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Supplementary Figures 1-5 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Medulloblastoma (MB) is a malignant cerebellar tumor that occurs primarily in children. The hepatocyte growth factor (HGF)/MET pathway has an established role in both normal cerebellar development as well as the development and progression of human brain tumors, including MB. To identify novel tumor suppressor genes involved in MB pathogenesis, we performed an epigenome-wide screen in MB cell lines, using 5-aza-2′deoxycytidine to identify genes aberrantly silenced by promoter hypermethylation. Using this technique, we identified an inhibitor of HGF/MET signaling, serine protease inhibitor kunitz-type 2 (SPINT2/HAI-2), as a putative tumor suppressor silenced by promoter methylation in MB. In addition, based on single nucleotide polymorphism array analysis in primary MB samples, we identified hemizygous deletions targeting the SPINT2 locus in addition to gains on chromosome 7 encompassing the HGF and MET loci. SPINT2 gene expression was down-regulated and MET expression was up-regulated in 73.2% and 45.5% of tumors, respectively, by quantitative real-time PCR. SPINT2 promoter methylation was detected in 34.3% of primary MBs examined by methylation-specific PCR. SPINT2 reexpression in MB cell lines reduced proliferative capacity, anchorage independent growth, cell motility in vitro, and increased overall survival times in vivo in a xenograft model (P < 0.0001). Taken together, these data support the role of SPINT2 as a putative tumor suppressor gene in MB, and further implicate dysregulation of the HGF/MET signaling pathway in the pathogenesis of MB. [Cancer Res 2008;68(23):9945–53]

Supplementary Figure 7 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

Supplementary Figure 6 from An Epigenetic Genome-Wide Screen Identifies SPINT2 as a Novel Tumor Suppressor Gene in Pediatric Medulloblastoma

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.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.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%, plt;0.001) and by neurosurgeons than orthopedic surgeons (21.0% vs. 12.4%, plt;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).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.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.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.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; p0,001) mais aussi plus souvent par des neurochirurgiens (21,0 % par opposition à 12,4 % par des chirurgiens orthopédiques; p0,001). 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.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.

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.

Intraoperative image-guided surgical navigation for craniospinal procedures has significantly improved accuracy by providing an avenue for the surgeon to visualize underlying internal structures corresponding to the exposed surface anatomy. Despite the obvious benefits of surgical navigation, surgeon adoption remains relatively low due to long setup and registration times, steep learning curves, and workflow disruptions. We introduce an experimental navigation system utilizing optical topographical imaging (OTI) to acquire the 3D surface anatomy of the surgical cavity, enabling visualization of internal structures relative to exposed surface anatomy from registered preoperative images. Our OTI approach includes near instantaneous and accurate optical measurement of >250,000 surface points, computed at >52,000 points-per-second for considerably faster patient registration than commercially available benchmark systems without compromising spatial accuracy. Our experience of 171 human craniospinal surgical procedures, demonstrated significant workflow improvement (41 s vs. 258 s and 794 s, p

Purpose To validate ferumoxytol-based quantitative blood oxygenation level-dependent (BOLD) MRI for mapping oxygenation of human infiltrative astrocytomas by using intraoperative measurement of tissue oxygen tension and histologic staining. Materials and Methods Fifteen patients with infiltrative astrocytomas were recruited into this prospective multicenter study between July 2014 and December 2016. Prior to treatment, participants underwent preoperative quantitative BOLD MRI with ferumoxytol to generate tissue oxygen saturation (StO2) maps. Two intratumoral sites were identified, one with low StO2 and one with high StO2. Neuronavigation was used to locate sites intraoperatively for insertion of oxygen-sensing probes to measure local tissue oxygen tension (PtO2). Biopsies from both sites were taken and stained for markers of hypoxia (hypoxia-inducible factor 1α, carbonic anhydrase IX) and neoangiogenesis (vascular endothelial growth factor, endoglin [CD105]). Spearman correlation and nonparametric sign-rank tests were used to analyze data. Results Ten patients with median age of 58.5 years (interquartile range, 25 years; four men and six women) completed the study. Because there is no linear relationship between StO2 and PtO2, the ratios of low to high StO2 versus low to high PtO2 in each patient were compared and a significant correlation was found (r = 0.73; P = .01). Pathologic analyses revealed differences between carbonic anhydrase IX (P = .03) for sites of low StO2 versus high StO2. CD105 displayed a similar trend but was not significant (P = .09). Conclusion Ferumoxytol-based quantitative blood oxygenation level-dependent MRI can potentially be used as a noninvasive surrogate for oxygenation mapping in infiltrative astrocytomas. This technique can potentially be integrated in treatment planning for aggressive targeting of hypoxic areas in tumors.

