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Abstract Titrating tacrolimus concentration in liver transplantation recipients remains a challenge in the early post-transplant period. This multicenter retrospective cohort study aimed to develop and validate a machine-learning algorithm to predict tacrolimus concentration. Data from 443 patients undergoing liver transplantation between 2017 and 2020 at an academic hospital in South Korea were collected to train machine-learning models. Long short-term memory (LSTM) and gradient-boosted regression tree (GBRT) models were developed using time-series doses and concentrations of tacrolimus with covariates of age, sex, weight, height, liver enzymes, total bilirubin, international normalized ratio, albumin, serum creatinine, and hematocrit. We conducted performance comparisons with linear regression and populational pharmacokinetic models, followed by external validation using the eICU Collaborative Research Database collected in the United States between 2014 and 2015. In the external validation, the LSTM outperformed the GBRT, linear regression, and populational pharmacokinetic models with median performance error (8.8%, 25.3%, 13.9%, and − 11.4%, respectively; P

Abstract To address the shortcomings of current hepatocellular carcinoma (HCC) surveillance tests, we set out to find HCC-specific methylation markers and develop a highly sensitive polymerase chain reaction (PCR)-based method to detect them in circulating cell-free DNA (cfDNA). The analysis of large methylome data revealed that Ring Finger Protein 135 (RNF135) and Lactate Dehydrogenase B (LDHB) are universally applicable HCC methylation markers with no discernible methylation level detected in any other tissue types. These markers were used to develop Methylation Sensitive High-Resolution Analysis (MS-HRM), and their diagnostic accuracy was tested using cfDNA from healthy, at-risk, and HCC patients. The combined MS-HRM RNF135 and LDHB analysis detected 57% of HCC, outperforming the alpha-fetoprotein (AFP) test’s sensitivity of 45% at comparable specificity. Furthermore, when used with the AFP test, the methylation assay can detect 70% of HCC. Our findings suggest that the cfDNA methylation assay could be used for HCC liquid biopsy.

Background : Pretransplant therapies such as rituximab and plasmapheresis have led to an increase in ABO-incompatible (ABOi) living donor liver transplantation (LDLT), thus helping to overcome organ shortages. This study evaluated the changes in anti-A/B titers and CD19 levels over time in patients undergoing ABOi LT and aimed to understand the effect of single-nucleotide polymorphisms (SNPs) in Fc gamma receptor (FcγR) on rituximab therapy. Methods : Two SNPs of FCGR2A (131H/R) and FCGR3A (158F/V) were identified. The clinical data on 44 patients who underwent ABOi LDLT between May 2019 and October 2021 at Seoul National University Hospital were reviewed retrospectively. Results : Following desensitization with rituximab and subsequent LDLT, the anti-A/B titer recovered within 1 week, but decreased thereafter. The CD19 level increased at 3 months after LT. The genotyping data for FCGR3A (158F/V) indicated that two patients had the V/V genotype, and 42 had the F/V genotype. In the genotyping data for FCGR2A (131H/R), 21 patients had the H/H genotype, three had the R/R genotype, and 20 had the H/R genotype. However, there were no significant differences in anti-A/B and CD19 levels, bacteremia rates, T cell-mediated rejection, antibody-mediated rejection, or the survival rate among the FCGR2A types. Conclusions: There were significant changes in the anti-A/B titers and CD19 levels over time in each patient after ABOi LDLT. The difference in outcomes following LT according to the FcγR SNP type for rituximab was unclear. Further studies with larger sample sizes are needed to confirm the effect of FcγR SNPs on rituximab therapy.

Abstract Antithrombin‐III (AT‐III) concentrates have been used in the immediate postoperative period after liver transplantation to prevent critical thrombosis. We aimed to investigate a more appropriate method for AT‐III concentrate administration to maintain plasma AT‐III activity level within the target range. In this randomized controlled trial, 130 adult patients undergoing living‐donor liver transplantation were randomized to either the intermittent group or continuous group. In the intermittent group, 500 international units (IU) of AT‐III concentrate were administered after liver transplantation and repeated every 6 h for 72 h. In the continuous group, 3000 IU of AT‐III were continuously infused for 71 h after a loading dose of 2000 IU over 1 h. Plasma AT‐III activity level was measured at 12, 24, 48, 72, and 84 h from the first AT‐III administration. The primary outcome was the target (80%–120%) attainment rate at 72 h. Target attainment rates at other timepoints and associated complications were collected as secondary outcomes. A total of 107 patients were included in the analysis. The target attainment rates at 72 h post‐dose were 30% and 62% in the intermittent group and continuous group, respectively (p = 0.003). Compared to the intermittent group, patients in the continuous group reached the target level more rapidly (12 vs. 24 h, median time, p

