Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

OBJECTIVE: The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. METHODS: The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. RESULTS: Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). CONCLUSIONS: In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

Autologous Heat Shock Protein Peptide Vaccination for Newly Diagnosed Glioblastoma: Impact of Peripheral PD-L1 Expression on Response to Therapy.

Purpose: Standard therapy for newly diagnosed glioblastoma (GBM) is surgical resection, followed by concurrent radiotherapy and temozolomide chemotherapy. In this phase II clinical trial, the addition of an autologous heat-shock protein vaccine to standard therapy was evaluated. Tumor-induced immunosuppression, mediated by expression of PD-L1 on tumor and circulating immune cells, may impact the efficacy of vaccination. Expression of PD-L1 on peripheral myeloid cells was evaluated for the first time as a predictor of survival.Experimental Design: In this single arm, phase II study, adult patients with GBM underwent surgical resection followed by standard radiation and chemotherapy. Autologous vaccine (Prophage) was generated from resected tumors and delivered in weekly vaccinations after completion of radiotherapy. The primary endpoint was overall survival.Results: Forty-six patients received the vaccine with a median overall survival of 23.8 months [95% confidence interval (CI), 19.8-30.2]. Median overall survival for patients with high PD-L1 expression on myeloid cells was 18.0 months (95% CI, 10.0-23.3) as compared with 44.7 months (95% CI, incalculable) for patients with low PD-L1 expression (hazard ratio 3.3; 95% CI, 1.4-8.6; P = 0.007). A multivariate proportional hazards model revealed MGMT methylation, Karnofsky performance status, and PD-L1 expression as the primary independent predictors of survival.Conclusions: Vaccination with autologous tumor-derived heat shock proteins may improve survival for GBM patients when combined with standard therapy and warrants further study. Systemic immunosuppression mediated by peripheral myeloid expression of PD-L1 is a recently identified factor that may significantly impact vaccine efficacy. Clin Cancer Res; 23(14); 3575-84. ©2017 AACR.

Beneficial use of a new hand-held CO2 laser fiber in resection of a calcified and vascular intraventricular tumor.

BACKGROUND: The progression of laser technology in neurosurgery has been limited by the poor maneuverability of traditional line-of-sight carbon dioxide (CO2) lasers and the propensity of other laser energies to cause collateral thermal injury to adjacent neural structures. The advent of a dielectric omnidirectional reflector and the subsequent development of phototonic bandgap fibers (PBF) have transformed the CO2 laser into a low-profile instrument with considerable dexterity and many potential new neurosurgical applications. CASE DESCRIPTION: A 48-year-old woman presented with a large mass in the left lateral ventricle that was first diagnosed>20 years ago. The patient was asymptomatic until 1 month before presentation, when she began to experience progressive memory loss and neurocognitive decline. RESULTS: The hand-held CO2 laser was used to debulk the tumor. The CO2 laser vaporized neoplastic cellular material and simultaneously cauterized microvascular structures. CONCLUSIONS: The CO2 laser was exceptionally useful in the resection of this long-standing and extremely calcified, yet vascular mass. A review of the evolution of laser technology applications in neurosurgery is presented, with a specific focus on the innovations that led to the development of the new PBF CO2 laser. This new technology may be advantageous in tumor surgery, particularly in the resection of long-standing calcified and vascular tumors that are not amendable to traditional surgical techniques.

Traumatic brain injury in pediatric patients: evidence for the effectiveness of decompressive surgery.

Traumatic brain injury (TBI) is the current leading cause of death in children over 1 year of age. Adequate management and care of pediatric patients is critical to ensure the best functional outcome in this population. In their controversial trial, Cooper et al. concluded that decompressive craniectomy following TBI did not improve clinical outcome of the analyzed adult population. While the study did not target pediatric populations, the results do raise important and timely clinical questions regarding the effectiveness of decompressive surgery in pediatric patients. There is still a paucity of evidence regarding the effectiveness of this therapy in a pediatric population, and there is an especially noticeable knowledge gap surrounding age-stratified interventions in pediatric trauma. The purposes of this review are to first explore the anatomical variations between pediatric and adult populations in the setting of TBI. Second, the authors assess how these differences between adult and pediatric populations could translate into differences in the impact of decompressive surgery following TBI.

Radiosurgical management of brain metastases.

