Endovascular treatment of brain arteriovenous malformations using a liquid embolic agent: results of a prospective, multicentre study (BRAVO).

OBJECTIVES: To evaluate the safety and efficacy of a new liquid embolic agent in brain arteriovenous malformation (bAVMs) embolisation. METHODS: A prospective, multicentre series was conducted at 11 interventional centres in Europe to evaluate embolisation of bAVMs with the new liquid embolic agent. Technical conditions, complications, clinical outcome and anatomical results were independently analysed. RESULTS: From December 2005 to December 2008, 117 patients (72 male; 45 female, aged 18-75 years) were included. Clinical presentation was mostly haemorrhage (34.2 %) and seizures (28.2 %). Most AVMs were located in the brain hemispheres (85.5 %). AVMs were <3 cm in 52.1 % of patients and ≥ 3 cm in 47.9 %. Morbidity was observed in 6/117 patients (5.1 %), related to haemorrhagic events in 2 cases and non-haemorrhagic complications in 4 cases. Five patients (4.3 %) died in relation to the treatment (bleeding in 4 patients and extensive venous thrombosis in 1). Complete occlusion of the AVM by embolisation alone was obtained in 23.5 % of patients. Complementary treatment was performed in 82.3 % of patients with partial AVM occlusion, mostly radiosurgery. CONCLUSIONS: In this prospective, multicentre, European, observational series, the new liquid embolic agent proved to be suitable for BAVM embolisation, with acceptable morbidity and mortality and good efficacy. KEY POINTS: • Numerous interventional techniques have been used to embolise brain arteriovenous malformations (AVMs). • This prospective multicentre study demonstrates the suitability of a liquid embolic agent. • The safety of treatment using Onyx is acceptable. • Such embolisation leads to complete AVM occlusion in 23.5 % of patients.

Total occlusion of a conus medullaris pial arteriovenous malformation obtained with one session of superselective embolization.

The authors report about a case of the endovascular treatment of a pial arteriovenous malformation (AVM). The lesion was located on the conus medullaris. This injury is a rare spinal AVM. The diagnostic management and surgical treatment was chosen with a collaboration between neurosurgeons and neuroradiologists. The diagnostic management was based on clinical validation and magnetic resonance with angiographic technique as a gold standard. With regard to the surgical treatment of spinal AVM, endovascular and radiotherapy is a decision which should be taken multidisciplinarily. The treatment is crucial in resolving this lesion. The authors describe the case of a 38-year-old girl with clinical findings of progressive radiculomedullary ischemic process caused by the presence of spinal AVM. The angiographic images showed a pial AVM of the conus medullaris fed by an anterior radiculomedullary artery (Adamckiewiz artery) originated from a left T11 dorsospinal artery and by a posterior radiculopial artery originated from the left L1 artery. The draining veins were posterior pial veins, and accessory anterior subpial veins. Even if the first treatment of a pial arteriovenous malformation (AVM) of conus medullaris can be the surgical treatment for posterior localization, a neurointerventional angiographic and modern materials make it possible to reach pial AVMS of conus medullaris avoiding surgery. The authors describe a successful treatment of conus medullaris arteriovenous malformation with a one session of superselective embolization.

Models of epithelial histogenesis.

Epithelial tissues emerge from coordinated sequences of cell renewal, specialization and assembly. Like corresponding immature tissues, adult epithelial tissues are provided by stem cells which are responsible for tissue homeostasis. Advances in epithelial histogenesis has permitted to clarify several aspects related to stem cell identification and dynamics and to understand how stem cells interact with their environment, the so-called stem cell niche. The development and maintenance of epithelial tissues involves epithelial-mesenchymal signalling pathways and cell-matrix interactions which control target nuclear factors and genes. The tooth germ is a prototype for such inductive tissue interactions and provides a powerful experimental system for the study of genetic pathways during development. Clonogenic epithelial cells isolated from developing as well mature epithelial tissues has been used to engineer epithelial tissue-equivalents, e.g. epidermal constructs, that are used in clinical practise and biomedical research. Information on molecular mechanisms which regulate epithelial histogenesis, including the role of specific growth/differentiation factors and cognate receptors, is essential to improve epithelial tissue engineering.