Abstract Early allograft dysfunction (EAD) and acute kidney injury (AKI) are common and clinically important complications after liver transplantation. Serum lactate level at the end of surgery could predict EAD and neutrophil gelatinase-associated lipocalin (NGAL) is known as a biomarker for AKI after liver transplantation. The authors investigated whether the combination of these two laboratory tests could be used as an early predictor of these two complications of EAD and AKI. We reviewed cases undergoing living donor liver transplantation (n = 353). Lactate-adjusted NGAL level, a combination of these two predictors, was calculated as the sum of each value multiplied by the odds ratio for EAD or AKI. We evaluated whether this combined predictor at the end of surgery is significantly associated with both postoperative AKI or EAD. We compared the area under the receiver operating characteristic curve (AUC) between our multivariable regression models with and without NGAL, lactate, or lactate-adjusted NGAL. NGAL, lactate and lactate-adjusted NGAL are significant predictors for EAD and AKI. The regression model for EAD or AKI including lactate-adjusted NGAL showed a greater AUC (for EAD: odds ratio [OR] 0.88, 95% confidence interval [CI] 0.84–0.91; for AKI: OR 0.89, 95% CI 0.85–0.92) compared to the AUC of the models including lactate (for EAD: OR 0.84, 95% CI 0.81–0.88; for AKI: OR 0.79, 95% CI 0.74–0.83) or NGAL alone (for EAD: OR 0.82, 95% CI 0.77–0.86; for AKI: OR 0.84, 95% CI 0.80–0.88) or the model without lactate or NGAL (for EAD: OR 0.64, 95% CI 0.58–0.69, for AKI: OR 0.75, 95% CI 0.70–0.79). In conclusion, lactate-adjusted NGAL level at the end of surgery could be a reliable combined laboratory predictor for postoperative EAD or AKI after liver transplantation with a greater discriminative ability than lactate or NGAL alone.

Adrenal and spinal metastases of hepatocellular carcinoma (HCC) are rare entities with significant morbidity and mortality, particularly after liver transplantation (LT). We report a case of a 49-year-old man who underwent LT for hepatitis B-related end-stage liver disease and HCC (single 4.5 cm lesion [T1N0], without vascular invasion) in 2016. Eighteen months later, adrenal metastasis and hepatitis B seropositive conversion were developed with normal serum tumor. Adrenal metastasis was treated with radiation therapy (RT) and hepatitis B showed spontaneous seronegative conversion. However, 35 months later, spinal metastasis occurred with elevation of the protein induced by vitamin K absence or antagonist-II (PIVKA-II) level (197 mAU/mL), along with hepatitis B seropositive conversion. After sorafenib, sequential regorafenib with RT led to partial response of the spinal lesions, along with hepatitis B seronegative conversion and normal PIVKA-II levels. After 9 months of regorafenib combined with RT, two recurrent lesions were found, as well as hepatitis B seropositive conversion and lesions were treated with transarterial chemoembolization. The patient survived for more than 71 months after LT and 53 months after recurrence under various combinations of therapy. Combined systemic and locoregional therapies can be a treatment option for HCC recurrence, even in LT patients.

Abstract Background In South Korea, the number of living-donor liver transplantations in 2019 was 1,188. Living liver donors (LLDs) undergo surgery and the postoperative recovery process for altruistic purposes. This study explored LLDs’ unmet expectations about surgical outcomes and examined their impact on the donors’ health-related quality of life (HRQOL). Methods This descriptive cross-sectional study utilized a self-reported survey. Data were collected at a university hospital in Seoul, South Korea. Among the 535 LLDs who underwent surgery for donation between January 2011 and March 2021, 124 participated in this study. The Korean version of the 12-item Short Form Health Survey version 2 (SF-12v2) was used to measure the HRQOL of LLDs. Unmet expectations regarding surgical outcomes were measured using four items: pain, length of hospital stay, speed of recovery, and complications. Logistic regression model was applied to determine whether the unmet expectations influence HRQOL in LLDs. Odds ratios with 95% confidence interval were used. Results The percentage of the participants who reported that their actual experiences for pain, speed of recovery, hospital stay, and complications were worse than expected were 34.7%, 22.6%, 9.7%, and 7.3%, respectively. Unmet expectations about surgical outcomes were significantly associated with physical and mental HRQOL after controlling for age, sex, education level, income, postoperative complications, recipients’ death, time since donation, and satisfaction with the decision to donate. Conclusion LLDs should be supported in obtaining more accurate and realistic information about surgical outcomes to decrease unmet expectations, which may help improve their quality of life.

