Open-cell stent and use of cone-beam CT enables a safe and effective coil embolization of true ophthalmic artery and anterior choroidal artery aneurysms with preservation of parent vessel: Clinical and angiographic results.

Background Treatment of true ophthalmic artery (OA) or anterior choroidal artery (AChA) aneurysms with preservation of the parent vessel may be challenging. Flow diverters have limitations when dealing with branch vessels arising from the aneurysm sac. Visual loss or AChA territory infarcts have been reported both for surgical and endovascular treatment. Methods We evaluated the safety and efficacy of an open-cell design, laser-cut, self-expanding Nitinol stent, and use of cone-beam computed tomography (CBCT) for stent-assisted coil embolization. Results A total of seven patients with unruptured OA or AChA aneurysms were enrolled in this prospective small case study and the data were analyzed retrospectively. A complete obliteration was achieved in all aneurysms immediately post-intervention or at six-month follow-up without any evidence for recanalization at up to three-year follow-up. All patients tolerated the procedure well and there was no change in baseline modified Rankin Scale. Conclusions Our study suggests that specific features of an open-cell stent allow a safe and effective treatment of OA or AChA aneurysms with a high technical success rate and excellent mid-term angiographic and clinical outcome. CBCT is a useful intraoperative imaging tool.

Pipeline Embolization Device for Pericallosal Artery Aneurysms: A Retrospective Single Center Safety and Efficacy Study.

BACKGROUND: Pericallosal artery aneurysm treatment may be challenging using traditional endovascular techniques. OBJECTIVE: To demonstrate the feasibility, efficacy, and safety of endovascular treatment of pericallosal artery aneurysm using flow diverters. METHODS: We performed a retrospective review of our institutional database from July 2013 through July 2016 and identified 7 subjects with a pericallosal artery aneurysm treated with the Pipeline embolization device (ev3 Neurovascular, Medtronic, Dublin, Ireland) and at least 1 follow-up angiogram. Technical feasibility, procedural complication, angiographic results, and clinical outcome were evaluated. RESULTS: Placement of the Pipeline embolization device was successful in all cases without evidence of procedural complication. Five out of 7 subjects showed a complete aneurysm occlusion at 6- to 12-mo follow-up angiogram. The 2 subjects with persistent aneurysm filling showed decreased aneurysm sac volume on follow-up angiograms (96% and 60%). There was no evidence of in-implant stenosis or intimal hyperplasia. No thromboembolic or hemorrhagic complications were seen during the follow-up period. Only 1 patient had a transient change in Modified Rankin scale score from baseline as a result of different unrelated procedure. CONCLUSION: Our preliminary results demonstrate feasibility of the use of flow diverter stent for treatment of aneurysms of the pericallosal artery with rate of aneurysm occlusion comparable to literature and without evidence of increased procedural or short-term morbidity. A long-term and larger cohort study is needed to validate our findings.

Endovascular reconstruction of unruptured intradural vertebral artery dissecting aneurysms with the Pipeline embolization device.

BACKGROUND: Dissecting aneurysms of the vertebral artery (VA) are difficult to treat using current surgical and endovascular techniques. OBJECTIVE: To analyze retrospectively the efficacy and safety of flow diverters in the treatment of dissecting aneurysms of the vertebral artery. METHODS: We identified six patients with six unruptured VA dissecting aneurysms either arising from the V4 or V3-V4 junction that were treated with the Pipeline embolization device (PED) at our institution between July 2012 and February 2015. Among other parameters, technical feasibility of the procedure, procedure-related complications, angiographic results, and clinical outcome were evaluated. RESULTS: PED placement was achieved in all cases and immediate angiography follow-up demonstrated intra-aneurysmal contrast stasis with parent artery preservation. A temporary episode of dysarthria was noted in one patient. Major procedure-related complications were not observed. The 6-month follow-up (n=6) demonstrated complete/near-complete aneurysm obliteration in five patients and partial obliteration in one. At the 1-year follow-up (n=5) stable complete aneurysm occlusion was seen in two patients. Two cases showed progression from near complete occlusion and partial occlusion at 6 months to complete occlusion and near complete occlusion. One cases showed unchanged near complete occlusion. No aneurysmal bleeding, in-stent stenosis or thromboembolic complication was seen. National Institutes of Health Stroke Scale and modified Rankin scale scores remained unchanged from admission to discharge. CONCLUSIONS: Our preliminary experience with the use of PED for the treatment of intradural VA dissecting aneurysms shows promising short-term results, making this technique a feasible and safe treatment option in patients suitable for this approach. However, long-term and larger cohort studies are needed to validate these results.

