In vivo Lesion Index (LSI) validation in percutaneous radiofrequency catheter ablation.

INTRODUCTION: Lesion Index (LSI) has been developed to predict lesion efficacy during radiofrequency (RF) catheter ablation. However, its value in predicting lesions size has still to be established. The aim of our study was to assess the lesions size reproducibility for prespecified values of LSI reached during RF delivery in an in vivo beating heart. METHODS: Ablation lesions were created with different values of LSI in seven domestic pigs by means of a contact force-sensing catheter (TactiCathTM , Abbott). Lesions were identified during RF delivery by means of a three-dimensional mapping system (EnSiteTM Precision, Abbott) and measured after heart explantation. Histology was carried out after gross examination on the first three lesions to confirm the accuracy of the macroscopic evaluation. RESULTS: A total of 64 myocardial lesions were created. Thirty-nine lesions were excluded from the analysis for the following reasons: histological confirmation of macroscopic lesion measurement (n = 3), transmurality (n = 24), unfavorable anatomic position (n = 10), not macroscopically identifiable (n = 2). In a final set of 25 nontransmural lesions, injury width and depth were, respectively, 4.6 ± 0.6 and 2.6 ± 0.8 mm for LSI = 4, 7.3 ± 0.8 and 4.7 ± 0.6 mm for LSI = 5, and 8.6 ± 1.2 and 7.2 ± 1.1 mm for LSI = 6. A strong linear correlation was observed between LSI and lesion width (r = .87, p < .00001) and depth (r = .89, p < .00001). Multiple linear regression analysis identified LSI as the only ablation parameter that significantly predicted lesion width (p < .001) and depth (p < .001). CONCLUSION: In our in vivo study, LSI proved highly predictive of lesion size and depth.

Comparison of the efficacy of five standard topical hemostats: a study in porcine liver and spleen models of surgical bleeding.

BACKGROUND: Several topical hemostats are available to help control surgical bleeding. Cutanplast is a highly absorbent and porous gelatin product that is available in Fast sponge and powder forms. This study investigated the hemostatic efficacy of Cutanplast Standard and Fast gelatin sponge and powder and Emosist oxidized regenerated cellulose (ORC) gauze in porcine liver and spleen surgical bleeding models. METHODS: Cutanplast Standard and Fast gelatin sponge and Emosist ORC gauze were tested in liver abrasion/incision, liver puncture and spleen incision/puncture injuries, and Cutanplast Standard and Fast gelatin powder products were tested in liver abrasion/incision injuries. There were 13 liver injury (five abrasion, five incision and three puncture) and six spleen injury (three puncture and three incision sites) sites per animal. RESULTS: Rapid hemostasis (≤ 2-5 min) was achieved in the liver abrasion and incision models with all Cutanplast gelatin sponge and powder products and Emosist ORC gauze, except in the liver incision model, time to hemostasis was > 5 min with Cutanplast Standard gelatin powder and Emosist ORC gauze. Rapid hemostasis occurred with Cutanplast Fast gelatin sponge and Emosist ORC gauze in the liver puncture and spleen puncture and incision models. In the spleen incision model, Cutanplast Standard gelatin sponge had a time to hemostasis approaching 10 min. CONCLUSION: Cutanplast gelatin sponge and powder products and Emosist ORC gauze may be suitable for surgical applications involving parenchymal organ bleeding, but certain products may perform better than others, including Cutanplast gelatin powder in diffuse mild bleeding (such as liver abrasion), and Cutanplast Fast gelatin sponge and Emosist ORC gauze for splenic bleeding.

Osseointegration of Titanium Implants With Different Rough Surfaces: A Histologic and Histomorphometric Study in an Adult Minipig Model.

BACKGROUND: Many chemical and physical modifications of titanium surfaces were introduced, aiming at improving surface bioactivity, but few comparative evidence exists. OBJECTIVE: To evaluate histologically in minipigs the osseointegration of implants made of commercially pure (CP) titanium or titanium alloy, treated by different roughening procedures. MATERIAL AND METHODS: Three sandblasted acid-etched (SA) surfaces, 2 anodized (AN), and 1 double acid-etched (DAE) were compared. Surface microtopography was characterized with scanning electron microscope; surface element composition was also assessed. One implant per group was inserted in each proximal tibia of 2 minipigs. Three months after healing, block biopsies were taken for histomorphometric analysis. Implant stability quotient (ISQ) was measured at insertion and before harvesting. RESULTS: The highest amount of cortical bone-implant contact was observed around SA implants and showed positive correlation with surface roughness. The greatest increase in ISQ was observed in CP-AN implants. In the medullary region, SA implants showed the best osteogenic response, whereas inflammatory cells were found around DAE and alloy-AN implants. CONCLUSIONS: SA surfaces were more osteogenic than anodized or dual acid-etched ones, although not significantly. Surface roughness affected osseointegration.

