Pioneering PGC-1α-boosted secretome: a novel approach to combating liver fibrosis.

Purpose: Liver fibrosis is a critical health issue with limited treatment options. This study investigates the potential of PGC-Sec, a secretome derived from peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α)-overexpressing adipose-derived stem cells (ASCs), as a novel therapeutic strategy for liver fibrosis. Methods: Upon achieving a cellular confluence of 70%-80%, ASCs were transfected with pcDNA-PGC-1α. PGC-Sec, obtained through concentration of conditioned media using ultrafiltration units with a 3-kDa cutoff, was assessed through in vitro assays and in vitro mouse models. Results: In vitro, PGC-Sec significantly reduced LX2 human hepatic stellate cell proliferation and mitigated mitochondrial oxidative stress compared to the control-secretome. In an in vivo mouse model, PGC-Sec treatment led to notable reductions in hepatic enzyme activity, serum proinflammatory cytokine concentrations, and fibrosis-related marker expression. Histological analysis demonstrated improved liver histology and reduced fibrosis severity in PGC-Sec-treated mice. Immunohistochemical staining confirmed enhanced expression of PGC-1α, optic atrophy 1 (a mitochondrial function marker), and peroxisome proliferator-activated receptor alpha (an antifibrogenic marker) in the PGC-Sec-treated group, along with reduced collagen type 1A expression (a profibrogenic marker). Conclusion: These findings highlight the therapeutic potential of PGC-Sec in combating liver fibrosis by enhancing mitochondrial biogenesis and function, and promoting antifibrotic processes. PGC-Sec holds promise as a novel treatment strategy for liver fibrosis.

The Usefulness of High-Magnification Loupe for Reducing Biliary Complications After Liver Transplantation.

BACKGROUND: Despite advances in surgical techniques, biliary complications are still considered to be a technical "Achilles' heel" of liver transplantation (LT). The purpose of this study was to evaluate the effect of loupe magnification in reducing biliary complications after LT. MATERIALS AND METHODS: From April 2017 to February 2022, LT was performed on 307 patients in our center. Among them, except for 3 patients who underwent hepaticojejunostomy, 304 adult patients with LT were enrolled. They were divided into 3 groups according to the loupe magnification: 2.5 times (×2.5 group, n = 105), 3.5 times (×3.5 group, n = 95), and 5.0 times (×5.0 group, n = 105). RESULTS: Biliary complications occurred in 63 (20.7%) patients. Anastomosis site leakage occurred in 37 patients (12.2%), and stricture occurred in 52 patients (17.1%). Anastomosis site leakage occurred in 15 patients (14.3%) in the ×2.5 group, 15 patients (16.0%) in the ×3.5 group, and 7 patients (6.7%) in the ×5.0 group (P = .097). Biliary stricture occurred in 26 patients (24.8%) in the ×2.5 group, 15 patients (16.0%) in the ×3.5 group, and 11 patients (10.5%) in the ×5.0 group (P = .021). Total biliary complications occurred in 31 patients (29.5%) in the ×2.5 group, 19 patients in the ×3.5 group (20.2%), and 13 patients in the ×5.0 group (12.4%) (P = .009). CONCLUSION: The use of a high magnification loupe can reduce biliary complications in liver transplantation. Further large-scale analyses of clinical data or randomized controlled trials are required to support this study.

Liver Transplantation at a Small Volume Center-The Role of Network System.

BACKGROUND: Liver transplantation (LT) is typically performed at specialized, high-volume centers. However, some smaller centers also offer liver transplantation services, but their outcomes and safety have been a subject of debate. To overcome these difficulties, we tried to build a Catholic Medical Center (CMC) network to share our experiences and overcome the lack of volume. In this study, we reviewed the overall outcome of patients undergoing LT at a small-volume procedure center, with a focus on patient and graft survival rates. METHODS: Between July 2014 and September 2021, 60 adults underwent LT at Bucheon Saint Mary's Hospital. The overall outcomes were analyzed in terms of perioperative outcomes, complications, and overall survival rate. In addition, the patients were divided into a benign end-stage liver disease (ESLD) group (n = 44) and a hepatocellular carcinoma (HCC) group (n = 16). The baseline characteristics, perioperative outcomes, complications, and overall survival rate were analyzed between the 2 groups. RESULTS: Of a total of 60 LT, living donor liver transplantation (LDLT) was 26, and deceased donor liver transplantation was 34. LDLT was 14 (31.8%) in the ESLD group and 12 (75.0%) in the HCC group. The overall 1-year, 3-year, and 5-year survival rates were 86.7%, 79.7%, and 77.7%, respectively. The survival difference was not statistically significant (P = .214) between the 2 groups. CONCLUSION: We suggest that with appropriate patient selection and adequate resources, LT can be safely performed at smaller centers with the assistance of the CMC network, thus expanding access to this life-saving procedure.