Embolization of Intracranial Dural Arteriovenous Fistulas Using PHIL Liquid Embolic Agent in 26 Patients: A Multicenter Study.

BACKGROUND AND PURPOSE: The introduction of liquid embolic agents has revolutionized endovascular approach to cranial vascular malformations. The aim of the study was to retrospectively assess the efficacy and safety of Precipitating Hydrophobic Injectable Liquid (PHIL), a new nonadhesive liquid embolic agent, in the treatment of patients with cranial dural arteriovenous fistulas. The primary end point was the rate of complete occlusion of dural arteriovenous fistulas. Secondary end points included the incidence of adverse events and clinical status at 3-month follow-up. MATERIALS AND METHODS: This was a retrospective multicenter study. Twenty-six consecutive patients with dural arteriovenous fistulas (de novo or previously treated) treated by injection of PHIL only or with PHIL in combination with other embolization products (such as Onyx or detachable coils) were included in the study. Recruitment started in August 2014 and ended in September 2015. RESULTS: Twenty-two (85%) patients were treated with PHIL only, with 3 patients treated with both PHIL and Onyx, and 1, with both PHIL and coils. Immediate complete angiographic occlusion was achieved in 20 (77%) patients. Of the 6 patients with residual fistulas, 3 were retreated with PHIL and 1 achieved angiographic cure. An adverse event was seen in 1 patient who developed worsening of preexisting ataxia due to acute thrombosis of the draining vein. CONCLUSIONS: PHIL appears to be safe and effective for endovascular treatment of cranial dural arteriovenous fistulas. Short-term angiographic and clinical results are comparable with those of Onyx, with the added advantage of easier preparation and improved homogeneous cast visualization. The use of iodine as a radio-opacifier also produces considerably less artifacts on CT compared with tantalum-based embolic materials.

Stimulation of osteoblast growth by an electromagnetic field in a model of bone-like construct.

The histogenesis of bone tissue is strongly influenced by physical forces, including magnetic fields. Recent advances in tissue engineering has permitted the generation of three dimensional bone-like constructs. We have investigated the effects of electromagnetic stimulation on human osteoblast cells grown in a hydrophobic polyurethane scaffold. Bone-like constructs were stimulated by pulsed electromagnetic fields in a bioreactor. Proliferation, bone protein expression and calcified matrix production by osteoblasts were measured using histochemical methods. In stimulated cultures, the number of cells was significantly higher compared to static (control) cultures. In both stimulated and control cultures, cells were immunoreactive to osteoblast markers, including type-I collagen, osteocalcin and osteopontin, thus suggesting that the expression of bone-related markers was maintained throughout the in vitro experiments. Morphometric analysis of von Kossa-stained sections revealed that stimulation with electromagnetic field significantly increased matrix calcification. The data lend support to the view that the application of a magnetic field can be used to stimulate cell growth in bone-like constructs in vitro. This finding may be of interest for the production of biomaterials designed for clinical applications.

Manual thromboaspiration technique as a first approach for endovascular stroke treatment: A single-center experience.

BACKGROUND: For intracranial large vessel occlusion in acute ischemic stroke (AIS), a high degree of revascularization in the minimal amount of time predicts good outcomes. Recently, different studies have shown that the direct aspiration first pass technique (ADAPT technique) for AIS obtains high recanalization rates, fast interventions and low costs when it works as first attempt. This study retrospectively describes revascularization efficacy, duration of procedure, intra and post-procedural complications, early and after 90-days clinical outcome in a group of patients who underwent ADAPT as the primary endovascular approach, eventually followed by stent retriever thrombectomy, for recanalization of large vessels in the anterior circulation. MATERIALS AND METHODS: We analyzed clinical and procedural data of patients treated from April 2014 to August 2015. Recanalization was assessed according to the Thrombolysis in Cerebral Infarction score. Clinical outcome was evaluated at discharge and after 3 months (modified Rankin Scale, mRS). RESULTS: Overall, 71 patients (mean age of 69.7 years) were treated. Sites of occlusion were anterior circulation (including seven tandem extracranial-intracranial occlusions). In 39 patients i.v. rtPA was attempted. Recanalization of the target vessel was obtained in 87.3% of cases whereas direct aspiration alone was successful in 46/71cases (64.8%) with an average puncture-to-revascularization time of 43.1 minutes. Symptomatic intracranial hemorrhage occurred in 7.8% and embolization to new territories in 5.6%. In total, 38 patients (53.5%) had a good outcome at 90 days follow-up. CONCLUSIONS: In our series, the manual thromboaspiration technique has been shown as fast and safe, with good rates of vessel revascularization in 87.3% of patients and neurological outcome <3 mRS in 53.5% of patients.

