Bullet embolism after high velocity penetrating trauma is a rare event that can have devastating and wide-ranging effects distant from the original site of injury. A 29-year-old presented with multiple gunshot wounds to the chest, back, abdomen, and lower extremities but no penetrating head injury. After proper resuscitation, the patient was noted to have left-sided hemiparesis and computed tomography angiography of the head showed a bullet fragment that had traveled to the right M1 segment of the middle cerebral artery resulting in occlusion of the vessel. Mechanical thrombectomy was performed in an attempt to remove the bullet fragment but this was unsuccessful as the fragment was firmly lodged in the blood vessel. Aspiration of clot distal to the fragment was then performed in hopes of preventing a large volume ischemic event which was angiographically successful resulting in TICI 2c revascularization. This case demonstrates that thrombectomy can be safely and successfully performed distal to a lodged foreign body.

BACKGROUND The timing of stroke onset among patients with blunt cerebrovascular injury (BCVI) is not well understood. All blunt trauma patients at our institution undergo a screening computed tomographic angiography (CTA) of the neck. Most patients with CTA evidence of BCVI are treated with aspirin, and all patients with clinical evidence of stroke are treated with aspirin and undergo magnetic resonance imaging (MRI) of the brain. We conducted a retrospective review to determine the incidence of stroke upon admission and following admission. METHODS All neck CTAs and head MRIs obtained in blunt trauma patients were reviewed from August 2017 to August 2019. All CTAs that were interpreted as showing BCVI were individually reviewed to confirm the diagnosis of BCVI. Stroke was defined as brain MRI evidence of new ischemic lesions, and each MRI was reviewed to identify the brain territory affected. We extracted the time to aspirin administration and the timing of stroke onset from patients' electronic health records. RESULTS Of the 6,849 blunt trauma patients, 479 (7.0%) had BCVIs. Twenty-four patients (5.0%) with BCVI had a stroke on admission. Twelve (2.6%) of the remaining 455 patients subsequently had a stroke during their hospitalization. The incidence of stroke among patients with BCVI was 7.5%; 2.6% were potentially preventable. Only 5 of the 12 patients received aspirin before the onset of stroke symptoms. All 36 patients with BCVI and stroke had thromboembolic lesions in the territory supplied by an injured vessel. CONCLUSION With universal screening, CTA evidence of BCVI is common among blunt trauma patients. Although acute stroke is also relatively common in this population, two thirds of strokes are already evident on admission. One third of BCVI-related strokes occur after admission and often relatively early, necessitating rapid commencement of preventative treatment. Further studies are required to demonstrate the value of antithrombotic administration in preventing stroke in BCVI patients. LEVEL OF EVIDENCE Prognostic and Epidemiologic; Level IV.

Isolated spinal artery aneurysms are a rare cause of intracranial subarachnoid hemorrhage (SAH). A 49-year-old female presented with severe headache. Initial imaging showed SAH and intraventricular hemorrhage (IVH), but no clear source of bleeding was identified. One week into being observed in the intensive care unit, she reported another severe headache. Computed tomography head showed more SAH and IVH. A second angiogram revealed a ruptured small anterior spinal artery (ASA) aneurysm at the craniocervical junction. She underwent a C1-2 fusion followed by an endoscopic endonasal transodontoid approach and wrapping of the ASA aneurysm. At 2 years' follow-up, there was no sign of aneurysm growth or rerupture. This is the first reported case of an endoscopic endonasal transodontoid approach to an aneurysm.