Effects of Livact Granule on Liver Function Recovery After Donor Right Hemi-Hepatectomy.

BACKGROUND: Living donor liver transplantation (LDLT) is currently widespread due to organ shortage. Because LDLT is a high-risk surgery for the donor, donor safety becomes an important issue. In adult LDLT, right lobe grafts are usually used, posing a greater risk to the donor than a left lobe. Reports have demonstrated that branched-chain amino acids help patients recover after hepatectomy. This study aimed to evaluate the effect of Livact granule on donor safety and recovery. METHODS: From January 2016 to December 2021, LDLT was performed on 258 patients at our center. Among them, 148 were in the non-Livact group, and 110 were in the Livact group. Six of 110 patients in the Livact group stopped taking the granules due to nausea and vomiting, leaving 104 patients in the Livact group to be analyzed. Various preoperative and postoperative factors were evaluated to assess donor safety and recovery. RESULTS: In the non-Livact group, the mean donor age was 35.8; in the Livact group, it was 40. There were no differences between the 2 groups in preoperative liver function tests and no difference in future liver remnant or steatosis. There was no difference in total bilirubin level between the 2 groups at 5 days postoperatively; however, in the Livact group, the prothrombin time international normalized ratio was lower, and albumin was higher. The days taken for total bilirubin to normalize were the same in both groups, but fewer days were needed for Livact to realize an international normalized ratio. More patients in the non-Livact group were discharged with the Jackson-Pratt drain because the drainage did not decrease. CONCLUSIONS: In donor right hepatectomy patients, taking Livact granules and branched-chain amino acids helps donor recovery. For donor safety, administration of Livact granules during the perioperative period should be considered.

Proposal of a Network System to Solve the Problem of Small Volume in Liver Transplantation; Catholic Medical Center Network.

INTRODUCTION: Liver transplantation (LT) is a complex and demanding procedure associated with significant perioperative challenges and risks. Concerns have arisen regarding LT outcomes in low-volume centers. We implemented an integrated training and surgical team network to address these concerns within the Catholic Medical Center (CMC) network. This study presents a comprehensive review of our 9-year LT experience within the CMC medical network. METHOD: A retrospective study of LT procedures conducted between January 2013 and August 2021 in 6 CMC-affiliated hospitals was performed. One center was categorized as a high-volume center, conducting over 60 cases annually, and the remaining 5 were considered small-volume centers. The primary endpoints assessed were 1-year and 5-year survival rates. RESULTS: A total of 793 LTs were performed during the study period. The high-volume center performed 411 living donor LT (LDLT) cases and 127 deceased donor LT (DDLT) cases. Also, 146 LDLT cases and 109 DDLT cases were performed in 5 small-volume centers. One-year and 5-year patient survival for LDLT recipients was 88.3% and 78.8% in the high-volume center and 85.6% and 80.6% in the low-volume center. Five-year survival was not significantly different in small-volume centers (P = .903). For DDLT recipients, 1-year and 5-year patient survival was 80.3% and 70.6% in the high-volume center and 76.1% and 67.6% in the low-volume center. In DDLT cases, 5-year survival was not significantly different in small-volume centers (P = .445). CONCLUSION: In conclusion, comparable outcomes for liver transplantation can be obtained in a small-volume center with a high level of integrated training systems and networks.

Safety of performing distal pancreatosplenectomy in patients who underwent distal gastrectomy previously: a multicenter cohort analysis with systematic literature review.

