David R. Santiago-Dieppa

Extracellular vesicles as a platform for ‘liquid biopsy’ in glioblastoma patients

Extracellular vesicles (EVs) are cell-secreted vesicles that range from 30–2000 nm in size. These vesicles are secreted by both normal and neoplastic cells. Physiologically, EVs serve multiple critical biologic functions, including cellular remodeling, intracellular communication, modulation of the tumor microenvironment and regulation of immune function. Because EVs contain genetic and proteomic contents that reflect the cell of origin, it is possible to detect tumor-specific material in EVs secreted by cancer cells. Importantly, EVs secreted by cancer cells transgress anatomic compartments and can be detected in the blood, cerebrospinal fluid, and other biofluids of cancer patients. In this context, there is a growing interest in analyzing EVs from the biofluid of cancer patients as a means of disease diagnosis and therapeutic monitoring. In this article, we review the development of EVs as a diagnostic platform for the most common form of brain cancer, glioblastoma, discuss potential clinical translational opportunities and identify the central challenges associated with future clinical applications.

Incidence and clinical significance of vascular encroachment resulting from freehand placement of pedicle screws in the thoracic and lumbar spine: analysis of 6816 consecutive screws.

Study Design. Retrospective case series. Objective. Evaluate the incidence and clinical significance of vascular encroachment resulting from freehand placement of pedicle screws in the thoracic and lumbosacral spine. Summary of Background Data. Pedicle screws are routinely used to effectively stabilize all 3 columns of the spine but can be technically demanding to place in the setting of variable anatomy. There is a paucity of data regarding iatrogenic major vascular injuries during posterior instrumentation procedures. Methods. We retrospectively reviewed the records of all patients undergoing freehand pedicle screw placement without image guidance in the thoracic or lumbar spine during a 7-year period. The incidence and extent of vascular encroachment by a pedicle screw was determined by review of routine postoperative computed tomographic scans obtained within 24 hours of all surgical procedures. Vascular encroachment was defined as a pedicle screw that was touching or deforming the wall of a major vessel. Results. A total of 964 patients received 6816 freehand-placed pedicle screws in the thoracolumbar spine. Fifteen (0.22%) screws that encroached a major vascular structure were identified. Ten (0.29%) thoracic pedicle screws encroached on the aorta, 4 (0.14%) lumbar screws on the common iliac vein, and 1 S1 screw (0.19%) on the internal iliac vein. In consultation with vascular surgery, it was determined whether revision surgery and the technique/approach for the revision procedure should be recommended. Two (0.21%) patients required revision surgery to remove the encroaching pedicle screw (T5 and T8) due to concern for vascular injury. Both patients were asymptomatic and recovered without further complications after revision surgery. Conclusion. Vascular encroachment of major vessels occurs rarely in the setting of freehand pedicle screw placement in the thoracolumbar spine. Although rare, delayed vascular injury from errant pedicle screw placement has been reported in the literature. The aorta seems to be the vessel at the highest risk of injury. Routine intraoperative or postoperative computed tomographic scanning allows for early identification of pedicle screws encroaching on vascular structures thereby facilitating early revision surgery. Level of Evidence: 4

Adjacent-segment disease in 511 cases of posterolateral instrumented lumbar arthrodesis: Floating fusion versus distal construct including the sacrum: Clinical article

