Michael Zhang

Disrupting the CD47-SIRPα anti-phagocytic axis by a humanized anti-CD47 antibody is an efficacious treatment for malignant pediatric brain tumors

Anti-CD47 antibody is effective for treating malignant pediatric brain tumors without detectable toxicity in patient-derived xenograft models. Brain tumors, meet macrophages A protein called CD47 is often expressed on the surface of tumor cells, where it serves as a “don’t eat me” signal that blocks macrophages from attacking the tumor. To overcome this signal and allow the macrophages to “eat” tumor cells, Gholamin et al. engineered a humanized antibody that blocks CD47 signaling. The researchers tested the efficacy of this antibody in patient-derived xenograft models of a variety of pediatric brain tumors. The treatment was successful at inhibiting CD47, killing tumor cells, and prolonging the animals’ survival, all without toxic effects on normal tissues. Morbidity and mortality associated with pediatric malignant primary brain tumors remain high in the absence of effective therapies. Macrophage-mediated phagocytosis of tumor cells via blockade of the anti-phagocytic CD47-SIRPα interaction using anti-CD47 antibodies has shown promise in preclinical xenografts of various human malignancies. We demonstrate the effect of a humanized anti-CD47 antibody, Hu5F9-G4, on five aggressive and etiologically distinct pediatric brain tumors: group 3 medulloblastoma (primary and metastatic), atypical teratoid rhabdoid tumor, primitive neuroectodermal tumor, pediatric glioblastoma, and diffuse intrinsic pontine glioma. Hu5F9-G4 demonstrated therapeutic efficacy in vitro and in vivo in patient-derived orthotopic xenograft models. Intraventricular administration of Hu5F9-G4 further enhanced its activity against disseminated medulloblastoma leptomeningeal disease. Notably, Hu5F9-G4 showed minimal activity against normal human neural cells in vitro and in vivo, a phenomenon reiterated in an immunocompetent allograft glioma model. Thus, Hu5F9-G4 is a potentially safe and effective therapeutic agent for managing multiple pediatric central nervous system malignancies.

Anti-CD47 Treatment Stimulates Phagocytosis of Glioblastoma by M1 and M2 Polarized Macrophages and Promotes M1 Polarized Macrophages In Vivo

Tumor-associated macrophages (TAMs) represent an important cellular subset within the glioblastoma (WHO grade IV) microenvironment and are a potential therapeutic target. TAMs display a continuum of different polarization states between antitumorigenic M1 and protumorigenic M2 phenotypes, with a lower M1/M2 ratio correlating with worse prognosis. Here, we investigated the effect of macrophage polarization on anti-CD47 antibody-mediated phagocytosis of human glioblastoma cells in vitro, as well as the effect of anti-CD47 on the distribution of M1 versus M2 macrophages within human glioblastoma cells grown in mouse xenografts. Bone marrow-derived mouse macrophages and peripheral blood-derived human macrophages were polarized in vitro toward M1 or M2 phenotypes and verified by flow cytometry. Primary human glioblastoma cell lines were offered as targets to mouse and human M1 or M2 polarized macrophages in vitro. The addition of an anti-CD47 monoclonal antibody led to enhanced tumor-cell phagocytosis by mouse and human M1 and M2 macrophages. In both cases, the anti-CD47-induced phagocytosis by M1 was more prominent than that for M2. Dissected tumors from human glioblastoma xenografted within NOD.Cg-Prkdcscid Il2rgtm1Wjl/SzJ mice and treated with anti-CD47 showed a significant increase of M1 macrophages within the tumor. These data show that anti-CD47 treatment leads to enhanced tumor cell phagocytosis by both M1 and M2 macrophage subtypes with a higher phagocytosis rate by M1 macrophages. Furthermore, these data demonstrate that anti-CD47 treatment alone can shift the phenotype of macrophages toward the M1 subtype in vivo.

Intraoperative neuromonitoring in single-level spinal procedures: a retrospective propensity score-matched analysis in a national longitudinal database.