Purpose: In patients who have previously undergone subtotal gastrectomy (STG), the remnant stomach is supplied with arterial blood through the splenic artery. It is currently unclear whether the remnant stomach can be safely preserved when performing distal pancreatosplenectomy (DPS) in these patients. Thus, this study aimed to evaluate the safety and feasibility of performing DPS in patients who had undergone a previous STG. Methods: A multicenter cohort study was performed to identify patients who underwent DPS. Electronic medical data of Clinical Data Warehouse from 7 representative high-volume centers in 5 cities were retrospectively reviewed. A propensity score-matched analysis was performed to match patients who had no history of upper abdominal surgery with patients who had undergone a previous STG. Results: Fourteen DPS patients who had a history of STG (STG group) were studied and matched to 70 patients who underwent DPS without any history of upper abdominal surgery (non-STG group). All patients in the STG group had the remnant stomach preserved. In most patients, the blood vessel supplying blood to the remnant stomach was the left inferior phrenic artery. There was no significant difference in the incidence of stomach-related complications or length of hospital stay between the 2 groups. Conclusion: Our study results suggest that the remnant stomach could be safely preserved when performing DPS in patients with a prior STG. However, it is necessary to carefully evaluate the vascular structure of the remnant stomach through preoperative imaging study and closely observe changes to the blue stomach during the operation.

Clinical Analysis of Factors Affecting Hospital Mortality After Liver Transplant in Patients With High Model for End-Stage Liver Disease Score.

BACKGROUND: This study was undertaken to identify poor prognostic factors in patients with high Model for End-Stage Liver Disease (MELD) scores. METHODS: From September 2001 to December 2017, living donor liver transplant and deceased donor liver transplant were performed in 851 (84.4%) and 157 patients (15.6%), respectively, in our center. Eighty-one patients (8.0%) with MELD scores ≥ 35 were classified as patients with high MELD scores. RESULTS: The overall survival rates in patients with high MELD scores were significantly worse than those in patients with low MELD scores (P = .005). However, no significant difference in survival was found between the 2 groups when in-hospital mortality was excluded. In-hospital mortality occurred in 18 patients (22.2%), and the main cause of death was sepsis (n = 14, 77.8%). On univariate analysis, the risk factors for in-hospital mortality were mean age (P = .028), mean MELD score (P = .045), intubation status (P < .001), culture positivity (P = .042), and encephalopathy grade 3 or 4 (P = .014). On multivariate analysis, age (P = .006), intubation status (P = .042), and culture positivity (P = .036) were significant. CONCLUSIONS: The main cause of in-hospital mortality was sepsis, and the risk factors for in-hospital mortality of patients with high MELD score were older age, preoperative intubation, and culture positivity. Special attention should be paid to the prevention and treatment of infection in the liver transplant of patient with high MELD scores.

Analysis of Prognostic Factors for Patients Undergoing Renal Replacement Therapy With Acute Kidney Injury Prior to Living Donor Liver Transplantation.

BACKGROUND: Acute kidney injury (AKI) is a common complication in patients undergoing liver transplantation (LT) for end-stage liver disease (ESLD), and renal replacement therapy (RRT) is required in many cases. This study was performed to identify the prognostic factors for patients undergoing RRT owing to AKI before living donor liver transplantation (LDLT). MATERIALS AND METHODS: From January 2010 to December 2018, LDLT was performed in 464 adult patients in our center. We reviewed 33 patients who underwent RRT before LDLT among 464 consecutive cases. Patients who continued to RRT after LDLT or who underwent subsequent kidney transplantation were considered to have not recovered from renal impairment. RESULTS: Among 33 patients, there were 23 patients in the recovery group and 10 patients in the nonrecovery group. The preoperative duration of RRT was shorter in the recovery group, but it was not statistically significant. In the nonrecovery group, diabetes mellitus was found to have a higher prevalence and ischemic time was longer. Other perioperative factors were not significantly different between the 2 groups. After LDLT, the peak total bilirubin level was higher, and the intensive care unit stay was longer in the nonrecovery group. The overall survival rate was higher in the recovery group. CONCLUSIONS: Liver transplant recipients who maintain RRT after LDLT have poor outcome. It is necessary to know the risk factors and manage them well, perioperatively.

Anticancer Effect of Statins in Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma.

The anticancer effect of statins is drawing attention. However, it is unclear whether statin use reduces the risk of hepatocellular carcinoma (HCC) recurrence in patients who undergo liver transplantation (LT) for HCC. Consecutive patients who underwent LT for HCC between 1995 and 2019 were enrolled. The effects of statins on HCC recurrence and mortality were compared between statin user and statin nonuser groups. We performed the analyses in a variety of ways, including inverse probability treatment weighting (IPTW) methods to balance any confounders and the landmark method to avoid immortal time bias. A total of 430 patients were enrolled, among whom 323 (75.1%) were statin nonusers and 107 (24.9%) were statin users. During a median of 64.9 months (IQR, 26.1-122.6 months) of follow-up, 79 patients (18.4%) had HCC recurrence and 111 (25.8%) died. Among those who died, 53 (47.7%) were identified as HCC-related mortalities. Statin use was a predictor of HCC recurrence (adjusted hazard ratio [HR], 0.3; 95% confidence interval [CI], 0.1-0.6; P = 0.002), all-cause mortality (adjusted HR, 0.3; 95% CI, 0.2-0.5; P < 0.001), and HCC-related mortality (adjusted HR, 0.4; 95% CI, 0.2-0.9; P = 0.03). The effects of statin use on clinical outcomes were also identified through IPTW analysis. There was a dose-dependent relationship between statin use and HCC recurrence. The anticancer effect of statins on HCC recurrence was consistently significant across multivariable-stratified and sensitivity analyses. Statin use significantly reduced the risk of HCC recurrence and improved the survival of patients who underwent LT for HCC.

Impact of the Reconstruction Material on the Patency of Middle Hepatic Vein in Living Donor Liver Transplantation Using the Right Liver.

BACKGROUND: A right liver graft with middle hepatic vein (MHV) reconstruction is the standard graft for adult-to-adult living donor liver transplantation (LDLT). The patency of reconstructed MHV affects the recovery and regeneration of graft. The aim of the study is to evaluate the patency rate of reconstructed MHV according to the reconstruction material in LDLT using the right liver. METHODS: The data was collected retrospectively on 521 patients who underwent LDLT with right liver graft form August 2003 to December 2012 at the Seoul St. Mary's Hospital in Seoul. Two serial comparisons were performed. At first, patients were divided into 2 groups: biologic graft group (n = 252) and synthetic graft group (n = 177). Second, patients were divided into 6 groups: No MHV reconstruction (n = 92); MHV was reconstructed by greater saphenous vein (GSV) (n = 20); recipient's portal vein (PV) (n = 219); cryopreserved iliac artery (CIA) (n = 2); cryopreserved iliac vein (CIV) (n = 11); polytetrafluoroethylene (PTFE) graft (n = 105); and polyethylene terephthalate (PETE) graft (n = 72). We compared the patency of reconstructed MHV among these groups by computed tomography angiography at 7 days, 20 days, 90 days, and 1 year. RESULTS: At the first comparison, the patency rate of the biologic graft group on the seventh postoperative day was 61.9%, and the synthetic graft group was 72.4% (P = .029). At postoperative 1 year, the patency rate of the biologic graft group was 42.9%, and the synthetic graft group was 24.1% (P = .001). At the second comparison, the MHV patency of GSV, PV, CIA, CIV, PTFE, and PETE was 65.0%, 62.5%, 50%, 63.6%, 75%, 72% on the seventh postoperative days (P = .318); 60%, 57.1%, 50%, 54.5%, 69%, 55.6% on the 20th postoperative days (P = .444); 40%, 48.8%, 50%, 27.3%, 47%, 34.1% on the 90th postoperative days (P = .294); and 30%, 45.2%, 50%, 27.3%, 27%, 26.4% at 1 postoperative year (P = .008). CONCLUSION: Although there was no statistical difference in comparison of each material, there were significant differences in MHV patency rates between the biologic and the synthetic group. Therefore, the synthetic graft could be considered in living donor liver transplantation with MHV reconstruction.

Invasive fungal infection in liver transplant recipients in a prophylactic era: A multicenter retrospective cohort study in Korea.

The epidemiology of invasive fungal infections (IFIs) after liver transplantation (LT) is continuing to evolve in the current era of antifungal prophylactic therapy. This multicenter retrospective cohort study aimed to evaluate the epidemiology, risk factors, and outcomes of IFIs among LT recipients in the current era.We analyzed a total of 482 LT recipients aged 18 years and older who were admitted to 3 tertiary hospitals in Korea between January 2009 and February 2012.Twenty-four episodes of IFIs occurred in 23 patients (4.77%; 23/482). Of these episodes, 20 were proven cases and 4 were probable cases according to EORTC/MSG criteria. Among these cases, IFI developed within 30 days of transplantation in 47.8% of recipients, from 31 to 180 days in 34.8% of recipients, and from 181 to 365 days in 17.4% of recipients. The most common isolates were Candida species (n = 12, 52.2%; Candida albicans, 6 cases; Candida tropicalis, 1 case; Candida glabrata, 1 case; Candida parapsilosis, 1 case; and unspecified Candida species, 1 case) and Aspergillus species (n = 7, 30.4%). The mortality in patients with IFIs was significantly higher than that in patients without IFIs (47.83% [11/23] vs 7.18% [33/459], P < .001). The incidence of late-onset IFIs is increasing in the antifungal prophylactic era, and fluconazole-resistant non-albicans Candida species have not yet emerged in Korea.

Efficacy and safety of a novel topical agent for gallstone dissolution: 2-methoxy-6-methylpyridine.

BACKGROUND: Although methyl-tertiary butyl ether (MTBE) is the only clinical topical agent for gallstone dissolution, its use is limited by its side effects mostly arising from a relatively low boiling point (55 °C). In this study, we developed the gallstone-dissolving compound containing an aromatic moiety, named 2-methoxy-6-methylpyridine (MMP) with higher boiling point (156 °C), and compared its effectiveness and toxicities with MTBE. METHODS: The dissolubility of MTBE and MMP in vitro was determined by placing human gallstones in glass containers with either solvent and, then, measuring their dry weights. Their dissolubility in vivo was determined by comparing the weights of solvent-treated gallstones and control (dimethyl sulfoxide)-treated gallstones, after directly injecting each solvent into the gallbladder in hamster models with cholesterol and pigmented gallstones. RESULTS: In the in vitro dissolution test, MMP demonstrated statistically higher dissolubility than did MTBE for cholesterol and pigmented gallstones (88.2% vs. 65.7%, 50.8% vs. 29.0%, respectively; P < 0.05). In the in vivo experiments, MMP exhibited 59.0% and 54.3% dissolubility for cholesterol and pigmented gallstones, respectively, which were significantly higher than those of MTBE (50.0% and 32.0%, respectively; P < 0.05). The immunohistochemical stains of gallbladder specimens obtained from the MMP-treated hamsters demonstrated that MMP did not significantly increase the expression of cleaved caspase 9 or significantly decrease the expression of proliferation cell nuclear antigen. CONCLUSIONS: This study demonstrated that MMP has better potential than does MTBE in dissolving gallstones, especially pigmented gallstones, while resulting in lesser toxicities.

Deep gray matter iron measurement in patients with liver cirrhosis using quantitative susceptibility mapping: Relationship with pallidal T1 hyperintensity.

BACKGROUND: The liver is a central organ for the metabolism of iron and manganese and the places where those metals are commonly deposited overlap in the brain. PURPOSE/HYPOTHESIS: To elucidate the relationship between pallidal T1 hyperintensity and iron deposition in the deep gray matter of liver cirrhosis patients using quantitative susceptibility mapping (QSM). STUDY TYPE: Retrospective case-control study SUBJECTS: In all, 38 consecutive liver cirrhosis patients who received brain magnetic resonance imaging (MRI) as pretransplant evaluation. FIELD STRENGTH/SEQUENCE: QSM was reconstructed from 3D multi- or single-echo phase images at 3T. T1 -weighted images were used for the assessment of pallidal hyperintensity and pallidal index (PI). ASSESSMENT: Patients were divided into two groups according to the presence of pallidal hyperintensity by consensus of two radiologists. Susceptibility values were acquired for five deep gray matter structures. STATISTICAL TEST: QSM measures were compared between two groups using the t-test. We also calculated Pearson correlations between QSM measures and PI. RESULTS: In all, 26 patients showed pallidal hyperintensity (T1 h group) and 12 did not (T1 n group). The susceptibility of the globus pallidus (GP) in the T1 h group (120.6 ± 38.1 ppb) was significantly lower than that in the T1 n group (150.0 ± 35.2, P = 0.030). The susceptibility of the dentate nucleus (DN) in the T1 h group (88.1 ± 31.0) was significantly lower than that in the T1 n group (125.6 ± 30.6, P = 0.001). Negative correlation between the susceptibility of GP (r = -0.37, P = 0.022) and the PI, and between DN (r = -0.43, P < 0.001) and the PI was found. DATA CONCLUSION: Liver cirrhosis patients with pallidal T1 hyperintensity had lower susceptibility values in the GP and DN than those without it. This suggests a possible interaction between iron and manganese in the brains of liver cirrhosis patients. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1342-1349.

A 6-month mixed-effect pharmacokinetic model for post-transplant intravenous anti-hepatitis B immunoglobulin prophylaxis.

BACKGROUND: Although individualized dosage regimens for anti-hepatitis B immunoglobulin (HBIG) therapy have been suggested, the pharmacokinetic profile and factors influencing the basis for individualization have not been sufficiently assessed. We sought to evaluate the pharmacokinetic characteristics of anti-HBIG quantitatively during the first 6 months after liver transplantation. METHODS: Identical doses of 10,000 IU HBIG were administered to adult liver transplant recipients daily during the first week, weekly thereafter until 28 postoperative days, and monthly thereafter. Blood samples were obtained at days 1, 7, 28, 84, and 168 after transplantation. Plasma HBIG titer was quantified using 4 different immunoassay methods. The titer determined by each analytical method was used for mixed-effect modeling, and the most precise results were chosen. Simulations were performed to predict the plausible immunoglobulin maintenance dose. RESULTS: HBIG was eliminated from the body most rapidly in the immediate post-transplant period, and the elimination rate gradually decreased thereafter. In the early post-transplant period, patients with higher DNA titer tend to have lower plasma HBIG concentrations. The maintenance doses required to attain targets in 90%, 95%, and 99% of patients were ~15.3, 18.2, and 25.1 IU, respectively, multiplied by the target trough level (in IU/L). CONCLUSION: The variability (explained and unexplained) in HBIG pharmacokinetics was relatively larger in the early post-transplant period. Dose individualization based upon patient characteristics should be adjusted focusing quantitatively on the early post-transplant period.

The clinical outcomes of patients with portal vein tumor thrombi after living donor liver transplantation.

The purpose of this study was to evaluate the feasibility of living donor liver transplantation for treatment of patients with hepatocellular carcinoma and segmental portal vein tumor thrombus (PVTT) below the second-order branch. Between January 2005 and December 2015, we retrospectively analyzed 242 patients in a control group (n = 184), a microvascular invasion (MVI) group (n = 24), and a PVTT group (n = 34). To assess the risks associated with PVTT, we evaluated recurrence, the disease-free survival (DFS) rate, the overall survival (OS) rate, and various other factors based on the characteristics of patients and tumors. Of the 242 patients, 5-year DFS and OS rates were 79.5% and 70.7%. A total of 34 (14.0%) patients had PVTT, of whom 7 had lobar PVTT in first-order branches. The control, MVI, and PVTT groups significantly differed in terms of tumor morphology (maximal and total diameters) and biology (alpha-fetoprotein [AFP] and protein induced by vitamin K absence or antagonist II). The control, MVI, and PVTT groups significantly differed in terms of the recurrence, DFS, and OS rates. Especially, lobar PVTT reduced the 5-year DFS and OS rates to dismal and 14.3%, respectively, but segmental PVTT was associated with favorable 5-year DFS and OS rates (63.9% and 50.3%, respectively). We found no statistically significant difference in the DFS and OS rates of patients with MVI alone and segmental PVTT alone. In patients in the segmental PVTT group with AFP levels of <100 ng/mL, the 5-year DFS and OS rates were 90.9% and 71.3%, respectively. In conclusion, a tumor thrombus in a lobar portal vein remains a contraindication to liver transplantation. However, a segmental PVTT is acceptable, especially when the AFP level is <100 ng/mL. Liver Transplantation 23 1023-1031 2017 AASLD.

