Intrahepatic IgA complex induces polarization of cancer-associated fibroblasts to matrix phenotypes in the tumor microenvironment of HCC.

BACKGROUND AND AIMS: Cancer-associated fibroblasts (CAFs) play key roles in the tumor microenvironment. IgA contributes to inflammation and dismantling antitumor immunity in the human liver. In this study, we aimed to elucidate the effects of the IgA complex on CAFs in Pil Soo Sung the tumor microenvironment of HCC. APPROACH AND RESULTS: CAF dynamics in HCC tumor microenvironment were analyzed through single-cell RNA sequencing of HCC samples. CAFs isolated from 50 HCC samples were treated with mock or serum-derived IgA dimers in vitro. Progression-free survival of patients with advanced HCC treated with atezolizumab and bevacizumab was significantly longer in those with low serum IgA levels ( p <0.05). Single-cell analysis showed that subcluster proportions in the CAF-fibroblast activation protein-α matrix were significantly increased in patients with high serum IgA levels. Flow cytometry revealed a significant increase in the mean fluorescence intensity of fibroblast activation protein in the CD68 + cells from patients with high serum IgA levels ( p <0.001). We confirmed CD71 (IgA receptor) expression in CAFs, and IgA-treated CAFs exhibited higher programmed death-ligand 1 expression levels than those in mock-treated CAFs ( p <0.05). Coculture with CAFs attenuated the cytotoxic function of activated CD8 + T cells. Interestingly, activated CD8 + T cells cocultured with IgA-treated CAFs exhibited increased programmed death-1 expression levels than those cocultured with mock-treated CAFs ( p <0.05). CONCLUSIONS: Intrahepatic IgA induced polarization of HCC-CAFs into more malignant matrix phenotypes and attenuates cytotoxic T-cell function. Our study highlighted their potential roles in tumor progression and immune suppression.

Outcomes and Risk Factors for Liver Transplantation Using graft-to-Recipient Weight Ratio Less than 0.8 Graft from Living Donors: Multicentric Cohort Study.

OBJECTIVE: To compare graft survival after LDLT in patients receiving GRWR<0.8 versus GRWR≥0.8 grafts and identify risk factors for graft loss using GRWR<0.8 grafts. SUMMARY BACKGROUND DATA: Favorable outcomes after living donor liver transplantation (LDLT) using graft-to-recipient weight ratio (GRWR)<0.8 grafts were recently reported; however, these results have not been validated using multicenter data. METHODS: This multicentric cohort study included 3450 LDLT patients. Graft survival was compared between 1:3 propensity score-matched groups and evaluated using various Cox models in the entire population. Risk factors for graft loss with GRWR<0.8 versus GRWR≥0.8 grafts were explored within various subgroups using interaction analyses, and outcomes were stratified according to the number of risk factors. RESULTS: In total, 368 patients (10.7%) received GRWR<0.8 grafts (GRWR<0.8 group), whereas 3082 (89.3%) received GRWR≥0.8 grafts (GRWR≥0.8 group). The 5-y graft survival rate was significantly lower with GRWR<0.8 grafts than with GRWR≥0.8 grafts (85.2% vs. 90.1%, P=0.013). Adjusted hazard ratio (HR) for graft loss using GRWR<0.8 grafts in the entire population was 1.66 (95% confidence interval [CI] 1.17-2.35, P=0.004). Risk factors exhibiting significant interactions with GRWR<0.8 for graft survival were age ≥60 y, MELD score ≥15, and male donor. When ≥2 risk factors were present, GRWR<0.8 grafts showed higher risk of graft loss compared to GRWR≥0.8 graft in LDLT (HR 2.98, 95% CI 1.79-4.88, P<0.001). CONCLUSIONS: GRWR<0.8 graft showed inferior graft survival than controls (85.2% vs. 90.1%), especially when ≥2 risk factors for graft loss (among age ≥60 y, MELD score ≥15, or male donor) were present.

Outcomes of sexagenarian living liver donors in Korea: A multicenter study.