Meniscus maturation in the swine model: changes occurring along with anterior to posterior and medial to lateral aspect during growth.

The meniscus plays important roles in knee function and mechanics and is characterized by a heterogeneous matrix composition. The changes in meniscus vascularization observed during growth suggest that the tissue-specific composition may be the result of a maturation process. This study has the aim to characterize the structural and biochemical variations that occur in the swine meniscus with age. To this purpose, menisci were collected from young and adult pigs and divided into different zones. In study 1, both lateral and medial menisci were divided into the anterior horn, the body and the posterior horn for the evaluation of glycosaminoglycans (GAGs), collagen 1 and 2 content. In study 2, the menisci were sectioned into the inner, the intermediate and the outer zones to determine the variations in the cell phenotype along with the inner-outer direction, through gene expression analysis. According to the results, the swine meniscus is characterized by an increasing enrichment in the cartilaginous component with age, with an increasing deposition in the anterior horn (GAGs and collagen 2; P < 0.01 both); moreover, this cartilaginous matrix strongly increases in the inner avascular and intermediate zone, as a consequence of a specific differentiation of meniscal cells towards a cartilaginous phenotype (collagen 2, P < 0.01). The obtained data add new information on the changes that accompany meniscus maturation, suggesting a specific response of meniscal cells to the regional mechanical stimuli in the knee joint.

Empty vein ablation (EVA) technique: an in-vivo animal model to assess the effects of sclerosing agent concentration and wall contact time on intima and media tunicae structure.

BACKGROUND: Sclerotherapy is a cornerstone of the treatment of chronic venous disease, despite some technical aspects (e.g., sclerosant liquid agent concentration [SLAC] and contact time between sclerosant agent and vein wall [ctSA/VW]) to maximize outcomes remain an unsolved problem and a source of debate. An innovative three-balloon catheter has been developed to allow sclerotherapy in empty vein conditions (Empty Vein Ablation technique, EVA), revolutionizing the definition of SLAC and ctSA/VW. Aim of this experimental study is to analyze EVA effects on intima and media vessel tunicae using different SLAC and ctSA/VW in an in-vivo animal model. METHODS: Two adult sheep were treated by EVA using jugular and common iliac vein axes (eight vein segments). Different SLAC (polidocanol 0.5% or 1%) and different ctSA/VW (3 or 5 minutes) were combined for testing residual circumferential intima percentage and media thickness after EVA. RESULTS: Intact circumferential residual intima after the treatment was 21.3±4.9%, 18.2±7.4%, 15.7±2.4% and 8.9±2.0% using 0.5% (3 min), 0.5% (5 min), 1% (3 min) and 1% (5 min), respectively (R2=0.945; control sample: 97.6%). Media thickness after the treatment was 121.6±35.3 µm, 110.9±7.8 µm, 96.1±30.4 µm and 79.1±34.1 µm using 0.5% (3 min), 0.5% (5 min), 1% (3 min) and 1% (5 min), respectively (R2=0.990; control sample 125.7 µm). No significant modifications were detected analyzing the adventitia in all samples. CONCLUSIONS: EVA proved to be effective in venous wall destruction even with a very low SLAC and ctSA/VW (0.5% in 3 minutes), in quite large caliber veins. Direct comparisons with foam/liquid sclerotherapy should be done to confirm therapeutic effectiveness of these results, despite EVA has provided a maximized and controlled SA/VW contact time and ratio.

Empty vein ablation innovative technique for chronic venous disease treatment: proof of concept and ex-vivo analysis.

