Utilization of Spinal Intra-operative Three-dimensional Navigation by Canadian Surgeons and Trainees: A Population-based Time Trend Study.

BACKGROUND: Computer-assisted navigation (CAN) improves the accuracy of spinal instrumentation in vertebral fractures and degenerative spine disease; however, it is not widely adopted because of lack of training, high capital costs, workflow hindrances, and accuracy concerns. We characterize shifts in the use of spinal CAN over time and across disciplines in a single-payer health system, and assess the impact of intra-operative CAN on trainee proficiency across Canada. METHODS: A prospectively maintained Ontario database of patients undergoing spinal instrumentation from 2005 to 2014 was reviewed retrospectively. Data were collected on treated pathology, spine region, surgical approach, institution type, and surgeon specialty. Trainee proficiency with CAN was assessed using an electronic questionnaire distributed across 15 Canadian orthopedic surgical and neurosurgical programs. RESULTS: In our provincial cohort, 16.8% of instrumented fusions were CAN-guided. Navigation was used more frequently in academic institutions (15.9% vs. 12.3%, p<0.001) and by neurosurgeons than orthopedic surgeons (21.0% vs. 12.4%, p<0.001). Of residents and fellows 34.1% were fully comfortable using spinal CAN, greater for neurosurgical than orthopedic surgical trainees (48.1% vs. 11.8%, p=0.008). The use of CAN increased self-reported proficiency in thoracic instrumentation for all trainees by 11.0% (p=0.036), and in atlantoaxial instrumentation for orthopedic trainees by 18.0% (p=0.014). CONCLUSIONS: Spinal CAN is used most frequently by neurosurgeons and in academic centers. Most spine surgical trainees are not fully comfortable with the use of CAN, but report an increase in technical comfort with CAN guidance particularly for thoracic instrumentation. Increased education in spinal CAN for trainees, particularly at the fellowship stage and, specifically, for orthopedic surgery, may improve adoption.

CONTEXTE: La chirurgie assistée par ordinateur (CAO) permet d'améliorer la précision de l'exploration instrumentale employée dans le cas de fractures vertébrales et de maladies dégénératives de la colonne vertébrale. Cela dit, elle n'a pas encore été adoptée à grande échelle en raison d'un manque de formation, de coûts d'immobilisation considérables, d'obstacles liés à l'organisation du travail et de doutes quant à son exactitude. C'est dans cette perspective que nous voulons décrire, parmi divers champs de pratique, les transformations se rapportant au fil du temps à l'utilisation de la CAO de la colonne vertébral dans le cadre d'un régime de santé universel à payeur unique. Qui plus est, nous voulons aussi évaluer l'impact de la CAO en ce qui a trait aux compétences des stagiaires partout au Canada. MÉTHODES: Pour ce faire, nous avons passé en revue de façon rétrospective une base de données tenue à jour prospectivement au sujet de patients ontariens ayant été soumis de 2005 à 2014 à une exploration instrumentale de la colonne vertébrale. Les données obtenues portaient sur le type de pathologie traitée, sur la région de la colonne vertébrale visée, sur l'approche chirurgicale privilégiée, sur le type d'établissement et sur la spécialité du chirurgien ayant intervenu. Les compétences des stagiaires en matière de CAO ont également été évaluées à l'aide d'un questionnaire en ligne diffusé au sein de 15 programmes canadiens de chirurgie orthopédique et de neurochirurgie. RÉSULTATS: En tout, 16,8 % des fusions instrumentées réalisées au sein de notre cohorte ontarienne l'ont été à l'aide de la technique de la CAO. Cette dernière a été utilisée plus fréquemment dans des établissements d'enseignement universitaire (15,9 % par opposition à 12,3 % pour les autres; p<0,001) mais aussi plus souvent par des neurochirurgiens (21,0 % par opposition à 12,4 % par des chirurgiens orthopédiques; p<0,001). En outre, 34,1 % des résidents et des médecins suivant une formation complémentaire étaient parfaitement à l'aise dans l'utilisation de la CAO de la colonne vertébrale (48,1 % de ceux se spécialisant en neurochirurgie par opposition à 11,8 % de ceux se spécialisant en chirurgie orthopédique; p = 0,008). L'utilisation de la CAO a par ailleurs entraîné une augmentation, auto-déclarée, de 11,0 % de l'aptitude à faire usage de l'exploration instrumentale thoracique chez tous les stagiaires (p = 0,036); dans le cas de l'exploration instrumentale atlanto-axiale, cette augmentation a été de 18,0 % (p = 0,014) chez les stagiaires en chirurgie orthopédique. CONCLUSIONS: La CAO de la colonne vertébrale est employée le plus souvent par les neurochirurgiens dans des établissements d'enseignement universitaire. La plupart des stagiaires en chirurgie de la colonne vertébrale ne sont pas entièrement à l'aise en ce qui concerne l'utilisation de la CAO. Toutefois, ils ont signalé une augmentation de leur aisance à utiliser la CAO et à bénéficier de son assistance, en particulier dans des cas d'exploration instrumentale thoracique. En somme, une plus ample formation en matière de CAO de la colonne vertébrale offerte aux stagiaires, particulièrement à ceux suivant une formation complémentaire et dans le champ de la chirurgie orthopédique, pourrait favoriser son adoption.

