Qualifying Event and Recurrence of Ischemic Stroke in Symptomatic Artery Occlusion: A Post Hoc Analysis of CMOSS.

BACKGROUND: The authors aimed to elucidate the relationship between latest ischemic event and the incidence of subsequent ischemic stroke in patients with symptomatic artery occlusion. METHODS AND RESULTS: We analyzed the association between qualifying event-the latest ischemic event (transient ischemic attack [TIA] or stroke)-and the incidence of ipsilateral ischemic stroke in patients with symptomatic artery occlusion treated with medical therapy alone in CMOSS (Carotid or Middle Cerebral Artery Occlusion Surgery Study). The incidence of CMOSS primary outcomes, including any stroke or death within 30 days after randomization or ipsilateral ischemic stroke between 30 days and 2 years, between the bypass surgical and medical groups, stratified by qualifying events, was also compared. Of the 165 patients treated with medical therapy alone, 75 had a TIA and 90 had a stroke as their qualifying event. The incidence of ipsilateral ischemic stroke did not significantly differ between patients with a TIA and those with a stroke as their qualifying event (13.3% versus 6.7%, P=0.17). In multivariate analysis, the qualifying event was not associated with the incidence of ipsilateral ischemic stroke. There were no significant differences in the CMOSS primary outcomes between the surgical and medical groups, regardless of the qualifying event being TIA (10.1% versus 12.2%, P=0.86) or stroke (6.7% versus 8.9%, P=0.55). CONCLUSIONS: Among patients with symptomatic artery occlusion and hemodynamic insufficiency, the risk of subsequent ipsilateral ischemic stroke does not appear to be lower in patients presenting with a TIA compared with those with a stroke. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01758614.

Potential of body mass index as a screening indicator for extracranial-intracranial bypass surgery in patients with symptomatic artery occlusion: a post-hoc analysis of the CMOSS trial.

BACKGROUND: To investigate the association between body mass index (BMI) and the incidence of ischemic stroke in patients with symptomatic artery occlusion, and further to evaluate the utility of BMI as a screening tool for identifying candidates for extracranial-intracranial bypass surgery. MATERIALS AND METHODS: We analyzed the relationship between BMI and the occurrence of ipsilateral ischemic stroke (IIS) among patients receiving only medical management in the Carotid or Middle cerebral artery Occlusion Surgery Study (CMOSS). Additionally, we compared the primary endpoint of CMOSS-stroke or death within 30 days, or IIS after 30 days up to two years-among patients with varying BMIs who underwent either surgery or medical treatment. RESULTS: Of the 165 patients who treated medically only, 16 (9.7%) suffered an IIS within two years. BMI was independently associated with the incidence of IIS (hazard ratio: 1.16 per kg/m2; 95% confidence interval: 1.06-1.27). The optimal BMI cutoff for predicting IIS was 24.5 kg/m2. Patients with BMI ≥24.5 kg/m2 experienced a higher incidence of IIS compared to those with BMI <24.5 kg/m2 (17.4% vs. 0.0%, P<0.01). The incidence of the CMOSS primary endpoint was significantly different between the surgical and medical groups for patients with BMI ≥24.5 kg/m2 (5.3% vs. 19.8%, P<0.01) and those with BMI <24.5 kg/m2 (10.6% vs. 1.4%; P=0.02). Surgical intervention was independently associated with a reduced rate of the CMOSS primary endpoint in patients with BMI ≥24.5 kg/m2. CONCLUSION: Data from the CMOSS trial indicate that patients with BMI ≥24.5 kg/m2 are at a higher risk of IIS when treated medically only and appear to derive greater benefit from bypass surgery compared to those with lower BMIs. Given the small sample size and the inherent limitations of retrospective analyses, further large-scale, prospective studies are necessary to confirm these findings.

Predictive factors of poor outcome and mortality among anterior ischaemic stroke patients despite successful recanalisation in China: a secondary analysis of the CAPTURE trial.

