PHIL® (precipitating hydrophobic injectable liquid): retrospective multicenter experience on 178 patients in peripheral embolizations.

PURPOSE: This study aims to analyze safety and effectiveness of PHIL® (Microvention, CA-USA) in peripheral endovascular embolization procedures, both in elective and emergent scenarios. MATERIALS AND METHODS: This is a multicenter retrospective study, involving 178 patients from five interventional radiology departments from January 2017 to December 2021. Patients treated by an endovascular embolization with PHIL® were included; different PHIL® viscosities were adopted. Exclusion criteria were: neuroradiological endovascular interventions, other cohesive liquid embolics adopted during the same procedure, follow-up < 30 days. Technical success was intended as definitive target vessel occlusion without the need for other embolics after PHIL® injection. Clinical success was considered as restoration of hemodynamic status in case of emergent embolization and improvement of clinical conditions in case of elective procedures, without additional interventions at 30 days. RESULTS: Sixty-four women and 114 men, mean age 62 years (range 6-91), were evaluated. Sixty-three patients were in elective scenarios (AVMs, type-II endoleaks, tumors, varices, aneurysms, varicoceles) and 115 were in emergent settings (hemorrhage, pseudoaneurysms, hemoptysis, priapism); 190 procedures were performed in 178 patients. Overall technical and clinical success rates were 94.7% and 92.1%, respectively. The complications rate was 7.4% (6 grade-I, 7 grade-III, 1 grade-IV). PHIL®-25 was the more adopted viscosity; totally, 311 vials were injected (rate: 1.64 vial/procedure). CONCLUSION: In this series, PHIL® proved to be a safe and effective liquid embolic in peripheral embolizations, both in elective and emergent scenarios. The pre-filled syringe preparation allowed operators to use it even when unplanned at beginning of the intervention.

Molecular Biomarkers and Drug Targets in Brain Arteriovenous and Cavernous Malformations: Where Are We?

Vascular malformations of the brain (VMB) comprise abnormal development of blood vessels. A small fraction of VMBs causes hemorrhages with neurological morbidity and risk of mortality in patients. Most often, they are symptomatically silent and are detected at advanced stages of disease progression. The most common forms of VMBs are arteriovenous and cavernous malformations in the brain. Radiopathological features of these diseases are complex with high phenotypic variability. Early detection of these malformations followed by preclusion of severe neurological deficits such as hemorrhage and stroke is crucial in the clinical management of patients with VMBs. The technological advances in high-throughput omics platforms have currently infused a zest in translational research in VMBs. Besides finding novel biomarkers and therapeutic targets, these studies have withal contributed significantly to the understanding of the etiopathogenesis of VMBs. Here we discuss the recent advances in predictive and prognostic biomarker research in sporadic and familial arteriovenous malformations as well as cerebral cavernous malformations. Furthermore, we analyze the clinical applicability of protein and noncoding RNA-based molecular-targeted therapies which may have a potentially key role in disease management.

Safety and Effectiveness of Ethylene Vinyl Alcohol Copolymer Embolization of Peripheral High-Flow Arteriovenous Malformations: Results of a Prospective Study.

