Assessing the Safety of Expanded Polytetrafluoroethylene Synthetic Grafts in Living Donor Liver Transplantation: Graft Migration Into Hollow Viscous Organs - Diagnosis and Treatment Options.

BACKGROUND Our recent studies have highlighted the importance and safety of backtable venoplasty for middle hepatic vein (MHV) and inferior right hepatic veins (IRHV) reconstruction using expanded polytetrafluoroethylene (ePTFE) vascular grafts. In this study, we aim to analyze the complications associated with ePTFE graft use and discuss the management of the rare, but, potentially life threatening complications directly related to ePTFE conduits. MATERIAL AND METHODS From January 2012 to October 2015 a total of 397 patients underwent living donor liver transplantation (LDLT). The ePTFE vascular grafts were used during the backtable venoplasty for outflow reconstruction in 262 of the liver allografts. Recipients who developed ePTFE-related complications were analyzed. RESULTS ePTFE-related complications developed in 1.52% (4/262) of the patients. One patient (0.38%) developed complete thrombosis with sepsis at 24 months post-transplantation and died due to multiorgan failure. Three patients (1.1%) developed graft migration into the second portion of the duodenum, without overt peritonitis. Surgical exploration and ePTFE graft removal was done in all the patients. One patient died due to overwhelming sepsis. CONCLUSIONS ePTFE graft migration into the duodenum causing perforation is a new set of complications that has been recently described in LDLT and can be treated effectively by surgical removal of the infected vascular graft and duodenal perforation closure. Despite of such complications, in our experience, ePTFE use in LDLT continues to have wide safety margin, with a complication rate of only 1.52%.

"Single Oval Ostium Technique" using Polytetrafluoroethylene Graft for Outflow Reconstruction in Right Liver Grafts with venous Anomalies in Living Donor Liver Transplantation.

Right lobe living donor liver transplantation form a major source of liver allografts in Asia because of the scarcity of deceased donation. However, the transplant surgeons often face challenges while managing right lobe liver allografts due to variations in vascular anatomy. Such variations have led the transplant team to adopt modifications in existing techniques of inflow and outflow reconstruction. One of such variations is presence of multiple draining inferior right hepatic veins (IRHVs). This hepatic venous anomaly pose a lot of technical difficulties in the outflow reconstruction as second and/or third anastomosis to inferior vena cava is not always possible in limited retrohepatic space. Herein, we describe the "Single oval ostium technique" using dual synthetic vascular grafts ensuring a common outflow channel for all the hepatic veins.

Engineered autologous bone marrow mesenchymal stem cells: alternative to cleft alveolar bone graft surgery.

Human recombinant bone morphogenetic protein 2 (rhBMP-2) accelerates bone regeneration but is associated with limited cementum and periodontal ligament regeneration, local root resorption, and ankylosis. This study assessed a new approach to the regeneration of the alveolar bone and periodontal attachment apparatus using a combination of ex vivo autologous bone marrow mesenchymal stem cells (MSCs) engineered by replication defective adenovirus to express the BMP-2 gene and pluronic F127 (PF127) in a large mammalian animal model. Bilateral maxillary periodontal defects were created over the premolar area in 9 mature male miniature swine. The 18 defects were randomly assigned to receive either BMP-2-expressing MSCs in the advBMP-2 group or MSCs alone in the MSC group. The regenerated periodontal attachment apparatus was evaluated histologically, and the total regenerated bone volume was calculated from three-dimensional computed tomography analysis. Three months after implantation, significant bone volume was regenerated in the advBMP-2 group. Periodontal apparatus regeneration was significantly better in the advBMP-2 group. New cementum and Sharpey fibers were observed on the denuded root surfaces in the advBMP-2 group, whereas incomplete healing with localized root surface resorption was noted in the control group. The use of ex vivo BMP-2-engineered autologous MSCs enhanced bone and periodontal apparatus regeneration in maxillary alveolar and periodontal defects in swine. This novel integrated approach might be suitable for clinical periodontal apparatus repair. This may be an alternative for cleft alveolar bone graft surgery.

Persistent transaminase elevations in chronic hepatitis C patients with virological response during peginterferon and ribavirin therapy.