The safety of elderly living liver donors and recipient outcomes are always of concern. In the present study, the effects of age in 2 donor groups, a 60+years old group and a 50-59 years old group (referred to as the 60s and 50s donor groups, respectively), on living donor liver transplantation were compared regarding donor safety and recipient outcomes. We retrospectively identified 209 patients 50 years and above of age at 9 centers from 2005 to 2017 in Korea. The 60s donor group represented 10% (n=21) of donor patients. One case in each group was a left liver graft, respectively, and the others were right liver grafts. Postoperative complications were more common in the 60s donor group, but the proportion of Clavien-Dindo grade III in the 60s donor group did not differ from that in the 50s donor group. In-hospital mortality did not occur among donors, and donor mortality was not reported during the observation period. Postoperative total bilirubin and hospitalization in recipients of the 60s donor group were higher and longer than in recipients of the 50s donor group, respectively. Although the cumulative overall survival of the recipients in the 60s donor group was significantly lower than that of the 50s donor group, a difference was not observed in graft survival. Multivariate analysis showed that increased living liver donors age, the coexistence of HCC, and increased intraoperative blood loss during the recipient operation were important predisposing factors for patient death. Present study suggests that highly selected elderly living donors (≥60 y) can safely donate with similar recipient graft survival rates though the recipient overall patient survival is inferior compared to the 50s donor group.

Entecavir versus tenofovir on the recurrence of hepatitis B-related HCC after liver transplantation: A multicenter observational study.

Considerable controversy exists regarding the superiority of tenofovir disoproxil fumarate (TDF) over entecavir (ETV) for reducing the risk of HCC. This study aimed to compare outcomes of ETV versus TDF after liver transplantation (LT) in patients with HBV-related HCC. We performed a multicenter observational study using data from the Korean Organ Transplantation Registry. A total of 845 patients who underwent LT for HBV-related HCC were divided into 2 groups according to oral nucleos(t)ide analogue used for HBV prophylaxis post-LT: ETV group (n = 393) and TDF group (n = 452). HCC recurrence and overall death were compared in naïve and propensity score (PS)-weighted populations, and the likelihood of these outcomes according to the use of ETV or TDF were analyzed with various Cox models. At 1, 3, and 5 years, the ETV and TDF groups had similar HCC recurrence-free survival (90.7%, 85.6%, and 84.1% vs. 90.9%, 84.6%, and 84.2%, respectively, p = 0.98) and overall survival (98.4%, 94.7%, and 93.5% vs. 99.3%, 95.8%, and 94.9%, respectively, p = 0.48). The propensity score-weighted population showed similar results. In Cox models involving covariates adjustment, propensity score-weighting, competing risk regression, and time-dependent covariates adjustment, both groups showed a similar risk of HCC recurrence and overall death. In subgroup analyses stratified according to HCC burden (Milan criteria, Up-to-7 criteria, French alpha-fetoprotein risk score), pretransplantation locoregional therapy, and salvage LT, neither ETV nor TDF was superior. In conclusion, ETV and TDF showed mutual noninferiority for HCC outcomes when used for HBV prophylaxis after LT.

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.

The chronological change of indications and outcomes for single-incision laparoscopic cholecystectomy: a Korean multicenter study.

