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Introduction: This study examined associations between the graft-to-recipient weight ratio (GRWR) for adult-to-adult living donor liver transplantation (LDLT) and hepatocellular carcinoma (HCC) outcomes., Materials and Methods: Data from patients in the Korean Organ Transplantation Registry who underwent LDLT for HCC from 2014 to 2021 were retrospectively reviewed. Patients were categorized using the cutoff GRWR for HCC recurrence determined by an adjusted cubic spline (GRWR <0.7% vs. GRWR ≥0.7%). Recurrence-free survival (RFS) and HCC recurrence were analyzed in the entire and a 1:5 propensity-matched cohort., Results: The eligible cohort consisted of 2005 LDLT recipients [GRWR <0.7 ( n =59) vs. GRWR ≥0.7 ( n =1946)]. In the entire cohort, 5-year RFS was significantly lower in the GRWR <0.7 than in the GRWR ≥0.7 group (66.7% vs. 76.7%, P =0.019), although HCC recurrence was not different between groups (77.1% vs. 80.7%, P =0.234). This trend was similar in the matched cohort ( P =0.014 for RFS and P =0.096 for HCC recurrence). In multivariable analyses, GRWR <0.7 was an independent risk factor for RFS [adjusted hazard ratio (aHR) 1.89, P =0.012], but the result was marginal for HCC recurrence (aHR 1.61, P =0.066). In the pretransplant tumor burden subgroup analysis, GRWR <0.7 was a significant risk factor for both RFS and HCC recurrence only for tumors exceeding the Milan criteria (aHR 3.10, P <0.001 for RFS; aHR 2.92, P =0.003 for HCC recurrence) or with MoRAL scores in the fourth quartile (aHR 3.33, P <0.001 for RFS; aHR 2.61, P =0.019 for HCC recurrence)., Conclusions: A GRWR <0.7 potentially leads to lower RFS and higher HCC recurrence after LDLT when the pretransplant tumor burden is high., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Curative surgery involving either resection or liver transplantation (LT) is indicated only for early-stage hepatocellular carcinoma (HCC). Over the years, numerous efforts have been made to downstage advanced HCC to curative surgery using various locoregional therapies. In this study, we investigated the role of liver-directed combined radiation therapy (LD-CRT) as a downstaging strategy for converting beyond-Milan advanced HCC to LT., Methods and Materials: From January 2009 to February 2022, 53 patients with HCC who were initially beyond-Milan criteria were treated with LD-CRT and subsequent LT. These patients were compared with those who underwent upfront LT for within-Milan HCCs. The primary endpoint was overall survival (OS) and the secondary endpoint recurrence-free survival (RFS)., Results: After LD-CRT, substantial downstaging was achieved in 35 patients (66%) who were initially beyond-Milan to within-Milan. At a median follow-up period of 47.6 months (range, 6.9-151.7 months), 5-year OS and 2-year RFS of the patients who received downstaging LD-CRT followed by LT were 66.9% and 63.2%, respectively. Patients who were successfully downstaged to within-Milan after LD-CRT had improved 5-year OS compared with their counterparts (81.9% vs 74.3%, P = .219). Recurrence after transplantation was observed in 18 patients (4 intrahepatic recurrences and 14 extrahepatic metastases)., Conclusions: LD-CRT achieved favorable oncological outcomes as a downstaging strategy for LT in patients with beyond-Milan HCC. The findings of this study suggest that the active adoption of LD-CRT needs full consideration for patients with beyond-Milan HCC, presenting the possibility of curing patients with advanced HCC., (Copyright © 2024 Elsevier Inc. All rights reserved.)

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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Background: Sorafenib improves the overall survival in patients with advanced hepatocellular carcinoma (HCC). Dickkopf-1 (DKK1) is commonly overexpressed in HCC. In this study, we investigated whether the inhibition of DKK1 enhances the anti-tumor efficacy of sorafenib in HCC., Methods: HCC cells were treated with sorafenib and WAY-262611, which is an inhibitor of DKK1. Transgenic mouse models were also developed using hydrodynamic tail vein injection. Mice were orally administered with sorafenib (32 mg/kg), WAY-262611 (16 mg/kg), or sorafenib + WAY-262611 for 10 days. Mechanisms of sorafenib and WAY-262611 were explored via western blotting, immunostaining, and RNA sequencing., Results: DKK1 was significantly overexpressed in patients with HCC than in the healthy controls and patients with liver diseases except HCC (all P < 0.05). Compared with sorafenib alone, sorafenib + WAY-262611 significantly inhibited the cell viability, invasion, migration, and colony formation by promoting apoptosis and altering the cell cycles in HCC cells (all P < 0.05). Moreover, sorafenib + WAY-262611 decreased the p110α, phospho-Akt (all P < 0.05), active β-catenin (all P < 0.05) and phospho-GSK-3β (Ser9) expression levels, while increasing the phospho-GSK-3β (Tyr216) expression levels compared with those in the sorafenib alone in vitro and in vivo. In addition, sorafenib + WAY-262611 inhibited tumor progression by regulating cell proliferation and apoptosis, significantly better than sorafenib alone in mouse models., Conclusions: Our results indicate that DKK1 inhibition significantly enhances the anti-tumor efficacy of sorafenib by inhibiting the PI3K/Akt and Wnt/β-catenin pathways via regulation of GSK3β activity, suggesting a novel therapeutic strategy for HCC. Video Abstract., (© 2023. The Author(s).)

The clinical effects of tacrolimus (TAC) exposure on hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) remain unclear. In this retrospective single centric study, 512 patients who underwent LT for HCC were divided into four groups according to cumulative exposure to tacrolimus (CET) during 3 months after LT: conventional (n = 218), aggressive minimization (n = 32), minimization (n = 161), and high exposure (n = 101). Impact of CET on HCC recurrence and death were analyzed. Compared with the conventional group, the other three CET groups showed a similar risk of HCC recurrence. The aggressive minimization group showed a higher risk [hazard ratio (HR) 5.64, P < 0.001] and the high exposure group showed a marginal risk (HR 1.67, P = 0.081) of overall death compared to the conventional group. CET during 3 months was not associated with HCC recurrence in the matched cohort and various subgroups. TAC minimization is not effective to prevent HCC recurrence but could result in higher mortality in LT recipients., (© 2023. The Author(s).)

Purpose: The model for end-stage liver disease (MELD) 3.0 has recently been suggested for determining liver allocation. We aimed to apply MELD 3.0 to a Korean population and to discover differences between patients with and without hepatocellular carcinoma (HCC)., Materials and Methods: This study is a retrospective study of 2203 patients diagnosed with liver cirrhosis at Severance Hospital between 2016-2022. Harrell's concordance index was used to validate the ability of MELD scores to predict 90-day survival., Results: During a mean follow-up of 12.9 months, 90-day survival was 61.9% in all patients, 50.4% in the HCC patients, and 74.8% in the non-HCC patients. Within the HCC patients, the concordance index for patients on the waitlist was 0.653 using MELD, which increased to 0.753 using MELD 3.0. Among waitlisted patients, the 90-day survival of HCC patients was worse than that of non-HCC patients with MELD scores of 31-37 only (69.7% vs. 30.0%, p =0.001). Applying MELD 3.0, the 90-day survival of HCC patients was worse than that of non-HCC patients across a wider range of MELD 3.0 scores, compared to MELD, with MELD 3.0 scores of 21-30 and 31-37 (82.0% vs. 72.5% and 72.3% vs. 24.3%, p =0.02 and p <0.001, respectively)., Conclusion: MELD 3.0 predicted 90-day survival of the HCC patients more accurately than original MELD score; however, the disparity between HCC and non-HCC patients increased, particularly in patients with MELD scores of 21-30. Therefore, a novel exception score is needed or the current exception score system should be modified., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2023.)