Age-related thiamin transport by small intestinal microvillous vesicles of rat.

The effect of aging on the intestinal transport of thiamin was studied using small intestinal microvillous vesicles prepared from groups of rats aged 1, 2, 6, 12 and 24 months, respectively. The vesicles (enrichment 14.6-17.8-fold) were incubated with 0.125 to 12.5 microM tritiated thiamin and the radioactivity taken up was measured radiometrically after rapid filtration. The time course and cumulative uptake curves of thiamin and the inhibiting potency of the thiamin structural analogs pyrithiamin, amprolium and oxythiamin on the saturable component of thiamin transport were determined. The vesicle diameter was measured by using a computerized morphometric procedure, and found to be decreased in aged rats. The Km and Jmax values of the saturable component of transport increased with increasing age, the difference with younger groups being statistically significant at 24 and 12 months. The inhibitory potencies of pyrithiamin and amprolium gradually decreased with increasing age, while oxythiamin was devoid of significant inhibitory activity. Passive permeability coefficients decreased with increasing age, reaching their lowest value at 24 months. These results show that aging is associated with intrinsic alterations of the enterocytic plasma membrane resulting in a decrease of the affinity for thiamin, associated with a faster rate of the saturable component of thiamin transport, and with a significant depression of the non-saturable component.

Immunohistochemical localization of lipoperoxidation products in normal human placenta.

4-Hydroxynonenal (4-HNE) is a major propagation product of lipid peroxidation that is supposed to be responsible for some of the effects associated with oxidative stress in tissues. We have investigated the possible occurrence and distribution of 4-HNE-immunoreactivity in human normal placenta using immunocytochemistry. Specific immunostaining was observed in cytotrophoblast cells, syncytiotrophoblast, some cells of the villous mesenchyme and some endothelial cells of first trimester and term placentae. The detection of 4-HNE-immunoreactivity in placenta raises the question whether lipoperoxidation products are produced locally in placental cells or represent exogenous products that derive from maternal blood flow. Since trophoblastic cells and villous macrophages are provided by a scavenger receptor, it is conceivable that these cells may play a protective role with regard to the diffusion of lipoperoxidation products from the mother to the embryo. However, since a significant degree of lipid oxidative modification does not take place in plasma, it is presumed that 4-HNE is a local product of placental metabolism. In line with this hypothesis, it is proposed that maternal low density lipoproteins, which are the major source of cholesterol for placental steroid synthesis, might be oxidized by villous cells during their traversal through the villous wall.

Detection and quantitation in rat tissues of the superparamagnetic magnetic resonance contrast agent dextran magnetite as demonstrated by electron spin resonance spectroscopy.

RATIONALE AND OBJECTIVES: The compound studies in this article is a superparamagnetic macromolecular complex of magnetite cores coated with hydrophilic dextran, which is under active investigation as a contrast agent for magnetic resonance imaging (MRI) in liver and spleen. The biodistribution of paramagnetic compounds is problematic and is usually studied by histochemical reactions or by radiolabeling the compound under study. The purpose of this article is to show how electron spin resonance (ESR) spectroscopy detects dextran magnetite (DM) particles in tissues. METHODS: DM injected intravenously in the experimental animal was detected in some reticulo-endothelial organs by ESR. The spectroscopic study was validated using electron microscopy and electron-probe microanalysis. RESULTS: DM exhibits an ESR spectrum; ESR delineated the distribution of DM distribution in liver, spleen, bone marrow, and blood as a function of time. The blood clearance was biphasic, dependent on the size of particles. CONCLUSIONS: ESR spectroscopy is a highly sensitive and reproducible method of studying DM distribution.