Economic Evaluations in the Diagnosis and Management of Traumatic Brain Injury: A Systematic Review and Analysis of Quality.

BACKGROUND: Economic evaluations provide a unique opportunity to identify the optimal strategies for the diagnosis and management of traumatic brain injury (TBI), for which uncertainty is common and the economic burden is substantial. OBJECTIVE: The objective of this study was to systematically review and examine the quality of contemporary economic evaluations in the diagnosis and management of TBI. METHODS: Two reviewers independently searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, NHS Economic Evaluation Database, Health Technology Assessment Database, EconLit, and the Tufts CEA Registry for comparative economic evaluations published from 2000 onward (last updated on August 30, 2013). Data on methods, results, and quality were abstracted in duplicate. The results were summarized quantitatively and qualitatively. RESULTS: Of 3539 citations, 24 economic evaluations met our inclusion criteria. Nine were cost-utility, five were cost-effectiveness, three were cost-minimization, and seven were cost-consequences analyses. Only six studies were of high quality. Current evidence from high-quality studies suggests the economic attractiveness of the following strategies: a low medical threshold for computed tomography (CT) scanning of asymptomatic infants with possible inflicted TBI, selective CT scanning of adults with mild TBI as per the Canadian CT Head Rule, management of severe TBI according to the Brain Trauma Foundation guidelines, management of TBI in dedicated neurocritical care units, and early transfer of patients with TBI with nonsurgical lesions to neuroscience centers. CONCLUSIONS: Threshold-guided CT scanning, adherence to Brain Trauma Foundation guidelines, and care for patients with TBI, including those with nonsurgical lesions, in specialized settings appear to be economically attractive strategies.

Economic evaluation of decompressive craniectomy versus barbiturate coma for refractory intracranial hypertension following traumatic brain injury.

OBJECTIVES: Decompressive craniectomy and barbiturate coma are often used as second-tier strategies when intracranial hypertension following severe traumatic brain injury is refractory to first-line treatments. Uncertainty surrounds the decision to choose either treatment option. We investigated which strategy is more economically attractive in this context. DESIGN: We performed a cost-utility analysis. A Markov Monte Carlo microsimulation model with a life-long time horizon was created to compare quality-adjusted survival and cost of the two treatment strategies, from the perspective of healthcare payer. Model parameters were estimated from the literature. Two-dimensional simulation was used to incorporate parameter uncertainty into the model. Value of information analysis was conducted to identify major drivers of decision uncertainty and focus future research. SETTING: Trauma centers in the United States. SUBJECTS: Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury. INTERVENTIONS: We compared two treatment strategies: decompressive craniectomy and barbiturate coma. MEASUREMENTS AND MAIN RESULTS: Decompressive craniectomy was associated with an average gain of 1.5 quality-adjusted life years relative to barbiturate coma, with an incremental cost-effectiveness ratio of $9,565/quality-adjusted life year gained. Decompressive craniectomy resulted in a greater quality-adjusted life expectancy 86% of the time and was more cost-effective than barbiturate coma in 78% of cases if our willingness-to-pay threshold is $50,000/quality-adjusted life year and 82% of cases at a threshold of $100,000/quality-adjusted life year. At older age, decompressive craniectomy continued to increase survival but at higher cost (incremental cost-effectiveness ratio = $197,906/quality-adjusted life year at mean age = 85 yr). CONCLUSIONS: Based on available evidence, decompressive craniectomy for the treatment of refractory intracranial hypertension following traumatic brain injury provides better value in terms of costs and health gains than barbiturate coma. However, decompressive craniectomy might be less economically attractive for older patients. Further research, particularly on natural history of severe traumatic brain injury patients, is needed to make more informed treatment decisions.