Background: Statins have been reported to reduce overall death and hepatocellular carcinoma (HCC) recurrence in liver transplantation (LT) recipients. However, previous retrospective studies have significant flaws in immortal time bias., Methods: Using data from 658 patients who received LT for HCC, we matched 140 statin users with statin nonusers in a 1:2 ratio at the time of the first statin administration after LT using the exposure density sampling (EDS). The propensity score, calculated using baseline variables (including explant pathology), was used for EDS to equilibrate both groups. HCC recurrence and overall death were compared after adjusting for information at the time of sampling., Results: Among statin users, the median time to statin start was 219 (IQR 98-570) days, and intensity of statins was mainly moderate (87.1%). Statin users and nonusers sampled using EDS showed well-balanced baseline characteristics, including detailed tumour pathology, and similar HCC recurrence with cumulative incidences of 11.3% and 11.8% at 5 years, respectively (p = .861). In multivariate Cox models (HR 1.04, p = .918) and subgroup analyses, statins did not affect HCC recurrence. Conversely, statin users showed a significantly lower risk of overall death than nonusers (HR 0.28, p < .001). There was no difference in the type and intensity of statin usage between statin users who experienced HCC recurrence and those who did not., Conclusion: Upon controlling immortal time bias by EDS, statins did not affect HCC recurrence but reduced mortality after LT. Statin usage is encouraged for survival benefits but not for preventing HCC recurrence in LT recipients., (© 2023 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Objective: The aim of this study is to validate the prognostic impact of ADV score (α-fetoprotein [AFP]-des-γ-carboxyprothrombin [DCP]-tumor volume [TV] score) for predicting prognosis of hepatocellular carcinoma (HCC) following liver transplantation (LT)., Background: ADV score has been reported as a prognostic surrogate biomarker of HCC following LT and hepatectomy., Methods: The study patients were 1599 LT recipients selected from the Korean Organ Transplantation Registry database., Results: Deceased-donor and living-donor LTs were performed in 143 and 1456 cases, respectively. Weak correlation was present among AFP, DCP, and TV. The viable HCC group showed ADV score-dependent disease-free survival (DFS) and overall patient survival (OS) rates from 1log to 10log (p<0.001). Prognosis of complete pathological response group was comparable to that of ADV score <1log (p≥0.099). ADV score cutoff of 5log (ADV-5log) for DFS and OS was obtained through receiver operating characteristic curve analysis with area under the curve ≥0.705. Both ADV-5log and Milan criteria were independent risk factors for DFS and OS, and their prognostic impacts were comparable to each other. Combination of these two factors resulted in further prognostic stratification, showing hazard ratios for DFS and OS as 2.98 and 2.26 respectively for one risk factor and 7.92 and 8.19 respectively for two risk factors (p<0.001). ABO-incompatible recipients with ADV score ≥8log or two risk factors showed higher recurrence rates., Conclusions: This validation study revealed that ADV score is a reliable surrogate biomarker for posttransplant HCC prognosis, which can be used for selecting LT candidates and guiding risk-based posttransplant follow-up surveillance., (© 2023. The Society for Surgery of the Alimentary Tract.)

Objectives: The risk factors for late-onset Pneumocystis jirovecii pneumonia (PCP) after liver transplantation (LT) have not been well studied. We aimed to analyze the clinical features preceding PCP in LT recipients that would guide individualized prophylaxis., Methods: Among 742 patients who underwent LT and routine PCP prophylaxis from January 2009 through December 2019 at Severance Hospital, 27 patients developed PCP. We conducted a retrospective case-control study matching each patient with four controls and analyzed the risk factors for late-onset PCP., Results: After 6 months, post-transplant PCP cases increased steadily with an overall incidence of 6.36 cases per 1000 patient-year. The PCP-related mortality was 37.0%. In the multivariate analyses, age at LT ≥65 years (odds ratio [OR], 13.305; 95% confidence interval [CI], 2.507-70.618; P = 0.002), cytomegalovirus infection (OR, 5.390; 95% CI, 1.602-18.132; P = 0.006), steroid pulse therapy (OR, 6.564; 95% CI, 1.984-21.719; P = 0.002), hepatocellular carcinoma recurrence (OR, 18.180; 95% CI, 3.420-96.636; P = 0.001), and lymphocytopenia (OR, 3.758; 95% CI, 1.176-12.013; P = 0.026) were independently associated with PCP., Conclusion: Late-onset PCP after routine prophylaxis after LT remains a lethal infection and is associated with age ≥65 years at LT, cytomegalovirus infection, steroid pulse therapy, hepatocellular carcinoma recurrence, and lymphocytopenia. Targeted prophylaxis considering these risk factors could improve the prevention of this potentially lethal complication., Competing Interests: Declaration of competing interest The authors have no competing interests to declare., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: We aimed to investigate the optimal radiologic method to determine Milan criteria (MC) for the prediction of recurrence in patients who underwent locoregional treatment (LRT) for hepatocellular carcinoma (HCC) and subsequent liver transplantation (LT)., Methods: This retrospective study included 121 HCC patients who underwent LRT and had both liver dynamic CT and MRI. They were classified with MC using four cross combinations of two imaging modalities (CT and MRI) and two diagnostic criteria (modified Response Evaluation Criteria in Solid Tumors [mRECIST] and Liver Imaging Reporting and Data System treatment response algorithm [LI-RADS TRA]). Competing risk regression was performed to analyze the time to recurrence after LT. The predictive abilities of the four methods for recurrence were evaluated using the time-dependent area under the curve (AUC)., Results: Competing risk regression analyses found that beyond MC determined by MRI with mRECIST was independently associated with recurrence (hazard ratio, 6.926; p = 0.001). With mRECIST, MRI showed significantly higher AUCs than CT at 3 years and 5 years after LT (0.597 vs. 0.756, p = 0.012 at 3 years; and 0.588 vs. 0.733, p = 0.024 at 5 years). Using the pathologic reference standard, MRI with LI-RADS TRA showed higher sensitivity (61.5%) than CT with LI-RADS TRA (30.8%, p < 0.001) or MRI with mRECIST (38.5%, p < 0.001)., Conclusions: MRI with mRECIST was the optimal radiologic method to determine MC for the prediction of post-LT recurrence in HCC patients with prior LRT., Key Points: • MRI with modified RECIST (mRECIST) is the optimal preoperative method to determine Milan criteria for the prediction of post-transplant HCC recurrence in patients with prior locoregional treatment. • With mRECIST, MRI was better than CT for the prediction of post-transplant recurrence., (© 2022. The Author(s), under exclusive licence to European Society of Radiology.)