BACKGROUND: Sclerotherapy is among the mainstays of chronic venous disease treatment, yet its occlusion rate remains suboptimal compared to thermal tumescent techniques. An innovative three-balloons catheter has been developed to allow sclerotherapy in empty vein conditions (empty vein ablation technique, EVA). Aim of this investigation was to describe the EVA technical aspects and related ex-vivo effects on vein wall. METHODS: Two samples from jugular veins of an adult sheep were treated by EVA or foam sclerotherapy (FS, Tessari method). Primary outcome was the percentage of circumferential intima treated by EVA or FS; secondary outcomes were intima and media thickness modifications after treatment. RESULTS: Intact circumferential residual intima were 6.07±2.94% and 16.55±0.70% after EVA and FS, respectively (P=0.020). Despite the average intima and media thickness did not differ between treatments, EVA demonstrated a homogenous damage throughout the vein segment, while FS effect was less destructive distally to the injection site, because moving away from the injection site and floating, it has a less contact with internal surface of the vein. CONCLUSIONS: EVA seems to overcome chemical ablation limits as flushing effect and the increases vein wall/sclerosant agent contact effect compared to FS. Ex-vivo encouraging results need in-vivo validation to evaluate other points like deactivation of sclerosing agent by blood protein and the contact time control between SA and the vein wall. If we have further confirmations in vivo we might think we have a potential higher occlusion rate compared to FS, paving the way for future clinical trials.

A New Anorganic Equine Bone Substitute for Oral Surgery: Structural Characterization and Regenerative Potential.

Different xenogeneic inorganic bone substitutes are currently used as bone grafting materials in oral and maxillo-facial surgery. The aim of the present study was to determine the physicochemical properties and the in vivo performance of an anorganic equine bone (AEB) substitute. AEB is manufactured by applying a process involving heating at >300 °C with the aim of removing all the antigens and the organic components. AEB was structurally characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), X-ray fluorescence (XRF), and Fourier-transformed infrared (FT-IR) spectroscopy and compared to the anorganic bovine bone (ABB). In order to provide a preliminary evaluation of the in vivo performance of AEB, 18 bone defects were prepared and grafted with AEB (nine sites), or ABB (nine sites) used as a control, in nine Yucatan Minipigs. De novo bone formation, residual bone substitute, as well as local inflammatory and tissue effects were histologically evaluated at 30 and 90 days after implantation. The structural characterization showed that the surface morphology, particle size, chemical composition, and crystalline structure of AEB were similar to cancellous human bone. The histological examination of AEB showed a comparable pattern of newly formed bone and residual biomaterial to that of ABB. Overall, the structural data and pre-clinical evidence reported in the present study suggests that AEB can be effectively used as bone grafting material in oral surgery procedures.

Effects of a calcium phosphate coating on the osseointegration of endosseous implants in a rabbit model.

OBJECTIVES: The aim of the present study was to evaluate a Ca-P coated implant surface in a rabbit model. The Ca-P surface (test) was compared to the titanium porous oxide surface (control) in terms of bone-to-implant contact (BIC) and removal torque value. MATERIALS AND METHODS: Two hundred and sixteen dental implants were inserted in the tibia and in the femur of 36 rabbits. One hundred and eight were represented by Ca-P oxidized surface implant and other 108 were titanium porous oxide surface modified implants. Each rabbit received six implants. Animals were sacrificed after 2, 4 and 9 weeks of healing. Each group included 12 rabbits. The femoral implant and the proximal implant of the tibia of each animal were subjected to the histologic analysis and the distal implants of the tibia underwent removal torque test (RTQ). RESULTS: Histological analysis in terms of BIC and RTQ did not revealed any significant difference between the Ca-P oxidized surface and the oxidized surface at 2 and 4 weeks. At 9 weeks, the oxidized surface demonstrated better results in terms of RTQ in the tibia. CONCLUSION: In conclusion, findings from the present study suggested that the Ca-P coating had no beneficial effect in improving bonding strength at the bone-implant interface either at 2, 4 and 9 weeks.

The Impact of Nandrolone Decanoate in the Osseointegration of Dental Implants in a Rabbit Model: Histological and Micro-Radiographic Results.