PURPOSE: To prospectively evaluate the efficacy and safety of a new ethylene vinyl alcohol (EVOH) copolymer-based embolic agent in the treatment of symptomatic peripheral arteriovenous malformations (AVMs). MATERIALS AND METHODS: This prospective single-center study evaluated EVOH embolization with 3 different formulations of EVOH (Squid Peri 12 cP, 18 cP, and 34 cP; BALT Germany GmbH, Düsseldorf, Germany) in patients with symptomatic AVMs. Between April 2018 and October 2019, 36 embolization procedures in 21 patients (3 males and 18 females; mean age, 34.7 years) were performed (inclusion criteria: symptomatic peripheral AVM, ≥14 years of age, and elective embolization). Symptoms, technical aspects (transarterial, transvenous, or percutaneous approach; plug or balloon occlusion), clinical and technical success (defined as the improvement of symptoms and complete angiographic eradication of the AVM nidus), adverse events, and short-term outcomes were assessed. RESULTS: The mean volume of the embolic agent used per session was 3.4 mL of EVOH 34 cP (standard deviation [SD], ± 5.4), 6.2 mL ± 8.1 of EVOH 18 cP, and 4.6 mL ± 10.1 of EVOH 12 cP. Angiographic success was achieved in 18 patients (85.7%). The mean follow-up was 190 days (range, 90-538 days; median, 182 days). In the follow-up assessment, findings of magnetic resonance imaging showed that 19 patients (90.5%) had a persistent state of devascularization compared with postinterventional angiography. Amelioration or complete elimination of pain was achieved in 90.0% of the patients. One patient experienced a major adverse event; minor adverse events developed in 2 patients. CONCLUSIONS: In this study, EVOH appeared to be a safe and effective embolic agent in peripheral AVMs and had a low rate of adverse events in a limited number of patients.

Multiple Arterial Vascular Anomalies in the Periorbital, Paranasal, and Intracranial Spaces Treated With Systemic Bevacizumab.

ABSTRACT: Arteriovenous malformations of the orbit are rare congenital hamartomas defined by a direct connection between the arterial and venous systems without an intervening capillary bed. Treatment can be challenging, as these lesions are anatomically complex, often involve multiple locations, and have a tendency to recur. A multidisciplinary approach is typically required, involving endovascular and surgical teams. The authors present a case of a 33-year-old man with a complex, recurrent orbital arteriovenous malformations in the context of wider head and neck vascular anomaly syndrome involving the paranasal sinuses, deep facial tissues, and intracranial spaces. The complex and evolving clinical manifestations of this disease are presented with emphasis on the interdependence of the anomalies and biologic management strategies.

Late recovery of stereotactic radiosurgery induced perilesional edema of an arteriovenous malformation after bevacizumab treatment.

MATERIALS AND METHODS: We present a 41-year old male patient who was admitted to our clinic with epileptic seizures, headaches and hemiparesis 14 months after SRS treatment for a left fronto-parietal Spetzler-Martin Grade III arteriovenous malformation (AVM). On his first-year follow-up perilesional edema was observed for which the patient received steroid treatment, but the patient did not show any benefit from it. In the cases of steroid resistant perilesional edemas, bevacizumab can be used for reducing symptoms and even radiological perilesional edema as well. RESULTS: In our case, we have seen the effect of bevacizumab for symptomatic perilesional edema in a AVM patient after SRS treatment after radiological / neurological recovery. Our patient's headaches decreased rapidly after 2 days after treatment and was able to mobilize himself after 2 months but total resolution of symptoms and radiological findings observed after 1,5 years. CONCLUSIONS: The duration and optimum dose of bevacizumab therapy needed to further investigation. Our study showed that bevacizumab was a long-term and effective treatment option for the cases with peritumoral edema resistant to glucocorticoid treatment, where the patient had conditions such as severe headache and neurological deficits.

Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial.