Abstract Background Combined hepatocellular‐cholangiocarcinoma (cHCC‐CCA) is a rare primary hepatic neoplasm. Currently, there are no well‐structured studies that analyze the feasibility of laparoscopic liver resection in cHCC‐CCA alone. This retrospective cohort study aimed to compare the long‐term survival of laparoscopic liver resection with open liver resection in cHCC‐CCA. Methods Patients with a postoperative pathologic report of cHCC‐CCA who underwent liver resection from August 2004 to December 2017 were included in this study. Kaplan–Meier survival analysis was performed to analyze the 3‐y disease‐free survival and 3‐y overall survival. Propensity score matching was done to reduce the influence of confounding variables. Results A total of 145 patients were pathologically confirmed to have cHCC‐CCA, of which 10 patients were excluded due to having received palliative surgery. Of the remaining 135 patients, 43 underwent laparoscopic and 92 underwent open liver resection; propensity score matching yielded 30 patients for each group. The 3‐y overall survival was 38 (88.4%) in the laparoscopic group and 84 (91.3%) in the open group before propensity score matching (P = .678), and 25 (83.3%) and 28 (93.3%), respectively, after matching (P = .257). The 3‐y disease‐free survival was 24 (55.8%) in the laparoscopic group and 32 (34.8%) in the open group before matching (P = .040), and 17 (56.7%) and 16 (53.3%), respectively, after matching (P = .958). The hospital stay was shorter in the laparoscopic group before and after matching, while other operative outcomes were similar in both groups. Conclusion Laparoscopic liver resection for cHCC‐CCA is technically feasible and safe, having a shorter hospital stay without compromising oncological outcomes.

Abstract We aimed to compare the short- and long-term outcomes of simultaneous laparoscopic, hybrid, and open resection for colorectal cancer and synchronous liver metastases. We retrospectively analyzed the data of 647 patients with simultaneous resection of colorectal cancer and liver metastases between January 2006 and December 2018 at three tertiary referral hospitals. Patient’s baseline characteristics, perioperative outcomes, pathological examination results, liver-specific recurrence rate and survivals were compared between the propensity score-matched groups. Forty-two and 81 patients were selected for the laparoscopic vs. hybrid groups, and 48 and 136 patients for laparoscopic vs. open groups, respectively. The laparoscopic group had fewer wound complications (2.1 vs. 13.2%; p = 0.028) than the open group, and a shorter postoperative hospital stay than the hybrid and open groups (8 vs. 11 days, p

Purpose The present study compared the performance of computed tomography (CT), magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF), controlled attenuation parameter (CAP), grayscale ultrasonography (US), and attenuation imaging (ATI) for the diagnosis of hepatic steatosis (HS). Methods In total, 120 prospectively recruited patients who underwent hepatic resection between June 2018 and June 2020 were retrospectively analyzed. CT, MRI-PDFF, CAP, grayscale US, and ATI were performed within 3 months before surgery. Diagnostic performance for HS ≥5% and HS >33% was compared using the area under the curve (AUC) of receiver operating characteristic curves. Histopathologic examinations served as the reference standard for the degree of HS. Results For detecting HS ≥5%, MRI-PDFF (AUC, 0.946) significantly outperformed CT, CAP and grayscale US (AUC, 0.807, 0.829, and 0.761, respectively) (P33%, all the modalities provided good diagnostic performance without significant differences (AUC, 0.887-0.947; P>0.05 for all). Conclusion For detecting HS ≥5%, MRI-PDFF was the best imaging modality, while ATI outperformed grayscale US. For detecting HS >33%, all five imaging tools demonstrated good diagnostic performance.

Background : Once-daily tacrolimus reduces non-compliance relative to twice-daily tacrolimus. However, little is known about the safety and efficacy of conversion from twice-daily tacrolimus to generic once-daily tacrolimus in liver transplantation (LT). Herein, we investigated the efficacy and safety of a switch from twice-daily tacrolimus to generic once-daily tacrolimus in patients with stable liver graft function. Methods : This prospective, multicenter, open-label, single-arm study was conducted in 17 medical centers for 1 year from July 2019 to July 2020 (NCT04069065). Primary endpoint was the incidence of biopsy-proven acute rejection (BPAR) for 24 weeks after conversion. Secondary endpoints were graft failure, patient death, and adverse events (AEs). Results : Of 151 screened LT patients, 144 patients were enrolled. BPAR, graft failure, and patient death did not occur in this patient population. There were no statistical differences in blood tests, liver function tests, or biochemical tests between visits in any of the patients. Median tacrolimus trough level decreased abruptly from 4.7 ng/mL to 3.2 ng/mL after generic once-daily tacrolimus conversion, but median tacrolimus dose increased due to low tacrolimus trough level. Ninety-two adverse events occurred in 54 patients. Liver enzyme levels increased in seven patients (4.9%) after the switch to generic once-daily tacrolimus, but the liver function tests of these patients normalized thereafter. There were three cases of severe AEs not related to investigational drug. Conclusions: Present study suggests that conversion from twice-daily tacrolimus to generic once-daily tacrolimus is effective and safe in stable LT patients.

