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BACKGROUND: Living-donor liver transplantation has been widely performed as an alternative to the scarce liver grafts from deceased donors. More studies are reporting favorable outcomes of left liver graft (LLG). This study compared the clinical outcomes between living-donor liver transplantation using LLG and right liver graft (RLG) with similar graft-to-recipient body weight ratios. METHODS: This study analyzed 4601 patients from a multicenter observational cohort using the Korean Organ Transplantation Registry between 2014 and 2021. After matching the Model for End-stage Liver Disease score and graft-to-recipient body weight ratios because of the extremely different number in each group, the LLG and RLG groups comprised 142 (25.1%) and 423 (74.9%) patients, respectively. RESULTS: For donors, the median age was higher in the LLG group than in the RLG group (34 y [range, 16-62 y] versus 30 y [16-66 y] ; P = 0.002). For recipients, the LLG group showed higher 90-d mortality than the RLG group (11 [7.7%] versus 9 [2.1%]; P = 0.004). The long-term graft survival was significantly worse in the LLG group (P = 0.011). In multivariate Cox proportional hazards regression analysis for graft survival, LLG was not a significant risk factor (hazard ratio, 1.01 [0.54-1.87]; P = 0.980). Otherwise, donor age (≥40 y; 2.18 y [1.35-3.52 y]; P = 0.001) and recipients' body mass index (<18.5 kg/m2; 2.98 kg/m2 [1.52-5.84 kg/m2]; P = 0.002) were independent risk factors for graft survival. CONCLUSIONS: Although the short-term and long-term graft survival was worse in the LLG group, LLG was not an independent risk factor for graft survival in multivariate analysis. LLGs are still worth considering for selected donors and recipients regarding risk factors for graft survival.

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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 < 0.001) and median absolute performance error (22.3%, 33.1%, 26.8%, and 23.4%, respectively; P < 0.001). Dosing based on the LSTM model's suggestions achieved therapeutic concentrations more frequently on the chi-square test (P < 0.001). Patients who received doses outside the suggested range were associated with longer ICU stays by an average of 2.5 days (P = 0.042). In conclusion, machine learning models showed excellent performance in predicting tacrolimus concentration in liver transplantation recipients and can be useful for concentration titration in these patients.

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Purpose: This study aimed to assess prognostic factors associated with combined hepatocellular-cholangiocarcinoma (cHCC-CCA) and to predict 5-year survival based on these factors. Materials and Methods: Patients who underwent definitive hepatectomy from 2006 to 2022 at a single institution was retrospectively analyzed. Inclusion criteria involved a pathologically confirmed diagnosis of cHCC-CCA. Results: A total of 80 patients with diagnosed cHCC-CCA were included in the analysis. The median progression-free survival (PFS) was 15.6 months, while distant metastasis-free survival (DMFS), hepatic progression-free survival (HPFS), and overall survival (OS) were 50.8, 21.5, and 85.1 months, respectively. In 52 cases of recurrence, intrahepatic recurrence was the most common initial recurrence (34/52), with distant metastasis in 17 cases. Factors associated with poor DMFS included tumor necrosis, lymphovascular invasion (LVI), perineural invasion and histologic compact type. Postoperative CA19-9, tumor necrosis, LVI, and close/positive margin were associated with poor overall survival. LVI emerged as a key factor affecting both DMFS and OS, with a 5-year OS of 93.3% for patients without LVI compared to 35.8% with LVI. Based on these factors, a nomogram predicting 3-year and 5-year DMFS and OS was developed, demonstrating high concordance with actual survival in the cohort (Harrell C-index 0.809 for OS, 0.801 for DMFS, respectively). Conclusion: The prognosis of cHCC-CCA is notably poor when combined with lymphovascular invasion. Given the significant impact of adverse features, accurate outcome prediction is crucial. Moreover, consideration of adjuvant therapy may be warranted for patients exhibiting poor survival and increased risk of local recurrence or distant metastasis.

