Peptic Ulcer Disease in Living Liver Donors: A Longitudinal Population-Based Study.

The objective of this nationwide cohort study was to investigate the risk of peptic ulcer disease (PUD) in living liver donors (LDs). A total of 1333 LDs and 5332 matched nondonors were identified during 2003-2011. Hospitalized patients identified as LDs were assigned to the LD cohort, and the non-LD comparison cohort comprised age- and sex-matched nondonors. Cumulative incidences and hazard ratios (HRs) were calculated. The overall incidence of PUD was 1.74-fold higher in the LD cohort than in the non-LD cohort (2.14 vs. 1.48 per 1000 person-years). After adjustment for age, sex, monthly income and comorbidities, we determined that the LD cohort exhibited a higher risk of PUD than did the non-LD cohort (adjusted HR 1.74, 95% confidence interval [CI] 1.45-2.09). The incidence of PUD increased with age; the risk of PUD was 2.53-fold higher in patients aged ≥35 years (95% CI 2.14-2.99) than in those aged ≤34 years. LDs with comorbidities of osteopathies, chondropathies and acquired musculoskeletal deformities exhibited a higher risk of PUD (adjusted HR 3.93, 95% CI 2.64-5.86) compared with those without these comorbidities. LDs are associated with an increased risk of PUD after hepatectomy.

Phenotypic spectrum associated with PTCHD1 deletions and truncating mutations includes intellectual disability and autism spectrum disorder.

Studies of genomic copy number variants (CNVs) have identified genes associated with autism spectrum disorder (ASD) and intellectual disability (ID) such as NRXN1, SHANK2, SHANK3 and PTCHD1. Deletions have been reported in PTCHD1 however there has been little information available regarding the clinical presentation of these individuals. Herein we present 23 individuals with PTCHD1 deletions or truncating mutations with detailed phenotypic descriptions. The results suggest that individuals with disruption of the PTCHD1 coding region may have subtle dysmorphic features including a long face, prominent forehead, puffy eyelids and a thin upper lip. They do not have a consistent pattern of associated congenital anomalies or growth abnormalities. They have mild to moderate global developmental delay, variable degrees of ID, and many have prominent behavioral issues. Over 40% of subjects have ASD or ASD-like behaviors. The only consistent neurological findings in our cohort are orofacial hypotonia and mild motor incoordination. Our findings suggest that hemizygous PTCHD1 loss of function causes an X-linked neurodevelopmental disorder with a strong propensity to autistic behaviors. Detailed neuropsychological studies are required to better define the cognitive and behavioral phenotype.

Management of extensive retrohepatic vena cava defect in recipients of living donor liver transplantation.

Certain complexities, such as extensive vena caval injury, unexpected dense adhesions between liver and retrohepatic vena cava, and liver tumor abutting retrohepatic vena cava, sometimes warrant resection of vena cava during living-donor liver transplantation. Because the donor graft is devoid of vena cava, reconstruction of the retrohepatic cava is required, which can be done with the use of either a cryopreserved venous graft or an artificial conduit. With only a few published reports, the experience in vena cava reconstruction with the use of expanded polytetrafluoroethylene (ePTFE) during living-donor liver transplantation remains limited. We present our experience of 4 patients who successfully underwent vena caval resection during liver transplantation for various indications, which was subsequently reconstructed with the use of ePTFE grafts. All of these patients except 1 recovered well without any undue complications, such as thrombosis or outflow inadequacies, thus proving this extensive surgical treatment to be a successful and life-saving procedure, though meticulous skills are prerequisite.

Experience of using everolimus in the early stage of living donor liver transplantation.

