It is now clear that microglia and macrophages are present in brain tumors, but whether or how they affect initiation and development of tumors is not known. Exploiting the advantages of the zebrafish (Danio rerio) model, we showed that macrophages and microglia respond immediately upon oncogene activation in the brain. Overexpression of human AKT1 within neural cells of larval zebrafish led to a significant increase in the macrophage and microglia populations. By using a combination of transgenic and mutant zebrafish lines, we showed that this increase was caused by the infiltration of peripheral macrophages into the brain mediated via Sdf1b-Cxcr4b signaling. Intriguingly, confocal live imaging reveals highly dynamic interactions between macrophages/microglia and pre-neoplastic cells, which do not result in phagocytosis of pre-neoplastic cells. Finally, depletion of macrophages and microglia resulted in a significant reduction of oncogenic cell proliferation. Thus, macrophages and microglia show tumor promoting functions already during the earliest stages of the developing tumor microenvironment.

The invasive nature of cancers in general, and malignant gliomas in particular, is a major clinical problem rendering tumors incurable by conventional therapies. Using a novel invasive glioma mouse model established by serial in vivo selection, we identified the p75 neurotrophin receptor (p75NTR) as a critical regulator of glioma invasion. Through a series of functional, biochemical, and clinical studies, we found that p75NTR dramatically enhanced migration and invasion of genetically distinct glioma and frequently exhibited robust expression in highly invasive glioblastoma patient specimens. Moreover, we found that p75NTR-mediated invasion was neurotrophin dependent, resulting in the activation of downstream pathways and producing striking cytoskeletal changes of the invading cells. These results provide the first evidence for p75NTR as a major contributor to the highly invasive nature of malignant gliomas and identify a novel therapeutic target.

Reovirus is an oncolytic virus with activity in in vivo models of malignant gliomas (MGs). The primary aims were to determine the dose-limiting toxicity (DLT) and maximum tolerated dose (MTD) of intratumoral administration of reovirus in patients with recurrent MGs. Response, survival, and time to progression (TTP) were secondary aims. Patients were adults, had Karnofsky Performance score > or = 60, received prior radiotherapy with or without chemotherapy, and had up to the third recurrence of MG. Reovirus was administered intratumorally stereotactically at 1 x 10(7), 1 x 10(8), or 1 x 10(9) tissue culture infectious dose 50 (TCID50) in a volume of 0.9 ml. Twelve patients were treated at three dose levels (3, 6, and 3 patients, respectively). Seven were men, median Karnofsky Performance score was 80, and median age was 53.5 years. There were no grade III or IV adverse events (AEs) definitely or probably related to treatment. Ten patients had tumor progression, one had stabilization, and one was not evaluable for response. Median survival was 21 weeks (range, 6-234), and one is alive 54 months after treatment. Median TTP was 4.3 weeks (range, 2.6-39). An MTD was not reached. The intratumoral administration of the genetically unmodified reovirus was well tolerated using these doses and schedule, in patients with recurrent MG.

Myxoma virus, a poxvirus previously considered rabbit specific, can replicate productively in a variety of human tumor cells in culture. The purpose of this study was to determine if there was efficacy or toxicities of this oncolytic virus against experimental models of human malignant gliomas in vitro, in vivo, and ex vivo in malignant glioma specimens. In vitro, the majority of glioma cell lines tested (7 of 8, 87.5%) were fully permissive for myxoma virus replication and killed by infection. In vivo, intracerebral (i.c.) myxoma virus inoculation was well tolerated and produced only minimal focal inflammatory changes at the site of viral inoculation. U87 and U251 orthotopic xenograft models were used to assess myxoma virus efficacy in vivo. A single intratumoral injection of myxoma virus dramatically prolonged median survival compared with treatment with UVinactivated myxoma virus. Median survival was not reached in myxoma virus-treated groups versus 47.3 days (U87; P = 0.0002) and 50.7 days (U251; P = 0.0027) in UV-inactivated myxoma virus-treated groups. Most myxoma virus-treated animals (12 of 13, 92%) were alive and apparently ''cured'' when the experiment was finished (>130 days). Interestingly, we found a selective and long-lived myxoma virus infection in gliomas in vivo. This is the first demonstration of the oncolytic activity of myxoma virus in vivo. The nonpathogenic nature of myxoma virus outside of the rabbit host, its capacity to be genetically modified, its ability to produce a long-lived infection in human tumor cells, and the lack of preexisting antibodies in the human population suggest that myxoma virus may be an attractive oncolytic agent against human malignant glioma. (Cancer Res 2005; 65(21): 9982-90)

Revascularization is an important component of treatment for complex aneurysms that cannot be directly clipped and instead require parent vessel occlusion. A consecutive series of 61 patients with 63 aneurysms requiring cerebral revascularization is presented. Aneurysms were located along the petrous internal carotid artery (ICA) (n = 5), the cavernous ICA (n = 16), the supraclinoid ICA (n = 12), the middle cerebral artery (n = 17), the anterior cerebral artery (n = 4), the vertebral artery/posterior inferior cerebellar artery (n = 5), and the midbasilar artery (n = 4). Aneurysms were treated by direct clipping (n = 8), trapping (n = 28), proximal vessel occlusion (n = 9), distal vessel occlusion (n = 1), excision (n = 15), and thrombotic occlusion (n = 2). Revascularization was performed with petrous to supraclinoid ICA bypass (n = 12), superficial temporal artery to middle cerebral artery bypass (n = 15), superficial temporal artery to middle cerebral artery bypass with saphenous graft (n = 5), superficial temporal artery to superior cerebellar artery bypass (n = 4) long saphenous bypass (n = 11), in situ bypass (n = 3), and primary reanastomosis (n = 13). Fifty-seven patients (93%) had good outcomes, and one patient died (surgical mortality, 2%). This experience demonstrates that revascularization can be performed with low morbidity and mortality. We think that the cumulative risks of not performing revascularization in patients who tolerate ICA balloon occlusion exceed the surgical risk of revascularization. We therefore favor revascularization in patients with complex aneurysms treated by surgical arterial occlusion.