Numerical simulations of atmospheric dispersion and dose assessment were performed for the Jordan Research and Training Reactor (JRTR) to evaluate its radiological effects on surrounding population and the environment. A three-dimensional atmospheric dispersion model was applied to investigate the behavior of the radionuclides released into the air, and a dose assessment model was used to estimate the radiological impact on the population residing in nearby cities around the JRTR. Considering full core meltdown an accidental scenario, most of the source term was assumed to be released from the JRTR. Simulations were performed to calculate the air and deposition concentrations of radioactive materials for July 2013 and January 2014. The monthly averaged values of concentrations, depositions, and dose rates were analyzed to identify the most harmful effects in each month. The results showed that relatively harmful effects occurred in January 2014, and the total annual dose rate was estimated to be approximately 1 mSv outside the 10 km radius from JRTR. However, the impact of a nuclear accident is not as severe as it might seem, as the affected area is not highly populated, and appropriate protective measures can significantly reduce the radiation exposure. This study provides useful information for emergency preparedness and response planning to mitigate the radiological consequences of a nuclear accident at the JRTR.

Background: Treatment outcomes of laparoscopic liver resection (LLR) and percutaneous radiofrequency ablation (p-RFA) for small single hepatocellular carcinomas (HCCs) have not yet been fully compared. The aim of this study was to compare LLR and p-RFA as first-line treatment options in patients with single nodular HCCs ≤3 cm. Methods: From January 2014 to December 2016, a total of 566 patients with single nodular HCC ≤3 cm treated by either LLR (n = 251) or p-RFA (n = 315) were included. The recurrence-free survival (RFS) and cumulative incidence of local tumor progression (LTP) were estimated using Kaplan-Meier methods and compared using the log-rank test. Treatment outcome of 2 treatment modalities was compared in the subgroup of patients according to the tumor location. Results: There were no significant differences in overall survival between LLR and p-RFA (p = 0.160); however, 3-year RFS was demonstrated to be significantly higher after LLR (74.4%) than after p-RFA (66.0%) (p = 0.013), owing to its significantly lower cumulative incidence of LTP (2.1% at 3 years after LLR vs. 10.0% after p-RFA, p < 0.001). The complication rate of p-RFA was significantly lower than that of LLR (5.1 vs. 10.0%, p = 0.026). LLR also provided significantly better local tumor control than p-RFA for subscapular tumors (3-year LTP rates: 1.9 vs. 8.8%, p = 0.012), perivascular tumors (3-year LTP rates: 0.0 vs. 17.2%, p = 0.007), and tumors located in anteroinfero-lateral liver portions (3-year LTP rates: 0.0 vs. 10.7%, p < 0.001). However, there were no significant differences in LTP rates between LLR and p-RFA for non-subcapsular and non-perivascular tumors (p = 0.482) and for tumors in postero-superior liver portions (p = 0.380). Conclusions: LLR can provide significantly better local tumor control than p-RFA for small single HCCs in subcapsular, perivascular, and anteroinferolateral liver portions and thus may be the preferred treatment option for these tumors.

BackgroundA short-term weight reduction program for potential living donors was introduced to reduce the extent of hepatic steatosis prior to liver transplantation. We aimed to investigate changes in non-invasive hepatic steatosis and fibrosis indices among those who completed the program.MethodsAmong 1,950 potential living liver donors between January 2011 and May 2019, 160 living donors joined the weight reduction program. The prospectively collected clinical data of these potential liver donors were analyzed retrospectively. Hepatic steatosis and fibrosis scores were determined using the fatty liver index (FLI), hepatic steatosis index (HSI), and NAFLD fibrosis score (NFS) and compared to MR spectroscopy (MRS) fat fraction results before and after weight reduction.ResultsThirty-nine potential living donors who had undergone MRS both before and after weight reduction were included in the analysis. Their body weight decreased from 78.02 ± 10.89 kg to 72.36 ± 10.38 kg over a mean of 71.74 ± 58.11 days. FLI, HSI, and MRS values decreased significantly from 41.52 ± 19.05 to 24.53 ± 15.93, 39.64 ± 3.74 to 35.06 ± 3.82, and 12.20 ± 4.05 to 6.24 ± 3.36, respectively. No significant decreases in NFS were observed. There was a significant correlation between the extent of HSI change and the extent of MRS change (R2 value = 0.69, P < 0.001), although there was no correlation between MRS and FLI.ConclusionThe weight reduction program significantly improved non-invasive indices of hepatic steatosis over a short period. HSI may allow for prediction of simple decreases in hepatic steatosis.

Background: Recently, there have been several reports on pure laparoscopic donor right hepatectomy (PLDRH), but the effect of pure laparoscopy on bench surgery has not been evaluated. This study aimed to compare bench-surgery time between PLDRH and conventional donor right hepatectomy (CDRH).Methods: We retrospectively reviewed the medical records of 758 live liver donors between January 2012 and December 2019. We divided the patients into two groups: between January 2012 and September 2015, when we exclusively performed CDRH, and between March 2016 and December 2019, when PLDRH was standardized. We excluded all other types of graft donor hepatectomy, laparoscopic assisted donor hepatectomy, and cases with no recorded data.Results: In total, 267 donors were included in the PLDRH group and were compared with 247 donors in the CDRH group. Similar proportions of graft vascular variations were observed between the two groups. The mean bench-surgery time was longer in the PLDRH group than in the CDRH group (49.3 ± 19.9 vs. 39.5 ± 17.5 min; P < 0.001).Conclusion: The bench-surgery time was longer in the PLDRH group than the CDRH group, regardless of whether the vascular network was reconstructed. Expertise in bench-surgery as well as donor surgery and recipient surgery is mandatory for PLDRH to be safe and feasible.

