The clinical outcomes of patients with vascular invasion after deceased donor liver transplantation.

Background: Vascular invasion is a major risk factor for poor prognosis of liver transplantation (LT) for hepatocellular carcinoma (HCC), and this study aimed to evaluate the feasibility and efficacy of deceased donor LT (DDLT) for the treatment of microvascular invasion (MVI) and segmental portal vein tumor thrombus (PVTT). Methods: We retrospectively analyzed 141 patients who received DDLT for HCC combined with vascular invasion from January 2016 to December 2023 at Shulan (Hangzhou) Hospital. To assess the risk of vascular invasion associated with the LT prognosis, we evaluated various clinicopathologic variables. The recurrence-free survival (RFS) and overall survival (OS) based on different types of vascular invasion were also analyzed. Results: A total of 141 patients were enrolled in this study, including patients with MVI (MVI group, n=60), segmental PVTT with segmental branches of the portal vein or above (segmental PVTT group, n=13), and lobar PVTT involving the left and right branches of the portal vein or the main portal vein (lobar PVTT group, n=68). Between the tumor recurrence group and the no recurrence group, there were significant differences in alpha-fetoprotein (AFP) level, tumor total diameter, pretransplant treatment, histological grade, and types of vascular invasion. Subgroup analyses were performed according to the types of vascular invasion, the lobar PVTT group had a significantly higher recurrence rate (lobar vs. MVI: 88.2% vs. 35.0%, lobar vs. segmental: 88.2% vs. 30.8%, both P<0.001), but there was no difference in recurrence rate between the MVI group and the segmental PVTT group (35.0% vs. 30.8%, P>0.99). The 3-year RFS rate and OS rate were as low as 9.1% and 45.9% in the lobar PVTT group, compared with 65.5% and 76.0% in the MVI group, 58.3% and 75.0% in the segmental PVTT group. Multivariate analysis showed that Child-Pugh classification, tumor total diameter, histological grade, and lobar PVTT were the main risk factors affecting RFS, whereas Child-Pugh classification, tumor total diameter, and lobar PVTT were the main risk factors affecting OS. Finally, analysis of the segmental PVTT group revealed that RFS was significantly higher in well and moderately-differentiated patients than in poor-differentiated patients (P=0.01). Conclusions: Lobar PVTT remains a contraindication to LT, whereas segmental PVTT can still be considered for LT after careful screening.

Structural social determinants of health as barriers to liver transplant waitlisting.

Social determinants of health, both individual and structural, impact access to liver transplantation (LT). We aimed to evaluate the association between structural social determinants of health (SSDoH) and individual-level psychosocial factors (as measured by the Stanford Integrated Psychosocial Assessment for Transplant, SIPAT score) on failure to waitlist for LT. We conducted a single-center retrospective cohort study of 2762 patients evaluated for LT. SSDoH exposures included the Social Deprivation Index (SDI), the proportion of households on cash public assistance or supplemental nutrition assistance (% public assistance), and distance to the transplant center. Neighborhood SDI score in the highest quartile (OR 1.32, 95 % CI 1.07-1.63) and % on public assistance in the highest quartile (OR 1.41, 95 % CI 1.14-1.75) were associated with increased odds of not being waitlisted for LT. These associations remained significant after adjusting for individual psychosocial risk using SIPAT scores (≥21, high psychosocial risk). Highest quartile neighborhood SDI (OR 1.70, 95 % CI 1.13-2.54) and the highest quartile of % on public assistance (OR 1.67, 95 % CI 1.11-2.53) were also associated with increased odds of failure to waitlist for psychosocial reasons. However, these associations were no longer significant after adjusting for individual SIPAT scores. High-risk SIPAT scores were more prevalent in neighborhoods with the highest quartile of SSDoH measures. Transplant centers can design initiatives to build individual psychosocial support to mitigate the impact of structural barriers.

Perioperative extracorporeal membrane oxygenation in liver transplantation-bridge to transplantation, intraoperative salvage, and postoperative support: outcomes and predictors for survival in a large-volume liver transplant center.