Safety, efficacy, and short-term follow-up of the use of Pipeline Embolization Device in small (<2.5 mm) cerebral vessels for aneurysm treatment: single institution experience.

INTRODUCTION: Flow diversion is being increasingly used to treat cerebral aneurysms. We present our experience using these stents to treat aneurysms distal to the circle of Willis with parent arteries smaller than 2.5 mm. METHODS: Aneurysms treated with a Pipeline Embolization Device in vessels less than 2.5 mm between June 2012 and August 2014 were included. We evaluated risk factors, family history of aneurysms, aneurysm characteristics, National Institute of Health Stroke Scale (NIHSS), and modified Rankin scale (mRS) on admission and angiography and clinical outcome at discharge, 6 months, and 1 year. RESULTS: We included seven patients with a mean age of 65 years. The parent vessel size ranged from 1.5 to 2.3 mm; mean 1.9 mm. Location of the aneurysms was as follows: two aneurysms centered along the pericallosal artery (one left, one right), one on the right angular artery, one aneurysm at the anterior communicating artery (ACom), one at the ACom-right A2 anterior cerebral artery (ACA), one at the lenticulostriate artery, and one at the A1-A2 ACA artery. Aneurysms ranged from 1 to 12 mm in diameter. All aneurysms were treated with a single Pipeline Embolization Device (PED). No peri- or post-procedural complications or mortality occurred. The patients were discharged with no change in NIHSS or mRS score. Angiographic follow-up was available in six patients. Angiography showed complete aneurysm occlusion in all. NIHSS and mRS remained unchanged at follow-up. CONCLUSION: Our preliminary results show that flow diversion technology is an effective and safe therapy for aneurysms located on small cerebral arteries. Larger studies with long-term follow-up are needed to validate our promising results.

Onyx embolization in distal dissecting posterior inferior cerebellar artery aneurysms.

BACKGROUND: Dissecting aneurysms located along the distal segments of the posterior inferior cerebellar artery (PICA) are extremely rare, accounting for only 0.5-0.7% of all intracranial aneurysms. Treatment of these aneurysms is challenging, both surgically and endovascularly. We present our preliminary experience and clinical data utilizing Onyx as an embolization agent in the treatment of these lesions with proximal parent artery preservation. METHODS: 7 consecutive ruptured peripheral PICA aneurysms, in 7 patients, were treated with superselective Onyx embolization at our institutions. According to the anatomical classification of Lister et al, these aneurysms were located in the lateral medullary segment (n=1), tonsillomedullary segment (n=1), and the telovelotonsillary segment (n=5) of the PICA. Technical feasibility, procedure related complications, angiographic results, follow-up diagnostic imaging, and clinical outcome were evaluated. RESULTS: In all cases, endovascular treatment was successful, with complete occlusion of the aneurysm with proximal parent artery preservation at the final postprocedural angiogram. Procedure related complications were not observed. One patient with a poor clinical condition at admission died during the initial hospital stay due to extensive subarachnoid and intraventricular hemorrhage. No rebleeding or recanalization was noted during follow-up. Two patients had a residual moderate to severe disability at follow-up. Favorable outcomes, with no or mild disability, were observed in four of the surviving patients. CONCLUSIONS: Angiographic, diagnostic imaging, and clinical results of our small series indicate that Onyx embolization of dissecting distal PICA aneurysms with parent artery preservation is an effective option with acceptable morbidity and mortality rate, in those cases in which surgical clipping or endovascular coiling of the aneurysmal sac is not suitable.

Stent-assisted coil embolization of aneurysms with small parent vessels: safety and efficacy analysis.

