Successful mechanical thrombectomy for terminal ICA bullet embolism: A case report.

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.

Endoscopic Endonasal Transodontoid Treatment of a Ruptured Anterior Spinal Artery Aneurysm.

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.

Imaging analysis of ischemic strokes due to blunt cerebrovascular injury.

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.

Cost-Effectiveness of Peptide Enhanced Bone Graft i-Factor versus Use of Local Autologous Bone in Anterior Cervical Discectomy and Fusion Surgery.

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.

Universal screening for blunt cerebrovascular injury.

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.

Rapid Evolution and Rupture of an Incidental Aneurysm During Hyperdynamic Therapy for Cerebral Vasospasm.

BACKGROUND: Aneurysmal subarachnoid hemorrhage (aSAH) is associated with 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 hyperdynamic 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.

Three-dimensional aneurysm volume measurements show no correlation between coil packing density and recurrence.

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.

Reduction of direct costs in high-risk lumbar discectomy patients during the 90-day post-operative period through annular closure.

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.

Postoperative direct health care costs of lumbar discectomy are reduced with the use of a novel annular closure device in high-risk patients.

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 healthcare costs in the control group, where the ACD was not used.

Glioblastoma Multiforme of the Conus Medullaris-Management Strategies and Complications.

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.

Cost-effectiveness of a Bone-anchored Annular Closure Device Versus Conventional Lumbar Discectomy in Treating Lumbar Disc Herniations.

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.

Interleukin-13 receptor alpha 2-targeted glioblastoma immunotherapy.

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.

Blood-brain barrier permeable gold nanoparticles: an efficient delivery platform for enhanced malignant glioma therapy and imaging.

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.

Significance of interleukin-13 receptor alpha 2-targeted glioblastoma therapy.

Glioblastoma multiforme (GBM) remains one of the most lethal primary brain tumors despite surgical and therapeutic advancements. Targeted therapies of neoplastic diseases, including GBM, have received a great deal of interest in recent years. A highly studied target of GBM is interleukin-13 receptor α chain variant 2 (IL13Rα2). Targeted therapies against IL13Rα2 in GBM include fusion chimera proteins of IL-13 and bacterial toxins, nanoparticles, and oncolytic viruses. In addition, immunotherapies have been developed using monoclonal antibodies and cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-modified T cells. Advanced therapeutic development has led to the completion of phase I clinical trials for chimeric antigen receptor-modified T cells and phase III clinical trials for IL-13-conjugated bacterial toxin, with promising outcomes. Selective expression of IL13Rα2 on tumor cells, while absent in the surrounding normal brain tissue, has motivated continued study of IL13Rα2 as an important candidate for targeted glioma therapy. Here, we review the preclinical and clinical studies targeting IL13Rα2 in GBM and discuss new advances and promising applications.

Usefulness of minimum clinically important difference for assessing patients with subaxial degenerative cervical spine disease: statistical versus substantial clinical benefit.

BACKGROUND: The measurement of the therapeutic outcome of cervical spine surgeries commonly relies on four main patient reported outcomes (PROs): Neck Disability Index (NDI), Visual Analog Scale (VAS) for pain, and Short Form-36 (SF-36) Physical (PCS) and Mental (MCS) Component Summary. However, the clinical impact of such scores and how they could effectively measure therapeutic efficacy remains unclear. In this context, the concept of minimum clinically important difference (MCID) is developing into the standard by which to evaluate treatments, patient satisfaction and cost-effectiveness. METHODS: Eighty-eight consecutive patients undergoing surgery for subaxial degenerative cervical spine disease were selected from a prospective blinded database. PROs (NDI, PCS, MCS and VAS) were collected preoperatively, and together with blinded Surgeon Ratings (SR) at 3 months and 6 months post-surgery. Four anchor-based approaches were used to calculate different MCIDs. Three anchors (VAS, HTI (Health Transition Item of the SF-36) and SR) were used to evaluate surgery outcome. The best clinically and statistically relevant MCID was chosen. RESULTS: On average, all patients presented with a statistically significant improvement (p < 0.001) postoperatively for NDI (27.42 to 19.42), PCS (33.02 to 42.03), MCS (44 to 50.74) and VAS (2.85 to 1.93). The four MCID anchor-based approaches yielded a range of values for each PRO: 2.23-16.59 for PCS, 0.11-16.27 for MCS and 2.72-12.08 for NDI. When compared to the VAS and HTI anchors, the area under the ROC curve was greater for SR. This finding suggests that SR may be a more reliable anchor for MCID calculation. CONCLUSION: The MDC (minimum detectable change) approach together with the SR anchor appears to be the most appropriate MCID method. It offers the greatest area under the ROC curve (threshold above the 95 % CI), and the choice of the anchor did not significantly affect this result. MCID values for this dataset were 5.6 for PCS, 5.12 for MCS and 2.41 for NDI.

Inhibition of MMP14 potentiates the therapeutic effect of temozolomide and radiation in gliomas.

