Identifying novel risk genes in intracranial aneurysm by integrating human proteomes and genetics.

Genome-wide association studies (GWAS) have become increasingly popular for detecting numerous loci associated with intracranial aneurysm (IA), but how these loci function remains unclear. In this study, we employed an integrative analytical pipeline to efficiently transform genetic associations and identify novel genes for IA. Using multidimensional high-throughput data, we integrated proteome-wide association studies (PWAS), transcriptome-wide association studies (TWAS), Mendelian randomization (MR) and Bayesian co-localization analyses to prioritize genes that can increase IA risk by altering their expression and protein abundances in the brain and blood. Moreover, single-cell RNA sequencing (scRNA-seq) of the circle of Willis was performed to enrich filtered genes in cells, and gene set enrichment analysis (GSEA) was conducted for each gene using bulk RNA-seq data for IA. No significant genes with cis-regulated plasma protein levels were proven to be associated with IA. The protein abundances of five genes in the brain were found to be associated with IA. According to cellular enrichment analysis, these five genes were expressed mainly in the endothelium, fibroblasts and vascular smooth muscle cells. Only three genes, CNNM2, GPRIN3 and UFL1, passed MR and Bayesian co-localization analyses. While UFL1 was not validated in confirmation PWAS as it was not profiled, it was validated in TWAS. GSEA suggested these three genes are associated with the cell cycle. In addition, the protein abundance of CNNM2 was found to be associated with IA rupture (based on PWAS, MR and co-localization analyses). Our findings indicated that CNNM2, GPRIN3 and UFL1 (CNNM2 correlated with IA rupture) are potential IA risk genes that may provide a broad hint for future research on possible mechanisms and therapeutic targets for IA.

Thrombectomy alone vs thrombectomy with over 2/3-dose intravenous thrombolysis pretreatment in the DIRECT-MT trial.

BACKGROUND: The DIRECT-MT trial showed that endovascular thrombectomy (EVT) alone was noninferior to EVT preceded by intravenous alteplase. However, the infusion of intravenous alteplase was uncompleted before the initiation of EVT in most cases of this trial. Therefore, the additional benefit and risk of over 2/3-dose intravenous alteplase pretreatment remain to be assessed. METHODS: We assessed patients with acute anterior circulation ischemic stroke who received EVT alone or with over 2/3-dose intravenous alteplase pretreatment from the DIRECT-MT trial. Patients were assigned to the thrombectomy-alone group and the alteplase pretreatment group. The primary outcome was the distribution of modified Rankin Scale (mRS) at 90 days. The interaction of treatment allocation and collateral capacity was assessed. RESULTS: A total of 393 patients (thrombectomy alone: 315; alteplase pretreatment: 78) were identified. The thrombectomy alone was comparable with alteplase pretreatment prior to the thrombectomy on the distribution of mRS at 90 days without significant effect modification by collateral capacity (adjusted common odds ratio (acOR), 1.12; 95% CI, 0.72-1.74; adjusted P for interaction = 0.83). Successful reperfusion before thrombectomy and the number of passes in the thrombectomy alone group differed significantly from the alteplase pretreatment group (2.6% vs. 11.5%; corrected P = 0.02 and 2 vs. 1; corrected P = 0.003). There was no interaction between treatment allocation and collateral capacity on all outcomes. CONCLUSIONS: EVT alone and EVT preceded by over 2/3-dose intravenous alteplase might have equal efficacy and safety for patients with acute anterior circulation large vessel occlusion, except for successful perfusion before thrombectomy and the number of passes.

Intensive blood pressure control after endovascular thrombectomy for acute ischaemic stroke (ENCHANTED2/MT): a multicentre, open-label, blinded-endpoint, randomised controlled trial.