Mutations in SUFU predispose to medulloblastoma.

The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.

Enhanced delivery of gold nanoparticles with therapeutic potential into the brain using MRI-guided focused ultrasound.

The blood brain barrier (BBB) is a major impediment to the delivery of therapeutics into the central nervous system (CNS). Gold nanoparticles (AuNPs) have been successfully employed in multiple potential therapeutic and diagnostic applications outside the CNS. However, AuNPs have very limited biodistribution within the CNS following intravenous administration. Magnetic resonance imaging guided focused ultrasound (MRgFUS) is a novel technique that can transiently increase BBB permeability allowing delivery of therapeutics into the CNS. MRgFUS has not been previously employed for delivery of AuNPs into the CNS. This work represents the first demonstration of focal enhanced delivery of AuNPs into the CNS using MRgFUS in a rat model both safely and effectively. Histologic visualization and analytical quantification of AuNPs within the brain parenchyma suggest BBB transgression. These results suggest a role for MRgFUS in the delivery of AuNPs with therapeutic potential into the CNS for targeting neurological diseases. FROM THE CLINICAL EDITOR: Gold nanoparticles have been successfully utilized in experimental diagnostic and therapeutic applications; however, the blood-brain barrier (BBB) is not permeable to these particles. In this paper, the authors demonstrated that MRI guided focused ultrasound is capable to transiently open the BBB thereby enabling CNS access.

Focused ultrasound disruption of the blood-brain barrier: a new frontier for therapeutic delivery in molecular neurooncology.

Recent advances in molecular neurooncology provide unique opportunities for targeted molecular-based therapies. However, the blood-brain barrier (BBB) remains a major limitation to the delivery of tumor-specific therapies directed against aberrant signaling pathways in brain tumors. Given the dismal prognosis of patients with malignant brain tumors, novel strategies that overcome the intrinsic limitations of the BBB are therefore highly desirable. Focused ultrasound BBB disruption is emerging as a novel strategy for enhanced delivery of therapeutic agents into the brain via focal, reversible, and safe BBB disruption. This review examines the potential role and implications of focused ultrasound in molecular neurooncology.

Intraoperative Error Propagation in 3-Dimensional Spinal Navigation From Nonsegmental Registration: A Prospective Cadaveric and Clinical Study.

STUDY DESIGN: Prospective pre-clinical and clinical cohort study. OBJECTIVES: Current spinal navigation systems rely on a dynamic reference frame (DRF) for image-to-patient registration and tool tracking. Working distant to a DRF may generate inaccuracy. Here we quantitate predictors of navigation error as a function of distance from the registered vertebral level, and from intersegmental mobility due to surgical manipulation and patient respiration. METHODS: Navigation errors from working distant to the registered level, and from surgical manipulation, were quantified in 4 human cadavers. The 3-dimensional (3D) position of a tracked tool tip at 0 to 5 levels from the DRF, and during targeting of pedicle screw tracts, was captured in real-time by an optical navigation system. Respiration-induced vertebral motion was quantified from 10 clinical cases of open posterior instrumentation. The 3D position of a custom spinous-process clamp was tracked over 12 respiratory cycles. RESULTS: An increase in mean 3D navigation error of ≥2 mm was observed at ≥2 levels from the DRF in the cervical and lumbar spine. Mean ± SD displacement due to surgical manipulation was 1.55 ± 1.13 mm in 3D across all levels, ≥2 mm in 17.4%, 19.2%, and 38.5% of levels in the cervical, thoracic, and lumbar spine, respectively. Mean ± SD respiration-induced 3D motion was 1.96 ± 1.32 mm, greatest in the lower thoracic spine (P < .001). Tidal volume and positive end-expiratory pressure correlated positively with increased vertebral displacement. CONCLUSIONS: Vertebral motion is unaccounted for during image-guided surgery when performed at levels distant from the DRF. Navigating instrumentation within 2 levels of the DRF likely minimizes the risk of navigation error.