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Backgrounds/Aims: Challenges arise when translating pure laparoscopic donor right hepatectomy (PLDRH) results from Asian to Western donors, due to differences in body mass index (BMI). This study compares the outcomes of PLDRH and conventional open donor right hepatectomy (CDRH) in donors with BMI over 30. Methods: Medical records of live liver donors (BMI > 30) undergoing right hepatectomy (2010-2021) were compared: 25 PLDRH cases vs. 19 CDRH cases. Donor and recipient demographics, operative details, and outcomes were analyzed. Results: PLDRH and CDRH had similar donor and recipient characteristics. PLDRH had longer liver removal and warm ischemic times, but a shorter post-liver removal duration than CDRH. Donor complication rates were comparable, with the highest complication being grade IIIa in PLDRH, necessitating needle aspiration for biloma on postoperative day 11. Fortunately, this donor fully recovered without additional treatment. No complications exceeding Clavien-Dindo grade IIIa occurred in either group. Recipient outcomes between the groups were similar. Conclusions: This study supports PLDRH as a viable option for donors with BMI over 30, challenging the notion that high BMI should deter considering PLDRH. The findings provide valuable insights into the safety and feasibility of PLDRH, encouraging further exploration of this technique in diverse donor populations.

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Following its initial execution in November 2015, pure laparoscopic donor hepatectomy (PLDH) has gained acceptance as a conventional practice at Seoul National University Hospital (SNUH). It is noteworthy that a significant proportion of cases entail full right hepatectomies, which are acknowledged to be technically demanding. As expertise and knowledge have been accrued, the pure laparoscopic technique has been extended to encompass liver recipients as a viable option in SNUH. The aim of this review is to present the developmental progression of PLDH, with a focus on pure laparoscopic donor right hepatectomy (PLDRH), at SNUH. This includes the standardization process, which can be achieved by sharing the hospital's accumulated experience and previous reports. Various types of graft, including full right, left, left lateral section, and monosegment, were procured by pure laparoscopic technique. The criteria for selection were expanded to include donors with variations in the anatomy of the portal vein and bile duct. Additionally, the procedure of PLDRH was determined to be safe and viable for donors with high body mass index and larger graft weight. In conclusion, this review demonstrates the alterations implemented throughout our evolution from restricted to inclusive criteria for donor selection, leading to a complete shift from open surgery to pure laparoscopic procedures in donor hepatectomy and eventually pure laparoscopic living donor liver transplantation (LDLT) in recipient.

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Calcineurin inhibitors (CNIs) are essential in liver transplantation (LT); however, their long-term use leads to various adverse effects. The anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody MD3 is a potential alternative to CNI. Despite its promising results with short-term therapy, overcoming the challenge of chronic rejection remains important. Thus, we aimed to investigate the outcomes of long-term MD3 therapy with monthly MD3 monomaintenance in nonhuman primate LT models. Rhesus macaques underwent major histocompatibility complex-mismatched allogeneic LT. The conventional immunosuppression group (Con-IS, n = 4) received steroid, tacrolimus, and sirolimus by 4 months posttransplantation. The induction MD3 group (IN-MD3, n = 5) received short-term MD3 therapy for 3 months with Con-IS. The maintenance MD3 group (MA-MD3, n = 4) received MD3 for 3 months, monthly doses by 2 years, and then quarterly. The MA-MD3 group exhibited stable liver function without overt infection and had significantly better liver allograft survival than the IN-MD3 group. Development of donor-specific antibody and chronic rejection were suppressed in the MA-MD3 group but not in the IN-MD3 group. Donor-specific T cell responses were attenuated in the MA-MD3 group. In conclusion, MD3 monomaintenance therapy without maintenance CNI provides long-term liver allograft survival by suppressing chronic rejection, offering a potential breakthrough for future human trials.