Study Design: We conducted decision analytical modeling using a Markov model to determine the ICER of i-factor compared to autograft in ACDF surgery. Objective: The efficacy and safety of traditional anterior cervical discectomy and fusion (ACDF) surgery has improved with the introduction of new implants and compounds. Cost-effectiveness of these innovations remains an often-overlooked aspect of this effort. To evaluate the cost-effectiveness of i-FACTOR compared to autograft for patients undergoing ACDF surgery. Methods: The patient cohort was extracted from a prospective, multicenter randomized control trial (RCT) from twenty-two North American centers. Patients randomly received either autograft (N = 154) or i-Factor (N = 165). We analyzed various real-world scenarios, including inpatient and outpatient surgical settings as well as private versus public insurances. Two primary outcome measures were assessed: cost and utility. In the base-case analysis, both health and societal system costs were evaluated. Health-related utility outcome was expressed in quality-adjusted life years (QALYs). Cost-effectiveness was expressed as an incremental cost-effectiveness ratio (ICER). Results: In all scenarios, i-FACTOR reduced costs within the first year by 1.4% to 2.1%. The savings proved to be incremental over time, increasing to 3.7% over an extrapolated 10 years. The ICER at 90 days was $13,333 per QALY and became negative ("dominated") relative to the control group within one year and onwards. In a threshold sensitivity analysis, the cost of i-FACTOR could theoretically be increased 70-fold and still remain cost-effective. Conclusion: The novel i-FACTOR is not only cost-effective compared to autograft in ACDF surgery but is the dominant economic strategy.

BACKGROUND Blunt cerebrovascular injury (BCVI) can result in thromboembolic stroke. Many trauma centers selectively screen patients with cervical computed tomographic angiography (CTA) based on clinical criteria. In 2016, our institution adopted universal screening for BCVI for all blunt trauma patients. The aim of this study was to accurately determine the incidence of BCVI and to evaluate the diagnostic performance of the Denver criteria (DC), expanded Denver criteria (eDC), and Memphis criteria (MC) in selecting patients for screening. METHODS Retrospective cohort study of adult (≥16 years) blunt trauma patients who presented to the Level I trauma center at University of Alabama at Birmingham. We reviewed all CTA reports and selected CTA images to obtain the true incidence rate of BCVI. We then evaluated the diagnostic performance of the DC, eDC, and MC. RESULTS A total of 6,800 patients who had suffered blunt trauma were evaluated, of whom 6,287 (92.5%) had a neck CTA. Of these, 480 (7.6%) patients had CTA evidence of BCVI. The eDC identified the most BCVI cases (sensitivity 74.7%) but had the lowest positive predictive value (14.6%). The DC and MC had slightly greater positive predictive values (19.6% and 20.6%, respectively) and had the highest diagnostic ability in terms of likelihood ratio (2.8 and 2.9) but had low sensitivity (57.5% and 47.3%). Consequently, if relying on the traditional screening criteria, the DC, eDC, and MC would have respectively resulted in 42.5%, 25.3%, and 52.7% of patients with BCVI identified by universal screening not receiving a neck CTA to screen for BCVI. CONCLUSION Blunt cerebrovascular injury is even more common than previously thought. The diagnostic performance of selective clinical screening criteria is poor. Consideration should be given to the implementation of universal screening for BCVI using neck CTA in all blunt trauma patients. LEVEL OF EVIDENCE Diagnostic, level III.

OBJECTIVE:Endovascular treatment is the mainstay therapy for brain aneurysms. About 15% of patients need re-treatment within six months due to early recanalization. In this study, we investigate risk factors associated with treatment failure.METHODS:This retrospective cohort study includes endovascularly treated aneurysm cases between July 2012 and December 2015 at the University of California Davis Medical Center with pre-treatment and early post-treatment imaging. Thin cut 3D aneurysm volume rendering was used for morphologic analyses. Univariate and bivariate analyses were conducted to evaluate differences between patients and clinical factors by treatment failure.RESULTS:Of the 50 patients who met the inclusion criteria, 41 (82.0%) were female, with an average age of 61 years. Most aneurysms were on the anterior communicating artery (40%) or posterior communicating artery (22.0%), and 34 (68%) aneurysms were ruptured. Early treatment failure was observed in 14 (28.0%) of endovascularly treated patients. Raymond-Roy class (RRC) was significantly associated with treatment failure (p = 0.0052), with 10 out of the 14 cases (71.4%) with early recanalization having an RRC of 3. Coil packing density did not associate with aneurysm recanalization (p = 0.61).CONCLUSION:In our single institution series, patient characteristics, aneurysm characteristics, or coil packing density did not affect early aneurysm recanalization. RRC was the best predictor of early recanalization; however, further confirmation with additional studies are required. Although this study focused on early treatment failure, late recanalization has been shown with longer follow up. Further investigation into factors associated with late treatment failure will need further investigation. New intrasaccular devices and flow diverters will also likely play a role in reducing recurrence in the future as these treatments gain usage.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated high morbidity and mortality. Among the most common sequelae of aSAH is delayed cerebral ischemia. Hyperdynamic therapy (fluid supplementation and hypertension) is used to increase cerebral perfusion. However, the safety of hyperdynamic therapy in patients with separate unruptured, unsecured intracranial aneurysms is not well-established. Herein, a rare case demonstrating the rapid evolution and rupture of an incidental unsecured aneurysm in the setting of hvperdynamic therapy is presented. CASE DESCRIPTION: A 56-year-old woman without significant medical history presented with aSAH secondary to rupture of a 3-mm left posterior inferior cerebellar artery aneurysm. After endovascular treatment of this aneurysm, she developed symptomatic vasospasm prompting initiation of hyperdynamic therapy. Seven days after initiation of hyperdynamic therapy, she experienced rupture of an incidental pericallosal artery aneurysm that was found to have increased in size during the hyperdynamic therapy. She ultimately survived and was functionally independent approximately 1 year after her initial ictus. CONCLUSIONS: This case demonstrates that enlargement and rupture of an incidental, previously unruptured aneurysm may occur during hyperdynamic therapy.

