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.

Characterization and immunotherapeutic implications for a novel antibody targeting interleukin (IL)-13 receptor α2.

The high affinity interleukin-13 receptor α2 (IL13Rα2) is selectively expressed at a high frequency by glioblastoma multiforme (GBM) as well as several other tumor types. One approach for targeting this tumor-specific receptor utilizes the cognate ligand, IL-13, conjugated to cytotoxic molecules. However, this approach lacks specificity because the lower affinity receptor for IL-13, IL13Rα1, is widely expressed by normal tissues. Here, we aimed to develop and characterize a novel monoclonal antibody (mAb) specific to IL13Rα2 for the therapeutic purpose of targeting IL13Rα2-expressing tumors. Hybridoma cell lines were generated and compared for binding affinities to recombinant human IL13Rα2 (rhIL13Rα2). Clone 47 demonstrated binding to the native conformation of IL13Rα2 and was therefore chosen for further studies. Clone 47 bound specifically and with high affinity (K(D) = 1.39 × 10(-9) M) to rhIL13Rα2 but not to rhIL13Rα1 or murine IL13Rα2. Furthermore, clone 47 specifically recognized wild-type IL13Rα2 expressed on the surface of CHO and HEK cells as well as several glioma cell lines. Competitive binding assays revealed that clone 47 also significantly inhibited the interaction between human soluble IL-13 and IL13Rα2 receptor. Moreover, we found that N-linked glycosylation of IL13Rα2 contributes in part to the interaction of the antibody to IL13Rα2. In vivo, the IL13Rα2 mAb improved the survival of nude mice intracranially implanted with a human U251 glioma xenograft. Collectively, these data warrant further investigation of this novel IL13Rα2 mAb with an emphasis on translational implications for therapeutic use.

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.

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.

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.

Clinical significance of KISS1 protein expression for brain invasion and metastasis.

BACKGROUND: Metastases to the brain represent a feared complication and contribute to the morbidity and mortality of breast cancer. Despite improvements in therapy, prognostic factors for development of metastases are lacking. KISS1 is a metastasis suppressor that demonstrates inhibition of metastases formation in several types of cancer. The purpose of this study was to determine the importance of KISS1 expression in breast cancer progression and the development of intracerebral lesions. METHODS: In this study, we performed a comparative analysis of 47 brain metastases and 165 primary breast cancer specimens by using the antihuman KISS1 antibody. To compare KISS1 expression between different groups, we used a 3-tier score and the automated score computer software (ACIS) evaluation. To reveal association between mRNA and protein expression, we used quantitative reverse transcription-polymerase chain reaction (qRT-PCR) analysis. Significance of immunohistochemistry stainings was correlated with clinicopathological data. RESULTS: We identified that KISS1 expression is significantly higher in primary breast cancer compared with brain metastases (P < .05). The mRNA analysis performed on 33 selected ductal carcinoma brain metastatic lesions and 36 primary ductal carcinomas revealed a statistically significant down-regulation of KISS1 protein in metastatic cases (P = .04). Finally, we observed a significant correlation between expression of KISS1 and metastasis-free survival (P = .04) along with progression of breast cancer and expression of KISS1 in primary breast cancer specimens (P = .044). CONCLUSIONS: In conclusion, our study shows that breast cancer expresses KISS1. Cytoplasmic expression of KISS1 may be used as a prognostic marker for increased risk of breast cancer progression.

Recent developments on immunotherapy for brain cancer.

INTRODUCTION: Brain tumors are a unique class of cancers since they are anatomically shielded from normal immunosurveillance by the blood-brain barrier, lack a normal lymphatic drainage system and reside in a potently immunosuppressive environment. Of the primary brain cancers, glioblastoma multiforme (GBM) is the most common and aggressive in adults. Although treatment options include surgery, radiation and chemotherapy, the average lifespan of GBM patients remains at only 14.6 months post-diagnosis. AREAS COVERED: A review of key cellular and molecular immune system mediators in the context of brain tumors including TGF-ß, cytotoxic T cells, Tregs, CTLA-4, PD-1 and IDO is discussed. In addition, prognostic factors, currently utilized immunotherapeutic strategies, ongoing clinical trials and a discussion of new or potential immunotherapies for brain tumor patients are considered. EXPERT OPINION: Current drugs that improve the quality of life and overall survival in patients with brain tumors, especially for GBM, are poorly effective. This disease requires a reanalysis of currently accepted treatment strategies, as well as newly designed approaches. Here, we review the fundamental aspects of immunosuppression in brain tumors, new and promising immunotherapeutic drugs as well as combinatorial strategies that focus on the simultaneous inhibition of immunosuppressive hubs, both in immune and brain tumor cells, which is critical to consider for achieving future success for the treatment of this devastating disease.

Neural stem cell-based cell carriers enhance therapeutic efficacy of an oncolytic adenovirus in an orthotopic mouse model of human glioblastoma.

The potential utility of oncolytic adenoviruses as anticancer agents is significantly hampered by the inability of the currently available viral vectors to effectively target micrometastatic tumor burden. Neural stem cells (NSCs) have the ability to function as cell carriers for targeted delivery of an oncolytic adenovirus because of their inherent tumor-tropic migratory ability. We have previously reported that in vivo delivery of CRAd-S-pk7, a glioma-restricted oncolytic adenovirus, can enhance the survival of animals with experimental glioma. In this study, we show that intratumoral delivery of NSCs loaded with the CRAD-S-pk7 in an orthotopic xenograft model of human glioma is able to not only inhibit tumor growth but more importantly to increase median survival by ~50% versus animals treated with CRAd-S-pk7 alone (P = 0.0007). We also report that oncolytic virus infection upregulates different chemoattractant receptors and significantly enhances migratory capacity of NSCs both in vitro and in vivo. Our data further suggest that NSC-based carriers have the potential to improve the clinical efficacy of antiglioma virotherapy by not only protecting therapeutic virus from the host immune system, but also amplifying the therapeutic payload selectively at tumor sites.

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.

A comparative study of neural and mesenchymal stem cell-based carriers for oncolytic adenovirus in a model of malignant glioma.

Glioblastoma multiforme is a primary malignancy of the central nervous system that is universally fatal due to its disseminated nature. Recent investigations have focused on the unique tumor-tropic properties of stem cells as a novel platform for targeted delivery of anticancer agents to the brain. Neural stem cells (NSCs) and mesenchymal stem cells (MSCs) both have the potential to function as cell carriers for targeted delivery of a glioma restricted oncolytic virus to disseminated tumor due to their reported tumor tropism. In this study, we evaluated NSCs and MSCs as cellular delivery vehicles for an oncolytic adenovirus in the context of human glioma. We report the first preclinical comparison of the two cell lines and show that, while both stem cell lines are able to support therapeutic adenoviral replication intracellularly, the amount of virus released from NSCs was a log higher than the MSC (p < 0.001). Moreover, only virus loaded NSCs that were administered intracranially in an orthotopic glioma model significantly prolonged the survival of tumor bearing animals (median survival for NSCs 68.5 days vs 44 days for MSCs, p < 0.002). Loading oncolytic adenovirus into NSCs and MSCs also led to expression of both pro- and anti-inflammatory genes and decreased vector-mediated neuroinflammation. Our results indicate that, despite possessing a comparable migratory capacity, NSCs display superior therapeutic efficacy in the context of intracranial tumors. Taken together, these findings argue in favor of NSCs as an effective cell carrier for antiglioma oncolytic virotherapy.

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.

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.

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.

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.

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.

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.

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.