BACKGROUND: The optimum systolic blood pressure after endovascular thrombectomy for acute ischaemic stroke is uncertain. We aimed to compare the safety and efficacy of blood pressure lowering treatment according to more intensive versus less intensive treatment targets in patients with elevated blood pressure after reperfusion with endovascular treatment. METHODS: We conducted an open-label, blinded-endpoint, randomised controlled trial at 44 tertiary-level hospitals in China. Eligible patients (aged ≥18 years) had persistently elevated systolic blood pressure (≥140 mm Hg for >10 min) following successful reperfusion with endovascular thrombectomy for acute ischaemic stroke from any intracranial large-vessel occlusion. Patients were randomly assigned (1:1, by a central, web-based program with a minimisation algorithm) to more intensive treatment (systolic blood pressure target <120 mm Hg) or less intensive treatment (target 140-180 mm Hg) to be achieved within 1 h and sustained for 72 h. The primary efficacy outcome was functional recovery, assessed according to the distribution in scores on the modified Rankin scale (range 0 [no symptoms] to 6 [death]) at 90 days. Analyses were done according to the modified intention-to-treat principle. Efficacy analyses were performed with proportional odds logistic regression with adjustment for treatment allocation as a fixed effect, site as a random effect, and baseline prognostic factors, and included all randomly assigned patients who provided consent and had available data for the primary outcome. The safety analysis included all randomly assigned patients. The treatment effects were expressed as odds ratios (ORs). This trial is registered at ClinicalTrials.gov, NCT04140110, and the Chinese Clinical Trial Registry, 1900027785; recruitment has stopped at all participating centres. FINDINGS: Between July 20, 2020, and March 7, 2022, 821 patients were randomly assigned. The trial was stopped after review of the outcome data on June 22, 2022, due to persistent efficacy and safety concerns. 407 participants were assigned to the more intensive treatment group and 409 to the less intensive treatment group, of whom 404 patients in the more intensive treatment group and 406 patients in the less intensive treatment group had primary outcome data available. The likelihood of poor functional outcome was greater in the more intensive treatment group than the less intensive treatment group (common OR 1·37 [95% CI 1·07-1·76]). Compared with the less intensive treatment group, the more intensive treatment group had more early neurological deterioration (common OR 1·53 [95% 1·18-1·97]) and major disability at 90 days (OR 2·07 [95% CI 1·47-2·93]) but there were no significant differences in symptomatic intracerebral haemorrhage. There were no significant differences in serious adverse events or mortality between groups. INTERPRETATION: Intensive control of systolic blood pressure to lower than 120 mm Hg should be avoided to prevent compromising the functional recovery of patients who have received endovascular thrombectomy for acute ischaemic stroke due to intracranial large-vessel occlusion. FUNDING: The Shanghai Hospital Development Center; National Health and Medical Research Council of Australia; Medical Research Futures Fund of Australia; China Stroke Prevention; Shanghai Changhai Hospital, Science and Technology Commission of Shanghai Municipality; Takeda China; Hasten Biopharmaceutic; Genesis Medtech; Penumbra.

Endovascular Thrombectomy with or without Intravenous Alteplase in Acute Stroke.

BACKGROUND: In acute ischemic stroke, there is uncertainty regarding the benefit and risk of administering intravenous alteplase before endovascular thrombectomy. METHODS: We conducted a trial at 41 academic tertiary care centers in China to evaluate endovascular thrombectomy with or without intravenous alteplase in patients with acute ischemic stroke. Patients with acute ischemic stroke from large-vessel occlusion in the anterior circulation were randomly assigned in a 1:1 ratio to undergo endovascular thrombectomy alone (thrombectomy-alone group) or endovascular thrombectomy preceded by intravenous alteplase, at a dose of 0.9 mg per kilogram of body weight, administered within 4.5 hours after symptom onset (combination-therapy group). The primary analysis for noninferiority assessed the between-group difference in the distribution of the modified Rankin scale scores (range, 0 [no symptoms] to 6 [death]) at 90 days on the basis of a lower boundary of the 95% confidence interval of the adjusted common odds ratio equal to or larger than 0.8. We assessed various secondary outcomes, including death and reperfusion of the ischemic area. RESULTS: Of 1586 patients screened, 656 were enrolled, with 327 patients assigned to the thrombectomy-alone group and 329 assigned to the combination-therapy group. Endovascular thrombectomy alone was noninferior to combined intravenous alteplase and endovascular thrombectomy with regard to the primary outcome (adjusted common odds ratio, 1.07; 95% confidence interval, 0.81 to 1.40; P = 0.04 for noninferiority) but was associated with lower percentages of patients with successful reperfusion before thrombectomy (2.4% vs. 7.0%) and overall successful reperfusion (79.4% vs. 84.5%). Mortality at 90 days was 17.7% in the thrombectomy-alone group and 18.8% in the combination-therapy group. CONCLUSIONS: In Chinese patients with acute ischemic stroke from large-vessel occlusion, endovascular thrombectomy alone was noninferior with regard to functional outcome, within a 20% margin of confidence, to endovascular thrombectomy preceded by intravenous alteplase administered within 4.5 hours after symptom onset. (Funded by the Stroke Prevention Project of the National Health Commission of the People's Republic of China and the Wu Jieping Medical Foundation; DIRECT-MT ClinicalTrials.gov number, NCT03469206.).

Treatment of intracranial bifurcation aneurysms with "X" stent-assisted coiling: A case series and literature review.