Background Intraosseous vascular anomalies (IOVA) are rare in the craniofacial skeleton and present a diagnostic and therapeutic challenge. This study aims to describe the clinical management based on a large case series. Methods A retrospective chart review was performed and 9 IOVA were identified over a 15-year period. Data on demographics, diagnostic features, clinical management, and outcomes were reviewed. Results Five frontal bone IOVA and 4 orbital IOVA were identified. The postoperative follow-up ranged from 4 months to 4 years. All 9 lesions were diagnosed with computed tomography (CT) imaging. Magnetic resonance imaging (MRI) was used to delineate soft tissue involvement in 2 patients presenting with oculo-orbital dystopia and ophthalmoplegia. En bloc excision was performed in all patients. Preoperative interventional embolization was critical in the successful resection of an orbital IOVA following 2 previously failed attempts that were aborted secondary to hemorrhage. Intraoperative 3-dimensional stereotactic navigation was used for the accurate en bloc excision of a frontal IOVA to prevent injury to the frontal sinus. Reconstruction of esthetic and functional deformities was successfully accomplished. Conclusion The diagnosis of IOVA relies primarily on clinical assessment and CT imaging. Further interpretation of the involvement of periorbital, facial, and intracranial soft tissue is best defined by MRI. Multidisciplinary care with interventional radiology and neurosurgery must be considered for ensuring the safe and adequate en bloc excision of craniofacial IOVA.

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.

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.

MR-guided focused ultrasound (MRgFUS) is an emerging technology that can accurately and transiently permeabilize the blood-brain barrier (BBB) for targeted drug delivery to the central nervous system. We conducted a single-arm, first-in-human trial to investigate the safety and feasibility of MRgFUS-induced BBB opening in eloquent primary motor cortex in four volunteers with amyotrophic lateral sclerosis (ALS). Here, we show successful BBB opening using MRgFUS as demonstrated by gadolinium leakage at the target site immediately after sonication in all subjects, which normalized 24 hours later. The procedure was well-tolerated with no serious clinical, radiologic or electroencephalographic adverse events. This study demonstrates that non-invasive BBB permeabilization over the motor cortex using MRgFUS is safe, feasible, and reversible in ALS subjects. In future, MRgFUS can be coupled with promising therapeutics providing a targeted delivery platform in ALS., MR-focused ultrasound can be used to transiently open the blood-brain barrier (BBB). Here, the authors report the results of a first-in-human trial on four patients with amyotrophic lateral sclerosis (ALS), showing that the procedure reversibly permeabilised the BBB in the motor cortex without complications, and suggest that the procedure could in the future be used to increase drug delivery in ALS patients.

Purpose Limited data exist quantifying the risk of adverse radiation effect (ARE) specific to hypofractionated stereotactic radiosurgery (HSRS). We present our analyses of the risk of ARE after 5 daily fractions of HSRS to surgical cavities and intact metastases. Methods and Materials One hundred and eighty-seven consecutively treated patients with 118 surgical cavities and 132 intact metastases were retrospectively reviewed. All patients were treated with 5 daily fractions with a 2 mm planning target volume applied. Clinical and dosimetric variables were assessed to identify predictors of ARE. Results The median total prescribed dose was 30 Gy (range, 20-35 Gy) and median follow-up was 12 months. One hundred forty-four patients (77%) received treatment to a single target. Median planning target volumes for resection cavity and intact metastases were 24.9 cm3 and 7.7 cm3, respectively. ARE and symptomatic ARE were observed 21.2% and 10.8% of targets, respectively, and the median time to ARE was 8 months. Time to ARE was 12 months for 19% of targets. Multivariable analysis identified intact metastases versus cavities (odds ratio [OR], 3.65; 95% confidence interval [CI], 1.33-10) as a significant predictor of symptomatic ARE. Specific to cavity HSRS, prior whole brain radiation therapy (OR 7.73; 95% CI, 1.67-35.69) and prior stereotactic radiosurgery (OR 8.66; 95% CI, 1.14-65.7) were significant predictors of symptomatic ARE. For intact metastases, the total brain minus gross tumor volume (GTV) receiving 30 Gy (BMC30) was a significant predictor of symptomatic ARE (OR, 1.21; 95% CI, 1.02-1.43), and a volume-based BMC30 threshold of 10.5 cm3 was significant with an OR of 7.21 (95% CI, 1.31-39.45). Conclusions The risk of ARE was greater for intact metastases compared with cavities after HSRS. For intact lesions, the BMC30 was predictive for symptomatic necrosis, and a threshold of 10.5 cm3 may guide treatment planning.