Stereotactic radiosurgery (SRS) should be considered in the comprehensive treatment paradigm for all patients with brain metastases. This technique has proven benefits for local tumor control in individuals with as many as 4 lesions, and when combined with structured radiographic follow-up, will likely preserve a better quality of life for appropriately selected patients. Institutions and physicians treating patients with brain metastases should have the capability of safely performing SRS and individual cases should be prospectively reviewed by multidisciplinary teams to provide the best comprehensive care.

Surgical management of brain metastases.

In the past 20 years, surgical resection has found an established role in the management of metastatic brain tumors. Several factors, however, make strong evidence-based medicine impossible to provide for all possible patient presentations. These important factors, such as patient variables (eg, age, medical comorbidities, preoperative performance), tumor variables (eg, number, size, location, histology), and primary disease status must be taken into account on a case-by-case basis to guide patient selection and treatment strategy. Although progress has been made to answer some of the major questions in the management of metastatic brain tumors, several important questions remain. Future studies comparing surgery with stereotactic radiosurgery, for example, are needed to delineate patient selection, complications, and outcome for both of these important modalities.

Preclinical evaluation of postischemic dehydroascorbic Acid administration in a large-animal stroke model.

Dehydroascorbic acid (DHA), a blood-brain barrier transportable form of ascorbic acid, confers robust neuroprotection following murine stroke. In an effort to translate this promising neuroprotective strategy into human clinical trial, we evaluated postischemic DHA administration in a large-animal stroke model. Thirty-six adult male baboons were initially randomized to undergo transorbital craniectomy to induce transient cerebral artery occlusion and to receive postischemic dosing of either 500 mg/kg of DHA or vehicle. Primary outcomes included infarct volume, determined by magnetic resonance imaging, as well as neurological function evaluated on the day of sacrifice. The midpoint interim analysis (n = 9 per cohort) revealed that DHA administration did not significantly improve either infarct volume or neurological function. The study was terminated after a determination of statistical futility. We were unable to confirm a neuroprotective effect for postischemic DHA administration in our large-animal model using a dosing scheme that was previously successful in rodents. Further analysis of the efficacy of DHA administration must thus be undertaken prior to clinical translation.

Simulation in neurosurgery: a review of computer-based simulation environments and their surgical applications.

BACKGROUND: Computer-based surgical simulators create a no-risk virtual environment where surgeons can develop and refine skills through harmless repetition. These applications may be of particular benefit to neurosurgeons, as the vulnerability of nervous tissue limits the margin for error. The rapid progression of computer-processing capabilities in recent years has led to the development of more sophisticated and realistic neurosurgery simulators. OBJECTIVE: To catalogue the most salient of these advances and characterize our current effort to create a spine surgery simulator. METHODS: An extensive search of the databases Ovid-MEDLINE, PubMed, and Google Scholar was conducted. Search terms included, but were not limited to: neurosurgery combined with simulation, virtual reality, haptics, and 3-dimensional imaging. RESULTS: A survey of the literature reveals that surgical simulators are evolving from platforms used for preoperative planning and anatomic education into programs that aim to simulate essential components of key neurosurgical procedures. This evolution is predicated upon the advancement of 3 main components of simulation: graphics/volume rendering, model behavior/tissue deformation, and haptic feedback. CONCLUSION: The computational burden created by the integration of these complex components often limits the fluidity of real-time interactive simulators. Although haptic interfaces have become increasingly sophisticated, the production of realistic tactile sensory feedback remains a formidable and costly challenge. The rate of future progress may be contingent upon international collaboration between research groups and the establishment of common simulation platforms. Given current limitations, the most potential for growth lies in the innovative design of models that expand the procedural applications of neurosurgery simulation environments.

Approaches to anterior and anterolateral foramen magnum lesions: A critical review.

Foramen magnum (FM) lesions represent some of the most complex cases for the modern neurosurgeon because of their location near vital brainstem structures, the vertebral arteries, and lower cranial nerves. In particular, anterior or anterolaterally located FM tumors have traditionally been most difficult to resect with high morbidity and mortality resulting from approaches through the posterior midline or transorally. For many neurosurgeons, the far lateral, extreme lateral approach, and more recently, endoscopic endonasal approaches have become the preferred modern methods for the resection of anterior or anterolateral FM tumors. In this review, we examine both operative and non-operative approaches to FM tumors, including surgical anatomy, surgical technique, and indications for operative intervention in these complex cases. In addition, we compared outcomes from prior series.