BACKGROUND: In A Randomized trial of Unruptured Brain Arteriovenous malformations (ARUBA), randomisation was halted at a mean follow-up of 33·3 months after a prespecified interim analysis showed that medical management alone was superior to the combination of medical management and interventional therapy in preventing symptomatic stroke or death. We aimed to study whether these differences persisted through 5-years' follow-up. METHODS: ARUBA was a non-blinded, randomised trial done at 39 clinical centres in nine countries. Adults (age ≥18 years) diagnosed with an unruptured brain arteriovenous malformation, who had never undergone interventional therapy, and were considered by participating clinical centres to be suitable for intervention to eradicate the lesion, were eligible for inclusion. Patients were randomly assigned (1:1) by a web-based data collection system, stratified by clinical centre in a random permuted block design with block sizes of two, four, and six, to medical management alone or with interventional therapy (neurosurgery, embolisation, or stereotactic radiotherapy, alone or in any combination, sequence, or number). Although patients and investigators at a given centre were not masked to treatment assignment, investigators at other centres and those in the clinical coordinating centre were not informed of assignment or outcomes at any of the centres. The primary outcome was time to death or symptomatic stroke confirmed by imaging, assessed by a neurologist at each centre not involved in the management of participants' care, and monitored by an independent committee using an adaptive approach with interim analyses. Enrolment began on April 4, 2007, and was halted on April 15, 2013, after which follow-up continued until July 15, 2015. All analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, NCT00389181. FINDINGS: Of 1740 patients screened, 226 were randomly assigned to medical management alone (n=110) or medical management plus interventional therapy (n=116). During a mean follow-up of 50·4 months (SD 22·9), the incidence of death or symptomatic stroke was lower with medical management alone (15 of 110, 3·39 per 100 patient-years) than with medical management with interventional therapy (41 of 116, 12·32 per 100 patient-years; hazard ratio 0·31, 95% CI 0·17 to 0·56). Two patients in the medical management group and four in the interventional therapy group (two attributed to intervention) died during follow-up. Adverse events were observed less often in patients allocated to medical management compared with interventional therapy (283 vs 369; 58·97 vs 78·73 per 100 patient-years; risk difference -19·76, 95% CI -30·33 to -9·19). INTERPRETATION: After extended follow-up, ARUBA showed that medical management alone remained superior to interventional therapy for the prevention of death or symptomatic stroke in patients with an unruptured brain arteriovenous malformation. The data concerning the disparity in outcomes should affect standard specialist practice and the information presented to patients. The even longer-term risks and differences between the two therapeutic approaches remains uncertain. FUNDING: National Institute of Neurological Disorders and Stroke for the randomisation phase and Vital Projects Fund for the follow-up phase.

An Update on Medications for Brain Arteriovenous Malformations.

Despite a variety of treatment options for brain arteriovenous malformations (bAVMs), many lesions remain challenging to treat and present significant ongoing risk for hemorrhage. In Vitro investigations have recently led to a greater understanding of the formation, growth, and rupture of bAVMs. This has, in turn, led to the development of therapeutic targets for medications for bAVMs, some of which have begun testing in clinical trials in humans. These include bevacizumab, targeting the vascular endothelial growth factor driven angiogenic pathway; thalidomide or lenalidomide, targeting blood-brain barrier impairment; and doxycycline, targeting matrix metalloproteinase overexpression. A variety of other medications appear promising but either requires adaptation from other disease states or development from early bench studies into the clinical realm. This review aims to provide an overview of the current state of development of medications targeting bAVMs and to highlight their likely applications in the future.

Role of aspirin and statin therapy in patients with cerebral cavernous malformations.

Stagnant blood flow and organizing thrombus are intralesional components of patients with cerebral cavernous malformations (CCM). Stasis and inflammation are mechanisms of growth, lesional instability and acute hemorrhages with or w/o symptoms. We evaluate the association of pre-diagnostic aspirin and/or statin use with acute hemorrhages at diagnosis. Patients with a CCM diagnosis were identified and categorized according to their medications on admission into four groups (no therapy, statin, aspirin, combined). The primary outcome was an acute hemorrhage (with or w/o symptoms) at diagnosis reported in a standardized manner from the T2 weighted magnetic resonance image. A multivariate generalized linear mixed models (GLMM) was utilized to conduct per-lesion analysis. We identified 446 patients with 635 lesions. An acute hemorrhage at diagnosis was observed in 31% of the patients. There were 328 patients without statin or aspirin therapy, 34% of whom presented with acute hemorrhage. Of patients on aspirin therapy at diagnosis, 25% presented with hemorrhage. Of patients on statin therapy, 26% had a hemorrhage at diagnosis. Combined therapy in 44 patients demonstrated a lower proportion of patients with acute hemorrhages (7 patients, 16% incidence). A GLMM showed that patients in the combined therapy group to have significantly lower odds of having an acute hemorrhage at diagnosis compared to the reference group of no therapy (OR 0.24; 95% CI 0.09-0.59; P = 0.002). Patients with a CCM receiving therapy with both aspirin and statins were less likely to present at diagnosis with acute hemorrhage.