PURPOSE: To clarify the safety and efficacy of "X" stent-assisted coiling (X-stenting) for the treatment of intracranial bifurcation aneurysms and to review the literature. METHODS: We retrospectively reported five consecutive patients with six intracranial bifurcation aneurysms who underwent X-stenting between June 2014 and June 2020. The clinical and angiographic results were analyzed. We also performed an extensive PubMed review of medical literature up to June 2021. RESULTS: Endovascular procedures were successfully applied to all six aneurysms. No procedure-related complications were noted. Follow-up angiograms were available for all patients and revealed occlusion in five aneurysms and improvement in one aneurysm. Clinical follow-up was performed for all patients, and the mRS score at follow-up was 0 in all patients. Thus, good outcomes were achieved in all patients, and no ischemic or hemorrhagic events were observed. CONCLUSIONS: X-stenting appears to be safe for treating intracranial bifurcation aneurysms and effective in immediate and short-term outcome. Further research is required with well-designed, prospective studies with large sample sizes.

Association of Intravenous Alteplase, Early Reperfusion, and Clinical Outcome in Patients With Large Vessel Occlusion Stroke: Post Hoc Analysis of the Randomized DIRECT-MT Trial.

BACKGROUND: The added value of intravenous alteplase in reperfusing ischemic brain tissue in patients undergoing endovascular treatment and directly presented to an endovascular treatment-capable hospital is uncertain. We conducted this post hoc analysis of a randomized trial (DIRECT-MT [Direct Intraarterial Thrombectomy in Order to Revascularize Acute Ischemic Stroke Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals: A Multicenter Randomized Clinical Trial]) to explore the association of intravenous alteplase, early (preendovascular treatment) reperfusion, and clinical outcome and to determine factors which may modify alteplase treatment effect on early reperfusion. METHODS: In this post hoc analysis of the DIRECT-MT randomized trial comparing intravenous alteplase before endovascular treatment versus endovascular treatment only, 623 of 656 randomized patients, with adequate angiographic evaluation for early reperfusion assessment, were included. The association of intravenous alteplase and early reperfusion (defined as expanded Thrombolysis in Cerebral Infarction score ≥2a on angiogram) was assessed using unadjusted comparisons and multivariable logistic regression. RESULTS: Among 623 patients included (317 received intravenous alteplase and 306 did not), early reperfusion occurred in 91 (15%) patients and was associated with better functional outcome (modified Rankin Scale score, 0-2 of 49/91 [54%] versus 178/531 [34%]; adjusted odds ratio, 1.92 [95% CI, 1.15-3.21]; P<0.001). Intravenous alteplase was independently associated with early reperfusion (59/317 [19%] versus 32/306 [10%]; adjusted odds ratio, 2.06 [95% CI, 1.27-3.33]; P=0.003), and the alteplase effect was modified by time from randomization to groin puncture (dichotomized by median, ≤33 minutes; adjusted odds ratio, 1.06 [95% CI, 0.53-2.10] versus >33 minutes; adjusted odds ratio, 4.07 [95% CI, 1.86-8.86]; Pinteraction=0.012). CONCLUSIONS: For patients with large vessel occlusion directly presenting to an endovascular treatment-capable hospital, intravenous alteplase increases early reperfusion when endovascular treatment gets delayed more than approximately half an hour. Thus, intravenous alteplase should be considered if endovascular treatment delays are anticipated by the treating medical team. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03469206.

Effect of Occlusion Site on the Safety and Efficacy of Intravenous Alteplase Before Endovascular Thrombectomy: A Prespecified Subgroup Analysis of DIRECT-MT.

BACKGROUND AND PURPOSE: Recent trials showed thrombectomy alone was comparable to bridging therapy in patients with anterior circulation large vessel occlusion eligible for both intravenous alteplase and endovascular thrombectomy. We performed this study to examine whether occlusion site modifies the effect of intravenous alteplase before thrombectomy. METHODS: This is a prespecified subgroup analysis of a randomized trial evaluating risk and benefit of intravenous alteplase before thrombectomy (DIRECT-MT [Direct Intra-Arterial Thrombectomy in Order to Revascularize AIS Patients With Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals]). Among 658 randomized patients, 640 with baseline occlusion site information were included. The primary outcome was the score on the modified Rankin Scale at 90 days. Multivariable ordinal logistic regression analysis with an interaction term was used to estimate treatment effect modification by occlusion location (internal carotid artery versus M1 versus M2). We report the adjusted common odds ratio for a shift toward better outcome on the modified Rankin Scale after thrombectomy alone compared with combination treatment adjusted for age, the National Institutes of Health Stroke Scale score at baseline, the time from stroke onset to randomization, the modified Rankin Scale score before stroke onset, and collateral score per the DIRECT-MT statistical analysis plan. RESULTS: The overall adjusted common odds ratio was 1.08 (95% CI, 0.82-1.43) with thrombectomy alone compared with combination treatment, and there was no significant treatment-by-occlusion site interaction (P=0.47). In subgroups based on occlusion location, we found the following adjusted common odds ratios: 0.99 (95% CI, 0.62-1.59) for internal carotid artery occlusions, 1.12 (95% CI, 0.77-1.64) for M1 occlusions, and 1.22 (95% CI, 0.53-2.79) for M2 occlusions. No treatment-by-occlusion site interactions were observed for dichotomized modified Rankin Scale distributions and successful reperfusion (extended thrombolysis in Cerebral Infarction score ≥2b) before thrombectomy. Differences in symptomatic hemorrhage rate were not significant between occlusion locations (internal carotid artery occlusion: 7.02% in bridging therapy versus 7.14% for thrombectomy alone, P=0.97; M1 occlusion: 5.06% versus 2.48%, P=0.22; M2 occlusion: 9.09% versus 4.76%; P=0.78). CONCLUSIONS: In this prespecified subgroup of a randomized trial, we found no evidence that occlusion location can inform intravenous alteplase decisions in endovascular treatment eligible patients directly presenting at endovascular treatment capable centers. Future studies are needed to confirm our findings. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03469206.

