[Show abstract][Hide abstract] ABSTRACT: Post orthotopic liver transplantation (OLT) viral hepatitis is an immunological condition where immune cells induce hepatitis during conditions of immune-suppression. The immune-regulatory programmed death-1 (PD-1)/PD-ligand 1 system is acknowledged to play important roles in immune-mediated diseases. However, the PD-1/PD-L2 interaction is not well characterized, with PD-L2 also exhibiting an immunostimulatory function. We hypothesized that this atypical molecule could affect the recurrence of post-OLT hepatitis. To test this hypothesis, we conducted immunohistochemical staining analysis and in vitro analysis of PD-L2.
The expression of PD-L2 was evaluated in liver biopsy specimens from patients with chronic hepatitis B (n = 15), post-OLT hepatitis B (n = 8), chronic hepatitis C (n = 48), and post-OLT hepatitis C (CH-C-OLT) (n = 14). The effect of calcineurin inhibitors (CNIs) and hepatitis C virus (HCV) on PD-L2 expression was investigated in hepatoma cell lines.
The PD-L2 was highly expressed on CH-C-OLT hepatocytes. Treatment of hepatoma cell lines with CNIs resulted in increased PD-L2 expression, especially in combination with HCV core or NS3 protein. Transfection of cell lines with PD-L2 containing plasmid resulted in high intercellular adhesion molecule-1 (ICAM-1) expression, which might enhance hepatitis activity.
The PD-L2 is highly expressed on CH-C-OLT hepatocytes, whereas HCV proteins, in combination with CNIs, induce high expression of PD-L2 resulting in elevated expression of ICAM-1. These findings demonstrate the effect of CNIs on inducing PD-L2 and subsequent ICAM-1 expression, effects that may produce inflammatory cell infiltration in post-OLT hepatitis C.This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 3.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially.
[Show abstract][Hide abstract] ABSTRACT: Solitary fibrous tumor (SFT) is a relatively rare tumor that develops mostly as an intrathoracic lesion related to the pleura. Hepatic malignant SFTs are rare. Here, we present a case of a 56-year-old man with a bulky tumor in the right hepatic lobe. The tumor was found incidentally by abdominal CT as part of an examination for hepatic dysfunction. The definitive diagnosis of SFT was established after liver biopsy, and the patient was referred to our hospital for surgical treatment. At the first visit, imaging studies revealed the primary focus of the malignancy as well as metastatic lesions in the hepatic S2 segment and pancreatic body. The treatment regimen was as follows: after antecedent TAE, primary hepatic and intrahepatic metastatic foci were first resected by extended resection of the two central areas. Nine months later, the pancreatic head tumor was enucleated and distal pancreatectomy was performed to remove metastatic foci including the new lesion on the pancreatic head. Postoperative adjunctive therapy was not administered, and the patient is currently alive without recurrence 22 months postoperatively. To the best of our knowledge, there have only been a few reports on primary hepatic malignant SFTs and this is the only SFT case involving pancreatic metastases reported thus far. This case indicates that total tumor resection allows patients with distant metastasis to achieve recurrence-free survival. Should recurrence occur, we would proactively consider the use of molecular-targeted drugs (approved in 2012), with re-resection in mind.
