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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.

BACKGROUND: Moyamoya (MM) disease is an idiopathic steno-occlusive angiopathy occurring more frequently in females. OBJECTIVE: To evaluate sex differences in preoperative symptoms and treatment outcomes after revascularization surgery. METHODS: We analyzed 430 MM disease patients undergoing 717 revascularization procedures spanning 19 years (1991-2010) and compared gender differences in preoperative symptoms and long-term outcomes after surgical revascularization. RESULTS: A total of 307 female and 123 male patients (ratio, 2.5:1) with a mean age of 31.0 ± 16.7 years and adults-to-children ratio of 2.5:1 underwent 717 revascularization procedures. Female patients were more likely to experience preoperative transient ischemic attacks (odds ratio: 2.1, P = .001) and less likely to receive a diagnosis of unilateral MM disease (odds ratio: 0.6, P = .04). No association was observed between sex and risk of preoperative ischemic or hemorrhagic stroke. There was no difference in neurological outcome because both male and female patients experienced significant improvement in the modified Rankin Scale score after surgery (P < .0001). On Kaplan-Meier survival analysis, 5-year cumulative risk of adverse postoperative events despite successful revascularization was 11.4% in female vs 5.3% in male patients (P = .05). In multivariate Cox proportional hazards analysis, female sex trended toward an association with adverse postoperative events (hazard ratio: 1.9, P = .14). CONCLUSION: Female patients are more susceptible to the development of preoperative transient ischemic attack and may be at higher risk of adverse postoperative events despite successful revascularization. There is, however, no sex difference in neurological outcome because patients of both sexes experience significant improvement in neurological status with low risk of the development of future ischemic events after surgical revascularization.

Clinical neuroproteomics aims to advance our understanding of disease and injury affecting the central and peripheral nervous systems through the study of protein expression and the discovery of protein biomarkers to facilitate diagnosis and treatment. The general premise of the biomarker field is that in vivo factors present in either tissue or circulating biofluids, reflect pathological changes, and can be identified and analyzed. This approach offers an opportunity to illuminate changes occurring at both the population and patient levels toward the realization of personalized medicine. This review is intended to provide research-driven clinicians with an overview of protein biomarkers of disease and injury for clinical use and to highlight methodology and potential pitfalls. We examine the neuroproteomic biomarker field and discuss the hallmarks and the challenges of clinically relevant biomarker discovery relating to central nervous system pathology. We discuss the issues in the maturation of potential biomarkers from discovery to Food and Drug Administration approval and review several platforms for protein biomarker discovery, including protein microarray and mass spectrometry-based proteomics. We describe the application of microfluidic technologies to the evolution of a robust clinical test. Finally, we highlight several biomarkers currently in use for cancer, ischemia, and injury in the central nervous system. Future efforts using these technologies will result in the maturation of existing and the identification of de novo biomarkers that could guide clinical decision making and advance diagnostic and therapeutic options for the treatment of neurological disease and injury.

Moyamoya disease is characterized by a chronic stenoocclusive vasculopathy affecting the terminal internal carotid arteries. The clinical presentation and outcome of moyamoya disease remain varied based on angiographic studies alone, and much work has been done to study cerebral hemodynamics in this group of patients. The ability to measure cerebral blood flow (CBF) accurately continues to improve with time, and with it a better understanding of the pathophysiological mechanisms in patients with moyamoya disease. The main imaging techniques used to evaluate cerebral hemodynamics include PET, SPECT, xenon-enhanced CT, dynamic perfusion CT, MR imaging with dynamic susceptibility contrast and with arterial spin labeling, and Doppler ultrasonography. More invasive techniques include intraoperative ultrasonography. The authors review the current knowledge of CBF in this group of patients and the role each main quantitative method has played in evaluating them, both in the disease state and after surgical intervention.

