Association Between Alberta Stroke Program Early Computed Tomography Score and Efficacy and Safety Outcomes With Endovascular Therapy in Patients With Stroke From Large-Vessel Occlusion: A Secondary Analysis of the Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT).

Importance: Endovascular therapy (EVT) has been found to reduce functional disability in patients with acute stroke due to large-vessel occlusion. However, the extent of the ischemic region, measured using Alberta Stroke Program Early Computed Tomography Scores, may limit the efficacy of EVT. Objective: To compare the efficacy and safety of EVT according to ASPECTS 3 or less vs 4 to 5. Design, Setting, and Participants: The Recovery by Endovascular Salvage for Cerebral Ultra-acute Embolism-Japan Large Ischemic Core Trial (RESCUE-Japan LIMIT) was an open-label randomized clinical trial conducted from November 2018 to December 2021 at 45 stroke centers across Japan. The trial enrolled adult patients with acute ischemic stroke with a large ischemic region, defined as ASPECTS 3 to 5 primarily determined by magnetic resonance imaging, with occlusion site at the internal carotid artery or middle cerebral artery segment 1. Among 203 enrolled patients, 1 withdrew consent and 202 were included in the original trial and secondary analysis. This secondary analysis was conducted in April 2022. Interventions: Patients were randomly assigned to EVT with medical therapy or medical therapy alone. Main Outcomes and Measures: Modified Rankin Scale (mRS) score at 90 days and symptomatic and any intracranial hemorrhage within 48 hours. Results: Among 202 patients, 106 (52%) had ASPECTS 3 or less (mean [SD] age, 76.7 [9.6] years; 54 female individuals [50.9%]) and 96 had ASPECTS 4 to 5 (mean [SD] age, 75.6 [10.6] years; 36 female individuals [37.5%]). Of patients with ASPECTS 3 or less, 12 (21.4%) in the EVT group and 9 (18.0%) in the no EVT group had an mRS score of 0 to 3 (odds ratio [OR], 1.24; 95% CI, 0.47-3.26). Of patients with ASPECTS 4 to 5, 19 patients (43.2%) in the EVT group and 4 (7.7%) in the no EVT group had an mRS score of 0 to 3 at 90 days (OR, 9.12; 95% CI, 2.80-29.70; interaction P = .01). The ordinal shift across the range of mRS scores toward a better outcome was not significant in those with ASPECTS or 3 or less (common OR, 1.56; 95% CI, 0.79-3.10) but was significant in those with ASPECTS 4 to 5 (common OR, 4.48; 95% CI, 2.07-9.71; interaction P = .046). The risk of intracranial hemorrhage was significantly increased in patients with ASPECTS 3 or less when EVT was conducted (OR, 4.14; 95% CI, 1.84-9.32) and nonsignificantly increased in those with ASPECTS 4 to 5 (OR, 2.05; 95% CI, 0.89-4.73; interaction P = .24). Conclusions and Relevance: In this study, EVT was associated with improved 90-day functional outcomes in patients with acute large vessel occlusive stroke and ASPECTS was 4 to 5 but not in those with ASPECTS 3 or less. Trial Registration: ClinicalTrials.gov Identifier: NCT03702413.

Ultrastructural analysis of apatite-degrading capability of extended invasive podosomes in resorbing osteoclasts.

Osteoclasts in culture are non-transformed cell types that spontaneously develop specific cell-adhesion devices such as podosomes. An individual podosome is a complex network of filamentous actin (F-actin) unit structure that collectively, with other proteins, self-organizes as the sealing zone. Major matrix degradation on apatite seems to proceed under the ruffled-border domain, which is an enclosed extracellular compartment tightly sealed off by this sealing zone. Presently we found that usually the top of finger-like projections of the ruffled border reached toward the plane of the apatite surface, where a shallow degradation of apatite took place. Simultaneously, we obtained several pieces of structural evidence indicating that a specific protrusion referred to as an invasive podosome (invadopodium), which was continuous with podosomes derived from the sealing zone, invaded deeply into apatite matrix and degraded it. The F-actin architecture of the invasive podosome - an active extracellular matrix-degrading, actin-rich cell protrusion - could be distinguished from that of other punctate F-actin structures including the individual podosome, sealing zone, and ruffled border projection. Invasive podosomes contained 2 different F-actin populations, i.e., an interconnected meshwork and a parallel array of bundles. The morphological variability of these protrusions was apparent, having a single cylindrical to lamella-shaped cytoskeletal organization. Our present observations strongly suggest that the degradation of apatite substrate-resorbing osteoclasts appears to have been preceded by the combined appearance of ruffled border and invasive podosomes, and also occurred simultaneously with cell migration during an alternating cycle of resorption and migration.