Simultaneous above and below approach to giant pituitary adenomas: surgical strategies and long-term follow-up.

INTRODUCTION: Giant pituitary adenomas of excessive size, fibrous consistency or unfavorable geometric configuration may be unresectable through conventional operative approaches. We present our select case series for operative resection and long-term follow-up for these unusual tumors, employing both a staged procedure and a combined transsphenoidal-transcranial above and below approach. METHOD: A retrospective chart review was performed on patients operated via the staged, and combined approaches by the senior author (J.N.B.). Preoperative characteristics and postoperative outcomes were reviewed. A detailed description of the operative technique and perioperative management is provided. RESULTS: Between 1993 and 1996, two patients harboring giant pituitary adenomas underwent an intentionally staged resection, and between 1997 and 2006, nine patients harboring giant pituitary adenomas underwent surgery via a single-stage above and below approach. Nine patients (82%) presented with non-secreting adenomas and two patients (18%) presented with prolactinomas refractory to medical management. Gross total resection was achieved in six patients (55%), near total resection in 1 (9%), and subtotal removal in 4 (36%). Seven patients (64%) experienced visual improvement postoperatively and no major complications occurred. Long-term follow-up averaged 51.6 months. Panhypopituitarism was observed in four patients, partial hypopituitarism in four, persistent DI in two, and persistent SIADH in one. CONCLUSIONS: The addition of a transcranial component to the transsphenoidal approach offers additional visualization of critical neurovascular structures during giant pituitary adenoma resection. Complications rates are similar to other series in which complex pituitary adenomas are resected by other means. The above and below approach is both safe and effective and the immediate and long-term advantages of a single-stage approach justify its utility in this select group of patients.

Asymmetry analysis in rodent cerebral ischemia models.

RATIONALE AND OBJECTIVES: An automated method for identification and segmentation of acute/subacute ischemic stroke, using the inherent bi-fold symmetry in brain images, is presented. An accurate and automated method for localization of acute ischemic stroke could provide physicians with a mechanism for early detection and potentially faster delivery of effective stroke therapy. MATERIALS AND METHODS: Segmentation of ischemic stroke was performed on magnetic resonance (MR) images of subacute rodent cerebral ischemia. Eight adult male Wistar rats weighing 225-300 g were anesthetized with halothane in a mix of 70% nitrous oxide/30% oxygen. Animal core temperature was maintained at 37 degrees C during the entire surgical procedure, including occlusion of the middle cerebral artery (MCA) and the 90-minute post-reperfusion period. To confirm cerebral ischemia, transcranial measurements of cerebral blood flow were performed with laser-Doppler flowmetry, using 15-mm flexible fiberoptic Doppler probes attached to the skull over the MCA territory. Animal MR scans were performed at 1.5 T using a knee coil. Three experts performed manual tracing of the stroke regions for each rat, using the histologic-stained slices to guide delineation of stroke regions. A strict tracing protocol was followed that included multiple (three) tracings of each stroke region. The volumetric MR image data were processed for each rat by computing the axis of symmetry and extracting statistical dissimilarities. A nonparametric Wilcoxon rank sum test operating on paired windows in opposing hemispheres identified seeds in the pixels exhibiting statistically significant bi-fold mirror asymmetry. Two brain reference maps were used for analysis: an absolute difference map (ADM) and a statistical difference map (SDM). Although an ADM simply displays the absolute difference by subtracting one brain hemisphere from its reflection, SDM highlights regions by labeling pixels exhibiting statistically significant asymmetry. RESULTS: To assess the accuracy of the proposed segmentation method, the surrogate ground truth (the stroke tracing data) was compared to the results of our proposed automated segmentation algorithm. Three accuracy segmentation metrics were utilized: true-positive volume fraction (TPVF), false-positive volume fraction (FPVF), and false-negative volume fraction (FNVF). The mean value of the TPVF for our segmentation method was 0.8877; 95% CI 0.7254 to 1.0500; the mean FPVF was 0.3370, 95% CI -0.0893 to 0.7633; the mean FNVF was 0.1122, 95% CI -0.0502 to 0.2747. CONCLUSIONS: Unlike most segmentation methods that require some degree of manual intervention, our segmentation algorithm is fully automated and highly accurate in identifying regions of brain asymmetry. This approach is attractive for numerous neurologic applications where the operator's intervention should be minimal or null.

