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Background and purposeStent-assisted coil embolization using the new generation Neuroform Atlas Stent System has shown promising safety and efficacy. The primary study results of the anterior circulation aneurysm cohort of the treatment of wide-neck, saccular, intracranial, aneurysms with the Neuroform Atlas Stent System (ATLAS trial [Safety and Effectiveness of the Treatment of Wide Neck, Saccular Intracranial Aneurysms With the Neuroform Atlas Stent System]) are presented.MethodsATLAS IDE trial (Investigational Device Exemption) is a prospective, multicenter, single-arm, open-label study of wide-neck (neck ≥4 mm or dome-to-neck ratio 50%) at the target location. The primary safety end point was any major stroke or ipsilateral stroke or neurological death within 12 months. Adjudication of the primary end points was performed by an independent Imaging Core Laboratory and the Clinical Events Committee.ResultsA total of 182 patients with wide-neck anterior circulation aneurysms at 25 US centers were enrolled. The mean age was 60.3±11.4 years, 73.1% (133/182) women, and 80.8% (147/182) white. Mean aneurysm size was 6.1±2.2 mm, mean neck width was 4.1±1.2 mm, and mean dome-to-neck ratio was 1.2±0.3. The most frequent aneurysm locations were the anterior communicating artery (64/182, 35.2%), internal carotid artery ophthalmic artery segment (29/182, 15.9%), and middle cerebral artery bifurcation (27/182, 14.8%). Stents were placed in the anticipated anatomic location in all patients. The study met both primary safety and efficacy end points. The composite primary efficacy end point of complete aneurysm occlusion (Raymond-Roy 1) without parent artery stenosis or aneurysm retreatment was achieved in 84.7% (95% CI, 78.6%-90.9%) of patients. Overall, 4.4% (8/182, 95% CI, 1.9%-8.5%) of patients experienced a primary safety end point of major ipsilateral stroke or neurological death.ConclusionsIn the ATLAS IDE anterior circulation aneurysm cohort premarket approval study, the Neuroform Atlas stent with adjunctive coiling met the primary end points and demonstrated high rates of long-term complete aneurysm occlusion at 12 months, with 100% technical success and

BackgroundDual antiplatelet therapy (DAT), most commonly with aspirin and Clopidogrel, is the standard of care for intracranial stenting, including flow diversion. Clopidogrel response varies by individual.ObjectiveTo investigate the real-world precision of VerifyNow P2Y12 assessment (Accumetrics, San Diego, California) of Clopidogrel response.MethodsUsing a prospectively-collected, IRB-approved cerebral aneurysm database 643 patients were identified who were treated with the Pipeline embolization device from 2011 to 2017. Patients with multiple P2Y12 assays drawn within a 24-h window were identified. A single patient could contribute multiple, independent sets. Levels drawn before a 5-d course of DAT and patients who received alternative antiplatelet agents were excluded. Therapeutic range was defined as platelet reaction units (PRU) 60-200.ResultsA total of 1586 P2Y12 measurements were recorded; 293 (46%) patients had more than one assay. One hundred forty (22%) patients had multiple P2Y12 measurements within 24 h. These patients accounted for 230 independent 24-h sets. The average P2Y12 fluctuation across all sets was 35 points; the 25th, 50th, and 75th percentiles were 12, 26, and 48 points, respectively. Of the 230 24-h sets of P2Y12 assays, 76% remained within their original therapeutic category: 100 (43%) all therapeutic, 54 (23%) all hypo-responsive, and 21 (9%) all hyper-responsive. Twenty-four percent of patients fluctuated between therapeutic categories when multiple P2Y12 assessments were drawn within a 24-h period: 29 (13%) between hypo-response and therapeutic, 23 (10%) between hyper-response and therapeutic, and 3 (1%) between hypo-response and hyper-response.ConclusionOur experience suggests P2Y12 is an often-imprecise measure, and this should be considered when utilizing P2Y12 levels for clinical decisions.