Elevated endothelial Sox2 causes lumen disruption and cerebral arteriovenous malformations.

Lumen integrity in vascularization requires fully differentiated endothelial cells (ECs). Here, we report that endothelial-mesenchymal transitions (EndMTs) emerged in ECs of cerebral arteriovenous malformation (AVMs) and caused disruption of the lumen or lumen disorder. We show that excessive Sry-box 2 (Sox2) signaling was responsible for the EndMTs in cerebral AVMs. EC-specific suppression of Sox2 normalized endothelial differentiation and lumen formation and improved the cerebral AVMs. Epigenetic studies showed that induction of Sox2 altered the cerebral-endothelial transcriptional landscape and identified jumonji domain-containing protein 5 (JMJD5) as a direct target of Sox2. Sox2 interacted with JMJD5 to induce EndMTs in cerebral ECs. Furthermore, we utilized a high-throughput system to identify the ß-adrenergic antagonist pronethalol as an inhibitor of Sox2 expression. Treatment with pronethalol stabilized endothelial differentiation and lumen formation, which limited the cerebral AVMs.

Defective vascular signaling & prospective therapeutic targets in brain arteriovenous malformations.

The neurovascular unit is composed of endothelial cells, vascular smooth muscle cells, pericytes, astrocytes and neurons. Through tightly regulated multi-directional cell signaling, the neurovascular unit is responsible for the numerous functionalities of the cerebrovasculature - including the regulation of molecular and cellular transport across the blood-brain barrier, angiogenesis, blood flow responses to brain activation and neuroinflammation. Historically, the study of the brain vasculature focused on endothelial cells; however, recent work has demonstrated that pericytes and vascular smooth muscle cells - collectively known as mural cells - play critical roles in many of these functions. Given this emerging data, a more complete mechanistic understanding of the cellular basis of brain vascular malformations is needed. In this review, we examine the integrated functions and signaling within the neurovascular unit necessary for normal cerebrovascular structure and function. We then describe the role of aberrant cell signaling within the neurovascular unit in brain arteriovenous malformations and identify how these pathways may be targeted therapeutically to eradicate or stabilize these lesions.

Seizure control after radiosurgery for cerebral arteriovenous malformations: a 25-year experience.

OBJECTIVE: Seizures are the second-most common presenting symptom in patients with lobar arteriovenous malformations (AVMs). However, few studies have assessed the long-term effect of stereotactic radiosurgery (SRS) on seizure control. The authors of this study assess the outcome of SRS for these patients to identify prognostic factors associated with seizure control. METHODS: Patients with AVM who presented with a history of seizure and underwent SRS at the authors' institution between 1987 and 2012 were retrospectively assessed. The total cohort included 155 patients with a mean follow-up of 86 months (range 6-295 months). Primary outcomes assessed were seizure frequency, antiepileptic drug regimen, and seizure freedom for 6 months prior to last follow-up. RESULTS: Seizure-free status was achieved in 108 patients (70%), with an additional 23 patients (15%) reporting improved seizure frequency as compared to their pre-SRS status. The median time to seizure-free status was estimated to be 12 months (95% CI 0-27 months) as evaluated via Kaplan-Meier survival analysis. The mean seizure frequency prior to SRS was 14.2 (95% CI 5.4-23.1) episodes per year. Although not all patients tried, the proportion of patients successfully weaned off all antiepileptic drugs was 18% (28/155 patients). On multivariate logistic regression, focal impaired awareness seizure type (also known as complex partial seizures) and superficial venous drainage were significantly associated with a decreased odds ratio for seizure-free status at last follow-up (OR 0.37 [95% CI 0.15-0.92] for focal impaired awareness seizures; OR 0.36 [95% CI 0.16-0.81] for superficial venous drainage). The effects of superficial venous drainage on seizure outcome were nonsignificant when excluding patients with < 2 years of follow-up. AVM obliteration did not correlate with long-term seizure freedom (p = 0.202, chi-square test). CONCLUSIONS: This study suggests that SRS improves long-term seizure control and increases the likelihood of being medication free, independently of AVM obliteration. Patients with focal impaired awareness seizures were less likely to obtain long-term seizure relief.

