Jayesh P. Thawani

A pH‐Responsive Drug‐Delivery Platform Based on Glycol Chitosan–Coated Liposomes

Currently, a substantial amount of effort is focused on developing actively targeted, receptor-specific nanoparticles for the delivery of anticancer drugs and diagnostic imaging contrast agents.[1–7] Receptor-targeted nanoparticles hold much promise and are often shown to provide nanoparticle delivery beyond that seen with the enhanced permeability and retention (EPR) effect alone. However, these nanoparticles still face considerable challenges as a result of the significant heterogeneity in receptor expression, not only between patients and tumor types, but also within individual tumors.[8] In many cases, the overexpressed receptor may also be present on normal tissues leading to detrimental off-target effects. Perhaps even more troubling is that several recent studies have shown that cancer stem cells may not even possess any known up-regulated receptor.[9] Therefore, targeting strategies that are more generalizable across a broad range of tumors than receptor-specific targeting are highly desirable.

Stereotactic radiosurgery to the resection bed for intracranial metastases and risk of leptomeningeal carcinomatosis

OBJECT Following resection of a brain metastasis, stereotactic radiosurgery (SRS) to the cavity is an emerging alternative to postoperative whole-brain radiation therapy (WBRT). This approach attempts to achieve local control without the neurocognitive risks associated with WBRT. The authors aimed to report the outcomes of a large patient cohort treated with this strategy. METHODS A retrospective review identified 91 patients without a history of WBRT who received Gamma Knife (GK) SRS to 96 metastasis resection cavities between 2007 and 2013. Patterns of intracranial control were examined in the 86 cases with post-GK imaging. Survival, local failure, and distant failure were estimated by the Kaplan-Meier method. Prognostic factors were tested by univariate (log-rank test) and multivariate (Cox proportional hazards model) analyses. RESULTS Common primary tumors were non-small cell lung (43%), melanoma (14%), and breast (13%). The cases were predominantly recursive partitioning analysis Class I (25%) or II (70%). Median preoperative metastasis diameter was 2.8 cm, and 82% of patients underwent gross-total resection. A median dose of 16 Gy was delivered to the 50% isodose line, encompassing a median treatment volume of 9.2 cm(3). Synchronous intact metastases were treated in addition to the resection bed in 43% of cases. Patients survived a median of 22.3 months from the time of GK. Local failure developed in 16 cavities, for a crude rate of 18% and 1-year actuarial local control of 81%. Preoperative metastasis diameter ≥ 3 cm and residual or recurrent tumor at the time of GK were associated with local failure (p = 0.04 and 0.008, respectively). Distant intracranial failure occurred in 55 cases (64%) at a median of 7.3 months from GK. Salvage therapies included WBRT and additional SRS in 33% and 31% of patients, respectively. Leptomeningeal carcinomatosis developed in 12 cases (14%) and was associated with breast histology and infratentorial cavities (p = 0.024 and 0.012, respectively). CONCLUSIONS This study bolsters the existing evidence for SRS to the resection bed. Local control rates are high, but patients with larger preoperative metastases or residual/recurrent tumor at the time of SRS are more likely to fail at the cavity. While most patients develop distant intracranial failure, an SRS approach spared or delayed WBRT in the majority of cases. The risk of leptomeningeal carcinomatosis does not appear to be elevated with this strategy.

Evaluating the use and utility of noninvasive angiography in diagnosing traumatic blunt cerebrovascular injury.