Differential distribution of elastic tissue in human natural skin and tissue-engineered skin.

Tissue-engineered skins (TES), manufactured by epidermal and dermal equivalents, are now being used in biological, pharmacotoxicological and clinical applications. It is thus interesting to know to what extent artificial organs are similar to natural counterparts. Elastic fibres are important constituents of the extracellular matrix of natural skin (NS). The aim of our study was to investigate the possible occurrence and distribution of elastic tissue in a model of human TES using different histochemical techniques, including classical Orcein and Fuchsin-Resorcin methods and immunohistochemistry, at both light and electron microscopical levels. Immunoperoxidase and high resolution immunogold methods were used. In NS, classical staining techniques and elastin-immunohistochemistry revealed a well-organized network of elastic fibres. High resolution immunocytochemistry revealed an intense labelling in the amorphous component of elastic fibres. Fibres of different diameters were immunostained. In TES, no stained elastic fibres were observed using classical staining techniques, and the interpretation of immunoperoxidase observations was not clear-cut. In contrast, immunogold staining at the electron microscopical level provided specific labelling of elastin-like immunoreactive material in the dermal equivalent. However, ultrastructural immunocytochemistry revealed that elastic tissue organization in TES was poor compared to that in NS. This study demonstrates that elastic fibres are a component of the extracellular matrix in this model of TES and suggests that fibroblasts of the dermal equivalent are engaged in matrix secretion. Nevertheless, the level of extracellular matrix organization in TES is low compared to NS. Moreover, this study also suggests that different models of bilayered TES may differ with respect to extracellular matrix organization. These aspects should be considered when TES is used in biological and pharmacotoxicological studies. A better understanding of the factors influencing extracellular matrix formation in TES is necessary to achieve further development of skin generation in vitro.

Percutaneous angioplasty of atherosclerotic and postsurgical stenosis of carotid arteries.

A technique for safe angioplasty of atherosclerotic stenosis of internal and common carotid arteries is described in which temporary balloon occlusion of the internal carotid artery is used to prevent cerebral embolization during manifestation of ulcerated plaques. Its successful use in six atherosclerotic stenosis is described. Five angioplasties of postsurgical stenoses are also reported in which the technique of temporary occlusion was not used. The future of carotid artery angioplasty is discussed.

Percutaneous transvenous embolization through the thrombosed sinus in transverse sinus dural fistula.

Each of two patients presented with a dural arteriovenous fistula involving the transverse sinus. The sinus was thrombosed proximal and distal to the dural arteriovenous fistula with the venous drainage being retrograde through cortical veins. An ipsilateral percutaneous transjugular approach was used in both cases and allowed recanalization of the thrombosed sinus and embolization of the dural arteriovenous fistula with coils. Complete cure was achieved in one patient and 95% reduction in arteriovenous shunting including elimination of the cortical venous reflux in the other. This technique avoided surgical exposure of the sinus.

Embolization of arteriovenous malformations of the temporal lobe via the anterior choroidal artery.

The indications, technique, and results of embolization of arteriovenous malformations with liquid adhesive agents delivered through the anterior choroidal artery are reported. Arteriovenous malformations of the temporal lobe were found in four patients with intracerebral bleeding and two with intractable epilepsy. In five of the six, the dominant arterial feeder was the anterior choroidal artery. All patients underwent superselective catheterization of the anterior choroidal artery and embolization of the arteriovenous malformation. Complications related to the anterior choroidal artery embolization developed after embolization in one patient, after which we changed our technique of embolizing arteriovenous malformations via this artery. A thorough understanding of the functional anatomic structures supplied by each segment of the artery is important. Guidelines for safe catheterization and embolization are given. Embolization of arteriovenous malformations fed predominantly by the anterior choroidal artery is difficult and dangerous. An understanding of the functional anatomy of this artery and proper technique can enable successful embolization of arteriovenous malformations via this route.