OBJECTIVES: The aim of our study was to review the experience of early use of everolimus for recipients after adult-to-adult living donor liver transplantation. METHODS: From February 2012 to December 2012, 80 recipients underwent living donor liver transplantation. Forty-three of them used everolimus as an adjunct to the calcineurin inhibitors (CNIs) in the early postoperative period. Thirty-nine patients had hepatocellular carcinoma (HCC) and poor renal function was noted in 9 patients. Ten of them were females and 33 were males. The age varied from 39 to 75 years old. The starting date of use was within 1 week in 33 patients, 2 weeks in 9 patients, and 1 patient was administered on postoperative day 20. The initial doses of everolimus were 0.25 mg every 12 hours and increased to 0.5 mg every 12 hours to target the level at 3-5 ng/mL. Doppler ultrasound was performed regularly postoperative days 1, 4, and 14. RESULTS: The mean time between liver transplantation and everolimus treatment was 12 ± 8 days. The maximum dose of everolimus used was 1 mg/d with a target trough level between 3 and 5 ng/mL. At 3 months, a target trough level of 3 ng/mL was achieved. Six of 9 renal failure patients showed significant recovery of renal function, whereas 3 of them showed further deterioration and 1 required hemodialysis. During the follow-up period of 9 ± 6 months, all showed good patency of hepatic artery without thrombosis. Three patients (7%) developed HCC recurrence, whereas 1 patient died at the 10th month postoperative due to sepsis. Elevation of lipid profile was noted in 5 patients. Stomatitis was the most frequent side effect and occurred in 15 patients. CONCLUSIONS: The early use of everolimus was safe and feasible. Also, it can be safely used in patients with prior renal failure while reducing the doses of CNIs. Although the recurrence rate of HCC was reduced, further study is ongoing to evaluate the long-term impact of everolimus on prevention of HCC recurrence.

Monotherapy with tacrolimus for heart and liver transplant: a case report.

BACKGROUND: Multiple-organ transplantation cases are rare, partly due to the shortage of donor organs. However, recent reports of outcomes of multiple-organ transplantations show encouraging survival rates for recipients as compared to single-organ transplant recipients. CASE REPORT: A 33-year-old female who was a known hepatitis B carrier and who had been diagnosed with peripartum dilated cardiomyopathy was experiencing end-stage heart failure. The patient received orthotopic heart transplantation. After heart transplantation, the recipient received prednisolone, cyclosporine, and mycophenolate mofetil for immunosuppressive therapy. Seventy-one days later, the recipient began to develop progressive jaundice, ascites, and hepatoencephalopathy and was re-admitted to the hospital. Fulminant hepatitis was diagnosed. She was referred for emergency cadaveric liver transplantation 110 days after the heart transplantation because of her critical condition. After transplantation, she was improved and her condition maintained by a single immunosuppressive therapy, tacrolimus, with mean dose of 0.06 mg/kg/d. CONCLUSION: We presented a case that was complicated by fulminant hepatitis after heart transplantation and successfully rescued by liver transplantation.

A high model for end-stage liver disease score should not be considered a contraindication to living donor liver transplantation.

OBJECTIVE: To analyze the outcomes of patients with high Model for End-Stage Liver Disease (MELD) scores who underwent adult-to-adult live donor liver transplantation (A-A LDLT). MATERIALS AND METHODS: From September 2002 to October 2010, a total of 152 adult patients underwent A-A LDLT in our institution. Recipients were stratified into a low MELD score group (Group L; MELD score≤30) and a high MELD score group (Group H; MELD score>30) to compare short-term and long-term outcomes. RESULTS: Of the 152 adult patients who underwent A-A LDLT, 9 were excluded from the analysis because they received ABO-incompatible grafts. Group H comprised 23 and Group L 120 patients. The median follow-up was 21.5 months (range, 3 to 102 m). The mean MELD score was 15.6 in Group L and 36.7 in Group H. There were no significant differences in the mean length of stay in the intensive care unit (Group L: 3.01 days vs Group H: 3.09 days, P=.932) or mean length of hospital stay (Group L: 17.89 days vs. Group H: 19.91 days, P=0.409). There were no significant differences in 1-, 3-, or 5-year survivals between patients in Groups L versus H (91.5% vs 94.7%; 86.4% vs 94.7%; and 86.4% vs 94.7%; P=.3476, log rank). CONCLUSION: The short-term and long-term outcomes of patients with high MELD scores who underwent A-A LDLT were similar to those of patients with low MELD scores. Therefore, we suggest that high MELD scores are not a contraindication to LDLT.