BACKGROUND The study objective was to evaluate the effect of everolimus (EVR) in combination with reduced tacrolimus (rTAC) compared with a standard TAC (sTAC) regimen on hepatocellular carcinoma (HCC) recurrence in de novo living-donor liver transplantation recipients (LDLTRs) with primary HCC at liver transplantation through 5 years after transplantation. MATERIAL AND METHODS In this multicenter, non-interventional study, LDLTRs with primary HCC, who were previously randomized to either everolimus plus reduced tacrolimus (EVR+rTAC) or standard tacrolimus (sTAC), and who completed the 2-year core H2307 study, were followed up. Data were collected retrospectively (end of core to the start of follow-up study), and prospectively (during the 3-year follow-up study). RESULTS Of 117 LDLTRs with HCC at LT in the core H2307 study (EVR+rTAC, N=56; sTAC, N=61), 86 patients (EVR+rTAC, N=41; sTAC, N=45) entered the follow-up study. Overall HCC recurrence was lower but statistically non-significant in the EVR+rTAC group (3.6% vs 11.5% in sTAC; P=0.136) at 5 years after LT. There was no graft loss or chronic rejection. Acute rejection and death were comparable between treatment groups. Higher mean estimated glomerular filtration rate in the EVR+rTAC group (76.8 vs 65.8 mL/min/1.73 m² in sTAC) was maintained up to 5 years. Reported adverse events were numerically lower in the EVR+rTAC group (41.0% vs 53.5% sTAC) but not statistically significant. CONCLUSIONS Although statistically not significant, early EVR initiation reduced HCC recurrence, with comparable efficacy and safety, and better long-term renal function, than that of sTAC treatment.

Purpose: We investigate whether low-dose rapamycin is effective in preventing hepatocellular carcinoma (HCC) growth and treating HCC after tumor development in transgenic mice., Materials and Methods: We established transgenic mice with HCC induced by activated HrasG12V and p53 suppression. Transgenic mice were randomly assigned to five experimental groups: negative control, positive control, tacrolimus only, rapamycin only, and tacrolimus plus rapamycin. The mice were further divided into two groups according to time to commencement of immunosuppressant treatment: de novo treatment and post-tumor development., Results: In the de novo treatment group, marked suppression of tumor growth was observed in the rapamycin only group. In the post-tumor development group, the rapamycin only group displayed no significant suppression of tumor growth, compared to the positive control group. In T lymphocyte subset analysis, the numbers of CD4 + effector T cells and CD4 + regulatory T cells were significantly lower in the positive control, tacrolimus only, and tacrolimus plus rapamycin groups than the negative control group. Immunohistochemical analysis revealed significantly higher expression of phosphorylated-mTOR, 4E-BP1, and S6K1 in the positive control group than in the rapamycin only group., Conclusion: Low-dose rapamycin might be effective to prevent HCC growth, but may be ineffective as a treatment option after HCC development., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

Tacrolimus is the mainstay of immunosuppression in liver transplantation to prevent rejection. However, the clinical use of tacrolimus is complicated by its narrow therapeutic window and significant intra-patient variability (IPV). High tacrolimus IPV is associated with overexposure and adverse effects, including malignancy. The effects of tacrolimus IPV in liver transplant recipients with and without hepatocellular carcinoma (HCC) are unknown. We investigated the association between tacrolimus IPV and transplant outcomes in 636 liver transplant patients. Tacrolimus IPV was determined by calculating the coefficient of variance (CV) of outpatient tacrolimus trough levels from 3 to 12 months after transplantation. High tacrolimus IPV was defined as CV > 30%. Patients were grouped according to tacrolimus IPV and HCC status. Among 636 liver transplant patients, 349 had HCC and 287 had no HCC. Overall survival in HCC patients was significantly reduced with high tacrolimus IPV (P < 0.001), whereas survival of non-HCC patients was not associated with tacrolimus IPV. Multivariable analysis confirmed the independent association between high tacrolimus IPV and overall mortality in HCC patients (HR, 3.010; 95% CI, 1.084-4.918). HCC recurred in 59 patients (16.9%) post-transplantation. After adjusting for donor/recipient factors, immunosuppression, and tumor characteristics, high tacrolimus IPV was independently associated with an increased risk of HCC recurrence (HR, 2.196; 95% CI, 1.272-3.791). High tacrolimus IPV was associated with significantly increased risks of overall mortality and HCC recurrence in liver transplant recipients with HCC., (© 2022. The Author(s).)

BACKGROUND This study analyzed pretransplant alpha-fetoprotein (AFP) and proteins induced by vitamin K absence or antagonist-II (PIVKA-II) in liver transplantation (LT) candidates. MATERIAL AND METHODS A total of 3,273 LT recipients enrolled at the Korean Organ Transplantation Registry were divided according to hepatocellular carcinoma (HCC) status and background liver disease, and AFP and PIVKA-II were compared. RESULTS In all patients, the median AFP and PIVKA-II were 6.3 ng/mL and 29 mAU/mL in the viable-HCC group and 3.3 ng/mL and 35 mAU/mL, respectively, in the no-HCC group (P<0.001 for AFP and p=0.037 for PIVKA-II). In patients with hepatitis B virus infection, they were 6.0 ng/mL and 26 mAU/mL in the HCC group and 3.2 ng/mL and 21 mAU/mL in the no-HCC group, respectively (P<0.001 and P<0.001). In patients with hepatitis C virus infection, they were 10.7 ng/mL and 37 mAU/mL in the HCC group and 2.6 ng/mL and 21 mAU/mL in the no-HCC group, respectively (P<0.001 and P=0.117). In alcoholic liver disease patients, they were 5.2 ng/mL and 61 mAU/mL in the HCC group and 6.4 ng/mL and 75 mAU/mL in the no-HCC group, respectively (P<0.001 and P=0.419). In patients with other diseases, they were 7.1 ng/mL and 32 mAU/mL in the HCC group and 3.3 ng/mL and 28 mAU/mL in the no-HCC group, respectively (P<0.001 and P=0.822). CONCLUSIONS The results of the present study indicate that pretransplant serum AFP and PIVKA-II were highly variably expressed in LT candidates with end-stage liver diseases; therefore, their values should be cautiously interpreted because their role in HCC diagnosis is limited.

Background/aims: Circulating tumor cells (CTCs) with cancer stemness have been demonstrated to be a direct cause of tumor recurrence, and only few studies have reported the role of CTCs in liver transplantation (LT) for hepatocellular carcinoma (HCC)., Methods: Epithelial cell adhesion molecule+ (EpCAM+), cluster of differentiation 90+ (CD90+) and EpCAM+/CD90+ CTCs were sorted via fluorescence-activated cell sorting, and transcripts level of EpCAM, K19 and CD90 in the peripheral blood were analyzed via real-time polymerase chain reaction preoperatively and on postoperative days 1 and 7 in 25 patients who underwent living donor liver transplantation (LDLT) for HCC. EpCAM protein was assessed in HCC tissue using immunohistochemical staining. The median follow-up duration was 40 months., Results: HCC after LDLT recurred in four out of 25 patients. Detection of EpCAM+ or CD90+ CTCs correlated well with their messenger RNA levels (p<0.05). EpCAM+ CTCs were readily detected in HCC tissue expressing EpCAM protein. The detection of EpCAM+ CTCs or EpCAM+/CD90+ CTCs before surgery and on postoperative day 1 was significantly associated with HCC recurrence after LT (all p<0.05). Pretransplant serum PIVKA-II >100 mAU/mL and postoperative day 1 EpCAM+/CD90+ CTCs were independent risk factors for HCC recurrence (hazard ratio, 14.64; 95% confidence interval, 1.08 to 198.20; p=0.043 and hazard ratio, 26.88; 95% confidence interval, 1.86 to 387.51; p=0.016, respectively)., Conclusions: EpCAM+/CD90+ CTCs can be used preoperatively and 1 day after LDLT as key biological markers in LT candidate selection and post-LDLT management.