OBJECT The aim of this study was to study the long-term outcomes of patients undergoing instrumented posterior fusion of the lumbar spine. METHODS The authors present 511 patients who underwent instrumented arthrodesis for lumbar degenerative disease over a 23-year period at a single institution. Patients underwent follow-up for an average of 39.73 ± 46.52 months (± SD) after the index lumbar arthrodesis procedure. RESULTS The average patient age was 59.45 ± 13.48 years. Of the 511 patients, 502 (98.24%) presented with back pain, 379 (74.17%) with radiculopathy, 76 (14.87%) with motor weakness, and 32 (6.26%) with preoperative bowel/bladder dysfunction. An average of 2.04 ± 1.03 spinal levels were fused. Postoperatively, patients experienced a significant improvement in back pain (p < 0.0001) and radiculopathy (p < 0.0001). Patients with fusions excluding the sacrum (floating fusions) were statistically more likely to develop adjacent-segment disease (ASD) than those with fusion constructs ending at S-1 distally (p = 0.030) but were less likely to develop postoperative radiculopathy (p = 0.030). In the floating fusion cohort, 31 (12.11%) of 256 patients had cephalad ASD, whereas 39 (15.29%) of 255 patients in the lumbosacral cohort had cephalad ASD development; this was not statistically different (p = 0.295). This suggests that caudad ASD development in the floating fusion cohort is due to the added risk of an unfused L5-S1 vertebral level. Because of the elevated risk of symptomatic radiculopathy but lower risk of ASD, patients in the lumbosacral fusion cohort had a reoperation rate similar to those undergoing floating fusions (p = 0.769). CONCLUSIONS In this paper, the authors present one of the largest cohorts in the Western literature of patients undergoing instrumented fusion for degenerative lumbar spine disease. Patients who had floating lumbar fusions were statistically more likely to develop ASD over time than those who had lumbosacral fusions incorporating the S-1 spinal segment, but were less likely to experience postoperative radicular symptoms. Additional prospective studies may more clearly delineate the long-term risks of instrumented posterolateral fusions of the lumbar spine.

Quantitative study of parathyroid hormone (1-34) and bone morphogenetic protein-2 on spinal fusion outcomes in a rabbit model of lumbar dorsolateral intertransverse process arthrodesis

Study Design. A posterolateral rabbit spinal fusion model was used to evaluate the effects of recombinant human bone morphogenetic protein-2 (rhBMP-2) and teriparatide (PTH [1–34]) used individually and in combination on spinal fusion outcomes. Objective. To test the efficacy of parathyroid hormone on improving spinal fusion outcomes when used with BMP-2. Summary of Background Data. Of the more than 250,000 spinal fusion surgical procedures performed each year, 5% to 35% of these will result in pseudarthrosis. Growing controversy on the efficacy and cost of rhBMP-2 for improving spinal fusion outcomes has presented a challenge for clinicians. Research into PTH as an adjunct therapy to rhBMP-2 for spinal fusion has not yet been investigated. Methods. Forty-eight male New Zealand white rabbits underwent bilateral posterolateral intertransverse process arthrodesis surgery at the L5–L6 level. Animals were divided into 6 groups. Two groups were treated with autograft alone or autograft and PTH (1-34), whereas the other 4 groups were treated with low-dose rhBMP-2 alone, high-dose rhBMP-2 alone, or either dose combined with PTH (1-34). All animals were euthanized 6 weeks after surgery. The L4–L7 spinal segment was removed and assessed using manual palpation, computed tomography (CT), and biomechanical testing. Results. CT assessments revealed fusion in 50% of autograft controls, 75% of autograft PTH (1-34) animals, 87.5% in the 2 groups treated with low-dose rhBMP-2, and 100% in the 2 groups treated with high-dose rhBMP-2. CT volumetric analysis demonstrated that all groups treated with biologics had fusion masses that were on average significantly larger than those observed in the control group (P < 0.0001). Biomechanical data demonstrated no statistical difference between controls, PTH (1-34), and low-dose rhBMP-2 in any testing orientation. PTH (1-34) did not increase bending stiffness when used adjunctively with either low-dose or high-dose rhBMP-2. Conclusion. Although intermittent teriparatide administration results in increased fusion mass volume, it does not improve biomechnical stiffness over use of autograft alone. When delivered concurrently with high- and low-dose rhBMP-2, teriparatide provided no statistically significant improvement in biomechanical stiffness. Level of Evidence: N/A

Vessel wall signal enhancement on 3-T MRI in acute stroke patients after stent retriever thrombectomy.