Hepatic artery reconstruction in living donor liver transplantation: running suture under surgical loupes by cardiovascular surgeons in 180 recipients.

OBJECTIVES: The aim of our study was to retrospectively investigate the outcomes of hepatic artery (HA) reconstruction by cardiovascular surgeons in adult-to-adult living donor liver transplantation (A-A LDLT). METHODS: From April 2007 to April 2011, 187 recipients underwent A-A LDLT. After excluding seven ABO-incompatible transplant recipients, we reviewed the courses of 180 patients including 125 men and 55 women of mean age 52.5±9.2 years (range=23-71). One hundred seventy-seven patients received right-lobe grafts with inclusion of middle hepatic vein (MHV); two, right-lobe grafts without MHV; and one, left-lobe graft. A continuous, single-stitch, running suture with the parachute technique was used for HA reconstruction. The anastomosis was performed by cardiovascular surgeons employing surgical loupes with 4.5× magnification. RESULTS: The mean time for an arterial reconstruction was 10.7±4.0 minutes (median=10, range=4-30). Hepatic arterial thrombosis (HAT) was encountered in 3 (1.66%) patients. One HAT that developed on postoperative day 1 was successfully rescued by the intra-arterial infusion of urokinase. Another patient required reoperation due to a redundant kinked HA. A third HAT patient underwent successful retransplantation with a cadaveric graft on postoperative day 6. In our series, no delayed HAT was detected and no recipient deaths were related to HAT. CONCLUSION: HA reconstruction with a running suture under surgical loupes is a feasible technique in A-A LDLT. A speedy reconstruction can be performed by an experienced cardiovascular surgeon with a low incidence of HAT.

Living donor right hepatectomy with inclusion of the middle hepatic vein: outcome in 200 donors.

Venous congestion of segments V and VIII of the graft is observed frequently in right-lobe living donor liver transplants (LDLT) without middle hepatic vein (MHV) drainage. It can cause graft dysfunction and failure. Inclusion of the MHV in the right lobe graft allows optimal venous drainage but can pose adverse effects for the donor. From May 2005 to April 2011, we performed 202 right-lobe LDLTs using grafts that all (except two) contained the MHV. The mean duration of donor surgery was 558±132 minutes (median 540, range 332-1100), and estimated blood loss 441±309 mL (median 350, range 35-3200). No donor was admitted to the intensive care unit postoperatively. The mean hospital stay was 8.7±2.1 days (median 8, range 6-22). Postoperatively, 39 donors (19.5%) experienced Clavien grade I and II complications, mostly minor wound infections or massive ascites necessitating diuretic therapy. Seven (3.5%) donors displayed Clavien grade III complications, including five bile leakages requiring endoscopic retrograde biliary drainage and two abdominal wound dehiscences requiring repair under general anesthesia. There was no donor death. In conclusion, inclusion of the MHV in a right-lobe LDLT was safe for most donors.

Simultaneous liver and kidney transplantation from different living donors.

OBJECTIVES: To present our experience with simultaneous living donor liver and kidney (SLK) transplantation from two different living donors. PATIENTS AND METHODS: We performed five SLK transplantations from two different living donors from November 2006 to December 2010. Four patients were males and one, female. Their age range was 47 to 66 years (mean, 55 years). The primary liver diseases included hepatitis B virus (n=2), alcoholic liver cirrhosis (n=2), cryptogenic liver disease (n=1), and hepatitis C virus with hepatocellular carcinoma (n=1). All five patients had chronic renal failure: four were on hemodialysis (H/D) and one on chronic ambulatory peritoneal dialysis for 1 to 20 years. Liver implantation was performed first, followed by kidney transplantation. The liver and kidney teams worked closely to shorten the ischemia time. RESULTS: All surgical procedures were performed uneventfully and all recipients and donors survived the operations. Good liver graft function was noted in all five patients. The patient with both anti-T- and anti-B-cell positive crossmatch tests developed hyperacute rejection of the kidney graft requiring its immediate removal. This patient was maintained on regular H/D afterward. The other four patients displayed good renal function. No evidence of severe acute rejection was noted during the follow-up period (range, 9-55 months) among patients treated with tacrolimus-based immunosuppression. CONCLUSION: We suggest that SLK transplantation be performed with organs from two different instead of a single live donor.