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.

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.

Introduction Glioblastoma is a highly malignant and infiltrative brain tumor, with a median overall survival of about 15 months. Gross-total resection using 5-aminolevulinic acid (5-ALA) assisted fluorescence-guided tumor resection has been shown to prolong progression free survival. Here, we report the utility of multi-modality imaging in conjunction with the 5-ALA fluorescence in resection of an IDH (R132H) wildtype malignant astrocytoma. Case background A 58-year old male, presented with a generalized seizure and was found to have a right-anterior temporal lobe lesion, measuring 7.42 cm3 in volume. Given the patient's left-hand dominance, functional-MRI and white-matter tractography using diffuse tensor imaging was performed. These image series, along with T1-weighted contrast enhanced MRI and CT scans were inter-registered and fused to create a multi-modality image dataset. This fused dataset was used in preoperative planning and intraoperatively for stereotactic surgical navigation. Discussion A gross-total resection of the tumor was achieved for this case. Three other glioblastoma cases were performed at this site using the same technique described. The average extent of resection achieved was 96 ± 4%, with no post-operative neurological complications. While it is not clear that 5-ALA fluorescence guided resection alone improves the overall survival of patients with glioblastoma, this intra-operative adjunct certainly enables complete resections of contrast-enhancing tumors, leading to improved progression-free survival. Conclusion This case study shows a single-institution experience with multi-modality fluoresce-guided tumor resection – providing the surgeon with the safest avenue to aggressively excise tumor with a goal to achieve maximal resection with greater efficacy and safety.

Background Cavity stereotactic radiotherapy has emerged as a standard option following resection of brain metastases. However, the optimal approach with either single-fraction or hypofractionated stereotactic radiotherapy (HSRT) remains a significant question. Objective To report outcomes for 5-fraction HSRT to the surgical cavity, based on contouring according to a recently reported international consensus guideline. Methods Patients treated with cavity HSRT were identified from a prospective institutional database. Local brain control (LC), distant brain failure (DBF), leptomeningeal disease (LMD), and overall survival rates were determined. Univariate and multivariable analyses were performed on potential predictive factors. Results One hundred thirty-seven cavities in 122 patients were treated at a median total dose of 30 Gy (range, 25-35 Gy). The median follow-up was 16 mo (range, 1-60 mo). Nonsmall cell lung cancer was the most common histology (44%), followed by breast cancer (21%). In 57% of surgical cavities, the preoperative tumor diameter was >3 cm. One-year LC, DBF, LMD, and overall survival rates were 84%, 45%, 22%, and 62%, respectively. Multivariable analyses identified colorectal (hazard ratio [HR] 4.1, P = .0066) and melanoma (HR 2.4, P = .012) metastases as predictors of local recurrence; preoperative tumor diameter >2 cm (HR 8.9, P = .012) and absence of targeted therapy (HR 4.4, P = .03) as predictors of DBF; and breast cancer histology (HR 2.1, P = .05) and subtotal resection (HR 2.6, P = .009) as predictors of LMD. Symptomatic radiation necrosis was observed in 7 patients (6%). Conclusion High rates of LC were observed following this 5-fraction HSRT regimen. Superiority as compared to single-fraction SRS requires a randomized trial.