Braided stents assisted coiling for endovascular management of posterior cerebral artery aneurysms: a preliminary mid-term experience.

PURPOSE: Posterior cerebral artery (PCA) aneurysms are rare. This study is to evaluate the preliminary experience of braided stents applied in PCA aneurysms treatment. METHODS: Angiographic and clinical data of 28 PCA patients treated with braided stents from July 2016 and September 2020 were retrospectively analyzed. RESULTS: A total of 28 PCA aneurysms were enrolled. 22 (78.6%) aneurysms were dissecting aneurysms, while 6 (21.4%) aneurysms were saccular aneurysms. Thirty-five braided stents were implanted with dual stents implanted in 7 cases. Immediate angiographic results show that Raymond class I was obtained in 13 patients (46.4%), Raymond class II was obtained in 4 patients (14.3%), and Raymond class III was obtained in 11 patients (39.3%). Perioperative hemorrhagic events occurred in 1 patient (3.6%). Twenty-four patients (85.7%) received angiographic follow-up, and the mean follow-up time was 11.2 ± 4.9 months. Two patients (8.3%) were confirmed with IA neck recurrence, and 3 patients (12.5%) were confirmed asymptomatic parent artery occlusion (PAO). The other 19 patients were confirmed promoted occlusion with 18 Raymond class I (75%) and 1 Raymond class II (4.2%). Twenty-seven patients (96.4%) received clinical follow-up, and the mean follow-up time was 32.2 ± 13.5 months. One patient (3.7%) confirmed the death event 2 weeks after discharge. The other 27 patients (96.3%) got favorable clinical outcomes with an mRS score of 0-2. CONCLUSIONS: Braided stent-assisted coiling with a high occlusion rate and relatively low complication rate provides an alternative strategy in treating PCA aneurysms. Long-term outcomes need further randomized study with larger case numbers.

The safety and efficacy of low-dosage tirofiban for stent-assisted coiling of ruptured intracranial aneurysms.

Stent-assisted coiling (SAC) of acutely ruptured aneurysms with antiplatelet therapy has been controversial. Tirofiban has been used for the treatment of thromboembolism of ruptured aneurysms with a stent. However, there are few comparative studies of a reasonable dosage for the prophylactic use of tirofiban. This study evaluated the safety and efficacy of reducing the dosage of tirofiban for the ruptured aneurysms with SAC. Patients with ruptured intracranial aneurysms in our institution from January 2014 to June 2018 were retrospectively reviewed. Three hundred and nine patients were treated using SAC within 72 h of onset. Patients were divided into either a standard group (211 patients, 10 µg/kg intravenous bolus within 3 min, maintained with 0.15 µg/kg/min) or a half-dose group (98 patients, 5 µg/kg intravenous bolus within 3 min, maintained with 0.075 µg/kg/min) according to the dose of tirofiban received intraoperatively. Medical records including clinical and radiological details were reviewed. No significant differences in demographic information or aneurysm characteristics existed between the two groups. Thromboembolic complications were found in 15 patients (4.9%), including 11 patients (5.2%) in the standard group and four patients (4.1%) in the half-dose group, without significant difference (P = 0.782). Intracranial hemorrhage was found in 13 patients (4.2%), and all occurred in the standard group, which was significantly different (6.2% vs 0%, P = 0.011). Of these 13 patients, four were left disabled and five died. Except for three patients who had intraoperative aneurysm rupture, the incidence of postoperative early rebleeding (10 patients) was significantly different between the two groups (4.7% vs 0%, P = 0.034). The rate of initial complete occlusion in the half-dose group was significantly higher than that in the standard group (55.1% vs 39.8%). The rate of a good outcome (modified Rankin Scale 0-2) was not significantly different between the standard group and half-dose group (78.7% vs 87.8%, P > 0.05). Intravenous tirofiban for SAC of acutely ruptured intracranial aneurysms is feasible and safe. The half-dose tirofiban treatment was associated with a decrease in the prevalence of intracranial hemorrhage but no increase in thromboembolic events compared with those in standard-dose tirofiban treatment.