OBJECTIVES: This work aimed to analyse the risk factors for poor outcomes and mortality among patients with anterior large vessel occlusion (LVO) ischaemic stroke, despite successful recanalisation. SETTING AND PARTICIPANTS: This study conducted a secondary analysis among patients who underwent successful recanalisation in the CAPTURE trial. The trial took place between March 2018 and September 2020 at 21 sites in China. The CAPTURE trial enrolled patients who had an acute ischaemic stroke aged 18-80 years with LVO in anterior circulation. INTERVENTIONS: Thrombectomy was immediately performed using Neurohawk or the Solitaire FR after randomisation in CAPTURE trial. Rescue treatment was available for patients with severe residual stenosis caused by atherosclerosis. PRIMARY AND SECONDARY OUTCOME MEASURES: The primary goal was to predict poor 90-day survival or mortality within 90 days post-thrombectomy. Univariate analysis, using the χ2 test or Fisher's exact test, was conducted for each selected factor. Subsequently, a multivariable analysis was performed on significant factors (p≤0.10) identified through univariate analysis using the backward selection logistic regression approach. RESULTS: Among the 207 recruited patients, 79 (38.2%) exhibited poor clinical outcomes, and 26 (12.6%) died within 90 days post-thrombectomy. Multivariate analysis revealed that the following factors were significantly associated with poor 90-day survival: age ≥67 years, internal carotid artery (ICA) occlusion (compared with middle cerebral artery (MCA) occlusion), initial National Institutes of Health Stroke Scale (NIHSS) score ≥17 and final modified Thrombolysis in Cerebral Infarction (mTICI) score 2b (compared with mTICI 3). Additionally, the following factors were significantly associated with mortality 90 days post-thrombectomy: initial NIHSS score ≥17, ICA occlusion (compared with MCA occlusion) and recanalisation with more than one pass. CONCLUSIONS: Age, NIHSS score, occlusion site, mTICI score and the number of passes can be independently used to predict poor 90-day survival or mortality within 90 days post-thrombectomy. TRIAL REGISTRATION NUMBER: NCT04995757.

Extracranial-Intracranial Bypass and Risk of Stroke and Death in Patients With Symptomatic Artery Occlusion: The CMOSS Randomized Clinical Trial.

Importance: Prior trials of extracranial-intracranial (EC-IC) bypass surgery showed no benefit for stroke prevention in patients with atherosclerotic occlusion of the internal carotid artery (ICA) or middle cerebral artery (MCA), but there have been subsequent improvements in surgical techniques and patient selection. Objective: To evaluate EC-IC bypass surgery in symptomatic patients with atherosclerotic occlusion of the ICA or MCA, using refined patient and operator selection. Design, Setting, and Participants: This was a randomized, open-label, outcome assessor-blinded trial conducted at 13 centers in China. A total of 324 patients with ICA or MCA occlusion with transient ischemic attack or nondisabling ischemic stroke attributed to hemodynamic insufficiency based on computed tomography perfusion imaging were recruited between June 2013 and March 2018 (final follow-up: March 18, 2020). Interventions: EC-IC bypass surgery plus medical therapy (surgical group; n = 161) or medical therapy alone (medical group; n = 163). Medical therapy included antiplatelet therapy and stroke risk factor control. Main Outcomes and Measures: The primary outcome was a composite of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years after randomization. There were 9 secondary outcomes, including any stroke or death within 2 years and fatal stroke within 2 years. Results: Among 330 patients who were enrolled, 324 patients were confirmed eligible (median age, 52.7 years; 257 men [79.3%]) and 309 (95.4%) completed the trial. For the surgical group vs medical group, no significant difference was found for the composite primary outcome (8.6% [13/151] vs 12.3% [19/155]; incidence difference, -3.6% [95% CI, -10.1% to 2.9%]; hazard ratio [HR], 0.71 [95% CI, 0.33-1.54]; P = .39). The 30-day risk of stroke or death was 6.2% (10/161) in the surgical group and 1.8% (3/163) in the medical group, and the risk of ipsilateral ischemic stroke beyond 30 days through 2 years was 2.0% (3/151) and 10.3% (16/155), respectively. Of the 9 prespecified secondary end points, none showed a significant difference including any stroke or death within 2 years (9.9% [15/152] vs 15.3% [24/157]; incidence difference, -5.4% [95% CI, -12.5% to 1.7%]; HR, 0.69 [95% CI, 0.34-1.39]; P = .30) and fatal stroke within 2 years (2.0% [3/150] vs 0% [0/153]; incidence difference, 1.9% [95% CI, -0.2% to 4.0%]; P = .08). Conclusions and Relevance: Among patients with symptomatic ICA or MCA occlusion and hemodynamic insufficiency, the addition of bypass surgery to medical therapy did not significantly change the risk of the composite outcome of stroke or death within 30 days or ipsilateral ischemic stroke beyond 30 days through 2 years. Trial Registration: ClinicalTrials.gov Identifier: NCT01758614.