BACKGROUND: Although single-incision laparoscopic cholecystectomy (SILC) is a common procedure, the change in its surgical indications and perioperative outcomes has not been analyzed. METHODS: We collected the clinical data of patients who underwent pure SILC in 9 centers between 2009 and 2018 and compared the perioperative outcomes. RESULTS: In this period, 6497 patients underwent SILC. Of these, 2583 were for gallbladder (GB) stone (39.7%), 774 were for GB polyp (11.9%), 994 were for chronic cholecystitis (15.3%), and 1492 were for acute cholecystitis (AC) (23%). 162 patients (2.5%) experienced complication, including 20 patients (0.2%) suffering from biliary leakage. The number of patients who underwent SILC for AC increased over time (p = 0.028), leading to an accumulation of experience (27.4 vs 23.7%, p = 0.002). The patients in late period were more likely to have undergone a previous laparotomy (29.5 vs 20.2%, p = 0.006), and to have a shorter operation time (47.0 vs 58.8 min, p < 0.001). Male (odds ratio [OR]; 1.673, 95% confidence interval [CI] 1.090-2.569, p = 0.019) and moderate or severe acute cholecystitis (OR; 2.602, 95% CI 1.677-4.037, p < 0.001) were independent predictive factors for gallbladder perforation during surgery, and open conversion (OR; 5.793, 95% CI 3.130-10.721, p < 0.001) and pathologically proven acute cholecystitis or empyema (OR; 4.107, 95% CI 2.461-6.854, p < 0.001) were related with intraoperative gallbladder perforation CONCLUSION: SILC has expanded indication in late period. In this period, the patients had shorter operation times and a similar rate of severe complications, despite there being more numerous patients with AC.

Radical antegrade modular pancreatosplenectomy (RAMPS) versus conventional distal pancreatectomy for left-sided pancreatic cancer: findings of a multicenter, retrospective, propensity score matching study.

PURPOSE: Radical antegrade modular pancreatosplenectomy (RAMPS) has been reported to achieve high rates of a negative margin and resected metastatic lymph nodes. However, many studies have used historical controls and the results remain controversial. We conducted this study to compare the surgical and long-term outcomes of RAMPS vs. conventional distal pancreatectomy (DP). METHODS: The subjects of this multicenter retrospective study were 106 patients who underwent curative resection for left-sided pancreatic cancer between 2012 and 2017. Overall survival (OS) and recurrence-free survival (RFS) rates were compared using Kaplan-Meier estimates. RESULTS: The RAMPS group had more advanced T (T3/T4) and N stages (N1/N2) and a larger tumor size than the conventional group (T stage, p = 0.04; N stage, p = 0.02; tumor size, p = 0.04). The RAMPS group had more harvested metastatic lymph nodes (p = 0.02). After propensity-score matching, 37 patients from each group were included in the final analysis. There was no significant difference in RFS (p = 0.463) or OS (p = 0.383) between the groups. Multivariate analyses revealed the completion of chemotherapy to be an independent factor for RFS and OS (both p < 0.001). CONCLUSIONS: There was no difference in the RFS or OS between RAMPS and conventional DP in this series. RAMPS may be an option for R0 resection of advanced tumors; however, postoperative chemotherapy has a greater influence than the surgical procedure on the prognosis of patients with pancreatic cancer.

Preferential Expression of Programmed Death Ligand 1 Protein in Tumor-Associated Macrophages and Its Potential Role in Immunotherapy for Hepatocellular Carcinoma.

A predictive biomarker of immune checkpoint inhibitor (ICI)-based treatments in hepatocellular carcinoma (HCC) has not been clearly demonstrated. In this study, we focused on the infiltration and programmed death ligand 1 (PD-L1) expression of tumor-associated macrophages (TAMs) in the tumor microenvironment of HCC. Immunohistochemistry demonstrated that PD-L1 was preferentially expressed on CD68+ macrophages in the tumor microenvironment of HCC, suggestive of its expression in TAMs rather than in T cells or tumor cells (P < 0.05). A co-culture experiment using activated T cells and M2 macrophages confirmed a significant increase in T cell functionality after the pretreatment of M2 macrophages with anti-PD-L1. Syngeneic mouse model experiments demonstrated that TAMs expressed PD-L1 and tumors treated with anti-PD-L1 showed smaller diameters than those treated with IgG. In these mice, anti-PD-L1 treatment increased activation markers in intratumoral CD8+ T cells and reduced the size of the TAM population. Regarding nivolumab-treated patients, three of eight patients responded to the anti-PD-1 treatment. The percentage of Ki-67-positive CD4+ and CD8+ T cells was higher in responders than non-responders after nivolumab. Overall, PD-L1 expression on TAMs may be targeted by immune-based HCC treatment, and ICI treatment results in the reinvigoration of exhausted CD8+ T cells in HCC.