Moyamoya disease is an uncommon cerebrovascular condition characterized by progressive stenosis of the bilateral internal carotid arteries with compensatory formation of an abnormal network of perforating blood vessels providing collateral circulation. The etiology and pathogenesis of moyamoya disease remain unclear. Evidence from histological studies, proteomics, and endothelial progenitor cell analyses suggests new theories underlying the cause of vascular anomalies, including moyamoya disease. Familial moyamoya disease has been noted in as many as 15% of patients, indicating an autosomal dominant inheritance pattern with incomplete penetrance. Genetic analyses in familial moyamoya disease and genome-wide association studies represent promising strategies for elucidating the pathophysiology of this condition. In this review, the authors discuss recent studies that have investigated possible mechanisms underlying the etiology of moyamoya disease, including stem cell involvement and genetic factors. They also discuss future research directions that promise not only to offer new insights into the origin of moyamoya disease but to enhance our understanding of new vessel formation in the CNS as it relates to stroke, vascular anomalies, and tumor growth.

Patients with brain arteriovenous malformations (BAVM) are at life-threatening risk of intracranial hemorrhage (ICH) (25). Obliteration or resection of the lesion to prevent future ICH is the primary motivation behind invasive therapy. Effective clinical management requires accurate estimates of natural history risks balanced against the hazards of invasive therapy. Clinical presentation of BAVM with ICH is the most widely demonstrated predictor of future ICH in the natural course of untreated BAVM (11, 12); predictors of future ICH risk in patients with nonhemorrhagic presentations are lacking (34). The absence of hemorrhagic presentation has recently been reported as an underappreciated risk factor predicting morbidity after microsurgical arteriovenous malformation resection (21), despite the fact that it is not part of major surgical risk prediction tools such as the Spetzler-Martin grading scale (32). Nonhemorrhagic presentation carries a similar risk magnitude for adverse outcome after microsurgical resection as the components of the Spetzler-Martin grade (21), underscoring weaknesses in current risk grading assessments and the need for additional predictors of future morbidity after treatment, particularly in patients with BAVMs with unruptured lesions. Identification of single nucleotide polymorphisms (SNPs) associated with increased risk of new ICH could facilitate risk stratification and therapeutic decision-making (28). We previously demonstrated that genetic variation might influence the natural course of BAVM. We reported an association between the −238G>A promoter polymorphism of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) (1) and the epsilon2 (e2) allele of the Apolipoprotein (ApoE) gene (27), and risk of new ICH in the untreated course of the disease. In the present study, we sought to determine whether or not these genotypes would independently predict posttreatment ICH risks in the clinical course after the initiation of BAVM treatment. Whereas previous reports focused on new ICH in longitudinal follow-up after initial presentation but before any intervening treatment, the present study focused on an entirely different period of observation, i.e., any new ICH in longitudinal follow-up after the initiation of treatment, using similar multivariate analysis with additional adjustment for any risks carried over from natural course events.

Background and Purpose— Race/ethnicity is associated with overall incidence of intracranial hemorrhage (ICH), but its impact in patients with brain arteriovenous malformation is unknown. We evaluated whether race/ethnicity was a risk factor for ICH in the natural course in a large, multiethnic cohort of patients with brain arteriovenous malformation followed longitudinally. Methods— Data were collected prospectively for patients with brain arteriovenous malformation evaluated at the University of California, San Francisco (n=436) and retrospectively through databases and chart review in the 20 hospitals of the Kaiser Permanente Medical Care Program (n=1028). Multivariate Cox regression was performed to assess the influence of race/ethnicity on subsequent ICH, adjusting for risk factors. Cases were censored at first treatment, loss to follow-up, or death. Results— Average follow up was 4.7±8.0 years for Kaiser Permanente Medical Care Program patients and 2.8±7.3 years for University of California, San Francisco patients with no difference in time to ICH between cohorts (log rank P =0.57). The annualized 5-year ICH rate was 2.1% (3.7% for ruptured at presentation; 1.4% for unruptured). Initial ICH presentation (hazard ratio: 3.0, 95% CI: 1.9 to 4.9, P P =0.02) were independent predictors of ICH, adjusting for age, gender, cohort, and a cohort–age interaction. The ICH risk for Hispanics versus whites increased to 3.1 (95% CI: 1.3 to 7.4, P =0.013) after further adjusting for arteriovenous malformation size and deep venous drainage in a subset of cases with complete data. Similar trends were observed for blacks (hazard ratio: 2.1, 95% CI: 0.9 to 4.8, P =0.09) and Asians (hazard ratio: 2.4, 95% CI: 0.8 to 7.1, P =0.11), although nonsignificant. Conclusions— This study reports the first description of race/ethnic differences in brain arteriovenous malformation, with Hispanics at an increased risk of subsequent ICH compared with whites.