The blood-brain barrier (BBB) has long limited therapeutic access to brain tumor and peritumoral tissue. In animals, MR-guided focused ultrasound (MRgFUS) with intravenously injected microbubbles can temporarily and repeatedly disrupt the BBB in a targeted fashion, without open surgery. Our objective is to demonstrate safety and feasibility of MRgFUS BBB opening with systemically administered chemotherapy in patients with glioma in a phase I, single-arm, open-label study. Five patients with previously confirmed or suspected high-grade glioma based on imaging underwent the MRgFUS in conjunction with administration of chemotherapy (n = 1 liposomal doxorubicin, n = 4 temozolomide) one day prior to their scheduled surgical resection. Samples of “sonicated” and “unsonicated” tissue were measured for the chemotherapy by liquid-chromatography-mass spectrometry. Complete follow-up was three months. The procedure was well-tolerated, with no adverse clinical or radiologic events related to the procedure. The BBB within the target volume showed radiographic evidence of opening with an immediate 15–50% increased contrast enhancement on T1-weighted MRI, and resolution approximately 20 hours after. Biochemical analysis of sonicated versus unsonicated tissue suggest chemotherapy delivery is feasible. In this study, we demonstrated transient BBB opening in tumor and peritumor tissue using non-invasive low-intensity MRgFUS with systemically administered chemotherapy was safe and feasible. The characterization of therapeutic delivery and clinical response to this treatment paradigm requires further investigation.

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.

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.

OBJECT Well-designed studies linking intracranial pressure (ICP) monitoring with improved outcomes among children with severe traumatic brain injury (TBI) are lacking. The main objective of this study was to examine the relationship between ICP monitoring in children and in-hospital mortality following severe TBI. METHODS An observational study was conducted using data derived from 153 adult or mixed (adult and pediatric) trauma centers participating in the American College of Surgeons (ACS) Trauma Quality Improvement Program (TQIP) and 29 pediatric trauma centers participating in the pediatric pilot TQIP between 2010 and 2012. Random-intercept multilevel modeling was used to examine the association between ICP monitoring and in-hospital mortality among children with severe TBI ≤16 years of age after adjusting for important confounders. This association was evaluated at the patient level and at the hospital level. In a sensitivity analysis, this association was reexamined in a propensity-matched cohort. RESULTS A total of 1705 children with severe TBI were included in the study cohort. The overall in-hospital mortality was 14.3% of patients (n = 243), whereas the mortality of the 273 patients (16%) who underwent invasive ICP monitoring was 11% (n = 30). After adjusting for patient- and hospital-level characteristics, ICP monitoring was associated with lower in-hospital mortality (adjusted OR 0.50; 95% CI 0.30–0.85; p = 0.01). It is possible that patients who were managed with ICP monitoring were selected because of an anticipated favorable or unfavorable outcome. To further address this potential selection bias, the analysis was repeated with the hospital-specific rate of ICP monitoring use as the exposure. The adjusted OR for death of children treated at high ICP–use hospitals was 0.49 compared with those treated at low ICP-use hospitals (95% CI 0.31–0.78; p = 0.003). Variations in ICP monitoring use accounted for 15.9% of the interhospital variation in mortality among children with severe TBI. Similar results were obtained after analyzing the data using propensity score-matching methods. CONCLUSIONS In this observational study, ICP monitoring use was associated with lower hospital mortality at both the patient and hospital levels. However, the contribution of variable ICP monitoring rates to interhospital variation in pediatric TBI mortality was modest.

Newly diagnosed elderly patients (age > 65–70 years) with glioblastoma should be treated with a patient-centred approach by a multi-disciplinary team. Chronological age alone should not be considered as a contraindication to treatment with maximal safe surgical resection. A 3-week course of adjuvant radiation and chemotherapy is appropriate in selected elderly patients with favourable Karnofsky performance status (KPS) who cannot tolerate a longer 6-week course of fractionated radiotherapy. The presence or absence of 06-methylguanine-DNA methyltransferase (MGMT) promoter methylation can be used to guide clinical decision-making as both prognostic and predictive biomarkers. This review provides an update and summary of the available evidence for treating newly diagnosed elderly patients with glioblastoma.

Somatosensory evoked potentials (SSEPs) are used for neuroprognosis after severe traumatic brain injury (TBI). However decompressive craniectomy (DC), involving removal of a portion of the skull to alleviate elevated intracranial pressure, is associated with an increase in SSEP amplitude. Accordingly, SSEPs are not available for neuroprognosis over the hemisphere with DC. We aim to determine the degree to which SSEP amplitudes are increased in the absence of cranial bone. This will serve as a precursor for translation to clinically prognostic ranges. Intra-operative SSEPs were performed before and after bone flap replacement in 22 patients with severe TBI. SSEP measurements were also performed in a comparison non-traumatic group undergoing craniotomy for tumor resection. N20/P25 amplitudes and central conduction time were measured with the bone flap in (BI) and out (BO). Linear regressions, adjusting for skull thickness and study arm, were performed to evaluate the contribution of bone presence to SSEP amplitudes. Latencies were not different between BO or BI trials in either group. Mean N20/P25 amplitudes recorded with BO were statistically different (p = 0.0001) from BI in both cohorts, showing an approximate doubling in BO amplitudes. For contralateral–ipsilateral montages r2 was 0.28 and for frontal pole montages r2 was 0.62. Cortical SSEP amplitudes are influenced by the presence of cortical bone as is particularly evident in frontal pole montages. Larger, longitudinal trials to assess feasibility of neuroprognosis over the hemisphere with DC in severe TBI patients are warranted.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12987-017-0061-6) contains supplementary material, which is available to authorized users.