Chagoya, Gustavo MD; Thaci, Bart MD; Elsayed, Galal; Salehani, Arsalaan; Pope, Brandon; Gupta, Saksham BA; Bernstock, Joshua MSc, MPH; Harrigan, Mark R MD Author Information

Primary spinal glioblastoma multiforme (GBM) of the conus medullaris is a rare and devastating pathologic entity. The presenting symptoms commonly include progressive neurologic deficits in the lower extremities, bowel and bladder dysfunction, and low back pain. Histologically, these tumors have high-grade features similar to their intracranial counterparts. However, recent advancements in the field of molecular oncology have been beginning to elucidate a unique molecular blueprint for these spinal gliomas. Given the lack of standardized treatment strategies, we have presented our institutional experience in treating a small series of patients with conus medullaris GBM and have reviewed the reported data on the relevant molecular markers, management strategies, and complication avoidance for this malignant pathologic entity.

BACKGROUND CONTEXT: Lumbar discectomy is largely successful surgical procedure; however, reherniation rates in patients with large annular defects are as high as 27%. The expense associated with a revision surgery places significant burden on the healthcare system. PURPOSE: To compare the direct health care costs through 5 years follow-up of conventional discectomy (Control) with those of discectomy supplemented by an adjunctive annular closure device (ACD) in high-risk patients with large annular defects. STUDY DESIGN: This was a cost-effectiveness study. METHODS: All-cause index level reoperations were reviewed from a multicenter, randomized controlled superiority trial that allocated 554 high-risk discectomy patients with large annular defects to either control or ACD. Medicare and private insurer (Humana) direct costs were derived from a commercially available payer database to estimate costs in the US healthcare system, including those associated with facility, surgeon, imaging, follow-up visits, physical therapy, and injections. A 50: 50 split between Medicare and commercial insurers was assumed for the base case analysis. The analysis was also performed on a 80: 20 commercial: Medicare payer basis. For the base case scenario, a 2-year time horizon and outpatient cost setting was established for the index procedure. Repeat discectomy was assumed to be performed on a 60: 40 outpatient-to-inpatient basis. Complications requiring surgery, revisions, and/or fusion were assumed to be managed in the inpatient setting. Total costs of reoperation and per-patient costs of reoperation were compared between groups for both forms of insurers. One author received consulting fees of <$50,000 for the completion of this study, and the other eight authors did not have any financial associations with the current work. Funding for this study was provided by Intrinsic Therapeutics, but all analyses, interpretation, and writing were performed independently by the authors. RESULTS: At two years follow-up, use of the ACD reduced the rate of symptomatic reherniations in a large defect population to 13% compared with 25% in the control group (p<.001). This reduction in symptomatic reherniations in the ACD group translated to a savings of $2,802 per patient in direct health care costs compared with Control at 2 years and $5,315 per patient by 5 years based on 50% private and 50% public (Medicare) payer split. Under the scenario of 80: 20 private: public insurance reimbursement, the estimated direct cost savings were $3,215 and $6,099 per patient at 2- and 5-years postoperatively, respectively, with the use of the ACD. CONCLUSIONS: Symptomatic reherniation and reoperation rates were nearly double among control patients compared with ACD-treated patients, which translated to markedly greater per-patient health-care costs in the control group, where the ACD was not used. (C) 2019 Published by Elsevier Inc.