Quantification of the frontotemporal orbitozygomatic approach using a three-dimensional visualization and modeling application.

OBJECTIVE: We sought to simulate the frontotemporal orbitozygomatic (FTOZ) craniotomy in a three-dimensional virtual environment on patient-specific data and to quantify the exposure afforded by the FTOZ while simulating controlled amounts of brain retraction. METHODS: Four computed tomographic angiograms were reconstructed with commercially available software (Amira 4.1.1; Mercury Computer Systems, Inc., Chelmsford, MA), and virtual FTOZ craniotomies were performed bilaterally (n = 8). Brain retraction was simulated at 1 and 2 cm. Surgical freedom and projection angle were measured and compared at each stage of the FTOZ. RESULTS: At 1 cm of retraction, surgical freedom increased by 27 +/- 14% for the removal of the orbital rim and by 31 +/- 18% for FTOZ (P < 0.01) when compared with frontotemporal (FT) craniotomy. At 2 cm of retraction, surgical freedom increased by 15 +/- 5% and 26 +/- 8% for the removal of the orbital rim and FTOZ, respectively (P < 0.01). With increased retraction, surgical freedom increased by 100 +/- 26%, 81 +/- 15%, and 82 +/- 27% for the FT, removal of the orbital rim, and FTOZ craniotomies, respectively (P < 0.001). Projection angle increased by 24.2% when orbital rim removal was added to the FT craniotomy (P < 0.01). CONCLUSION: Surgical freedom increases significantly at every step of the FTOZ craniotomy. This effect is less robust when brain retraction is increased. Brain retraction alone has a greater impact on surgical freedom than bone removal alone. Projection angle is significantly increased when orbital rim removal is added to the FT craniotomy. This model overcomes two major limitations of cadaver-based models: quantification of brain retraction and incorporation of patient-specific anatomy.

Post-carotid endarterectomy neurocognitive decline is associated with cerebral blood flow asymmetry on post-operative magnetic resonance perfusion brain scans.

OBJECTIVE: Up to 25% of patients experience subtle declines in post-operative neurocognitive function following, otherwise uncomplicated, carotid endarterectomy (CEA). We sought to determine if post-CEA neurocognitive deficits are associated with cerebral blood flow (CBF) abnormalities on post-operative MR perfusion brain scans. METHODS: We enrolled 22 CEA patients to undergo a battery of neuropsychometric tests pre-operatively and on post-operative day 1 (POD 1). Neurocognitive dysfunction was defined as a two standard deviation decline in performance in comparison to a similarly aged control group of lumbar laminectomy patients. All patients received MR perfusion brain scans on POD 1 that were analysed for asymmetries in CBF distribution. One patient experienced a transient ischemic attack within 24 hours before the procedure and was excluded from our analysis. RESULTS: Twenty-nine percent of CEA patients demonstrated neurocognitive dysfunction on POD 1. One hundred percent of those patients with cognitive deficits demonstrated CBF asymmetry, in contrast to only 27% of those patients without cognitive impairment. Post-CEA cognitive dysfunction was significantly associated with CBF abnormalities (RR=3.75, 95% CI: 1.62-8.67, p=0.004). CONCLUSION: Post-CEA neurocognitive dysfunction is significantly associated with post-operative CBF asymmetry. These results support the hypothesis that post-CEA cognitive impairment is caused by cerebral hemodynamic changes. Further work exploring the relationship between CBF and post-CEA cognitive dysfunction is needed.

Prognosis in patients presenting with brain metastasis from an undiagnosed primary tumor.

