Impact of a Liver Immune Status Index among Living Liver Transplant Recipients with Hepatocellular Carcinoma.

Introduction: Hepatocellular carcinoma (HCC) is a major global health challenge, being the fifth most prevalent neoplasm and the third leading cause of cancer-related deaths worldwide. Liver transplantation offers a potentially curative approach for HCC, yet the risk of recurrence posttransplantation remains a significant concern. This study investigates the influence of a liver immune status index (LISI) on the prognosis of patients undergoing living-donor liver transplantation for HCC. Methods: In a single-center study spanning from 2001 to 2020, 113 patients undergoing living-donor liver transplantation for HCC were analyzed. LISI was calculated for each donor liver using body mass index, serum albumin levels, and the fibrosis-4 index. This study assessed the impact of donor LISI on short-term recurrence rates and survival, with special attention to its correlation with the antitumor activity of natural killer (NK) cells in the liver. Results: The patients were divided into two grades (high donor LISI, >-1.23 [n = 43]; and low donor LISI, ≤-1.23 [n = 70]). After propensity matching to adjust the background of recipient factors, the survival rates at 1 and 3 years were 92.6% and 88.9% and 81.5% and 70.4% in the low and high donor LISI groups, respectively (p = 0.11). The 1- and 3-year recurrence-free survival were 88.9% and 85.2% and 74.1% and 55.1% in the low and high donor LISI groups, respectively (p = 0.02). Conclusions: This study underscores the potential of an LISI as a noninvasive biomarker for assessing liver NK cell antitumor capacity, with implications for living-donor liver transplantation for HCC. Donor LISI emerges as a significant predictor of early recurrence risk following living-donor liver transplantation for HCC, highlighting the role of the liver antitumor activity of liver NK cells in managing liver malignancies.

An updated analysis of retransplantation following living donor liver transplantation in the US: insights from the latest UNOS database.

BACKGROUND: There is no recent update on the clinical course of retransplantation(re-LT) after living-donor liver transplantation (LDLT) in the US using recent national data. METHOD: The UNOS database (2002-2023) was used to explore patient characteristics in initial LT, comparing deceased-donor liver transplantation (DDLT) and LDLT for graft survival (GS), reasons for graft failure, and GS after re-LT. It assesses waitlist dropout and re-LT likelihood, categorizing re-LT cohort based on time to re-listing as acute or chronic (≤ or >1 mo). RESULTS: Of 132,323 DDLT and 5,955 LDLT initial transplants, 3,848 DDLT and 302 LDLT recipients underwent re-LT. Of the 302 re-LT following LDLT, 156 were acute and 146 chronic. Primary non-function (PNF) was more common in DDLT, although the difference was not statistically significant (17.4%vs14.8% for LDLT; p=0.52). Vascular complications were significantly higher in LDLT (12.5%vs8.3% for DDLT; p<0.01). Acute re-LT showed a larger difference in PNF between DDLT and LDLT (49.7%vs32.0%; p<0.01). Status 1 patients were more common in DDLT (51.3%vs34.0% in LDLT; p<0.01). In the acute cohort, Kaplan-Meier curves indicated superior GS post-re-LT for initial LDLT recipients in both short-term and long-term (p=0.02 and <0.01, respectively), with no significant difference in the chronic cohort. No significant differences in waitlist dropout were observed, but the initial LDLT group had a higher re-LT likelihood in the acute cohort (sHR 1.40, p<0.01). A sensitivity analysis focusing on the most recent 10-year cohort revealed trends consistent with the overall study findings. CONCLUSION: LDLT recipients had better GS in re-LT than DDLT. Despite a higher severity of illness, the DDLT cohort was less likely to undergo re-LT.

LightGBM outperforms other machine learning techniques in predicting graft failure after liver transplantation: Creation of a predictive model through large-scale analysis.