Antithrombotic therapy and intracranial bleeding in subjects with sporadic brain arteriovenous malformations: preliminary results from a retrospective study.

Whether antithrombotic treatment is safe and/or affects the risk of intracranial bleeding in subjects with sporadic brain arteriovenous malformations (AVMs) is unknown. We conducted a retrospective analysis on the use of antithrombotics among patients affected by brain AVMs in follow-up at our institution. Attention was paid to the type of antithrombotic drug (either antiplatelets or anticoagulants), current or past use, dosage, and duration of treatment. Several clinical and angioarchitectural features of brain AVMs were also taken into consideration. The association between the use of antithrombotics and haemorrhagic onset was analyzed. A total of 77 patients were included in this study. Among them, ten patients were taking antithrombotic drugs at the time of AVM diagnosis. The rate of haemorrhagic onset was not significantly different between subjects who were and were not taking antithrombotic drugs (40 vs 55.2%, p = ns). Among the many clinical and angioarchitectural features analyzed, the only parameter that showed a statistically significant association with haemorrhagic onset was the size of the nidus. Patients who took antithrombotic treatments after being diagnosed with a brain AVM did not show an increased rate of intracranial haemorrhage over time considering a mean follow-up 4 years. In our study, antithrombotic treatment was not associated with increased intracranial bleeding among subjects with brain AVMs. In the presence of a strong clinical indication, antiplatelet and anticoagulant medications should not be denied a priori to patients with brain AVMs. Studies on larger populations are necessary to confirm these data.

Intraventricular hemorrhage related to AVM rupture: Description, outcomes and impact of intraventricular fibrinolysis.

OBJECTIVES: Arteriovenous malformation (AVM) rupture could lead to intraventricular hemorrhage (IVH), a particularly severe form of intracranial bleeding. The epidemiology, presentation, management and outcomes of IVH related to AVM rupture have not been clearly addressed yet. The aim of the present study was to investigate the characteristics of IVH related to AVM rupture, with particular attention paid to functional outcomes and to the impact of intraventricular fibrinolysis (IVF). PATIENTS AND METHODS: Between 2011 and 2015, all patients suffering from IVH admitted in two tertiary neurosurgical centers were included in a prospective register. Patient with IVH related to AVM rupture were identified (n=29) and their data retrospectively collected. Particular attention was paid on patients who received IVF. We also compared them to 29 apparied aneurysmal IVH. RESULTS: IVH related to AVM rupture often occurred in young patients. In most cases, intracerebral hemorrhage was associated to IVH. 17% of the patients died, and functional outcome at 6 months was similar to those with aneurysmal IVH. Interestingly, 5 patients received IVF and none experienced any rebleeding. CONCLUSION: IVH related to AVM rupture is a severe form of hemorrhagic stroke, with a poor neurologic prognosis. IVF seems to be safe and may be considered in this particular form of IVH.

Functional impairments for outcomes in a randomized trial of unruptured brain AVMs.