BACKGROUND/AIMS: The aim of this study was to determine the incidence of persistently abnormal transaminase levels despite clearance of serum hepatitis C virus (HCV) RNA during antiviral therapy for chronic hepatitis C. METHODOLOGY: One hundred and fifty-one patients with chronic hepatitis C undergoing peginterferon alpha and ribavirin therapy and post-treatment follow-up for 24 weeks were included. The blood cell counts, liver biochemistry and serum HCV RNA levels were determined before, during and at 24 weeks after treatment. RESULTS: Overall, 104 patients (68.9%) achieved sustained virological response. Fifty-four of them (52%) had persistently abnormal transaminase levels during treatment despite clearance of serum HCV RNA. Among them, 27 patients (26%) had persistently abnormal serum AST and ALT levels and another 17 patients (16.3%) displayed isolated elevated AST levels. These 44 patients had normalized transaminase levels by two to three months after the end of treatment. The delayed biochemical response correlated with a higher baseline hepatic fibrosis stage (p=0.017) and liver cirrhosis (p=0.001). CONCLUSIONS: Approximately 42% of the patients eventually achieving sustained virological response following peginterferon alpha and ribavirin therapy showed delayed biochemical normalization. Delayed biochemical response was associated with the baseline hepatic fibrosis stage and liver cirrhosis.

Role of Insulin-like Growth Factor 1 Receptor Signaling in Stem Cell Stemness and Therapeutic Efficacy.

Evidence has emerged that stem cells represent a promising therapeutic tool for tissue engineering and regenerative medicine. Thus, identifying functional markers for selecting stem cells capable of superior self-renewal and pluripotency (or multipotency) and maintaining stem cell identity under appropriate culture conditions are critical for guiding the use of stem cells toward clinical applications. Many investigations have implicated the insulin-like growth factor 1 receptor (IGF1R) signaling in maintenance of stem cell characteristics and enhancement of stem cell therapy efficacy. IGF1R-expressing stem cells display robust pluripotent or multipotent properties. In this review, we summarize the essential roles of IGF1R signaling in self-renewal, pluripotency (or multipotency), and therapeutic efficacy of stem cells, including human embryonic stem cells, neural stem cells, cardiac stem cells, bone marrow mesenchymal stem cells, placental mesenchymal stem cells, and dental pulp mesenchymal stem cells. Modifying IGF1R signaling may thus provide potential strategies for maintaining stem cell properties and improving stem-cell-based therapeutic applications.

Postoperative adverse outcomes among physicians receiving major surgeries: A nationwide retrospective cohort study.

Outcomes after surgeries involving physicians as patients have not been researched. This study compares postoperative adverse events between physicians as surgical patients and nonhealth professional controls.Using reimbursement claims data from Taiwan's National Health Insurance Program, we conducted a matched retrospective cohort study of 7973 physicians as surgical patients and 7973 propensity score-matched nonphysician controls receiving in-hospital major surgeries between 2004 and 2010. We compared postoperative major complications, length of hospital stay, intensive care unit (ICU), medical expenditure, and 30-day mortality.Compared with nonphysician controls, physicians as surgical patients had lower adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of postoperative deep wound infection (OR 0.63, 95% CI 0.40-0.99; P < 0.05), prolonged length of stay (OR 0.68, 95% CI 0.62-0.75; P < 0.0001), ICU admission (OR 0.74, 95% CI 0.66-0.83; P < 0.0001), and increased medical expenditure (OR 0.80, 95% CI 0.73-0.88; P < 0.0001). Physicians as surgical patients were not associated with 30-day in-hospital mortality after surgery. Physicians working at medical centers (P < 0.05 for all), dentists (P < 0.05 for all), and those with fewer coexisting medical conditions (P < 0.05 for all) had lower risks for postoperative prolonged length of stay, ICU admission, and increased medical expenditure.Although our study's findings suggest that physicians as surgical patients have better outcomes after surgery, future clinical prospective studies are needed for validation.

Reconstruction of Isolated Inferior Right Hepatic Vein(s) in Right Lobe Living Donor Liver Transplantation Using Polytetrafluoroethylene Grafts: A New Feasible Concept, Technique of 'Bridging Conduit Venoplasty' and Outcomes.

