Eunyoung Tak

ABO-Incompatible Adult Living Donor Liver Transplantation Under the Desensitization Protocol With Rituximab

ABO incompatibility is no longer considered a contraindication for adult living donor liver transplantation (ALDLT) due to various strategies to overcome the ABO blood group barrier. We report the largest single‐center experience of ABO‐incompatible (ABOi) ALDLT in 235 adult patients. The desensitization protocol included a single dose of rituximab and total plasma exchange. In addition, local graft infusion therapy, cyclophosphamide, or splenectomy was used for a certain time period, but these treatments were eventually discontinued due to adverse events. There were three cases (1.3%) of in‐hospital mortality. The cumulative 3‐year graft and patient survival rates were 89.2% and 92.3%, respectively, and were comparable to those of the ABO‐compatible group (n = 1301). Despite promising survival outcomes, 17 patients (7.2%) experienced antibody‐mediated rejection that manifested as diffuse intrahepatic biliary stricture; six cases required retransplantation, and three patients died. ABOi ALDLT is a feasible method for expanding a living liver donor pool, but the efficacy of the desensitization protocol in targeting B cell immunity should be optimized.

Protective role of hypoxia-inducible factor-1α-dependent CD39 and CD73 in fulminant acute liver failure

Abstract Acute liver failure (ALF) is a severe life‐threatening disease which usually arises in patients with‐irreversible liver illnesses. Although human ectonucleotide triphosphate diphosphohydrolase‐1, E‐NTPDase1 (CD39) and ecto‐5′‐nucleotidase, Ecto5′NTase (CD73) are known to protect tissues from ALF, the expression and function of CD39 and CD73 during ALF are currently not fully investigated. We tested whether CD39 and CD73 are upregulated by hypoxia inducible factor (HIF)‐1&agr;, and improve ischemic tolerance to ALF. To test our hypothesis, liver biopsies were obtained and we found that CD39 and CD73 mRNA and proteins from human specimens were dramatically elevated in ALF. We investigated that induction of CD39 and CD73 in ALF‐related with wild type mice. In contrast, deletion of cd39 and cd73 mice has severe ALF. In this study, we concluded that CD39 and CD73 are molecular targets for the development of drugs for ALF patients care. Graphical abstract Figure. No Caption available. HighlightsHIF‐1a is stabilized during acute liver failureUpregulation of CD39 and CD73 following acute liver failureCD39 and CD73 are transcriptionally induced by HIF‐1aDeletion of Cd39 and CD73 aggravates murine acute liver failureDMOG treatment induces HIF‐1a stabilization, CD39 and CD73 during acute liver failure in WT mice

Combined Detection of Serum IL-10, IL-17, and CXCL10 Predicts Acute Rejection Following Adult Liver Transplantation.

Discovery of non-invasive diagnostic and predictive biomarkers for acute rejection in liver transplant patients would help to ensure the preservation of liver function in the graft, eventually contributing to improved graft and patient survival. We evaluated selected cytokines and chemokines in the sera from liver transplant patients as potential biomarkers for acute rejection, and found that the combined detection of IL-10, IL-17, and CXCL10 at 1-2 weeks post-operation could predict acute rejection following adult liver transplantation with 97% specificity and 94% sensitivity.

Epigallocatechin-3-gallate protects against hepatic ischaemia–reperfusion injury by reducing oxidative stress and apoptotic cell death

Objective To investigate the protective effects of epigallocatechin-3-gallate (EGCG), a major polyphenol source in green tea, against hepatic ischaemia–reperfusion injury in mice. Methods The partial hepatic ischaemia–reperfusion injury model was created by employing the hanging-weight method in C57BL/6 male mice. EGCG (50 mg/kg) was administered via an intraperitoneal injection 45 min before performing the reperfusion. A number of markers of inflammation, oxidative stress, apoptosis and liver injury were measured after the ischaemia–reperfusion injury had been induced. Results The treatment groups were: sham-operated (Sham, n = 10), hepatic ischaemia–reperfusion injury (IR, n = 10), and EGCG with ischaemia–reperfusion injury (EGCG-treated IR, n = 10). Hepatic ischaemia–reperfusion injury increased the levels of biochemical and histological markers of liver injury, increased the levels of malondialdehyde, reduced the glutathione/oxidized glutathione ratio, increased the levels of oxidative stress and lipid peroxidation markers, decreased B-cell lymphoma 2 levels, and increased the levels of Bax, cytochrome c, cleaved caspase-3, and cleaved caspase-9. Pretreatment with EGCG ameliorated all of these changes. Conclusion The antioxidant and antiapoptotic effects of EGCG protected against hepatic ischaemia–reperfusion injury in mice.

