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. 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. 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 (KRAS^G12V) 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. 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.)

BACKGROUND: The role of expanded endonasal endoscopic surgery for primary and recurrent craniopharyngioma is not yet fully established. OBJECTIVE: To report and evaluate our experience with the endoscopic endonasal approach (EEA) for the resection of primary and recurrent craniopharyngiomas. METHODS: This is a retrospective cohort analysis of 43 consecutive EEA procedures in 40 patients operated from September 2006 to February 2012 for suprasellar craniopharyngiomas. In 21 patients (48.8%) the disease was recurrent. We have assessed the surgical results, visual, endocrinological, and functional outcomes and resection rates in this patient cohort. RESULTS: At presentation, 31 (72.1%) patients had visual deficits, 15 patients (34.9%) complained of headaches, 25 patients (58.1%) had anterior pituitary insufficiency, and 14 (32.5%) had diabetes insipidus. Total resection was achieved in 44.2% surgeries, of which 77.3% were in primary lesions and 9.5% in recurrent lesions (P < .001). Vision improved in 92.6% patients and worsened in 2.3%. Complications other than vision were encountered in 25.6% including 9/43 cerebrospinal fluid leak, 2/43 meningitis. A total of 51.9% of patients with preoperative residual anterior pituitary function had new anterior pituitary deficiencies and 42.8% had new diabetes insipidus. There was no mortality. Six patients (14%) had recurrence of disease during the follow-up period (mean 56.8 mo), 5 of which required repeat surgery. CONCLUSION: The EEA can be integrated in the overall management of both primary and recurrent craniopharyngiomas with good results; however, in our series recurrent surgery was associated with significantly lower rates of gross total resection.

OBJECTIVE: Despite the prevalence and impact of intracranial aneurysms (IAs), the molecular basis of their pathogenesis remains largely unknown. Moreover, there is a dearth of clinically validated biomarkers to efficiently screen patients with IAs and prognosticate risk for rupture. The aim of this study was to survey the literature to systematically identify the spectrum of genetic aberrations that have been identified in IA formation and risk of rupture. METHODS: A literature search was performed using the Medical Subject Headings (MeSH) system of databases including PubMed, EMBASE, and Google Scholar. Relevant studies that reported on genetic analyses of IAs, rupture risk, and long-term outcomes were included in the qualitative analysis. RESULTS: A total of 114 studies were reviewed and 65 were included in the qualitative synthesis. There are several well-established mendelian syndromes that confer risk to IAs, with variable frequency. Linkage analyses, genome-wide association studies, candidate gene studies, and exome sequencing identify several recurrent polymorphic variants at candidate loci, and genes associated with the risk of aneurysm formation and rupture, including ANRIL ( CDKN2B-AS1 , 9p21), ARGHEF17 (11q13), ELN (7q11), SERPINA3 (14q32), and SOX17 (8q11). In addition, polymorphisms in eNOS/NOS3 (7q36) may serve as predictive markers for outcomes following intracranial aneurysm rupture. Genetic aberrations identified to date converge on posited molecular mechanisms involved in vascular remodeling, with strong implications for an associated immune-mediated inflammatory response. CONCLUSIONS: Comprehensive studies of IA formation and rupture have identified candidate risk variants and loci; however, further genome-wide analyses are needed to identify high-confidence genetic aberrations. The literature supports a role for several risk loci in aneurysm formation and rupture with putative candidate genes. A thorough understanding of the genetic basis governing risk of IA development and the resultant aneurysmal subarachnoid hemorrhage may aid in screening, clinical management, and risk stratification of these patients, and it may also enable identification of putative mechanisms for future drug development.

Vascular malformations are anomalies in vascular development that portend a significant risk of hemorrhage, morbidity and mortality. Conventional treatments with surgery, radiosurgery and/or endovascular approaches are often insufficient for cure, thereby presenting an ongoing challenge for physicians and their patients. In the last two decades, we have learned that each type of vascular malformation harbors inherited germline and somatic mutations in two well-known cellular pathways that are also implicated in cancer biology: the PI3K/AKT/mTOR and RAS/RAF/MEK pathways. This knowledge has led to recent efforts in: (1) identifying reliable mechanisms to detect a patient's mutational burden in a minimally-invasive manner, and then (2) understand how cancer drugs that target these mutations can be repurposed for vascular malformation care. The idea of precision medicine for vascular pathologies is growing in potential and will be critical in expanding the clinician's therapeutic armamentarium.

OBJECTIVE: The goal of this study was to describe changes in the angioarchitecture of brain arteriovenous malformations (bAVMs) between acute and delayed cerebral digital subtraction angiography (DSA) obtained after hemorrhage, and to examine bAVM characteristics predicting change.METHODS: This is a retrospective study of a prospective institutional bAVM database. The authors included all patients with ruptured bAVMs who had DSA in both acute and delayed phases, with no interval treatment of their bAVM, between January 2000 and April 2017. The authors evaluated the existence or absence of angioarchitectural changes. Demographic data, radiological characteristics of hemorrhages, and angioarchitectural features of the bAVMs of the two patients’ groups were analyzed. Univariate and multivariate logistic analyses were performed to identify predictors of angioarchitectural change.RESULTS: A total of 42 patients were included in the series. Seventeen (40.5%) patients had angioarchitectural changes including bAVM only visible on the delayed DSA study (n = 8), spontaneous thrombosis of the AVM (n = 3), or alteration of the size or the opacification of the nidus (n = 6). The factors associated with angioarchitectural changes were a small nidus (3.8 ± 7.9 ml vs 6.1 ± 9.5 ml, p = 0.046), a superficial location (94.1% vs 5.9%, p = 0.016), and a single superficial draining vein (58.8% vs 24.0%, p = 0.029).CONCLUSIONS: Angioarchitectural changes can be seen in 40% of ruptured bAVMs between the acute- and delayed-phase DSA. A small nidus, a superficial location, and a single superficial draining vein were statistically associated with the occurrence of angioarchitectural changes. These changes included either enlargement or spontaneous occlusion of the bAVM, as well as subsequent diagnosis of a bAVM following an initial negative DSA study.