Local intraarterial fibrinolysis in the carotid territory.

A series comprising 12 patients who had intraarterial local fibrinolysis in the carotid territory is reported. A classification is proposed that divides the different types of occlusions into three groups on the basis of angiographic location. Group 1 (two cases) comprises occlusion of the extra- and/or intracranial carotid artery with patency of the circle of Willis and the lenticulostriate arteries. In this group, there is no brain infarction, the CT findings are normal, and the clinical signs are mainly hemodynamic and intermittent. Fibrinolysis may be performed late and rather safely and completed by surgery or angioplasty of the neck vessel stenosis responsible for the occlusion. Group 2 (five cases) comprises occlusions of the cortical arteries without involvement of the lenticulostriate arteries. The mechanism of the occlusion can be hemodynamic or embolic. Group 3 (five cases) comprises occlusions of intracerebral arteries involving the lenticulostriate arteries. In groups 2 and 3 with brain infarction, fibrinolysis will only be able to restore viability of the area of cerebral tissue surrounding the infarction (penumbra). The time factor is particularly critical in group 3 because lenticulostriate arteries are terminal vessels whose revascularization may induce hemorrhages with increasing frequency as the occlusion time is prolonged. The time factor is less critical in group 2 because collaterals make the ischemia less severe in the infarcted area and the vital and functional consequences of hemorrhage are not as serious as in group 3 because of the location. In this series, all the symptomatic complications of hemorrhage (two cases) occurred in group 3, in patients treated later than 6 hr after clinical onset. Given the time delay inherent in performing CT and angiography and in making the medical decision, it is considered dangerous to undertake fibrinolytic therapy in group 3, unless it can be started before 4 or 5 hr after clinical onset.

Immunohistochemical evidence for the occurrence of endothelin in the vascular endothelium of normal and inflamed human dental pulp.

The occurrence and distribution of the regulatory peptide endothelin in normal and inflamed human dental pulp was studied by immunocytochemistry. Endothelial cells in both normal and inflamed pulp displayed endothelin-like immunoreactivity. Neither pulp cells nor dental nerves were immunoreactive. No significant change in the distribution of endothelin immunoreactivity could be detected in the samples of inflamed pulp tissue, the immunoreactive material being detectable only within the endothelium. However, the intensity of the immunostaining was less intense in the samples of inflamed pulp. It is reasonable to presume that endothelin, produced and released locally by endothelial cells, may participate via a paracrine mechanism in the regulation of blood pressure and flow in normal and pathological human dental tissues.

Major complications of percutaneous embolization of skull-base tumors.

The technique of direct intratumoral injection of permanent liquid polymerizing agent was initially described in 1994 and has evolved significantly with experience. We report complications that occurred in two patients during injection of Histoacryl and offer suggestions to prevent such complications in the future. In one patient, the glue settled in the right middle cerebral artery; in the second, the glue entered the left ophthalmic artery through a collateral branch. Although the fundamental injection technique has not changed, we suggest additional precautions and modifications to make this procedure a safer and more valuable element in the overall management of patients with difficult skull-base tumors.

Immunocytochemical evidence for the presence of somatostatin-like immunoreactive nerves in human dental pulp.

Specific antiserum to somatostatin was used for the immunocytochemical detection of this neuropeptide in human dental pulp. Immunoreactive axon varicosities were observed in the radicular as well as coronal pulp. Fibers displaying somatostatin-like immunoreactivity were detectable within radicular nerve trunks and were found to be associated mainly with blood vessels. Nevertheless, positive fibers with no apparent relation to blood vessels were also observed. No pulp cell was found to be immunoreactive. Previous physiological studies demonstrated that somatostatin may function as a regulatory peptide in feline dental pulp via a pre-synaptic inhibition of substance P release from sensory nerve terminals. It is tempting to speculate that such a mechanism may also be effective in human teeth and may be of value in the regulation of pulpal blood flow and in situations when sensory nerve fibers are activated, e.g., during pulpal inflammation.