BACKGROUND Right lobe living donor liver transplantation (LDLT) remains the most common form of liver transplantation in Asia. However, reconstruction of the venous outflow in a right liver allograft may pose technical difficulties if hepatic venous variations are present. Recently, much emphasis has been given to the reconstruction of large and multiple inferior right hepatic veins (IRHVs). The method of reconstructive technique, type of vascular grafts, and the outcome after the procedure have been a point of debate. In this report we discuss the IRHV reconstruction techniques using expanded polytetrafluoroethylene (ePTFE) vascular grafts and the outcomes after such reconstruction. MATERIAL AND METHODS Out of 262 right liver allografts that underwent venous reconstruction using ePTFE vascular grafts, IRHVs required either venoplasty or second inferior vena cava (IVC) anastomosis in 99 recipients. Depending upon type of IRHV reconstruction, the recipients were divided in 2 groups: Group A (n=52): IRHV venoplasty using ePTFE graft, and group B (n=47): Direct IRHV-to-IVC anastomosis. The outcome after LDLT was compared for these 2 groups. RESULTS The ePTFE venoplasty group had significantly shorter warm ischemia time as compared to the direct to IVC anastomosis group (p<0.01, 95% confidence interval -10.96 to -2.92). There were no thrombotic complications in either group of recipients; 4.2% of the recipients from group B developed hepatic venous stenosis but with no clinical deterioration; and 1 patient from group A developed ePTFE graft migration in the second portion of the duodenum that required surgical exploration. CONCLUSIONS The IRHVs drain a considerable portion of the posterior sector of right liver allografts and thus must be reconstructed. Use of ePTFE vascular grafts for IRHV venoplasty is a safe and feasible concept that facilitates the outflow reconstruction of liver allografts.

Comparison and efficacy of LigaSure and rubber band ligature in closing the inflamed cecal stump in a rat model of acute appendicitis.

Safety of either LigaSure or rubber band in closing inflamed appendiceal stump in acute appendicitis has been less investigated. In this study, cecal ligation followed by resecting inflamed cecum was performed to mimic appendectomy in a rat model of acute appendicitis. Rats were sacrificed immediately (Group A) and 7 days (Group B) after cecal resection, respectively. The cecal stumps were closed by silk ligature (S), 5 mm LigaSure (L), or rubber band (R). Seven days after cecal resection, the LigaSure (BL) and silk subgroups (BS) had significantly less intra-abdominal adhesion and better laparotomy wound healing than rubber band subgroup (BR). The initial bursting pressure at cecal stump was comparable among the three methods; along with tissue healing process, both BL and BS provided a higher bursting pressure than BR 7 days after appendectomy. BL subgroup had more abundant hydroxyproline deposition than BS and BR subgroup. Furthermore, serum TNF-α in BR group kept persistently increasing along with time after cecal resection. Thus, the finding that LigaSure but not rubber band is safe in sealing off the inflamed cecal stump in rat model of acute appendicitis suggests the possibility of applying LigaSure for appendectomy via single port procedure or natural orifice transluminal endoscopic surgery (NOTES).

"V-Plasty" technique using dual synthetic vascular grafts to reconstruct outflow channel in living donor liver transplantation.

BACKGROUND: The reconstruction of outflow is a crucial step in living donor liver transplantation. This study describes a suitable technique that uses synthetic vascular conduits in presence of multiple draining veins of right lobe of liver and the outcome of the recipients to evaluate safety of using multiple synthetic grafts. METHODS: From March 2011 to September 2014, 325 patients underwent right lobe living donor liver transplantation. Expanded polytetra-fluoroethylene (ePTFE) grafts were used in total 155 of the liver allografts. Among these, 16 liver grafts required dual ePTFE grafts to reconstruct the outflow due to presence of multiple hepatic veins. RESULTS: The mean diameters for venous branches of segment 5 (V5) and 8 (V8) were 5 mm (range, 4-8 mm) and 7 mm (range, 5-9 mm). The mean diameter of inferior right hepatic veins was 8 mm (7-10 mm). All the recipients who received the right liver with dual ePTFE grafts showed satisfactory inflow and outflow immediately after reconstruction as measured by Doppler flowmetry. Postoperative ultrasonographic studies showed no disturbances in outflow. Protocol dynamic computed tomography performed in the second postoperative month showed 100% patency rates of the artificial grafts. At median follow-up of 24 months graft survival was achieved in 88%, whereas the patency rates of the ePTFE grafts were 100%. CONCLUSION: The use of "V-Plasty" technique using dual artificial vascular grafts is a safe and feasible technique in the presence of various allograft venous anomalies & ensures a single venous channel for outflow reconstruction. Our study also suggests that ePTFE graft may be a useful interposition material without serious complications.

Durable expression of minicircle DNA-liposome-delivered androgen receptor cDNA in mice with hepatocellular carcinoma.