Solitaire stents deployment may reduce ischemic events in staged angioplasty for severe carotid stenosis.

OBJECTIVES: Cerebral hyperperfusion syndrome is a fatal complication that can occur after stent angioplasty in patients with severe carotid artery stenosis. Staged angioplasty can prevent cerebral hyperperfusion syndrome. Conventional staged angioplasty consists of small balloon angioplasty in the first stage and carotid artery stenting in the second stage two to four weeks later. Sometimes, antegrade flow during stage 1 could hardly be maintained and stent will be needed. Solitaire stents were used in some patients in our center. This study aimed to examine the safety and effectiveness of Solitaire stents in staged angioplasty. METHODS: A retrospective analysis was performed on patients with severe carotid artery stenosis and preoperative computed tomography perfusion indicating risk of cerebral hyperperfusion syndrome from 2011 to 2018. Small balloon angioplasty (<3 mm in diameter) only was performed in stage 1 (group 1). If antegrade flow during stage 1 is compromised, then a solitaire stent is deployed (group 2). After two to four weeks, cerebral angiography was undertaken in both groups to determine whether to perform stage 2. If the residual stenosis was more than 50%, carotid artery stenting was deployed. Angiographic results, clinical results, and follow-up results were collected and analyzed. RESULTS: Twenty-five patients were included in the study (group 1, n = 19; group 2, n = 6). After stage 1, no patient in group 2 and two patients in group 1 developed new symptomatic cerebral infarction (0.0% vs. 10.5%, p = 1.000). One patient in group 2 and three patients in group 1 (16.7% vs. 15.8%, p = 1.000) developed symptomatic cerebral hyperperfusion syndrome. One patient in group 2 (n = 4) and three patients in group 1 (n = 12) (25% vs. 25%, p = 1.000) developed hyperperfusion phenomenon. Two patients in group 2 and five patients in group 1 (33.3% vs. 26.3%, p = 1.000) developed symptomatic cerebral hyperperfusion syndrome or hyperperfusion phenomenon. One patient in group 1 developed symptomatic cerebral hyperperfusion syndrome and hyperperfusion phenomenon. After stage 2, no new cerebral infarction occurred in both groups. No patient in group 2 (n = 3) and one patient in group 1 (n = 17) developed symptomatic cerebral hyperperfusion syndrome (0.0% vs. 5.9%, p = 1.000). In the combined analysis of both stages, two patients (10.5%) developed new symptomatic cerebral infarction and four patients (21.1%) developed symptomatic cerebral hyperperfusion syndrome in group 1, no patient (0.0%) developed symptomatic cerebral infarction and one patient (16.7%) developed symptomatic cerebral hyperperfusion syndrome in group 2. There was no significant difference in symptomatic cerebral infarction and symptomatic cerebral hyperperfusion syndrome between the two groups (p = 1.000; p = 1.000). Three patients in group 2 and 17 patients in group 1 (50% vs. 89.5%, p = 0.070) underwent stage 2 angioplasty. No cerebral hemorrhage or cerebral infarction occurred in the Solitaire group during the one-year follow-up period. CONCLUSIONS: Solitaire stents deployment may reduce ischemic events in staged angioplasty for severe carotid stenosis.

The development and understanding of intracranial aneurysm based on rabbit model.

In modern society, intracranial aneurysms have seriously affected people's life. To better study and treat intracranial aneurysm, animal models are ideal candidates to perform biological research and preclinical endovascular device testing. Rabbit aneurysm model is one of the most commonly used animal models, and the rabbit aneurysms share similarities in histology, morphology, and hemodynamic aspects with human intracranial aneurysms, which is an ideal model for intracranial aneurysm pre-clinical and basic research. In this review, we will summarize the main methods of establishing rabbit aneurysms model and will further discuss the current biological mechanisms of intracranial aneurysms based on rabbit model. Further improvements of rabbit aneurysm model and more deep studies based on this model are needed to provide new insights into studying and clinical treating intracranial aneurysm.

The "distal-to-proximal" strategy for the treatment of posterior circulation tandem occlusions: a single-centre experience.