BACKGROUND: Stent-assisted coil embolization (SACE) is a viable therapeutic approach for wide-neck intracranial aneurysms. However, it can be technically challenging in small cerebral vessels (≤2 mm). OBJECTIVE: To present our experience with stents approved for SACE in aneurysms with small parent arteries. METHODS: All patients who underwent stent-assisted aneurysm treatment with either a Neuroform or an Enterprise stent device at our institution between June 2006 and October 2012 were identified. Additionally, we evaluated each patient's vascular risk factors, aneurysm characteristics (ruptured vs non-ruptured, incidental finding, recanalized) and follow-up angiography data. RESULTS: A total of 41 patients with 44 aneurysms met our criteria, including 31 women and 10 men. Most of the aneurysms were located in the anterior circulation (75%). Stent placement in vessels 1.2-2 mm in diameter was successful in 93.2%. Thromboembolic complications occurred in 6 cases and vessel straightening was seen in 1 case only. Initial nearly complete to complete aneurysm obliteration was achieved in 88.6%. Six-month follow-up angiography showed coil compaction in three cases, one asymptomatic in-stent stenosis and stent occlusion. Twelve to 20-months' follow-up showed stable coil compaction in two patients compared with previous follow-up, and aneurysm recanalization in two patients. Twenty-four to 36-months' follow-up showed further coil compaction in one of these patients and aneurysm recanalization in a previous case of stable coil compaction on mid-term follow-up. CONCLUSIONS: Our results suggest that SACE of aneurysms with small parent vessels is feasible in selected cases and shows good long-term patency rates of parent arteries.

Endovascular treatment of tandem vascular occlusions in acute ischemic stroke.

BACKGROUND AND PURPOSE: Tandem vascular occlusions are an important cause of acute ischemic stroke (AIS) and present unique treatment challenges. We report our experience of managing a subset of AIS patients with extracranial vascular stenting/angioplasty and intracranial revascularization. METHODS: Consecutive patients who presented at three centers with AIS from tandem vascular occlusions confirmed by brain and neck CT imaging were included in the study. We retrospectively analyzed the patient demographics, National Institute of Health Stroke Scale (NIHSS) score and modified Rankin Scale (mRS) score at the time of admission, treatment strategy, angiographic results using the Thrombolysis In Cerebral Infarction (TICI) score, and clinical and imaging follow-up. RESULTS: Twenty-eight patients were included. The mean NIHSS score at admission was 18. Extracranial carotid occlusions with a concomitant middle cerebral artery occlusion were seen in 89.3% of patients (n=25) and vertebral artery combined with basilar artery lesions in 10.7% (n=3). An antegrade approach (ie, treatment of the extracranial lesion first) was used in 24 patients (85.7%). Proximal occlusion recanalization was achieved usually with a stent (n=27; 96.4%). Pursuant to intracranial revascularization techniques, ≥ TICI 2A recanalization was seen in 96.4% of patients. An mRS score of ≤ 2 at 90 days was achieved in 56.5% of patients. CONCLUSIONS: Our study shows preliminary data from three centers on recanalization of tandem occlusions in patients presenting with AIS. There was a preference to revascularize the proximal occlusion using a stent followed by distal recanalization with mechanical thrombectomy, intra-arterial thrombolysis or a combination of these. This approach has low periprocedural complications and can achieve an excellent angiographic and clinical outcome.

Flow diverter stents for unruptured saccular anterior circulation perforating artery aneurysms: safety, efficacy, and short-term follow-up.

BACKGROUND: Anterior circulation perforating artery aneurysms including anterior choroidal artery and lenticulostriate artery aneurysms are rare. Injury to these vessels can lead to severe debilitating symptoms. OBJECTIVE: To present a new approach to treatment using flow diversion technology. METHODS: Patients treated with a Pipeline embolization device (PED) for perforator artery aneurysms at our institution between June 2012 and May 2013 were identified and included in our retrospective analysis. We evaluated patient vascular risk factors; family history of aneurysms; aneurysm characteristics; National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) on admission; and angiography follow-up and patient clinical outcome at discharge, 6 months, and 1 year. RESULTS: We included four patients with a mean age of 59.8 years. Two patients had a positive family history of aneurysms. Patient vascular risk factors included smoking, dyslipidemia, and hypertension. All patients presented with a NIHSS and mRS of 0 on admission. Aneurysms were located at the anterior choroidal (n=2) or lenticulostriate artery (n=2) and were treated with a single PED. No periprocedural or postprocedural complications occurred. The patients were discharged with no change in NHISS or mRS score. Six-month and 1-year follow-up angiography showed complete aneurysm occlusion. Mild intimal hyperplasia was seen in 2 cases at 6 months, but was resolved at the 1-year follow-up. No re-treatment was necessary. NIHSS and mRS remained 0 at follow-up time points. CONCLUSIONS: Our preliminary results show that flow diversion technology is an effective and safe therapy for complex, hard-to-treat aneurysms in perforating arteries. Larger studies with long-term follow-up are needed to validate our promising results.

Use of intermediate guide catheters as an adjunct in extracranial embolization to avoid onyx reflux into the anastomotic vasculature. A technical note.