Background: Liver transplantation (LT) is considered a contraindication in patients with a history of hepatocellular carcinoma (HCC) rupture because ruptured HCCs are classified as T4 in the current American Joint Committee on Cancer TNM system. This study aimed to assess living donor liver transplantation (LDLT) in these patients and elucidate the factors that may have affected their outcomes.Methods: Data of patients with a history of ruptured HCC who underwent LDLT between January 1999 and December 2019 were retrospectively reviewed.Results: Among 789 patients who underwent LDLT for HCC, five (0.64%) had a history of HCC rupture. Three patients (60%) were treated with transarterial chemoembolization (TACE) or transarterial embolization (TAE) for hemostasis, and two patients (40%) achieved spontaneous hemostasis. One of two patients who achieved spontaneous hemostasis underwent surgical resection and LT at 1 week and 6 years after the rupture, respectively. The other patient underwent LT 2 days after the rupture. Four patients (80%) survived for >5 years, while two patients (40%) experienced recurrence and succumbed during the median follow-up duration of 85.3 months (range, 12.4–182.7). The recurrence first developed at 4.3 and 17.0 months after LT; these patients were managed well using surgical resection for peritoneal seeding and TACE for intrahepatic HCC.Conclusion: LDLT can be considered a treatment method even in patients with a history of HCC rupture after full evaluation of tumor biology and risk of recurrence.

BTLA is established as a negative regulator of natural killer T (NKT) cell function, and share its ligand HVEM with CD160. Here the authors show, by analyzing NKT activation in CD160-deficient mice or with BTLA blockade, that CD160 synergizes with BTLA to negatively regulate NKT cells during hepatic injury.

A large amount of radioactive material was released from the Fukushima Daiichi Nuclear Power Plant (FDNPP) in 2011 and dispersed into the environment. Though seven years have passed since the Fukushima Daiichi Nuclear Power Plant accident, some parts of Japan are still under the influence of radionuclide contamination, especially Fukushima Prefecture and prefectures neighboring Fukushima Prefecture. The long-term effective doses and the contributions of each exposure pathway (5 exposure pathways) and radionuclide (131I, 134Cs, and 137Cs) were evaluated for people living in the regions of Fukushima and neighboring prefectures in Japan using a developed dose assessment code system with Japanese specific input data. The results estimated in this study were compared with data from previously published reports. Groundshine and ingestion were predicted to contribute most significantly to the total long-term dose for all regions. The contributions of each exposure pathway and radionuclide show different patterns for certain regions of Japan. Keywords: Radionuclide, Radiological dose, Long-term effective dose, Exposure pathway, Fukushima Daiichi nuclear power plant accident

BackgroundTherapeutic strategies and good prognostic factors are important for patients with single large hepatocellular carcinoma (HCC). This retrospective study aimed to identify the prognostic factors in patients with single large HCC with good performance status and Child-Pugh A cirrhosis using a large national cancer registry database and to recommend therapeutic strategies.MethodsAmong 12139 HCC patients registered at the Korean Primary Liver Cancer Registry between 2008 and 2015, single large (≥ 5 cm) HCC patients with Eastern Cooperative Oncology Group (ECOG) performance status 0 and Child-Pugh score A were selected.ResultsOverall, 466 patients were analyzed. The 1-,2-,3-, and 5-year survival rates after initial treatment were 84.9%, 71.0%, 60.1%, and 51.6%, respectively, and progression-free survival rates were 43.6%, 33.0%, 29.0%, and 26.8%, respectively. Platelet count

Background/AimsGuidelines recommend surveillance for hepatocellular carcinoma (HCC) recurrence at 3-month intervals during the first year after curative treatment and 6-month intervals thereafter in all patients. This strategy does not reflect individual risk of recurrence. We aimed to stratify risk of recurrence to optimize surveillance intervals 1 year after treatment.Methods : We retrospectively analyzed 1,316 HCC patients treated with resection/radiofrequency ablation at Barcelona Clinic Liver Cancer stage 0/ A. In patients without 1-year recurrence under 3-monthly surveillance, a new model for recurrence was developed using backward elimination methods: training (n=582)/ validation cohorts (n=291). Overall survival (OS) according to risk stratified by the new model was compared according to surveillance intervals: 3-monthly versus 6-monthly (n=401) after lead time bias correction and propensity-score matching analyses.Results : Among patients without 1-year recurrence, age and international normalized ratio values were significant factors for recurrence (hazard ratio [HR], 1.03; 95% confidence interval [CI], 1.00 to 1.03; p=0.009 and HR, 5.63; 95% CI, 2.24 to 14.18; p

Hepatocellular carcinoma is known to harbour numerous genomic and epigenomic aberrations, driving transcriptomic deregulation. Here, the authors integrate genomic, epigenomic, and expression data to reveal three prognostic subtypes, providing insight to the pathobiology of hepatocellular carcinoma.

