Endoscopic Cyanoacrylate Injection with Post-injection Audible Doppler Assessment of Gastric Varices: A Single-Institution Experience.

BACKGROUND AND AIMS: Gastric varices (GV) have higher rates of morbidity and mortality from hemorrhage than esophageal varices. Several studies have shown the safety and efficacy of cyanoacrylate (CA) injection for acute gastric variceal hemorrhage. We report data from our experience with CA injection for GV before and after routine use of post-injection audible Doppler assessment (ADA) for GV obturation and describe long-term outcomes after this therapy. METHODS: We retrospectively identified patients who had documented GV, underwent CA injection, and had at least 2 weeks of follow-up. We recorded and analyzed the survival and rebleeding rates with patient demographics, clinical data, and endoscopy findings between two groups of patients who were categorized by CA injection prior to and after inception of the ADA technique. RESULTS: Seventy-one patients were identified with 16 patients analyzed in a group where ADA was not used (Pre-ADA) and 55 analyzed where ADA was used (Post-ADA). No rebleeding events were observed within 1 week of initial CA injection. No embolic events were reported after any initial CA injection within 4 weeks. The rate of bleed-free survival at 1 year was 69.6% in the Pre-ADA group and 85.8% in the Post-ADA without statistical significance. The all-cause 1-year mortality was 13.8% in the Pre-ADA group and 10.7% in the Post-ADA group without statistical significance. CONCLUSIONS: ADA of CA-injected GV does not appear to significantly affect adverse events or clinical outcomes; however, our findings are limited by small sample size and cohort proportions allowing for significant type II statistical error. Further prospective investigation is required to determine the impact of ADA on clinical outcomes after GV obturation.

[COMPLICATIONS OF VIDEOTHORACOSCOPIC BIOPSY OF INTRATHORACIC LYMPH NODES AND METHODS OF THEIR PROPHYLAXIS].

Videothoracoscopy constitute a secure miniinvasive method of diagnosis of intrathoracic lymphadenopathy syndrome. Pulmonary hemorrhage and injury constitute intraoperative videothoracoscopic complications, and pulmonary collapse, hemorrhage, purulent complications ­ postoperative complications. Satisfactory intraoperative visualization, guaranteeing optimal position of the patient's body on operative table and sufficient pulmonary collapse on the intervention side, application of medical аlpha­cyanacrylate adhesive with hemostatic sponge for hemostasis in a biopsy zone, systemic application of antibiotics constitute the main prophylactic methods for videothoracoscopic complications and optimization of conditions for videothoracoscopic biopsy of intrathoracic lymphatic nodes. Application of the methods proposed have permitted to reduce the intraoperative complications rate from 19.2 tо 2.8%, and a postoperative one ­ from 23 tо 2.8%.

Intraarterial polidocanol injection for the treatment of peripheral arteriovenous malformations.

PURPOSE: The purpose of this study was to investigate the efficacy and safety of intraarterial transcatheter administration of polidocanol as an alternative treatment for peripheral arteriovenous malformations (AVMs). METHODS: The study comprised 10 patients (six males and four females) with a mean age of 28.8 years (range 8-52 years). All patients had trunk or extremity AVMs. Following the administration of general anesthesia or intravenous (IV) sedation, the patients underwent staged intraarterial polidocanol sclerotherapy with or without additional embolizations for their AVMs. The administration of polidocanol was executed by intraarterial infusion through a microcatheter or by direct percutaneous entry into the nidus under ultrasound guidance. RESULTS: A total of 19 sessions were accomplished in 10 patients. Polidocanol was used alone in six of the 19 sessions. In 13 sessions, polidocanol was used in combination with another agent (including n-butyl cyanoacrylate (NBCA), lipiodol, and ethanol) and/or coils. In two sessions, polidocanol was administered percutaneously under ultrasound guidance directly into the nidus documented by arteriography. No major complications occurred. CONCLUSION: Intraarterial transcatheter administration of polidocanol alone or in combination with other agents is a safe and effective alternative treatment for peripheral AVMs.