BACKGROUND Digital subtraction angiography (DSA) is the gold standard for radiographic diagnosis of blunt cerebrovascular injury (BCVI), but use of computed tomography angiography (CTA) and magnetic resonance angiography (MRA) has increased dramatically in BCVI screening. This study explores the utility, effectiveness, and cost of noninvasive CTA and MRA screening for BCVI. METHODS Medical records of 2,025 consecutive adults evaluated for acute blunt neck trauma and BCVI were reviewed retrospectively. The incidence of BCVI, level(s) of cervical injury, involvement of foramina transversaria and internal carotid canals, presence of bony dislocation or subluxation, and subsequent treatment received were assessed. Asymptomatic patients were analyzed based on fracture and injury patterns. The cost effectiveness of CTA compared with DSA and the effects of CTA sensitivity and screening yield were determined. RESULTS Of reviewed patients, 196 received CTA or MRA. Thirty-eight patients (19.4%) were diagnosed with BCVI. Screening yield in patients symptomatic at presentation was 48.8%. Large-vessel internal carotid, vertebral, anterior spinal, and basilar artery occlusion were associated with a positive screen, as were concurrent stroke and spinal cord injury (p < 0.01). Of patients with injuries found with noninvasive imaging, 50.0% of BCVI involved C1-3 fracture, 34.2% involved subluxation, and 65.8% involved foramina transversaria. In both symptomatic and asymptomatic patients, CTA screening was more cost effective than DSA. CONCLUSION Noninvasive imaging is a safe, accurate, and cost-effective tool for BCVI screening. Symptomatic presentation was the best predictor of BCVI. Significant cost savings were realized using CTA rather than DSA, with similar effectiveness and patient outcomes. LEVEL OF EVIDENCE Diagnostic study, level III; economic analysis, level IV.

Long-term outcome after resection of brainstem hemangioblastomas in von Hippel-Lindau disease

OBJECT Brainstem hemangioblastomas are frequently encountered in patients with von Hippel-Lindau (VHL) disease. These tumors can cause significant morbidity, and their optimal management has not been defined. To better define the outcome and management of these tumors, the authors analyzed the long-term results in patients who underwent resection of brainstem hemangioblastomas. METHODS Consecutive patients with VHL disease who underwent resection of brainstem hemangioblastomas with a follow-up of 12 months or more were included in this study. Serial functional assessments, radiographic examinations, and operative records were analyzed. RESULTS Forty-four patients (17 male and 27 female) underwent 51 operations for resection of 71 brainstem hemangioblastomas. The most common presenting symptoms were headache, swallowing difficulties, singultus, gait difficulties, and sensory abnormalities. The mean follow-up was 5.9 ± 5.0 years (range 1.0-20.8 years). Immediately after 34 operations (66.7%), the patients remained at their preoperative functional status; they improved after 8 operations (15.7%) and worsened after 9 operations (17.6%) as measured by the McCormick scale. Eight (88.9%) of the 9 patients who were worse immediately after resection returned to their preoperative status within 6 months. Two patients experienced functional decline during long-term follow-up (beginning at 2.5 and 5 years postoperatively) caused by extensive VHL disease-associated CNS disease. CONCLUSIONS Generally, resection of symptomatic brainstem hemangioblastomas is a safe and effective management strategy in patients with VHL disease. Most patients maintain their preoperative functional status, although long-term decline in functional status may occur due to VHL disease-associated progression.

Seizure outcomes and mesial resection volumes following selective amygdalohippocampectomy and temporal lobectomy

OBJECT Anterior temporal lobectomy (ATL) and selective amygdalohippocampectomy (SelAH) are the preferred surgical approaches for the treatment of medically refractory epilepsy involving the nondominant and dominant temporal lobes, respectively. Both techniques provide access to mesial structures-with the ATL providing a wider surgical corridor than SelAH. Because the extent of mesial temporal resection potentially impacts seizure outcome, the authors examined mesial resection volumes, seizure outcomes, and neuropsychiatric test scores in patients undergoing either ATL or transcortical SelAH at a single institution. METHODS A retrospective study was conducted in 96 patients with medically refractory mesial temporal lobe epilepsy. Fifty-one patients who had nondominant temporal lobe epilepsy underwent standard ATL, and 45 patients with language-dominant temporal lobe epilepsy underwent transcortical SelAH. Volumetric MRI analysis was used to quantify the mesial resection in both groups. In addition, the authors examined seizure outcomes and the change in neuropsychiatric test scores. RESULTS Seizure-free outcome in the entire patient cohort was 94% at a mean follow-up of 44 months. There was no significant difference in the seizure outcome between the 2 groups. The extent of resection of the mesial structures following ATL was slightly higher than for SelAH (98% vs. 91%, p < 0.0001). The change in neuropsychiatric test scores largely reflected the side of surgery, but overall IQ and memory function did not change significantly in either group. CONCLUSIONS Transcortical SelAH provides adequate access to the mesial structures, and allows for a resection that is nearly as extensive as that achieved with standard ATL. Seizure outcomes and neuropsychiatric sequelae are similar in both procedures.