Hepatitis B Prophylaxis after Liver Transplantation in Korea: Analysis of the KOTRY Database.

BACKGROUND: Prophylaxis for hepatitis B virus (HBV) recurrence is essential after liver transplantation (LT) in HBV-associated recipients. We conducted real-world analysis of HBV prophylaxis after LT in the Korean population. METHODS: Korean Organ Transplantation Registry (KOTRY) database and additionally collected data (n = 326) were analyzed with special reference to types of HBV prophylaxis. RESULTS: The study cohort comprised 267 cases of living-donor LT and 59 cases of deceased-donor LT. Hepatocellular carcinoma (HCC) was diagnosed in 232 (71.2%) of these subjects. Antiviral agents were used in 255 patients (78.2%) prior to LT. HBV DNA was undetectable in 69 cases (21.2%) and detectable over wide concentrations in the other 257 patients (78.8%) prior to LT. Polymerase chain reaction analysis of the store blood samples detected HBV DNA in all patients, with 159 patients (48.9%) showing concentrations > 100 IU/mL. Post-transplant HBV regimens during the first year included combination therapy in 196 (60.1%), hepatitis B immunoglobulin (HBIG) monotherapy in 121 (37.1%), and antiviral monotherapy in 9 (2.8%). In the second post-transplant year, these regimens had changed to combination therapy in 187 (57.4%), HBIG monotherapy in 112 (34.4%), and antiviral monotherapy in 27 (8.3%). Trough antibody to hepatitis B surface antigen titers > 500 IU/mL and >1,000 IU/mL were observed in 61.7% and 25.2%, respectively. The mean simulative half-life of HBIG was 21.6 ± 4.3 days with a median 17.7 days. Up to 2-year follow-up period, HCC recurrence and HBV recurrence developed in 18 (5.5%) and 6 (1.8%), respectively. HCC recurrence developed in 3 of 6 patients with HBV recurrence. CONCLUSION: Combination therapy is the mainstay of HBV prophylaxis protocols in a majority of Korean LT centers, but HBIG was often administered excessively. Individualized optimization of HBIG treatments using SHL is necessary to adjust the HBIG infusion interval.

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.

The Role of Phospho-c-Jun N-Terminal Kinase Expression on hepatocyte Necrosis and Autophagy in the Cholestatic Liver.

BACKGROUND: Clinically, liver fibrosis and cholestasis are two major disease entities, ultimately leading to hepatic failure. Although autophagy plays a substantial role in the pathogenesis of these diseases, its precise mechanism has not been determined yet. MATERIALS AND METHODS: Mouse models of liver fibrosis or cholestasis were obtained after the serial administration of thioacetamide (TAA) or surgical bile duct ligation (BDL), respectively. Then, after obtaining liver specimens at specific time points, we compared the expression of makers related to apoptosis (cleaved caspases), inflammation (CD68), necrosis (high-mobility group box 1), phospho-c-Jun N-terminal kinase (p-JNK), and autophagy (microtubule-associated protein light chain 3B and p62) in the fibrotic or cholestatic mouse livers, by polymerase chain reaction, Western blot analysis, immunohistochemistry, and immunofluorescence. RESULTS: Although cholestatic livers exhibited the tendency of progressively increasing the expression of most apoptosis-related markers (cleaved caspases), it was not prominent when it was compared with the tendency found in the livers of TAA-treated mice. Contrastingly, the necrosis-related factor (high-mobility group box 1) was significantly increased in the livers of BDL mice over time, reaching their peak values on day 7 after BDL. In addition, the inflammation-related factor (CD68) was highly expressed in BDL mice compared with TAA-treated mice over time. Autophagy marker studies indicated that autophagy was upregulated in fibrotic livers, whereas it was downregulated in cholestatic livers. We also observed mild to moderate activation of p-JNK in the livers of TAA-treated mice, whereas significantly higher p-JNK activation was detected in the livers of BDL mice. CONCLUSIONS: Unlike TAA-treated mice, BDL mice exhibited higher expression of the markers related with inflammation and necrosis, especially including p-JNK, while maintaining low levels of autophagic process. Therefore, obstructive cholestasis is characterized by higher p-JNK activation, which could be related with marked necrotic cell death resulting from extensive inflammation and little chance of compensatory autophagy.