OBJECTIVE In vivo and in vitro studies have demonstrated histological evidence of iatrogenic endothelial injury after stent retriever thrombectomy. However, noncontrast vessel wall (VW)-MRI is insufficient to demonstrate vessel injury. Authors of this study prospectively evaluated iatrogenic endothelial damage after stent retriever thrombectomy in humans by utilizing high-resolution contrast-enhanced VW-MRI. Characterization of VW-MRI changes in vessels subject to mechanical injury from thrombectomy may allow better understanding of the biological effects of this intervention. METHODS The authors prospectively recruited 11 patients for this study. The treatment group included 6 postthrombectomy patients and the control group included 5 subjects undergoing MRI for nonvascular indications. All subjects were evaluated on a Signa HD× 3.0-T MRI scanner with an 8-channel head coil. Both pre- and postcontrast T1-weighted Cube VW images as well as MR angiograms were acquired. Sequences obtained for evaluation of the brain parenchyma included diffusion-weighted, gradient echo, and T2-FLAIR imaging. Two independent neuroradiologists, who were blinded to the treatment status of each patient, determined the presence of VW enhancement. Patient age, National Institutes of Health Stroke Scale score on presentation, location of occlusion, stroke etiology, type of device used, number of device deployments, Thrombolysis in Cerebral Infarction (TICI) reperfusion score, stroke volume, and 90-day modified Rankin Scale score were also noted. RESULTS Postcontrast T1-weighted VW enhancement was detected in the M2 segment in 100% of the thrombectomy patients, in the M1 segment in 83%, and in the internal carotid artery in 50%. One patient also demonstrated A1 segment enhancement, which was attributable to thrombectomy treatment of that vessel segment during the same procedure. None of the control patients demonstrated VW enhancement of their intracranial vasculature on T1-weighted images. CONCLUSIONS The study findings suggest that VW injury incurred during stent retriever thrombectomy can be reliably detected utilizing contrast-enhanced 3-T VW-MRI. The results further demonstrate that endothelial injury is associated with oversizing of stent retrievers relative to the treated vessel. Further studies are needed to evaluate the clinical significance of endothelial injury and to characterize the differential effects of various devices.

L4 and L5 Spondylectomy for En Bloc Resection of Giant Cell Tumor and Review of the Literature

Study Design Case report and review of the literature. Objective We present the case of a two-level lumbar spondylectomy at L4 and L5 for en bloc resection of a giant cell tumor (GCT) and lumbopelvic reconstruction. Methods A 58-year-old woman presented with a 7-month history of progressive intractable back and leg pain secondary to a biopsy-proven Enneking stage III GCT of the L4 and L5 vertebrae. The patient underwent a successful L4–L5 spondylectomy and lumbopelvic reconstruction using a combined posterior and anterior approach over two operative stages. Results Postoperative complications included a deep wound infection and a cerebrospinal fluid leak; however, following surgical debridement and long-term antibiotic treatment, the patient was neurologically intact with minimal pain and there was no evidence of tumor recurrence or instrumentation failure at more than 2 years of follow-up. Conclusion Spondylectomy that achieves en bloc resection is a viable and effective treatment option that can be curative for Enneking stage III GCTs involving the lower lumbar spine. The lumbosacral junction represents a challenging anatomic location for spinal reconstruction after spondylectomy with unique technical considerations.

Interventional Management of Acute Ischemic Stroke: A Systematic Review

Opinion statementHistorically, acute ischemic stroke (AIS) trials defined syndromes according to acute clinical presentation and post-ictus parenchymal imaging. With improvements in real-time arterial imaging, modern AIS treatment demands a structural approach based upon the level of cerebrovascular occlusion. The poor concordance of presenting National Institute of Health Stroke Scale (NIHSS) with vessel occlusion in recent trials bespeaks the need for an anatomic perspective. Specifically, patients with large-vessel occlusion (LVO) represent a distinct entity with a poorer prognosis than general AIS patients. Ongoing clinical trials and therapeutic strategies must recognize the varied natural history of AIS patients. Endovascular therapy offers promise in patients with the most severe strokes.

