World-Wide Efficacy of Bone Marrow Derived Mesenchymal Stromal Cells in Preclinical Ischemic Stroke Models: Systematic Review and Meta-Analysis

Background: Following extensive, positive results in pre-clinical experiments, Bone Marrow Derived-Mesenchymal Stromal Cells (BM-MSCs) are now being tested as a novel therapy for ischemic stroke in ongoing clinical trials. However, multiple critical questions relating to their translational application remain to be clarified. We performed a comprehensive, systematic review and meta-analysis of pre-clinical studies to evaluate the efficacy of BM-MSCs on functional outcomes after ischemic stroke, as well as the independent role of translational factors on their effect size.Methods: We systematically reviewed the literature and identified articles using BM-MSCs in animal models of focal ischemic stroke. After abstraction of all relevant data, we performed a meta-analysis to estimate the combined effect size of behavioral endpoints after BM-MSC administration. To describe the effect size across many behavioral outcomes, we divided these outcomes into four categories: (1) Composite scores, (2) Motor Tests, (3) Sensorimotor Tests, and (4) Cognitive Tests. We also performed a meta-regression analysis for measuring the effect of individual characteristics of BM-MSC administration on the effect size.Results: Our results from 141 articles indicate a significant beneficial effect on composite, motor, and sensorimotor outcomes after treatment with BM-MSCs compared to control groups. We found no major differences in treatment effect based on delivery route, dose, fresh vs. frozen preparation, or passage number. There were no consistent findings supporting a difference in treatment effect based on time windows from acute periods (0–6 h) vs. later windows (2–7 days). Furthermore, these positive treatment effects on functional outcome were consistent across different labs in different parts of the world as well as over the last 18 years. There was a negative correlation between publication year and impact factor.Conclusions: Our results show worldwide efficacy of BM-MSCs in improving functional outcomes in pre-clinical animal models of stroke and support testing these cells in clinical trials in various ranges of time windows using different delivery routes. The continued growing number of publications showing functional benefit of BM-MSCs are now adding limited value to an oversaturated literature spanning 18 years. Researchers should focus on identifying definitive mechanisms on how BM-MSCs lead to benefit in stroke models

Endovascular Thrombectomy for Mild Strokes: How Low Should We Go? A Multicenter Cohort Study

Background and Purpose:Endovascular thrombectomy (EVT) is effective for acute ischemic stroke with large vessel occlusion (LVO) and NIHSS ≥6. However, EVT benefit for mild deficits LVOs (NIHSS Methods: A retrospective cohort of patients with anterior circulation LVO and NIHSSoutcome; mRS=0–2 was the secondary. Symptomatic intracerebral hemorrhage (sICH) was the safety outcome. Clinical outcomes were compared through a multivariable logistic regression after adjusting for age, presentation NIHSS, time-last-seen-normal-to-presentation, center, IV-alteplase, ASPECTS, and thrombus location. We then performed propensity score matching as a sensitivity analysis. Results were also stratified by thrombus location. Results: 214 patients (EVT-124, medical management-90) were included from 8 US and Spain centers between January/2012 and March/2017. The groups were similar in age, ASPECTS, IValteplase rate and time-last-seen-normal-to-presentation. There was no difference in mRS=0–1 between EVT and medical management (55.7% versus 54.4%, respectively, aOR=1.3, 95%CI=0.64–2.64, p=0.47). Similar results were seen for mRS=0–2 (63.3% EVT versus 67.8% medical management, aOR=0.9, 95%CI=0.43–1.88, p=0.77). In a propensity matching analysis, there was no treatment effect in 62 matched pairs (53.5%EVT, 48.4% medical management; OR=1.17, 95%CI=0.54–2.52, p=0.69). There was no statistically significant difference when stratified by any thrombus location; M1 approached significance (p=0.07). sICH rates were higher with thrombectomy (5.8% EVT versus 0% medical management, p=0.02). Conclusions: Our retrospective multicenter cohort study showed no improvement in excellent and independent functional outcomes in mild strokes (NIHS

Cryopreservation of Bone Marrow Mononuclear Cells Alters Their Viability and Subpopulation Composition but Not Their Treatment Effects in a Rodent Stroke Model