OBJECTIVE: To investigate the effects of medical vs interventional management on functional outcome in A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA). METHODS: We used the initial results of a nonblinded, randomized, controlled, parallel-group trial involving adults ≥18 years of age with an unruptured brain arteriovenous malformation (AVM) to compare the effects of medical management (MM) with or without interventional therapy (IT) on functional impairment, defined by a primary outcome of death or symptomatic stroke causing modified Rankin Scale (mRS) score ≥2. ARUBA closed recruitment on April 15, 2013. RESULTS: After a median of 33.3 months of follow-up (interquartile range 16.3-49.8 months), of the 223 enrolled in the trial, those in the MM arm were less likely to experience primary outcomes with an mRS score ≥2 than those who underwent IT. The results applied for both those as randomized (MM n = 109 vs IT n = 114) (hazard ratio [HR] 0.25, 95% confidence interval [CI] 0.11-0.57, p = 0.001) and as treated (MM n = 125 vs IT n = 98) (HR 0.10, 95% CI 0.04-0.28, p < 0.001). Functional impairment for the outcomes showed no significant difference by Spetzler-Martin grade for MM but was more frequent with increasing grades for IT (p < 0.001). CONCLUSION: Death or stroke with functional impairment in ARUBA after a median follow-up of 33 months was significantly lower for those in the MM arm both as randomized and as treated compared with those with IT. Functional severity of outcomes was lower in the MM arm, regardless of Spetzler-Martin grades. CLINICALTRIALSGOV IDENTIFIER: NCT00389181. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for adults with unruptured brain AVMs, interventional management compared to MM increases the risk of disability and death over ≈3 years.

Liquid Embolic Agents for Endovascular Embolization: Evaluation of an Established (Onyx) and a Novel (PHIL) Embolic Agent in an In Vitro AVM Model.

BACKGROUND AND PURPOSE: Embolization plays a key role in the treatment of arteriovenous malformations. The aim of this study was to evaluate an established (Onyx) and a novel (precipitating hydrophobic injectable liquid [PHIL]) liquid embolic agent in an in vitro AVM model. MATERIALS AND METHODS: An AVM model was integrated into a circuit system. The artificial nidus (subdivided into 28 honeycomb-like sections) was embolized with Onyx 18 (group Onyx; n = 8) or PHIL 25 (group PHIL; n = 8) with different pause times between the injections (30 and 60 seconds, n = 4 per study group) by using a 1.3F microcatheter. Procedure times, number of injections, embolization success (defined as the number of filled sections of the artificial nidus), volume of embolic agent, and frequency and extent of reflux and draining vein embolization were assessed. RESULTS: Embolization success was comparable between Onyx and PHIL. Shorter pause times resulted in a significantly higher embolization success for PHIL (median embolization score, 28 versus 18; P = .011). Compared with Onyx, lower volumes of PHIL were required for the same extent of embolization (median volume per section of the artificial nidus, 15.5 versus 3.6 µL; P < .001). CONCLUSIONS: While the embolization success was comparable for Onyx and PHIL, pause time had a considerable effect on the embolization success in an in vitro AVM model. Compared with Onyx, lower volumes of PHIL were required for the same extent of embolization.

Derivation of Self-inhibitory Helical Peptides to Target Rho-kinase Dimerization in Cerebrovascular Malformation: Structural Bioinformatics Analysis and Peptide Binding Assay.

Rho-kinase dimerization is essential for its kinase activity and biological function; disruption of the dimerization has recently been established as a new and promising therapeutics strategy for cerebrovascular malformation (CM). Based on Rho-kinase dimer crystal structure we herein combined in silico analysis and in vitro assay to rationally derive self-inhibitory peptides from the dimerization interface. Three peptides namely Hlp1, Hlp2 and Hlp3 were successfully designed that have potential capability to rebind at the dimerization domain of Rho-kinase. Molecular dynamics (MD) simulations revealed that these peptides are helically structured when bound to Rho-kinase, but exhibit partially intrinsic disorder in unbound state. Binding free energy (BFE) analysis suggested that the peptides have a satisfactory energetic profile to interact with Rho-kinase. The computational findings were then substantiated by fluorescence anisotropy assays, conforming that the helical peptides can bind tightly to Rho-kinase with affinity KD at micromolar level. These designed peptides are considered as lead molecular entities that can be further modified and optimized to obtain more potent peptidomimetics as self-competitors to disrupt Rho-kinase dimerization in CM.