[Show abstract][Hide abstract] ABSTRACT: We evaluated the antitumor effect of a telomerase-specific replication-selective adenovirus (Telomelysin, OBP-301) for adenoid cystic carcinoma (ACC) in vitro and in vivo. Adenovirus E1 gene expression was controlled by human telomerase reverse transcription (hTERT). Infection of ACC cells by OBP-301 induced high E1A mRNA expression and subsequent oncolytic cell death in a dose-dependent manner. Using OBP-401 (TelomeScan), a genetically engineered adenovirus that carries the GFP gene under the control of the cytomegalovirus (CMV) promoter at the deleted E3 region of OBP-301, ACC cells expressed bright GFP fluorescence as early as 12 h after OBP-401 infection. The fluorescence intensity gradually increased in a time-dependent manner, followed by rapid cell death due to the cytopathic effect of OBP-401, as evidenced by the floating, highly light-refractive cells using phase-contrast microscopy. Effects of intratumorally injected OBP-401 against established Acc2 xenograft tumors were seen in BALB/c nu/nu mice. The levels of GFP expression following ex vivo infection of OBP-401 may be of value as a positive predictive marker for the outcome of telomerase-specific virotherapy. Our data clearly indicated that telomerase-specific oncolytic adenoviruses have significant therapeutic potential against human ACC in vitro and in vivo. These results suggest that treatment with OBP-301 and OBP-401 may improve the quality of life of oral cancer patients.
[Show abstract][Hide abstract] ABSTRACT: Establishment of a preferential liver allocation rule for the simultaneous liver and kidney transplantation (SLK) and revisions of laws regarding organ transplants from deceased donors have paved the way for SLK in Japan. AIM: Very few cases of SLK have been attempted in Japan, and no such recipients have survived for longer than 40 days. The present report describes a case of a 50-year-old woman who had undergone living donor liver transplantation at the age of 38 years for management of postpartum liver failure. METHODS: After the first transplant surgery, she developed hepatic vein stenosis and severe hypersplenism requiring splenectomy. She was then initiated on hemodialysis (HD) due to the deterioration of renal function after insertion of a hepatic vein stent. She was listed as a candidate for SLK in 2011 because she required frequent plasma exchange for hepatic coma. When her Model for End-stage Liver Disease score reached 46, the new liver was donated 46 days after registration. The reduced trisegment liver and the kidney grafts were simultaneously transplanted under veno-venous bypass and intraoperative HD. The hepatic artery was reconstructed prior to portal reconstruction in order to shorten anhepatic time. RESULTS: Although she developed subcapsular bleeding caused by hepatic contusion on the next day, subsequent hemostasis was obtained by transcatheter embolization. CONCLUSIONS: Thereafter, her recovery was uneventful, except for mild rejection and renal tubular acidosis of the kidney graft. This case highlights the need to establish Japanese criteria for SLK.
Hepatology Research 04/2013; 44(3). DOI:10.1111/hepr.12122 · 2.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We present a case of living donor liver transplantation to a 3-year disease-free survivor of liver resection for hepatocellular carcinoma (HCC) with major portal vein invasion. A 48-year-old man had HCC in the right lobe with a portal venous tumor thrombus extending into the left portal vein. An extended right lobectomy with thrombectomy was performed to remove the thrombus. Three years after liver resection, the patient experienced liver failure, with massive ascites and jaundice due to the formation of a thrombus in the main and left portal veins. During the 3 years after liver resection, no metastasis or recurrence of HCC had been detected, and tumor markers had been within normal ranges. The portal venous thrombus did not show any arterial enhancement under contrast-enhanced computed tomography, suggesting that the co-existence of any HCC component in the portal venous thrombus may have been negative. Based on these findings, living donor liver transplantation was performed using a right lobe graft from the patient's son. The patient is alive at 87 months after the transplantation, with no evidence of HCC recurrence.
[Show abstract][Hide abstract] ABSTRACT: Background
A combination of hepatitis B immunoglobulin and nucleos(t)ide analogues is the current standard of care for controlling hepatitis B recurrence after orthotopic liver transplantation (OLT). However, frequent immunoglobulin treatment is expensive and inconvenient. This study investigated the efficacy of hepatitis B virus (HBV) vaccination in preventing the recurrence of hepatitis B after living donor OLT.