Cranial neurosurgical procedures are especially delicate considering that the surgeon must localize the subsurface anatomy with limited exposure and without the ability to see beyond the surface of the surgical field. Surgical accuracy is imperative as even minor surgical errors can cause major neurological deficits. Traditionally surgical precision was highly dependent on surgical skill. However, the introduction of intraoperative surgical navigation has shifted the paradigm to become the current standard of care for cranial neurosurgery. Intra-operative image guided navigation systems are currently used to allow the surgeon to visualize the three-dimensional subsurface anatomy using pre-acquired computed tomography (CT) or magnetic resonance (MR) images. The patient anatomy is fused to the pre-acquired images using various registration techniques and surgical tools are typically localized using optical tracking methods. Although these techniques positively impact complication rates, surgical accuracy is limited by the accuracy of the navigation system and as such quantification of surgical error is required. While many different measures of registration accuracy have been presented true navigation accuracy can only be quantified post-operatively by comparing a ground truth landmark to the intra-operative visualization. In this study we quantified the accuracy of cranial neurosurgical procedures using a novel optical surface imaging navigation system to visualize the three-dimensional anatomy of the surface anatomy. A tracked probe was placed on the screws of cranial fixation plates during surgery and the reported position of the centre of the screw was compared to the co-ordinates of the post-operative CT or MR images, thus quantifying cranial neurosurgical error.

The ability to focus acoustic energy through the intact skull on to targets millimeters in size represents an important milestone in the development of neurotherapeutics. Magnetic resonance-guided focused ultrasound (MRgFUS) is a novel, noninvasive method, which—under real-time imaging and thermographic guidance—can be used to generate focal intracranial thermal ablative lesions and disrupt the blood–brain barrier. An established treatment for bone metastases, uterine fibroids, and breast lesions, MRgFUS has now been proposed as an alternative to open neurosurgical procedures for a wide variety of indications. Studies investigating intracranial MRgFUS range from small animal preclinical experiments to large, late-phase randomized trials that span the clinical spectrum from movement disorders, to vascular, oncologic, and psychiatric applications. We review the principles of MRgFUS and its use for brain-based disorders, and outline future directions for this promising technology. Electronic supplementary material The online version of this article (doi:10.1007/s13311-014-0281-2) contains supplementary material, which is available to authorized users.

The optimal timing of tracheostomy in patients with severe traumatic brain injury (TBI) is controversial; observational studies have been challenged through confounding by indication, and interventional studies have rarely enrolled patients with isolated TBI.We included a cohort of adults with isolated TBI who underwent tracheostomy within 1 of 135 participating centers in the American College of Surgeons' Trauma Quality Improvement Program, during 2009 to 2011. Patients were classified as having undergone early tracheostomy (ET, ≤8 days) versus late tracheostomy (8 days). Outcomes were compared between propensity score-matched groups to reduce confounding by indication. In sensitivity analyses, we used time-dependent proportional hazard regression to address immortal time bias and assessed the association between hospital ET rate and patients' outcome at the hospital level.From 1,811 patients, a well-balanced propensity-matched cohort of 1,154 patients was defined. After matching, ET was associated with fewer mechanical ventilation days (median, 10 days vs. 16 days; rate ratio [RR], 0.70; 95% confidence interval [CI], 0.66-0.75), shorter intensive care unit stay (median, 13 days vs. 19 days; RR, 0.70; 95% CI, 0.66-0.75), shorter hospital length of stay (median, 20 days vs. 27 days; RR, 0.80; 95% CI, 0.74-0.86), and lower odds of pneumonia (41.7% vs. 52.7%; odds ratio [OR], 0.64; 95% CI, 0.51-0.80), deep venous thrombosis (8.2% vs. 14.4%; OR, 0.53; 95% CI, 0.37-0.78), and decubitus ulcer (4.0% vs. 8.9%; OR, 0.43; 95% CI, 0.26-0.71) but no significant difference in pulmonary embolism (1.8% vs. 3.3%; OR, 0.52; 95% CI, 0.24-1.10). Hospital mortality was similar between both groups (8.4% vs. 6.8%; OR, 1.25; 95% CI, 0.80-1.96). Results were consistent using several alternate analytic methods.In this observational study, ET was associated with a shorter duration of mechanical ventilation, intensive care unit stay, and hospital stay but not hospital mortality. ET may represent a mechanism to reduce in-hospital morbidity for patients with TBI.Therapeutic study, level II.