Abstract Background The Hippo pathway plays a vital role in liver regeneration and development by determining cellular lineage and regulating cell proliferation and apoptosis. In this study, we aimed to assess the role of the Hippo pathway in hepatic carcinogenesis and morphogenesis by examining Yes-associated protein 1 (YAP1) expression in the spectrum of hepatic carcinomas based on cellular lineage. Methods We examined 913 primary hepatic carcinomas, including hepatocellular carcinomas (HCCs), combined hepatocellular and cholangiocarcinomas (cHC-CCAs), intrahepatic cholangiocarcinomas (IHCCAs) and perihilar extrahepatic bile duct carcinomas (EHBCAs). Our study group was categorized into 8 disease groups, based on histological diagnosis and cytokeratin 19 (CK19) expression, and immunohistochemistry was used to detect and compare YAP1 expression levels between the groups. The eight disease groups we identified were: 1) CK19(−) HCC, 2) CK19(−) scirrhous HCC, 3) CK19(+) HCC, 4) stem cell feature of cHC-CCA, 5) classical cHC-CCA, 6) cholangiolocellular IHCCA, 7) non-cholangiolocellular IHCCA, and 8) EHBCA. Results Positive rates of YAP1 were the highest in the EHBCA group (21%). CK19(+) HCC and non-cholangiolocellular IHCCA groups also showed high expression levels (10% -11%), while the CK19 (−) HCC, CK19 (−) scirrhous HCC, cHC-CCA, and cholangiolocellular IHCCA groups showed low expression levels, ranging between 0% and 5%. Survival analysis, restricted to pT1 stage HCCs and IHCCAs, showed poor overall survival for YAP1(+) IHCCA patients (39 ± 17 vs. 109 ± 10 months, mean ± SD, log rank p-value 0.005). For HCCs, a trend of poor progression-free survival for YAP1(+) HCCs was observed (39 ± 18 vs. 81 ± 5 months, mean ± SD, log rank p-value 0.205) Conclusions YAP1 activation was more commonly found in CCAs than in pure HCCs. However, a differing pattern of YAP1 expression between cHC-CCAs and CK19(+) HCCs and the poor prognosis of YAP1 positive hepatic carcinomas suggests that YAP1 may have a preferential role in aggressive tumor behavior, rather than in the determination of cellular lineage in hepatic carcinomas.

Abstract Alterations in mitochondrial respiration contribute to the development and progression of cancer via abnormal biogenesis, including generation of reactive oxygen species. Ubiquinol–cytochrome c reductase hinge protein (UQCRH) consists of the cytochrome bc1 complex serving respiration in mitochondria. In the present study, we analyzed UQCRH abnormalities in hepatocellular carcinoma (HCC) and its association with clinical outcomes of patients. UQCRH expression in HCC was determined via semiquantitative and quantitative real‐time reverse transcriptase polymerase chain reaction of 96 surgically resected HCC tissues positive for hepatitis B virus surface antigen. UQCRH was frequently overexpressed in HCC tissues (46.8%, based on 2.1‐fold cutoff). UQCRH overexpression was observed in HCCs with larger tumor size, poorer differentiation, or vascular invasion. Kaplan–Meier analysis revealed significantly shorter overall (P = 0.005) and recurrence‐free survival (P = 0.027) in patients with tumors overexpressing UQCRH. The prognostic impact of UQCRH was significant in subgroups of patients divided according to the α‐fetoprotein (AFP) level. The patient subgroup with higher AFP levels (≥20 ng/mL) exhibited significant differences in 5‐year overall (18.5% vs. 67.9%) and recurrence‐free survival rates (11.1% vs. 46.4%) between groups with and without UQCRH overexpression. In contrast, no marked survival differences were observed between subgroups with lower AFP levels (

Background Liver transplantation (LT) is the treatment of choice for hepatocellular carcinoma (HCC). The aim of this study was to investigate the recurrence rate of HCC after LT and prognostic factors for recurrence by comparing LT with non-transplanted resection. Methods The participants were 338 patients who underwent LT between 1996 and 2012 at Seoul National University Hospital (LT group) and 520 HCC patients who underwent partial hepatectomy between 1995 and 2006 (control group, non-LT group). Results In the LT group, 68 of 338 patients (19.8%) showed relapse, and the recurrence rate was lower than that in the non-LT group (64.9%, 357/520, p < .001). Stratification analysis by American Joint Committee on Cancer (AJCC) stage showed that the stage I-II LT group had a lower recurrence rate than the non-LT group. Univariate comparative analysis demonstrated that multiplicity of tumor, tumor size, gross type, Edmondson- Steiner (ES) nuclear grade, extent of tumor, angioinvasion, AJCC stage, Milan criteria, University of California at San Francisco criteria on explant pathology (all p < .001), positive expression of cytokeratin 19 (p = .002), and preoperative α-fetoprotein (AFP) (p < .001) were predictors of tumor recurrence. In multivariate analysis, LT, preoperative AFP, multiplicity of tumor, extent of tumor, size of tumor, and ES nuclear grade were independent prognostic factors. Conclusions LT might have a protective effect against the late recurrence of stage I-II HCC compared to non-LT, and the prognostic factors for recurrence were similar to previously well-known prognostic factors for HCC.