BackgroundDual antiplatelet therapy (DAT), most commonly with aspirin and Clopidogrel, is the standard of care for intracranial stenting, including flow diversion. Clopidogrel response varies by individual.ObjectiveTo investigate the real-world precision of VerifyNow P2Y12 assessment (Accumetrics, San Diego, California) of Clopidogrel response.MethodsUsing a prospectively-collected, IRB-approved cerebral aneurysm database 643 patients were identified who were treated with the Pipeline embolization device from 2011 to 2017. Patients with multiple P2Y12 assays drawn within a 24-h window were identified. A single patient could contribute multiple, independent sets. Levels drawn before a 5-d course of DAT and patients who received alternative antiplatelet agents were excluded. Therapeutic range was defined as platelet reaction units (PRU) 60-200.ResultsA total of 1586 P2Y12 measurements were recorded; 293 (46%) patients had more than one assay. One hundred forty (22%) patients had multiple P2Y12 measurements within 24 h. These patients accounted for 230 independent 24-h sets. The average P2Y12 fluctuation across all sets was 35 points; the 25th, 50th, and 75th percentiles were 12, 26, and 48 points, respectively. Of the 230 24-h sets of P2Y12 assays, 76% remained within their original therapeutic category: 100 (43%) all therapeutic, 54 (23%) all hypo-responsive, and 21 (9%) all hyper-responsive. Twenty-four percent of patients fluctuated between therapeutic categories when multiple P2Y12 assessments were drawn within a 24-h period: 29 (13%) between hypo-response and therapeutic, 23 (10%) between hyper-response and therapeutic, and 3 (1%) between hypo-response and hyper-response.ConclusionOur experience suggests P2Y12 is an often-imprecise measure, and this should be considered when utilizing P2Y12 levels for clinical decisions.

IntroductionInternal carotid artery termination (ICAT) and proximal A1 aneurysms can be challenging for open surgical clipping or endovascular coiling. Treatment with flow diversion covering the middle cerebral artery (MCA), an end vessel supplying a terminal circulation, has not been reported.MethodsA prospective, Institutional Review Board-approved database was analysed for patients with pipeline embolisation device (PED) placement from the anterior cerebral artery (ACA) to the ICA during cerebral aneurysm treatment.ResultsNine cases were identified, including five proximal A1, three posterior communicating artery and one ICAT aneurysm locations. Average aneurysm size was 8.3 mm (range 3-17), with 67% saccular and 78% right-sided. Primary indication for treatment was significant dome irregularity (44%), recurrence or enlargement (33%), underlying collagen vascular disorder (11%) and traumatic pseudoaneurysm (11%). Preservation of the ipsilateral ACA (with PED placed in A1) was performed when the anterior communicating artery (67%) or contralateral A1 (33%) were absent on angiography. Adjunctive coiling was done in four cases (44%). There was one major stroke leading to mortality (11%) and one minor stroke (11%). Clinical follow-up was 27 months on average. Follow-up digital subtraction angiography (average interval 15 months) showed complete aneurysm obliteration (88%) or dome occlusion with entry remnant (12%). The jailed MCA showed minimal or mild delay (primarily anterograde flow) in 75% of cases and significant delay (reliance primarily on ACA and external carotid artery collaterals) in 25%.ConclusionsCovering the MCA with a flow diverting stent should be reserved for select rare cases. Strict attention to blood pressure augmentation during the periprocedural period is necessary to minimise potential ischaemic compromise.

