A review of technological innovations leading to modern endovascular brain aneurysm treatment

Tools and techniques utilized in endovascular brain aneurysm treatment have undergone rapid evolution in recent decades. These technique and device-level innovations have allowed for treatment of highly complex intracranial aneurysms and improved patient outcomes. We review the major innovations within neurointervention that have led to the current state of brain aneurysm treatment

Somatic PDGFRB activating variants in fusiform cerebral aneurysms

The role of somatic genetic variants in the pathogenesis of intracranial-aneurysm formation is unknown. We identified a 23-year-old man with progressive, right-sided intracranial aneurysms, ipsilateral to an impressive cutaneous phenotype. The index individual underwent a series of genetic evaluations for known connective-tissue disorders, but the evaluations were unrevealing. Paired-sample exome sequencing between blood and fibroblasts derived from the diseased areas detected a single novel variant predicted to cause a p.Tyr562Cys (g.149505130T>C [GRCh37/hg19]; c.1685A>G) change within the platelet-derived growth factor receptor β gene (PDGFRB), a juxtamembrane-coding region. Variant-allele fractions ranged from 18.75% to 53.33% within histologically abnormal tissue, suggesting post-zygotic or somatic mosaicism. In an independent cohort of aneurysm specimens, we detected somatic-activating PDGFRB variants in the juxtamembrane domain or the kinase activation loop in 4/6 fusiform aneurysms (and 0/38 saccular aneurysms; Fisher's exact test, p < 0.001). PDGFRB-variant, but not wild-type, patient cells were found to have overactive auto-phosphorylation with downstream activation of ERK, SRC, and AKT. The expression of discovered variants demonstrated non-ligand-dependent auto-phosphorylation, responsive to the kinase inhibitor sunitinib. Somatic gain-of-function variants in PDGFRB are a novel mechanism in the pathophysiology of fusiform cerebral aneurysms and suggest a potential role for targeted therapy with kinase inhibitors

Characterization of the genomic and immunologic diversity of malignant brain tumors through multisector analysis

Despite some success in secondary brain metastases, targeted or immune-based therapies have shown limited efficacy against primary brain malignancies such as glioblastoma (GBM). Although the intratumoral heterogeneity of GBM is implicated in treatment resistance, it remains unclear whether this diversity is observed within brain metastases and to what extent cancer cell-intrinsic heterogeneity sculpts the local immune microenvironment. Here, we profiled the immunogenomic state of 93 spatially distinct regions from 30 malignant brain tumors through whole-exome, RNA, and T-cell receptor sequencing. Our analyses identified differences between primary and secondary malignancies, with gliomas displaying more spatial heterogeneity at the genomic and neoantigen levels. In addition, this spatial diversity was recapitulated in the distribution of T-cell clones in which some gliomas harbored highly expanded but spatially restricted clonotypes. This study defines the immunogenomic landscape across a cohort of malignant brain tumors and contains implications for the design of targeted and immune-based therapies against intracranial malignancies. SIGNIFICANCE: This study describes the impact of spatial heterogeneity on genomic and immunologic characteristics of gliomas and brain metastases. The results suggest that gliomas harbor significantly greater intratumoral heterogeneity of genomic alterations, neoantigens, and T-cell clones than brain metastases, indicating the importance of multisector analysis for clinical or translational studies

Single-cell multi-omic analysis of the vestibular schwannoma ecosystem uncovers a nerve injury-like state

Vestibular schwannomas (VS) are benign tumors that lead to significant neurologic and otologic morbidity. How VS heterogeneity and the tumor microenvironment (TME) contribute to VS pathogenesis remains poorly understood. In this study, we perform scRNA-seq on 15 VS, with paired scATAC-seq (n = 6) and exome sequencing (n = 12). We identify diverse Schwann cell (SC), stromal, and immune populations in the VS TME and find that repair-like and MHC-II antigen-presenting SCs are associated with myeloid cell infiltrate, implicating a nerve injury-like process. Deconvolution analysis of RNA-expression data from 175 tumors reveals Injury-like tumors are associated with larger tumor size, and scATAC-seq identifies transcription factors associated with nerve repair SCs from Injury-like tumors. Ligand-receptor analysis and in vitro experiments suggest that Injury-like VS-SCs recruit myeloid cells via CSF1 signaling. Our study indicates that Injury-like SCs may cause tumor growth via myeloid cell recruitment and identifies molecular pathways that may be therapeutically targeted

Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response

BACKGROUND: Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS: Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS: In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS: Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura

Outcomes of Mechanical Thrombectomy for Patients With Stroke Presenting With Low Alberta Stroke Program Early Computed Tomography Score in the Early and Extended Window