Intraoperative Near-Infrared Optical Imaging Can Localize Gadolinium-Enhancing Gliomas During Surgery

BACKGROUND Although real-time localization of gliomas has improved with intraoperative image guidance systems, these tools are limited by brain shift, surgical cavity deformation, and expense. OBJECTIVE To propose a novel method to perform near-infrared (NIR) imaging during glioma resections based on preclinical and clinical investigations, in order to localize tumors and to potentially identify residual disease. METHODS Fifteen patients were identified and administered a Food and Drug Administration-approved, NIR contrast agent (Second Window indocyanine green [ICG], 5 mg/kg) before surgical resection. An NIR camera was utilized to localize the tumor before resection and to visualize surgical margins following resection. Neuropathology and magnetic resonance imaging data were used to assess the accuracy and precision of NIR fluorescence in identifying tumor tissue. RESULTS NIR visualization of 15 gliomas (10 glioblastoma multiforme, 1 anaplastic astrocytoma, 2 low-grade astrocytoma, 1 juvenile pilocytic astrocytoma, and 1 ganglioglioma) was performed 22.7 hours (mean) after intravenous injection of ICG. During surgery, 12 of 15 tumors were visualized with the NIR camera. The mean signal-to-background ratio was 9.5 ± 0.8 and fluorescence was noted through the dura to a maximum parenchymal depth of 13 mm. The best predictor of positive fluorescence was enhancement on T1-weighted imaging; this correlated with signal-to-background ratio (P = .03). Nonenhancing tumors did not demonstrate NIR fluorescence. Using pathology as the gold standard, the technique demonstrated a sensitivity of 98% and specificity of 45% to identify tumor in gadolinium-enhancing specimens (n = 71). CONCLUSION With the use of Second Window ICG, gadolinium-enhancing tumors can be localized through brain parenchyma intraoperatively. Its utility for margin detection is promising but limited by lower specificity. ABBREVIATIONS 5-ALA, 5-aminolevulinic acidEPR, enhanced permeability and retentionFDA, Food and Drug AdministrationGBM, glioblastomaICG, indocyanine greenNIR, near-infraredNPV, negative predictive valuePPV, positive predictive valueROC, receiver operating characteristicROI, region of interestSBR, signal-to-background ratioWHO, World Health Organization.

Cost-effectiveness of confirmatory techniques for the placement of lumbar pedicle screws

OBJECT There is considerable variation in the use of adjunctive technologies to confirm pedicle screw placement. Although there is literature to support the use of both neurophysiological monitoring and isocentric fluoroscopy to confirm pedicle screw positioning, there are no studies examining the cost-effectiveness of these technologies. This study compares the cost-effectiveness and efficacy of isocentric O-arm fluoroscopy, neurophysiological monitoring, and postoperative CT scanning after multilevel instrumented fusion for degenerative lumbar disease. METHODS Retrospective data were collected from 4 spine surgeons who used 3 different strategies for monitoring of pedicle screw placement in multilevel lumbar degenerative disease. A decision analysis model was developed to analyze costs and outcomes of the 3 different monitoring strategies. A total of 448 surgeries performed between 2005 and 2010 were included, with 4 cases requiring repeat operation for malpositioned screws. A sample of 64 of these patients was chosen for structured interviews in which the EuroQol-5D questionnaire was used. Expected costs and quality-adjusted life years were calculated based on the incidence of repeat operation and its negative effect on quality of life and costs. RESULTS The decision analysis model demonstrated that the O-arm monitoring strategy is significantly (p < 0.001) less costly than the strategy of postoperative CT scanning following intraoperative uniplanar fluoroscopy, which in turn is significantly (p < 0.001) less costly than neurophysiological monitoring. The differences in effectiveness of the different monitoring strategies are not significant (p = 0.92). CONCLUSIONS Use of the O-arm for confirming pedicle screw placement is the least costly and therefore most cost-effective strategy of the 3 techniques analyzed.

