Small graft size and hepatocellular carcinoma outcomes in living donor liver transplantation: a retrospective multicentric cohort study.

INTRODUCTION: This study examined associations between the graft-to-recipient weight ratio (GRWR) for adult-to-adult living donor liver transplantation (LDLT) and HCC outcomes. MATERIALS AND METHODS: Data from patients in the Korean Organ Transplantation Registry who underwent LDLT for HCC from 2014-2021 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 HR [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.

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

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

Liver transplantation for combined hepatocellular carcinoma and cholangiocarcinoma: A multicenter study.

BACKGROUND: Patients with combined hepatocellular carcinoma and cholangiocarcinoma (cHCC-CC) are not traditionally considered eligible for liver transplantation (LT) due to poor outcomes. AIM: To compare outcomes between living donor LT (LDLT) patients with hepatocellular carcinoma (HCC) and LT patients with cHCC-CC and to identify risk factors for tumor recurrence and death after LT in cHCC-CC patients. METHODS: Data for pathologically diagnosed cHCC-CC patients (n = 111) who underwent LT from 2000 to 2018 were collected for a nine-center retrospective review. Patients (n = 141) who received LDLT for HCC at Samsung Medical Center from January 2013 to March 2017 were selected as the control group. Seventy patients in two groups, respectively, were selected by 1:1 matching. RESULTS: Cumulative disease-free survival (DFS) and overall survival (OS) in the cHCC-CC group were significantly worse than in the HCC group both before and after matching. Extrahepatic recurrence incidence in the cHCC-CC group was higher than that in the HCC group (75.5% vs 33.3%, P < 0.001). Multivariate analysis demonstrated that the cHCC-CC group had significantly higher rates of tumor recurrence and death compared to the HCC group. In cHCC-CC subgroup analysis, frequency of locoregional therapies > 3, tumor size > 3 cm, and lymph node metastasis were predisposing factors for tumor recurrence in multivariate analysis. Only a maximum tumor size > 3 cm was a predisposing factor for death. CONCLUSION: The poor prognosis of patients diagnosed with cHCC-CC after LT can be predicted based on the explanted liver. Frequent regular surveillance for cHCC-CC patients should be required for early detection of tumor recurrence.

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

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

Errate: Modification of Venous Outflow to Avoid Thrombotic Graft Failure in Pancreas Transplantation.

The authors asked for an errata to correct the affiliation information. The corrected affiliations are as follows:Je Ho Ryu1,2, Jae Ryong Shim1, Tae Beom Lee1, Kwang Ho Yang1, Taeun Kim3, Seo Rin Kim4, Byung Hyun Choi1,21 Division of Hepato-Biliary-Pancreatic Surgery and Transplantation, Department of Surgery, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, South Korea2 Research Institute for Convergence of Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan, South Korea3 Department of Radiology, Pusan National University Yangsan Hospital, Pusan National University School of Medicine, Yangsan, South Korea4 Department of Internal medicine, Pusan National University Yangsan Hospital, Pusan National University School of Medicine,  Yangsan, South KoreaThe change of affiliation does not affect the content or findings of the publication in any way. It is solely an update to the -authors' institutional affiliations.Reference:Je Ho Ryu, Jae Ryong Shim, Tae Beom Lee, Kwangho Yang, Taeun Kim, Seo Rin Kim, Byunghyun Choi. Modification of Venous Outflow to Avoid Thrombotic Graft Failure in Pancreas Transplantation. Ann Transplant. 2022; 27: e937514. DOI: 10.12659/AOT.937514.

Quantitative Prediction of Posttransplant Hepatocellular Carcinoma Prognosis Using ADV Score: Validation with Korea-Nationwide Transplantation Registry Database.

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.

Histological subtypes of hepatocellular carcinoma: Their clinical and prognostic significance.

Assigning a hepatocellular carcinoma (HCC) to an appropriate subtype is important because this guarantees the diagnosis and treatment and allows decisions regarding the prognosis of the patient. HCC subtyping is usually based on the World Health Organization (WHO) classification and the 2019 fifth edition is the latest version. However, the WHO classification system is still in evolution and has limited clinical relevance. We aimed to evaluate the clinical relevance of HCC subtyping and to reappraise some of the major subtypes of HCC. Our archived cases (n = 589) were reclassified according to the 2019 WHO system. The percentage of each subtype was mostly similar to that in the WHO classification. However, on the contrary to the 2019 WHO system, clear cell type HCC was associated with more frequent recurrence or metastasis. Meanwhile, macrotrabecular massive HCC was related to poor prognosis as demonstrated in the 2019 WHO system and should be described in the pathology report. For steatohepatitic HCC, there is a debate on whether it is a true subtype because the steatohepatitis morphology may or may not be present in the background liver. In our study, 44 % of steatohepatitic HCCs (n = 19/43) presented underlying steatohepatitis. Additionally, the background cirrhosis did not influence survival in the HCC patients, although the 2019 WHO system indicates the presence of cirrhosis as a poor prognostic factor. In conclusion, although it is not perfect yet, HCC subtyping based on the 2019 WHO system provides valuable information to manage patients with HCC.

Surgical Outcomes of Laparoscopic versus Open Hepatectomy for Left Hepatocellular Carcinoma: Propensity Score Analyses Using Retrospective Japanese and Korean Individual Patient Data.

Introduction: This study aimed to compare the prognostic impact of laparoscopic left hepatectomy (LLH) with that of open left hepatectomy (OLH) on patient survival after resection of left hepatocellular carcinoma (HCC). Methods: Among the 953 patients who received initial treatment for primary HCC that was resectable by either LLH or OLH from 2013 to 2017 in Japan and Korea, 146 patients underwent LLH and 807 underwent OLH. The inverse probability of treatment weighting approach based on propensity scoring was used to address the potential selection bias inherent in the recurrence and survival outcomes between the LLH and OLH groups. Results: The occurrence rate of postoperative complications and hepatic decompensation was significantly lower in the LLH group than in the OLH group. Recurrence-free survival (RFS) was better in the LLH group than in the OLH group (hazard ratio, 1.33; 95% confidence interval, 1.03-1.71; p = 0.029), whereas overall survival (OS) was not significantly different. Subgroup analyses of RFS and OS revealed an almost consistent trend in favor of LLH over OLH. In patients with tumor sizes of ≥4.0 cm or those with single tumors, both RFS and OS were significantly better in the LLH group than in the OLH group. Conclusions: LLH decreases the risk of tumor recurrence and improves OS in patients with primary HCC located in the left liver.

Physical Performance Decline During the Early Posttransplantation Period Affects Survival After Living Donor Liver Transplantation.

BACKGROUND: Patient physical performance has been emphasized in liver transplant recipients; however, evidence for living donor liver transplantation (LDLT) patients is lacking. This study investigated the impact of physical performance decline during the early posttransplantation period on survival and risk factors for this decline in LDLT recipients. METHODS: From national registry data, 2703 LDLT patients were divided into 2 groups based on the change in their Karnofsky performance status (KPS) between 1 and 6 mo posttransplantation: declined KPS (n = 188) and control (n = 2515). Multivariable analyses were conducted to control for confounders, including posttransplantation complications. RESULTS: Estimated 5-y patient survival rates were 91.6% in the declined KPS group and 96.3% in the control group, favoring the latter ( P = 0.003). The survival hazard of KPS decline was significant in a baseline covariates-adjusted Cox model (hazard ratio [HR], 2.60; 95% confidence interval [CI], 1.37-4.95) and an adjusted model accounting for posttransplantation complications (HR, 3.38; 95% CI, 1.70-6.72). In subgroup analyses, KPS decline independently reduced survival in patients without complications (HR, 3.95; 95% CI, 1.67-9.34), and the trend was similar in patients with complications, although significance was marginal (HR, 3.02; 95% CI, 0.98-9.27). We found that only posttransplantation complications, such as rejection, infection, bile duct complication, and vascular complication, were significant risk factors for KPS decline after LDLT. CONCLUSIONS: Physical performance decline during the early posttransplantation period independently reduced survival rates, and posttransplantation complications were the only significant risk factors for physical performance decline in LDLT recipients.

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

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

A Multicenter, Randomized, Open-Label Study to Compare the Efficacy and Safety of Tacrolimus and Corticosteroids in Combination With or Without Mycophenolate Mofetil in Liver Transplantation Recipients Infected With Hepatitis B Virus.

BACKGROUND: Mycophenolate mofetil exhibits pharmacologic mechanisms different from calcineurin inhibitors. Therefore, the dose of calcineurin inhibitors can be reduced along with side effects for effective immunosuppression. We aimed to evaluate the efficacy and safety of tacrolimus and corticosteroid in combination with or without mycophenolate mofetil in living donor liver transplantation (LDLT) recipients infected with hepatitis B virus (HBV). METHODS: A randomized, open-label, comparative, multicenter, phase IV study was conducted with 119 patients from January 2014 to September 2017. In the full analysis set population, 58 and 59 patients were included in the study group (triple-drug regimen: TacroBell + My-rept + corticosteroid) and the control group (dual-drug regimen: TacroBell + corticosteroid), respectively. In the per protocol set population, 49 and 42 patients were included in the study and control groups, respectively. RESULTS: In the full analysis set population, the incidence of biopsy-proven acute cellular rejection (rejection activity index score ≥4) was 3.4% in the study group; however, this finding was not observed in the control group (P = .468). Hepatitis B virus recurrence was observed in one patient in the control group. No cases of biopsy-proven acute cellular rejection and HBV recurrence were observed in the per protocol set population. The incidences of serious adverse events were 25.9% and 18.0% in the study and control groups, respectively; however, the difference between the groups was not statistically significant (P = .376). CONCLUSION: Although the study involved a small number of patients, the triple-drug regimen can be considered safe and effective for immunosuppression after living donor liver transplantation in patients infected with HBV.

Orally bioavailable BTK PROTAC active against wild-type and C481 mutant BTKs in human lymphoma CDX mouse models.

Bruton tyrosine kinase (BTK) is an important signaling hub that activates the B-cell receptor (BCR) signaling cascade. BCR activation can contribute to the growth and survival of B-cell lymphoma or leukemia. The inhibition of the BCR signaling pathway is critical for blocking downstream events and treating B-cell lymphomas. Herein, we report potent and orally available proteolysis-targeting chimeras (PROTACs) that target BTK to inactivate BCR signaling. Of the PROTACs tested, UBX-382 showed superior degradation activity for wild-type (WT) and mutant BTK proteins in a single-digit nanomolar range of half-maximal degradation concentration in diffuse large B-cell lymphoma cell line. UBX-382 was effective on 7 out of 8 known BTK mutants in in vitro experiments and was highly effective in inhibiting tumor growth in murine xenograft models harboring WT or C481S mutant BTK-expressing TMD-8 cells over ibrutinib, ARQ-531, and MT-802. Remarkably, oral dosing of UBX-382 for <2 weeks led to complete tumor regression in 3 and 10 mg/kg groups in murine xenograft models. UBX-382 also provoked the cell type-dependent and selective degradation of cereblon neosubstrates in various hematological cancer cells. These results suggest that UBX-382 treatment is a promising therapeutic strategy for B-cell-related blood cancers with improved efficacy and diverse applicability.

Modification of Venous Outflow to Avoid Thrombotic Graft Failure in Pancreas Transplantation.

BACKGROUND Even with recent data, 5-10% of pancreas transplants experience early technical failure. Graft thrombosis is the primary cause of early technical failure, even when only optimal grafts are used, as is the case in Korea. The purpose of this study was to determine whether we can avoid thrombotic graft failure by modifying venous outflow. MATERIAL AND METHODS Between March 2017 and December 2021, a total of 59 pancreas transplantations were performed. Until May 2019, 31 cases of fence-angioplasty with cadaveric vena cava were performed to graft portal veins (the vena cava group). Since then, a total of 28 aortic interposition grafts have been performed to graft portal veins (the aortic group). RESULTS Between the 2 groups, there was no significant difference in baseline characteristics. Each group had 1 instance of technical failure. Early graft failure rates were 3.2% and 3.4%, respectively (P=1.000), while 1-year graft survival rates were 96.8% and 94.4%, respectively (P=0.991). Although a graft-threatening thrombosis occurred in the vena cava group, neither group experienced thrombotic graft failure, despite the decreased (vena cava group) or absence of heparin use (aorta group). CONCLUSIONS When the optimal graft is used, both techniques of modifying venous outflow can significantly reduce thrombotic graft failure.

Percutaneous N-Butyl-Cyanoacrylate Embolization for Treating Ruptured Pancreaticoduodenal Aneurysm: A Case Report.

Background and Objectives: Pancreaticoduodenal artery aneurysms are rare visceral artery aneurysms. Interventional treatments, including transcatheter embolization, have an acceptable success rate. We report a case of ruptured pancreaticoduodenal aneurysm that was successfully treated with percutaneous N-Butyl-cyanoacrylate (NBCA) embolization after failed transcatheter embolization. Materials and Methods: A 53-year-old man presented to the emergency department with abdominal pain. Computed tomography (CT) revealed a ruptured aneurysm in the inferior pancreaticoduodenal artery (IPDA) with retrohemoperitoneum. The patient underwent percutaneous NBCA embolization after transcatheter embolization failure. Results: On CT, the pancreaticoduodenal aneurysm was completely embolized. No additional bleeding events occurred. Conclusions: Percutaneous NBCA embolization is safe and effective for treating patients with ruptured pancreaticoduodenal aneurysms after failed transcatheter embolization.