To derive quantitative image features from magnetic resonance (MR) images that characterize the radiographic phenotype of glioblastoma multiforme (GBM) lesions and to create radiogenomic maps associating these features with various molecular data.Clinical, molecular, and MR imaging data for GBMs in 55 patients were obtained from the Cancer Genome Atlas and the Cancer Imaging Archive after local ethics committee and institutional review board approval. Regions of interest (ROIs) corresponding to enhancing necrotic portions of tumor and peritumoral edema were drawn, and quantitative image features were derived from these ROIs. Robust quantitative image features were defined on the basis of an intraclass correlation coefficient of 0.6 for a digital algorithmic modification and a test-retest analysis. The robust features were visualized by using hierarchic clustering and were correlated with survival by using Cox proportional hazards modeling. Next, these robust image features were correlated with manual radiologist annotations from the Visually Accessible Rembrandt Images (VASARI) feature set and GBM molecular subgroups by using nonparametric statistical tests. A bioinformatic algorithm was used to create gene expression modules, defined as a set of coexpressed genes together with a multivariate model of cancer driver genes predictive of the module's expression pattern. Modules were correlated with robust image features by using the Spearman correlation test to create radiogenomic maps and to link robust image features with molecular pathways.Eighteen image features passed the robustness analysis and were further analyzed for the three types of ROIs, for a total of 54 image features. Three enhancement features were significantly correlated with survival, 77 significant correlations were found between robust quantitative features and the VASARI feature set, and seven image features were correlated with molecular subgroups (P.05 for all). A radiogenomics map was created to link image features with gene expression modules and allowed linkage of 56% (30 of 54) of the image features with biologic processes.Radiogenomic approaches in GBM have the potential to predict clinical and molecular characteristics of tumors noninvasively. Online supplemental material is available for this article.

Brain arteriovenous malformations (BAVM) have high matrix metalloproteinase-9 (MMP-9) expression, the source of which is unclear. We hypothesized MMP-9 production might be due to inflammation in BAVM. Compared to control brain tissues (n = 5), BAVM tissue (n = 139) had a higher expression (by ELISA) of myeloperoxidase (MPO) (193 +/- 189 vs. 6 +/- 3, ng/mg, P < .001), MMP-9 (28 +/- 32 vs. 0.7 +/- 0.6, ng/mg, P < .001), and IL-6 (102 +/- 218 vs. 0.1 +/- 0.1, pg/mg, P < .001), but not eNOS (114 +/- 87 vs. 65 +/- 9, pg/mg, P = .09). MMP-9 expression in BAVM highly correlated with myeloperoxidase (R2 = .76, P < .001), as well as with IL-6 (R2 = .32, P < .001). In contrast, MMP-9 in BAVM poorly correlated with the endothelial marker, eNOS (R2 = .03, P = .05), and CD31 (R2 = .004, P = .57). Compared to non-embolized patients (n = 46), patients with pre-operative embolization (n = 93) had higher levels of myeloperoxidase (236 +/- 205 vs. 106 +/- 108, ng/mg, P < .001) and MMP-9 (33 +/- 35 vs. 16 +/- 20, ng/mg, P < .001), however the correlation between MMP-9 and myeloperoxidase was equally strong for both groups (R2 = .69, n = 93, P < .001, for both). MMP-9 expression correlated with the lipocalin-MMP-9 complex, suggesting neutrophils as the MMP-9 source. MPO co-localized with majority of MMP-9 signal by immunohistochemistry. Our data suggest that inflammation is a prominent feature of BAVM lesional phenotype, and neutrophils appear to be a major source of MMP-9 in these lesions.

