OBJECTIVE:To evaluate the effectiveness and safety of sonolysis using a low intensity 2 MHz pulsed wave ultrasound beam during carotid endarterectomy. DESIGN:Multicentre, phase 3, double blind, randomised controlled trial. SETTING:16 European centres. PARTICIPANTS:1004 patients (mean age 68 years; 312 (31%) female) were enrolled in the study between 20 August 2015 and 14 October 2020 until the interim analysis was performed. INTERVENTIONS:Sonolysis (n=507) versus sham procedure (n=497). MAIN OUTCOME MEASURES:The primary endpoint was the composite incidence of ischaemic stroke, transient ischaemic attack, and death within 30 days. The incidence of new ischaemic lesions on follow-up brain magnetic resonance imaging was the main substudy endpoint, and incidence of intracranial bleeding was the main safety endpoint. RESULTS:The results favoured the sonolysis group for the primary endpoint (11 (2.2%) v 38 (7.6%); risk difference -5.5%, 95% confidence interval (CI) -8.3% to -2.8%; P<0.001), as well as in the substudy for magnetic resonance imaging detected new ischaemic lesions (20/236 (8.5%) v 39/224 (17.4%); risk difference -8.9%, -15% to -2.8%; P=0.004). Sensitivity analysis resulted in a risk ratio for sonolysis of 0.25 (95% CI 0.11 to 0.56) for ischaemic stroke and 0.23 (0.07 to 0.73) for transient ischaemic attack within 30 days. Sonolysis was found to be safe, and 94.4% of patients in the sonolysis group were free from serious adverse events 30 days after the procedure. CONCLUSION:Sonolysis was safe for patients undergoing carotid endarterectomy and resulted in a significant reduction in the composite incidence of ischaemic stroke, transient ischaemic attack, and death within 30 days. TRIAL REGISTRATION:Clinicaltrials.gov NCT02398734.

Background: Carotid plaque composition plays a key role in plaque stability and patient risk stratification. Of unstable plaque features, intraplaque hemorrhage (IPH) is considered the main risk factor for stroke development. Aims: We aimed to assess an association between the presence of IPH and other plaque characteristics detectable by computed tomography (CT) or magnetic resonance imaging (MRI) and stroke. Material and methods: Of all consecutive patients from the ANTIQUE study, 132 (91 males; aged 70.0 [8.6] years) with 59 symptomatic and 157 asymptomatic stable carotid plaques were included in the retrospective analysis of prospectively collected data. Plaques in the vascular territory of ischemic stroke within 90 days were classified as symptomatic and were diagnosed by CT and MRI after symptoms occurred. Plaques without progression and clinical infarction were classified as asymptomatic stable. Univariate and multivariate logistic regression analyses were performed to identify risk factors. Results: The presence, age, location, and volume of IPH were not related to stroke risk (P >0.05). Patients with symptomatic plaque were more likely to consume alcohol (P = 0.005), had more severe stenosis (CT median: 80% vs. 72%; P = 0.005; MRI median: 79% vs. 72%; P = 0.01), lower American Heart Association grade (P = 0.03), and more frequent lipid plaque (89.8% vs. 76.4%; P = 0.04) compared to patients with asymptomatic stable plaques. Stenosis severity (odds ratio [OR], 1.037; 95% CI, 1.015-1.059) and additionally alcohol consumption (OR, 3.571; 95% CI, 1.694-7.527) were found to be the only significant predictors of a recent stroke. Conclusions: In this cohort, no IPH or other plaque characteristics were associated with stroke risk. The degree of stenosis and alcohol consumption were the only factors associated with ipsilateral stroke. Larger prospective studies considering plaque characteristics are needed.