Twenty-seven patients who had undergone living donor OLT participated in the study; five had acute HBV infected liver failure (ALF-OLT) and 22 had HBV related liver cirrhosis (LC-OLT). Hepatitis B surface antigen (HBsAg)-containing vaccine was administered to them for at least 1 year after transplantation and continued once monthly for up to 36 months post-OLT. Patients who had anti-HBs antibody titers above 100 mIU/mL for a minimum of 6 months without immunoglobulin administration were defined as good responders; the others were defined as poor responders. Interferon-γ enzyme-linked immunospot assays against HBs and HBc antigens were used to assay cellular immune responses.
All five of the ALF-OLT patients had good responses after a median of four (range 2.5–5) vaccinations. Nine of the 22 LC-OLT patients had good responses after a median of 19 (range 11.5–30) vaccinations. Among the LC-OLT group, those with livers donated by relatively higher-aged, marital and high-titer anti-HBs antibody donors were good responders. LC-OLT patients classed as good responders showed interferon-γ responses comparable to those of the ALF-OLT patients.
The ALF-OLT and LC-OLT patients who received livers from relatively higher-aged, marital, high-titer anti-HBs antibody donors were the best candidates for HBV vaccine administration. Boosting donors before transplantation may facilitate later vaccine response of the recipients.
Journal of Gastroenterology 02/2013; 48(12). DOI:10.1007/s00535-013-0763-8 · 4.52 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Various herb products derived from plants have potent biological effects including anticancer activity. In the present study, the antitumor activity of a herbal product derived from the Scutellaria baicalensis (S. baicalensis) was examined, using in vitro assays in a human oral squamous cell carcinoma (OSCC) cell line. Results showed that S. baicalensis root extract at the concentration of 100 μg/ml inhibited monolayer- and anchorage-independent growth in human OSCC cell lines, while not affecting the adhering abilities of cells. This suggested that it did not alter the expression of any of the adhesion receptors that mediate cell-extracellular matrix (ECM) interactions. The S. baicalensis root extract demonstrated potent cytostatic and apoptotic effects due to the downregulation of the cyclin-dependent kinase 4 expression and its partner cyclin D1, resulting in G1 arrest and poly (ADP-ribose) polymerase (PARP) cleavage. Additionally, the S. baicalensis root extract was found to have blocked vascular endothelial growth factor (VEGF)-induced migration and tube formation in human endothelial cells. Taken together, these results demonstrate that as a herbal product, the S. baicalensis root extract is a potential inhibitor of tumori- and angiogenesis and may be valuable in the development of pharmaceutical medications for the treatment of oral squamous cell carcinoma.
Molecular and Clinical Oncology 01/2013; 1(1):105-111. DOI:10.3892/mco.2012.14
[Show abstract][Hide abstract] ABSTRACT: Currently there is growing use of complementary and alternative anticancer medicines worldwide, and considerable interest in finding anticancer drugs among Chinese medicinal herbs. The aim of this study was to determine the antitumor activity of the root bark of Paeonia moutan (RBPM) in human squamous cell carcinoma (OSCC) cells. Cell lines derived from human oral squamous cell carcinoma (HSC2, 3, 4, SAS) were tested with different concentrations of RBPM (1-100 μg/ml) using a series of in vitro assay systems. RBPM at a concentration of 100 μg/ml inhibited monolayer and anchorage-independent growth, and interrupted coordinated migration. RBPM activated the phosphorylation of extracellular signal-regulated kinase (ERK) and serine/threonine kinase AKT in 30 min; then, at a later stage (after 6 hours) exhibited potent cytostatic, pro-apoptotic effects through the down-regulation of the expression of cyclin-dependent kinase 4 and its partner cyclin D1, and poly(ADP-ribose) polymerase cleavage. We found direct evidence that RBPM induces apoptotic cell death via DNA fragmentation. Taken together, the antitumor activity of RBPM was demonstrated through antiproliferative and apoptotic effects.