Multi-wavelength surveys covering large sky volumes are necessary to obtain an accurate census of rare objects such as high luminosity and/or high redshift active galactic nuclei (AGN). Stripe 82X is a 31.3 deg 2 X-ray survey with Chandra and XMM-Newton observations overlapping the legacy Sloan Digital Sky Survey (SDSS) Stripe 82 field, which has a rich investment of multi-wavelength coverage from the ultraviolet to the radio. The wide-area nature of this survey presents new challenges for photometric redshifts for AGN compared to previous work on narrow-deep fields because it probes different populations of objects that need to be identified and represented in the library of templates. Here we present an updated X-ray plus multi-wavelength matched catalog, including Spitzer counterparts, and estimated photometric redshifts for 5961 (96% of a total of 6181) X-ray sources, which have a normalized median absolute deviation, σ nmad = 0.06 and an outlier fraction, η = 13.7%. The populations found in this survey, and the template libraries used for photometric redshifts, provide important guiding principles for upcoming large-area surveys such as eROSITA and 3XMM (in X-ray) and the Large Synoptic Survey Telescope (LSST; optical).

BackgroundHydrocephalus is a debilitating disorder, affecting all age groups. Evaluation of its global epidemiology is required for healthcare planning and resource allocation.ObjectivesTo define age-specific global prevalence and incidence of hydrocephalus.MethodsPopulation-based studies reporting prevalence of hydrocephalus were identified (MEDLINE, EMBASE, Cochrane, and Google Scholar (1985–2017)). Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed. Two authors reviewed abstracts, full text articles and abstracted data. Metanalysis and meta-regressions were used to assess associations between key variables. Heterogeneity and publication bias were assessed. Main outcome of interest was hydrocephalus prevalence among pediatric (≤ 18 years), adults (19–64 years), and elderly (≥ 65) patients. Annual hydrocephalus incidence stratified by country income level and folate fortification requirements were obtained (2003–2014) from the International Clearinghouse for Birth Defects Surveillance and Research (ICBDSR).ResultsOf 2,460 abstracts, 52 met review eligibility criteria (aggregate population 171,558,651). Mean hydrocephalus prevalence was 85/100,000 [95% CI 62, 116]. The prevalence was 88/100,000 [95% CI 72, 107] in pediatrics; 11/100,000 [95% CI 5, 25] in adults; and 175/100,000 [95% CI 67, 458] in the elderly. The ICBDSR-based incidence of hydrocephalus diagnosed at birth remained stable over 11 years: 81/100,000 [95% CI 69, 96]. A significantly lower incidence was identified in high-income countries.ConclusionThis systematic review established age-specific global hydrocephalus prevalence. While high-income countries had a lower hydrocephalus incidence according to the ICBDSR registry, folate fortification status was not associated with incidence. Our findings may inform future healthcare resource allocation and study.

Abstract. Objectives:To compare the utilization rates of CT scans in investigating minor head trauma in children in Canada, to identify the injuries determined by these scans, and to identify clinical findings that are highly associated with its diagnosis and the injury itself. Methods: A retrospective cohort study involving nine pediatric hospitals in Canada was conducted. A structured data collection method was used. Inclusion criteria included age 16 years or less, history of blunt head trauma, and a Glasgow Coma Scale score (GCS) greater than or equal to 13. Data collected included demographic information, type of injury, relevant clinical information, computed tomography (CT) scan data, and clinical outcome. Clinical findings associated with CT scan and positive CT scan were identified using logistic regression. Results: One thousand one hundred sixty-four children were included in the study. One hundred seventy-one (15%) had a CT scan, of which 60 (35%) were abnormal. There was a significant difference in the rate of ordering of CT scans among the participating hospitals, but no significant difference in the rate of abnormal CT scans. Mechanism of injury, GCS, and loss of consciousness were significantly related to the presence of an abnormal CT scan. Conclusions: Although there is a significant difference in the utilization of CT scans to investigate minor head trauma in children across Canada, there is no significant difference in the frequency of head injuries in these patients. This suggests that it may be possible to determine clinical criteria that are predictive of a head injury in these patients. Key words: CT scan; pediatrics; minor head trauma. ACADEMIC EMER-GENCY MEDICINE 2000; 7:739-744 This retrospective cohort study was designed with two purposes. The primary purpose was to compare the utilization rates of CT scans in the investigation of minor head trauma in children in the nine collaborating pediatric hospitals in Canada, and to determine the frequency and types of intracranial abnormalities demonstrated by these scans. The second purpose was to identify clinical findings that are highly associated with its diagnosis and the injury itself.