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BACKGROUND: Immunological factors play a pivotal role in the outcomes of solid organ transplantation. We aimed to elucidate the effects of donor-specific antibodies (DSAs) and ABO compatibility on living donor liver transplantation (LDLT) outcomes. METHODS: A retrospective analysis was conducted on 584 LDLT recipients from 2015 to 2020. The recipients were stratified into 3 groups: ABO-compatible recipients without DSAs (group 1), ABO-compatible recipients with DSAs (group 2), and ABO-incompatible recipients without DSAs (group 3). Propensity score matching was used for balanced comparisons. RESULTS: In the matched comparisons, group 2 exhibited a higher incidence of T cell-mediated rejection compared with group 1 (22.7% versus 4.5%, P  = 0.030). Despite this, the 5-y survival rates were similar between groups 1 and 2 (81.6% versus 95.5%, P  = 0.085). Group 3, in comparison with group 1, showed elevated rates of cytomegalovirus infection (23.2% versus 7.3%, P  = 0.008), T cell-mediated rejection (28.0% versus 7.3%, P  = 0.001), and antibody-mediated rejection (13.4% versus 0%, P  = 0.001). However, the survival rates were comparable between group 3 and group 1 (82.0% versus 86.5%, P  = 0.220, respectively). Comparisons between group 2 and group 3 did not reveal significant differences in postoperative outcomes or survival rates ( P  > 0.05). CONCLUSIONS: DSA positivity and ABO incompatibility contribute to distinct posttransplant complications in LDLT. The integrated consideration of both factors in pretransplant assessment may enhance risk stratification and inform tailored interventions. Further research is required to corroborate these findings and provide mechanistic insights.

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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 open-donor 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.

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Purpose: Incisional hernia (IH) is a common complication after liver transplantation (LT) with an incidence rate of 5% to 46%. This retrospective study aimed to evaluate the risk factors for IH development after LT in the era of mammalian target of rapamycin (mTOR) inhibitors use. Methods: Data on patients who underwent LT between 2015 and 2021 were retrospectively reviewed. The patients were divided into 2 groups (IH group and non-IH group) according to the postoperative occurrence of IH. Results: We analyzed data from 878 patients during the study period, with 28 patients (3.2%) developing IH. According to multivariate analysis, body mass index exceeding 25 kg/m2 and the use of mTOR inhibitors within the first month after LT were the sole significant factors for both IH occurrence and the subsequent need for repair operations. Notably, a history of wound complications, a Model for End-stage Liver Disease score, and the timing of LT-whether conducted during regular hours or at night-did not emerge as significant risk factors for IH after LT. Conclusion: Our study reveals a higher incidence of IH among obese patients following LT, often requiring surgical repair, particularly in cases involving mTOR inhibitor usage within the initial month after LT. Consequently, it is crucial to exercise increased vigilance, especially in obese patients, and exercise caution when considering early mTOR inhibitor administration after LT.

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Liver transplantation is a highly complex and challenging field of clinical practice. Although it was originally developed in western countries, it has been further advanced in Asian countries through the use of living donor liver transplantation. This method of transplantation is the only available option in many countries in the Asia-Pacific region due to the lack of deceased organ donation. As a result of this clinical situation, there is a growing need for guidelines that are specific to the Asia-Pacific region. These guidelines provide comprehensive recommendations for evidence-based management throughout the entire process of liver transplantation, covering both deceased and living donor liver transplantation. In addition, the development of these guidelines has been a collaborative effort between medical professionals from various countries in the region. This has allowed for the inclusion of diverse perspectives and experiences, leading to a more comprehensive and effective set of guidelines.

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BACKGROUND: Gut microbial dysbiosis is implicated in chronic liver disease and hepatocellular carcinoma (HCC), but the role of microbiomes from various body sites remains unexplored. We assessed disease-specific alterations in the urinary microbiome in HCC patients, investigating their potential as diagnostic biomarkers. METHODS: We performed cross-sectional analyses of urine samples from 471 HCC patients and 397 healthy controls and validated the results in an independent cohort of 164 HCC patients and 164 healthy controls. Urinary microbiomes were analyzed by 16S rRNA gene sequencing. A microbial marker-based model distinguishing HCC from controls was built based on logistic regression, and its performance was tested. RESULTS: Microbial diversity was significantly reduced in the HCC patients compared with the controls. There were significant differences in the abundances of various bacteria correlated with HCC, thus defining a urinary microbiome-derived signature of HCC. We developed nine HCC-associated genera-based models with robust diagnostic accuracy (area under the curve [AUC], 0.89; balanced accuracy, 81.2%). In the validation, this model detected HCC with an AUC of 0.94 and an accuracy of 88.4%. CONCLUSIONS: The urinary microbiome might be a potential biomarker for the detection of HCC. Further clinical testing and validation of these results are needed in prospective studies.