Simulator-Based Angiography and Endovascular Neurosurgery Curriculum: A Longitudinal Evaluation of Performance Following Simulator-Based Angiography Training

This study establishes performance metrics for angiography and neuroendovascular surgery procedures based on longitudinal improvement in individual trainees with differing levels of training and experience. Over the course of 30 days, five trainees performed 10 diagnostic angiograms, coiled 10 carotid terminus aneurysms in the setting of subarachnoid hemorrhage, and performed 10 left middle cerebral artery embolectomies on a Simbionix Angio Mentor™ simulator. All procedures were nonconsecutive. Total procedure time, fluoroscopy time, contrast dose, heart rate, blood pressures, medications administered, packing densities, the number of coils used, and the number of stent-retriever passes were recorded. Image quality was rated, and the absolute value of technically unsafe events was recorded. The trainees’ device selection, macrovascular access, microvascular access, clinical management, and the overall performance of the trainee was rated during each procedure based on a traditional Likert scale score of 1=fail, 2=poor, 3=satisfactory, 4=good, and 5=excellent. These ordinal values correspond with published assessment scales on surgical technique. After performing five diagnostic angiograms and five embolectomies, all participants demonstrated marked decreases in procedure time, fluoroscopy doses, contrast doses, and adverse technical events; marked improvements in image quality, device selection, access scores, and overall technical performance were additionally observed (p < 0.05). Similarly, trainees demonstrated marked improvement in technical performance and clinical management after five coiling procedures (p < 0.05). However, trainees with less prior experience deploying coils continued to experience intra-procedural ruptures up to the eighth embolization procedure; this observation likely corresponded with less tactile procedural experience to an exertion of greater force than appropriate for coil placement. Trainees across all levels of training and prior experience demonstrated a significant performance improvement after completion of our simulator curriculum consisting of five diagnostic angiograms, five embolectomy cases, and 10 aneurysm coil embolizations.

Hemorrhagic intramedullary solitary fibrous tumor of the conus medullaris: case report

The differential diagnosis of spinal tumors is guided by anatomical location and imaging characteristics. Diagnosis of rare tumors is made challenging by abnormal features. The authors present the case of a 47-year-old woman who presented with progressive subacute right lower-extremity weakness and numbness of the right thigh. Physical examination further revealed an extensor response to plantar reflex on the right and hyporeflexia of the right Achilles and patellar reflexes. Magnetic resonance imaging of the lumbar spine demonstrated an 8-mm intramedullary exophytic nodule protruding into a hematoma within the conus medullaris. Spinal angiography was performed to rule out an arteriovenous malformation, and resection with hematoma evacuation was completed. Pathological examination of the resected mass demonstrated a spindle cell neoplasm with dense bundles of collagen. Special immunostaining was performed and a diagnosis of solitary fibrous tumor (SFT) was made. SFTs are mesenchymally derived pleural neoplasms, which rarely present at other locations of the body, but have been increasingly described to occur as primary neoplasms of the spine and CNS. The authors believe that this case is unique in its rare location at the level of the conus, and also that this is the first report of a hemorrhagic SFT in the spine. Therefore, with this report the authors add to the literature the fact that this variant of an increasingly understood but heterogeneous tumor can occur, and therefore should be considered in the differential of clinically similar tumors.

Nerve transfer versus muscle transfer to restore elbow flexion after pan–brachial plexus injury: a cost-effectiveness analysis

OBJECTIVE Pan-brachial plexus injury (PBPI), involving C5-T1, disproportionately affects young males, causing lifelong disability and decreased quality of life. The restoration of elbow flexion remains a surgical priority for these patients. Within the first 6 months of injury, transfer of spinal accessory nerve (SAN) fascicles via a sural nerve graft or intercostal nerve (ICN) fascicles to the musculocutaneous nerve can restore elbow flexion. Beyond 1 year, free-functioning muscle transplantation (FFMT) of the gracilis muscle can be used to restore elbow flexion. The authors present the first cost-effectiveness model to directly compare the different treatment strategies available to a patient with PBPI. This model assesses the quality of life impact, surgical costs, and possible income recovered through restoration of elbow flexion. METHODS A Markov model was constructed to simulate a 25-year-old man with PBPI without signs of recovery 4.5 months after injury. The management options available to the patient were SAN transfer, ICN transfer, delayed FFMT, or no treatment. Probabilities of surgical success rates, quality of life measurements, and disability were derived from the published literature. Cost-effectiveness was defined using incremental cost-effectiveness ratios (ICERs) defined by the ratio between costs of a treatment strategy and quality-adjusted life years (QALYs) gained. A strategy was considered cost-effective if it yielded an ICER less than a willingness-to-pay of