Anticancer research 07/2012; 32(7):2625-30. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The small diameter of the hepatic artery is one of the complexities of living donor liver transplantation (LDLT). We analyzed whether the direct suture technique using surgical loupes can simplify the operative process for LDLT compared with fixed microscopic reconstruction. We applied the direct technique to rationalize the operative process and abolished routine microsurgery from 2004. Two hundred and nine LDLT with a postoperative period over 34 months were carried out from 1996 to 2008. The patients were divided into two groups: the micro group (children: 20, adults: 72) and the non-micro group (children: 12, adults: 97). Running anastomosis was undertaken in the non-micro group. The anastomotic size of the children was significantly smaller than that of the adults, but larger than 2 mm (2.38 ± 0.4 vs. 2.7 ± 0.47 mm, p = 0.0005). By appropriate choice of the proximal artery, direct anastomosis is possible even in children. Early complications occurred in seven cases in the micro group, but none occurred in the non-micro group (p < 0.05). Significant reductions were observed in operation time (p < 0.0001), blood loss (p < 0.05), and hospital stay (p < 0.01) in the non-micro group. Non-microscopic anastomosis is useful for the rationalization of LDLT.
[Show abstract][Hide abstract] ABSTRACT: Malnutrition and metabolic disorder of patients undergoing living donor liver transplantation (LDLT) can affect post-transplant prognosis. The aim of this study was to establish whether perioperative usage of branched-chain amino-acid (BCAA)-enriched nutrients improve metabolic abnormalities of patients undergoing LDLT.
We designed a randomized pilot study (UMIN registration number; 000004323). Twenty-five consecutive adult elective LDLT recipients were enroled and divided into two groups: the BCAA group (BCAA-enriched nutrients, n = 12) and the control group (standard diet, n = 13). Metabolic and nutritional parameters, including BCAA-to-tyrosine ratio (BTR), retinol binding protein (RBP), and prealbumin were regularly measured from 1 week before to 4 weeks after LDLT. Non-protein respiratory quotient (npRQ) was measured before and 4 weeks after LDLT.
BTR and RBP improved considerably in the BCAA group compared with the controls. npRQ significantly increased from 1 week before LDLT to 4 weeks after LDLT in the BCAA group (0.77 ± 0.05 to 0.84 ± 0.06, P = 0.002), but not in the control group (0.78 ± 0.04 to 0.81 ± 0.05).
Supplementation with BCAA-enriched nutrients might improve persistent nutritional and metabolic disorders associated with end-stage liver disease in the early post-transplant period, and consequently shorten the post-transplant catabolic phase after LDLT. A larger multicenter trial is needed to confirm these findings.
[Show abstract][Hide abstract] ABSTRACT: Leukoencephalopathy syndrome is a neurologic complication after organ transplantation caused predominantly by the neurotoxic effects of immunosuppressive agents on cerebral white matter. We determined the incidence and features of leukoencephalopathy syndrome in recipients after living-donor liver transplantations.
We retrospectively investigated 205 patients who had a living-donor liver transplantation performed at our institution between August 1998 and October 2008.
Leukoencephalopathy syndrome developed in 7 of 205 patients (3.9%) and in 4.7% of the 150 patients treated with tacrolimus-based immunosuppression after their living-donor liver transplantation. The underlying diseases were alcoholic cirrhosis in 3 cases, viral cirrhosis in 2, biliary atresia in 1, and Wilson disease in 1. Time to clinical onset after tacrolimus medication was 15.6 days (range, 6-30 days). The neurologic symptoms included headache, confusion, myoclonus, seizures, and visual disturbances. The mean serum trough level of tacrolimus at clinical onset was not very high (11.7 ng/mL [range, 6.0-14.2 ng/mL]). T2-weighted magnetic resonance imaging in all cases showed diffuse high signal in the white matter of the frontal, parieto-occipital, and temporal lobes. Treatment with antihypertensives, anticonvulsants, and withdrawal of tacrolimus resulted in amelioration of symptoms and magnetic resonance imaging abnormalities. Six patients showed complete recovery, while the seventh had residual rigidity and cognitive impairment caused by hypoxia during a convulsion.