Congenital diaphragmatic hernia in Smith-Magenis syndrome: a possible locus at chromosome 17p11.2.

We report on a 7-month-old girl with Smith-Magenis syndrome (SMS) due to a 4.76-Mb deletion of 17p12-17p11.2 detected by array comparative genomic hybridization. She was also affected with a left-sided congenital diaphragmatic hernia (CDH) and cardiac anomalies including an atypical atrioventricular canal defect and a cleft mitral valve. To our knowledge, this is the first reported case of a patient with both SMS and CDH. There are numerous chromosomal regions in which duplications, deletions, inversions, or translocations have been associated with CDH, but none have previously been reported at or close to 17p11.2. We discuss candidate genes for the diaphragmatic defect in this patient. Our case demonstrates that it is important to consider the possibility of SMS in non-isolated cases of diaphragmatic hernia.

Targeted hepatocellular carcinoma proapoptotic BikDD gene therapy.

Hepatocellular carcinoma (HCC), the third leading cause of cancer death in the world, is the most general type of primary liver cancer. Although current treatment modalities, such as liver transplantation, resection, percutaneous ablation, transarterial embolization, chemotherapy and radiotherapy are potentially curative, these methods are not universally applicable to all of HCC patients, especially for those with poor prognosis in which no effective remedy is available. Therefore, development of novel therapeutic approach for the treatment of HCC is urgently needed. In the current study, we developed a promising HCC-targeted gene therapy vector driven by liver cancer-specific α-fetoprotein promoter/enhancer coupled to an established platform technology. The activity of this expression vector is comparable with or even higher than that of strong cytomegalovirus (CMV) promoter and exhibits strong promoter activity in liver cancer cells/tumors, but has nearly no or very low activity in normal cells/organs in vitro and in orthotopic animal models in vivo. Its cancer specificity exceeds that of the CMV promoter, which expresses non-specifically in both normal and tumor cells. In addition, targeted expression of a therapeutic BikDD, a mutant of proapoptotic gene Bik effectively and preferentially killed liver cancer cells, but not normal cells and significantly repressed growth of HCC tumors, and prolonged survival in multiple xenograft and syngeneic orthotopic mouse models of HCC through intravenous systemic gene delivery. Importantly, systemic administration of BikDD by our expression vector exerted no systemically acute toxicity compared with CMV-BikDD in mice. Taken together, this study elucidates a relatively safe and highly effective and specific systemic gene therapy strategy for liver cancer, and is worthy of further development for future clinical trials.

The reproducibility of the virtual organ computer-aided analysis program for evaluating 3-dimensional power Doppler ultrasonography of diffuse thyroid disorders.

AIM: The aim of this study was to evaluate the intra- observer and inter-observer reproducibility of 3-dimensional (3D) power Doppler ultrasonography with the virtual organ computer-aided analysis (VOCAL) program for measuring thyroid volume and vascular indices in patients with diffuse thyroid disorders. MATERIALS AND METHODS: Patients with diffuse goiters were examined by 3D ultrasonography from August 2005 to July 2006. The parameters for vascular assessment included the vascularization index (VI), flow index (FI), vascularization-flow index (VFI), and thyroid size, and were obtained using the VOCAL program. This program used plane A and a 30 degrees rotational step. Intra-observer and inter-observer repeatability are presented as intra-class correlation coefficient (intra-CC) and inter-class correlation coefficient (inter-CC), with values >0.70 being acceptable. RESULTS: Sixty-three patients in total were enrolled for this study, including 19 patients with simple goiter and 44 patients with autoimmune thyroid disease (AITD) (23 Graves' disease, 21 Hashimoto's thyroiditis). Thyroid volume and 3 vascular indices showed excellent reproducibility in the AITD group (intra- CC>0.9373 and inter-CC>0.8763) and its subgroups. The VI had excellent consistent reproducibility in the simple goiter group (intra-CC>0.8987 and inter-CC>0.8881), but the other parameters did not. CONCLUSIONS: Based on this study, 3D power Doppler ultrasonography with the VOCAL program is a reliable tool for evaluating diffuse thyroid disorders due to an autoimmune process. The VI is the most reliable parameter.