The counterbalanced effect of size and surface properties of chitosan-coated poly(isobutylcyanoacrylate) nanoparticles on mucoadhesion due to pluronic F68 addition.

PURPOSE: To evaluate of the effect of size and surface characteristics of poly(isobutylcyanoacrylate) nanoparticles coated with pluronic F68 and thiolated chitosan on mucoadhesion. METHODS: Nanoparticles were obtained by radical emulsion polymerization in presence of different amounts of F68 (0-4%w/v). Mucoadhesion was ex vivo evaluated by applying nanoparticle suspension on rat intestinal mucosa and quantifying the amount of attached nanoparticles after incubation. RESULTS: F68 unimers added in the polymerization medium allowed decreasing nanoparticle size from 251 to 83 nm, but resulted in nanoparticle surface modification. The amount of thiolated chitosan onto nanoparticle surface was decreased resulting in lower thiol groups and zeta potential. Consequently, the decrease of nanoparticle hydrodynamic diameter resulted in eight-fold-increase of the number of nanoparticles attached to the mucosa but a significant decrease of the weight of attached nanoparticles was observed. This unexpected result was due to a decrease of the amount of chitosan and thiolated chitosan available to interact with mucus upon addition of F68 in the polymerization medium. CONCLUSIONS: Addition of F68 should not be recommended to improve the amount of mucoadherent nanoparticles. Further studies could allow understanding if the low amount of small size nanoparticles could be able to improve oral bioavailability.

siRNA nanoformulation against the ret/PTC1 junction oncogene is efficient in an in vivo model of papillary thyroid carcinoma.

Delivery is a very important concern for therapeutic applications of siRNA. In this study, we have used chitosan-coated poly(isobutylcyanoacrylate) nanoparticles to deliver siRNA with a complementary sequence to the fusion oncogene ret/PTC1. By screening the mRNA junction we have selected a potent siRNA sequence able to inhibit this oncogene in a model of Papillary Thyroid Carcinoma cells. This siRNA sequence has then been validated by a shRNA approach using the same sequence. Furthermore, the high ret/PTC1 inhibition has triggered a phenotypic reversion of the transformed cells. We have designed well-defined chitosan decorated nanoparticles and succeeded to reduce their size. They have allowed to protect ret/PTC1 siRNA from in vivo degradation and leading to significant tumour growth inhibition after intratumoral administration.

[Case of repeated hemoptysis successfully treated with bronchial artery embolization with N-butyl cyanoacrylate].

We report a case of repeated hemoptysis successfully treated with bronchial artery embolization (BAE) with N-butyl cyanoacrylate (NBCA). A 75-year-old woman with non-tuberculous mycobacteriosis and pulmonary aspergillosis was admitted with recurrent hemoptysis despite repeated BAE. Considering the ineffectiveness of BAE with Spongel or polyvinyl alcohol, BAE with NBCA was selected. Immediate cessation of hemoptysis was obtained and it has not been seen for 2 years. Although NBCA is the most widely used liquid embolic material to treat brain aneurysm, arteriovenous malformations or gastric varices, there are only a few cases are reported in the treatment of hemoptysis. It seems to be a possible useful treatment for patients with repeated hemoptysis.

Preparation of a Carrier to Achieve In Vivo Delivery of siRNA: The Example of Chitosan-Coated Poly(isobutylcyanoacrylate) Nanoparticles.

This chapter describes the preparation of chitosan-coated poly(isobutylcyanoacrylate) nanoparticles as a suitable carrier to deliver siRNAs to two types of xenograft tumor models of mice. The nanoparticles are prepared by a method of emulsion polymerization that includes steps of polymerization and purification. The polymerization method is carried out in a single pot in an aqueous medium. siRNAs are coupled with the nanoparticles at the end of the preparation by adsorption. The protocol also explains how to determine optimum yield/the titer of association of siRNA with the nanoparticles. It is described for a preparation scale at 4 mL of nanoparticle dispersion at a concentration of 42-46 mg nanoparticles/mL. Optimal loading capacity of the nanoparticles with the siRNA can be achieved by performing an association yield above 90% using a mass ratio of 1 mg siRNA/50 mg of nanoparticles (20 µg siRNA/mg nanoparticles, 1 nmol siRNA (Mw 14 kDa)/mg nanoparticles).