BackgroundAcute in situ thrombosis is an ischaemic phenomenon during Pipeline embolisation device (PED) procedures with potentially high morbidity and mortality. There is controversy regarding the role of platelet function testing with P2Y12 assay as a predictor of intraprocedural thromboembolic events. There is limited knowledge on whether procedural complexity influences these events.MethodsData were collected retrospectively on 742 consecutive PED cases at a single institution. Patients with intraprocedural acute thrombosis were compared with patients without these events.ResultsA cohort of 37 PED cases with acute in situ thrombosis (mean age 53.8 years, mean aneurysm size 8.4 mm) was matched with a cohort of 705 PED cases without intraprocedural thromboembolic events (mean age 56.4 years, mean aneurysm size 6.9 mm). All patients with in situ thrombosis received intra-arterial and/or intravenous abciximab. The two groups were evenly matched in patient demographics, previous treatment/subarachnoid hemorrhage (SAH) and aneurysm location. There was no statistical difference in postprocedural P2Y12 reaction unit (PRU) values between the two groups, with a mean of 156 in the in situ thrombosis group vs 148 in the control group (p=0.5894). Presence of cervical carotid tortuosity, high cavernous internal carotid artery grade, need for multiple PED and vasospasm were not significantly different between the two groups. The in situ thrombosis group had statistically significant longer fluoroscopy time (60.4 vs 38.4 min, p

Endovascular treatment of cerebral aneurysm continues to evolve with the development of new technologies. This review provides an overview of the recent major innovations in the neurointerventional space in recent years.

Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.

Cancer-associated isocitrate dehydrogenase (IDH) 1 and 2 mutations gain a new activity of reducing α-KG to produce D-2-hydroxyglutarate (D-2-HG), which is proposed to function as an oncometabolite by inhibiting α-KG dependent dioxygenases. We investigated the function of D-2-HG in tumorigenesis using IDH1 and IDH2 mutant cancer cell lines. Inhibition of D-2-HG production either by specific deletion of the mutant IDH1-R132C allele or overexpression of D-2-hydroxyglutarate dehydrogenase (D2HGDH) increases α-KG and related metabolites, restores the activity of some α-KG-dependent dioxygenases, and selectively alters gene expression. Ablation of D-2-HG production has no significant effect on cell proliferation and migration, but strongly inhibits anchorage independent growth in vitro and tumor growth in xenografted mouse models. Our study identifies a new activity of oncometabolite D-2-HG in promoting tumorigenesis.

Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation.

Phosphoglycerate kinase 1 (PGK1) catalyzes the reversible transfer of a phosphoryl group from 1, 3-bisphosphoglycerate (1, 3-BPG) to ADP, producing 3-phosphoglycerate (3-PG) and ATP. PGK1 plays a key role in coordinating glycolytic energy production with one-carbon metabolism, serine biosynthesis, and cellular redox regulation. Here, we report that PGK1 is acetylated at lysine 220 (K220), which inhibits PGK1 activity by disrupting the binding with its substrate, ADP. We have identified KAT9 and HDAC3 as the potential acetyltransferase and deacetylase, respectively, for PGK1. Insulin promotes K220 deacetylation to stimulate PGK1 activity. We show that the PI3K/AKT/mTOR pathway regulates HDAC3 S424 phosphorylation, which promotes HDAC3-PGK1 interaction and PGK1 K220 deacetylation. Our study uncovers a previously unknown mechanism for the insulin and mTOR pathway in regulation of glycolytic ATP production and cellular redox potential via HDAC3-mediated PGK1 deacetylation.

Flow diverters are increasingly used for the endovascular treatment of cerebral aneurysms. A rare complication from flow diversion is delayed aneurysm rupture, which can lead to carotid-cavernous fistula (CCF) in the setting of cavernous carotid aneurysms (CCAs). Direct CCFs pose unique management challenges, given the lack of transarterial access to the fistula. We present two cases of direct CCFs following treatment of CCAs with the Pipeline embolization device (PED). Case 1 was a middle-aged patient with a symptomatic 10 mm wide-necked left CCA. Six weeks after PED treatment the patient developed diplopia secondary to direct CCF. Case 2 was a middle-aged patient with a symptomatic 17 mm left CCA treated with PED. One-month follow-up angiography demonstrated a direct CCF. Both patients underwent successful coil embolization of the CCF through a transvenous approach. Direct CCF formation following PED deployment for CCA is a rare complication. Parent vessel sacrifice may be avoided with transvenous occlusion of the fistula.