Onyx is a non-adhesive polymer used for embolization of arteriovenous malformations and dural arteriovenous fistulas (DAVFs). The limiting factor for Onyx embolization is usually the amount of microcatheter reflux, which can be safely tolerated. The dual microcatheter technique, compliant balloon use proximally and the use of the dual lumen Scepter balloon have been described to prevent and limit proximal Onyx reflux. We describe the use the Navien 058 intermediate guide catheter to accept the Onyx reflux in its lumen and possibly also serve as a mechanical barrier to avoid reflux into the anastomotic channel connecting the occipital artery to the vertebral artery during DAVF embolization via the occipital artery. Complete embolization of the DAVF was achieved using the lumen of the Navien catheter to accept aggressive Onyx reflux. Complete cure of the DAVF was obtained with Onyx cast filling the entire venous pouch. Besides providing distal access support, intermediate guide catheters can also prevent embolic material reflux by accepting reflux into the lumen and providing a mechanical barrier.

Visualization of a small hidden intracranial aneurysm during endovascular thrombectomy for acute MCA occlusion.

Spontaneous aneurysmal thrombosis as a cause for acute ischemic stroke is a rarely described complication of small unruptured intracranial aneurysms. We present an interesting case of a stroke in a woman with an occult acutely thrombosed middle cerebral artery bifurcation aneurysm that was found during successful thrombus aspiration of the occluded parent vessel. Although rare, small aneurysms have to be considered as a possible cause for a thrombotic vessel occlusion. Catheters and thrombectomy devices have to be used carefully while performing mechanical revascularization.

A novel anti-CD19 monoclonal antibody (GBR 401) with high killing activity against B cell malignancies.

BACKGROUND: CD19 is a B cell lineage specific surface receptor whose broad expression, from pro-B cells to early plasma cells, makes it an attractive target for the immunotherapy of B cell malignancies. In this study we present the generation of a novel humanized anti-CD19 monoclonal antibody (mAb), GBR 401, and investigate its therapeutic potential on human B cell malignancies. METHODS: GBR 401 was partially defucosylated in order to enhance its cytotoxic function. We analyzed the in vitro depleting effects of GBR 401 against B cell lines and primary malignant B cells from patients in the presence or in absence of purified NK cells isolated from healthy donors. In vivo, the antibody dependent cellular cytotoxicity (ADCC) efficacy of GBR 401 was assessed in a B cell depletion model consisting of SCID mice injected with healthy human donor PBMC, and a malignant B cell depletion model where SCID mice are xenografted with both primary human B-CLL tumors and heterologous human NK cells. Furthermore, the anti-tumor activity of GBR 401 was also evaluated in a xenochimeric mouse model of human Burkitt lymphoma using mice xenografted intravenously with Raji cells. Pharmacological inhibition tests were used to characterize the mechanism of the cell death induced by GBR 401. RESULTS: GBR 401 exerts a potent in vitro and in vivo cytotoxic activity against primary samples from patients representing various B-cell malignancies. GBR 401 elicits a markedly higher level of ADCC on primary malignant B cells when compared to fucosylated similar mAb and to Rituximab, the current anti-CD20 mAb standard immunotherapeutic treatment for B cell malignancies, showing killing at 500 times lower concentrations. Of interest, GBR 401 also exhibits a potent direct killing effect in different malignant B cell lines that involves homotypic aggregation mediated by actin relocalization. CONCLUSION: These results contribute to consolidate clinical interest in developing GBR 401 for treatment of hematopoietic B cell malignancies, particularly for patients refractory to anti-CD20 mAb therapies.

Double embolic protection during carotid artery stenting with persistent hypoglossal artery.

A woman presented with 75% stenosis of the right internal carotid artery (ICA) with extension to the origin of a persistent hypoglossal artery (PHA). The PHA is a rare fetal variant of carotid-basilar anastomosis that elevates the risk of ischemia and embolic infarction within the posterior cerebral circulation in patients with carotid disease proximal to the anastomosis. Our case is highly unique because of the extremely rare nature of the PHA with associated ICA stenosis that extended to the PHA. Additionally, a novel treatment approach was employed by stenting and angioplasty while protecting both the anterior and posterior cerebral circulations.

Double embolic protection during carotid artery stenting with persistent hypoglossal artery.