Objective: To investigate whether subclassification of microscopic vascular invasion (MiVI) affects the long-term outcome after curative surgical resection or liver transplantation (LT) in patients with hepatocellular carcinoma (HCC)., Summary of Background Data: The most important factor for TNM staging in HCC is MiVI, which includes all vascular invasions detected on microscopic examination. However, there is a broad spectrum of current definitions for MiVI., Methods: In total, 412 consecutive patients with HCC who underwent curative surgical resection without any preoperative treatment or gross vascular invasion were histologically evaluated for MiVI. Patients with MiVI were subclassified into 2 groups: microvessel invasion (MI; n = 164) only and microscopic portal vein invasion (MPVI; n = 36). Clinicopathologic features were compared between 2 groups (MI vs MPVI), whereas disease-free survival (DFS) and overall survival (OS) after resection were analyzed among 3 groups (no vascular invasion [NVI] vs MI vs MPVI). These subclassifications were validated in a cohort of 197 patients with HCC who underwent LT., Results: The MPVI group showed more aggressive tumor characteristics, such as higher tumor marker levels (alpha-fetoprotein, P = 0.006; protein induced by vitamin K absence-II, P = 0.001) and poorer differentiation (P = 0.011), than the MI group. In multivariate analysis, both MI and MPVI were independent prognostic factors for DFS (P = 0.001 and <0.001, respectively) and OS (P = 0.005 and <0.001, respectively). In the validation cohort, 5-year DFS was 89%, 67.9%, and 0% in the NVI, MI, and MPVI groups, respectively (P < 0.001), whereas 5-year OS was 79.1%, 55.0%, and 15.4%, respectively (P < 0.001)., Conclusions: Based on subclassification of MiVI in HCC, MPVI was associated with more aggressive clinicopathologic characteristics and poorer survival than MI only. Therefore, the original MiVI classification should be divided into MI and MPVI., Competing Interests: The authors report no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background/aims: This study aimed to investigate whether everolimus (EVR) affects long-term survival after liver transplantation (LT) in patients with hepatocellular carcinoma (HCC)., Methods: The data from 303 consecutive patients with HCC who had undergone LT from January 2012 to July 2018 were retrospectively reviewed. The patients were divided into two groups: 1) patients treated with EVR in combination with calcineurin inhibitors (CNIs) (EVR group; n=114) and 2) patients treated with CNI-based therapy without EVR (non-EVR group; n=189). Time to recurrence (TTR) and overall survival (OS) after propensity score (PS) matching were compared between the groups, and prognostic factors for TTR and OS were evaluated., Results: The EVR group exhibited more aggressive tumor biology than the non-EVR group, such as a higher number of tumors (P=0.003), a higher prevalence of microscopic vascular invasion (P=0.017) and exceeding Milan criteria (P=0.029). Compared with the PS-matched non-EVR group, the PS-matched EVR group had significantly better TTR (P<0.001) and OS (P<0.001). In multivariable analysis, EVR was identified as an independent prognostic factor for TTR (hazard ratio [HR], 0.248; P=0.001) and OS (HR, 0.145; P<0.001)., Conclusion: Combined with CNIs, EVR has the potential to prolong long-term survival in patients undergoing LT for HCC. These findings warrant further investigation in a well-designed prospective study.

Background and Purpose: Liver-directed combined radiotherapy (LDCRT) can provide substantial tumor control, which may be an effective bridge to curative surgery for selected patients. We aimed to investigate the outcomes of LDCRT for locally advanced hepatocellular carcinoma (LAHCC) beyond the Milan criteria., Materials and Methods: We identified 1078 patients diagnosed with LAHCC who received LDCRT and compared the outcomes based on no surgery, conversion to surgical resection, and liver transplantation (LT). Predictive factors for conversion to curative surgery were identified using logistic regression analysis., Results: The most frequently used LDCRT strategies were concurrent chemoradiation (CCRT) (497 patients, 46.1%) and transarterial chemoembolization (TACE) plus radiotherapy (251 patients 23.3%). After LDCRT, 96 (8.9%) and 42 patients (3.9%) received surgical resection and LT, respectively. After a median follow-up of 14.4 months, the 5-year overall survival (OS) rate was 16.5% for all patients. Conversion to curative surgery group had higher 5-year OS (surgical resection vs. LT vs. no surgery: 58.1% vs. 54.3% vs. 10.2%, p < 0.001). Patients aged < 60 years with a single tumor, no treatment history, pre-treatment Child class A, lower pre-treatment tumor marker levels, and radiologic complete or partial response (all p < 0.050) had a higher chance of conversion to surgery., Conclusion: LDCRT could convert tumors to within the Milan criteria as a bridge to curative surgery, and improved long-term survival for the selected patients. Clinicians should consider LDCRT followed by curative surgery for young patients who are treatment-naïve and have good liver function with favorable tumor characteristics showing radiologic response to LDCRT., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Objective: To compare the diagnostic performance of various guidelines for hepatocellular carcinoma (HCC) diagnosis using computed tomography (CT) in patients undergoing liver transplantation (LT)., Methods: In total, 216 patients who underwent preoperative CT and subsequent LT were included. Two radiologists retrospectively evaluated focal hepatic lesions independently according to various guidelines and allocated patients according to the Milan criteria. The diagnostic performance of the guidelines was compared using alternative free-response receiver-operating characteristics (AFROC) analysis with bootstrapping. Comparisons of sensitivity, specificity, and accuracy of patient allocation based on the Milan criteria between guidelines were performed using logistic regression with generalized estimating equations (GEE)., Results: Fifty-two of 216 patients had 87 HCCs. The reader-averaged figure of merit obtained using AFROC analysis was 0.738 for the AASLD/EASL or KLCSG-NCC guidelines and 0.728 for the LI-RADS v2014 or OPTN/UNOS (bootstrapping, p = 0.005). The per-lesion sensitivity for HCCs (all and 1-2-cm lesions) was significantly higher with the AASLD/EASL (37.9-41.4% and 30.8-41.0%) than with LI-RADS (28.7% and 15.4-18.0%) (logistic regression with GEE, p = 0.008 and 0.030 for reader 1 and p = 0.005 for reader 2). The per-patient specificity (98.8-99.4%) was the same for all guidelines. The accuracy of the Milan criteria was 81.5-83.3% without significant differences among the four guidelines (logistic regression with GEE, p > 0.05)., Conclusion: AASLD/EASL showed higher diagnostic performance and sensitivity, particularly for 1-2-cm HCCs, and the same specificity with LI-RADS. All guidelines are comparable for patient allocation based on the Milan criteria for LT., Key Points: • The overall diagnostic performance of CT for HCC diagnosis was highest with AASLD/EASL. • AASLD/EASL showed higher sensitivity for diagnosis of 1-2-cm HCCs than LI-RADS. • The accuracy of the Milan criteria using CT was comparable among the four guidelines.