Metalloproteinases are membrane-bound proteins that play a role in the cellular responses to antiglioma therapy. Previously, it has been shown that treatment of glioma cells with temozolomide (TMZ) and radiation (XRT) induces the expression of metalloproteinase 14 (MMP14). To investigate the role of MMP14 in gliomagenesis, we used several chemical inhibitors which affect MMP14 expression. Of all the inhibitors tested, we found that Marimastat not only inhibits the expression of MMP14 in U87 and U251 glioma cells, but also induces cell cycle arrest. To determine the relationship between MMP14 inhibition and alteration of the cell cycle, we used an RNAi technique. Genetic knockdown of MMP14 in U87 and U251 glioma cells induced G2/M arrest and decreased proliferation. Mechanistically, we show that TMZ and XRT regulated expression of MMP14 in clinical samples and in vitro models through downregulation of microRNA374. In vivo genetic knockdown of MMP14 significantly decreased tumor growth of glioma xenografts and improved survival of glioma-bearing mice. Moreover, the combination of MMP14 silencing with TMZ and XRT significantly improved the survival of glioma-bearing mice compared to a single modality treatment group. Therefore, we show that the inhibition of MMP14 sensitizes tumor cells to TMZ and XRT and could be used as a future strategy for antiglioma therapy.

The timing of neural stem cell-based virotherapy is critical for optimal therapeutic efficacy when applied with radiation and chemotherapy for the treatment of glioblastoma.

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.

A preclinical evaluation of neural stem cell-based cell carrier for targeted antiglioma oncolytic virotherapy.

BACKGROUND: Oncolytic adenoviral virotherapy (OV) is a highly promising approach for the treatment of glioblastoma multiforme (GBM). In practice, however, the approach is limited by poor viral distribution and spread throughout the tumor mass. METHODS: To enhance viral delivery, replication, and spread, we used a US Food and Drug Administration-approved neural stem cell line (NSC), HB1.F3.CD, which is currently employed in human clinical trials. HB1.F3.CD cells were loaded with an oncolytic adenovirus, CRAd-Survivin-pk7, and mice bearing various human-derived GBMs were assessed with regard to NSC migration, viral replication, and therapeutic efficacy. Survival curves were evaluated with Kaplan-Meier methods. All statistical tests were two-sided. RESULTS: Antiglioma activity of OV-loaded HB1.F3.CD cells was effective against clinically relevant human-derived glioma models as well as a glioma stem cell-enriched xenograft model. Median survival was prolonged by 34% to 50% compared with mice treated with OV alone (GBM43FL model median survival = 19.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.26, 95% confidence interval [CI] = 1.21 to 12.23, P = .02; GBM12 model median survival = 43.5 days, OV alone vs NSC + OV, hazard ratio of survival = 2.53, 95% CI = 1.21 to 10.38, P = .02). OV-loaded HB1.F3.CD cells were shown to effectively migrate to the contralateral hemisphere and hand off the therapeutic payload of OV to targeted glioma cells. In vivo distribution and migratory kinetics of the OV-loaded HB1.F3.CD cells were successfully monitored in real time by magnetic resonance imaging. OV-loaded NSCs retained their differentiation fate and were nontumorigenic in vivo. CONCLUSIONS: HB1.F3.CD NSCs loaded with CRAd-Survivin-pk7 overcome major limitations of OV in vivo and warrant translation in a phase I human clinical trial for patients with GBM.

Comparison between patient and surgeon perception of degenerative spine disease outcomes--a prospective blinded database study.

BACKGROUND: Few have studied the correlation between patients' and spine surgeons' perception on outcomes, or compared these with patient-reported outcome scores. Outcomes studies are increasingly important in evaluating costs and benefits to patients and surgeons, and in developing metrics for payer evaluation and health care policy-making. OBJECTIVE: To compare patients' and surgeons' assessment of spine treatment outcome in a prospective blinded patient-driven spine surgery outcomes registry, and to correlate perceived outcomes ratings to validated outcomes scores. METHODS: Patients filled out surveys at baseline, 3 months and 6 months postoperatively, including Visual Analog Scale (VAS), and Neck Disability Index (NDI) or Oswestry Disability Index (ODI). Outcome was rated independently by patients and surgeons on a 7-point Likert-type scale. RESULTS: Two-hundred and sixty-five consecutive adult patients were surgical candidates. Of these, 154 (58.1 %) opted for surgery, with 69 (44.8 %) cervical and 85 (55.2 %) lumbar patients. One hundred and thirty-five (87.7 %) had both patient and surgeon postoperative ratings. Surgeons' and patients' ratings correlated strongly (Spearman rho = 0.53, p < 0.0001, 45.9 % identical, 88.2 % +/- 1 grade). The surgeon rated outcomes were better than patients in 29.8 % and worse in 21.15 %. Patient rating correlated better with the most recent NDI/ODI and pain scores than with incremental change from baseline. In multivariate analysis, age, location (cervical vs lumbar), pain ratings, and functional scores (NDI, ODI) did not have significant impact on the discrepancy between patient and surgeon ratings. CONCLUSIONS: Patients' and surgeons' global outcome ratings for spinal disease correlate highly. Patients' ratings correlate better with most recent functional scores, rather than incremental change from baseline.