A woman presented with 75% stenosis of the right internal carotid artery (ICA) with extension to the origin of a persistent hypoglossal artery (PHA). The PHA is a rare fetal variant of carotid-basilar anastomosis that elevates the risk of ischemia and embolic infarction within the posterior cerebral circulation in patients with carotid disease proximal to the anastomosis. Our case is highly unique because of the extremely rare nature of the PHA with associated ICA stenosis that extended to the PHA. Additionally, a novel treatment approach was employed by stenting and angioplasty while protecting both the anterior and posterior cerebral circulations.

The value of arterial spin-labeled perfusion imaging in acute ischemic stroke: comparison with dynamic susceptibility contrast-enhanced MRI.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the potential clinical value of arterial spin-labeled (ASL) perfusion MRI in acute ischemic stroke (AIS) through comparison with dynamic susceptibility contrast (DSC) enhanced perfusion MRI. METHODS: Pseudocontinuous ASL with 3-dimensional background-suppressed gradient and spin echo readout was applied with DSC perfusion MRI on 26 patients with AIS. ASL cerebral blood flow and multiparametric DSC perfusion maps were rated for image quality and lesion severity/conspicuity. Mean ASL cerebral blood flow and DSC perfusion values were obtained in main vascular territories. Kendall coefficient of concordance was calculated to evaluate the reliability of ratings. Spearman correlation coefficients were calculated to compare ratings and quantitative perfusion values between ASL and DSC perfusion maps. RESULTS: ASL cerebral blood flow and DSC perfusion maps provided largely consistent results in delineating hypoperfused brain regions in AIS. Hyperemic lesions, which also appeared frequently in the AIS cases studied, were more conspicuous on ASL cerebral blood flow than on DSC cerebral blood flow, mean transit time and time to the maximum of the tissue residual function maps. CONCLUSIONS: As a rapid, noninvasive, and quantitative technique, ASL has clinical use in detecting blood flow abnormalities in patients with AIS.

Brd4 links chromatin targeting to HPV transcriptional silencing.

The E2 protein encoded by human papillomaviruses (HPVs) inhibits expression of the viral E6 oncoprotein, which, in turn, regulates p53 target gene transcription. To identify cellular proteins involved in E2-mediated transcriptional repression, we isolated an E2 complex from human cells conditionally expressing HPV-11 E2. Surprisingly, the double bromodomain-containing protein Brd4, which is implicated in cell cycle control and viral genome segregation, was found associated with E2 and conferred on E2 the ability to inhibit AP-1-dependent HPV chromatin transcription in an E2-binding site-specific manner as illustrated by in vitro reconstituted chromatin transcription experiments. Knockdown of Brd4 in human cells alleviates E2-mediated repression of HPV transcription. The E2-interacting domain at the extreme C terminus and the chromatin targeting activity of a bromodomain-containing region are both essential for the corepressor activity of Brd4. Interestingly, E2-Brd4 blocks the recruitment of TFIID and RNA polymerase II to the HPV E6 promoter region without inhibiting acetylation of nucleosomal histones H3 and H4, indicating an acetylation-dependent role of Brd4 in the recruitment of E2 for transcriptional silencing of HPV gene activity. Our finding that Brd4 is a component of the virus-assembled transcriptional silencing complex uncovers a novel function of Brd4 as a cellular cofactor modulating viral gene expression.

Transcriptional activity among high and low risk human papillomavirus E2 proteins correlates with E2 DNA binding.

The full-length E2 protein, encoded by human papillomaviruses (HPVs), is a sequence-specific transcription factor found in all HPVs, including cancer-causing high risk HPV types 16 and 18 and wart-inducing low risk HPV types 6 and 11. To investigate whether E2 proteins encoded by high risk HPVs may function differentially from E2 proteins encoded by low risk HPVs and animal papillomaviruses, we conducted comparative DNA-binding and transcription studies using electrophoretic mobility shift assays and cell-free transcription systems reconstituted with purified general transcription factors, cofactor, RNA polymerase II, and with E2 proteins encoded by HPV-16, HPV-18, HPV-11, and bovine papillomavirus type 1 (BPV-1). We found that although different types of E2 proteins all exhibited transactivation and repression activities, depending on the sequence context of the E2-binding sites, HPV-16 E2 shows stronger transcription activity and greater DNA-binding affinity than those displayed by the other E2 proteins. Surprisingly, HPV-18 E2 behaves more similarly to BPV-1 E2 than HPV-16 E2 in its functional properties. Our studies thus categorize HPV-18 E2 and BPV-1 E2 in the same protein family, a finding consistent with the available E2 structural data that separate the closely related HPV-16 and HPV-18 E2 proteins but classify together the more divergent BPV-1 and HPV-18 E2 proteins.