Endovascular treatment of acute ischemic stroke with a fully radiopaque retriever: A randomized controlled trial.

Objective: The Neurohawk retriever is a new fully radiopaque retriever. A randomized controlled non-inferiority trial was conducted to compare the Neurohawk and the Solitaire FR in terms of safety and efficacy. In order to evaluate the efficacy and safety of endovascular treatment in acute ischemic stroke (AIS) caused by intracranial atherosclerotic disease (ICAD) larger vessel occlusion (LVO), a sub-analysis was performed. Methods: Acute ischemic stroke patients aged 18-80 years with LVO in the anterior circulation were randomly assigned to undergo thrombectomy with either the Neurohawk or the Solitaire FR. The primary efficacy endpoint was successful reperfusion (mTICI 2b-3) rate by the allocated retriever. A relevant non-inferiority margin was 12.5%. Safety outcomes were symptomatic intracranial hemorrhage (sICH) and all-cause mortality within 90 days. Secondary endpoints included first-pass effect (FPE), modified FPE, and favorable outcomes at 90 days. In subgroup analysis, the patients were divided into the ICAD group and non-ICAD group according to etiology, and baseline characteristics, angiographic, and clinical outcomes were compared. Results: A total of 232 patients were involved in this analysis (115 patients in the Neurohawk group and 117 in the Solitaire group). The rates of successful reperfusion with the allocated retriever were 88.70% in the Neurohawk group and 90.60% in the Solitaire group (95%CI of the difference, -9.74% to 5.94%; p = 0.867). There were similar results in FPE and mFPE in both groups. The rate of sICH seemed higher in the Solitaire group (13.16% vs. 7.02%, p = 0.124). All-cause mortality and favorable outcome rates were comparable as well. In subgroup analysis, 58 patients were assigned to the ICAD group and the remaining 174 to the non-ICAD group. The final successful reperfusion and favorable outcome rates showed no statistically significant differences in two groups. Mortality within 90 days was relatively lower in the ICAD group (6.90% vs. 17.24%; p = 0.054). Conclusion: The Neurohawk retriever is non-inferior to the Solitaire FR in the mechanical thrombectomy of large vessel occlusion-acute ischemic stroke (LVO-AIS). The sub-analysis suggested that endovascular treatment including thrombectomy with the retriever and essential rescue angioplasty is effective and safe in AIS patients with intracranial atherosclerotic disease-larger vessel occlusion (ICAD-LVO). Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT04995757, number: NCT04995757.

Screening of potential gene markers for predicting carotid atheroma plaque formation using bioinformatics approaches.

The present study aimed to investigate potential gene markers for predicting the formation of carotid atheroma plaques using high­throughput bioinformatics methods. The GSE43292 gene expression profile was downloaded from the Gene Expression Omnibus database. Following data processing, differentially expressed genes (DEGs) were screened using a paired t­test in the Linear Models for Microarray Data package with the criteria of a false discovery rate of P<0.05 and |log2 fold­change| ≥0.58, followed by functional enrichment, protein­protein interaction (PPI) network construction, key node and module analysis, and prediction of transcription factors (TFs) targeting genes in the significant modules. The results revealed that the gene expression profiles from 32 paired samples of carotid atheroma plaque tissue and macroscopically intact tissue were obtained, based on which 886 DEGs, including 513 upregulated genes and 373 downregulated genes, were identified. The upregulated and downregulated gene sets were enriched in 24 and 13 pathways, respectively. The PPI network constructed with these DEGs comprised 35 key nodes with degrees ≥20, among which spleen tyrosine kinase (SYK), LYN and phosphatidylinositol­4,5­bisphosphate 3­kinase catalytic subunit Î³ (PIK3CG) were the three highest. A significant module was mined in the PPI network, which consisted of 29 DEGs targeted by 11 TFs. The DEGs between the carotid atheroma plaque and macroscopically intact tissue samples may be involved in carotid atherogenesis. Key nodes in the PPI network constructed from these DEGs and the genes involved in the significant module, including SYK, LYN and PIK3CG, are promising for the prediction of carotid plaque formation.

The Carotid and Middle cerebral artery Occlusion Surgery Study (CMOSS): a study protocol for a randomised controlled trial.