OBJECT: The aim of this study was to test the validity of the hypothesis that patients in whom brain metastasis is the first indication of an undiagnosed primary tumor have a better chance of survival than similar patients with a known primary lesion. METHODS: Between January 1983 and December 1998, 342 patients with computed tomography-diagnosed brain metastases were treated at a single institution. Information on potential prognostic factors, including primary diagnosis status, was collected retrospectively. Univariate and multivariate analyses were performed to identify prognostic factors related to survival. Survival was not statistically different between patients with an undiagnosed primary (UDP) lesion and those with a diagnosed primary (DP) tumor (6 and 4.5 months, respectively; p = 0.097). In the UDP group (122 patients [36%]), survival was not affected by the eventual identification of the primary disease (p = 0.905). The median survival for the entire population was 5.2 months, with 1-, 2-, and 3-year survival rates of 25, 11, and 4%, respectively. Prognostic factors for the overall population included treatment (p < 0.0001), an age less than 65 years (p = 0.004), discharge status (p < 0.001), absence of systemic metastasis (p = 0.036), and asymptomatic cerebral metastasis (p = 0.05). CONCLUSIONS: Treatment modality was the most significant independent variable affecting survival in patients with brain metastases. Eventual identification of a primary tumor does not affect overall survival; therefore, delaying therapeutic intervention in pursuit of a primary diagnosis may not be appropriate. Data in this study failed to demonstrate a statistically significant difference in survival between patients with UDP and those with DP lesions, on first presenting with brain metastases.

An improved test of neurological dysfunction following transient focal cerebral ischemia in rats.

The Adhesive Removal (sticky-tape) test is a commonly used test of somatosensory dysfunction following cerebral ischemia in rats. This test requires several days of pre-training prior to surgery, which can be time consuming. We present our results with an improved version of the sticky-tape test. Male Wistar rats were subjected to either sham surgery (n = 4) or right middle cerebral artery occlusion (rMCAo) using an intraluminal filament (n = 9), followed by a 10-day survival period. On post-operative days (POD) 1, 3, 7, and 10 animals underwent both the conventional sticky-tape test (CST) with measurement of the time to remove the stimulus (trs), as well as a modified sticky-tape test (MST), in which a non-removable tape sleeve was placed around the animal's paw. Time spent attending to this stimulus (tas) was recorded. Despite 3 days of pre-training, animals undergoing baseline CST still exhibited marked variability in pre-operative baseline test performance (trs range 1-60s). In contrast, animals undergoing MST for the first time demonstrated nearly uniformly excellent performance (% tas range 91.5-98.5% of the 30s testing period). Although, affected (left) limb performance on both CST (6.8-fold increase in trs on POD 1 compared to baseline) and MST (100% decrease in tas on POD 1 compared to baseline) was markedly altered by rMCAo, CST performance declined bilaterally, and no significant differences in the ratio of affected (left) and unaffected (right) limb performance between sham-operated and rMCAo animals were observed at any time point. In contrast, the ratio of left to right performance on the MST was significantly different at all time points (P<0.01). In conclusion, we present a simple modification of the widely used Adhesive Removal test and provide evidence that this test can accurately assess neurological dysfunction in rodents, not only with minimal pre-training, but also with improved localization of the side of injury.

Symmetry identification using partial surface matching and tilt correction in 3D brain images.

We propose a novel method to automatically compute the symmetry plane and correct the 3D orientation of patient brain images. Many images of the brain are clinically unreadable because of the misalignment of the patient's head in the scanner. We proposed an algorithm that represents the brain volume as a re-parameterized surface point cloud where each location has been parameterized by its elevation (latitude), azimuth (longitude) and radius. The removal of the interior contents of the brain makes this approach perform robustly in the presence of the brain pathologies, e.g. tumor, stroke and bleed. Thus, we decompose the symmetry plane computation problem into a surface matching routine. The search for the best matching surface is implemented in a multi-resolution paradigm so as to decrease computational time considerably. Spatial affine transform then is performed to rotate the 3D brain images and align them within the coordinate system of the scanner. The corrected brain volume is re-sliced such that each planar image represents the brain at the same axial level.

Statistical bilateral asymmetry measurement in brain images.

We present an improvement of an automated generic methodology for symmetry identification, asymmetry quantification, and segmentation of brain pathologies, utilizing the inherent bi-fold mirror symmetry in brain imagery. In the pipeline of operations starting with detection of the symmetry axis, hemisphere-wise cross registration, statistical correlation and quantification of asymmetries, we segment a target brain pathology. The detection of pathological difference left to right in brain imagery is complicated by normal variations as well as geometric misalignment in anatomical structures between two hemispheres. Introducing hemisphere-wise registration and spatial correlation makes our approach perform robustly in the presence of normal asymmetries and systematic artifacts such as bias field and acquisition noise.