Adjuvant Transjugular Variceal Occlusion at Creation of a Transjugular Intrahepatic Portosystemic Shunt (TIPS): Efficacy and Risks of Bucrylate Embolization.

Adjuvant embolization of varices may reduce rebleeding in patients with a transjugular intrahepatic portosystemic shunt (TIPS). The aim of this study was to investigate the efficacy and the risks of adjuvant variceal embolization at TIPS implantation using bucrylate. PATIENTS AND METHODS: The retrospective study evaluated 104 of 237 cirrhotic patients with TIPS for variceal bleeding who received adjuvant bucrylate embolization. For TIPS creation, bare stents were used in 35 patients (33.7%) and covered stents in 69 patients (66.3%) patients. Isolated gastric varices were seen in 10 patients (9.6%). RESULTS: Six patients (5.8%) rebled during a median follow-up time of 26 months (1-57 months). Rebleeding occurred in 14% (5/35) of patients with a bare stent but only in 1.4% (1/69) of patients with a covered stent. The 1- and 2-year rebleeding rates of all patients were 0.9 and 2.9% and of patients receiving a bare stent were 2.9 and 8.6%, respectively. Bucrylate migration was seen in 13 patients (12.5%). In 9 of these patients (8.7%), asymptomatic lung embolization occurred. This was rare in patients with esophageal varices (3.1%) but frequent (60%) in patients with isolated gastric varices and a spontaneous splenorenal shunt. CONCLUSIONS: Our results suggest that adjuvant embolization using bucrylate is effective and delays variceal rebleeding. The general use of covered stents, however, alleviates the utility of adjuvant bucrylate embolization which may be restricted to patients with a high risk of rebleeding indicated by large varices, active, acute or recent variceal bleeding and advanced cirrhosis. Bucrylate should not be used in isolated gastric varices because it bears a high risk of migration into the lungs.

Functionalized polymer microbubbles as new molecular ultrasound contrast agent to target P-selectin in thrombus.

Thrombotic diseases rarely cause symptoms until advanced stage and sudden death. Thus, early detection of thrombus by a widely spread imaging modality can improve the prognosis and reduce mortality. Here, polymer microbubbles (MBs) made of degradable poly(IsoButylCyanoAcrylate) and functionalized with fucoidan (Fucoidan-MBs) were designed as a new targeted ultrasound contrast agent to image venous thrombus. The physicochemical characterizations demonstrate that the MBs with fucoidan surface exhibit a size of 2-6 µm and stability in suspension at 4 °C up to 2 months. MBs exhibit high echogenicity and could be completely burst under high destructive pulse. Flow chamber experiments on activated human platelets show a higher affinity of Fucoidan-MBs than control anionic MBs (CM-Dextran-MBs) under shear stress conditions. In vivo analysis by ultrasound and histological results demonstrate that Fucoidan-MBs are localized in rat venous thrombotic wall, whereas few CM-Dextran-MBs are present. In addition, the binding of Fucoidan-MBs in healthy vein is not observed. Collectively, Fucoidan-MBs appear as a promising functionalized carrier for ultrasound molecular imaging in thrombotic diseases.

Percutaneous injection of hemostatic agents for severe blunt hepatic trauma: an experimental study.