Diagnostic Role of Tumor Markers for Hepatocellular Carcinoma in Liver Transplantation Candidates: An Analysis Using the Korean Organ Transplantation Registry Database.

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.

Artificial intelligence for predicting survival following deceased donor liver transplantation: Retrospective multi-center study.

BACKGROUND: Previous studies have indicated that the model for end-stage liver disease (MELD) score may fail to predict post-transplantation patient survival. Similarly, other scores (donor MELD score, balance of risk score) that have been developed to predict transplant outcomes have not gained widespread use. These scores are typically derived using linear statistical models. This study aimed to compare the performance of traditional statistical models with machine learning approaches for predicting survival following liver transplantation. MATERIALS AND METHODS: Data were obtained from 785 deceased donor liver transplant recipients enrolled in the Korean Organ Transplant Registry (2014-2019). Five machine learning methods (random forest, artificial neural networks, decision tree, naïve Bayes, and support vector machine) and four traditional statistical models (Cox regression, MELD score, donor MELD score and balance of risk score) were compared to predict survival. RESULTS: Among the machine learning methods, the random forest yielded the highest area under the receiver operating characteristic curve (AUC-ROC) values (1-month = 0.80; 3-month = 0.85; and 12-month = 0.81) for predicting survival. The AUC-ROC values of the Cox regression analysis were 0.75, 0.86, and 0.77 for 1-month, 3-month, and 12-month post-transplant survival, respectively. However, the AUC-ROC values of the MELD, donor MELD, and balance of risk scores were all below 0.70. Based on the variable importance of the random forest analysis in this study, the major predictors associated with survival were cold ischemia time, donor ICU stay, recipient weight, recipient BMI, recipient age, recipient INR, and recipient albumin level. As with the Cox regression analysis, donor ICU stay, donor bilirubin level, BAR score, and recipient albumin levels were also important factors associated with post-transplant survival in the RF model. The coefficients of these variables were also statistically significant in the Cox model (p < 0.05). The SHAP ranges for selected predictors for the 12-month survival were (-0.02,0.10) for recipient albumin, (-0.05,0.07) for donor bilirubin and (-0.02,0.25) for recipient height. Surprisingly, although not statistically significant in the Cox model, recipient weight, recipient BMI, recipient age, or recipient INR were important factors in our random forest model for predicting post-transplantation survival. CONCLUSION: Machine learning algorithms such as the random forest were superior to conventional Cox regression and previously reported survival scores for predicting 1-month, 3-month, and 12-month survival following liver transplantation. Therefore, artificial intelligence may have significant potential in aiding clinical decision-making during liver transplantation, including matching donors and recipients.

Non-Renal Risk Factors for Chronic Kidney Disease in Liver Recipients with Functionally Intact Kidneys at 1 Month.

Chronic kidney disease (CKD) is a critical complication of liver transplants, of which non-renal risk factors are not fully understood yet. This study aimed to reveal pre- and post-transplant risk factors for CKD (<60 mL/min/1.73 m2), examining liver recipients with functionally intact kidneys one month after grafting using nationwide cohort data. Baseline risk factors were analyzed with multivariable Cox regression analyses and post-transplant risk factors were investigated with the time-dependent Cox model and matched analyses of time-conditional propensity scores. Of the 2274 recipients with a one-month eGFR ≥ 60 mL/min/1.73 m2, 494 (22.3%) developed CKD during a mean follow-up of 36.6 ± 14.4 months. Age, female sex, lower body mass index, pre-transplant diabetes mellitus, and lower performance status emerged as baseline risk factors for CKD. Time-dependent Cox analyses revealed that recurrent hepatocellular carcinoma (HR = 1.93, 95% CI 1.06−3.53) and infection (HR = 1.44, 95% CI 1.12−1.60) were significant post-transplant risk factors for CKD. Patients who experienced one of those factors showed a significantly higher risk of subsequent CKD compared with the matched controls who lacked these features (p = 0.013 for recurrent hepatocellular carcinoma, and p = 0.003 for infection, respectively). This study clarifies pre- and post-transplant non-renal risk factors, which lead to renal impairment after LT independently from patients' renal functional reserve.

Safety of Tacrolimus Monotherapy within 12 Months after Liver Transplantation in the Era of Reduced Tacrolimus and Mycophenolate Mofetil: National Registry Study.

