Blood-Brain Barrier Disruption in Neuro-Oncology: Strategies, Failures, and Challenges to Overcome.

The blood-brain barrier (BBB) presents a formidable challenge in the development of effective therapeutics in neuro-oncology. This has fueled several decades of efforts to develop strategies for disrupting the BBB, but progress has not been satisfactory. As such, numerous drug- and device-based methods are currently being investigated in humans. Through a focused assessment of completed, active, and pending clinical trials, our first aim in this review is to outline the scientific foundation, successes, and limitations of the BBBD strategies developed to date. Among 35 registered trials relevant to BBBD in neuro-oncology in the ClinicalTrials.gov database, mannitol was the most common drug-based method, followed by RMP-7 and regadenoson. MR-guided focused ultrasound was the most common device-based method, followed by MR-guided laser ablation, ultrasound, and transcranial magnetic stimulation. While most early-phase studies focusing on safety and tolerability have met stated objectives, advanced-phase studies focusing on survival differences and objective tumor response have been limited by heterogeneous populations and tumors, along with a lack of control arms. Based on shared challenges among all methods, our second objective is to discuss strategies for confirmation of BBBD, choice of systemic agent and drug design, alignment of BBBD method with real-world clinical workflow, and consideration of inadvertent toxicity associated with disrupting an evolutionarily-refined barrier. Finally, we conclude with a strategic proposal to approach future studies assessing BBBD.

Propagating the "SEAD": Exploring the Value of an Overnight Call Shift in the Surgical Exploration and Discovery (SEAD) Program.

OBJECTIVE: Attrition of general surgery residents highlights a need to support well-informed specialty selection. This study evaluated preclerkship medical students' perception of overnight call shifts in surgical career exploration. DESIGN: A mixed-methods design was used, involving entry and postcall shift surveys and focus groups. Survey data characterized the population and call shift, guided focus group segmentation by baseline interest in surgery, and provided context for interpretation of qualitative data. Focus groups were transcribed and analyzed with a phenomenological approach using thematic analysis. SETTING: Call shifts took place at the University of Toronto's Sunnybrook Health Sciences Centre and St. Michael's Hospital, 2 Level 1 trauma centers in Toronto, Canada. PARTICIPANTS: Twenty-five first-year medical students participating in the Surgical Exploration and Discovery program. RESULTS: Sixty-four percent (n = 16) of the participants were male. Students in the high interest group (n = 9) had more prior operating room exposure than students in the moderate (n = 12) and low (n = 4) interest groups (p = 0.039). Most students valued participating in a call shift; 80% (n = 20) rated the experience "positive" or "very positive." Thematic analysis yielded 2 categories of themes: (1) Valuable aspects of the experience, including being part of a team, mentorship, understanding the clerk's role, dispelling misconceptions, trial of working overnight, and influencing interest in a surgical career; and (2) Determinants of an enjoyable experience, including resident engagement and number of traumas. CONCLUSIONS: An overnight call shift experience was valuable to preclerkship medical students regardless of baseline interest in surgery. While it only influenced a few students' specialty preferences, exposure facilitated a better understanding of a unique component of surgical careers and provided valuable mentorship. These findings support implementing calls shifts in other curricular or extracurricular programs to make the experience more widely available and enable earlier, informed career decision-making.

Surgical outcomes for medically intractable epilepsy in low- and middle-income countries: a systematic review and meta-analysis.

OBJECTIVEThe aim of this study was to describe the current state of epilepsy surgery and establish estimates of seizure outcomes following surgery for medically intractable epilepsy (MIE) in low- and middle-income countries (LMICs).METHODSThe MEDLINE and Embase databases were searched without publication date restriction. This search was supplemented by a manual screen of key epilepsy and neurosurgical journals (January 2005 to December 2016). Studies that reported outcomes for at least 10 patients of any age undergoing surgery for MIE in LMICs over a defined follow-up period were included. A meta-analysis with a random-effects model was performed in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. Pooled estimates of seizure freedom and favorable seizure outcomes following anterior temporal lobectomy with or without amygdalohippocampectomy (ATL ± AH) were reported.RESULTSTwenty studies were selected, of which 16 were from Asian centers. The average age at surgery in all studies was less than 30 years, and the average preoperative duration of epilepsy ranged from 3 to 16.1 years. Mesial temporal sclerosis accounted for 437 of 951 described pathologies, and 1294 of the 1773 procedures were ATL ± AH. Based on 7 studies (646 patients) the pooled seizure freedom estimate following ATL ± AH was 68% (95% CI 55%-82%). Based on 8 studies (1096 patients), the pooled estimate for favorable seizure outcomes was 79% (95% CI 74%-85%).CONCLUSIONSSurgery for MIE in LMICs shows a high percentage of seizure freedom and favorable outcomes. These findings call for a concerted global effort to improve timely access to surgery for MIE patients in these regions, including investments aimed at refining existing and establishing additional centers.

Exploratory Analysis into Reasonable Timeframes for the Provision of Neurosurgical Care in Low- and Middle-Income Countries.

BACKGROUND: In low- and middle-income countries (LMICs), 11.8% of the need for neurosurgical care is met. Delays in seeking and receiving care may further exacerbate this situation. Objective analysis of delay and its consequences is contingent on reference to established resource-appropriate acceptable timeframes. This study sought to 1) establish an estimate of the landscape of care provided in LMICs and 2) explore reasonable timeframes for various stages of patient-health care interaction. METHODS: Consensus input from neurosurgeons in select LMICs was collected; 1 high-income country was included for comparison. In phase 1, participants were asked to select neurosurgical procedures performed at their centers. In phase 2, based on procedures shared among all LMICs, representative case scenarios were generated and participants provided input on acceptable timeframes for each stage of patient-health care interaction: 1) presentation to health services, 2) diagnosis by primary care physician, 3) referral to neurosurgical specialist care, and 4) definitive neurosurgical management. RESULTS: Twenty neurosurgeons across 18 centers were identified; 12 participated in phase 1 and 7 in phase 2. The range of procedures offered was broad, similar in scope to high-income countries, and included pediatric and adult neurosurgery, trauma, degenerative spine, and hemorrhagic stroke. Acceptable timeframes had wide ranges in certain cases; however, the overall trend showed agreement between the participants. CONCLUSIONS: This exploratory analysis identified reasonable timeframes for the provision of neurosurgical care in LMICs. If validated, these data can be used to more objectively assess the prevalence of delay in neurosurgical care in individual LMICs, along with its consequences.