PURPOSE: Data on posterior circulation tandem occlusions in acute ischemic stroke are scarce: recognition may be challenging and little is known about optimal treatment strategy. We report our endovascular treatment strategy for posterior circulation tandem occlusion. METHODS: Consecutive patients with posterior circulation tandem occlusions in our centre were enrolled retrospectively. The preferred strategy was "distal-to-proximal" strategy, which means opening the distal occlusion first followed by treatment of the proximal pathology. The imaging characteristics, treatment strategy, clinical outcomes, and complications of patients with posterior circulation tandem occlusions were analyzed. RESULTS: In total, 21 patients with posterior circulation tandem occlusions were enrolled in the study, which accounted for 23.6% of patients with posterior circulation stroke in our centre. The mean age was 60 years (range 32 to 80), and median pre-procedure NIHSS score was 28 (interquartile range: 13-31). Eighteen patients (85.7%) had vertebrobasilar artery tandem occlusions and 3 (14.3%) had basilar artery to basilar artery tandem occlusions. All distal occlusions were successfully recanalized (modified TICI 2b/3). Two (9.5%) of the proximal lesions were not treated. A total of 57.1% of the patients had stents implanted on the proximal occlusions. The rate of mRS 0-3 at 3 months was 57.1% and the mortality rate was 19.0%. CONCLUSION: In patients with acute ischaemic stroke caused by posterior circulation tandem occlusions, we favor "distal-to-proximal" strategy based on the positive results in this small series. Nevertheless, a more extensive study is required to explore the optimal treatment strategy further.

Feasibility and midterm outcomes of endovascular embolization for true posterior communicating artery aneurysms.

PURPOSE: Endovascular treatment (EVT) of true posterior communicating artery (PcomA) aneurysms has been rarely reported. This study reports the outcomes on a single-center cohort with true PcomA aneurysms who underwent EVT. METHODS: Between June 2011 and June 2017, clinical data from 42 patients with 43 true PcomA aneurysms who underwent EVT were retrieved from a prospectively maintained single-center database. Endovascular techniques, perioperative complications, clinical outcomes, and angiographic results were retrospectively evaluated. RESULTS: All aneurysms were treated successfully. Treatment modalities included simple coiling in 30 aneurysms, balloon-assisted coiling in two, and stent-assisted coiling in 11 cases. Immediate angiograms showed complete occlusion in 23 aneurysms (53.5%), residual neck in 8 cases (18.6%), and residual sac in 12 (27.9%). No procedure-related complications or mortality were observed. Of the 34 aneurysms that underwent angiographic follow-up at an average duration of 7.1 months post-procedure, complete occlusion was achieved in 22 (64.7%), neck remnant in eight (23.5%), and residual sac in four (11.8%) aneurysms, respectively. Six aneurysms (18.2%) that underwent conventional coiling developed recanalization and required retreatment. Seven cases that received stent-assisted coiling did not develop recurrence. Clinical follow-up (mean, 24.3 months) of all patients demonstrated no neurologic deterioration or (re)bleeding. CONCLUSION: EVT of the true PcomA aneurysm is a safe and feasible procedure but may be associated with recurrence in midterm follow-up, requiring close surveillance and potential retreatment.

Two Closely Spaced Aneurysms of the Supraclinoid Internal Carotid Artery: How Does One Influence the Other?

The objective of this study was to use image-based computational fluid dynamics (CFD) techniques to analyze the impact that multiple closely spaced intracranial aneurysm (IAs) of the supra-clinoid segment of the internal carotid artery (ICA) have on each other's hemodynamic characteristics. The vascular geometry of fifteen (15) subjects with 2 IAs was gathered using a 3D digital subtraction angiography clinical system. Two groups of computer models were created for each subject's vascular geometry: both IAs present (model A) and after removal of one IA (model B). Models were separated into two groups based on IA separation: tandem (one proximal and one distal) and adjacent (aneurysms directly opposite on a vessel). Simulations using a pulsatile velocity waveform were solved by a commercial CFD solver. Proximal IAs altered flow into distal IAs (5 of 7), increasing flow energy and spatial-temporally averaged wall shear stress (STA-WSS: 3-50% comparing models A to B) while decreasing flow stability within distal IAs. Thus, proximal IAs may "protect" a distal aneurysm from destructive remodeling due to flow stagnation. Among adjacent IAs, the presence of both IAs decreased each other's flow characteristics, lowering WSS (models A to B) and increasing flow stability: all changes statistically significant (p < 0.05). A negative relationship exists between the mean percent change in flow stability in relation to adjacent IA volume and ostium area. Closely spaced IAs impact hemodynamic alterations onto each other concerning flow energy, stressors, and stability. Understanding these alterations (especially after surgical repair of one IA) may help uncover risk factor(s) pertaining to the growth of (remaining) IAs.

Discovery of Centrosomal Protein 70 as an Important Player in the Development and Progression of Breast Cancer.