Quantification of computational geometric congruence in surface-based registration for spinal intra-operative three-dimensional navigation.

BACKGROUND CONTEXT: Computer-assisted navigation (CAN) may guide spinal instrumentation, and requires alignment of patient anatomy to imaging. Iterative closest-point (ICP) algorithms register anatomical and imaging surface datasets, which may fail in the presence of geometric symmetry (congruence), leading to failed registration or inaccurate navigation. Here we computationally quantify geometric congruence in posterior spinal exposures, and identify predictors of potential navigation inaccuracy. METHODS: Midline posterior exposures were performed from C1-S1 in four human cadavers. An optically-based CAN generated surface maps of the posterior elements at each level. Maps were reconstructed to include bilateral hemilamina, or unilateral hemilamina with/without the base of the spinous process. Maps were fitted to symmetrical geometries (cylindrical/spherical/planar) using computational modelling, and the degree of model fit quantified based on the ratio of model inliers to total points. Geometric congruence was subsequently assessed clinically in 11 patients undergoing midline exposures in the cervical/thoracic/lumbar spine for posterior instrumented fusion. RESULTS: In cadaveric testing, increased cylindrical/spherical/planar symmetry was seen in the high-cervical and subaxial cervical spine relative to the thoracolumbar spine (p<0.001). Extension of unilateral exposures to include the ipsilateral base of the spinous process decreased symmetry independent of spinal level (p<0.001). In clinical testing, increased cylindrical/spherical/planar symmetry was seen in the subaxial cervical relative to the thoracolumbar spine (p<0.001), and in the thoracic relative to the lumbar spine (p<0.001). Symmetry in unilateral exposures was decreased by 20% with inclusion of the ipsilateral base of the spinous process. CONCLUSIONS: Geometric congruence is most evident at C1 and the subaxial cervical spine, warranting greater vigilance in navigation accuracy verification. At all levels, inclusion of the base of the spinous process in unilateral registration decreases the likelihood of geometric symmetry and navigation error. This work is important to allow the extension of line-of-sight based registration techniques to minimally-invasive unilateral approaches.

Optical Topographic Imaging for Spinal Intraoperative Three-Dimensional Navigation in Mini-Open Approaches: A Prospective Cohort Study of Initial Preclinical and Clinical Feasibility.

OBJECTIVE: Computer-assisted three-dimensional navigation often guides spinal instrumentation. Optical topographic imaging (OTI) offers comparable accuracy and significantly faster registration relative to current navigation systems in open posterior thoracolumbar exposures. We validate the usefulness and accuracy of OTI in minimally invasive spinal approaches. METHODS: Mini-open midline posterior exposures were performed in 4 human cadavers. Square exposures of 25, 30, 35, and 40 mm were registered to preoperative computed tomography imaging. Screw tracts were fashioned using a tracked awl and probe with instrumentation placed. Navigation data were compared with screw positions on postoperative computed tomography imaging, and absolute translational and angular deviations were computed. In vivo validation was performed in 8 patients, with mini-open thoracolumbar exposures and percutaneous placement of navigated instrumentation. Navigated instrumentation was performed in the previously described manner. RESULTS: For 37 cadaveric screws, absolute translational errors were (1.79 ± 1.43 mm) and (1.81 ± 1.51 mm) in the axial and sagittal planes, respectively. Absolute angular deviations were (3.81 ± 2.91°) and (3.45 ± 2.82°), respectively (mean ± standard deviation). The number of surface points registered by the navigation system, but not exposure size, correlated positively with the likelihood of successful registration (odds ratio, 1.02; 95% confidence interval, 1.009-1.024; P < 0.001). Fifty-five in vivo thoracolumbar pedicle screws were analyzed. Overall (mean ± standard deviation) axial and sagittal translational errors were (1.79 ± 1.41 mm) and (2.68 ± 2.26 mm), respectively. Axial and sagittal angular errors were (3.63° ± 2.92°) and (4.65° ± 3.36°), respectively. There were no radiographic breaches >2 mm or any neurovascular complications. CONCLUSIONS: OTI is a novel navigation technique previously validated for open posterior exposures and in this study has comparable accuracy for mini-open minimally invasive surgery exposures. The likelihood of successful registration is affected more by the geometry of the exposure than by its size.