BACKGROUND: The incidence of graft failure following liver transplantation (LTx) is consistent. While traditional risk scores for LTx have limited accuracy, the potential of machine learning (ML) in this area remains uncertain, despite its promise in other transplant domains. This study aims to determine ML's predictive limitations in LTx by replicating methods used in previous heart transplant research. METHODS: This study utilized the UNOS STAR database, selecting 64,384 adult patients who underwent LTx between 2010 and 2020. Gradient boosting models (XGBoost and LightGBM) were used to predict 14, 30, and 90-day graft failure compared to conventional logistic regression model. Models were evaluated using both shuffled and rolling cross-validation (CV) methodologies. Model performance was assessed using the AUC across validation iterations. RESULTS: In a study comparing predictive models for 14-day, 30-day and 90-day graft survival, LightGBM consistently outperformed other models, achieving the highest AUC of.740,.722, and.700 in shuffled CV methods. However, in rolling CV the accuracy of the model declined across every ML algorithm. The analysis revealed influential factors for graft survival prediction across all models, including total bilirubin, medical condition, recipient age, and donor AST, among others. Several features like donor age and recipient diabetes history were important in two out of three models. CONCLUSIONS: LightGBM enhances short-term graft survival predictions post-LTx. However, due to changing medical practices and selection criteria, continuous model evaluation is essential. Future studies should focus on temporal variations, clinical implications, and ensure model transparency for broader medical utility.

Enhancing the Usability of older DCD donors through strategic approaches in liver transplantation in the US.

BACKGROUND: The use of older donors after circulatory death(DCD) for liver transplantation(LT) has increased over the past decade. This study examined whether outcomes of LT using older DCD(≥50 y) have improved with advancements in surgical/perioperative care and normothermic machine perfusion(NMP) technology. METHOD: 7,602 DCD LT cases from the UNOS database(2003-2022) were reviewed. The impact of older DCD donors on graft survival(GS) was assessed using Kaplan-Meier and hazard ratio(HR) analyses. RESULTS: 1,447 LT cases(19.0%) involved older DCD donors. Although there was a decrease in their use from 2003-2014, a resurgence was noted post-2015 and reached 21.9% of all LT in the last four years(2019-2022). Initially, 90-day and one-year GS for older DCDs were worse than younger DCDs, but this difference decreased over time and there was no statistical difference after 2015. Similarly, HRs for graft loss in older DCD have recently become insignificant. In older DCD LT, NMP usage has increased recently, especially in cases with extended donor-recipient distances, while the median time from asystole to aortic cross-clamp has decreased. Multivariable Cox regression analyses revealed that in the early phase, asystole to cross-clamp time had the highest HR for graft loss in older DCD LT without NMP, while in the later phases, the CIT(>5.5 h) was a significant predictor. CONCLUSION: LT outcomes using older DCD donors have become comparable to those from young DCD donors, with recent HRs for graft loss becoming insignificant. The strategic approach in the recent period could mitigate risks, including managing CIT(≤5.5 h), reducing asystole to cross-clamp time, and adopting NMP for longer distances. Optimal use of older DCD donors may alleviate the donor shortage.

Decreased Utilization Rate of Grafts for Liver Transplantation After Implementation of Acuity Circle-based Allocation.

BACKGROUND: The allocation system for livers began using acuity circles (AC) in 2020. In this study, we sought to evaluate the impact of AC policy on the utilization rate for liver transplantation (LT). METHODS: Using the US national registry data between 2018 and 2022, LTs were equally divided into 2 eras: pre-AC (before February 4, 2020) and post-AC (February 4, 2020, and after). Deceased potential liver donors were defined as deceased donors from whom at least 1 organ was procured. RESULTS: The annual number of deceased potential liver donors increased post-AC (from 10 423 to 12 259), approaching equal to that of new waitlist registrations for LT (n = 12 801). Although the discard risk index of liver grafts was comparable between the pre- and post-AC eras, liver utilization rates in donation after brain death (DBD) and donation after circulatory death (DCD) donors were lower post-AC ( P < 0.01; 79.8% versus 83.4% and 23.7% versus 26.0%, respectively). Recipient factors, ie, no recipient located, recipient determined unsuitable, or time constraints, were more likely to be reasons for nonutilization after implementation of the AC allocation system compared to the pre-AC era (20.0% versus 12.3% for DBD donors and 50.1% versus 40.8% for DCD donors). Among non-high-volume centers, centers with lower utilization of marginal DBD donors or DCD donors were more likely to decrease LT volume post-AC. CONCLUSIONS: Although the number of deceased potential liver donors has increased, overall liver utilization among deceased donors has decreased in the post-AC era. To maximize the donor pool for LT, future efforts should target specific reasons for liver nonutilization.