Tacrolimus neurotoxicity can occur despite low trough levels; it depends on variations in pharmacokinetics, such as absorption and maximum concentration level. Early diagnosis and treatment of leukoencephalopathy syndrome should contribute to complete remission.
[Show abstract][Hide abstract] ABSTRACT: In this article, we describe a safe technique and the outcome of anatomical subsegmentectomies of segments 2 and 3 in patients with chronic liver disease. In cases of subsegmentectomy of segment 2, Arantius duct is transected at the side of umbilical portion and then the liver parenchyma located just above the root of the glissonean pedicle feeding segment 2 is transected. This procedure allows to encircle and dissect the root of the glissonean pedicle feeding segment 2 safely even in cirrhotic patients. After marking the discolored area on the liver surface, parenchymal transection between segment 2 and segment 3 was performed. In cases of subsegmentectomy of segment 3, the root of the glissonean pedicle feeding subsegment 3 is encircled and dissected from the ventral side of the umbilical portion before liver parenchymal resection. Using our technique, we performed subsegmentectomies of segment 3 in four hepatocellular carcinoma (HCC) patients and of segment 2 in two HCC patients. There was no postoperative liver failure and remnant liver function was adequate in all six of our cases. Although three of the six patients had HCC recurrence after hepatectomy, various and multiple treatments for HCC recurrence could be performed in these three patients. Subsegmentectomies for HCC located in the lateral segment were performed safely and could contribute to preservation of remnant liver function.
[Show abstract][Hide abstract] ABSTRACT: The purpose of this study was to analyze various risk factors and to assess the preoperative risk score, which can predict the prognosis after living donor liver transplantation (LDLT).
From February 2002 to August 2007, 84 adult to adult living donor liver transplantation donors and recipients were analyzed. First, the donor, recipient, and intraoperative factors were examined by univariate and multivariate analyses. We then gave a score of one point for each significant marginal factor (total point scores were called "risk score") and each risk score was examined by univariate analyses.
Recipients with the donor age 50 years or older, Model for End-Stage Liver Disease (MELD) score (> or =21), and hepatitis C virus-positive status had a significantly poor survival. Recipients between the risk score of 0 vs. scores of 2 + 3 (p < 0.001, log-rank) and risk score of 1 vs. scores of 2 + 3 (p = 0.003, log-rank) had significantly different survival.
Preoperative assessment of the risk score might help to predict recipient outcomes after living donor liver transplantation.
World Journal of Surgery 10/2008; 32(11):2419-24. DOI:10.1007/s00268-008-9715-5 · 2.64 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The negative effects of increased donor age on liver transplantation became evident in deceased donor liver transplantation. In living donor liver transplantation (LDLT), the details remain unclear.
Initially, 137 adult LDLT recipients from August 1996 to May 2005 were divided into two groups (donors <50 years of age: n=99, donors >or= 50 years of age: n=38) for the retrospective study. Then, 24 recipients who received LDLT from June 2005 to July 2006 were divided into two groups: group 1 (donors <50 years of age, n=14) and group 2 (donors >or= 50 years of age, n=10) and enrolled in the prospective study to analyze their clinical course and prognostic factors in the aged graft.
In the retrospective study, the younger donor group had significantly better survival than that of the aged donor group (P=0.015, Log rank test). In the prospective study, the postoperative graft functions showed that the serum total bilirubin levels were significantly lower in group 1 (P<0.02, by ANOVA analysis). The phosphorylated-Signal Transducer and Activator of Transcription3 expression at 4 hr after reperfusion (RT2) in group 2 was significantly lower than that in group 1. At RT2, the expressions were up-regulated in group 1, but were down-regulated in group 2. The serum 8-hydroxydeoxyguanosine value became significantly higher in group 1 two weeks after LDLT.
In the near term, Signal Transducer and Activator of Transcription3 gene induction during cold preservation may be of great use in improving the outcome of aged grafts in LDLT.