BACKGROUND AND OBJECTIVES:Endovascular treatment of cerebral aneurysms has tremendously advanced over the past decades. Nevertheless, aneurysm residual and recurrence remain challenges after embolization. The objective of this study was to elucidate the portion of embolized aneurysms requiring open surgery and evaluate whether newer endovascular treatments have changed the need for open surgery after failed embolization. METHODS:All 15 cerebrovascular centers in Austria and the Czech Republic provided overall aneurysm treatment frequency data and retrospectively reviewed consecutive cerebral aneurysms treated with open surgical treatment after failure of embolization from 2000 to 2022. All endovascular modalities were included. RESULTS:On average, 1362 aneurysms were treated annually in the 2 countries. The incidence increased from 0.006% in 2005 to 0.008% in 2020 in the overall population. Open surgery after failed endovascular intervention was necessary in 128 aneurysms (0.8%), a proportion that remained constant over time. Subarachnoid hemorrhage was the initial presentation in 70.3% of aneurysms. The most common location was the anterior communicating artery region (40.6%), followed by the middle cerebral artery (25.0%). The median diameter was 6 mm (2-32). Initial endovascular treatment included coiling (107 aneurysms), balloon-assist (10), stent-assist (4), intrasaccular device (3), flow diversion (2), and others (2). Complete occlusion after initial embolization was recorded in 40.6%. Seventy-one percent of aneurysms were operated within 3 years after embolization. In 7%, the indication for surgery was (re-)rupture and, in 88.3%, reperfusion. Device removal was performed in 16.4%. Symptomatic intraoperative and postoperative complications occurred in 10.2%. Complete aneurysm occlusion after open surgery was achieved in 94%. CONCLUSION:Open surgery remains a rare indication for cerebral aneurysms after failed endovascular embolization even in the age of novel endovascular technology, such as flow diverters and intrasaccular devices. Regardless, it is mostly performed for ruptured aneurysms initially treated with primary coiling that are in the anterior circulation.

Background: This study investigates changes in cognitive function in patients with severe carotid stenosis who underwent carotid endarterectomy (CEA) and carotid stenting (CAS) over two decades. Methods: We compared cognitive function within 30 days after the procedure in 267 patients (first 100 each for CEA and CAS in two periods: 2008–2012 and 2018–2022) in a single institution. Assessments used Adenbrooke’s Cognitive Examination–Revised (ACE-R), the Mini-Mental State Examination (MMSE), Speech Fluency Test (SFT), and Clock Drawing Test (CDT), conducted before and 30 ± 2 days after surgery. Results: Patients (mean age 67.2 years, 70%+ carotid stenosis) exhibited different cognitive changes over periods. In 2008–2012, significant declines in MMSE (CEA, p = 0.049) and CDT (CAS, p = 0.015) were observed among asymptomatic patients. On the contrary, in 2018–2022, improvements were observed in ACE-R and MMSE for symptomatic and asymptomatic patients undergoing CEA and CAS. Conclusion: Over a decade, advances in interventional techniques and patient management have reduced risks of cognitive decline in patients with asymptomatic carotid stenosis and also have improved cognitive functions in both symptomatic and asymptomatic individuals.

Background and aim In-stent restenosis (ISR) belongs to an infrequent but potentially serious complication after carotid angioplasty and stenting in patients with severe carotid stenosis. Some of these patients might be contraindicated to repeat percutaneous transluminal angioplasty with or without stenting (rePTA/S). The purpose of the study is to compare the safety and effectiveness of carotid endarterectomy with stent removal (CEASR) and rePTA/S in patients with carotid ISR. Methods Consecutive patients with carotid ISR (≥80%) were randomly allocated to the CEASR or rePTA/S group. The incidence of restenosis after intervention, stroke, transient ischaemic attack myocardial infarction and death 30 days and 1 year after intervention and restenosis 1 year after intervention between patients in CEASR and rePTA/S groups were statistically evaluated. Results A total of 31 patients were included in the study; 14 patients (9 males; mean age 66.3±6.6 years) were allocated to CEASR and 17 patients (10 males; mean age 68.8±5.6 years) to the rePTA/S group. The implanted stent in carotid restenosis was successfully removed in all patients in the CEASR group. No clinical vascular event was recorded periproceduraly, 30 days and 1 year after intervention in both groups. Only one patient in the CEASR group had asymptomatic occlusion of the intervened carotid artery within 30 days and one patient died in the rePTA/S group within 1 year after intervention. Restenosis after intervention was significantly greater in the rePTA/S group (mean 20.9%) than in the CEASR group (mean 0%, p=0.04), but all stenoses were <50%. Incidence of 1-year restenosis that was ≥70% did not differ between the rePTA/S and CEASR groups (4 vs 1 patient; p=0.233). Conclusion CEASR seems to be effective and save procedures for patients with carotid ISR and might be considered as a treatment option. Trial registration number NCT05390983 .

