Cerebral endothelial cell-derived small extracellular vesicles enhance neurovascular function and neurological recovery in rat acute ischemic stroke models of mechanical thrombectomy and embolic stroke treatment with tPA.

Treatment of patients with cerebral large vessel occlusion with thrombectomy and tissue plasminogen activator (tPA) leads to incomplete reperfusion. Using rat models of embolic and transient middle cerebral artery occlusion (eMCAO and tMCAO), we investigated the effect on stroke outcomes of small extracellular vesicles (sEVs) derived from rat cerebral endothelial cells (CEC-sEVs) in combination with tPA (CEC-sEVs/tPA) as a treatment of eMCAO and tMCAO in rat. The effect of sEVs derived from clots acquired from patients who had undergone mechanical thrombectomy on healthy human CEC permeability was also evaluated. CEC-sEVs/tPA administered 4 h after eMCAO reduced infarct volume by ∼36%, increased recanalization of the occluded MCA, enhanced cerebral blood flow (CBF), and reduced blood-brain barrier (BBB) leakage. Treatment with CEC-sEVs given upon reperfusion after 2 h tMCAO significantly reduced infarct volume by ∼43%, and neurological outcomes were improved in both CEC-sEVs treated models. CEC-sEVs/tPA reduced a network of microRNAs (miRs) and proteins that mediate thrombosis, coagulation, and inflammation. Patient-clot derived sEVs increased CEC permeability, which was reduced by CEC-sEVs. CEC-sEV mediated suppression of a network of pro-thrombotic, -coagulant, and -inflammatory miRs and proteins likely contribute to therapeutic effects. Thus, CEC-sEVs have a therapeutic effect on acute ischemic stroke by reducing neurovascular damage.

Histopathologic outcome of neoadjuvant image-guided therapy of hepatocellular carcinoma.

BACKGROUND AND AIMS: The best curative treatment for hepatocellular carcinoma (HCC) is liver transplant (LT), with the limitation to either a solitary lesion < 5 cm or up to three lesions < 3 cm each. Arresting tumor growth or downstaging to make patients eligible for LT can be obtained by neoadjuvant treatments such as transarterial chemoembolization (TACE), selective internal radiation therapy (SIRT), chemical or radiofrequency ablation (RFA). We evaluated the histopathologic response in explant specimens to neoadjuvant image-guided therapy of HCC prior to LT. METHODS: Twenty-eight patients with 39 HCC nodules eligible for LT underwent neoadjuvant image-guided therapy 1-393 days prior to transplant. Treatment included TACE (5 nodules), SIRT (7 nodules), RFA (12 nodules), chemical ablation (3 nodules) combined TACE and acetic acid injection (1 nodule) and combined TACE and RFA (11 nodules). 19/28 patients not transplanted within 30 days had interval MRI and 3 patients with progressive disease were retreated. RESULTS: Residual viable tumor was seen in 42% of patients with post-treatment imaging. Explant pathology revealed viable tumor in 35 of 39 (90%) treated nodules and somewhere in the explanted liver in all patients. Viability and/or progression of the treated tumor was noted in 5/5 nodules treated with TACE, 6/7 with SIRT, 11/12 with RFA, 2/3 with chemical ablation and 11/12 with combined treatment. CONCLUSION: Viable local or remote tumor was identified on explanted liver in the majority of patients with HCC after neoadjuvant therapy, despite apparent successful treatment on MRI.