Despite high rates of osseointegration in healthy patients, complex cases present an increased risk of osseointegration failure when treated with dental implants. Furthermore, if immediate loading of the implants is used, maximizing the response of the host organism would be desirable. Anabolic steroids, such as Nandrolone Decanoate (ND), are reported to have beneficial clinical effects on various bone issues such as osteoporosis and bone fractures. However, their beneficial effects in promoting osseointegration in dental implant placement have not been documented. The study aimed to examine histological changes induced by ND in experimental dental implants in rabbit models. Two dental implants were placed in the tibias of 24 adult rabbits. Rabbits were allocated to one of two groups: control group or test group. Rabbits in the latter group were given nandrolone decanoate (15 mg/kg, immediately after implant placement and after 1 week). Micro-radiographic and histological analyses were assessed to characterize the morphological changes promoted by the nandrolone decanoate use. Total bone volume and fluorescence were significantly higher in the control group after 2 weeks. Such a difference between the two groups might indicate that, initially, nandrolone lengthens the non-specific healing period characteristic of all bone surgeries. However, after the beginning of the reparative processes, the quantity of newly formed bone appears to be significantly higher, indicating a positive stimulation of the androgen molecule on bone metabolism. Based on micro-radiology and fluorescence microscopy, nandrolone decanoate influenced bone regeneration in the implant site. The anabolic steroid nandrolone decanoate affects the healing processes of the peri-implant bone and therefore has the potential to improve the outcomes of implant treatment in medically complex patients.

Surface-modified zirconia implants: tissue response in rabbits.

AIM: To evaluate the bone tissue response to zirconia implants with three different surface modifications in comparison with the oxidized titanium surface with the goal to optimize osseointegration in terms of strength and speed. MATERIALS AND METHODS: A total of 18 rabbits with 143 implants were used. One hundred and twenty-three were threaded zirconia ceramic implants with three different surface topographies and 20 modified titanium oxide implants were controls. Each rabbit received eight implants and sacrificed after 3 weeks. The removal torque test (RTQ) and histology were performed. RESULTS: Sixteen out of 18 rabbits completed the study with a total of 110 implants. No statistical significance was observed between the chemical modification implants compared with the topographically modified zirconia implant in terms of interfacial shear strength proven by the RTQ applied. No statistical significance was also observed in the bone-to-implant contact between the zirconia implants and the control oxidized implants. CONCLUSIONS: The findings suggest that additional specific chemical modifications of the topographically modified zirconia implants do not seem to enhance the bone-to-implant contact and appear not to increase the interfacial shear strength.

Time sequence of bone healing around two implant systems in minipigs: preliminary histologic results.

The aim of this study was to evaluate the early phases of bone healing around two different implant surfaces. For this purpose, four minipigs were used. Implants with rough titanium surfaces (ITI sandblasted/acid-etched and Branemark TiUnite) were placed in the maxillae of the animals and sacrifice was scheduled in such a way that healing times of 3 days, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, and 7 weeks were obtained. Histologic analysis revealed that a similar pattern was observed in the phases of bone healing around both types of implants between 3 days and 7 weeks. This pattern consisted of the replacement of blood clot and bone debris with a provisional connective tissue in the first few weeks and with mineralized tissue and marrow spaces later on. Both rough surfaces allowed for "contact osteogenesis" to take place. (Int J Periodontics Restorative Dent 2009;29:549-555.).

Self-closing surgical clips for use in pericallosal artery-pericallosal artery side-to-side bypass.

The authors demonstrate the feasibility of a new procedure to create intracranial interrupted microvascular anastomosis. Self-closing nitinol surgical clips were used for a pericallosal artery-pericallosal artery side-to-side bypass in a 52-year-old man harboring an unruptured large aneurysm located on the right A2 segment. The outflow artery was found to arise from the dome of the aneurysm, which was considered unsuitable for stand-alone clip ligation or coil occlusion. After bypass patency was intraoperatively confirmed using near-infrared indocyanine green videoangiography, the aneurysm and feeding artery were embolized with coils and safely occluded. Both postoperative courses were uneventful. The patient was discharged neurologically intact on the 5th postembolization day. Postprocedure angiography demonstrated no ipsilateral aneurysm filling and excellent bilateral distal outflow from the left anterior cerebral artery.

Porcine models in spinal research: calibration and comparative finite element analysis of various configurations during flexion-extension.

This study was conducted to develop and calibrate a detailed 3-dimensional finite element model of the porcine lumbar spine and to compare this model with various configurations in flexion and extension. Computed tomography scans obtained from the L4-L5 lumbar segment of a Landrace x Large White pig were used to generate a solid volume. The various passive components were characterized by using a step-by-step calibration procedure in which the material properties of the anatomic structures were modified to match the corresponding in vitro data set-points retrieved from the literature. The range of motion of the totally assembled intact model was assessed under a 10-Nm flexion-extension moment and compared with data from a bilateral complete and hemifacetectomy configuration. In addition, the results from our porcine model were compared with published data regarding range of motion in a human finite element model in order to predict the configuration of the porcine model that most closely represented the human spine. Both the intact and hemifacetectomy configurations of the porcine model were comparable to the human spine. However, qualitative analysis of the instantaneous axis of rotation revealed a dissimilarity between the intact porcine model and human spine behavior, indicating the hemifacetectomy configuration of the porcine model as the most appropriate for spinal instrumentation studies. The present 3-dimensional finite element porcine model offers an additional tool to improve understanding of the biomechanics of the porcine spine and to decrease the expense of spinal research.