Microsurgical treatment of sacral perineural (Tarlov) cysts: case series and review of the literature

OBJECTIVE Tarlov cysts (TCs) occur most commonly on extradural components of the sacral and coccygeal nerve roots. These lesions are often found incidentally, with an estimated prevalence of 4%-9%. Given the low estimated rates of symptomatic TC and the fact that symptoms can overlap with other common causes of low-back pain, optimal management of this entity is a matter of ongoing debate. Here, the authors investigate the effects of surgical intervention on symptomatic TCs and aim to solidify the surgical criteria for this disease process. METHODS The authors performed a retrospective review of data from consecutive patients who were surgically treated for symptomatic TCs from September 2011 to March 2013. Clinical evaluations and results from surveying pain and overall health were used. Univariate statistical analyses were performed. RESULTS Twenty-three adults (4 males, 19 females) who had been symptomatic for a mean of 47.4 months were treated with laminectomy, microsurgical exposure and/or imbrication, and paraspinous muscle flap closure. Eighteen patients (78.3%) had undergone prior interventions without sustained improvement. Thirteen patients (56.5%) underwent lumbar drainage for an average of 8.7 days following surgery. The mean follow-up was 14.4 months. Univariate analyses demonstrated that an advanced age (p = 0.045), the number of noted perineural cysts on preoperative imaging (p = 0.02), and the duration of preoperative symptoms (p = 0.03) were associated with a poor postoperative outcome. Although 47.8% of the patients were able to return to normal activities, 93.8% of those surveyed reported that they would undergo the operation again if given the choice. CONCLUSIONS This is one of the largest published studies on patients with TCs treated microsurgically. The data suggest that patients with symptomatic TCs may benefit from open microsurgical treatment. Although outcomes seem related to patient age, duration of symptoms, and extent of disease demonstrated on imaging, further study is warranted and underway.

3D printing in neurosurgery: A systematic review

Background: The recent expansion of three-dimensional (3D) printing technology into the field of neurosurgery has prompted a widespread investigation of its utility. In this article, we review the current body of literature describing rapid prototyping techniques with applications to the practice of neurosurgery. Methods: An extensive and systematic search of the Compendex, Scopus, and PubMed medical databases was conducted using keywords relating to 3D printing and neurosurgery. Results were manually screened for relevance to applications within the field. Results: Of the search results, 36 articles were identified and included in this review. The articles spanned the various subspecialties of the field including cerebrovascular, neuro-oncologic, spinal, functional, and endoscopic neurosurgery. Conclusions: We conclude that 3D printing techniques are practical and anatomically accurate methods of producing patient-specific models for surgical planning, simulation and training, tissue-engineered implants, and secondary devices. Expansion of this technology may, therefore, contribute to advancing the neurosurgical field from several standpoints.

Endoscopic approaches to brainstem cavernous malformations: Case series and review of the literature

Background: Symptomatic cavernous malformations involving the brainstem are frequently difficult to access via traditional methods. Conventional skull-base approaches require significant brain retraction or bone removal to provide an adequate operative corridor. While there has been a trend toward limited employment of the most invasive surgical approaches, recent advances in endoscopic technology may complement existing methods to access these difficult to reach areas. Case Descriptions: Four consecutive patients were treated for symptomatic, hemorrhagic brainstem cavernous malformations via fully endoscopic approaches (endonasal, transclival; retrosigmoid; lateral supracerebellar, infratentorial; endonasal, transclival). Together, these lesions encompassed all three segments of the brainstem. Three of the patients had complete resection of the cavernous malformation, while one patient had stable residual at long-term follow up. Associated developmental venous anomalies were preserved in the two patients where one was identified preoperatively. Three of the four patients maintained stable or improved neurological examinations following surgery, while one patient experienced ipsilateral palsies of cranial nerves VII and VIII. The first transclival approach resulted in a symptomatic cerebrospinal fluid leak requiring re-operation, but the second did not. Although there are challenges associated with endoscopic approaches, relative to our prior microsurgical experience with similar cases, visualization and illumination of the surgical corridors were superior without significant limitations on operative mobility. Conclusion: The endoscope is a promising adjunct to the neurosurgeons ability to approach difficult to access brainstem cavernous malformations. It allows the surgeon to achieve well-illuminated, panoramic views, and by combining approaches, can provide minimally invasive access to most regions of the brainstem.