Long-Term Outcome of Liver Resection Versus Transplantation for Hepatocellular Carcinoma in a Region Where Living Donation is a Main Source.

BACKGROUND The aim of this study was to define the best curative strategy in patients with hepatocellular carcinoma (HCC) in a hepatitis B virus (HBV)-endemic region where living donation dominates the type of cadaveric donation for liver transplantation (LT). MATERIAL AND METHODS A retrospective cohort comprised those patients whose clinical course could potentially be traced for at least 10 years. We found 262 HCC patients who had undergone curative surgical treatment from March 1997 to August 2006. Among these patients, 156 were treated with liver resection (LR) (R group) and 106 patients underwent LT (T group, 100 patients with living donor). Tumor characteristics, overall survival (OS), and recurrence-free survival (RFS) were analyzed. RESULTS Postoperative mortality was not significantly different between the groups, whereas recurrence rate during the study period (until August 2016) was higher in the R group (56% in the R group versus 19% in the T group, p<0.001). The 10-year and 15-year OS and RFS were better in the T group. Subgroup analysis with patients having solitary and £5 cm tumor by preoperative imaging showed that the 10-year and 15-year OS and RFS were much better in the T group, irrespective of their preoperative liver function defined by MELD score. In the T group, resection as the surgical procedure and tumor size on histology were poor prognostic factors for RFS. Importantly, this superiority of LT over LR in OS and RFS applied only to the patients with relatively low preoperative alpha-fetoprotein (AFP) levels (AFP <100 ng/mL), because patients with higher levels compared with lower levels of AFP tended to have more recurrent tumors after LT, but not in the case of LR during long-term follow-up. CONCLUSIONS Overall, LT was associated with better survival outcomes than resection in patients with HCC in Korea, where living donation is a main transplant source.

Human Leukocyte Antigen-C Genotype and Killer Immunoglobulin-like Receptor-Ligand Matching in Korean Living Donor Liver Transplantation.

BACKGROUND: The interaction between killer immunoglobulin-like receptors (KIRs) and HLA class I regulates natural killer (NK) cell cytotoxicity and function. The impact of NK cell alloreactivity through KIR in liver transplantation remains unelucidated. Since the frequency of HLA-C and KIR genotypes show ethnic differences, we assessed the impact of HLA-C, KIR genotype, or KIR-ligand mismatch on the allograft outcome of Korean liver allografts. METHODS: One hundred eighty-two living donor liver transplant patients were studied. Thirty-five patients (19.2%) had biopsy-confirmed acute rejection (AR), and eighteen (9.9%) had graft failure. The HLA-C compatibility, KIR genotypes, ligand-ligand, and KIR-ligand matching was retrospectively investigated for association with allograft outcomes. RESULTS: Homozygous C1 ligands were predominant in both patients and donors, and frequency of the HLA-C2 allele in Koreans was lower than that in other ethnic groups. Despite the significantly lower frequency of the HLA-C2 genotype in Koreans, donors with at least one HLA-C2 allele showed higher rates of AR than donors with no HLA-C2 alleles (29.2% vs 15.7%, P=0.0423). Although KIR genotypes also showed ethnic differences, KIR genotypes and the number of activating KIR/inhibitory KIR were not associated with the allograft outcome. KIR-ligand mismatch was expected in 31.6% of Korean liver transplants and had no impact on AR or graft survival. CONCLUSIONS: This study could not confirm the clinical impact of KIR genotypes and KIR-ligand mismatch. However, we demonstrated that the presence of HLA-C2 allele in the donor influenced AR of Korean liver allografts.

Immunohistochemical markers for hepatocellular carcinoma prognosis after liver resection and liver transplantation.