Experimental comparison of type of Tissucol dilution and composite mesh (Parietex) for laparoscopic repair of groin and abdominal hernia: observational study conducted in a university laboratory.

PURPOSE: The primary objective of this observational study was to determine the best possible dilution of fibrin glue (Tissucol) to employ for prosthesis fixing in laparoscopic treatment of abdominal wall defects and, secondly, to assess its feasibility and safety. MATERIALS AND METHODS: This study was carried out in a university experimental animal laboratory in accordance with all international laws, ethics regulations and quality criteria associated with animal experiments. The tests were carried out on two pigs, using four samples of mesh (Parietex). All meshes were fixed using two different Tissucol dilutions (standard with distilled water and that with calcium chloride). Follow-up evaluations were at 15 days after 30 days, with the latter consisting of traction tests and a biopsy for histological analysis. RESULTS: No post-operative complications were observed. The collagen-coated polyester meshes showed 0% adhesions, and reperitonealization had ensued after 15 days. We saw no shrinkage or migration of any of the meshes. Histopathological analyses confirmed a greater stability, greater tissue integration and the largest number of fibroblasts in meshes fixed with a 1/10 Tissucol dilution without calcium chloride. CONCLUSIONS: This observational study using animals showed that the 1/10 standard dilution - not that with calcium chloride - provided the best fixation and integration and prevented the formation of intraperitoneal adhesions, provided a hydrophilic collagen film-covered mesh was used.

Therapeutic synergism of gemcitabine and CpG-oligodeoxynucleotides in an orthotopic human pancreatic carcinoma xenograft.

CpG-oligodeoxynucleotides (CpG-ODN) exhibit potent immunostimulatory activity by binding with Toll-like receptor 9 (TLR9). Based on the finding that TLR9 is highly expressed and functional in pancreatic tissue, we evaluated the antitumor effects of chemotherapy combined with CpG-ODNs in the orthotopic mouse model of a human pancreatic tumor xenograft. Chemotherapy consisted of the maximum tolerated dose of gemcitabine (i.v., 100 mg/kg, q3dx4). CpG-ODNs were delivered (i.p., 20 microg/mouse), weekly, after the end of chemotherapy. CpG-ODNs alone had little effect on tumor growth, whereas gemcitabine alone significantly delayed the median time of disease onset (palpable i.p. tumor) and of bulky disease development (extensive peritoneal tumor burden), but did not enhance survival time. When the gemcitabine regimen was followed by administration of the immunostimulator, development of bulky disease was delayed, survival time was significantly improved (median survival time, 106 days; P < 0.02 versus gemcitabine-treated mice). Autoptic examination showed that tumor spread in the peritoneal cavity was reduced to a greater extent than with gemcitabine alone. All treatment regimens were well-tolerated. The use of nude mice excluded a T cell-mediated immune response, whereas the high pancreatic expression of TLR9 might have contributed to the tumor response. The clear improvement of survival observed in an orthotopic murine model of human pancreatic cancer by the combined use of CpG-ODNs with chemotherapy suggests the promise of this therapeutic regimen in the clinical setting.

Transcatheter direct mitral annuloplasty with Cardioband: feasibility and efficacy trial in an acute preclinical model.