Percutaneous puncture of the external carotid artery or its branches after surgical ligation.

PURPOSE: To describe the technique and results of percutaneous puncture of the external carotid artery or one of its branches distal to a surgical arterial ligation. METHODS: Forty-three patients underwent 64 embolization attempts by percutaneous arterial puncture distal to an external carotid artery ligation. The punctured arteries were the trunk of the external carotid artery in 31 patients, the internal maxillary artery in nine, the facial artery in nine, the lingual artery in eight, the occipital artery in four, and the superficial temporal artery in three. RESULTS: In 64 attempts 57 were successful in one session, six were successful in two sessions, and one failed. Puncture-related complications were eight spontaneously resolving hematomas and six asymptomatic punctures of the internal carotid artery. CONCLUSION: After surgical ligation of the external carotid artery or its branches, arterial puncture above the ligation allowed selective catheterization and endovascular occlusion of vascular lesions.

Devascularization of craniofacial tumors by percutaneous tumor puncture.

PURPOSE: To present and evaluate a devascularization technique for hypervascular tumors of the head and neck by direct tumor puncture. METHODS: Tumor puncture was performed percutaneously or via natural orifices (nose and mouth). In one case, an intrasellar tumor was embolized via a transseptosphenoidal surgical approach. The embolization material used was NBCA, lipiodol, and tungsten in the majority of tumors (14 out of 17) and alcohol for 3 metastases of the calvarium. We used this technique to embolize 10 nasopharyngeal fibromas, 4 tumors of the calvarium (3 metastases and 1 hemangiopericytoma), 1 intrasellar hemangiopericytoma, and 2 glomus tumors. Reflux of blood was obtained in every case after direct puncture of the tumor. Direct injection of contrast agent into the tumor revealed local parenchymography followed by local and regional venous drainage without extravasation. RESULTS: Total devascularization was obtained in 14 cases, and devascularization greater than 90% was obtained in 3 cases. Thirteen tumors were totally resected without requiring blood transfusion. During surgery, the limits of the exsanguinated tumor were very well defined in every case by the black staining induced by tungsten. Of the 4 tumors embolized but not operated on (3 metastases and 1 glomus tumor), 2 metastases needed retreatment after 6 and 8 months of remission, respectively. The other metastasis is still in remission after 3 months, and the volume of the glomus tumor decreased by 80% remains unchanged after 8 months. CONCLUSION: This technique was initially used to devascularize tumors with difficult or dangerous intravascular access, but in view of the hemodynamic and surgical results obtained, we believe that the indications for this technique can be extended to hypervascular tumors accessible to conventional embolization.

Trisacryl gelatin microspheres for therapeutic embolization, II: preliminary clinical evaluation in tumors and arteriovenous malformations.

PURPOSE: To evaluate an embolic agent that is precisely calibrated, perfectly spherical in shape, and soft but nonresorbable for use in the embolization of vascular disease of the head, neck, and spine in humans. METHODS: We used supple, hydrophilic, and calibrated trisacryl gelatin microspheres 200, 400, 600, 800 and 1000 microns in diameter for superselective embolization in 105 patients (27 tumors, 14 facial arteriovenous malformations [AVMs], 37 spinal cord AVMs, 21 cerebral AVMs, and 6 miscellaneous diseases). We used particles in 200 to 600 microns in diameter for tumors and for facial AVMs, particles 400 to 600 microns in diameter for spinal cord AVMs, and particles over 1000 micros in diameter for cerebral AVMs. RESULTS: Delivery of the embolic material was easy: microspheres did not aggregate and catheters did not become obstructed by particles. It was possible to control the embolization through precise accounting of the amount of microspheres and matching of the particle size to the size of the pathologic vascular network. CONCLUSION: The microspheres are easy to use and allow precise control of the embolization procedure. Their physical characteristics make them a safe embolic agent.