Centrosome abnormalities have been implicated in the development and progression of breast cancer. However, the molecular players involved in the above processes remain largely uncharacterized. Herein, we identify centrosomal protein 70 (Cep70) as an important factor that mediates breast cancer growth and metastasis. Cep70 is up-regulated in breast cancer tissues and cell lines, and its expression is closely correlated with several clinicopathologic variables associated with breast cancer progression. Mechanistic studies reveal that the up-regulation of Cep70 in breast cancer occurs at the mRNA level and is independent of gene amplification. Cep70 promotes breast cancer cell proliferation and colony formation in vitro and increases tumor growth in mice. In addition, Cep70 stimulates breast cancer cell migration and invasion in vitro. Bioluminescence imaging analysis further shows that Cep70 enhances breast cancer lung metastasis in mice. Together, these results demonstrate a critical role for Cep70 in the development and progression of breast cancer and have important implications in the diagnosis and therapy of this malignancy.

Stromal cell-derived factor 1α facilitates aneurysm remodeling in elastase-induced rabbit saccular aneurysm.

AIMS: Inflammation plays a crucial role in aneurysm wall remodeling, which could lead to the rupture of intracranial aneurysms. Stromal cell-derived factor 1α (SDF-1α), a vital inflammation cytokine, is also related to aneurysm pathogenesis. However, the characteristics of SDF-1α expression and its role in aneurysm remodeling remain largely unknown. In this study, we aimed to investigate the expression dynamics of SDF-1α and its correlation with aneurysm remodeling. METHODS: Saccular aneurysms were induced by porcine pancreatic elastase in New Zealand White rabbits. Aneurysm size was measured by digital subtraction angiography. Endothelial-like cells on the aneurysm wall were assessed on postoperative days 1, 3, 7, 14, 21, and 30. SDF-1α levels in the aneurysmal wall and serum were examined at several follow-up time points. Adherent molecule expression was examined, and migration assays were performed in vitro. After SDF-1α stimulation, the mobilization of endothelial-lineage cells and its role in the reendothelialization of the aneurysm wall were investigated in a saccular aneurysm rabbit model. RESULTS: After the creation of saccular aneurysms in rabbits, the aneurysm sacs were filled with acute thrombosis within 3days, followed by a significant enlargement on day 14 and maturation on day 21. Serum SDF-1α levels increased in a bimodal fashion on day 1 and day 14, whereas SDF-1α expression in the aneurysm wall reached its maximum on day 14. VE-cadherin was up-regulated after SDF-1α stimulation and down-regulated by the SDF-1α ligand blocker AMD3100. Endothelial progenitor cell migration was enhanced by SDF-1α and blocked by AMD3100. The in vivo administration of SDF-α to rabbits with saccular aneurysms promoted endothelial-lineage cell mobilization into the peripheral blood and reendothelialization of the aneurysm wall. CONCLUSIONS: The SDF-1α expression level in the peripheral blood and local aneurysm wall correlated with the aneurysm remodeling process in rabbits with elastase-induced saccular aneurysms. We conclude that SDF-1α may facilitate aneurysm wall remodeling by up-regulating VE-cadherin expression and mobilizing endothelial-lineage cells.

Recombinant human SDF-1α administration accelerates aneurysm neck reendothelialization in rabbit saccular aneurysm after flow diverter treatment.

Reendothelialization in the aneurysm neck is pivotal to vascular repair for intracranial aneurysm after flow diverter (FD) implantation. Recombinant human stromal cell-derived factor 1α (rhSDF-1α) is a vital chemoattractant to stem cells and potentially facilitates reendothelialization. Here, we sought to investigate the therapeutic effects of intravenous administration of rhSDF-1α and uncover its potential mechanism for promoting aneurysm neck reendothelialization. Recombinant pET32a-186 plasmid was transformed into Escherichia coli to produce the rhSDF-1α protein with biological activity. FD was implanted into the elastase-induced saccular aneurysm in New Zealand white rabbits. rhSDF-1α (50 µg/kg/day) was intravenously administrated for consecutive 7 days after FD implantation. After these procedures, aneurysms were harvested after 2 or 4 weeks. Scanning electron microscopy was used to measure the neointima thickness and count the endothelial-like cells at aneurysm neck. Four weeks later, the mRNA levels of endothelial markers in the neointima at aneurysm neck were examined. Migration assay showed that rhSDF-1α could induce migration of endothelial progenitor cells in a dose-dependent manner. Two weeks after stent implantation, follow-up angiography showed partial aneurysm occlusion in one of each group and total aneurysm occlusion in 17 saccular aneurysm rabbits (9 of the rhSDF-1α group and 8 of the control group). No significant change of neointima thickness at aneurysm neck was observed. Intriguingly, more endothelial-like cells were observed at aneurysm neck in the rhSDF-1α group at 2 weeks (55 vs 13 cells per high-power field) and 4 weeks (104 vs 60 cells per high-power field). The mRNA levels of Tie-2, VE-cadherin, KDR and E-selectin were significantly enhanced compared with those of the control group. These results showed that intravenous administration of rhSDF-1α can accelerate reendothelialization in the aneurysm neck after FD implantation. Our study reveals an important role of rhSDF-1α in inducing aneurysm occlusion and suggests that it achieves its function through modulating the reendothelialization.