Purpose Despite being an extremely successful procedure, recurrent disc herniation is one of the most common post-discectomy complications in the lumbar spine and contributes significant health care and socioeconomic costs. Patients with large annular defects are at a high risk for reherniation, but an annular closure device (ACD) has been designed to reduce reherniation risk in this population and may, in turn, help control direct health care costs after discectomy. Patients and methods This analysis examined the 90-day post-discectomy cost estimates among ACD-treated (n=272) and control (discectomy alone; n=278) patients in a randomized controlled trial (RCT). Direct medical costs were estimated based on 2017 Humana and Medicare claims. Index discectomies were assumed to occur in an outpatient (OP) setting, whereas repeat discectomies were assumed to be 60% in OP and 40% in inpatient (IP). A sensitivity analysis was performed on this assumption. The device cost was not included in the analysis in order to focus on costs in the 90-day post-operative period. Results Within 90 days of follow-up, post-operative complications occurred in 3.3% of the ACD patients and 8.6% of the control patients (P=0.01). The average 90-day cost to treat an ACD patient was $10,257 compared to $11,299 per control patient for a 80:20 distribution of Commercial:Medicare coverage ($1,042 difference). This difference varied from $687 with 100% Medicare to $1,132 with 100% Commercial coverage. Varying the IP vs OP distribution resulted in a cost difference range of $968 to $1,156 with the ACD. Conclusion Augmenting discectomy with an ACD in high-risk patients with a large annular defect reduced reherniation and reoperation rates, which translated to a reduction of direct health care costs between $687 and $1,156 per patient during the 90-day post-operative period. Large annular defect patients are an easily identifiable high-risk population. Operative strategies that reduce complication risks in these patients, such as the ACD, could be advantageous from both patient care and economic perspectives.

Primary spinal glioblastoma multiforme (GBM) of the conus medullaris is a rare and devastating pathologic entity. The presenting symptoms commonly include progressive neurologic deficits in the lower extremities, bowel and bladder dysfunction, and low back pain. Histologically, these tumors have high-grade features similar to their intracranial counterparts. However, recent advancements in the field of molecular oncology have been beginning to elucidate a unique molecular blueprint for these spinal gliomas. Given the lack of standardized treatment strategies, we have presented our institutional experience in treating a small series of patients with conus medullaris GBM and have reviewed the reported data on the relevant molecular markers, management strategies, and complication avoidance for this malignant pathologic entity.

Study Design. Cost-utility analysis of an annular closure device (ACD) based on data from a prospective, multicenter randomized controlled trial (RCT) Objective. The aim of this study was to determine the cost-effectiveness of a novel ACD in a patient population at high risk for recurrent herniation following discectomy. Summary of Background Data. Lumbar disc herniation patients with annular defect widths ≥6 mm are at high risk for recurrent herniation following limited discectomy. Recurrent herniation is associated with worse clinical outcomes and greater healthcare costs. A novel ACD may reduce the incidence of recurrent herniation and the associated burdens. Methods. A decision analytical modeling approach with a Markov method was used to evaluate the cost-effectiveness of the ACD versus conventional discectomy. Health states were created by projecting visual analogue scale (VAS) onto Oswestry Disability Index (ODI). Direct costs were calculated based on Humana and Medicare 2014 claims to represent private and public payer data, respectively. Indirect costs were calculated for lost work days using 2016 US average annual wages. The incremental cost-effectiveness ratio (ICER) in dollars per quality-adjusted life year (QALY) was compared to willingness-to-pay thresholds. Sensitivity analyses were also conducted. Results. Patients with the ACD had less symptomatic reherniations, reoperations, and complications and gained 0.0328 QALYs within the first 2 years. Total direct medical costs for the ACD group were similar to control. When productivity loss was considered, using the ACD became $2076 cheaper, per patient, than conventional discectomy. Based on direct costs alone, the ICER comparing ACD to control equaled $6030 per QALY. When indirect costs are included, the ICER became negative, which indicates that superior quality of life was attained at less cost. Conclusion. For lumbar disc herniations patients with annular defects ≥6 mm, the ACD was, at 2 years, a highly cost-effective surgical modality compared to conventional lumbar discectomy. Level of Evidence: 1