Fatal duodenal hemorrhage complicated after living donor liver transplantation: case report.

Fatal hemorrhage caused by duodenal ulcer is rarely seen after liver transplantation. We report a case with penetrating duodenal ulcer resulting in massive gastrointestinal tract hemorrhage from a ruptured pseudoaneurysm of the hepatic artery. The patient, a 54-year-old man, had undergone living donor liver transplantation with a graft from his son. Massive hematelnesis occurred 7 days after transplantation. Endoscopy revealed a penetrating duodenal ulcer. Repeated episodes of hemorrhage resulted in shock. Angiography showed a ruptured pseudoaneurysm of the proper hepatic artery. Embolization controlled the bleeding; however, the grafted liver became ischemic. The patient subsequently developed ischemic cholangitis, which was treated with percutaneous transhepatic cholangial drainage. Repeat transplantation was performed 30 months later. The patient was doing well at 10-month follow-up.

Persistent dizziness and nausea in patients receiving postoperative epidural pain control after living donor liver transplantation: case reports.

Dizziness and nausea are frequent problems among patients receiving patient-controlled epidural analgesia (PCEA) after major surgery. It is important to consider the various etiologies that might cause these adverse events, especially among patients who have undergone massive hepatic resection for living donor liver transplantation (LDLT). We have described 2 LDLT cases with persistent dizziness and nausea postoperatively despite several adjustments in PCEA management. Their symptoms were quickly relieved after suspension of PCEA medication. Our 2 cases of LDLT represented a unique setting for this type of complication.

Innovative technique to reconstruct two branches of the right hepatic artery in living donor liver transplantation.

Hepatic arterial thrombosis is a critical complication in living donor liver transplantation (LDLT). Two separate branches of the right hepatic artery (RHA) are sometimes observed and addressed by anastomosis of the larger branch first, then checking backflow from the smaller branch. If not good, the smaller branch must be reconstructed. We used the cystic artery as a conduit for the reconstruction. Meticulous dissection was performed to identify all branches of the hepatic artery in the donor operation. The length of cystic artery preserved was as long as possible. The cystic arterial stump was anastomosed to the stump of the posterior branch the of RHA under microscopic guidance on the back table. Patency was checked through the stump of the anterior branch of the RHA. With this technique, only one orifice, the stump of right anterior hepatic artery, was used for hepatic artery reconstruction. We have performed this technique in two patients. Both had good arterial flow after living donor liver transplantation. This innovative technique is easy and safe, and requires only one anastomosis, which, in theory, decreases the adds of developing hepatic arterial thrombosis.

Artificial vascular graft for inferior vena cava reconstruction in living donor liver transplantation: a case report.

Artificial grafts are not recommended because of the high incidence of thrombogenic effects. However, in some situations, such as emergency or when no vascular bank is available, an artificial graft must be used. We present a case in which a polytetrafluoroethyline graft was used as a conduit to reconstruct the retrohepatic vena cava severed during living donor liver transplantation (LDLT). A 48-year-old woman had end-stage primary biliary cirrhosis for 5 years received a right lobe liver graft from her son. The retrohepatic vena cava was divided and ligated in several sequences. The upper end of the severed retrohepatic vena cava retracted into the liver parenchyma. The lower end of the severed vena cava was distended, with multiple stitches. A 16-mm artificial graft was used as a conduit to replace the inferin vena cava for outflow reconstruction. The patient tolerated the complicated procedure well. No anticoagulant was used throughout the entire course. The patient has been well with excellent liver function after follow-up for more than 5 years. Magnetic resonance imaging and Doppler ultrasonographic studies showed good patency of the cava with no evidence of thrombosis. We suggest use of an artificial graft in living donor liver transplantation, in particular in urgent situations when autologous or allogeneic vessels are not available.