Upregulation of P2Y2 nucleotide receptor in human hepatocellular carcinoma cells

Objective To examine if hypoxia inducible factor-1α (HIF-1α) can induce the upregulation of the purinergic receptor P2Y2 (P2Y2) and thereby promote the viability of human hepatocellular carcinoma (HCC) cells under hypoxic conditions. Methods Archival HCC tumour specimens and corresponding non-cancerous tissues were examined immunohistochemically for P2Y2 protein. A series of in vitro experiments were undertaken using HCC cell lines to determine the effect of hypoxia on HIF-1α and P2Y2 levels, the effect of HIF-1α upregulation on P2Y2 levels, and the effect of P2Y2 upregulation on cell viability under hypoxic conditions. Results Human HCC specimens were positive for P2Y2. Hypoxia and upregulated HIF-1α both upregulated the P2Y2 levels in HCC cell lines. P2Y2 upregulation using plasmid transfection resulted in enhanced cell viability under hypoxia. Treatment of HepG2 cells with the selective P2Y2 antagonist MRS2312 downregulated P2Y2 and reduced cell viability in five HCC cell lines. P2Y2 knockdown reduced HepG2 cell viability under hypoxia. Conclusions These present results suggest that HCC cells upregulate P2Y2 levels during hypoxia, which in turn promotes their growth. P2Y2 could be a potential therapeutic target for treating HCC.

Living Donor Liver Transplantation for Patients Older Than Age 70 Years: A Single-Center Experience

Over the past two decades, the age of liver transplantation (LT) recipients has been increasing. We reviewed our experience with LT for patients aged ≥70 years (range: 70–78 years) and investigated the feasibility of performing LT, especially living donor LT (LDLT), for older patients. We retrospectively reviewed the medical records of 25 patients (15 LDLT recipients, 10 deceased donor LT recipients) aged ≥70 years who underwent LT from January 2000 to April 2016. Their perioperative morbidity rate was 28.0%, and the in‐hospital mortality rate was 16.0%; these results were comparable to those of matched patients in their 60s (n = 73; morbidity, p = 0.726; mortality, p = 0.816). For patients in their 70s, the 1‐ and 5‐year patient survival rates were 84.0% and 69.8%, and the 1‐ and 5‐year graft survival rates were 83.5% and 75.1%, respectively. Comparisons of patient and graft survival rates between matched patients in their 60s and 70s showed no statistically significant differences (patient survival, p = 0.372; graft survival, p = 0.183). Our experience suggests that patients aged ≥70 years should not be excluded from LT, or even LDLT, based solely on age and implies that careful selection of recipients and donors as well as meticulous surgical technique are necessary for successful results.

East vs West: Predictors of Oncologic Outcomes Following DD and LD Liver Transplantation for HCC