Clinical Course of Hepatic Artery Thrombosis After Living Donor Liver Transplantation Using the Right Lobe.

Hepatic artery thrombosis (HAT) can result in biliary tree necrosis and graft loss, necessitating retransplantation. The most effective treatment approach is still controversial. This study was performed to review the outcomes of HAT after living donor liver transplantation (LDLT) and to clarify the feasibility of different strategies. From May 1996 to August 2017, LDLT using the right lobe was performed in 827 adult patients in our center. Our technique of hepatic artery (HA) reconstruction is end-to-end anastomosis under a microscope (10×). Diagnosis of HAT was performed using Doppler sonography and computed tomography (CT) angiography. HAT was initially treated with surgical or endovascular procedure, and retransplantation was considered according to the graft condition. Among the 827 cases of LDLT using the right lobe, HAT occurred in 16 (1.9%) cases within 1 month after transplantation. Within the first week, 7 of these HAT cases (43.8%) occurred (early HAT), while the remaining 9 cases (56.2%) occurred between the first week and 1 month (late HAT). The incidence of graft failure was high in early HAT (42.9%), and the frequency of biliary complications was high in late HAT (77.8%). The success rate of HA recanalization was 62.5% (10/16): 100% (5/5) after reoperation and 45.5% (5/11) after the endovascular procedure. Of the patients in whom treatment failed in late HAT (n = 5), 4 underwent neovascularization during observation. A total of 5 patients underwent graft failure, and 3 of these patients underwent repeat liver transplantation (LT). Mortality occurred in 3 patients, including 1 in the surgical group and 2 in the endovascular group. In conclusion, early diagnosis and aggressive treatment of HAT are necessary to avoid graft failure, and the choice of treatment depends on various factors. Although further studies are required, early HAT requires preparation for graft failure, while late HAT requires treatment for biliary complications.

Perioperative outcomes of laparoscopic pancreaticoduodenectomy for benign and borderline malignant periampullary disease compared to open pancreaticoduodenectomy.

PURPOSE: The objective of this study was to compare perioperative outcomes between laparoscopic pancreaticoduodenectomy (LPD) and open pancreaticoduodenectomy (OPD) for benign and borderline malignant periampullary diseases. METHODS: Of 107 pancreaticoduodenectomy cases for non-malignant diseases from March 1993 to July 2017, 76 patients underwent OPD and 31 patients received LPD. To adjust for baseline differences and selection bias, operative outcomes and complications were compared after propensity score matching (PSM). RESULTS: After 1:1 PSM, well-matched 31 patients in each group were evaluated. As a result, significant differences were observed between two groups in some aspects: mean operative time (LPD 426.8 ± 98.58 vs. OPD 355.03 ± 100.0 min, p = 0.031), estimated blood loss (LPD 477.42 ± 374.80 vs. OPD 800.00 ± 531.35 ml, p = 0.008), and postoperative hospital stay (LPD 14.74 ± 5.40 vs. OPD 23.81 ± 11.63 days, p < 0.001). The average visual analogue scores for pain observed from patients in LPD group on postoperative day (POD) 1 (4.23 ± 1.83 vs. 5.55 ± 2.50, p = 0.021) and POD 3 (3.32 ± 1.66 vs. 5.26 ± 2.76, p = 0.002) were significantly less than those from patients in OPD group, as well. There were no significant differences between groups about major complications including the rate of postoperative pancreatic fistula. CONCLUSIONS: LPD is a safe procedure and provides less postoperative pain and the shortening length of hospitalization. LPD may serve the feasible alternative approach for benign and borderline malignant periampullary disease.