Optical Topographic Imaging for Spinal Intraoperative 3-Dimensional Navigation in the Cervical Spine: Initial Preclinical and Clinical Feasibility.

OF BACKGROUND DATA: Computer-assisted 3-dimensional navigation may guide spinal instrumentation. Optical topographic imaging (OTI) is a novel navigation technique offering comparable accuracy and significantly faster registration workflow relative to current navigation systems. It has previously been validated in open posterior thoracolumbar exposures. OBJECTIVE: To validate the utility and accuracy of OTI in the cervical spine. STUDY DESIGN: This is a prospective preclinical cadaveric and clinical cohort study. METHODS: Standard midline open posterior cervical exposures were performed, with segmental OTI registration at each vertebral level. In cadaveric testing, OTI navigation guidance was used to track a drill guide for cannulating screw tracts in the lateral mass at C1, pars at C2, lateral mass at C3-6, and pedicle at C7. In clinical testing, translaminar screws at C2 were also analyzed in addition. Planned navigation trajectories were compared with screw positions on postoperative computed tomographic imaging, and quantitative navigation accuracies, in the form of absolute translational and angular deviations, were computed. RESULTS: In cadaveric testing (mean±SD) axial and sagittal translational navigation errors were (1.66±1.18 mm) and (2.08±2.21 mm), whereas axial and sagittal angular errors were (4.11±3.79 degrees) and (6.96±5.40 degrees), respectively.In clinical validation (mean±SD) axial and sagittal translational errors were (1.92±1.37 mm) and (1.27±0.97 mm), whereas axial and sagittal angular errors were (3.68±2.59 degrees) and (3.47±2.93 degrees), respectively. These results are comparable to those achieved with OTI in open thoracolumbar approaches, as well as using current spinal neuronavigation systems in similar applications. There was no radiographic facet, canal or foraminal violations, nor any neurovascular complications. CONCLUSIONS: OTI is a novel navigation technique allowing efficient initial and repeat registration. Accuracy even in the more mobile cervical spine is comparable to current spinal neuronavigation systems.

High-Intensity Focused Ultrasound Ablation Therapy of Gliomas.

Ultrasound in clinical medicine is most commonly associated with imaging, but can be harnessed to yield an array of biological effects, including thermal ablation of brain tumors. Therapeutic ultrasound has been studied for many years, but only within the last decade has the technology reached a point where it is safe and practical for clinical adoption. Using large, multi-element arrays, ultrasound can be focused through the skull, and combined with MRI for image guidance and real-time thermometry, to create lesions in the brain with millimeter accuracy. Using this technology, true non-invasive surgery can be accomplished with immediate tumor killing. Combining the ablative capabilities of focused ultrasound with its other unique effects, such as blood-brain barrier disruption and radiosensitization, may eventually result in change of the current glioma treatment paradigm.

Understanding Hospital Volume-Outcome Relationship in Severe Traumatic Brain Injury.

BACKGROUND: The hospital volume-outcome relationship in severe traumatic brain injury (TBI) population remains unclear. OBJECTIVE: To examine the relationship between volume of patients with severe TBI per hospital and in-hospital mortality, major complications, and mortality following a major complication (ie, failure to rescue). METHODS: In a multicenter cohort study, data on 9255 adults with severe TBI were derived from 111 hospitals participating in the American College of Surgeons Trauma Quality Improvement Program over 2009-2011. Hospitals were ranked into quartiles based on their volume of severe TBI during the study period. Random-intercept multilevel models were used to examine the association between hospital quartile of severe TBI volume and in-hospital mortality, major complications, and mortality following a major complication after adjusting for patient and hospital characteristics. In sensitivity analyses, we examined these associations after excluding transferred cases. RESULTS: Overall mortality was 37.2% (n = 3447). Two thousand ninety-eight patients (22.7%) suffered from 1 or more major complication. Among patients with major complications, 27.8% (n = 583) died. Higher-volume hospitals were associated with lower mortality; the adjusted odds ratio of death was 0.50 (95% confidence interval: 0.29-0.85) in the highest volume quartile compared to the lowest. There was no significant association between hospital-volume quartile and the odds of a major complication or the odds of death following a major complication. After excluding transferred cases, similar results were found. CONCLUSION: High-volume hospitals might be associated with lower in-hospital mortality following severe TBI. However, this mortality reduction was not associated with lower risk of major complications or death following a major complication.

Structure, Process, and Culture of Intensive Care Units Treating Patients with Severe Traumatic Brain Injury: Survey of Centers Participating in the American College of Surgeons Trauma Quality Improvement Program.

Outcome after severe traumatic brain injury (TBI) differs substantially between hospitals. Explaining this variation begins with understanding the differences in structures and processes of care, particularly at intensive care units (ICUs) where acute TBI care takes place. We invited trauma medical directors (TMDs) from 187 centers participating in the American College of Surgeons Trauma Quality Improvement Program (ACS TQIP) to complete a survey. The survey domains included ICU model, type, availability of specialized units, staff, training programs, standard protocols and order sets, approach to withdrawal of life support, and perceived level of neurosurgeons' engagement in the ICU management of TBI. One hundred forty-two TMDs (76%) completed the survey. Severe TBI patients are admitted to dedicated neurocritical care units in 52 hospitals (37%), trauma ICUs in 44 hospitals (31%), general ICUs in 34 hospitals (24%), and surgical ICUs in 11 hospitals (8%). Fifty-seven percent are closed units. Board-certified intensivists directed 89% of ICUs, whereas 17% were led by neurointensivists. Sixty percent of ICU directors were general surgeons. Thirty-nine percent of hospitals had critical care fellowships and 11% had neurocritical care fellowships. Fifty-nine percent of ICUs had standard order sets and 61% had standard protocols specific for TBI, with the most common protocol relating to intracranial pressure management (53%). Only 43% of TMDs were satisfied with the current level of neurosurgeons' engagement in the ICU management of TBI; 46% believed that neurosurgeons should be more engaged; 11% believed they should be less engaged. In the largest survey of North American ICUs caring for TBI patients, there is substantial variation in the current approaches to ICU care for TBI, highlighting multiple opportunities for comparative effectiveness research.

NIH workshop report on the trans-agency blood-brain interface workshop 2016: exploring key challenges and opportunities associated with the blood, brain and their interface.

A trans-agency workshop on the blood-brain interface (BBI), sponsored by the National Heart, Lung and Blood Institute, the National Cancer Institute and the Combat Casualty Care Research Program at the Department of Defense, was conducted in Bethesda MD on June 7-8, 2016. The workshop was structured into four sessions: (1) blood sciences; (2) exosome therapeutics; (3) next generation in vitro blood-brain barrier (BBB) models; and (4) BBB delivery and targeting. The first day of the workshop focused on the physiology of the blood and neuro-vascular unit, blood or biofluid-based molecular markers, extracellular vesicles associated with brain injury, and how these entities can be employed to better evaluate injury states and/or deliver therapeutics. The second day of the workshop focused on technical advances in in vitro models, BBB manipulations and nanoparticle-based drug carrier designs, with the goal of improving drug delivery to the central nervous system. The presentations and discussions underscored the role of the BBI in brain injury, as well as the role of the BBB as both a limiting factor and a potential conduit for drug delivery to the brain. At the conclusion of the meeting, the participants discussed challenges and opportunities confronting BBI translational researchers. In particular, the participants recommended using BBI translational research to stimulate advances in diagnostics, as well as targeted delivery approaches for detection and therapy of both brain injury and disease.

Spinal intraoperative three-dimensional navigation: correlation between clinical and absolute engineering accuracy.