This study was designed to evaluate whether percutaneous injection of hemostatic agents under the guidance of contrast-enhanced ultrasound (CEUS) can stop hemorrhage from severe hepatic trauma. Eighteen dogs were impacted by a miniature impactor to create blunt hepatic trauma. Fourteen with appropriate liver lesions were divided into two groups: the treatment group (n = 7) and the control group (n = 7). In the treatment group, hemocoagulase atrox and alpha-cyanoacrylate were respectively injected into the injury sites and transected micro-vessels under the guidance of CEUS. In the control group, normal saline was injected into the injury sites. CEUS and CT were performed at 3, 7, 14, and 21 days after the focal injection. Surviving animals were killed on the 21st day for pathologic examination. All animals of the treatment group survived. Three dogs of the control group died in the first 24 h. In the treatment group, CEUS and CT demonstrated that hepatic lesions became smaller gradually from the 3rd to the 21st day after injection. The focal injection of hemostatic agents under the guidance of CEUS can stop hemorrhage from hepatic trauma of grade III~IV or IV. During the period of 3 weeks, no side effect was found.

Tuning of shell and core characteristics of chitosan-decorated acrylic nanoparticles.

The aim of the work was to develop a new family of chitosan-coated acrylic nanoparticles to increase the specificity of absorption of drugs associated given by the mucosal route. To achieve this goal, techniques of radical and anionic emulsion polymerisation of isobutylcyanoacrylate (IBCA) were used. Changes in the shell composition were made by using chitosan of different molecular weight and thiolated chitosan to modify the particle surface properties in order to vary the mucosae-nanoparticle interactions. The core was also modified by the inclusion of methyl methacrylate (MMA) as second monomer potentially able to improve the control of drug release. Finally, the labelling of nanoparticles core with a fluorophore, methacryloxyethyl thiocarbamoyl rhodamine B (Polyfluor), was successfully achieved, necessary for the in vitro and in vivo evaluation of the systems created. Results showed that nanoparticle size varied from 200 to 500 nm, depending on the molecular weight of chitosan used. Positive surface charge values were obtained in all cases. In addition, evidences of the presence of thiol groups were obtained (0.03-0.16 x 10(-3)micromol/cm(2) of nanoparticle).

In vitro evaluation of calcium binding capacity of chitosan and thiolated chitosan poly(isobutyl cyanoacrylate) core-shell nanoparticles.

The ability of chitosan and its derivatives to bind cations is well known. Chitosan and thiolated chitosan were recently associated with poly(isobutyl cyanoacrylate) (PIBCA) nanoparticles leading to very promising results in terms of bioadhesion and permeation enhancement properties. Taking into account the influence that cations concentration have in the maintenance of both the permeation and the enzymatic barrier of the oral route, the possible cation binding capacity of these colloidal systems might be interesting in the use of these nanocarriers for the oral administration of pharmacologically active peptides. The aim of the present work was to in vitro evaluate the capacity of these colloidal systems to bind calcium, a model cation of physiological interest in the intestinal tract. The presence of chitosan on the nanoparticle surface importantly increased the calcium binding ability, in comparison to non-coated PIBCA nanoparticles. In addition, its presentation in the gel layer surrounding the nanoparticles, also beneficiated its binding capacity, obtaining 2-3 folds higher values when the polymer coated the nanoparticles than when it was in solution. The cross-linked structure observed for thiolated chitosan, due to the formation of inter- and intra-chain disulphide bonds, diminished the accessibility of cation to active sites of the polymer, decreasing the binding capacity of the calcium ion. However, when the amount of free thiol groups on the nanoparticle surface was high enough, the binding behaviour observed was higher than for nanoparticles elaborated with non-modified polymer.

Tissue reactions induced by different embolising agents in cerebral arteriovenous malformations: a histopathological follow-up.