Contrast-enhanced ultrasound (CEUS) is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to verify the characteristics of CEUS in distinguishing small (≤3 cm) hepatocellular carcinoma (HCC) from intrahepatic cholangiocarcinoma (ICC).A total of 65 patients with a liver nodule (HCC, n = 58; ICC, n = 7) smaller than 3 cm who underwent liver CEUS and pathologic confirmation were retrospectively reviewed. CEUS findings were compared with histopathologic and clinical data.Arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS were observed in 77.6% (45/58) of HCCs and 85.7% (6/7) of ICCs. Time of arterial-phase hyperenhancement (11 seconds [6-20] vs 16 seconds [14-19], P = .008), time of portal-delayed-phase wash-out (65 seconds (15-260) vs 35 secconds (27-54), P = .002), and time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out (50 seconds [5-249] vs 19 seconds [13-35], P < .001) on CEUS were significantly different between HCCs and ICCs showing arterial-phase hyperenhancement and portal-delayed-phase wash-out. The sensitivity, specificity, positive predictive value, and negative predictive value of time interval more than 25 seconds between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS for the differentiation of HCCs and ICCs were 91.1%, 83.3%, 97.6%, and 55.6%, respectively.The time interval between arterial-phase hyperenhancement and portal-delayed-phase wash-out on CEUS was the most sensitive indicator in distinguishing small HCC from ICC showing arterial-phase hyperenhancement and portal-delayed-phase wash-out.

Background/aims: B-mode ultrasound (US) has difficulty targeting small hepatocellular carcinomas (HCCs) with poor conspicuity during radiofrequency ablation (RFA). Contrast-enhanced ultrasound (CEUS) can improve visualization of small or inconspicuous HCCs. This study was conducted to evaluate the effectiveness of CEUS-guided RFA electrode insertion during the arterial phase in inconspicuous HCCs., Materials and Methods: Ninety-three treatment-naïve HCCs from 80 patients treated with RFA from August 2012 to December 2014 were retrospectively reviewed. Seventy-five HCCs from 65 patients underwent B-mode US-guided RFA, and 15 HCCs from 14 patients that were inconspicuous on B-mode US underwent CEUS-guided RFA during the arterial phase after injection of sulfur hexafluoride microbubbles (SonoVue®). Technical success was assessed by contrast-enhanced computed tomography within 1 week and 3 months after the procedure., Results: The mean size of HCCs treated with CEUS-guided RFA was smaller than that of HCCs treated with B-mode US-guided RFA (1.17±0.36 vs. 1.63±0.55 cm, p=0.003). Technical success rates of CEUS-guided RFA within 1 week and 3 months were 100% (15/15) and 93.3% (14/15), respectively. Technical success rates of B-mode US-guided RFA were 97.3% (73/75) and 94.5% (69/73), respectively., Conclusion: CEUS-guided RFA is highly efficacious for ablation of very small and inconspicuous HCCs.

Recently, it has been suggested that peritumoral decreased uptake area (PDUA) in the hepatobiliary phase (HBP) of gadoxetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) was associated with vascular invasion in hepatocellular carcinoma (HCC). We aimed to investigate correlations between microvascular invasion and PDUA, and elucidate the predictability of PDUA for tumor recurrence after resection.We retrospectively analyzed clinicopathological and radiological data from 126 consecutive patients with single HCC ≤5 cm without macrovascular invasion who underwent preoperative Gd-EOB-DTPA-enhanced MRI and surgical resection. The presence of a faint and hypointense area around the tumor in the HBP was defined as PDUA.Among 126 patients with HCCs, microvascular invasion was observed in 29 (23.0%) patients and PDUA was observed in 15 (11.9%) patients. PDUA [odds ratio (OR) 20.06, confidence interval (CI) 4.74-84.96, P < .001] was an independent risk factor for microvascular invasion. In multivariate survival analysis using Cox regression, PDUA [hazard ratio (HR) 4.51, CI 2.17-9.38, P < .001], pathologically confirmed satellite nodules (HR 5.18, CI 1.50-17.88, P = .009), and AFP (≥100 ng/mL, HR 2.28, CI 1.04-5.01, P = .040) were independent risk factors for recurrence after resection. Recurrence-free survival in the group with PDUA was significantly lower than that in the group without PDUA according to analysis using the Kaplan-Meier method with the log-rank test (P < .001).PDUA in the HBP of Gd-EOB-DTPA-enhanced MRI could be a useful preoperative predictor of microvascular invasion and independent prognostic factor after surgical resection in patients with single HCC ≤5 cm without macrovascular invasion.

Background: The Milan criteria are widely accepted for indicating liver transplantation in patients with hepatocellular carcinoma (HCC). However, a 7% to 20% possibility of HCC recurrence remains, even among patients who fulfill the Milan criteria., Methods: We retrospectively reviewed 88 patients with HCC who underwent liver transplantation at Pusan National University Yangsan Hospital between May 2010 and December 2014. The risk factors for HCC recurrence were analyzed, and the overall survival and disease-free survival rates were calculated based on each risk factor., Results: Seventeen patients (19.3%) experienced HCC recurrence. Multivariate analyses revealed that the independent risk factors for HCC recurrence were protein induced by vitamin K absence or antagonist II (PIVKA-II) levels of >200 mAU/mL, levels of >200 for alpha-fetoprotein (ng/mL) or PIVKA-II (mAU/mL), and microvascular invasion. Therefore, we defined the A-P 200 criteria as simultaneously exhibiting alpha-fetoprotein levels of ≤200 ng/mL and PIVKA-II levels of ≤200 mAU/mL. The 3-year overall survival rates among patients who fulfilled or exceeded the A-P 200 criteria were 89.2% and 80.0%, respectively (P = .79). The 3-year disease-free survival rates among patients who fulfilled or exceeded the A-P 200 criteria were 89.9% and 43.1%, respectively (P < .001). We also applied the A-P 200 criteria to patient data from another major center and observed similar results., Conclusion: These findings confirm that the A-P 200 criteria can be used to predict recurrence after liver transplantation among patients with HCC., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Locally advanced hepatocellular carcinoma (HCC) with portal vein thrombosis carries a 1-year survival rate <10%. Localized concurrent chemoradiotherapy (CCRT), followed by hepatic arterial infusion chemotherapy (HAIC), was recently introduced in this setting. Here, we report our early experience with living donor liver transplantation (LDLT) in such patients after successful down-staging of HCC through CCRT and HAIC. Between December 2011 and September 2012, eight patients with locally advanced HCC at initial diagnosis were given CCRT, followed by HAIC, and underwent LDLT at the Severance Hospital, Seoul, Korea. CCRT [45 Gy over 5 weeks with 5-fluorouracil (5-FU) as HAIC] was followed by HAIC (5-FU/cisplatin combination every 4 weeks for 3-12 months), adjusted for tumor response. Down-staging succeeded in all eight patients, leaving no viable tumor thrombi in major vessels, although three patients first underwent hepatic resections. Due to deteriorating liver function, transplantation was the sole therapeutic option and offered a chance for cure. The 1-year disease-free survival rate was 87.5%. There were three instances of post-transplantation tumor recurrence during follow-up monitoring (median, 17 months; range, 10-22 months), but no deaths occurred. Median survival time from initial diagnosis was 33 months. Four postoperative complications recorded in three patients (anastomotic strictures: portal vein, 2; bile duct, 2) were resolved through radiologic interventions. Using an intensive tumor down-staging protocol of CCRT followed by HAIC, LDLT may be a therapeutic option for selected patients with locally advanced HCC and portal vein tumor thrombosis.