Study Design. Retrospective propensity score–matched analysis on a national database (MarketScan) between 2006 and 2010. Objective. To compare rates of neurological deficits after elective single-level spinal procedures with and without intraoperative neuromonitoring, as well as associated payment differences and geographic variance. Summary of Background Data. Intraoperative neurophysiologic monitoring is a technique that may contribute to avoiding permanent neurological injury during some spine surgery procedures. However, it is unclear whether all patients undergoing spine surgery benefit from neuromonitoring. Methods. An identified 85,640 patients underwent single-level spinal procedures including anterior cervical discectomy and fusion (ACDF), lumbar fusion, lumbar laminectomy, or lumbar discectomy. Neuromonitoring was identified with appropriate Current Procedural Terminology (CPT) codes. Cohorts were balanced on baseline comorbidities and procedure characteristics using propensity score matching. Trauma and spinal tumors cases were excluded. Results. Patients (12.66%) received neuromonitoring intraoperatively. Lumbar laminectomies had reduced 30-day neurological complication rate with neuromonitoring (0.0% vs. 1.18%, P = 0.002). Neuromonitoring did not correlate with reduced intraoperative neurological complications in ACDFs (0.09% vs. 0.13%), lumbar fusions (0.32% vs. 0.58%), or lumbar discectomy (1.24% vs. 0.91%). With the addition of neuromonitoring, payments for ACDFs increased 16.24% (

Anterior Versus Posterior Approach for Multilevel Degenerative Cervical Disease: A Retrospective Propensity Score-Matched Study of the MarketScan Database.

3842), lumbar fusions 7.84% (

Deep Brain Stimulation for Obesity

3540), lumbar laminectomies 24.33% (

Surgeon Procedure Volume and Complication Rates in Anterior Cervical Discectomy and Fusions: Analysis of a National Longitudinal Database.

3704), and lumbar discectomies 22.54% (

Retrosigmoid Versus Translabyrinthine Approach for Acoustic Neuroma Resection: An Assessment of Complications and Payments in a Longitudinal Administrative Database

2859). Significant geographic variation was evident. Some states had no recorded single-level spinal cases with concurrent neuromonitoring. Rates for ACDFs and lumbar fusions, laminectomies, and discectomies ranged as high as 61%, 58%, 22%, and 21%, respectively. Conclusion. With intraoperative neurological monitoring in single-level procedures, neurological complications were decreased only among lumbar laminectomies. No difference was observed in ACDFs, lumbar fusions, or lumbar discectomies. There was a significant increase in total payments associated with the index procedure and hospitalization. We demonstrate significant geographic variation in neuromonitoring. Level of Evidence: 3

CyberKnife stereotactic radiosurgery for the treatment of symptomatic vertebral hemangiomas: a single-institution experience

Study Design. Retrospective 2:1 propensity score-matched analysis on a national longitudinal database between 2006 and 2010. Objective. To compare rates of adverse events, revisions procedure rates, and payment differences in anterior cervical fusion procedures compared with posterior laminectomy and fusion procedures with at least 3 levels of instrumentation. Summary of Background Data. The comparative benefits of anterior versus posterior approach to multilevel degenerative cervical disease remain controversial. Recent systematic reviews have reached conflicting conclusions. We demonstrate the comparative economic and clinical outcomes of anterior and posterior approaches for multilevel cervical degenerative disk disease. Methods. We identified 13,662 patients in a national billing claims database who underwent anterior or posterior cervical fusion procedures with 3 or more levels of instrumentation. Cohorts were balanced using 2:1 propensity score matching and outcomes were compared using bivariate analysis. Results. With the exception of dysphagia (6.4% in anterior and 1.4% in posterior), overall 30-day complication rates were lower in the anterior approach group. The rate of any complication excluding dysphagia with anterior approaches was 12.3%, significantly lower (P < 0.0001) than that of posterior approaches, 17.8%. Anterior approaches resulted in lower hospital (

Management of Arteriovenous Malformations Associated with Developmental Venous Anomalies: A Literature Review and Report of 2 Cases

18,346 vs.

Intracranial Dislocation of the Mandibular Condyle: A Case Report and Literature Review

23,638) and total payments (