AIM: There were differences in progression and prognosis of hepatocellular carcinoma (HCC) after surgery between liver resection (LR) and liver transplantation (LT). In this study, immunohistochemical (IHC) markers associated with the prognosis of HCC were assessed. METHODS: Data were collected from 167 patients who underwent LT (n=41) or LR (n=126) for HCC. IHC markers including alpha-fetoprotein (AFP), p53, Ki-67, cytokeratin 7 (CK7), and cytokeratin 19 (CK19) were compared between the treatment methods in tumor tissue. RESULTS: AFP- and p53-negative patients had a significantly higher survival rate than AFP- and p53-positive patients (AFP: disease-free survival [DFS] P=.006, overall survival [OS] P=.016; p53: DFS P=.005, OS P=.038) in the LR group. CK19 was related to DFS (P=.005), while CK7 (P=.014) and CK19 (P=.06) were related to OS in the LT group. When we combined factors that were significant in both groups (LR: AFP and p53, LT: CK7 and CK19), all-negative patients had a higher survival rate (LR: DFS P=.025, OS P=.043, LT: DFS P=.034, OS P=.008). CONCLUSION: p53 and AFP were predictors for poor prognosis of HCC after LR; CK7 and CK19 could be predictors for poor prognosis of patients with HCC after LT.

Clinical analysis of patients with hepatocellular carcinoma recurrence after living-donor liver transplantation.

AIM: To evaluated patterns and outcomes of hepatocellular carcinoma (HCC) recurrence after living donor liver transplantation (LDLT). METHODS: From 2001 to 2014, 293 patients underwent LDLT for HCC at our transplant center. We retrospectively reviewed 54 (18.4%) patients with HCC recurrence after LDLT. We evaluated patterns and outcomes of HCC recurrence after LDLT, with particular attention to the Milan criteria at transplantation, treatments for HCC-recurrent patients, and factors related to survival after HCC recurrence. Furthermore, we evaluated the efficacy of combination treatment of sorafenib and an mTOR inhibitor. RESULTS: The 1-, 2-, and 3-year overall survival rates after HCC recurrence were 41.1%, 20.5%, and 15.4%, respectively. The median time interval between LDLT and HCC recurrence was 6.5 mo. Although recurrence rates according to the Milan criteria at LDLT were significantly different, HCC recurrence patterns and survival rates after HCC recurrence were not significantly different between the two groups. Time to recurrence < 12 mo (P = 0.048), multiple recurrences at HCC recurrence (P = 0.038), and palliative treatment for recurrent tumors (P = 0.003) were significant independent prognostic factors for poor survival after HCC recurrence in a multivariate analysis. The combination treatment of sorafenib and sirolimus showed survival benefits in the palliative treatment group (P = 0.005). CONCLUSION: Curative treatment for recurrent HCC after LDLT is the most important factor in survival rates after HCC recurrence and combination treatments of sorafenib and an mTOR inhibitor could have survival benefits in patients with HCC recurrence after LT in the palliative treatment group.

De novo hepatitis B virus infection developing after liver transplantation using a graft positive for hepatitis B core antibody.

PURPOSE: The use of hepatitis B core antibody (HBcAb)-positive grafts is increasing, especially where hepatitis B is endemic. However, this remains controversial because of the risk of development of de novo HBV infection. METHODS: We collected information obtained between January 2000 and December 2012 and retrospectively analyzed data on 187 HBsAg-negative donors and recipients were analyzed retrospectively. De novo HBV infection was defined as development of HBsAg positivity with or without detection of HBV DNA. RESULTS: Forty patients (21.4%) received HBcAb-positive grafts. Survival rate did not differ by donor HBcAb status (P = 0.466). De novo HBV infection occurred in five patients (12.5%) who were not treated with anti-HBV prophylaxis, and was significantly more prevalent in hepatitis B surface antibody (HBsAb)- and HBcAb-negative than HBsAb- and HBcAb-positive recipients (50% vs. 4.2%, P = 0.049). All patients except one were treated with entecavir with/without antihepatitis B immunoglobulin and four were negative in terms of HBV DNA seroconversion. No patient died. CONCLUSION: HBcAb-positive grafts are safe without survival difference. However, the risk of de novo hepatitis B virus infection was significantly increased in HBsAb- and HBcAb-negative recipients. All patients were successfully treated even after recurrence.