Centrosomal Protein 70 Is a Mediator of Paclitaxel Sensitivity.

Centrosome aberrations have been implicated in the development and progression of breast cancer. Our previous worked show that centrosomal protein 70 (Cep70) regulates breast cancer growth and metastasis. However, it remains elusive whether Cep70 is implicated in the sensitivity of the anti-microtubule drug paclitaxel in breast cancer. Here we provide evidence that Cep70 is a mediator of paclitaxel sensitivity in breast cancer. Cell proliferation assays show that Cep70 expression correlates with paclitaxel sensitivity in breast cancer cell lines. In addition, paclitaxel sensitivity varies when altering Cep70 expression level. Mechanistic studies reveal that Cep70 interacts with tubulin, and promotes the ability of paclitaxel to stimulate microtubule assembly. These data demonstrate that Cep70 mediates paclitaxel sensitivity in breast cancer.

Comparison of the flow diverter and stent-assisted coiling in large and giant aneurysms: safety and efficacy based on a propensity score-matched analysis.

OBJECTIVES: The flow diverter (FD) is a device aimed at reconstructing the parent artery and occluding an aneurysm. We performed a propensity score-matched analysis to compare safety and efficacy between the FD and stent-assisted coiling. METHODS: A database review was conducted to identify patients with large and giant unruptured aneurysms (aneurysms located in the ACA, MCA, or PCA were excluded) treated with the FD or stent-assisted coiling. A propensity score, representing the probability of using the FD, was generated for each aneurysm using the relevant patient and aneurysmal variables. Angiographic results, complications, and clinical outcomes were compared. RESULTS: Forty-five aneurysms treated with the FD (FD alone: 32; FD+Coils: 13) and 45 treated with stent-assisted coiling were matched. The rate of complete occlusion was significantly (P = 0.0002) higher in the FD cohort than the conventional stent cohort at the 6-month follow-up. The FD cohort achieved greater improvement (P < 0.0001) and a lower rate of recurrence (P = 0.0001). The rate of periprocedural complications was similar, as was the proportion of patients who attained mRS ≤ 2 at discharge and at the 6-month follow-up. CONCLUSIONS: Our findings provide reliable evidence demonstrating that the FD may be a preferred treatment option for large and giant unruptured aneurysms. KEY POINTS: • Flow Diverter provided a higher complete occlusion rate at 6-month follow-up. • Flow Diverter achieved more progress occlusion and less recurrence. • Compared with the conventional stents, procedure-related morbidity of Flow Diverter was similar. • Flow Diverter is a preferred treatment for large and giant unruptured aneurysms.

Stepwise stent deployment technique for tandem intracranial aneurysms: a review of 21 cases.

OBJECTIVES: We performed this study to report our experience using a stepwise stent deployment technique for the treatment of tandem intracranial aneurysms. METHODS: Patients with intracranial tandem aneurysms that were treated with a stepwise stent deployment technique between May 2009 and June 2013 were retrospectively reviewed. RESULTS: Twenty-one patients with 42 tandem aneurysms were identified (11 men, 10 women), with a mean age of 53.7 years (range, 17-82 years). Subarachnoid haemorrhage was confirmed in 12 patients using computed tomography at onset. Complete occlusion was achieved in 20 of the aneurysms (47.6%) after the procedure, neck remnant in 9 (21.4%), and aneurysm remnant in 13 (31.0%). The perioperative complications included in-stent thrombosis in one case and vasospasm in two cases, none of which left a permanent neurological deficit. The modified Rankin Scale (mRS) score at discharge was 0-2 in 20 cases and 3 in one case. The follow-up angiograms available for 17 patients showed complete occlusion in 26 aneurysms, improved in 4, and stable in 4. All of the patients had mRS scores of 0-1 during the clinical follow-up period. CONCLUSIONS: The stepwise stent deployment technique is feasible and helpful in the treatment of intracranial tandem aneurysms. KEY POINTS: • Treating wide-necked intracranial aneurysms with stent-assisted coiling is preferable. • Tandem wide-necked intracranial aneurysms can be treated with a single stent. • Stepwise stent deployment is technically feasible for embolizing tandem intracranial aneurysms.