Citations

Background: Unprecedented clinical outcomes were reported after CD19 chimeric antigen receptor T-cell (CART19) therapy. However, the complete response rate in chronic lymphocytic leukemia (CLL) is much lower, at approximately 20%–30%. Several immune defects have been identified in CLL that result from the complex interaction between CLL cells and the microenvironment. This leukemic microenvironment is rich with extracellular vesicles (EVs) secreted by B-CLL cells. Here, we aimed to investigate the role of EVs play in the diminished CART response seen in some CLL patients. Methods: EVs were isolated from peripheral blood of 16 patients with untreated CLL at different Rai stages and risk profile by FISH. Cytometry was used to determine size, number of particles per μl, and CD19 expression. To investigate the impact of EVs on CAR T-cell functions, CART19 cells were stimulated with either CLL B cells or the CD19-positive cell line JEKO and different effector functions were analyzed. Results: Two patterns of EVs in CLL patients were identified; a single versus 2 distinct EV populations, characterized by size (small [EVssmall] and large [EVslarge], Fig 1A). In 25% of patients, EVs were CD19 positive (EVCD19+). CD19 positivity was detected only in patients with the EVslarge (Fig 1B). The EVs concentration, CD19 expression (EVsCD19+ vs EVsCD19-), or the size (EVssmall vs EVslarge) did not correlate with disease stage (early vs advanced Rai stage) or risk profile of CLL (low vs high risk). To investigate our hypothesis that EVs could modulate CART19 function, CART19 cell effector functions were examined in the presence of EVsCD19+, EVsCD19-, EVssmall, or EVslarge. EVs alone were insufficient to stimulate CART19 cells. However when CART19 cells were stimulated with the CD19-positive cell line JEKO, their effector functions were reduced only in the presence of EVsCD19+ but not EVsCD19-. This included a significant reduction in CART-specific killing (Fig 1C) and a reduction in cytokine production. The impairment of CART cell functions was independent of the size of EVs, ie, there was no impairment of CART functions with large or small size EVCD19- in co-culture. Conclusion: We identify CD19-positive large size EVs from patients with CLL and demonstrate that these EVs play a role in the leukemic microenvironment by reducing CAR T-cell activity. Studies are ongoing to define the mechanism(s).

Objectives This video describes the surgical indications, relevant anatomy, and surgical steps of routine translabyrinthine surgery for gross total resection of sporadic vestibular schwannoma. Design The procedure is presented through a surgical instructional video. Setting The surgery took place at tertiary skull base referral center. Parcipant A 47-year-old patient reported with nonserviceable hearing, frequent episodes of vertigo, recurrent severe headache, and a small unilateral right sided vestibular schwannoma. Results Gross total resection with preservation of facial nerve function was achieved. Conclusion This instructional video documents the surgical steps and relevant anatomy for translabyrinthine resection of vestibular schwannoma.The link to the video can be found at: https://youtu.be/CJ2vKMLs7aI.

OBJECTIVEThe role of CT perfusion (CTP) in the management of patients with acute ischemic stroke (AIS) remains a matter of debate. The primary aim of this study was to evaluate the correlation between the areas of infarction and penumbra on CTP scans and functional outcome in patients with AIS.METHODSThis was a retrospective review of 100 consecutively treated patients with acute anterior circulation ischemic stroke who underwent CT angiography (CTA) and CTP at admission between February 2011 and October 2014. On CTP, the volume of ischemic core and penumbra was measured using the Alberta Stroke Program Early CT Score (ASPECTS). CTA findings were also noted, including the site of occlusion and regional leptomeningeal collateral (rLMC) score. Functional outcome was defined by modified Rankin Scale (mRS) score obtained at discharge. Associations of CTP and CTA parameters with mRS scores at discharge were assessed using multivariable proportional odds logistic regression models.RESULTSThe median age was 67 years (range 19–95 years), and the median NIH Stroke Scale score was 16 (range 2–35). In a multivariable analysis adjusting for potential confounding variables, having an infarct on CTP scans in the following regions was associated with a worse mRS score at discharge: insula ribbon (p = 0.043), perisylvian fissure (p < 0.001), motor strip (p = 0.007), M2 (p < 0.001), and M5 (p = 0.023). A worse mRS score at discharge was more common in patients with a greater volume of infarct core (p = 0.024) and less common in patients with a greater rLMC score (p = 0.004).CONCLUSIONSThe results of this study provide evidence that several CTP parameters are independent predictors of functional outcome in patients with AIS and have potential to identify those patients most likely to benefit from reperfusion therapy in the treatment of AIS.

Background: The importance of physical activity in preventing major vascular events has received increased attention in the past decade. Due to the inclusion of the INTERVENT lifestyle modification program, the CREST2 trial provides a unique opportunity to study physical activity profiles in patients with severe asymptomatic extracranial carotid stenosis. Hypothesis: Based on data from a trial of intracranial stenosis patients, we aimed to evaluate the hypothesis that <40% of carotid stenosis subjects will have optimal physical activity levels. We also assessed key subgroups to determine patterns of physical activity. Methods: We analyzed 1087 CREST2 participants with baseline data on physical activity. The Physician-based Assessment and Counseling for Exercise (PACE) score is recorded for each patient and dichotomized as “in target” (4-8 points) or “out of target” (<4 points). A PACE score of <4 indicates a subject who does not engage in regular exercise. Results are analyzed for the entire trial. Chi square testing and t-tests were performed for evaluation of subgroup differences. Results: The mean age of the study population is 69.5±7.8 years (60% male). The median PACE score at baseline is 4.0 (mean 3.8±2.1; IQR 2 to 6). The Table shows baseline characteristics of patients by mean PACE score. Being male, not having diabetes mellitus, having a body mass index <30kg/m2, being a non-smoker, and not having a history of peripheral arterial disease were associated with significantly higher mean PACE scores (P<0.01). Conclusions: We have defined several patient groups with asymptomatic carotid stenosis that have suboptimal physical activity. These results provide opportunities for targeted efforts to improve primary stroke prevention. These baseline data will also allow investigators to determine if trial involvement and the INTERVENT program leads to improvement in the level of physical activity.

TPS475 Background: The prognosis of pancreas adenocarcinoma (PCA) remains poor. A chemotherapy backbone is the current standard of care in PCA. The choice of a chemotherapeutic backbone may impact the efficacy of anti-angiogenic therapy in PCA. Ramucirumab has increased activity with fluoropyrimidines (5FU) because 5FU increases VEGF expression. Methods: This is a double-blind, placebo controlled Phase II study. Subjects will receive either Ramucirumab or a placebo followed by mFOLFIRINOX every two weeks of a 28 day cycle until progression or discontinuation for other reasons. The primary endpoint of this clinical trial is nine month PFS defined as the time from enrollment to the time of progression or death. Among the key inclusion criteria, subjects must have recurrent or metastatic pancreas adenocarcinoma (PCA) with no prior first-line systemic treatment, ECOG PS 0-1, adequate organ function, no DVT, PE or other thromboembolism within three months of randomization. Total number of patient enrolled as of September 19, 2018 is 48 of 85 at eight sites; 27 male (56%), 42 Caucasians (87.5%), three African American (6.2%), one Asian (2%). Median age is 63 (40 - 76). Majority of patients (41) had de novo metastatic disease and six with recurrent disease after surgery. Regimen has been tolerated well with no unanticipated events. Clinical trial information: NCT02581215.