Tacrolimus monotherapy is accepted as a feasible option during early post-liver transplantation as per current international consensus guidelines. However, its effects in the recent era of reduced tacrolimus (TAC) and mycophenolate mofetil (MMF) remain unclear. Liver recipients who either received TAC monotherapy from the treatment onset or switched from TAC/MMF to TAC-mono within 12 months (TAC-mono group; n = 991) were chronologically matched to patients who continued to receive TAC/MMF (TAC/MMF group; n = 991) at the corresponding time points on time-conditional propensity scores. Outcomes within 12 months after matched time points were compared. Biopsy-proven rejection (TAC/MMF: 3.5% vs. TAC-mono: 2.6%; p = 0.381) and graft failure (0.2% vs. 0.7%; p = 0.082) were similar in both groups. However, the decline in eGFR was 3.1 mL/min/1.73 m2 (95% CI: 0.8-5.3) greater at six months (p = 0.008) and 2.4 mL/min/1.73 m2 (95% CI: -0.05-4.9) greater at 12 months (p = 0.048) after the matched time points in TAC-mono group than that in TAC/MMF group. TAC trough levels were also higher in the TAC-mono group throughout the study period. TAC-mono within 12 months after liver transplantation is immunologically safe. However, it can increase the required TAC dose and the decline in renal function than that in TAC/MMF combination therapy.

Renal safety of tenofovir disoproxil fumarate and entecavir in liver transplant patients: a nationwide Korean registry study.

BACKGROUND AND AIMS: Tenofovir disoproxil fumarate (TDF) and entecavir (ETV) have been recommended after liver transplantation to prevent recurrence of hepatitis B virus infection. Despite its proven efficacy, the renal safety of TDF has not been established in liver transplant recipients. We aimed to compare the effects of TDF and ETV on renal function in liver transplant recipients and to evaluate risk factors for renal dysfunction after liver transplantation. METHODS: This is a retrospective, observational multicenter study of data from the Korean Organ Transplantation Registry. We included adults who underwent liver transplantation for hepatitis B virus-related complications from April 2014 to December 2017 and received TDF or ETV post-transplantation. Renal dysfunction was defined as an estimated glomerular filtration rate decline by at least 20% from baseline (1 month post-transplantation). Median duration of follow-up was 29 months (interquartile range 19-42). RESULTS: A total of 804 liver transplant patients were included. The cumulative probability of renal dysfunction was significantly higher in the TDF group than in the ETV group. Multivariable analysis confirmed that TDF was independently associated with an increased risk of renal dysfunction (hazard ratio = 1.47, 95% confidence interval 1.12-1.92; p = 0.005). Independent risk factors for renal dysfunction included older age, worse baseline renal function, and low body mass index. Overall survival rate was significantly lower in patients with renal dysfunction than in those without. CONCLUSIONS: In this nationwide study, the use of TDF was associated with an increased risk of renal dysfunction, when compared with ETV.

A multicenter, prospective, randomized clinical trial of marine mussel-inspired adhesive hemostatic materials, InnoSEAL Plus.

PURPOSE: InnoSEAL Plus is an adhesive, coagulant-free hemostatic material that mimics the adhesion mechanism of marine mussels. This study reports on the safety and efficacy of InnoSEAL Plus for patients with hemorrhage after hepatectomy despite first-line hemostasis treatments. METHODS: This is a multicenter, prospective, single-blinded, randomized clinical trial involving 96 hepatectomy patients. TachoSil was used as a comparator group. Three-minute and 10-minute hemostatic success rates were monitored. Rebleeding rates were also observed. Safety was assessed by recording all novel undesirable symptoms. RESULTS: InnoSEAL Plus showed a 3-minute hemostasis rate of 100%, while TachoSil had a rate of 98.0% (48 of 49 patients), demonstrating that the 2 had similar hemostatic efficacies. The difference in efficacy between the test and comparator group was 2.04%, and the lower limit of the one-sided 97.5% confidence interval was -1.92%; as this is greater than the noninferiority limit of -23.9%, the 2 treatments were equivalent. Meanwhile, the 10-minute hemostatic success rate was the same in both groups (100%). No rebleeding occurred in either group. In the safety evaluation, 89 patients experienced adverse events (45 in the test group and 44 in the comparator group). The difference between the 2 groups was not significant. No death occurred after application of the test or comparator group product. CONCLUSION: Given that InnoSEAL Plus is a coagulation factor-free product, the hemostasis results are encouraging, especially considering that TachoSil contains a coagulation factor. InnoSEAL Plus was found to be a safe and effective hemostatic material for control of bleeding in hepatectomy patients.