BACKGROUND CONTEXT: Spinal intraoperative computer-assisted navigation (CAN) may guide pedicle screw placement. Computer-assisted navigation techniques have been reported to reduce pedicle screw breach rates across all spinal levels. However, definitions of screw breach vary widely across studies, if reported at all. The absolute quantitative error of spinal navigation systems is theoretically a more precise and generalizable metric of navigation accuracy. It has also been computed variably and reported in less than a quarter of clinical studies of CAN-guided pedicle screw accuracy. PURPOSE: This study aimed to characterize the correlation between clinical pedicle screw accuracy, based on postoperative imaging, and absolute quantitative navigation accuracy. DESIGN/SETTING: This is a retrospective review of a prospectively collected cohort. PATIENT SAMPLE: We recruited 30 patients undergoing first-time posterior cervical-thoracic-lumbar-sacral instrumented fusion±decompression, guided by intraoperative three-dimensional CAN. OUTCOME MEASURES: Clinical or radiographic screw accuracy (Heary and 2 mm classifications) and absolute quantitative navigation accuracy (translational and angular error in axial and sagittal planes). METHODS: We reviewed a prospectively collected series of 209 pedicle screws placed with CAN guidance. Each screw was graded clinically by multiple independent raters using the Heary and 2 mm classifications. Clinical grades were dichotomized per convention. The absolute accuracy of each screw was quantified by the translational and angular error in each of the axial and sagittal planes. RESULTS: Acceptable screw accuracy was achieved for significantly fewer screws based on 2 mm grade versus Heary grade (92.6% vs. 95.1%, p=.036), particularly in the lumbar spine. Inter-rater agreement was good for the Heary classification and moderate for the 2 mm grade, significantly greater among radiologists than surgeon raters. Mean absolute translational-angular accuracies were 1.75 mm-3.13° and 1.20 mm-3.64° in the axial and sagittal planes, respectively. There was no correlation between clinical and absolute navigation accuracy. CONCLUSIONS: Radiographic classifications of pedicle screw accuracy vary in sensitivity across spinal levels, as well as in inter-rater reliability. Correlation between clinical screw grade and absolute navigation accuracy is poor, as surgeons appear to compensate for navigation registration error. Future studies of navigation accuracy should report absolute translational and angular errors. Clinical screw grades based on postoperative imaging may be more reliable if performed in multiple by radiologist raters.

Defining the Pathway to Definitive Care and Surgical Decompression after Traumatic Spinal Cord Injury: Results of a Canadian Population-Based Cohort Study.

Early access to specialized care after acute traumatic spinal cord injury (SCI) is associated with improved outcomes. However, many SCI patients do not receive timely access to such care. To characterize and quantify patients' pathway to definitive care and surgery post SCI, and to identify factors that may delay expeditious care, a population based cohort study was performed in Ontario. Using provincial administrative health data, adult patients with acute traumatic SCI who underwent surgery between 2002 and 2011 were identified using SCI specific ICD-10 codes. The relationship between predictor variables and a) time to arrival at the site of definitive care and b) time to surgery was statistically evaluated. Of 1,111 patients meeting eligibility criteria, mean times to arrival at the site of definitive care and to surgery were 8.1 ± 25.5 and 49.4 ± 65.0 hours respectively, with 53.3% of patients having surgery prior to 24 hours. While most patients (88.4%) reached the site of definitive care within 6 hours, only 34.2% reached surgery within 12 hours of arrival. Older age (IRR = 1.01; 95% CI: 1.01, 1.02), increased number of stops at intermediate health care centers (IRR = 7.70; 95% CI: 7.54, 7.86), higher comorbidity index (IRR = 1.43; 95% CI: 1.14, 1.72) and fall related SCI etiology (IRR = 1.16; 95% CI: 1.02, 1.29) were associated with increased time to arrival at definitive care. For surgery, increased age (OR = 1.02; 95% CI: 1.01, 1.03) and stops at intermediate health centers (OR = 2.48; 95% CI: 1.35, 4.56) were associated with a greater odds of undergoing late surgery (>24hrs). These results can inform policy decisions and facilitate creation of a streamlined path to specialized care for patients with acute SCI.

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling.

Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, beta-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind beta-catenin, export it from the nucleus, and thereby repress beta-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of beta-catenin, and cannot inhibit beta-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.