AIMS: The aim of the study was to report preclinical safety and feasibility of a new transcatheter direct mitral annuloplasty intervention in an acute animal model. METHODS AND RESULTS: Twenty healthy pigs underwent Cardioband (Valtech Cardio, Or Yehuda, Israel) transcatheter implantation under intracardiac echocardiographic and fluoroscopic guidance. Through a neo inferior vena cava approach, transseptal access was arranged. The device was delivered into the left atrium using a multi-steerable catheter and fixed to the mitral annulus with multiple helix anchors. Following device cinching, reduction of annular size was evaluated. In all animals the device could be successfully implanted and displayed 100% function, with the average procedure duration and fluoroscopy times being 78±23 minutes and 27±9 minutes, respectively. In total, 246 anchors (average 12.3 per device) were delivered and optimal anchor placement was achieved in 95.1%, while inadequate anchor position (4%) and injury of the coronary sinus or atrium (0.8%) occurred in the rest. Following maximal cinching, diastolic transmitral flow velocity and coaptation lengths were markedly increased (p<0.001), whereas septolateral and intercommissural distances were significantly decreased (p<0.001), when compared to pre-contraction baseline, demonstrating efficient annular reduction by the device. CONCLUSIONS: Transcatheter direct annuloplasty with a surgical-like adjustable device is feasible in the porcine animal model. The humanised porcine model has been instrumental in demonstrating feasibility and in establishing the procedural steps.

Percutaneous repair of the tricuspid valve using a novel cinching device: acute and chronic experience in a preclinical large animal model.

AIMS: The aim of this study was to evaluate the safety, technical feasibility and performance of a new trans-catheter tricuspid repair system. METHODS AND RESULTS: Thirty-one adult swine underwent implantation of a transcatheter tricuspid remodelling system under general anaesthesia. The steerable transcatheter device was introduced through a 24 Fr femoral sheath into the right femoral vein and delivered to the tricuspid annulus on the beating heart. A fixation element was implanted into the tricuspid annulus. Following implantation, a second delivery system was used to couple the fixation element with a self-expanding nitinol stent. The device was tensioned to reshape the tricuspid valve and increase the coaptation length of the valve leaflets under echo guidance. Finally, the stent was deployed in the inferior vena cava (IVC) to maintain the tension applied. The transcatheter device was successfully implanted in all animals (n=31). Doppler echocardiography prior to sacrifice showed that tricuspid valve function was stable and normal tricuspid leaflet motion was observed. Cinching of the tricuspid annulus resulted in an increase of leaflet coaptation length of 70% (4.5±0.7 mm to 7.78±1.3 mm), an increase in trans-tricuspid peak velocity of 79% (0.38±0.1 m/s to 0.68±0.1 m/s), and a reduction in septolateral tricuspid valve dimension of 30% (35.2±5 mm to 24.8±5 mm). At necropsy, the fixation element was firmly attached to the annulus within a fibrotic tissue, with no coronary lesions observed and no abnormality visible. The stent was fully deployed in the IVC, without displacement or change in the stent shape. CONCLUSIONS: Percutaneous beating heart remodelling of the tricuspid annulus with a cinching device is safe and feasible.

Pre-clinical In Vitro and In Vivo Models for Heart Valve Therapies.

Heart valve disease is a frequently encountered pathology, related to high morbidity and mortality rates. Animal models are interesting to investigate the causality but also underlying mechanisms and potential treatments of human heart valve diseases. Strongly believing that both in vivo and ex vivo models are fundamental to support research and development of new technologies, we here report some examples of heart valve disease models, which in our experience have been actively used to support the development of new valve therapies.

A translational "humanised" porcine model for transcatheter mitral valve interventions: the neo inferior vena cava approach.

AIMS: Preclinical studies and translational animal models are fundamental for the development of new clinical interventions. Compared to human anatomy, pigs present a more anterior heart position in the chest which may jeopardise the imaging and testing of devices designed to be delivered to the human mitral valve. To imitate human anatomy, we developed a novel model to "humanise" a pig heart. METHODS AND RESULTS: The creation of a neo inferior vena cava with a Dacron tube grafted to the right atrium was tested for transseptal delivery of an experimental mitral annuloplasty device in 35 animals. In 15 animals with native anatomy a conventional right transfemoral access was used. Imaging guidance was achieved with intracardiac or epicardial echocardiography. In all transfemoral approaches (n=15), the delivery of the device was unsuccessful and the handling was dissimilar to a human implant. In all neo-cava approaches (n=35), the handling and manoeuvring were as expected in humans, the targets were reached as intended and all procedures but one were successful. CONCLUSIONS: A translational "humanised" animal model with the creation of a neo cava eliminates the differences between pig and human anatomy and is suitable for testing human grade devices.

XPO1/CRM1-selective inhibitors of nuclear export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa).

BACKGROUND: Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus. AIM AND METHODS: To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT- 330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread. RESULTS: In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor- and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor- and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor- and KPT-251-treated animals when compared to controls. CONCLUSIONS: Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.