BACKGROUND: Patients with symptomatic internal carotid artery (ICA) or middle cerebral artery (MCA) occlusion with haemodynamic insufficiency are at high risk for recurrent stroke when treated medically. METHODS: The Carotid or Middle cerebral artery Occlusion Surgery Study (CMOSS) trial is an ongoing, government-funded, prospective, multicentre, randomised controlled trial. The CMOSS will recruit 330 patients with symptomatic ICA or MCA occlusion (parallel design, 1:1 allocation ratio) and haemodynamic insufficiency. Participants will be allocated to best medical treatment alone or best medicine plus extracranial-intracranial (EC-IC) bypass surgery. The primary outcome events are all strokes or deaths occurring between randomisation and 30 days post operation or post randomisation and ipsilateral ischaemic stroke within 2 years. Recruitment will be finished by December 2016. All the patients will be followed for at least 2 years. The trial is scheduled to complete in 2019. DISCUSSION: The CMOSS will test the hypothesis that EC-IC bypass surgery plus best medical therapy reduces subsequent ipsilateral ischaemic stroke in patients with symptomatic ICA or MCA occlusion and haemodynamic cerebral ischaemia. This manuscript outlines the rationale and the design of the study. CMOSS will allow for more critical reappraisal of the EC-IC bypass for selected patients in China. TRIAL REGISTRATION: NCT01758614 with ClinicalTrials.gov. Registered on 24 December 2012.

Reduced expression of microRNA-497 is associated with greater angiogenesis and poor prognosis in human gliomas.

MicroRNA (miR)-497 plays a tumor-suppressive role in several malignancies and is involved in glioma invasiveness and resistance to chemotherapy. To add to the knowledge of the clinical significance of miR-497 in human gliomas, quantitative real-time polymerase chain reaction was performed to detect the expression of miR-497 in 110 pairs of freshly prepared glioma and nonneoplastic brain tissues. Then the associations of miR-497 expression with various clinicopathological characteristics and overall survival of glioma patients were estimated statistically. Gain-of-function assays were also performed to examine the role of miR-497 in glioma angiogenesis. The expression of miR-497 in human glioma tissues was significantly lower than in nonneoplastic brain tissues (P<.001). In addition, low miR-497 expression was significantly associated with advanced World Health Organization grade (P<.001) and low Karnofsky performance scores (P=.02). Moreover, the survival of glioma patients with low miR-497 expression was dramatically shorter than that of patients with high miR-497 expression (P=.001). Forced expression of miR-497 in glioma cells inhibited tube formation by cocultured human brain microvascular endothelial cells. We also found that miR-497 overexpression in glioma cells led to decreased expression of vascular endothelial growth factor. In conclusion, miR-497 may be a favorable prognostic marker in human gliomas, in part by being a negative regulator of angiogenesis, implying its potential as a therapeutic target for this cancer.

Knockdown of FRAT1 expression by RNA interference inhibits human glioblastoma cell growth, migration and invasion.

BACKGROUND: FRAT1 positively regulates the Wnt/ß-catenin signaling pathway by inhibiting GSK-3-mediated phosphorylation of ß-catenin. It was originally characterized as a protein frequently rearranged in advanced T cell lymphoma, but has recently also been identified as a proto-oncogene involved in tumorigenesis. Our previous studies showed that FRAT1 was dramatically overexpressed in gliomas and its expression level was significantly increased along with clinicopathological grades. METHODS: In the current study, we used RT-PCR and Western blotting to assess the mRNA and protein levels of FRAT1 in three glioma cell lines. In addition, to evaluate its functional role in gliomas, we examined the effects of FRAT1 knockdown on proliferation, migration and invasion in vitro and tumor growth in vivo using glioblastoma U251 cells and RNAi. RESULTS: FRAT1 was highly expressed in all three glioma cell lines. RNAi-mediated down-regulation of endogenous FRAT1 in human glioblastoma U251 cells resulted in suppression of cell proliferation, arrest of cell cycle, inhibition of cell migration and invasion in vitro. Moreover, FRAT1 depletion significantly impaired tumor xenograft growth in nude mice. CONCLUSIONS: Our results highlight the potential role of FRAT1 in tumorigenesis and progression of glioblastoma. These findings provide a biological basis for FRAT1 as a potential molecular marker for improved pathological grading and as a novel candidate therapeutic target for glioblastoma management.