Background: Contrast-enhanced ultrasound is highly accurate in depicting the vascularity of liver nodules. The aim of this study was to evaluate the usefulness of contrast-enhanced ultrasound for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules showing atypical or not coincidental typical vascular pattern on two dynamic imaging techniques (computed tomography and magnetic resonance imaging)., Methods: A total of 46 patients with cirrhosis and a liver nodule smaller than 3cm showing an atypical or non-coincident typical vascular pattern on two dynamic imaging techniques, who underwent liver contrast-enhanced ultrasound and ultrasound-guided liver biopsy, were retrospectively reviewed. Contrast-enhanced ultrasound findings were compared with histopathological and clinical data, and with the two dynamic imaging findings., Results: Significantly different contrast-enhanced ultrasound enhancement patterns were observed among dysplastic nodules, Edmondson grade I and grade II-III hepatocellular carcinomas. Ten out of 11 (90.9%) non-hypervascular hepatocellular carcinomas on two dynamic imaging techniques showed a hypervascular pattern on contrast-enhanced ultrasound, and these made it possible to distinguish hepatocellular carcinomas from dysplastic nodules., Conclusion: Contrast-enhanced ultrasound is useful for the differentiation of hepatocellular carcinomas from dysplastic nodules in cirrhotic patients with small liver nodules., (Copyright © 2015 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: There is debate over whether T1b gallbladder cancer (GBC) should be treated by simple cholecystectomy (SC) or by extended cholecystectomy (EC). The aim of this study is to compare and analyze the results of these two procedures., Patients and Methods: The archived medical records of 805 patients with GBC who had undergone surgical resection in Asan Medical Center, or were referred from other hospitals after undergoing surgery, between 1997 and 2010 were retrospectively reviewed. Of these, 85 patients were diagnosed with pathologic stage T1b (muscular layer) GBC. By using propensity scoring, the EC group and the SC group were matched in the proportion of 1:2; so, 54 patients were enrolled in this study., Results: Among the 54 pathologic stage T1b cancer patients, SC was performed in 36 (66.7 %) and EC in 18 (33.4 %). The mean operation time and hospital stay after surgery of the SC group was significantly shorter than in the EC group (83.2 vs. 356.4 min, 7.8 vs. 15.2 days; both p = 0.000). Disease recurrence was noted in four cases (11.1 %), all in the SC group; 50 % of recurred patients experienced recurrence at the lymph node. There was no significant intergroup difference in the 5-year survival rate (5-YSR) (88.8 % for SC vs. 93.3 % for EC, p = 0.521)., Conclusions: In this study, for stage T1b GBC, both EC and SC offered similar cure rates. However, recurrence is associated with SC and inadequate lymph node dissection (LND). Therefore, EC including regional LND may be justified and preferred because of the possibility of lymph node metastasis and the accurate assessment of stage (LN status), except that the patients have a high risk of operation.

Background: This study aimed to classify transplantable recurrent hepatocellular carcinoma (HCC) after resection into subgroups according to the pattern of progression and to identify risk factors for each subgroup to select optimal candidates for salvage liver transplantation (LT)., Methods: The patients that met the Milan criteria (MC) and were child-pugh class A at initial hepatectomy were included in the study. Of these patients, the patients with transplantable recurrence were identified and further divided into two groups according to the recurrent HCC progression pattern. Group 1 contained patients with controlled tumors within the MC. Group 2 contained patients with progressive tumors that spread beyond the MC. A controlled tumor was defined as the absence of tumor recurrence after locoregional treatment for ≥12 months or control of a recurrent tumor within the MC by active locoregional treatment., Results: After curative resection of HCC, 114 patients with transplantable recurrence were identified: 70 were classified as group 1 and 44 as group 2. Overall survival after recurrence was significantly higher in group 1 compared to group 2 (65.4 vs 35.7 %, respectively; P < 0.003). Multiple logistic regression analysis showed that risk factors in group 1 were age >50 years and an indocyanine green retention at 15 min >10 %. The presence of a satellite nodule (SN) and/or microscopic portal vein invasion (mPVI) was the only independent risk factor identified in group 2. Among the 15 patients that underwent salvage LT, 2 of 3 patients (66.7 %) with SN and/or mPVI at initial hepatectomy developed extrahepatic recurrence., Conclusions: The patients with SN and/or mPVI at initial hepatectomy may not be candidates for salvage LT, and an extended observation time is required to determine tumor biology.

Background/aims: Nonalcoholic fatty liver disease (NAFLD) may be one of the important causes of cryptogenic hepatocellular carcinoma (HCC). The aim of this study was to evaluate whether patients with cryptogenic HCC share clinical features similar to that of NAFLD., Methods: Cryptogenic HCC was defined as HCC that occurs in patients with the following conditions: HBsAg(-), anti-HCV(-), and alcohol ingestion of less than 20 g/day. All patients diagnosed with cryptogenic HCC from 2005 to 2012 (cryptogenic HCC group), and all patients diagnosed with HBV associated HCC between 2008 and 2012 (HBV-HCC group) were enrolled in the present study. Clinical features, BMI, lipid profiles, presence of diabetes mellitus, hypertension, and metabolic syndrome were compared between the two groups., Results: Cryptogenic HCC group was composed of 35 patients (19 males and 16 females) with a mean age of 70 ± 11 years. HBV-HCC group was composed of 406 patients (318 males and 88 females) with a mean age of 56 ± 7 years. Patients in the cryptogenic HCC group were older (p=0.001) and female dominant (p=0.042) than those in the HBV-HCC group. There were no differences in the laboratory test results including lipid profiles and Child-Turcotte-Pugh class between the two groups. Patients in the cryptogenic HCC group had higher prevalence of diabetes (37% vs. 17%, p=0.015), hypertension (49% vs.27%, p=0.051), metabolic syndrome (37% vs. 16%, p=0.001), and higher BMI (25.3 kg/m(2) vs. 24.1 kg/m(2), p=0.042) than those in the HBV- HCC group. The tumor stage was more advanced (stage III and IV) at diagnosis in the cryptogenic HCC group than in the HBV-HCC group (60% vs. 37%, p=0.007)., Conclusions: Cryptogenic HCC has clinical features similar to that of NAFLD and is diagnosed at a more advanced tumor stage.

Hepatocellular carcinoma (HCC) is a critical global health issue and the third most common cause of cancer-related deaths worldwide. The majority of patients who present HCC are already at an advanced stage and their tumors are unresectable. Sorafenib is a multi-kinase inhibitor of the vascular endothelial growth factor pathway and was recently introduced as a therapy for advanced HCC. Furthermore, studies have shown that oral sorafenib has beneficial effects on survival. However, many patients experience diverse side effects, and some of these are severe. Liver abscess development has not been previously documented to be associated with sorafenib administration in HCC. Here, we report the case of a HCC patient that developed a liver abscess while being treated with sorafenib.