Polytetrafluoroethylene patch venoplasty for outflow reconstruction in living donor liver transplantation: two case reports.

Outflow obstruction may lead to liver congestion and eventual graft failure after living donor liver transplantation. Various methods of venoplasty provide wider outflow tracts. Most series have suggested use of autologous or allogenic grafts for patch venoplasty. We used a polytetrafluorethylene patch in two patients. Both showed good patency of the outflow tract at Doppler ultrasonography at 7 months and 4 months posttransplantation. A polytetrafluoroethylene patch may be a good alternative when no other autologous or allogeneic vascular patch is available or when the situation is critical.

Indication for splenectomy in the era of living-donor liver transplantation.

Although end-stage liver disease (ESLD) is often associated with splenomegaly and thrombocytopenia, splenectomy is not necessary in liver transplantation (OLT) except in special situations. In this paper, we examined the indications for splenectomy in the era of living-donor living transplantation. Six of 46 patients underwent splenectomies. Among them, one received a cadaveric graft. Three splenectomies were performed at 6, 7, and 44 days after OLT because of a huge spleen, massive ascites, or impaired liver function. The other two patients received simultaneous splenectomy during OLT to prevent rejection of ABO-incompatible grafts with a positive anti-T-cell test; and one, for postoperative therapy of hepatitis C. All six patients had a good response to splenectomy. We concluded that splenectomy may be indicated for recipients with severe thrombocytopenia, small-for-size syndrome, ABO incompatibility with positive anti-T/B-cell tests and post-OLT therapy for hepatitis C.

Periodontal regeneration using ex vivo autologous stem cells engineered to express the BMP-2 gene: an alternative to alveolaplasty.

The regeneration of the periodontal attachment apparatus remains clinically challenging because of the involvement of three tissue types and the complexity of their relationship. Human recombinant bone morphogenic protein-2 (rhBMP-2) can accelerate the regeneration of bone and cementum and the insertion of periodontal ligament fibers but may lead to a deranged periodontal relationship, ankylosis and root resorption.This study evaluated a novel approach to regeneration of the 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). Twenty-four periodontal defects were surgically created in 12 New Zealand white rabbits and randomly assigned to three experimental groups with MSCs: the advBMP-2 group; the advbetagal group; the MSC group and one control group: PF127 only. The regenerated periodontal attachment apparatus was assessed histologically and the total regenerated bone volume was calculated from three-dimensional computed tomography analysis.This approach regenerated not only cementum with Sharpey's fiber insertion, but also statistically significant quantities of bone, re-establishing a more normal relationship among the components of the regenerated periodontal attachment apparatus, which is beneficial for the maintenance of periodontal health.Ex vivo gene transfer using stem cells as vectors may provide an advantage of slower BMP-2 release, increasing cementogenesis. There is regeneration of the periodontal attachment apparatus, whereas direct usage of the protein (rhBMP-2) yields unhinged periodontal relationship. Thus, this approach may represent an alternative means for periodontal alveolar bone graft in clinical settings.

Contraction of collagen gels seeded with tendon cells.

Knowledge of the adaptation of the soft tissue to mechanical factors and biomolecules would be essential to better understand the mechanism of tendon injury and to improve the outcome of tendon repair. The responses to these factors could be different for the distinct types of cells in the tendon: cells from the tendon sheath, fibroblasts from the epitenon surface, or fibroblasts from the internal endotenon. In this study, we examined the mechanical and histological characteristics of the rate of contraction of the collagen gel seeded with epitenon and endotenon fibroblasts. The rate of contraction and the mechanical property of the contracted construct depend on the gel concentration and also the treatment of TGF-beta1.