BACKGROUND: The most common gene-based cancer therapies involve the suppression of oncogenic molecules and enhancement of the expression of tumor-suppressor genes. Studies in noncancer disease animal models have shown that minicircle (MC) DNA vectors are easy to deliver and that the proteins from said MC-carrying DNA vectors are expressed over a long period of time. However, delivery of therapeutic genes via a liposome-mediated, MC DNA complex has never been tested in vascular-rich hepatocellular carcinoma (HCC). Liposome-mediated DNA delivery exhibits high in vivo transfection efficiency and minimal systemic immune response, thereby allowing for repetitive interventions. In this study, we evaluated the efficacy of delivering an MC-liposome vector containing a 3.2 kb androgen receptor (AR; HCC metastasis suppressor) cDNA into Hepatitis B Virus- (HBV-) induced HCC mouse livers. RESULTS: Protein expression and promoter luciferase assays revealed that liposome-encapsulated MC-AR resulted in abundant functional expression of AR protein (100 kD) for up to two weeks. The AR cDNA was also successfully delivered into normal livers and diseased livers, where it was persistently expressed. In both normal livers and livers with tumors, the expression of AR was detectable for up to 60 days. CONCLUSION: Our results show that an MC/liposome delivery system might improve the efficacy of gene therapy in patients with HCC.

Repair of large cranial defects by hBMP-2 expressing bone marrow stromal cells: comparison between alginate and collagen type I systems.

Despite a wide range of available sources for bone repair, significant limitations persist. To bioengineer bone, we have previously transferred adenovirus-mediated human BMP-2 gene into autologous bone marrow stromal cells (MSC). We have successfully repaired large, full thickness, cranial defects using this approach. We report now the effectiveness of various hydrogels as the scaffold for this type of bone regeneration, comparing specifically alginate with Type I collagen. Cultured MSC of miniature swine were infected with BMP-2 or beta-gal adenovirus 7 days before implantation. These cells were mixed with alginate, ultrapure alginate, alginate-RGD, or type I collagen to fabricate the MSC/biomaterial constructs. The results of cranial bone regeneration were assessed by gross examination, histology, 3D CT, and biomechanical tests at 6 weeks and 3 months after implantation. We found that the BMP-2 MSC/collagen type I construct, but not the beta-gal control, effectively achieved nearly complete repair of the cranial defects. No bone regeneration was observed with the other hydrogels. Biomechanical testing showed that the new bone strength was very close and only slightly inferior to that of normal cranial bone. Controlling for the integration of stem cells and ex vivo gene transfer, the alginate scaffolds has a significant negative impact on the success of the construct. Our study demonstrates better bone regeneration by collagen type I over alginate. This may have therapeutic implications for tissue engineered bone repair.

Large-scale bicortical skull bone regeneration using ex vivo replication-defective adenoviral-mediated bone morphogenetic protein-2 gene-transferred bone marrow stromal cells and composite biomaterials.

OBJECTIVE: Bone marrow stromal cells (BMSCs) have great potential in bone repair. We developed an animal model to test the hypothesis that ex vivo gene transfer of human bone morphogenetic protein (BMP)-2 to BMSCs via a replication-defective (E1A-deleted) adenovirus vector (AdV) with appropriate biopolymers would enhance autologous bone formation during repair of a large-scale skull defect. METHODS: Eighteen miniature swine were treated with AdV BMP-2-transduced BMSCs in biopolymer (group 1), BMSCs in biopolymer (group 2), or biopolymer alone (group 3). After 6 months, the swine were killed, and the skull repair was examined by gross pictures, histology, 3-dimensional computed tomography, and biomechanical study. RESULTS: Group 1 showed complete solid bone formation after 6 months, and hematoxylin and eosin staining demonstrated the presence of mature, woven, well-mineralized bone. Computed tomography showed wholesome repair of the skull defect. Statistical analysis demonstrated a significant difference in bone thickness between groups 1 and 2. Biomechanical testing showed a statistically significant difference in the stiffness of new bone formed in group 1 compared with group 2. CONCLUSION: The Ad5 E1A-deleted AdV may be the optimal starting vector in ex vivo gene therapy for benign skeletal diseases. Additionally, the use of the gelatin/tricalcium phosphate ceramic/glutaraldehyde biopolymer with AdV BMP-2 gene transfer strongly enhances the bony healing of critical-size bicortical craniofacial defects. This method can be used by modifying the delivery of constructs to malunion treatment, in regional osteoporosis therapy, and spinal fusion.