Background/aims: Recurrence after hepatic resection is one of the most important factors impacting the prognosis and survival of patients with hepatocellular carcinoma (HCC). We identified prognostic factors affecting overall survival (OS) and disease-free survival (DFS) in patients with HCC after hepatic resection., Methods: This study was of a retrospective cohort design, and 126 patients who underwent hepatic resection for HCC at Gachon University Gil Medical Center between January 2005 and December 2010 were enrolled. Various clinical, laboratory, and pathological data were evaluated to determine the prognostic factors affecting OS and DFS., Results: Two- and 4-year OS and 2- and 4-year DFS were 78.1% and 65% and 51.1% and 26.6%, respectively. In a multivariate analysis, preoperative α-fetoprotein (> 400 ng/mL), tumor size (≥ 5 cm), multiple tumors (two or more nodules), presence of portal vein invasion, modified Union for International Cancer Control (UICC) stage III/IV, and Barcelona Clinic Liver Cancer (BCLC) stage B/C were independent prognostic factors affecting a shorter OS. In the multivariate analysis, presence of microvascular invasion, modified UICC stage III/IV, and BCLC stage B/C were independent prognostic factors for a shorter DFS., Conclusions: The presence of vascular invasion was an independent poor prognostic factor for OS and DFS in patients with HCC after hepatic resection. Thus, close postoperative surveillance for early detection of recurrence and additional treatments are urgently needed in patients with vascular invasion after hepatic resection.

Aim: To clarify the role of surgical resection for multiple hepatocellular carcinomas (HCCs) compared to transarterial chemoembolization (TACE) and liver transplantation (LT)., Methods: Among the HCC patients who were managed at Yonsei University Health System between January 2003 and December 2008, 160 patients who met the following criteria were retrospectively enrolled: (1) two or three radiologically diagnosed HCCs; (2) no radiologic vascular invasion; (3) Child-Pugh class A; (4) main tumor smaller than 5 cm in diameter; and (5) platelet count greater than 50 000/mm(3). Long-term outcomes were compared among the following three treatment modalities: surgical resection or combined radiofrequency ablation (RFA) (n = 36), TACE (n = 107), and LT (n = 17). The survival curves were computed using the Kaplan-Meier method and compared with a log-rank test. To identify the patients who gained a survival benefit from surgical resection, we also investigated prognostic factors for survival following surgical resection. Multivariate analyses of the prognostic factors for survival were performed using the Cox proportional hazard model., Results: The overall survival (OS) rate was significantly higher in the surgical resection group than in the TACE group (48.1% vs 28.9% at 5 years, P < 0.005). LT had the best OS rate, which was better than that of the surgical resection group, although the difference was not statistically significant (80.2% vs 48.1% at 5 years, P = 0.447). The disease-free survival rates were also significantly higher in the LT group than in the surgical resection group (88.2% vs 11.2% at 5 years, P < 0.001). Liver cirrhosis was the only significant prognostic factor for poor OS after surgical resection. Clinical liver cirrhosis rates were 55.6% (20/36) in the resection group and 93.5% (100/107) in the TACE group. There were 19 major and 17 minor resections. En bloc resection was performed in 23 patients, multi-site resection was performed in 5 patients, and combined resection with RFA was performed in 8 patients. In the TACE group, only 34 patients (31.8%) were recorded as having complete remission after primary TACE. Seventy-two patients (67.3%) were retreated with repeated TACE combined with other therapies. In patients who underwent surgical resection, the 16 patients who did not have cirrhosis had higher 5-year OS and disease-free survival rates than the 20 patients who had cirrhosis (80.8% vs 25.5% 5-year OS rate, P = 0.006; 22.2% vs 0% 5-year disease-free survival rate, P = 0.048). Surgical resection in the 20 patients who had cirrhosis did not provide any survival benefit when compared with TACE (25.5% vs 24.7% 5-year OS rate, P = 0.225). Twenty-nine of the 36 patients who underwent surgical resection experienced recurrence. Of the patients with cirrhosis, 80% (16/20) were within the Milan criteria at the time of recurrence after resection., Conclusion: Among patients with two or three HCCs, no radiologic vascular invasion, and tumor diameters ≤ 5 cm, surgical resection is recommended only in those without cirrhosis.

During islet transplantation into the portal vein of the liver, the islet cells are expected to have complex interactions with hepatocytes. However, the mechanism underlying this interaction is not yet understood. Hence, we developed cellular complexes containing a mixture of human hepatocellular carcinoma cell line (Hep-G2) and rat insulin-secreting cell line (RIN-5F) by using a co-culture model and studied the function and morphology of the resultant hybrid cellular spheroids (HCSs). The RIN-5F and Hep-G2 cells were suspension cultured and, within 5 days of culture, the two types of cells aggregated to yield spheroids. The functionality of the thus formed HCSs was evaluated by measuring the levels of insulin and albumin in the culture supernatant. The HCSs retained their insulin- and albumin-secreting ability and their morphology, as revealed by immunohistological staining. The insulin and albumin levels secreted by the HCSs were considerably higher than those secreted by spheroids of single-cell origin. Generally, obtaining complexes from more than two types of cells is difficult. However, we were able to generate HCSs. We believe that this culture method could have various applications such as studying the in vitro cell-cell interactions and developing new cell transplantation models., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Encapsulation of transplanted cells within an immunoisolating membrane may provide a new strategy for protecting these cells from recipient immune responses without the use of immunosuppressive drugs. We have previously reported a novel concept of immunoisolation and immunodelusion using recipient cells instead of traditional artificial materials. We developed a chondrocyte sheeting immunodelusive immunoisolated bioartificial pancreas (CSI-BAP) that would enable transplantation of cells across allogeneic and xenogeneic barriers without the cells being recognized as donor cells and without the need for immunosuppression. Recently, we have constructed hybrid cellular spheroids (HCSs) containing cells from two different cell lines (RIN-5F, an insulin-secreting cell line, and Hep-G2, a hepatocellular carcinoma cell line) to enhance the function and biocompatibility of the HCSs. These HCSs were then encapsulated with multiple layers of chondrocyte sheets obtained from the auricular cartilage of Sprague-Dawley (SD) rats. The in vitro ability of the CSI-BAP to secrete insulin was tested before transplantation. Histological evaluation of CSI-BAP chondrocyte microencapsulated immunoisolated islet morphology and viability of allogeneic or xenogeneic cell lines was performed 100 days after the CSI-BAP was transplanted into SD rats. Morphological evaluations revealed good viability of the islets and progression of islet encapsulation. In vitro insulin secretion from the CSI-BAP was well maintained. Additionally, insulin and albumin secretion from the CSI-BAP was confirmed by in vivo immunohistochemical examination. Moreover, the cell lines transplanted into the subcutaneous space in the form of HCSs within the chondrocyte sheets showed good viability of more than 100 days and sustained insulin and albumin secreting ability., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Introduction: Although Islet cell isolation and culture have been well developed, there has been little progress to prolong transplanted islet survival. Hepatic ischemia and insufficient neovascularization of islets are considered to be the barriers to long-term survival, Hepatocytes that survive ischemic injury have been reported to protect themeslves and regenerate using the IL-6 interleukin 6 and STAT3 pathways., Materials and Methods: The hepatocellular carcinoma (Hep-G2) cell line preconditioned for 0, 2, 4, 6, and 24 hours in a hypoxic chamber, was cocultured with rat insulin-secreting celline (RIN-5F) cells. We measured cell viabilities, insulin secretion, and p-STAT3, IL-6, and NF-κB levels., Results: Cocultured Hep-G2 and RIN-5F cells aggregated to form spheroids. Viabilities of Hep-G2 cells were no different after various ischemic preconditioning times, but insulin secretion increased in a time-dependent fashion with preconditioning. Western blotting showed p-STAT3, NF-κB, and IL-6 levels to increase with preconditioning time., Conclusion: The IL-6/STAT3 pathway of Hep-G2 cells after ischemic injury showed beneficial effects on insulin secretion of RIN-5f cells cocultured with themselves., (Copyright © 2012 Elsevier Inc. All rights reserved.)