Background and objectivesCerebrospinal fluid (CSF) leakage is a significant complication in cranial and spinal interventions.Hemostatic patches such as Hemopatch ® are therefore used to support the watertight closure of the dura mater.Recently, we published the results of a large registry documenting the effectiveness and safety of Hemopatch ® in various surgical specialties, including neurosurgery.Here we aimed to analyze the outcomes from the neurological/spinal cohort of this registry in more detail. MethodsBased on the data from the original registry, we performed a post hoc analysis for the neurological/spinal cohort.The Hemopatch ® registry was designed as a prospective, multicenter, single-arm observational study.All surgeons were familiar with the application of Hemopatch ® and it was used at the discretion of the responsible surgeon.The neurological/spinal cohort was open for patients of any age if they had received Hemopatch ® during an open or minimally invasive cranial or spinal procedure.Patients with known hypersensitivity to bovine proteins or brilliant blue, intraoperative pulsatile severe bleeding, or an active infection at the potential target application site (TAS) were excluded from the registry.For the posthoc evaluation, we stratified the patients of the neurological/spinal cohort into two sub-cohorts: cranial and spinal.We collected information about the TAS, intraoperative achievement of watertight closure of the dura, and occurrence of postoperative CSF leaks. ResultsThe registry comprised 148 patients in the neurological/spinal cohort when enrolment was stopped.The dura was the application site for Hemopatch ® in 147 patients (in one patient in the sacral region after tumor excision), of which 123 underwent a cranial procedure.Twenty-four patients underwent a spinal procedure.Intraoperatively, watertight closure was achieved in 130 patients (cranial sub-cohort: 119; spinal subcohort: 11).Postoperative CSF leakage occurred in 11 patients (cranial sub-cohort: nine; spinal sub-cohort: two).We observed no serious adverse events related to Hemopatch ® . ConclusionOur post hoc analysis of real-world data from a European registry confirms the safe and effective use of Hemopatch ® in neurosurgery, including cranial and spinal procedures, as also observed in some case series.

Introduction The prognosis of glioblastoma remains unfavorable. TTFields utilize low intensity electric fields (frequency 150–300 kHz) that disrupt cellular processes critical for cancer cell viability and tumor progression. TTFields are delivered via transducer arrays placed on the patients’ scalp. Methods: Between the years 2004 and 2022, 55 patients (20 female), aged 21.9–77.8 years (mean age 47.3±11.8 years; median 47.6 years) were treated with TTFields for newly-diagnosed GBM, and compared to 54 control patients (20 females), aged 27.0–76.7 years (mean age 51.4±12.2 years; median 51.7 years) (p=0.08). All patients underwent gross total or partial resection of GBM. One patient had biopsy only. When available, MGMT promoter methylation status and IDH mutation was detected. Results Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.64, p=0.031; and 0.61, p=0.028 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 19.75 months. Seven patients with TTFields usage ≤60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 12.45 months. Median OS of TTF patients was 31.67 months compared to 24.80 months for controls. Discussion This is the most extensive study on newly-diagnosed GBM patients treated with TTFields, covering a period of 18 years at a single center and presenting not only data from clinical trials but also a group of 36 patients treated with TTFields as a part of routine clinical practice.

Objectives: The morphology and histological structure of the atherosclerotic plaque seem critical to its stability. Our study aimed to identify the epidemiological, morphological and histological parameters associated with stable and unstable plaques. Materials and Methods: The study included 280 plaques harvested from 269 consecutive patients. Epidemiological and demographic data were recorded as well as the histological features of plaque, i.e. calcifications, myxoid changes, bleeding into plaque, presence of thrombus, inflammation, macrophages, giant cell reaction, siderophages, neovascularization and plaque ossification. All specimens were classified according to the American Heart Association (AHA). Results: Monofactorial analysis identified three significant histological predictors for the symptomatic plaque: a plaque with a large necrotic core (odds ratio, OR=2.0, p = 0.03), thrombosis (OR=3.7, p = 0.01) and the formation of foamy macrophages (OR=2.0, p = 0.01). Multifactorial logistic regression revealed that the presence of foamy macrophages (OR=1.9, p = 0.03) and thrombosis (OR=3.5, p = 0.02) were significant predictors of symptomatic stenosis. Symptomatic plaques were significantly more frequently classified as AHA type VI than AHA type IV-V compared to asymptomatic ones (OR=1.8, p = 0.03). Conclusions: Our study shows that no single histological feature, except for the presence of foamy macrophages and thrombosis on the plaque, is predictive of plaque instability. Rather, a complex plaque structure (AHA type VI) is predictive of plaque instability. Our findings should be kept in mind during the assessment of non-invasive imaging and stroke risk estimation.