Background/Aims The relationship between patient survival and biopsy-proven acute rejection (BPAR) in liver transplant recipients with hepatitis C remains unclear. The aims of this study were to compare the characteristics of patients with and without BPAR and to identify risk factors for BPAR. Methods We retrospectively reviewed the records of 169 HCV-RNA-positive patients who underwent LT at three centers. Results BPAR occurred in 39 (23.1%) of the HCV-RNA-positive recipients after LT. The 1-, 3-, and 5-year survival rates were 92.1%, 90.3%, and 88.5%, respectively, in patients without BPAR, and 75.7%, 63.4%, and 58.9% in patients with BPAR (P

There has been ongoing debate that the Milan criteria may be too strict that a significant number of patients who could benefit from liver transplantation (LT) might have been excluded. Based on this idea, various studies have been conducted to further expand the Milan criteria and give more HCC patients a chance of cure. In deceased donor LT (DDLT) setting, expansion of the criteria is relatively tempered because the results of LT for HCC should be comparable to those of patients with non-malignant indications. On the other hand, in living donor LT (LDLT) situation, liver grafts are not public resources. The acceptable target outcomes for LDLT might be much lower than those for DDLT. Patients with biologically favorable tumors might have excellent survivals after LT despite morphological advanced HCCs. Therefore, the significance and utility of biological tumor parameters for selecting suitable LT candidates have been increased to predict HCC recurrence after LT. Although there is no consensus regarding the use of prognostic biomarkers in LT selection criteria for HCC, the combination of conventional morphological parameters and new promising biomarkers could help us refine and expand the LT criteria for HCC in the near future.

Background: Hepatitis B virus (HBV) plays well-known roles in tumorigenesis of hepatocellular carcinoma (HCC) in infected patients. However, HBV-associated protein status in tumor tissues and the relevance to tumor behavior has not been reported. Our study aimed to examine the expression of HBV-associated proteins in HCC and adjacent nontumorous tissue and their clinicopathologic implication in HCC patients. Methods: HBV surface antigen (HBsAg), HBV core antigen (HBcAg), and HBV X protein (HBx) were assessed in 328 HBV-associated HCCs and in 155 matched nontumorous tissues by immunohistochemistry staining. Results: The positive rates of HBsAg and cytoplasmic HBx staining in tumor tissue were lower than those in nontumorous tissue (7.3% vs. 57.4%, p < .001; 43.4% vs. 81.3%, p < .001). Conversely, nuclear HBx was detected more frequently in tumors than in nontumorous tissue (52.1% vs. 30.3%, p < .001). HCCs expressing HBsAg, HBcAg, or cytoplasmic HBx had smaller size; lower Edmondson-Steiner (ES) nuclear grade, pT stage, and serum alpha-fetoprotein, and less angioinvasion than HCCs not expressing HBV-associated proteins. Exceptionally, nuclear HBx-positive HCCs showed higher ES nuclear grade and more frequent large-vessel invasion than did nuclear HBx-negative HCCs. In survival analysis, only nuclear HBx-positive HCCs had shorter disease-free survival than nuclear HBx-negative HCCs in pT1 and ES nuclear grade 1–2 HCC subgroup (median, 126 months vs. 35 months; p = .015). Conclusions: Our data confirmed that expression of normal HBV-associated proteins generally decreases in tumor cells in comparison to nontumorous hepatocytes, with the exception of nuclear HBx, which suggests that nuclear HBx plays a role in recurrence of well-differentiated and early-stage HCCs.

Background/AimsThe dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT).MethodsTwo sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC0-12) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT.ResultsIn the first part of study, AUC0-12 was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively.ConclusionsA reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.

Background/AimsThe most commonly used immunosuppressant therapy after liver transplantation (LT) is a combination of tacrolimus and steroid. Basiliximab induction has recently been introduced; however, the most appropriate immunosuppression for hepatocellular carcinoma (HCC) patients after LT is still debated.MethodsNinety-three LT recipients with HCC who took tacrolimus and steroids as major immunosuppressants were included. Induction with basiliximab was implemented in 43 patients (46.2%). Mycophenolate mofetil (MMF) was added to reduce the tacrolimus dosage (n=28, 30.1%). The 1-year tacrolimus exposure level was 7.2 ± 1.3 ng/mL (mean ± SD).ResultsThe 1- and 3-year recurrence rates of HCC were 12.9% and 19.4%, respectively. Tacrolimus exposure, cumulative steroid dosages, and MMF dosages had no impact on HCC recurrence. Induction therapy with basiliximab, high alpha fetoprotein (AFP; >400 ng/mL) and protein induced by vitamin K absence/antagonist-II (PIVKA-II; >100 mAU/mL) levels, and microvascular invasion were significant risk factors for 1-year recurrence (P