AIMS: Comparative histopathological analysis was performed in 47 incompletely embolised and resected cerebral arteriovenous malformations (AVMs). METHODS: Thirty-three AVMs were embolised with n-butyl-cyanoacrylate (NBCA), four with iso-butyl-cyanoacrylate (IBCA), seven with polyvinyl alcohol particles (PVA), one with a fibrin mixture, one with silicon pellets, and one with microcatheter balloons. Maximum exposure time (MET) of the embolising agent (interval between embolisation and surgery) ranged from <24 hours to 80 months. All AVMs were investigated regarding angionecrosis, angiofibrosis, acute inflammation, chronic inflammation, foreign-body reactions, vascular calcification, blood admixture to embolising cast, and capillary recanalisation within the AVMs. These parameters were correlated with MET, comparing different embolising agents, age, and sex. RESULTS: A typical sequence of events depending on MET is observed in all embolised AVMs: acute inflammation with mural angionecrosis is soon replaced by prominent chronic granulomatous vasculitis, which remains stable and is detectable for a very long time, even in AVMs with a MET of more than 6 years. CONCLUSION: Capillary recanalisation is always present in incompletely embolised AVMs, detectable after 3 months of MET, irrespective of the embolising agent used. Age and sex does not influence pattern and time course of tissue lesions and recanalisation in incompletely embolised AVMs.

Preparation and characterization of carbonyl iron/poly(butylcyanoacrylate) core/shell nanoparticles.

In this article a method is described to prepare composite colloidal nanoparticles, consisting of a magnetic core (carbonyl iron) and a biodegradable polymeric shell [poly(butylcyanoacrylate) or PBCA]. The method is based on the so-called anionic polymerization procedure, often used in the synthesis of poly(alkylcyanoacrylate) nanospheres designed for drug delivery. Interest of this investigation is based upon the fact that the heterogeneous structure of the particles can confer them both the possibility to respond to external magnetic fields and to be used as drug carriers. In order to investigate to what extent do the particles participate of this mixed properties, we compare in this work the physical characteristics (structure, chemical composition, specific surface area and surface electrical and thermodynamic properties) of the core/shell particles with those of both the nucleus and the coating material. This preliminary study shows that the mixed particles display an intermediate behavior between that of carbonyl iron and PBCA spheres. Electrophoretic mobility measurements as a function of pH and as a function of KNO3 concentration, show a great similarity between the core/shell and pure polymer nanoparticles. Similarly, a surface thermodynamic study performed on the three types of particles demonstrated that the electron-donor component of the surface free energy of the solids is very sensitive to the surface composition. In fact, a measurable decrease of such component is found for core/shell particles as compared to carbonyl iron. We also analyzed the influence of the relative amounts of polymer and carbonyl iron on the characteristics of the composite particles: data on the coating thickness, the amount of polymer bound to the magnetic nuclei, the redispersibility characteristics of the suspensions and the surface electrical and thermodynamic properties, suggest that the optimal synthesis conditions are obtained for a 4/3 initial monomer/carbonyl iron weight ratio.

Determinants of staged endovascular and surgical treatment outcome of brain arteriovenous malformations.

BACKGROUND AND PURPOSE: Therapy of brain arteriovenous malformations (AVMs) often requires the combination of different treatment modalities. Independently assessed data on neurologic outcome after multidisciplinary AVM therapy are scarce. METHODS: The 119 consecutive patients (49% women, mean age 34+/-13 years) with brain AVMs receiving endovascular embolization followed by surgical treatment were analyzed. Neurologic impairment was assessed prospectively by a neurologist using the modified Rankin Scale (mRS) before, during, and after completed AVM therapy. The association of demographic, clinical, and morphologic characteristics with new treatment-related neurologic deficits was calculated. RESULTS: The 119 patients were treated with 240 superselective embolizations (median, 2; range, 1 to 8) using n-butyl cyanoacrylate. Mean follow-up time after surgery was 9.6+/-13.2 months. On the Spetzler-Martin scale, 8% of the AVMs were grade 1, 27% grade 2, 40% grade 3, 22% grade 4, and 3% grade 5. Disabling treatment-related complications (mRS> or =3) occurred in 5% (95% confidence interval [CI], 1% to 9%) of the patients. Nondisabling new deficits were observed in another 42% (95% CI, 33% to 51%). No patient died. Nonhemorrhagic AVM presentation (odds ratio [OR], 5.00; 95% CI, 1.75 to 14.29), deep venous drainage (OR, 3.09; 95% CI, 1.43 to 6.64), AVM location in an eloquent brain region (OR, 2.42; 95% CI, 1.10 to 5.33), and large AVM size (OR, 1.05; 95% CI, 1.01 to 1.09) were independently associated with new treatment-related deficits. CONCLUSIONS: Our results suggest an increased treatment risk for patients with previously unbled AVMs from combined endovascular and surgical AVM therapy. Additional risk factors for treatment-related neurologic deficits may be large AVM size, deep venous drainage, and AVM location in eloquent brain regions.