The recurrence of hepatocellular carcinoma (HCC) after transplantation is the main limitation of liver transplantation. Therefore, several selection criteria for liver transplantation in HCC patients have been established. The objective of this study was to verify the clinical validity of selection criteria evaluated by pre-transplant radiologic imaging study. Sixty-nine participants were enrolled for this study between September 2005 and May 2007. We analyzed the post-transplant survival and recurrence rate using radiologic selection criteria and other clinical factors. Grouping by pretransplant criteria for liver transplantation, 16 recipients (23.2%) were above Milan criteria and 7 recipients (10.1%) were above UCSF criteria. Nine recipients (13.0%) were grouped as above Milan/below UCSF. The recipients who met Milan showed 85.8% 1-year survival rates, which was comparable to that of non-HCC (91.6%) (p = 0.767). During the post-transplant follow-up period (1-52 months, 14.81 +/- 12.0 months), 16 recurrences (23.2%) were diagnosed. The 1-year recurrence-free survival rate of recipients who met the Milan criteria was 78.6%, and those that did not meet these criteria was 22.7% (p < 0.0001). With regard to UCSF criteria, these percentages were 72.0% and 14.2%, respectively (p < 0.0001). According to a combined grouping, the 1-year recurrence-free survival rate was 25.4% in the above Milan/below UCSF group. There were significant differences among each of the groups (overall p < 0.0001). The application of UCSF criteria that are defined by pre-transplant radiologic findings as patient selection criteria for liver transplantation is limited.

Primary hepatic epithelioid hemangioendothelioma is a rare neoplasm of endothelial origin. The clinical manifestations are nonspecific, ranging from complete absence of symptoms to hepatic failure and death. Spontaneous rupture of a hepatic epithelioid hemangioendothelioma is an extremely rare presentation. We present a case of primary hepatic epithelioid hemangioendothelioma in a 65-year-old male patient with alcoholic liver cirrhosis. He was hospitalized due to epigastric pain and multiple liver masses on abdominal ultrasound. Dynamic liver CT imaging revealed multiple peripheral nodular enhanced mass lesions with delayed centripetal enhancement, and the adjacent collection of high-attenuation fluid along the liver capsule. Abdominal tapping revealed blood in the peritoneal cavity. Primary hepatic epithelioid hemangioendothelioma with spontaneous rupture was finally diagnosed based on a histopathologic examination revealing positive immunohistochemical staining for CD34.

The potassium channels are ubiquitous multisubunit membrane proteins, and potassium-dependent alterations in the membrane potential play an important role in the proliferation of many types of cells. This study analyzed the mutation, allelic loss and expression patterns of the KCNRG gene in 77 HCCs in order to determine if the KCNRG gene, which encodes the potassium channel regulating protein, is involved in the tumorigenesis of hepatocellular carcinoma (HCC). One KCNRG missense mutation, CGT CAT (Arg His) was found at codon 92 within the T1 domain. Hep3B hepatoma cells were transfected with the wild- or mutant-KCNRG to determine the effect of this mutation in KCNRG. Interestingly, the suppressive cell growth activity of the mutant-type KCNRG was significantly lower than that of the wild-type KCNRG. In addition, allelic loss was detected in 17 out of 64 (26.5%) informative HCC cases, and all were hepatitis B virus (HBV)-positive. Moreover, the allelic loss was closely related to an intrahepatic metastasis (P=0.0247), higher grade (P=0.0078) and clinical stage (P=0.0071). Expression analysis revealed 22 tumor tissues to have a loss of expression of the KCNRG transcript. These results suggest that genetic alterations and the expression of KCNRG might play an important role in the development and/or progression of a subset of HCCs.

Background/aims: Gelatinase (matrix metalloproteinase (MMP) -2 and 9) has an important role in the pathogenesis of liver cirrhosis (LC) and hepatocellular carcinoma (HCC). In this study, we evaluated the relationship of gelatinase to chronic liver disease., Methods: Four groups of subjects were examined; healthy control (10 cases), chronic hepatitis (18 cases), LC (15 cases), and HCC (28 cases). The plasma of each subject was obtained, and the equal quantification of plasma protein was done. The plasma activities of MMP-2 and 9 were measured by zymography., Results: The activities of plasma MMP-2 in patients with LC were significantly higher than those in controls (p=0.009) and in patients with chronic hepatitis (p=0.011), but not different from those in patients with HCC. The activities of plasma MMP-9 in patients with LC were significantly higher than those in controls, but not different from those in patients with chronic hepatitis or HCC. In patients with LC (regardless of having HCC), the activities of MMP-2 correlated with total bilirubin (r=0.323, p=0.048) and Child-Pugh score (r=0.414, p=0.012). The activities of MMP-2 and 9 were higher in patients with LC (regardless of having HCC) caused by alcohol than caused by HBV (p=0.009 and 0.002 for each one)., Conclusions: The plasma activity of MMP-2 may be a useful marker for the diagnosis and determination of the severity of LC. The plasma activity of MMP-9 was not useful for HCC, but may be a marker for alcoholic LC. Further study is needed to determine why the plasma activity of gelatinase was higher in patients with LC caused by alcohol than by HBV.

Background/aims: The genetic polymorphism of transforming growth factor-beta1 (TGF-beta1) at codons 10 and 25 which influences the production of TGF-beta1 is related to fibrogenesis in the lung and liver. We evaluated the genetic polymorphism at codons 10 and 25 in controls and in patients with liver cirrhosis (LC) and hepatocellular carcinoma (HCC)., Methods: Blood samples were collected from controls (n=35), patients with LC (n=64), and HCC (n=49). Genomic DNA was isolated and polymerase chain reaction (PCR) was done for a segment including codons 10 and 25. The results of direct sequencing for PCR products were compared between the controls and the patients., Results: There was no genetic polymorphism at codon 25 and three types of genetic polymorphism at codon 10. The leucine homozygous genotype (CTG/CTG) at codon 10 was more common in patients with LC than the controls (p=0.01) and especially in patients with LC caused by HBV (p=0.004). The polymorphism at codons 10 in patients with HCC was similar to the controls. However, leucine homozygous genotype was more common in patients with HCC of uninodular morphology than those of massive morphology (p=0.007)., Conclusions: The genetic polymorphism of TGF-beta1 at codon 10 might be associated with LC and morphology of HCC. The potential usefulness of TGF-beta1 genotyping needs further studies in large scale.