Surgical procedures are often impeded by bleeding and/or leakage of body fluids. These complications cannot always be resolved by conventional surgical techniques. Hemopatch® is a hemostatic patch that also functions as a sealant. Here we document the effectiveness and safety of Hemopatch® for routine procedures of multiple surgical disciplines. To this end, we performed a prospective, multicenter, single-arm, observational registry study. Patients were eligible if they had received Hemopatch® during an open or minimally invasive procedure in one of these specialties: hepatobiliary, cardiovascular, urological, neurological/spinal, general, or lung surgery. Patients were excluded if they had a known hypersensitivity to bovine proteins or brilliant blue, intraoperative pulsatile or severe bleeding and/or infection at the target application site (TAS). The primary endpoint for intraoperative effectiveness was hemostasis assessed as the percentage of patients achieving hemostasis within 2 min and the percentage of patients achieving hemostasis without re-bleeding at the time of surgical closure. The registry enrolled 621 patients at 23 study sites in six European countries. Six hundred twenty patients had completed follow-up information. Hemostasis within 2 min was achieved at 463 (74.5%) of all 621 TASs. Hemostasis without re-bleeding was observed at 620 (99.8%) TASs. Adverse events were reported in 64 patients (10.3%). This Hemopatch® registry shows that Hemopatch® efficiently establishes hemostasis and sealing in a variety of surgical specialties, including minimally invasive procedures. Furthermore, we provide evidence for the safety of Hemopatch® across all the specialties included in the registry. This study is registered at clinicaltrials.gov: NCT03392662.

Despite considerable progress in the management of many malignant tumors, the prognosis of the most malignant primary brain tumor, GBM, remains unfavorable. TTFields utilize low intensity electric fields with intermediate frequency (100–500 kHz) that act as an antimitotic, selectively inhibiting growth of rapidly dividing tumor cells by disrupting multiple phases of the cell cycle (metaphase, anaphase, and telophase) resulting in cellular apoptosis. TTFields are delivered via arrays of transducers placed on the patients’ scalp. Between 2004 and August 2021, 54 patients (KPS ≥, 20 female), aged 21.85–77.77 years (mean age 47.41 ± 11.92 years; median 47.88 years) were treated with TTFields for ndGBM, and compared to 52 control patients (15 females); aged 27.03–76.67 years (mean age 51.38 ± 12.55 years; median 51.74 years. All patients from both groups underwent gross total or partial resection of GBM. When available, MGMT promoter methylation status was comparable in both groups. The most frequent AE from TTFields therapy was skin irritation at the array site that usually responded to local corticosteroid application. Patients on TTFields therapy demonstrated improvements in PFS and OS relative to controls (hazard ratio: 0.55, p=0.006; and 0.61, p=0.027 respectively). TTFields average time on therapy was 74.8% (median 82%): median PFS of these patients was 18.16 months. Seven patients with TTFields usage ≤ 60% (23–60%, mean 46.3%, median 53%) had a median PFS of 7.95 months (p=0.0356). Control patients with no TTFields exposure had a median PFS of 11.04 months. In conclusion, this is one of the most extensive studies of ndGBM patients treated with TTFields, covering a period of 18 years in a single center. We demonstrate positive effects of TTFields on both PFS and OS in patients with ndGBM.

Background/Aim: Glioblastoma (GBM) is one of the deadliest human cancers responding very poorly to therapy. Although the central nervous system has been traditionally considered an immunologically privileged site with an enhanced immune response, GBM appears to benefit from this immunosuppressive milieu. Immunomodulatory molecules play an important role in immune tumor-host interactions. Non-classical human leukocyte antigens (HLA) class Ib molecules HLA-E, HLA-F, and HLA-G have been previously described to be involved in protecting semi-allogeneic fetal allografts from the maternal immune response and in transplant tolerance as well as tumoral immune escape. Unfortunately, their role in GBM remains poorly understood. Our study, therefore, aimed to characterize the relationship between the expression of these molecules in GBM on the transcriptional level and clinico-pathological and molecular features of GBM as well as the effect of ionizing radiation. Materials and Methods: We performed the analysis of HLA-E, HLA-F, and HLA-G mRNA expression in 69 GBM tissue samples and 21 non-tumor brain tissue samples (controls) by reverse transcription polymerase chain reaction. Furthermore, two primary GBM cell cultures had been irradiated to identify the effect of ionizing radiation on the expression of non-classical HLA molecules. Results: Analyses revealed that both HLA-E and HLA-F are significantly up-regulated in GBM samples. Subsequent survival analysis showed a significant association between low expression of HLA-E and shorter survival of GBM patients. The dysregulated expression of both molecules was also observed between patients with methylated and unmethylated O-6-methylguanine-DNA methyltransferase (MGMT) promoter. Finally, we showed that ionizing radiation increased HLA-E expression level in GBM cells in vitro. Conclusion: HLA-E and HLA-F play an important role in GBM biology and could be used as diagnostic biomarkers, and in the case of HLA-E also as a prognostic biomarker.

