessment is an error list-based tool, which involves exposing the intimal surface of a vessel and analysis of the quality of suture placement. Errors in end-to side anastomosis were classified according to the potential clinical significance (high, medium, or low) perceived by the senior authors. Intimal surface suture line assessment provides constructive feedback during microsurgery training, helping to minimize technical errors, which are likely to impact on the final outcome in a clinical environment. Intimal surface suture line assessment lends itself to nonliving simulation training courses as an end-product self-assessment tool, especially during the early learning curve, to demonstrate progression. It has intraoperative relevance by assessment of the intimal surface suture line as the final sutures are placed in an end-to-side anastomosis to provide objective feedback to trainees in relation to likely physiological anastomotic outcome.