Ament, Jared MD, MPH; Thaci, Bart MD; Said, Mena BS; Panchal, Ripul Rajen DO; Kim, Kee Duk MD; Johnson, J Patrick MD, MS

Thaci, Bart MD; Ferry, Chris MS; Ventimiglia, Brieta; Glorioso, Tom; Martin, Kim; Martineck, Sarah; Panchal, Ripul R DO; Arnold, Paul M MD; Passias, Peter G MD; Moura, Alex De MD; Strenge, Brandon; Hill, Clint; Denhaese, Ryan Peter MD, MS; Kim, Kee Duk MD

Glioblastoma (GBM) is the most lethal primary brain tumor, and despite several refinements in its multimodal management, generally has very poor prognosis. Targeted immunotherapy is an emerging field of research that shows great promise in the treatment of GBM. One of the most extensively studied targets is the interleukin-13 receptor alpha chain variant 2 (IL13Rα2). Its selective expression on GBM, discovered almost two decades ago, has been a target for therapy ever since. Immunotherapeutic strategies have been developed targeting IL13Rα2, including monoclonal antibodies as well as cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-expressing T cells. Advanced therapeutic development has led to the completion of several clinical trials with promising outcomes. In this review, we will discuss the recent advances in the IL13Rα2-targeted immunotherapy and evaluate the most promising strategy for targeted GBM immunotherapy.

Myeloid-derived suppressor cells (MDSCs) accumulate in the glioma microenvironment during tumor progression and promote immunosuppression. Interleukin-12 (IL-12) immunogene therapy can alter MDSCs toward an antigen-presenting cell phenotype and these mature cells can have a central role in antigen presentation. It remains unclear, however, how MDSC depletion can affect glioma immunotherapy. In this study, we generated a replication-deficient adenoviral vector, Ad.5/3.cRGD-mIL12p70, that transduces the GL261-based murine glioma cell line, resulting in the induction of biologically active, murine IL12p70 expression. Ex vivo, IL-12 expressed by GL261 cells induced interferon-γ synthesis in CD8(+) T cells (P<0.001), CD4(+) T cells (P=0.009) and natural killer cells (P=0.036). When injected 1 week after tumor implantation, Ad.5/3.cRGD-mIL12p70 successfully prolonged the survival of glioma-bearing mice. Sixty percent of animals treated with IL-12 immunotherapy were long-term survivors over 175 days, whereas all the control group animals expired by 40 days after tumor implantation (P=0.026). Mice receiving Ad.5/3.cRGD-mIL12p70 also accumulated 50% less MDSCs in the brain than the control group (P=0.007). Moreover, in the IL-12 group, MDSCs significantly overexpressed CD80 and major histocompatibility complex class II molecules (P=0.041). Depletion of MDSCs with Gr1(+) antibody had no survival benefit induced by IL-12-mediated immunotherapy. Of note, IL-12 therapy increased the presence of myeloid dendritic cells (mDCs) in the glioma microenvironment (P=0.0069). Ultimately, the data show that in the context of IL-12 immunogene therapy, MDSCs are dispensable and mDCs may provide the majority of antigen presentation in the brain.

The blood-brain barrier (BBB) remains a formidable obstacle in medicine, preventing efficient penetration of chemotherapeutic and diagnostic agents to malignant gliomas. Here, a transactivator of transcription (TAT) peptide-modified gold nanoparticle platform (TAT-Au NP) with a 5 nm core size is demonstrated to be capable of crossing the BBB efficiently and delivering cargoes such as the anticancer drug doxorubicin (Dox) and Gd(3+) contrast agents to brain tumor tissues. Treatment of mice bearing intracranial glioma xenografts with pH-sensitive Dox-conjugated TAT-Au NPs via a single intravenous administration leads to significant survival benefit when compared to the free Dox. Furthermore, it is demonstrated that TAT-Au NPs are capable of delivering Gd(3+) chelates for enhanced brain tumor imaging with a prolonged retention time of Gd(3+) when compared to the free Gd(3+) chelates. Collectively, these results show promising applications of the TAT-Au NPs for enhanced malignant brain tumor therapy and non-invasive imaging.