Our purpose was to report efficacy of hypofractionated cavity stereotactic radiotherapy (HCSRT) in patients with and without prior whole brain radiotherapy (WBRT). 32 surgical cavities in 30 patients (20 patients/21 cavities had no prior WBRT and 10 patients/11 cavities had prior WBRT) were treated with image-guided linac stereotactic radiotherapy. 7 of the 10 prior WBRT patients had “resistant” local disease given prior surgery, post-operative WBRT and a re-operation, followed by salvage HCSRT. The clinical target volume was the post-surgical cavity, and a 2-mm margin applied as planning target volume. The median total dose was 30 Gy (range: 25–37.5 Gy) in 5 fractions. In the no prior and prior WBRT cohorts, the median follow-up was 9.7 months (range: 3.0–23.6) and 15.3 months (range: 2.9–39.7), the median survival was 23.6 months and 39.7 months, and the 1-year cavity local recurrence progression-free survival (LRFS) was 79 and 100%, respectively. At 18 months the LRFS dropped to 29% in the prior WBRT cohort. Grade 3 radiation necrosis occurred in 3 prior WBRT patients. We report favorable outcomes with HCSRT, and well selected patients with prior WBRT and “resistant” disease may have an extended survival favoring aggressive salvage HCSRT at a moderate risk of radiation necrosis.

Although existing guidelines support the utilization of intracranial pressure (ICP) monitoring in patients with traumatic brain injury (TBI), the evidence suggesting benefit is limited. To evaluate the impact on outcome, we determined the relationship between ICP monitoring and mortality in centers participating in the American College of Surgeons Trauma Quality Improvement Program (TQIP). Data on 10,628 adults with severe TBI were derived from 155 TQIP centers over 2009–2011. Random-intercept multilevel modeling was used to evaluate the association between ICP monitoring and mortality after adjusting for important confounders. We evaluated this relationship at the patient level and at the institutional level. Overall mortality (n=3769) was 35%. Only 1874 (17.6%) patients underwent ICP monitoring, with a mortality of 32%. The adjusted odds ratio (OR) for mortality was 0.44 [95% confidence interval (CI), 0.31–0.63], when comparing patients with ICP monitoring to those without. It is plausible that patients receiving ICP monitoring were selected because of an anticipated favorable outcome. To overcome this limitation, we stratified hospitals into quartiles based on ICP monitoring utilization. Hospitals with higher rates of ICP monitoring use were associated with lower mortality: The adjusted OR of death was 0.52 (95% CI, 0.35–0.78) in the quartile of hospitals with highest use, compared to the lowest. ICP monitoring utilization rates explained only 9.9% of variation in mortality across centers. Results were comparable irrespective of the method of case-mix adjustment. In this observational study, ICP monitoring utilization was associated with lower mortality. However, variability in ICP monitoring rates contributed only modestly to variability in institutional mortality rates. Identifying other institutional practices that impact on mortality is an important area for future research.

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.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.

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.

The revolution in molecular biology that has taken place over the past 2 decades has provided researchers with new and powerful tools for detailed study of the molecular mechanisms giving rise to the spectrum of pediatric brain tumors. Application of these tools has greatly advanced our understanding of the molecular pathogenesis of these lesions.After familiarizing readers with some promising new techniques in the field of oncogenomics, this review will present the current state of knowledge as it pertains to the molecular biology of pediatric brain neoplasms. Along the way, we hope to highlight specific instances where the detailed mechanistic knowledge acquired thus far may be exploited for therapeutic advantage.

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.

