Somatic Activating KRAS Mutations in Arteriovenous Malformations of the Brain.

BACKGROUND: Sporadic arteriovenous malformations of the brain, which are morphologically abnormal connections between arteries and veins in the brain vasculature, are a leading cause of hemorrhagic stroke in young adults and children. The genetic cause of this rare focal disorder is unknown. METHODS: We analyzed tissue and blood samples from patients with arteriovenous malformations of the brain to detect somatic mutations. We performed exome DNA sequencing of tissue samples of arteriovenous malformations of the brain from 26 patients in the main study group and of paired blood samples from 17 of those patients. To confirm our findings, we performed droplet digital polymerase-chain-reaction (PCR) analysis of tissue samples from 39 patients in the main study group (21 with matching blood samples) and from 33 patients in an independent validation group. We interrogated the downstream signaling pathways, changes in gene expression, and cellular phenotype that were induced by activating KRAS mutations, which we had discovered in tissue samples. RESULTS: We detected somatic activating KRAS mutations in tissue samples from 45 of the 72 patients and in none of the 21 paired blood samples. In endothelial cell-enriched cultures derived from arteriovenous malformations of the brain, we detected KRAS mutations and observed that expression of mutant KRAS (KRASG12V) in endothelial cells in vitro induced increased ERK (extracellular signal-regulated kinase) activity, increased expression of genes related to angiogenesis and Notch signaling, and enhanced migratory behavior. These processes were reversed by inhibition of MAPK (mitogen-activated protein kinase)-ERK signaling. CONCLUSIONS: We identified activating KRAS mutations in the majority of tissue samples of arteriovenous malformations of the brain that we analyzed. We propose that these malformations develop as a result of KRAS-induced activation of the MAPK-ERK signaling pathway in brain endothelial cells. (Funded by the Swiss Cancer League and others.).

Endovascular treatment of intracranial vertebrobasilar artery dissecting aneurysms: Parent artery occlusion versus flow diverter.

PURPOSE: To compare the safety and efficacy of endovascular parent artery occlusion (PAO) and flow diverter (FD) treatment in treating vertebrobasilar dissecting aneurysms (VBDAs). METHODS: A review of a prospective aneurysm database at our institution was performed to identify all consecutive patients with intracranial VBDAs managed with endovascular treatment, which were either PAO or FD. Clinical and imaging findings were compared between the two groups. RESULTS: A total of 25 consecutive patients with 27 VBDAs were included. Seventeen VBDAs were treated by PAO, and 11 VBDAs were treated with FDs. Immediate total occlusion rate after initial treatment was higher in the PAO group than in the FD group (62.5% v.s. 9.1%, p = .018). Complete occlusion on follow-up at 18 months was more frequently observed in the PAO group (81.8%) compared to the FD group (55.6%), although the difference was not statistically significant (p = .433). Procedure related complication rate and mortality for the whole case series was 28% and 24% respectively, and were comparable in the two groups. Excellent outcome at discharge was achieved in 77.8% and 40% of patients treated with FD and PAO respectively, which was not statistically significant (p = .169). Excellent outcome at followed-up was comparable as well. CONCLUSIONS: PAO and FD treatment are both feasible options for treatment of VBDAs. PAO provide higher immediate complete occlusion rate compared to FD. Despite low initial complete occlusion rates, FD group presented a comparable long-term outcome and similar perioperative events rate compared to the PAO group.