OBJECTIVE: Patients with brain arteriovenous malformation (AVM) are at life-threatening risk of intracranial hemorrhage (ICH). Identification of genetic variants associated with increased new ICH risk would facilitate risk stratification and guide therapeutic intervention. METHODS: Brain AVM patients evaluated at University of California, San Francisco or Kaiser Permanente Northern California were followed longitudinally. Primary outcome was new ICH after diagnosis; censoring events were any AVM treatment or last follow-up examination. The association of ApoE ɛ2 and ɛ4 genotype with new ICH was evaluated by Kaplan-Meier survival analysis and further characterized via a Cox proportional hazards model. RESULTS: We genotyped 284 brain AVM patients (50% women; 57% Caucasian; median follow-up time, 0.3 yr) including 18 patients with a history of new ICH). ApoE ɛ2, but not ApoE ɛ4 genotype, was associated with new ICH (P = 0.0052). ApoE ɛ2 carriers had fivefold increased risk of new ICH (hazard ratio, 5.09; 95% confidence interval, 1.46–17.7; P = 0.010; Cox proportional hazards model adjusting for race/ethnicity and clinical presentation). Subset analysis in the largest homogenous ethnic subcohort (Caucasians) confirmed the increased risk of new ICH in ApoE ɛ2 carriers (hazard ratio, 8.71; 95% confidence interval, 1.4–53.9; P = 0.020; multivariate model adjusting for clinical presentation). CONCLUSION: ApoE genotype may influence the risk of ICH in the natural course of brain AVM. The identification of genetic predictors of ICH risk may facilitate estimation of AVM natural history risk and individualize clinical decision-making and therapeutic recommendations.

CD47 is an anti-phagocytic cell surface protein mediating cancer cell evasion of phagocytosis by the innate immune system. Preclinical data suggest that CD47 is appears to be an indispensable means by which many cancer cells, including cancer stem cells, overcome intrinsic expression of their pro-phagocytic “eat me” signals. Blockade of CD47 with mAbs enables phagocytosis of cancer cells in vitro and in vivo. We have developed a novel humanized mAb (huCD47-Ab) that specifically binds CD47 and blocks it from interacting with its ligand, signal regulatory protein–α; (SIRPα), on phagocytic cells, resulting in the phagocytosis and elimination of cancer cells through their “eat me” signals. Normal cells generally do not express eat me signals, and are unaffected by CD47 blocking mAb. We observed expression of CD47 on aggressive pediatric tumors, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), Ewing's sarcoma, neuroblastoma, and several cancers of the central nervous system (CNS), including atypical tetroid rhabdoid tumor (ATRT), primitive neuroectodermal tumor (PNET), medulloblastoma (MB), and pediatric high-grade glioma (pHGG). In-vitro phagocytosis assays, of primary patient samples shows significant engulfment by human peripheral blood derived macrophages upon incubation with the HuCD47-Ab antibody as compared to control. Furthermore we observe potent anti-tumor efficacy and survival benefit in MB, pHGG, ATRT and PNET orthotopic xenografts models establishing the ability of the huCD47 antibody to across the blood brain barrier by the CD47 blocking antibody. Using a novel human neural stem cell/brain tumor co-engraftment orthotopic xenograft model we show specificity of the HuCD47 antibody to only tumor cells and not normal human cells. We further observe potent anti-tumor efficacy in non-CNS tumor (ALL, AML and Osteosarcoma) xenograft models as well. Furthermore we demonstrate that HuCD47-Ab can be administered safely to non-human primates at therapeutic serum levels. Pre-IND and IMPD meetings with the FDA in the US and the MHRA in the UK, have been held, and the clinical trials for adult patients with advanced stage malignancies will start in early 2014. After determining safety in these phase I trials, we initiate protocols for adult CNS tumors as part of expansion cohorts, and subsequently extend the trials to pediatric cancer patients, given manageable toxicity and signs of efficacy in the adult patients. This abstract is also presented as Poster A86. Citation Format: Siddhartha S. Mitra, Sharareh Gholamin, Jens-Peter Volkmer, Abdullah Feroze, Jie Liu, Achal Achrol, Lijuan Wang, Leanne Sayles, Michael Zhang, Kathleen Sakamoto, Michelle Monje-Deisseroth, Yoon-Jae Cho, Alejandro Sweet-Cordero, Ravi Majeti, Samuel Cheshier, Irving Weissman. Overcoming immune evasion in pediatric hematologic and solid tumor malignancies: A preclinical study using a humanized anti-CD47 antibody. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr PR12.