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INTRODUCTION: There is insufficient evidence regarding the optimal regimen for ascites replacement after living donor liver transplantation (LT) and its effectiveness. The aim of this study is to evaluate the impact of replacing postoperative ascites after LT with albumin on time to first flatus during recovery with early ambulation and incidence of acute kidney injury (AKI). METHODS: Adult patients who underwent elective living donor LT at Seoul National University Hospital from 2019 to 2021 were randomly assigned to either the albumin group or lactated Ringer's group, based on the ascites replacement regimen. Replacement of postoperative ascites was performed for all patients every 4 h after LT until the patient was transferred to the general ward. Seventy percent of ascites drained during the previous 4 h was replaced over the next 4 h with continuous infusion of fluids with a prescribed regimen according to the assigned group. In the albumin group, 30% of a total of 70% of drained ascites was replaced with 5% albumin solution, and remnant 40% was replaced with lactated Ringer's solution. In the lactated Ringer's group, 70% of drained ascites was replaced with only lactated Ringer's solution. The primary outcome was the time to first flatus from the end of the LT and the secondary outcome was the incidence of AKI for up to postoperative day 7. RESULTS: Among the 157 patients who were screened for eligibility, 72 patients were enrolled. The mean age was 63 ± 8.2 years, and 73.0 % (46/63) were male. Time to first flatus was similar between the two groups (66.7 ± 24.1 h vs. 68.5 ± 25.6 h, p = .778). The albumin group showed a higher glomerular filtration rate and lower incidence of AKI until postoperative day 7, compared to the lactated Ringer's group. CONCLUSIONS: Using lactated Ringer's solution alone for replacement of ascites after living donor LT did not reduce the time to first flatus and was associated with an increased risk of AKI. Further research on the optimal ascites replacement regimen and the target serum albumin level which should be corrected after LT is required.

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Pure laparoscopic donor hepatectomy (PLDH) has become a routine procedure at Seoul National University Hospital, and the pure laparoscopic method is now being applied to liver recipients as well. This study aimed to review the procedure and outcomes of PLDH to identify any areas that required improvement. Data from 556 donors who underwent PLDH between November 2015 and December 2021 and their recipients were retrospectively reviewed. Among these, 541 patients underwent pure laparoscopic donor right hepatectomy (PLDRH). The mean hospital stay of the donor was 7.2 days, and the rate of grade I, II, IIIa, and IIIb complications was 2.2%, 2.7%, 1.3%, and 0.9%, respectively, without any irreversible disabilities or mortalities. The most common early and late major complications in the recipient were intraabdominal bleeding (n = 47, 8.5%) and biliary problems (n = 198, 35.6%), respectively. Analysis of the PLDRH procedure showed that operative time, liver removal time, warm ischemic time, Δhemoglobin%, Δtotal bilirubin%, and postoperative hospital stay decreased significantly as the number of cases accumulated. In conclusion, the operative outcomes of PLDRH improved as the number of cases increased. However, continuous caution is needed because major complications still occur in donors and recipients even after hundreds of cases.

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Purpose: The tablet form of tacrolimus is more convenient for drug ingestion than the capsule form. We examined the efficacy and safety of tacrolimus tablets and a satisfaction survey after formula conversion in liver transplant (LT) recipients. Methods: This study was an open-label, prospective clinical trial for tacrolimus formula 1:1 conversion from capsule to tablet in 41 adult LT recipients with tacrolimus maintenance therapy of more than 1 month. The primary endpoint was incidence of biopsy-proven acute rejection (BPAR) within 24 weeks. Surveys 1 week before and 4 weeks after formula conversion were conducted for total daily dose of medication, number, scale of discomfort and satisfaction. Results: The overall incidence of BPAR was 0% and there was no graft loss or patient death. The incidence of adverse effects was 34.1% (n = 14) after formula conversion. The most common severe adverse effect was abnormal liver function test (n = 5): biliary complications (n = 4) and alcoholic recidivism (n = 1). Total daily dose and number of tacrolimus doses were significantly lower after formula conversion (P < 0.05) without changes in trough level. According to survey analysis, there was no significant difference in discomfort and satisfaction scales from capsule to tablet conversion (P < 0.05). Conclusion: The present study suggests that the new tablet formula can be a useful treatment option to maintain a consistent level of tacrolimus with a lower total daily dose and number in adult LT recipients.