Glioblastoma multiforme (GBM) remains fatal despite intensive surgical, radiotherapeutic, and chemotherapeutic interventions. Neural stem cells (NSCs) have been used as cellular vehicles for the transportation of oncolytic virus (OV) to therapeutically resistant and infiltrative tumor burdens throughout the brain. The HB1.F3-CD human NSC line has demonstrated efficacy as a cell carrier for the delivery of a glioma tropic OV CRAd-Survivin-pk7 (CRAd-S-pk7) in vitro and in animal models of glioma. At this juncture, no study has investigated the effectiveness of OV-loaded NSCs when applied in conjunction with the standard of care for GBM treatment, and therefore this study was designed to fill this void. Here, we show that CRAd-S-pk7-loaded HB1.F3-CD cells retain their tumor-tropic properties and capacity to function as in situ viral manufacturers in the presence of ionizing radiation (XRT) and temozolomide (TMZ). Furthermore, for the first time, we establish a logical experimental model that aims to recapitulate the complex clinical scenario for the treatment of GBM and tests the compatibility of NSCs loaded with OV. We report that applying OV-loaded NSCs together with XRT and TMZ can increase the median survival of glioma bearing mice by approximately 46%. Most importantly, the timing and order of therapeutic implementation impact therapeutic outcome. When OV-loaded NSCs are delivered prior to rather than after XRT and TMZ treatment, the median survival of mice bearing patient-derived GBM43 glioma xenografts is extended by 30%. Together, data from this report support the testing of CRAd-S-pk7-loaded HB1.F3-CD cells in the clinical setting and argue in favor of a multimodality approach for the treatment of patients with GBM.

Abstract Glioblastoma multiforme patients present a poor prognosis due to therapeutic resistance and tumor recurrence after surgical resection. It has been suggested that gliomas are driven by a rare subset of tumor cells, known as cancer stem cells (CSCs). These tumor-initiating cells are considered to be responsible for sustaining long-term tumor growth and disease recurrence. Today, two popular hypotheses try to explain the origin of CSCs: one postulates that CSCs represent an adult stem cell population with tumorigenic alterations, while the second argues that CSCs were once differentiated tumor cells that have re-initiated a self-renewal program. In this study, we first show that exposure to the therapeutic dose of 5 μM (the peak concentration in patient's cerebral spinal fluid) or 50 μM (the concentration in patient's blood) of temozolamide (TMZ), the most commonly used alkylating agent to treat GBM patients, consistently increase the CSC pool over time both in vitro and in vivo. Second, lineage-tracing analysis of genetically tagged glioma cells suggests that TMZ induces a phenotypic shift in the non-CSC population to mimic that of CSCs. These newly formed CSC-like cells co-express markers of pluripotency and stemness (CD133, CD15, Sox-2, Oct-4 and Nestin), a classical characteristic of CSCs. We further show that intracranial implantation of TMZ-treated non-CSC cells in athymic nude mice result in more efficient grafting (100% grafting as compared to 60% for DMSO treated control group). Moreover, these TMZ-treated non-CSC xenografts demonstrate extremely invasive characteristics, which is similar to the CSC enriched xenografts. In addition, they express elevated levels of HIF2α, a critical factor for maintaining the CSC pool. These findings strongly corroborate that chemotherapy-induced selection pressure can facilitate a CSC specific ‘niche’, which may provide the necessary signals to induce an interconversion between differentiated tumor cells and cancer “stem like” cells, leading to a more infiltrative glioma phenotype thereby resulting in therapeutic relapse and may frustrate our attempts to develop effective anti-glioma therapy. Citation Format: Atique U. Ahmed, Brenda Auffinger, Alex Tobias, Bart Thaci, Yu Han, Maciej S. Lesniak. Temozolomide-induced conversion of glioma cells into glioma “stem-like” cells with enhanced invasion properties. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5021. doi:10.1158/1538-7445.AM2013-5021