Background and Purpose Ultrasonographic plaque echolucency has been studied as a stroke risk marker in carotid atherosclerotic disease. We performed a systematic review and meta-analysis to summarize the association between ultrasound determined carotid plaque echolucency and future ipsilateral stroke risk. Methods We searched the medical literature for studies evaluating the association between carotid plaque echolucency and future stroke in asymptomatic patients. We included prospective observational studies with stroke outcome ascertainment after baseline carotid plaque echolucency assessment. We performed a meta-analysis and assessed study heterogeneity and publication bias. We also performed subgroup analyses limited to patients with stenosis ≥50%, studies in which plaque echolucency was determined via subjective visual interpretation, studies with a relatively lower risk of bias, and studies published after the year 2000. Results We analyzed data from 7 studies on 7557 subjects with a mean follow up of 37.2 months. We found a significant positive relationship between predominantly echolucent (compared to predominantly echogenic) plaques and the risk of future ipsilateral stroke across all stenosis severities (0-99%) (relative risk [RR], 2.31, 95% CI, 1.58-3.39, P<.001) and in subjects with ≥50% stenosis (RR, 2.61 95% CI, 1.47-4.63, P=.001). A statistically significant increased RR for future stroke was preserved in all additional subgroup analyses. No statistically significant heterogeneity or publication bias was present in any of the meta-analyses. Conclusions The presence of ultrasound-determined carotid plaque echolucency provides predictive information in asymptomatic carotid artery stenosis beyond luminal stenosis. However, the magnitude of the increased risk is not sufficient on its own to identify patients likely to benefit from surgical revascularization.

Object The authors assessed the safety and maximum tolerated dose of superselective intraarterial cerebral infusion (SIACI) of bevacizumab after osmotic disruption of the blood-brain barrier (BBB) with mannitol in patients with recurrent malignant glioma. Methods A total of 30 patients with recurrent malignant glioma were included in the current study. Results The authors report no dose-limiting toxicity from a single dose of SIACI of bevacizumab up to 15 mg/kg after osmotic BBB disruption with mannitol. Two groups of patients were studied; those without prior bevacizumab exposure (naïve patients; Group I) and those who had received previous intravenous bevacizumab (exposed patients; Group II). Radiographic changes demonstrated on MR imaging were assessed at 1 month postprocedure. In Group I patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 34.7%, a median reduction in the volume of tumor enhancement of 46.9%, a median MR perfusion (MRP) reduction of 32.14%, and a T2-weighted/FLAIR signal decrease in 9 (47.4%) of 19 patients. In Group II patients, MR imaging at 1 month showed a median reduction in the area of tumor enhancement of 15.2%, a median volume reduction of 8.3%, a median MRP reduction of 25.5%, and a T2-weighted FLAIR decrease in 0 (0%) of 11 patients. Conclusions The authors conclude that SIACI of mannitol followed by bevacizumab (up to 15 mg/kg) for recurrent malignant glioma is safe and well tolerated. Magnetic resonance imaging shows that SIACI treatment with bevacizumab can lead to reduction in tumor area, volume, perfusion, and T2-weighted/FLAIR signal.

Purpose: Upregulation of programmed death-ligand 1 (PD-L1) on circulating and tumor-infiltrating myeloid cells is a critical component of GBM-mediated immunosuppression that has been associated with diminished response to vaccine immunotherapy and poor survival. Although GBM-derived soluble factors have been implicated in myeloid PD-L1 expression, the identity of such factors has remained unknown. This study aimed to identify factors responsible for myeloid PD-L1 upregulation as potential targets for immune modulation.Experimental Design: Conditioned media from patientderived GBM explant cell cultures was assessed for cytokine expression and utilized to stimulate na€ ve myeloid cells. Myeloid PD-L1 induction was quantified by flow cytometry. Candidate cytokines correlated with PD-L1 induction were evaluated in tumor sections and plasma for relationships with survival and myeloid PD-L1 expression. The role of identified cytokines on immunosuppression and survival was investigated in vivo utilizing immunocompetent C57BL/6 mice bearing syngeneic GL261 and CT-2A tumors.Results: GBM-derived IL6 was identified as a cytokine that is necessary and sufficient for myeloid PD-L1 induction in GBM through a STAT3-dependent mechanism. Inhibition of IL6 signaling in orthotopic murine glioma models was associated with reduced myeloid PD-L1 expression, diminished tumor growth, and increased survival. The therapeutic benefit of anti-IL6 therapy proved to be CD8 þ T-cell dependent, and the antitumor activity was additive with that provided by programmed death-1 (PD-1)-targeted immunotherapy.Conclusions: Our findings suggest that disruption of IL6 signaling in GBM reduces local and systemic myeloid-driven immunosuppression and enhances immune-mediated antitumor responses against GBM. Ã , P < 0.05; ÃÃ , P < 0.01; ÃÃÃ , P < 0.001; ÃÃÃÃ , P < 0.0001.Lamano et al. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis):