Percutaneous transluminal angioplasty and stenting for symptomatic intracranial arterial stenosis: a systematic review and meta-analysis

OBJECTIVES: The cumulative safety and efficacy measures of percutaneous transluminal angioplasty and stenting (PTAS) for secondary stroke prevention in patients with symptomatic intracranial arterial stenosis (sICAS) have not previously been evaluated using a meta-analytical approach. METHODS: We conducted a systematic review and random effects meta-analysis of all available randomized controlled trials (RCTs) evaluating the safety and efficacy of PTAS (in comparison with medical therapy) for sICAS. RESULTS: Three RCTs (678 total patients) were included in the quantitative analysis. PTAS was associated with a higher risk of recurrent ischemic stroke in the territory of qualifying artery both within 30 days [risk ratio (RR) = 2.21, 95% confidence interval (CI) 1.10-4.43] and 1 year (RR = 1.92, 95% CI 1.10-3.36). PTAS was also related to a higher risk of any ischemic stroke within 30 days from the index event (RR = 2.08, 95% CI 1.17-3.71). The risk for intracranial hemorrhage was found to be higher in PTAS patients both within 30 days (RR = 10.60, 95% CI 1.98-56.62) and 1 year (RR = 8.15, 95% CI 1.50-44.34). The composite outcome of any stroke or death within 1 year (RR = 2.29, 95% CI 1.13-4.66) and 2 years (RR = 1.52, 95% CI 1.04-2.21) was higher in PTAS than in medical therapy. PTAS was associated with a higher risk of any stroke or death within 2 years in the sICAS subgroup located in posterior circulation (RR = 2.37, 95% CI 1.27-4.42). CONCLUSIONS: PTAS is associated with adverse early and long-term outcomes and should not be recommended in patients with sICAS. Further research to identify subgroups of patients who could also serve as candidates for future interventional trials along with efforts to reduce procedure-related complications are needed

Intravenous thrombolysis for acute ischemic stroke in Greece: the Safe Implementation of Thrombolysis in Stroke registry 15-year experience

Background: Intravenous thrombolysis (IVT) remains the only approved systemic reperfusion treatment for acute ischemic stroke (AIS), however there are scarce data regarding outcomes and complications of IVT in Greece. We evaluated safety and efficacy outcomes of IVT for AIS in Greece using the Safe Implementation of Thrombolysis in Stroke: International Stroke Thrombolysis Register (SITS-ISTR) dataset. Methods: All AIS patients treated with IVT in Greece between December 2002 and July 2017 and recorded in the SITS-ISTR were evaluated. Demographics, risk factors, baseline stroke severity [defined using National Institutes of Health Stroke Scale (NIHSS)], and onset-to-treatment time (OTT) were recorded. Safety outcomes included symptomatic intracranial hemorrhage (sICH) and 3-month mortality rates. The efficacy outcomes evaluated a reduction in baseline NIHSS score at 2 and 24 h following IVT onset, 3-month favorable functional outcome [FFO; modified Rankin scale (mRS) scores of 0-1] and 3-month functional independence (FI; mRS-scores of 0-2). The safety and efficacy outcomes were assessed comparatively with previously published data from SITS national and international registries. Results: A total of 523 AIS patients were treated with IVT in 12 Greek centers participating in the SITS-ISTR during the study period (mean age 62.4 ± 12.7; 34.6% women; median baseline NIHSS score: 11 points; median OTT: 150 min). The rates of sICH were 1.4%, 2.3%, and 3.8% according to the SIST-MOST, ECASS II, and NINDS criteria respectively. The median reduction in NIHSS score at 2 and 24 h was 3 [interquartile range (IQR): 1-5] and 5 (IQR: 2-8) points respectively. The 3-month FI, FFO and mortality were 66.5%, 55.6% and 7.9%. All safety and efficacy outcomes were comparable with available data from SITS-ISTR in other European countries. Conclusions: Our study underscores the safety and efficacy of IVT for AIS in Greece. Additional action is necessary in order to increase the availability of IVT in the Greek population and to include more centers in the SITS-ISTR

Endovascular Treatment for Anterior Circulation Large-Vessel Occlusion Ischemic Stroke with Low ASPECTS: a Systematic Review and Meta-Analysis

Background: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with Alberta Stroke Program Early CT Score (ASPECTS) 0-5 has not yet proven safe and effective by clinical trials. Objectives: The aim of the study was to assess whether EVT in AIS patients presenting with low ASPECTS is beneficial. Design: Systematic review and meta-analysis of available studies in accordance with the PRISMA statement. Data sources and methods: We have searched MEDLINE, the Cochrane Central Register of Controlled Trials, and reference lists of articles published until 28 May 2022 with the aim to calculate (1) modified Rankin scale (mRS) score 0-3 at 3 months, (2) mRS score 0-2 at 3 months, (3) symptomatic intracranial hemorrhage (sICH), and (3) mortality at 3 months. Results: Overall, 24 eligible studies were included in the meta-analysis, comprising a total of 2539 AIS patients with ASPECTS 0-5 treated with EVT. The pooled proportion of EVT-treated patients achieving mRS 0-3 at 3 months was calculated at 38.4%. The pooled proportion of EVT-treated patients achieving mRS 0-2 at 3 months was 25.7%. Regarding safety outcomes, sICH occurred in 12.8% of patients. The 3-month pooled mortality was 30%. In pairwise meta-analysis, patients treated with EVT had a higher likelihood of achieving mRS 0-3 at 3 months compared with patients treated with best medical therapy (BMT, OR: 2.41). sICH occurred more frequently in EVT-treated patients compared with the BMT-treated patients (OR: 2.30). Mortality at 3 months was not different between the two treatment groups (OR: 0.71). Conclusion: EVT may be beneficial for AIS patients with low baseline ASPECTS despite an increased risk for sICH. Further data from randomized-controlled clinical trials are needed to elucidate the role of EVT in this subgroup of AIS patients. Registration: The protocol has been registered in the International Prospective Register of Ongoing Systematic Reviews PROSPERO; Registration Number: CRD42022334417.info:eu-repo/semantics/publishedVersio

Microbleed Prevalence and Burden in Anticoagulant-Associated Intracerebral Bleed

Prior studies suggest an association between Vitamin K antagonists (VKA) and cerebral microbleeds (CMBs); less is known about nonvitamin K oral anticoagulants (NOACs). In this observational study we describe CMB profiles in a multicenter cohort of 89 anticoagulation-related intracerebral hemorrhage (ICH) patients. CMB prevalence was 51% (52% in VKA-ICH, 48% in NOAC-ICH). NOAC-ICH patients had lower median CMB count [2(IQR:1–3) vs. 7(4–11); P \u3c 0.001]; ≥5 CMBs were less prevalent in NOAC-ICH (4% vs. 31%, P = 0.006). This inverse association between NOAC exposure and high CMB count persisted in multivariable logistic regression models adjusting for potential confounders (OR 0.10, 95%CI: 0.01–0.83; P = 0.034)

Prediction of early recurrent thromboembolic event and major bleeding in patients with acute stroke and atrial fibrillation by a risk stratification schema: the ALESSA score study

Background and Purposes—This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods—The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P=0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion >1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P=0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P=0.10) for major bleedings. Results—The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P=0.009) for ischemic outcome events and 0.407 (0.275–0.540; P=0.14) for hemorrhagic outcome events. Conclusions—In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings

Melatonin Enhances the Usefulness of Ionizing Radiation: Involving the Regulation of Different Steps of the Angiogenic Process

Radiotherapy is a part of cancer treatment. To improve its efficacy has been combined with radiosensitizers such as antiangiogenic agents. Among the mechanisms of the antitumor action of melatonin are antiangiogenic effects. Our goal was to investigate whether melatonin may modulate the sensitivity of endothelial cells (HUVECs) to ionizing radiation. Melatonin (1 mM) enhanced the inhibition induced by radiation on different steps of the angiogenic process, cell proliferation, migration, and tubular network formation. In relation with the activity and expression of enzymes implicated in estrogen synthesis, in co-cultures HUVECs/MCF-7, radiation down-regulated aromatase mRNA expression, aromatase endothelial-specific promoter I.7, sulfatase activity and expression and 17?-HSD1 activity and expression and melatonin enhanced these effects. Radiation and melatonin induced a significant decrease in VEGF, ANG-1, and ANG-2 mRNA expression. In ANG-2 and VEGF mRNA expression melatonin potentiated the inhibitory effect induced by radiation. In addition, melatonin counteracted the stimulatory effect of radiation on FGFR3, TGF?, JAG1, IGF-1, and KDR mRNA expression and reduced ANPEP expression. In relation with extracellular matrix molecules, radiation increased MMP14 mRNA expression and melatonin counteracted the stimulatory effect of radiation on MMP14 mRNA expression and increased TIMP1 expression, an angiogenesis inhibitor. Melatonin also counteracted the stimulatory effect of radiation on CXCL6, CCL2, ERK1, ERK2, and AKT1 mRNA expression and increased the inhibitory effect of radiation on NOS3 expression. In CAM assay, melatonin enhanced the reduction of the vascular area induced by radiation. Melatonin potentiated the inhibitory effect on the activation of p-AKT and p-ERK exerted by radiation. Antiangiogenic effect of melatonin could be mediated through AKT and ERK pathways, proteins involved in vascular endothelial (VE) cell growth, cell proliferation, survival, migration, and angiogenesis. In addition, radiation increased endothelial cell permeability and melatonin counteracted it by regulating the internalization of VE-cadherin. Radiation has some side effects on angiogenesis that may reduce its effectiveness against tumor growth and melatonin is able to neutralize these negative actions of radiation. Additionally, melatonin potentiated radiation-induced antiangiogenic actions on several steps of the angiogenic process and enhanced its antitumor action. Our findings point to melatonin as a useful molecule as adjuvant to radiotherapy in cancer treatment.FUNDING: This work was supported by grants from the Spanish Economy and Competitiveness Ministry (SAF2016-77103-P) and from the Instituto de Investigación Sanitaria Valdecilla (IDIVAL) (APG/12)

Suppression of uPA and uPAR Attenuates Angiogenin Mediated Angiogenesis in Endothelial and Glioblastoma Cell Lines

In our earlier reports, we showed that downregulation of uPA and uPAR inhibited glioma tumor angiogenesis in SNB19 cells, and intraperitoneal injection of a hairpin shRNA expressing plasmid targeting uPA and uPAR inhibited angiogenesis in nude mice. The exact mechanism by which inhibition of angiogenesis takes place is not clearly understood.In the present study, we have attempted to investigate the mechanism by which uPA/uPAR downregulation by shRNA inhibits angiogenesis in endothelial and glioblastoma cell lines. uPA/uPAR downregulation by shRNA in U87 MG and U87 SPARC co-cultures with endothelial cells inhibited angiogenesis as assessed by in vitro angiogenesis assay and in vivo dorsal skin-fold chamber model in nude mice. Protein antibody array analysis of co-cultures of U87 and U87 SPARC cells with endothelial cells treated with pU2 (shRNA against uPA and uPAR) showed decreased angiogenin secretion and angiopoietin-1 as well as several other pro-angiogenic molecules. Therefore, we investigated the role of angiogenin and found that nuclear translocation, ribonucleolytic and 45S rRNA synthesis, which are all critical for angiogenic function of angiogenin, were significantly inhibited in endothelial cells transfected with uPA, uPAR and uPA/uPAR when compared with controls. Moreover, uPA and uPAR downregulation significantly inhibited the phosphorylation of Tie-2 receptor and also down regulated FKHR activation in the nucleus of endothelial cells via the GRB2/AKT/BAD pathway. Treatment of endothelial cells with ruPA increased angiogenin secretion and angiogenin expression as determined by ELISA and western blotting in a dose-dependent manner. The amino terminal fragment of uPA down regulated ruPA-induced angiogenin in endothelial cells, thereby suggesting that uPA plays a critical role in positively regulating angiogenin in glioblastoma cells.Taken together, our results suggest that uPA/uPAR downregulation suppresses angiogenesis in endothelial cells induced by glioblastoma cell lines partially by downregulation of angiogenin and by inhibition of the angiopoietin-1/AKT/FKHR pathway