Brain tumors are a heterogeneous group of neoplasms with different origins, pathobiologies, treatments and prognoses. The collective contributions from the fields of neuro-oncology, neurosurgery, radiation oncology, neurology, neuropathology, neuroradiology and molecular biology have all led to significant advances in the treatment of certain brain tumors. Ideas from these fields, under the cooperative umbrella of clinical cancer trial consortia, have been tested in large-scale studies. As a result, patient survivals have increased markedly for these tumor types. Unfortunately, there are certain brain tumors in childhood, such as the diffuse intrinsic pontine glioma and atypical teratoid rhabdoid tumor, for which survival advantages have not been found. This review will discuss the current and possible future therapies of the most common pediatric brain tumors and highlight some of the novel imaging modalities that are used pre- and intraoperatively.

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.

Background:In this study, we investigated the feasibility of using a 1.5 Tesla (T) clinical magnetic resonance imaging (MRI) system for in vivo assessment of three histopathologically different brain tumor models in mice.Methods:We selected mouse models in which tumor growth was observed in different intracranial compartments: Patched+/- heterozygous knock-out mice for tumor growth in the cerebellum (n = 5); U87 MG human astrocytoma cells xenografted to the frontal lobe of athymic mice (n =15); and F5 (n = 15) or IOMM-Lee (n = 15) human malignant meningioma cells xenotransplanted to the athymic mouse skull base or convexity. Mice were imaged using a small receiver surface coil and a clinical 1.5 T MRI system. T1- and fast spin echo T2-weighted image sequences were obtained in all animals. Gadolinium was injected via tail vein to better delineate the intracranial tumors. Twenty mice were followed by serial MRI to study tumor growth over time. In these mice, images were typically performed after tumor implantation, and at two week intervals. Mice were euthanized following their last imaging procedure, and their tumors were examined by histopathology. The histopathological preparations were then compared to the last MR images to correlate the imaging features with the pathology.Results:Magnetic resonance imaging delineated the tumors in the cerebellum, frontal lobes and skull base in all mouse models. The detection of intracranial tumors was enhanced with prior administration of gadolinium, and the limit of resolution of brain tumors in the mice was 1-2 mm3. Sequential images performed at different time intervals showed progressive tumor growth in all animals. The MR images of tumor size and location correlated accurately with the results of the histopathological analysis.Conclusion:Magnetic resonance imaging of murine brain tumors in different intracranial compartments is feasible with a 1.5 T clinical MR system and a specially designed surface coil. Tumors as small as 1-2 mm3 can be detected with good image resolution. Mice harbouring nascent brain tumors can be followed sequentially by serial MR imaging. This may allow for a noninvasive means by which tumor growth can be measured, and novel therapies tested without resorting to sacrifice of the mice.

WITH THE COMPLETION of the Human Genome Project, the amount of molecular biological sequence data available in public databases has reached staggering proportions. Data continue to accumulate at an exponential rate in the postgenomic era. Compilation, storage, searching, sharing, studying, and transmitting of all these data present formidable challenges. To keep pace with this extant database, the science of bioinformatics (sometimes called computational biology) has evolved. Bioinformatics is the combination of biology and computers and usually involves the storage or analysis of molecular biological sequence data at either the deoxyribonucleic acid, ribonucleic acid, or protein (amino acid) level. Most bioinformatics tools are freely available on the Internet for use by investigators around the globe. The collective wisdom from bioinformatics databases worldwide will continue to spawn advances in the neurological sciences for generations to come. Neurosurgeons must be aware of the power and potential applications of bioinformatics for the analysis of neurosurgical diseases.

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.

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.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.Trauma centers in the United States.Base case was a population of patients (mean age = 25 yr) who developed refractory intracranial hypertension following traumatic brain injury.We compared two treatment strategies: decompressive craniectomy and barbiturate coma.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).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.