Background and Purpose— Mutations in endoglin ( ENG ) and activin-like kinase ( ALK1 ) cause hereditary hemorrhagic telangiectasias, disorders characterized by pulmonary and brain arteriovenous malformations (BAVMs). We investigated whether polymorphisms in these genes are also associated with sporadic BAVM. Methods— A total of 177 sporadic BAVM patients and 129 controls (all subjects white) were genotyped for 2 variants in ALK1 and 7 variants in ENG . Results— The ALK1 IVS3-35A>G polymorphism was associated with BAVM: (AnyA [AA+AG] genotype: odds ratio, 2.47; 95% CI, 1.38 to 4.44; P =0.002). Two ENG polymorphisms, ENG −1742A>G and ENG 207G>A, showed a trend toward association with BAVM that did not reach statistical significance. Conclusions— A common polymorphism in ALK1 is associated with sporadic BAVM, suggesting that genetic variation in genes mutated in familial BAVM syndromes may play a role in sporadic BAVMs.

Background and Purpose— Children with brain arteriovenous malformations (BAVMs) are said to be at higher risk for intracranial hemorrhage (ICH) than adults. Although this notion affects treatment decisions, the evidence to support this claim is limited. Methods— To compare the risk of ICH in children versus adults with BAVM, we studied all cases of BAVM evaluated at the University of California, San Francisco (January 2000 to December 2004; n=400) and Kaiser Permanente Northern California (January 1993 to December 2004; n=819). In Kaplan–Meier survival analyses, the index date was the date of initial BAVM detection; cases were censored at time of subsequent ICH (the primary outcome, defined as ICH after initial presentation), first BAVM treatment, or loss to follow-up. Cox proportional hazards models included childhood presentation ( Results— Our study included 996 person-years of follow-up in the childhood presentation group and 3260 in the adult presentation group. In the unadjusted survival analysis, the subsequent ICH rates were similar for the 2 age groups (average annual rate 2.0% for children; 2.2% for adults; P =0.82 by log-rank test). BAVMs in childhood were more likely to present initially with ICH ( P P =0.036). Conclusions— Children with BAVMs do not appear to be at increased risk for a subsequent ICH compared with adults, and may even be relatively protected. Confounding by hemorrhagic presentation should be considered in any study comparing BAVM hemorrhage rates in children versus adults.