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Acute kidney injury is considered an independent prognostic factor for mortality in patients with liver cirrhosis. Non-treated acute kidney injury can progress to hepatorenal syndrome with a poor prognosis. As suppression of tumorigenicity 2 (ST2) is a member of the interleukin-1 receptor family that aggravates inflammation and fibrotic changes in multiple organs, we measured soluble ST2 (sST2) level in the serum and urine of liver-transplant recipients at the time of transplantation. The serum sST2 level significantly increased in liver-transplant recipients with suppressed kidney function compared with that in recipients with normal function. In recipients with severely decreased liver function (model for end-stage liver disease score ≥ 30), the serum sST2 level was higher than that in recipients with preserved liver function (model for end-stage liver disease score ≤ 20, P = 0.028). The serum sST2 level in recipients with hepatorenal syndrome was higher than that in liver-transplant recipients without hepatorenal syndrome (P = 0.003). The serum sST2 level in patients with hepatorenal syndrome was higher than that in recipients without a history of acute kidney injury (P = 0.004). Recipients with hepatorenal syndrome and recovered kidney function showed higher sST2 levels than those who did not recover (P = 0.034). Collectively, an increase in the serum sST2 level reflects a decrease in both kidney and liver functions. Thus, measuring sST2 level at the time of liver transplantation can help predict renal outcomes.

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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.

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BACKGROUND AND AIMS: Although the main action of human hepatitis B immunoglobulin (HBIG) is to neutralize hepatitis B virus surface antigen (HBsAg) in serum, HBIG is known to be localized in the cell. However, the effect of intracellularly located HBIG is poorly understood because of the low purity of conventional plasma-derived HBIG (cHBIG). We attempted to elucidate the mechanism of action of internalized HBIG using recombinant HBIG (lenvervimab). METHODS: We used HBsAg producing cell lines, non-HBsAg cell lines and human HBsAg-producing hepatocytes. The autophagosome lysis pathway-related proteins Rab5, calnexin, giantin, and Rab7 were used to localize HBsAg and anti-HBs-IgG in the cytoplasm using Western blotting and confocal microscopy. RESULTS: Intracellular anti-HBs-IgG (lenvervimab and cHBIG) transported via Fc receptor-mediated endocytosis increased the number of autophagosomes. However, there was no change in autolysis. HBsAg and anti-HBs-IgG co-localized in the multivesicular body and precipitated in the cytoplasm. HBsAg secretion into culture medium decreased after lenvervimab treatment. Simultaneously, the amount of cellular HBsAg increased in the cell lines but decreased in human hepatocytes. Furthermore, intracellular lenvervimab is not easily removed from HBsAg cell lines. CONCLUSIONS: Lenvervimab decreases HBsAg secretion, and HBsAg antibody precipitation in the multivesicular body may play an important role.

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Backgrounds/Aims: While single-incision laparoscopic cholecystectomy (SILC) has advantages in cosmesis and postoperative pain, its utilization has been limited. This study raises the possibility of expanding its indication to acute cholecystitis with the novel method of solo surgery under retrospective analysis. Methods: We compared the outcomes of SILC (n = 58) to those of three-incision laparoscopic cholecystectomy (TILC; n = 117) for acute cholecystitis, being performed from March 2014 to December 2015. Results: Intraoperative results, including the operation time, did not differ significantly, except for drain catheter insertion (p = 0.004). Each group had 1 case of open conversion due to common bile duct injury. There was no significant difference in the length of hospital stay. Either group by itself was not a risk factor for complications, but in preoperative drainage for intraoperative perforation, 3 factors of intraoperative perforation, biliary complication, and history of upper abdominal operation for additional port, only American Society of Anesthesiology (ASA) scores for postoperative complication of Clavien-Dindo grades III and IV were significant risk factors. Conclusions: Our study findings showed comparative outcomes between both groups, providing evidence for the safety and feasibility of SILC for acute cholecystitis.