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.

Donor safety in living donor liver transplantation: The Korean organ transplantation registry study.

Major concerns about donor safety cause controversy and limit the use of living donor liver transplantation to overcome organ shortages. The Korean Organ Transplantation Registry established a nationwide organ transplantation registration system in 2014. We reviewed the prospectively collected data of all 832 living liver donors who underwent procedures between April 2014 and December 2015. We allocated the donors to a left lobe group (n = 59) and a right lobe group (n = 773) and analyzed the relations between graft types and remaining liver volumes and complications (graded using the Clavien 5-tier grading system). The median follow-up was 19 months (range, 10-31 months). During the study period, 553 men and 279 women donated livers, and there were no deaths after living liver donation. The overall, biliary, and major complication (grade ≥ III) rates were 9.3%, 1.7%, and 1.9%, respectively. The graft types and remaining liver volume were associated with significantly different overall, biliary, and major complication rates. Of the 16 patients with major complications, 9 (56.3%) involved biliary complications (2 biliary strictures [12.5%] and 7 bile leakages [43.8%]). Among the 832 donors, the mean aspartate transaminase, alanine aminotransferase, and total bilirubin levels were 23.9 ± 8.1 IU/L, 20.9 ± 11.3 IU/L, and 0.8 ± 0.4 mg/dL, respectively, 6 months after liver donation. In conclusion, biliary complications were the most common types of major morbidity in living liver donors. Donor hepatectomy can be performed successfully with minimal and easily controlled complications. Our study shows that prospective, nationwide cohort data provide an important means of investigating the safety in living liver donation. Liver Transplantation 23 999-1006 2017 AASLD.

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.

Performance of Gadoxetic Acid-Enhanced Liver Magnetic Resonance Imaging for Predicting Patient Eligibility for Liver Transplantation Based on the Milan Criteria.

PURPOSE: This study aimed to evaluate the accuracy of gadoxetic acid-enhanced magnetic resonance imaging (Gd-EOB-MRI) in predicting eligibility for liver transplantation in patients with hepatocellular carcinoma (HCC) based on Milan criteria (MC). MATERIALS AND METHODS: We reviewed Gd-EOB-MRI of 44 patients who underwent liver transplantation for HCC with cirrhosis for the presence/size of HCCs, vascular invasion, and transplant eligibility based on MC. Hepatocellular carcinoma was diagnosed based on conventional radiological hallmarks (arterial enhancement and washout) or the modified criteria. RESULTS: Among 44 patients, 16 was beyond MC. Sensitivity, specificity, and accuracy of conventional radiological hallmark and the modified criteria for predicting eligibility by MC were 31.3%, 96.3%, and 72.7%, and 68.8%, 96.3%, and 86.4%, respectively. CONCLUSIONS: Gd-EOB-MRI showed high specificity but poor sensitivity for assessing transplant eligibility based on MC when adopting the conventional radiological hallmarks of HCC. Our modified criteria showed significantly better sensitivity and accuracy than the conventional radiological hallmarks.

Clinical significance of isolated biliary candidiasis in patients with unresectable cholangiocarcinoma.