Aims Many elderly glioblastoma patients are excluded from randomised trials due to age, comorbidity or poor functional status. The purpose of this study was to describe the survival outcomes in all elderly patients with glioblastoma managed at a tertiary cancer centre. Materials and methods A retrospective chart review identified 235 elderly patients (age 65 years or over) with a histological diagnosis of glioblastoma between 1 December 2006 and 31 December 2013. The primary outcome of this study was overall survival by treatment type. Univariate and multivariate Cox proportional hazard models were used to explore significant prognostic variables associated with overall survival. Results The median survival for all patients was 6.5 months (95% confidence interval 5.3–7.7), with 1 year overall survival of 23.7% (95% confidence interval 18.8–30.0). The median survival for patients treated with radiation and chemotherapy was 11.1 months (95% confidence interval 8.1–13.7). Patients treated with radiation alone had a median survival of 6.8 months (95% confidence interval 5.6–7.9). For patients managed with comfort measures only, the median survival was 1.9 months (95% confidence interval 1.6–2.6). Univariate analysis revealed age, performance status, surgery type (biopsy, subtotal resection, gross total resection) and type of treatment received (comfort measures only, radiotherapy alone, radiotherapy and chemotherapy) to be statistically associated with overall survival. In the multivariate analysis, only two predictive factors (treatment received and surgery type) were significant. Conclusions Elderly patients with glioblastoma selected for treatment (surgery followed by radiation alone or radiation and chemotherapy) survive longer than patients managed with comfort measures. Prospective randomised trials will help guide management for patients eligible for therapy. Elderly patients with glioblastoma who are deemed not eligible for active therapy have very short survival.

After the tragic death of a young woman named Libby Zion in a New York Hospital, resident duty hour (RDH) restrictions were introduced in this state. An investigation ruled that lack of supervision, the resident's lack of familiarity with this woman's complex diagnosis and resident fatigue were contributing factors in the tragic outcome. In July 2003, the Accreditation Council for Graduate Medical Education (ACGME) mandated an 80-hour duty limit on residents, averaged over a 4-week period. In 2011, the ACGME mandated 16-hour duty periods for first year residents whereas the province of Quebec instituted 16-hour periods for all in-house residents in 2012. The stated goals of duty hour limitations were to improve patient safety, resident well-being, and education.1 Surgical disciplines have expressed concern with the contraction of duty hours stating that the impact on training time could have a negative effect on educational and patient outcomes.2 Specifically, the American College of Surgeons, Division of Education, has stated that mastery in surgery requires extensive and immersive experiences.3 A “one-size fits all” approach to RDHs may not be appropriate given the variation in training needs, diversity of practice patterns, and various competencies required among disciplines.4,5 In March 2012, the Royal College of Physicians and Surgeons of Canada undertook a project to develop a pan-Canadian consensus on issues related to RDH. A national steering committee was struck and this committee further created 6 expert working groups. Recognizing that surgical training is unique in many aspects and that there have been significant obstacles related to the implementation of RDH in surgery, a specific working group entitled Special Considerations for Procedural and Surgical Disciplines was created. The National Steering Committee's full report is published elsewhere (www.residentdutyhours.ca).5 As part of this process, the Procedural/Surgical discipline working group performed a systematic review and meta-analysis to evaluate the association between RDH and clinical and educational outcomes in surgery.

The extracellular matrix (ECM) of the central nervous system (CNS) is enriched in hyaluronate (HA). Ubiquitous receptors for HA are CD44 and the Receptor for HA-Mediated Motility known as RHAMM. In the present study, we have investigated the potential role of CD44 and RHAMM in the migration and proliferation of human astrocytoma cells. HA-receptor expression in brain tumor cell lines and surgical specimens was determined by immunocytochemistry and western blot analyses. The ability of RHAMM to bind ligand was determined through cetylpyridinium chloride (CPC) precipitations of brain tumor lysates in HA-binding assays. The effects of HA, CD44 blocking antibodies, and RHAMM soluble peptide on astrocytoma cell growth and migration was determined using MTT and migration assays. Our results show that the expression of the HA-receptors, CD44, and RHAMM, is virtually ubiquitous amongst glioma cell lines, and glioma tumor specimens. There was a gradient of expression amongst gliomas with high grade gliomas expressing more RHAMM and CD44 than did lower grade lesions or did normal human astrocytes or non-neoplastic specimens of human brain. Specific RHAMM variants of 85- and 58-kDa size were shown to bind avidly to HA following CPC precipitations. RHAMM soluble peptide inhibited glioma cell line proliferation in a dose-dependent fashion. Finally, while anti-CD44 antibodies did not inhibit the migration of human glioma cells, soluble peptides directed at the HA-binding domain of RHAMM inhibited glioma migration both on and off an HA-based ECM. These data support the notion that HA-receptors contribute to brain tumor adhesion, proliferation, and migration, biological features which must be better understood before more effective treatment strategies for these tumors can be found.