The systemic administration of autologous bone marrow (BM) derived mononuclear cells (MNCs) is under investigation as a novel therapeutic modality for the treatment of ischemic stroke. Autologous applications raise the possibility that MNCs could potentially be stored as a banked source. There have been no studies that investigate the effects of cryopreservation of BM-MNCs on their functional abilities in stroke models. In the present study, C57BL/6 mice were subjected to middle cerebral artery occlusion (MCAo) for 60 minutes and then divided into two treatment groups: fresh MNCs versus cryopreserved MNCs. BM-MNCs were collected at 22 hours after MCAo and were stored in liquid nitrogen for 12 months in cryopreserved MNCs group. BM-MNCs cellular viability, composition, and phenotype of the various subpopulations of mice BM-MNCs were evaluated by flow cytometry, and the behavioral recovery of stroke animals was tested with freshly harvested MNCs versus cryopreserved MNCs by corner test and ladder rung test. We found that long-term cryopreservation negatively impacts the cellular viability of bone marrow MNCs. Cryopreservation also alters the cellular composition of various subpopulations within the MNCs. However, despite the changes observed in cryopreserved cells, both fresh and frozen MNCs have similar beneficial effect on behavioral and histological outcomes

Direct to Angiography vs Repeated Imaging Approaches in Transferred Patients Undergoing Endovascular Thrombectomy

IMPORTANCE A direct to angiography (DTA) treatment paradigm without repeated imaging for transferred patients with large vessel occlusion (LVO) may reduce time to endovascular thrombectomy (EVT). Whether DTA is safe and associated with better outcomes in the late (>6 hours) window is unknown. Also, DTA feasibility and effectiveness in reducing time to EVT during on-call vs regular-work hours and the association of interfacility transfer times with DTA outcomes have not been established. OBJECTIVE To evaluate the functional and safety outcomes of DTA vs repeated imaging in the different treatment windows and on-call hours vs regular hours. DESIGN, SETTING, AND PARTICIPANTS This pooled retrospective cohort study at 6 US and European comprehensive stroke centers enrolled adults (aged >= 18 years) with anterior circulation LVO (internal cerebral artery or middle cerebral artery subdivisions M1/M2) and transferred for EVT within 24 hours of the last-known-well time from January 1, 2014, to February 29, 2020. EXPOSURES Repeated imaging (computed tomography with or without computed tomographic angiography or computed tomography perfusion) before EVT vs DTA. MAIN OUTCOMES AND MEASURES Functional independence (90-day modified Rankin Scale score, 0-2) was the primary outcome. Symptomatic intracerebral hemorrhage, mortality, and time metrics were also compared between the DTA and repeated imaging groups. RESULTS A total of 1140 patients with LVO received EVT after transfer, including 327 (28.7%) in the DTA group and 813 (71.3%) in the repeated imaging group. The median age was 69 (interquartile range [IQR], 59-78) years; 529 were female (46.4%) and 609 (53.4%) were male. Patients undergoing DTA had greater use of intravenous alteplase (200 of 327 [61.2%] vs 412 of 808 [51.0%]; P = .002), but otherwise groups were similar. Median time from EVT center arrival to groin puncture was faster with DTA (34 [IQR, 20-62] vs 60 [IQR, 37-95] minutes; P < .001), overall and in both regular and on-call hours. Three-month functional independence was higher with DTA overall (164 of 312 [52.6%] vs 282 of 763 [37.0%]; adjusted odds ratio [aOR], 1.85 [95% CI, 1.33-2.57]; P < .001) and during regular (77 of 143 [53.8%] vs 118 of 292 [40.4%]; P = .008) and on-call (87 of 169 [51.5%] vs 164 of 471 [34.8%]; P < .001) hours. The results did not vary by time window (0-6 vs >6 to 24 hours; P = .88 for interaction). Three-month mortality was lower with DTA (53 of 312 [17.0%] vs 186 of 763 [24.4%]; P = .008). A 10-minute increase in EVT-center arrival to groin puncture in the repeated imaging group correlated with 5% reduction in the functional independence odds (aOR, 0.95 [95% CI, 0.91-0.99]; P = .01). The rates of modified Rankin Scale score of 0 to 2 decreased with interfacility transfer times of greater than 3 hours in the DTA group (96 of 161 [59.6%] vs 15 of 42 [35.7%]; P = .006), but not in the repeated imaging group (75 of 208 [36.1%] vs 71 of 192 [37.0%]; P = .85). CONCLUSIONS AND RELEVANCE The DTA approach may be associated with faster treatment and better functional outcomes during all hours and treatment windows, and repeated imaging may be reasonable with prolonged transfer times. Optimal EVT workflow in transfers may be associated with faster, safe reperfusion with improved outcomes