This study was conducted to evaluate the outcomes of multi-channel switching RFA using a separable cluster electrode in patients with HCC.From November 2011 to July 2013, 79 patients with 98 HCCs < 5 cm were enrolled and treated with RFA using a multi-channel switching radiofrequency system and a separable cluster electrode under the guidance of a real-time fusion imaging system. The primary and secondary endpoints were the 3-year local tumor progression (LTP) rate and recurrence-free survival (RFS) rate, respectively. For post hoc analyses, LTP, RFS, and major complication rates were retrospectively compared with a historical control group treated with RFA using the same radiofrequency system but with multiple internally-cooled electrodes.The technique success rate of the 98 tumors was 100%. Cumulative 1-year, 2-year, and 3-year LTP rates were 3.4%, 6.9%, and 12.4%, respectively. For patient-level data, cumulative 1-year, 2-year, and 3-year RFS rates were 83.9%, 68.6%, and 45.4%, respectively. On post hoc analyses, none of the baseline characteristics showed a significant difference between the separable cluster electrode and multiple internally-cooled electrodes group. Cumulative LTP and RFS rates of the two groups also showed no significant difference (p = 0.401 and p = 0.881, respectively). Finally, major complication rates of the separable cluster electrode group (5.0%, 4/79) and multiple internally-cooled electrodes group (5.9%, 4/74) were also comparable (p = 1.000).Switching monopolar RFA using a separable cluster electrode is a feasible and efficient technique for the treatment of HCCs smaller than 5 cm, providing comparable local tumor control to multiple internally-cooled electrodes.ClinicalTrials.gov NCT02745483.

Background: Although the adoption of pure laparoscopic donor hepatectomy has expanded driven by considerations of donor cosmesis and function, the criteria for selecting candidates for pure laparoscopic donor right hepatectomy (PLDRH) continue to be debated. This study aimed to delineate the distinctive characteristics of donors and recipients who underwent conventional opendonor right hepatectomy (CDRH) during the era of PLDRH. Materials and methods: The authors conducted a retrospective review of a prospectively collected single-centre database encompassing all right hepatectomies at Seoul National University Hospital from April 2016 to December 2021, a period during which there were no absolute contraindications for PLDRH. Results: During the exclusive PLDRH period, there were still 63 cases of CDRH alongside 362 cases of PLDRH. The CDRH donors were older, had a lower estimated remnant liver volume, and a higher incidence of expected multiple openings in the portal vein and bile duct based on preoperative imaging compared with PLDRH donors. In the subgroup analysis, including only donors meeting two or more criteria (age =40 years, estimated remnant liver volume =35%, or multiple anticipated vessel openings), recipients in the PLDRH group exhibited significantly more early major complications (P =0.029) compared with those in the CDRH group. Conclusion: As PLDRH gains traction in practice, it is essential to acknowledge that specific donor conditions, such as advanced age, limited remnant liver volume, and anticipation of multiple portal or bile duct openings, may merit contemplating CDRH as a means of optimizing recipient outcomes. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to identify safety and risk factors of living donor after pure laparoscopic donor right hepatectomy in a Korean multicenter cohort study. Background: Pure laparoscopic donor right hepatectomy is not yet a standardized surgical procedure due to lack of data. Methods: This retrospective study included 543 patients undergoing PLRDH between 2010 and 2018 in 5 Korean transplantation centers. Complication rates were assessed and multivariate logistic regression analyses were performed to identify risk factors of open conversion, overall complications, major complications, and biliary complications. Results: Regarding open conversion, the incidence was 1.7% and the risk factor was body mass index > 30 kg/m2 [P=0.001, odds ratio (OR)= 22.72, 95% CI= 3.56-146.39]. Rates of overall, major (Clavien-Dindo classification III-IV), and biliary complications were 9.2%, 4.4%, and 3.5%, respectively. For overall complications, risk factors were graft weight >700 g (P= 0.007, OR=2.66, 95% CI=1.31-5.41), estimated blood loss (P<0.001, OR= 4.84, 95% CI=2.50-9.38), and operation time >400 minutes (P=0.01, OR=2.46, 95% CI=1.25-4.88). For major complications, risk factors were graft weight > 700 g (P=0.002, OR=4.01, 95% CI=1.67-9.62) and operation time >400 minutes (P=0.003, OR=3.84, 95% CI=1.60-9.21). For biliary complications, risk factors were graft weight >700 g (P= 0.01, OR=4.34, 95% CI= 1.40-13.45) and operation time >400 minutes (P=0.01, OR=4.16, 95% CI=1.34-12.88). Conclusion: Careful donor selection for PLRDH considering body mass index, graft weight, estimated blood loss, and operation time combined with skilled procedure can improve donor safety. [ABSTRACT FROM AUTHOR]