Importance: Limited data are available about the outcomes of mechanical thrombectomy (MT) for real-world patients with stroke presenting with a large core infarct. Objective: To investigate the safety and effectiveness of MT for patients with large vessel occlusion and an Alberta Stroke Program Early Computed Tomography Score (ASPECTS) of 2 to 5. Design, setting, and participants: This retrospective cohort study used data from the Stroke Thrombectomy and Aneurysm Registry (STAR), which combines the prospectively maintained databases of 28 thrombectomy-capable stroke centers in the US, Europe, and Asia. The study included 2345 patients presenting with an occlusion in the internal carotid artery or M1 segment of the middle cerebral artery from January 1, 2016, to December 31, 2020. Patients were followed up for 90 days after intervention. The ASPECTS is a 10-point scoring system based on the extent of early ischemic changes on the baseline noncontrasted computed tomography scan, with a score of 10 indicating normal and a score of 0 indicating ischemic changes in all of the regions included in the score. Exposure: All patients underwent MT in one of the included centers. Main outcomes and measures: A multivariable regression model was used to assess factors associated with a favorable 90-day outcome (modified Rankin Scale score of 0-2), including interaction terms between an ASPECTS of 2 to 5 and receiving MT in the extended window (6-24 hours from symptom onset). Results: A total of 2345 patients who underwent MT were included (1175 women [50.1%]; median age, 72 years [IQR, 60-80 years]; 2132 patients [90.9%] had an ASPECTS of ≥6, and 213 patients [9.1%] had an ASPECTS of 2-5). At 90 days, 47 of the 213 patients (22.1%) with an ASPECTS of 2 to 5 had a modified Rankin Scale score of 0 to 2 (25.6% [45 of 176] of patients who underwent successful recanalization [modified Thrombolysis in Cerebral Ischemia score ≥2B] vs 5.4% [2 of 37] of patients who underwent unsuccessful recanalization; P = .007). Having a low ASPECTS (odds ratio, 0.60; 95% CI, 0.38-0.85; P = .002) and presenting in the extended window (odds ratio, 0.69; 95% CI, 0.55-0.88; P = .001) were associated with worse 90-day outcome after controlling for potential confounders, without significant interaction between these 2 factors (P = .64). Conclusions and relevance: In this cohort study, more than 1 in 5 patients presenting with an ASPECTS of 2 to 5 achieved 90-day functional independence after MT. A favorable outcome was nearly 5 times more likely for patients with low ASPECTS who had successful recanalization. The association of a low ASPECTS with 90-day outcomes did not differ for patients presenting in the early vs extended MT window

Are Aneurysms Treated With Balloon-Assisted Coiling and Stent-Assisted Coiling Different? Morphological Analysis of 113 Unruptured Wide-Necked Aneurysms Treated With Adjunctive Devices

Abstract BACKGROUND: In the endovascular treatment of wide-necked unruptured aneurysms, there is controversy over which adjunctive device (stent vs balloon) is appropriate. At the payer level it has been posited that stents and balloons treat the same aneurysms, and, as such, the more expensive stents should not be reimbursed. OBJECTIVE: We challenge this assertion, and instead hypothesize that aneurysms treated with stent assistance are morphologically different than those selected for balloon assistance. METHODS: Retrospective review of unruptured aneurysms treated with an adjunctive device between 2008 and 2010. Morphological analysis was performed on the pretreatment 2-D catheter angiogram. The immediate posttreatment Raymond score was compared with that seen on the 12-month follow-up angiogram. RESULTS: One hundred six unruptured aneurysms were treated with an adjunctive device and followed for a mean of 24.5 months. Morphological analysis revealed a lower dome-to-neck ratio (1.5 vs 1.2) and aspect ratio (1.44 vs 1.16) in the aneurysms treated with stent assistance vs balloon assistance. Of the 15.3% that were worse on follow-up angiography, there was no statistical difference between those treated with a stent vs a balloon (17.1% vs 14.2%). The overall re-treatment rate was 10.2% and was not statistically different between the 2 groups (12.7% vs 5.7%). CONCLUSION: We found that unruptured aneurysms selected for treatment with stent-assisted coiling are morphologically different from those selected for treatment with balloon assistance. Despite the more challenging morphology, Raymond scores and re-treatment rates at 1 year were not statistically different between the 2 groups, suggesting an important role for stents in the treatment of unruptured aneurysms

Validating a Curvature‐Based Marker of Cervical Carotid Tortuosity for Risk Assessment in Heritable Aortopathies