The effectiveness of isobutyl cyanoacrylate tissue adhesive for the treatment of corneal perforations.

PURPOSE: To study the results of treatment of corneal perforations with isobutyl cyanoacrylate tissue adhesive. DESIGN: Retrospective case series. METHODS: The charts of 20 patients (22 eyes) with corneal perforation

Therapeutic renal arterial occlusion for elimination of proteinuria: 'medical nephrectomy'.

A patient with severe nephrotic syndrome who was too debilitated to undergo surgical nephrectomies, underwent therapeutic bilateral renal artery occlusion by the selective injection of isobutyl 2-cyanoacrylate into the renal arteries. The therapy resulted in dramatic cessation of urine flow and elimination of proteinuria.

The use of isobutylcyanoacrylate as a tissue adhesive in abdominal surgery.

BACKGROUND: The use of cyanoacrylate substances as tissue adhesives is of valuable aid in surgery, especially in cases of injuries of the intraabdominal organs, where the haemorrhage is very difficult to control. MATERIALS AND METHODS: We investigated the efficiency of isobutyl-2-cyanoacrylate as a tissue adhesive in the haemostasis and adhesion of different types of wounds in solid and hollow organs. Forty-six dogs underwent single-organ (26 dogs) and combined-organ (20 dogs) procedures; cuneiform excisions of the liver and the spleen, as well as incisions of the small intestine were carried out. The wound surfaces were coated with isobutyl-2-cyanoacrylate and approximated. RESULTS: The majority (91.3%) of the surgical operations were uncomplicated, in which a very good macroscopical and histological result was achieved. Histological examination of the surgical injuries, performed 4 months later, confirmed complete wound healing. CONCLUSION: Isobutyl-2-cyanoacrylate proved to be a very effective tissue adhesive for both solid and hollow organs, even for high risk surgical operations.

Left main-stem bronchial stenosis complicating bronchial artery embolization.

A 36-year-old patient was found to have severe left main-stem bronchial stenosis two years after bronchial artery embolization (BAE) for hemoptysis. Embolization-induced bronchial ischemia appeared to be the only potential cause for the observed lesions, and, to our knowledge, this constitutes the first report of late bronchial sequelae following BAE. Despite balloon-catheter dilatation of the stenosis, the severity of poststenotic lesions led to left pneumonectomy. The anatomic data further supported the hypothesis of a complication of BAE. Clinicians and radiologists should be aware of this potential complication of a widely used therapeutic procedure.

Experimental catheter obstruction of the gastric coronary vein. Possible technique for percutaneous intravascular tamponade of the gastroesophageal varices.

Experimental catheter obstruction of the left gastric (coronary) vein was explored in 10 dogs. Using a transjugular approach, the liver was punctured and the portal vein catheterized. Coaxially introduced catheters were then used to catheterize selectively and produce an intravascular obstruction (tamponade) of the gastric coronary vein. Ballon catheters were used for a temporary occlusion. Injection of a tissue adhesive, isobutyl 2-cyanoacrylate, was used for a definitive obliteration. The achieved results show the anatomical feasibility of this approach and give good perspective for development of a clinical method for percutaneous intravascular tamponade of the bleeding gastroesophageal varices in cirrhotics.