Background and Purpose— To compare magnetic resonance (MR) perfusion to gold-standard cerebral blood flow (CBF) determined by intra-arterial 133 Xe washout method. Methods— Eight patients with high-grade carotid stenoses underwent bolus-tracking MR perfusion and intra-arterial 133 Xe washout before and after carotid stenting. MR perfusion was compared with 133 Xe-CBF values using Pearson linear correlation analysis. Results— We observed a mean 37±38% increase in 133 Xe-CBF and a mean 19±27% increase in relative CBF (rCBF) by MR perfusion immediately after stent placement. Relative (percent) changes in MR-rCBF showed a close and linear correlation to those seen in 133 Xe-CBF ( r =0.91; R 2 =0.84; P =0.002). There was a trend for MR perfusion to underestimate change in CBF at higher relative changes in flow. Conclusion— Bolus-tracking MR perfusion correlates with 133 Xe-CBF in estimating postprocedural increases in blood flow but may underestimate the magnitude of the change with higher relative changes.

Background and Purpose— Accurate estimates of intracranial hemorrhage (ICH) risk in patients harboring brain arteriovenous malformation (BAVM) are needed to evaluate interventional strategies and to help guide clinical management. Identification of genetic polymorphisms associated with ICH would facilitate risk stratification in BAVM patients. Methods— We identified patients with BAVM and documented clinical presentation, demographic data, venous drainage pattern, and BAVM size. Patients were genotyped for 5 polymorphisms in 3 inflammatory cytokine genes, and 9 polymorphisms in 5 angiogenesis-related genes. Association of genotype with risk of hemorrhagic BAVM presentation was evaluated using logistic regression analysis. Results— We genotyped 180 patients with BAVM (53% female, 57% white, mean age at diagnosis 35±17 years, 41% presenting with ICH). BAVM patients homozygous for the interleukin 6 ( IL6 )–174G allele had a greater risk of ICH presentation (OR, 2.62, P =0.003) than IL6 –174C carriers. In a multivariate logistic regression model, IL6 –174G>C genotype, small BAVM size, and exclusively deep venous drainage were independent predictors of ICH presentation. A similar univariate trend was noted for the TNF α-308 GG genotype ( P =0.055). The other polymorphisms genotyped were not associated with ICH. Conclusions— A polymorphism in the inflammatory cytokine IL6, but not polymorphisms in angiogenesis-related genes, was associated with ICH presentation of BAVM. Further studies are needed to define the role of inflammatory cytokines in the pathogenesis of BAVM hemorrhage.

Background and Purpose— Accurate estimates for risk and rates of intracranial hemorrhage (ICH) in the natural course of patients harboring brain arteriovenous malformation (BAVM) are needed to provide a quantitative basis for planning clinical trials to evaluate interventional strategies and to help guide practice management. Methods— We identified patients with BAVM at the Kaiser Permanente Northern California health maintenance organization and documented their clinical course. The influences of age at diagnosis, gender, race-ethnicity, ICH at presentation, venous draining pattern, and BAVM size on ICH subsequent to presentation were studied using the multivariate Cox proportional hazards model and Kaplan-Meier curves. Results— We identified 790 patients with BAVM (51% female; 63% white; mean age±SD at diagnosis: 38±19 years) between 1961 and 2001. Patients who presented with ICH experienced a higher rate of subsequent ICH than those who presented without ICH under multivariate analysis (hazard ratio, 3.6; 95% CI, 1.1 to 11.9; P Conclusions— Presentation with ICH was the most important predictor of future ICH, confirming previous studies. Future ICH had similar impact on functional outcome as incident ICH. Intervention to prevent ICH would be of potentially greater benefit to patients presenting with ICH, although the advantage decreases over time.