AMIT - Asan and University of Minnesota Collaboration. Background Tumor recurrence is the most common cause of recipient death following liver transplantation(LT) for HCC. Outcomes following DD(deceased donor) vs. LD(living donor) LT for HCC have been variable. The aim of the current international collaboration is to elucidate predictors of the oncologic outcomes following DDLT and LDLT for HCC between two centers in Korea and US. Methods Between 2005-2015, 1175 LTs were performed for HCC(Korea:85/921; US:DD/LD:147/22). HCC recurrence, patient survival(PS) and recurrence-free survival(RFS) following DD and LDLT were compared between centers. Recipient and donor characteristics, median time from HCC diagnosis to LT, pre-LT HCC treatment, AFP, radiologic characteristics, and explant data were studied for recipients with and without HCC recurrence. Timing and inital recurrence site were analyzed. Results Recurrence rates were 17%/10% for DDLT and 14%/41% for LDLT(P<0.05), for Korean and US centers respectively. For Korea/US: 1-yr PS 85%/87%, 5-yr PS 70%/69% following DDLT. For Korea/US: 1-yr PS 94%/82%, 5-yr PS 82%/50% following LDLT(P<0.05)(Figure 1). For For Korea/US, 5-yr RFS 86%/92% following DDLT, 83%/65% following LDLT (Figure 2). HBV was prevalent cause of liver disease among Korean population(86%); HCV for US(79%)(p<0.05). Korean/US DD recipients had higher mean MELD(25/29) vs Korean/US LD recipients(13/18)(p<0.05). US recipients had shorter wait time from HCC dz to transplant(9/17 months for LD/DD) vs. Korean recipients(22/>25 months for LD/DD)(Table 1,2) (p<0.05). Specific pre-tx tumor characteristics are reported, Tables 1&2. Among US recipients, tumor recurrence was later, but pattern of recurrence was similar between centers and donor types(graft 21%, extrahepatic 71%, graft/extrahepatic 8%). More aggressive explant pathology was associated with higher recurrence rate for LD/DD Korean and DD US recipients. Figure. No caption available. Figure. No caption available. Conclusion Better predictors of HCC recurrence in LDLT need to be delineated other than time from diagnosis to transplant. AFP, tumor size, and number didn’t provide sufficient discrimination. Better predictors would identify a population with low recurrence risk and allow early LDLT with improved outcomes.

Methionine Adenosyltransferase 1: A Proteomic Surrogate Marker of Early Hepatocellular Carcinoma in Cirrhotic Patients

Methionine Adenosyltransferase 1: A Proteomic Surrogate Marker of Early Hepatocellular Carcinoma in Cirrhotic Patients Joo Ho Lee, Mi Jung Jun, Ju Hyun Shim, Gi-Won Song, Eunyoung Tak, Bora Oh, Eunsil Yu, Sang-Woon Choi, Jihyun An, Danbi Lee, Kang Mo Kim, Young-Suk Lim, Han Chu Lee, Young-Hwa Chung, Yung Sang Lee Department of Internal Medicine, CHA Bundang Medical Center, CHA University, Seongnam; Department of Gastroenterology, Department of Surgery, Asan Institute for Life Sciences, and Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

Once-daily, prolonged-release tacrolimus vs twice-daily, immediate-release tacrolimus in de novo living-donor liver transplantation: A Phase 4, randomized, open-label, comparative, single-center study

Randomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0‐24 and C24, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.

Synergistic effect of metformin on sorafenib in in vitro study using hepatocellular carcinoma cell lines

Backgrounds/Aims Hepatocellular carcinoma (HCC) recurrence remains a great concern following hepatic resection and liver transplantation. We investigated the metformin-induced cytotoxic effects on sorafenib in an in vitro study using HCC cell lines. Methods This research was conducted through an in vitro study using one HepG2.2.15 liver tumor and two patient-derived graft HCC cell lines. Results An in vitro study revealed noticeable cytotoxic effects of metformin as well as noticeable synergistic cytotoxic effects of metformin and sorafenib on cell viability. Assays for the mechanisms of action of antitumor effects revealed that alpha-fetoprotein expression was suppressed by both metformin and sorafenib, but no synergistic effect was observed. LC3-I and LC3-II assays revealed the synergistic upregulation of autophagy and assays for IL-1β, IL-6, p53, and TNF-α revealed the synergistic upregulation of cell damage and apoptosis. In contrast, metformin did not affect HBx expression, thus no noticeable synergistic effect was considered to be present. Conclusions Our in vitro study demonstrated cytotoxic effects of metformin and synergistic antitumor effects of sorafenib. These results should be verified in further clinical studies with patients of advanced HCC.