Adverse Radiation Effect After Hypofractionated Stereotactic Radiosurgery in 5 Daily Fractions for Surgical Cavities and Intact Brain Metastases.

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 <6 months for 38%, 6 to 12 months for 43%, and >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.

First-in-human trial of blood-brain barrier opening in amyotrophic lateral sclerosis using MR-guided focused ultrasound.

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.

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.

Image-Guided, Linac-Based, Surgical Cavity-Hypofractionated Stereotactic Radiotherapy in 5 Daily Fractions for Brain Metastases.

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.

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.

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.

Blood-Brain Barrier Opening in Primary Brain Tumors with Non-invasive MR-Guided Focused Ultrasound: A Clinical Safety and Feasibility Study.

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.

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.

High Speed, High Density Intraoperative 3D Optical Topographical Imaging with Efficient Registration to MRI and CT for Craniospinal Surgical Navigation.

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 < 0.05) relative to benchmark navigation systems without compromising surgical accuracy. Our advancements provide the cornerstone for widespread adoption of image guidance technologies for faster and safer surgeries without intraoperative CT or MRI scans. This work represents a major workflow improvement for navigated craniospinal procedures with possible extension to other image-guided applications.

Stereotactic radiosurgery for resected brain metastasis: Cavity dynamics and factors affecting its evolution.

OBJECTIVE: To determine changes in post-surgical cavity volume for metastases based on time from surgery, pre-operative tumor dimensions and other predictors, in patients planned for post-operative stereotactic radiosurgery (SRS). METHODS: Patients with resected brain metastases from a primary solid tumor, treated with post-operative surgical cavity SRS from 2008 to 2014 were identified from an institutional prospective database. The segmented three-dimensional (3D) volume of the pre-operative tumor and post-operative surgical cavity were determined based on MRI and percent volume change was calculated. Patients were grouped according to early (<21 days), intermediate (22-42 days), and late (>42 days) intervals based on the number of days between the date of surgery and the treatment planning MRI. Potential predictive factors including tumor size, location, age, dural involvement, and degree of surgical resection were also analyzed. RESULTS: Sixty-one cavities in 59 patients were evaluated. Overall, a significant volume reduction (4cm3, p=0.03) was observed comparing tumor and cavity volumes. For larger tumors, an average volume reduction of 11.6% (p=0.01) was observed compared to an increase of 34.4% in smaller tumors (p=0.69). For both large and small tumors, cavities were larger in the early interval especially for smaller tumors. During the intermediate interval, a significant volume reduction was observed for larger tumors (28%, p=0.0007). Tumor size, dural involvement, age and time from surgery were significant predictors for volume change on univariate analysis. On multivariate analysis, tumor size, dural involvement and time from surgery were significant. CONCLUSION: Tumor size (>3cm), dural involvement and longer time from surgery were significant predictors of cavity volume reduction. Caution must be taken when treating cavities in the early (<21 days) interval after surgery as it may lead to irradiating more normal tissue especially in small tumors.

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.

Hypoxia Detection in Infiltrative Astrocytoma: Ferumoxytol-based Quantitative BOLD MRI with Intraoperative and Histologic Validation.

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.

To frame or not to frame? Cone-beam CT-based analysis of head immobilization devices specific to linac-based stereotactic radiosurgery and radiotherapy.

PURPOSE: Noninvasive frameless systems are increasingly being utilized for head immobilization in stereotactic radiosurgery (SRS). Knowing the head positioning reproducibility of frameless systems and their respective ability to limit intrafractional head motion is important in order to safely perform SRS. The purpose of this study was to evaluate and compare the intrafractional head motion of an invasive frame and a series of frameless systems for single fraction SRS and fractionated/hypofractionated stereotactic radiotherapy (FSRT/HF-SRT). METHODS: The noninvasive PinPoint system was used on 15 HF-SRT and 21 SRS patients. Intrafractional motion for these patients was compared to 15 SRS patients immobilized with Cosman-Roberts-Wells (CRW) frame, and a FSRT population that respectively included 23, 32, and 15 patients immobilized using Gill-Thomas-Cosman (GTC) frame, Uniframe, and Orfit. All HF-SRT and FSRT patients were treated using intensity-modulated radiation therapy on a linear accelerator equipped with cone-beam CT (CBCT) and a robotic couch. SRS patients were treated using gantry-mounted stereotactic cones. The CBCT image-guidance protocol included initial setup, pretreatment and post-treatment verification images. The residual error determined from the post-treatment CBCT was used as a surrogate for intrafractional head motion during treatment. RESULTS: The mean intrafractional motion over all fractions with PinPoint was 0.62 ± 0.33 mm and 0.45 ± 0.33 mm, respectively, for the HF-SRT and SRS cohort of patients (P-value = 0.266). For CRW, GTC, Orfit, and Uniframe, the mean intrafractional motions were 0.30 ± 0.21 mm, 0.54 ± 0.76 mm, 0.73 ± 0.49 mm, and 0.76 ± 0.51 mm, respectively. For CRW, PinPoint, GTC, Orfit, and Uniframe, intrafractional motion exceeded 1.5 mm in 0%, 0%, 5%, 6%, and 8% of all fractions treated, respectively. CONCLUSIONS: The noninvasive PinPoint system and the invasive CRW frame stringently limit cranial intrafractional motion, while the latter provides superior immobilization. Based on the results of this study, our clinical practice for malignant tumors has evolved to apply an invasive CRW frame only for metastases in eloquent locations to minimize normal tissue exposure.

An Algorithm for Managing Intraosseous Vascular Anomalies of the Craniofacial Skeleton.

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.

Somatosensory evoked potentials after decompressive craniectomy for traumatic brain injury.

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.

Optimal Therapies for Newly Diagnosed Elderly Patients with Glioblastoma.

OPINION STATEMENT: 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.

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.

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.

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.