Background Cervical arterial tortuosity is associated with adverse outcomes in Loeys‐Dietz syndrome and other heritable aortopathies. Methods and Results A method to assess tortuosity based on curvature of the vessel centerline in 3‐dimensional space was developed. We measured cervical carotid tortuosity in 65 patients with Loeys‐Dietz syndrome from baseline computed tomography angiogram/magnetic resonance angiogram and all serial images during follow‐up. Relations between baseline carotid tortuosity, age, aortic root diameter, and its change over time were compared. Patients with unoperated aortic roots were assessed for clinical end point (type A aortic dissection or aortic root surgery during 4 years of follow‐up). Logistic regression was performed to assess the likelihood of clinical end point according to baseline carotid tortuosity. Total absolute curvature at baseline was 11.13±5.76 and was relatively unchanged at 8 to 10 years (fold change: 0.026±0.298, P=1.00), whereas tortuosity index at baseline was 0.262±0.131, with greater variability at 8 to 10 years (fold change: 0.302±0.656, P=0.818). Baseline total absolute curvature correlated with aortic root diameter (r=0.456, P=0.004) and was independently associated with aortic events during the 4‐year follow‐up (adjusted odds ratio [OR], 2.64 [95% CI, 1.02–6.85]). Baseline tortuosity index correlated with age (r=0.532, P<0.001) and was not associated with events (adjusted OR, 1.88 [95% CI, 0.79–4.51]). Finally, baseline total absolute curvature had good discrimination of 4‐year outcomes (area under the curve=0.724, P=0.014), which may be prognostic or predictive. Conclusions Here we introduce cervical carotid tortuosity as a promising quantitative biomarker with validated, standardized characteristics. Specifically, we recommend the adoption of a curvature‐based measure, total absolute curvature, for early detection or monitoring of disease progression in Loeys‐Dietz syndrome

Abstract 1122‐000154: Effect of Intravenous Thrombolysis on Early Clot Lysis in Large Vessel Occlusion Strokes Undergoing Thrombectomy

Introduction: Intravenous thrombolysis (IVT) and endovascular thrombectomy (EVT) are both standard of care treatments for acute ischemic stroke patients with large vessel occlusion (LVO) who are eligible for one or both treatments. IVT may result in early recanalization in some patients with LVO. The objective of this study is to analyze whether IVT influences pre‐thrombectomy clot lysis in LVO acute ischemic strokes. Methods: We reviewed prospectively collected data for all patients with LVO ischemic strokes who were transferred to the angiography suite with intention to perform EVT at a single comprehensive stroke center between January 2016 to December 2018. We identified subjects who showed partial or complete clot lysis vs no lysis based on the first angiographic picture of the occluded territory at the time of the initial vessel selection. Descriptive statistics were used to summarize demographic and clinical characteristics. We compared key predictor variables between lysis and no lysis groups including baseline variables, effect of IVT, time from IVT to groin puncture, LVO location, final modified treatment in cerebral ischemia (mTICI) score and discharge Modified Rankin Scale (mRS). t‐test or Kruskal‐Wallis test for continuous variables and chi square test or Fisher’s Exact test for categorical variables. Results: Two hundred and fifty‐nine patients were included. Among these patients, 10.8% (28/259) showed partial or complete lysis of the clot vs 89.2% (231/259) with no lysis. Among these patients who showed clot lysis, 16/28 (57.1%) received IVT. The use of IVT did not show differences between both groups (p = 0.18). There were no differences in the baseline characteristics except for gender, which was the only variable significantly associated with clot lysis. Men had 2‐fold higher odds of spontaneous lysis compared to females (OR [95%CI]: 2.39 [1.01, 5.65], p = 0.04). There was significant difference in the final mTICI between both groups (p <0.001). Conclusions: Our study showed that IVT in a modern practice was not associated with pre‐thrombectomy lysis. Some patients had pre‐thrombectomy lysis despite not receiving IVT

Left transradial access for cerebral angiography

IntroductionTransradial access is increasingly used among neurointerventionalists as an alternative to the transfemoral route. Currently available data, building on the interventional cardiology experience, primarily focus on right radial access. However, there are clinical scenarios when left-sided access may be indicated. The purpose of this study was to evaluate the technical feasibility of left transradial access to cerebral angiography across three institutions.MethodsA retrospective chart review was performed for patients who underwent cerebral angiography accessed via the left radial artery at three institutions between January 2018 and July 2019. The outcome variables studied were successful catheterization, vascular complications, and fluoroscopic time.ResultsNineteen patients underwent a total of 25 cerebral angiograms via left transradial access for cerebral aneurysms (n=15), basilar occlusion (n=1), carotid stenosis (n=1), arteriovenous malformation (n=1), and cervical neurofibroma (n=1). There were 12 diagnostic angiograms and 13 interventional angiograms. The left transradial approach was chosen due to left vertebrobasilar pathology (n=22), right subclavian stenosis (n=2), and previous right arm amputation (n=1). There was one instance of radial artery spasm, which resolved after catheter removal, and one conversion to transfemoral access in an interventional case due to lack of distal catheter support. There were no procedural complications.ConclusionsLeft transradial access in diagnostic and interventional cerebral angiography is a technically feasible, safe, and an effective alternative when indicated, and may be preferable for situations in which pathology locations or anatomic limitations preclude right-sided radial access