BACKGROUND: The frequency of isolated biliary candidiasis is increasing in cancer patients. The clinical significance of isolated biliary candidiasis remains unclear. We analyzed the risk factors of biliary candidiasis and outcomes of the patients with unresectable cholangiocarcinoma after percutaneous transhepatic biliary drainage (PTBD). METHODS: Among 430 patients who underwent PTBD between January 2012 and March 2015, 121 patients had unresectable cholangiocarcinoma. Bile and blood samples were collected for consecutive fungal culture. RESULTS: The study cohort included 49 women and 72 men with a median age of 71 years. Multivariate analysis showed that cancer progression (P=0.013), concurrent presence of another microorganism (P=0.010), and previous long-term (>7 days) antibiotic use (P=0.011) were potential risk factors of biliary candidiasis. Chemotherapy was not associated with overall biliary candidiasis (P=0.196), but was significantly related to repeated biliary candidiasis (P=0.011). Patients with isolated biliary candidiasis showed remarkably reduced survival compared with those without [median overall survival (OS): 32 vs 62 days, P=0.011]. Subgroup analysis was also performed. Patients with repeated candidiasis had markedly decreased survival compared with those with transient candidiasis (median OS: 30 vs 49 days, P=0.046). Biliary candidiasis was identified as a poor prognostic factor by univariate and multivariate analyses (P=0.033). Four cases of repeated candidiasis (4/19, 21%) showed Candida species in consecutive blood culture until the end of the study, but others showed no candidemia. CONCLUSIONS: Isolated biliary candidiasis may be associated with poor prognosis in patients with unresectable cholangiocarcinoma. Especially, repeated biliary candidiasis may have the possibility of progression to candidemia. We suggest that biliary dilatation treatment or antifungal agents might be helpful for patients with biliary candidiasis.

Prevention and risk factors of hepatitis B recurrence after living donor liver transplantation.

BACKGROUND AND AIM: Without effective prophylaxis, liver transplantation (LT) for hepatitis B virus (HBV)-related liver disease is frequently complicated by severe and rapidly progressive HBV recurrence. The combination of low-dose hepatitis B immunoglobulin (HBIG) and the new nucleos(t)ide analog, entecavir, as prophylaxis for HBV recurrence after living-donor LT (LDLT) were analyzed. METHODS: A total of 315 patients with positive hepatitis B surface antigen underwent LDLT at our transplant center between July 2003 and December 2011. Our protocol for post-transplantation HBV prophylaxis was a combination of low-dose HBIG and nucleos(t)ide analog. RESULTS: During a median follow-up period of 49 months post-transplant, 10 patients (3.2%) had HBV recurrence, which was significantly related to hepatocellular carcinoma (HCC) at transplantation (P = 0.041) and post-LT antiviral agent (P < 0.001) in multivariate analysis. The level of HBV DNA and hepatitis B e antigen state at transplantation were not significant factors for HBV recurrence (P = 0.342 and P = 0.802, respectively). In 170 patients with HCC at LDLT, HCC recurrence was significantly related to HBV recurrence (P < 0.001). Among 10 patients with HBV recurrence, three are alive and two had lost hepatitis B surface antigen. The remaining seven patients died of HCC recurrence. CONCLUSIONS: The combination of low-dose HBIG and nucleos(t)ide analogs is safe and effective for HBV prophylaxis after LDLT. As a post-LT antiviral treatment, entecavir is more effective than lamivudine. HCC at transplantation was significantly associated with HBV recurrence. HBV-related HCC patients who undergo LDLT require close virological monitoring.

Interventional treatment of a biliary stricture after adult right-lobe living-donor liver transplantation with duct-to-duct anastomosis.

BACKGROUND: [corrected] A biliary stricture is the most common complication after living-donor liver transplantation (LDLT). The present study was performed to examine treatment methods and outcomes after treatment for a biliary stricture after LDLT. METHODS AND RESULTS: From January 2000 to December 2010, 488 patients underwent LDLT using the right lobe with duct-to-duct anastomosis at our transplantation centre. Overall biliary strictures were detected in 160 patients (32.8%), and the majority occurred within 2 years after LDLT. Biliary strictures were related to bile leakage (P < 0.001) and the urgency of the surgery (P = 0.012) in a multivariate analysis. All biliary strictures were treated with interventional modalities including an endoscopic or a percutaneous approach. Failure of interventional treatment was demonstrated in 13 patients (8.5%), among them, four (2.6%) underwent re-transplantation and nine (5.9%) died of sepsis and biliary cirrhosis during the follow-up period. A biliary stricture was not related to the survival rate (P = 0.586). CONCLUSION: The incidence of overall biliary stricture was related to bile leakage and the urgency of the surgery. All biliary strictures could be treated by interventional modalities. These approaches are effective, complementary and help to avoid the need for surgery for a biliary stricture.