Background and aimCarotid plaque progression contributes to increasing stroke risk. The study aims to identify factors influencing carotid plaque thickness progression after changing the preventive treatment to the ‘treating arteries instead of risk factors’ strategy, that is, change in treatment depending on the progression of atherosclerosis.MethodsThe study participants who completed sonographic controls over the course of 3 years were enrolled to the analysis. Duplex sonography of cervical arteries was performed in 6-month intervals with measurement of carotid plaque thickness. Plaque thickness measurement error (σ) was set as 3 SD. Only evidently stable and progressive plaques (defined as plaque thickness difference between initial and final measurements of ˂σ and >2σ, respectively) were included to analysis. Univariate and multivariate logistic regression analysis was performed to identify factors influencing plaque progression.ResultsA total of 1391 patients (466 males, age 67.2±9.2 years) were enrolled in the study. Progressive plaque in at least one carotid artery was detected in 255 (18.3%) patients. Older age, male sex, greater plaque thickness, coronary heart disease, vascular surgery/stenting history and smoking were more frequently present in patients with progressive plaque (p˂0.05 in all cases). Multivariate logistic regression analysis identified only the plaque thickness (OR 1.850 for left side, 95% CI 1.398 to 2.449; and OR 1.376 for right side, 95% CI 1.070 to 1.770) as an independent factor influencing plaque progression.ConclusionCarotid plaque thickness corresponding to stenosis severity is the only independent risk factor for plaque thickness progression after optimising the prevention treatment.Trial registration numberNCT02360137.

Shear-wave elastography (SWE) is a novel ultrasound technique for quantifying tissue elasticity. The aim of this study was to identify differences in atherosclerotic plaque elasticity measured using SWE among individuals with symptomatic, asymptomatic progressive and asymptomatic stable carotid plaques. Consecutive patients from the Atherosclerotic Plaque Characteristics Associated with a Progression Rate of the Plaque and a Risk of Stroke in Patients with the Carotid Bifurcation Plaque Study were screened for this research. Neurosonography examination of carotid arteries was performed to identify plaque stenosis of ≥50% using B-mode ultrasound and SWE imaging to measure the mean, maximal and minimal elasticity. The set consisted of 97 participants-74 with asymptomatic stable stenosis, 12 with asymptomatic progressive stenosis and 11 with symptomatic stenosis. The mean elasticity in the asymptomatic stable plaque group was significantly higher than in the asymptomatic progressive (52.2 vs. 30.4 kPa; p < 0.001) and symptomatic (52.2 vs. 36.4 kPa; p = 0.033) plaque groups. No significant differences were found between asymptomatic progressive and symptomatic (p > 0.1) plaque groups. Asymptomatic stable, asymptomatic progressive and symptomatic plaques did not differ in echogenicity, calcifications, homogeneity, occurrence of ulcerated surface, or intra-plaque hemorrhage (p > 0.05 in all cases). SWE was a helpful modality for differentiating between stable and unstable atherosclerotic plaques in carotid arteries.

Aim: Early identification of patients at higher risk of unstable atherosclerotic plaque development is essential for successful preventive treatment. The aim of the study was to identify the duplex sonography carotid atherosclerotic plaque risk characteristics for plaque progression. Methods: All patients who underwent regular sonographic examinations within 36 months were included in the analysis. At each control, the following characteristics of the atherosclerotic plaque in the carotid artery were evaluated: maximum width, echogenicity, homogeneity, plaque surface and the presence of calcifications. Univariate and multivariate logistic regression analyses were used for the statistical evaluation. Results: Stable atherosclerotic plaques in both carotid arteries were detected in 332 patients (125 males, mean age 66.7 +/- 9.7 years). Progressive atherosclerotic plaque in at least one carotid artery was detected in 255 patients (126 males, mean age 69.5 +/- 8.3 years). Multivariate logistic regression analysis identified 3 risk factors for carotid atherosclerotic plaque progression: plaque width (increasing the risk of plaque progression within 3 years by 73.5% per 1 mm; P < 0.0001), irregular plaque surface (increasing the risk of progression by 56.4%; P = 0.007) and exulcerated plaque (increasing the risk of progression by 81.9%; P = 0.025). Conclusion: The width and irregular and exulcerated surface of the carotid atherosclerotic plaque are independent risk factors for plaque progression.