Identification of differentially expressed and developmentally regulated genes in medulloblastoma using suppression subtraction hybridization.

To increase our understanding of the molecular pathogenesis of medulloblastoma (MB), we utilized the technique of suppression subtractive hybridization (SSH) to identify genes that are dysregulated in MB when compared to cerebellum. SSH-enriched cDNA libraries from both human and Ptch+/- heterozygous murine MBs were generated by subtracting common cDNAs from corresponding non-neoplastic cerebellum. For the human classic MB library, total human cerebellar RNA was used as control tissue; for the Ptch+/- heterozygous MB, non-neoplastic cerebellum from an unaffected Ptch+/- littermate was used as the control. Through differential screening of these libraries, over 100 upregulated tumor cDNA fragments were isolated, sequenced and identified with the NCBI BLAST program. From these, we selected genes involved in cellular proliferation, antiapoptosis, and cerebellar differentiation for further analysis. Upregulated genes identified in the human MB library included Unc33-like protein (ULIP), SOX4, Neuronatin (NNAT), the mammalian homologue of Drosophila BarH-like 1(BARHL1), the nuclear matix protein NRP/B (ENC1), and the homeobox OTX2 gene. Genes found to be upregulated in the murine MB library included cyclin D2 (Ccnd2), thymopoietin (Tmpo), Musashi-1 (Msh1), protein phosphatase 2A inhibitor-2 (I-2pp2a), and Unc5h4(D). Using semiquantitative reverse transcription-polymerase chain reaction (RT-PCR), the mRNA expression levels for these genes were markedly higher in human MBs than in cerebellum. Western blot analysis was used to further confirm the overexpression of a subset of these genes at the protein level. Notch pathway overactivity was demonstrated in the TE671 MB cell line expressing high levels of MSH1 through HES1-Luciferase transfections. This study has revealed a panel of developmentally regulated genes that may be involved in the pathogenesis of MB.

A clinicobiological model predicting survival in medulloblastoma.

PURPOSE: The purpose of this study was to determine the relative contributions of biological and clinical predictors of survival in patients with medulloblastoma (MB). EXPERIMENTAL DESIGN: Clinical presentation and survival information were obtained for 119 patients who had undergone surgery for MB at the Hospital for Sick Children (Toronto, Ontario, Canada) between 1985 and 2001. A tissue microarray was constructed from the tumor samples. The arrays were assayed for immunohistochemical expression of MYC, p53, platelet-derived growth factor receptor-alpha, ErbB2, MIB-1, and TrkC and for apoptosis (terminal deoxynucleotidyl transferase-mediated nick end labeling). Both univariable and multivariable analyses were conducted to characterize the association between survival and both clinical and biological markers. For the strongest predictors of survival, a weighted predictive score was calculated based on their hazard ratios (HRs). The sum of these scores was then used to give an overall prediction of survival using a nomogram. RESULTS: The four strongest predictors of survival in the final multivariable model were the presence of metastatic disease at presentation (HR, 2.02; P=0.01) and p53 (HR, 2.29; P=0.02), TrkC (HR, 0.65; P=0.14), and ErbB2 (HR, 1.51; P=0.21) immunopositivity. A linear prognostic index was derived, with coefficients equal to the logarithm of these HRs. The 5-year survival rate for patients at the 10th, 50th, and 90th percentiles of the score distribution was 80.0%, 71.0%, and 35.7%, respectively, with radiation therapy and 70.5%, 58.5%, and 20.0%, respectively, without radiation therapy. CONCLUSIONS: In this study, we demonstrate an approach to combining both clinical and biological markers to quantify risk in MB patients. This provides further prognostic information than can be obtained when either clinical factors or biological markers are studied separately and establishes a framework for comparing prognostic markers in future clinical studies.

Dramatic Cataplexy Improvement Following Right Parietal Surgery.

This is the case of a 34-year-old woman with severe narcolepsy with cataplexy who experienced a dramatic reduction in cataplexy symptoms after resection of a right parietal astrocytoma. The patient underwent detailed neurological exam, neuropsychological testing, polysomnography and multiple sleep latency testing following surgery.