Overcoming the hurdles of steatotic grafts in liver transplantation: Insights into survival and prognostic factors.

With increasing metabolic dysfunction-associated steatotic liver disease, the use of steatotic grafts in liver transplantation (LT) and their impact on postoperative graft survival (GS) needs further exploration. Analyzing adult LT recipient data (2002-2022) from the United Network for Organ Sharing database, outcomes of LT using steatotic (≥30% macrosteatosis) and nonsteatotic donor livers, donors after circulatory death, and standard-risk older donors (age 45-50) were compared. GS predictors were evaluated using Kaplan-Meier and Cox regression analyses. Of the 35,345 LT donors, 8.9% (3,155) were fatty livers. The initial 30-day postoperative period revealed significant challenges with fatty livers, demonstrating inferior GS. However, the GS discrepancy between fatty and nonfatty livers subsided over time ( p = 0.10 at 5 y). Long-term GS outcomes showed comparable or even superior results in fatty livers relative to nonsteatotic livers, conditional on surviving the initial 90 postoperative days ( p = 0.90 at 1 y) or 1 year ( p = 0.03 at 5 y). In the multivariable Cox regression analysis, the high body surface area (BSA) ratio (≥1.1) (HR 1.42, p = 0.02), calculated as donor BSA divided by recipient BSA, long cold ischemic time (≥6.5 h) (HR 1.72, p < 0.01), and recipient medical condition (intensive care unit hospitalization) (HR 2.53, p < 0.01) emerged as significant adverse prognostic factors. Young (<40 y) fatty donors showed a high BSA ratio, diabetes, and intensive care unit hospitalization as significant indicators of a worse prognosis ( p < 0.01). Our study emphasizes the initial postoperative 30-day survival challenge in LT using fatty livers. However, with careful donor-recipient matching, for example, avoiding the use of steatotic donors with long cold ischemic time and high BSA ratios for recipients in the intensive care unit, it is possible to enhance immediate GS, and in a longer time, outcomes comparable to those using nonfatty livers, donors after circulatory death livers, or standard-risk older donors can be anticipated. These novel insights into decision-making criteria for steatotic liver use provide invaluable guidance for clinicians.

Breaking distance barriers in liver transplantation: Risk factors and outcomes of long-distance liver grafts.

BACKGROUND: Long-distance-traveling liver grafts in liver transplantation present challenges due to prolonged cold ischemic time and increased risk of ischemia-reperfusion injury. We identified long-distance-traveling liver graft donor and recipient characteristics and risk factors associated with long-distance-traveling liver graft use. METHODS: We conducted a retrospective analysis of data from donor liver transplantation patients registered from 2014 to 2020 in the United Network for Organ Sharing registry database. Donor, recipient, and transplant factors of graft survival were compared between short-travel grafts and long-distance-traveling liver grafts (traveled >500 miles). RESULTS: During the study period, 28,265 patients received a donation after brainstem death liver transplantation and 3,250 a donation after circulatory death liver transplantation. The long-distance-traveling liver graft rate was 6.2% in donation after brainstem death liver transplantation and 7.1% in donation after circulatory death liver transplantation. The 90-day graft survival rates were significantly worse for long-distance-traveling liver grafts (donation after brainstem death: 95.7% vs 94.5%, donation after circulatory death: 94.5% vs 93.9%). The 3-year graft survival rates were similar for long-distance-traveling liver grafts (donation after brainstem death: 85.5% vs 85.1%, donation after circulatory death: 81.0% vs 80.4%). Cubic spline regression analyses revealed that travel distance did not linearly worsen the prognosis of 3-year graft survival. On the other hand, younger donor age, lower donor body mass index, and shorter cold ischemic time mitigated the negative impact of 90-day graft survival in long-distance-traveling liver grafts. CONCLUSION: The use of long-distance-traveling liver grafts negatively impacts 90-day graft survival but not 3-year graft survival. Moreover, long-distance-traveling liver grafts are more feasible with appropriate donor and recipient factors offsetting the extended cold ischemic time. Mechanical perfusion can improve long-distance-traveling liver graft use. Enhanced collaboration between organ procurement organizations and transplant centers and optimized transportation systems are essential for increasing long-distance-traveling liver graft use, ultimately expanding the donor pool.

Color-coded laparoscopic liver resection using artificial intelligence: A preliminary study.

Tashiro and colleagues demonstrated for the first time that an artificial intelligence system can precisely identify intrahepatic vascular structures during laparoscopic liver resection in real time through color coding under bleeding and indocyanine green fluorescent imaging. The system supports real-time navigation and offers potentially safer laparoscopic or robotic liver surgery.

The short and long-term prognostic influences of liver grafts with high bilirubin levels at the time of organ recovery.

BACKGROUND: Donors with hyperbilirubinemia are often not utilized for liver transplantation (LT) due to concerns about potential liver dysfunction and graft survival. The potential to mitigate organ shortages using such donors remains unclear. METHODS: This study analyzed adult deceased donor data from the United Network for Organ Sharing database (2002-2022). Hyperbilirubinemia was categorized as high total bilirubin (3.0-5.0 mg/dL) and very high bilirubin (≥5.0 mg/dL) in brain-dead donors. We assessed the impact of donor hyperbilirubinemia on 3-month and 3-year graft survival, comparing these outcomes to donors after circulatory death (DCD). RESULTS: Of 138 622 donors, 3452 (2.5%) had high bilirubin and 1999 (1.4%) had very high bilirubin levels. Utilization rates for normal, high, and very high bilirubin groups were 73.5%, 56.4%, and 29.2%, respectively. No significant differences were found in 3-month and 3-year graft survival between groups. Donors with high bilirubin had superior 3-year graft survival compared to DCD (hazard ratio .83, p = .02). Factors associated with inferior short-term graft survival included recipient medical condition in intensive care unit (ICU) and longer cold ischemic time; factors associated with inferior long-term graft survival included older donor age, recipient medical condition in ICU, older recipient age, and longer cold ischemic time. Donors with ≥10% macrosteatosis in the very high bilirubin group were also associated with worse 3-year graft survival (p = .04). DISCUSSION: The study suggests that despite many grafts with hyperbilirubinemia being non-utilized, acceptable post-LT outcomes can be achieved using donors with hyperbilirubinemia. Careful selection may increase utilization and expand the donor pool without negatively affecting graft outcome.

Efficacy and safety of postoperative preemptive use of tolvaptan for patients with cirrhosis undergoing hepatectomy for hepatocellular carcinoma.

PURPOSE: Optimal choice of diuretics in perioperative management remains unclear in enhanced recovery after liver surgery. This study investigated the efficacy and safety of tolvaptan (oral vasopressin V2-receptor antagonist) in postoperative management of patients with liver injury and hepatocellular carcinoma. METHODS: The patients clinically diagnosed with liver cirrhosis were included in this study. Clinical outcomes of 51 prospective cohort managed with a modified postoperative protocol using tolvaptan (validation group) were compared with 83 patients treated with a conventional management protocol (control group). RESULTS: Postoperative urine output were significantly larger and excessive body weight increase were reduced with no impairment in renal function or serum sodium levels in the validation group. Although the total amount of discharge and trend of serum albumin level were not significantly different among the groups, global incidence of postoperative morbidity was less frequent (19.6% vs. 44.6%, P=0.005) and postoperative stay was significantly shorter (8 days vs.10 days, P=0.008) in the validation group compared with the control group. CONCLUSIONS: Tolvaptan could be safely used for the patients with injured liver in postoperative management after hepatectomy and potentially advantageous in the era of enhanced recovery after surgery with its strong diuretic effect and better fluid management.

Has the risk of liver re-transplantation improved over the two decades?

BACKGROUND: Despite advancements in liver transplantation (LT) over the past two decades, liver re-transplantation (re-LT) presents challenges. This study aimed to assess improvements in re-LT outcomes and contributing factors. METHODS: Data from the United Network for Organ Sharing database (2002-2021) were analyzed, with recipients categorized into four-year intervals. Trends in re-LT characteristics and postoperative outcomes were evaluated. RESULTS: Of 128,462 LT patients, 7254 received re-LT. Graft survival (GS) for re-LT improved (91.3%, 82.1%, and 70.8% at 30 days, 1 year, and 3 years post-LT from 2018 to 2021). However, hazard ratios (HRs) for GS remained elevated compared to marginal donors including donors after circulatory death (DCD), although the difference in HRs decreased in long-term GS. Changes in re-LT causes included a reduction in hepatitis C recurrence and an increase in graft failure post-primary LT involving DCD. Trends identified included recent decreased cold ischemic time (CIT) and increased distance from donor hospital in re-LT group. Meanwhile, DCD cohort exhibited less significant increase in distance and more marked decrease in CIT. The shortest CIT was recorded in urgent re-LT group. The highest Model for End-Stage Liver Disease score was observed in urgent re-LT group, while the lowest was recorded in DCD group. Analysis revealed shorter time interval between previous LT and re-listing, leading to worse outcomes, and varying primary graft failure causes influencing overall survival post-re-LT. DISCUSSION: While short-term re-LT outcomes improved, challenges persist compared to DCD. Further enhancements are required, with ongoing research focusing on optimizing risk stratification models and allocation systems for better LT outcomes.

Disease-Free Interval and Tumor Stage Complementarily Predict the Biological Behavior of Recurrent Hepatocellular Carcinoma.

BACKGROUND: Currently used treatment algorithms were originally established based on the clinical outcomes of the initial treatment for primary hepatocellular carcinoma (HCC), and no strong evidence exists yet to suggest if these algorithms could also be applicable to patients with recurrent HCC after surgery. As such, this study sought to explore an optimal risk stratification method for cases of recurrent HCC for better clinical management. METHODS: Among the 1616 patients who underwent curative resection for HCC, the clinical features and survival outcomes of 983 patients who developed recurrence were examined in detail. RESULTS: Multivariate analysis confirmed that both the disease-free interval (DFI) from the previous surgery and tumor stage at recurrence were significant prognostic factors. However, the prognostic impact of DFI seemed different according to the tumor stages at recurrence. While curative-intent treatment showed strong influence on survival [hazard ratio (HR), 0.61; P < 0.001] regardless of the DFI in patients with stage 0 or stage A disease at recurrence, early recurrence (< 6 months) was a poor prognostic marker in patients with stage B disease. The prognosis of patients with stage C disease was exclusively influenced by the tumor distribution or choice of treatment than by the DFI. CONCLUSIONS: The DFI complementarily predicts the oncological behavior of recurrent HCC, with its predictive value differing depending on the tumor stage at recurrence. These factors should be considered for selection of the optimal treatment in patients with recurrent HCC after curative-intent surgery.

Evaluating the outcomes of donor-recipient age differences in young adults undergoing liver transplantation.

The current liver allocation system may be disadvantaging younger adult recipients as it does not incorporate the donor-recipient age difference. Given the longer life expectancy of younger recipients, the influences of older donor grafts on their long-term prognosis should be elucidated. This study sought to reveal the long-term prognostic influence of the donor-recipient age difference in young adult recipients. Adult patients who received initial liver transplants from deceased donors between 2002 and 2021 were identified from the UNOS database. Young recipients (patients 45 years old or below) were categorized into 4 groups: donor age younger than the recipient, 0-9 years older, 10-19 years older, or 20 years older or above. Older recipients were defined as patients 65 years old or above. To examine the influence of the age difference in long-term survivors, conditional graft survival analysis was conducted on both younger and older recipients. Among 91,952 transplant recipients, 15,170 patients were 45 years old or below (16.5%); these were categorized into 6,114 (40.3%), 3,315 (21.9%), 2,970 (19.6%), and 2,771 (18.3%) for groups 1-4, respectively. Group 1 demonstrated the highest probability of survival, followed by groups 2, 3, and 4 for the actual graft survival and conditional graft survival analyses. In younger recipients who survived at least 5 years post-transplant, inferior long-term survival was observed when there was an age difference of 10 years or above (86.9% vs. 80.6%, log-rank p <0.01), whereas there was no difference in older recipients (72.6% vs. 74.2%, log-rank p =0.89). In younger patients who are not in emergent need of a transplant, preferential allocation of younger aged donor offers would optimize organ utility by increasing postoperative graft survival time.

Subserosal vascular density predicts oncological features of T2 gallbladder cancer.

PURPOSE: Tumor sidedness (hepatic side vs. peritoneal side) reportedly predicts microvascular invasion and survival outcomes of T2 gallbladder cancer, although the actual histopathological mechanism is not fully understood. METHODS: The clinical relevance of tumor sidedness was revisited in 84 patients with gallbladder cancer using histopathological analysis of the vascular density of the gallbladder wall. RESULTS: Hepatic-side tumor location was associated with overall survival (OS) (hazard ratio [HR], 13.62; 95% confidence interval [CI], 2.09-88.93) and recurrence-free survival (RFS) (HR, 8.70; 95% CI, 1.36-55.69) in T2 tumors. The Adjusted Kaplan-Meier curve indicated a clear survival difference between T2a (peritoneal side) and T2b (hepatic side) tumors (P = 0.006). A review of 56 pathological specimens with gallbladder cancer and 20 control specimens demonstrated that subserosal vascular density was significantly higher on the hepatic side of the gallbladder, regardless of the presence of cancer (P < 0.001). Multivariate analysis also confirmed that higher subserosal vascular density was significantly associated with poor OS (HR, 1.73; 95% CI, 1.10-2.73 per 10 microscopic fields) and poor RFS (HR, 1.62; 95% CI, 1.06-2.49) in T2  gallbladder cancer. CONCLUSION: Higher subserosal vascular density may account for the higher incidence of cancer spread and the poor prognosis of T2b gallbladder cancer.

Risk Stratification of Patients with Marginal Hepatic Functional Reserve Using the Remnant Hepatocyte Uptake Index in Gadoxetic Acid-Enhanced Magnetic Resonance Imaging for Safe Liver Surgery.

BACKGROUND: This study aimed to explore the efficacy of gadoxetic acid-enhanced (Gd-EOB) magnetic resonance imaging (MRI) in surgical risk estimation among patients with marginal hepatic function estimated by indocyanine green (ICG) clearance test. METHODS: This analysis focused on 120 patients with marginal hepatic functional reserve (ICG clearance rate of future liver remnant [ICG-Krem] < 0.10). Preoperative Gd-EOB MRI was retrospectively reviewed, and the remnant hepatocyte uptake index (rHUI) was calculated for quantitative measurement of liver function. The predictive power of rHUI for posthepatectomy liver failure was compared with several clinical measures used in current risk estimation before hepatectomy. RESULTS: Receiver operating curve analysis showed that rHUI had the best predictive power for posthepatectomy liver failure among the tested variables (ICG-R15, ICG-Krem, albumin + bilirubin score, and albumin + ICG-R15 score). Cross-validation showed that a threshold of 925 could be the best cut-off value for estimating the postoperative risk of liver failure with sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of 0.689, 0.884, 5.94, and 0.352, respectively. CONCLUSION: rHUI could be a sensitive substitute measure for posthepatectomy liver failure risk estimation among patients with marginal hepatic functional reserve.