Introduction: Extensive molecular characterization of Brain tumors done in recent years has proven valuable for tumor classification, risk stratification and outcome prediction for current treatment modalities. However the current standard of care has not improved the prognosis and carries an increased risk of cognitive impairments for children with brain tumors. A characteristic feature of tumor progression and recurrence is its ability to evade the immune system. Our hypothesis is that by modulating the innate immune system we can enhance the ability of macrophages to ‘eat and kill’ brain cancer cells. Recent data suggests that the interaction between the cell surface antigen CD47 and its binding partner SIRPα is a mechanism by which non-solid and solid tumors can evade the innate immune system. To see if anti-CD47 therapy is a potential therapy in malignant pediatric brain tumors we first looked at CD47 expression in freshly isolated patient and postmortem samples from 4 different tumor types; Diffused Intrinsic Pontine Glioma, Medulloblastoma, Ependymoma and ATRTs. We tested the hypothesis that blocking CD47- SIRPα interaction induced phagocytosis in an in-vitro phagocytosis assay. We next established orthotopic xenografts models in immune compromised mice and treated them with anti-CD47 humanized antibody, which is currently being developed for clinical trials in hematopoietic and non-CNS malignancies. Result: CD47 expression was upregulated in all tumor types and was present in >90% of the cells in high grade tumors. Increased CD47 expression was observed in CD15+ and CD133+ putative cancer stem cell population. Blocking the CD47- SIRPα interaction increases tumor phagocytosis by macrophages in-vitro. Systemic treatment with anti-CD47 antibody significantly reduced tumor burden in an orthotopic xenograft setting. Conclusion: Anti-CD47 therapy is a viable and effective treatment modality for pediatric high grade brain tumors. Citation Format: Sharareh Gholamin, Siddhartha S. Mitra, Chase Elliott Richard, Achal Achrol, Doosik Kong, Jun Jae Shin, Michelle Monje-Deisseroth, Yoon-Jae Cho, Irving Weissman, Samuel H. Cheshier. Development of Anti-CD47 therapy for pediatric brain tumors. [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 5218. doi:10.1158/1538-7445.AM2013-5218

Brain arteriovenous malformations (BAVMs) are an important cause of intracerebral hemorrhage (ICH) in young adults. Biological predictors of future ICH risk are lacking, and controversy exists over previous studies of natural history risk among predominantly ruptured BAVM cohorts. Recent studies have suggested that the majority of BAVMs are now diagnosed as unruptured lesions, and that the risk according to natural history among these lesions may be less than previously assumed. In the first part of this review, the authors discuss available data on the natural history of BAVMs and highlight the need for future studies that aim to develop surrogate biomarkers of disease progression that accurately predict future risk of ICH in BAVMs. The etiology of BAVM remains unknown. Recent studies have suggested a role for genetic factors in the pathogenesis of sporadic BAVM, which is further supported by reports of familial occurrence of BAVM and association with known systemic genetic disorders (such as Osler-Weber-Rendu disease, Sturge-Weber disease, and Wyburn-Mason syndrome). Molecular characterization of BAVM tissue demonstrates a highly angiogenic milieu with evidence of increased endothelial cell turnover. Taken together with a number of reports of de novo BAVM formation, radiographic growth after initial BAVM diagnosis, and regrowth after successful treatment of BAVM, these findings challenge the long-held assumption that BAVMs are static lesions of congenital origin. In the second part of this review, the authors discuss available data on the origins of BAVM and offer insights into future investigations into genetics and endothelial progenitor cell involvement in the pathogenesis of BAVM. Current treatment options for BAVM focus on removal or obliteration of the lesion in an attempt to protect against future ICH risk, including microsurgical resection, endovascular embolization, and stereotactic radiosurgery (SRS). In the third part of this review, the authors discuss available data on SRS in BAVMs and highlight the need for future studies on the radiobiology of BAVMs, especially in regard to biomarker detection for tracking SRS response during the latency period. Insights from future investigations in BAVM may not only prove important for the development of novel therapies and relevant biomarkers for BAVM, but could also potentially benefit a variety of other disorders involving new vessel formation in the CNS, including stroke, tumors, moyamoya disease, and other cerebrovascular malformations.

Response: We were interested to read Dr Atanassova’s comments regarding our article. In the design of our study, we excluded patients with a history of myocardial infarction and congestive heart failure (CHF) in order to focus on the pathogenesis of acute cardiac injury and dysfunction. Though subarachnoid hemorrhage (SAH) patients have …