Data on perioperative extracorporeal membrane oxygenation (ECMO) in liver transplantation (LT) are scarce. ECMO has been used preoperatively, intraoperatively, and postoperatively for a variety of indications at our center. This retrospective, single-center study of ECMO use peri-LT aimed to describe predictors for successful outcome in this highly select cohort of patients. Demographics, support method, and indication for LT were compared between survivors and nonsurvivors. Twenty-nine patients received venovenous (V-V; n = 20), venoarterial (V-A; n = 8), and venoarteriovenous (n = 1) ECMO. Twelve (41.4%) patients were bridged to emergency LT for acute liver failure, and emergency redo LT. Four (13.3%) patients required intraoperative V-A ECMO salvage, 2 necessitating extracorporeal cardiopulmonary resuscitation. Thirteen (43.3%) patients required ECMO support after LT: V-V ECMO (n = 9); V-A ECMO (n = 1); and extracorporeal cardiopulmonary resuscitation (n = 3) between postoperative days 2 to 30. Overall, 19 patients (65.5%) were successfully weaned off ECMO; 15 (51.7%) survived to intensive care unit discharge. All patients who underwent intraoperative salvage ECMO and all who were bridged to emergency redo LT died. Peri-LT ECMO is feasible. Post-LT ECMO outcomes are encouraging, in particular for V-V ECMO. Intraoperative ECMO salvage, uncontrolled sepsis, and graft failure are associated with poor outcomes.

Beyond the Rex: an innovative meso-intrahepatic portal vein bypass for late-onset extrahepatic portal vein occlusion after living donor liver transplantation.

The Meso-Rex bypass (MRB) is recognized as an effective treatment for portal hypertension secondary to extrahepatic portal vein occlusion (EHPVO) both in the pediatric and adult population, within or outside the context of liver transplantation. It is the preferred surgical treatment in most centers because not only does it addresses the portal hypertension, but also restores physiologic portal hepatopetal flow. However, the Rex recess, the landmark for this technique, may not be safely accessible in some patients. We present a 22-year-old male who underwent living donor liver transplant (LDLT) for neonatal hepatitis. He presented with variceal bleeding due to EHPVO at 13 years after transplant. Various endoscopic, radiologic, and surgical interventions were employed to address the recurrent gastrointestinal bleeding, but results have been unsatisfactory. We performed a meso-intrahepatic portal vein bypass (MIPVB), an innovative alternative to the MRB, for this patient with extensive post-operative adhesions, perihilar collaterals, and cavernous transformation. MIPVB creation in patients where the Rex recess is inaccessible is technically challenging. But with a multidisciplinary team approach, meticulous preoperative planning, and close follow-up, the authors have demonstrated that it is a safe and feasible option for patients with late-onset EHPVO after liver transplantation.

The Spread Pattern of New Practice in Liver Transplantation in the United States.

BACKGROUND: Introducing new liver transplantation (LT) practices, like unconventional donor use, incurs higher costs, making evaluation of their prognostic justification crucial. This study reexamines the spread pattern of new LT practices and its prognosis across the United States. METHODS: The study investigated the spread pattern of new practices using the UNOS database (2014-2023). Practices included LT for hepatitis B/C (HBV/HCV) nonviremic recipients with viremic donors, LT for COVID-19-positive recipients, and LT using onsite machine perfusion (OMP). One year post-LT patient and graft survival were also evaluated. RESULTS: LTs using HBV/HCV donors were common in the East, while LTs for COVID-19 recipients and those using OMP started predominantly in California, Arizona, Texas, and the Northeast. K-means cluster analysis identified three adoption groups: facilities with rapid, slow, and minimal adoption rates. Rapid adoption occurred mainly in high-volume centers, followed by a gradual increase in middle-volume centers, with little increase in low-volume centers. The current spread patterns did not significantly affect patient survival. Specifically, for LTs with HCV donors or COVID-19 recipients, patient and graft survivals in the rapid-increasing group was comparable to others. In LTs involving OMP, the rapid- or slow-increasing groups tended to have better patient survival (p = 0.05) and significantly improved graft survival rates (p = 0.02). Facilities adopting new practices often overlap across different practices. DISCUSSION: Our analysis revealed three distinct adoption groups across all practices, correlating the adoption aggressiveness with LT volume in centers. Aggressive adoption of new practices did not compromise patient and graft survivals, supporting the current strategy. Understanding historical trends could predict the rise in future LT cases with new practices, aiding in resource distribution.

The suggestion of mitigating disparity in the liver transplantation field among ABO blood type.

Medical literature highlights differences in liver transplantation (LT) waitlist experiences among ABO blood types. Type AB candidates reportedly have higher LT rates and reduced mortality. Despite liver offering guidelines, ABO disparities persist. This study examines LT access discrepancies among blood types, focusing on type AB, and seeks equitable strategies. Using the United Network for Organ Sharing database (2003-2022), 170 276 waitlist candidates were retrospectively analyzed. Dual predictive analyses (LT opportunity and survival studies) evaluated 1-year recipient pool survival, considering waitlist and post-LT survival, alongside anticipated allocation value per recipient, under 6 scenarios. Of the cohort, 97 670 patients (57.2%) underwent LT. Type AB recipients had the highest LT rate (73.7% vs 55.2% for O), shortest median waiting time (90 vs 198 days for A), and lowest waitlist mortality (12.9% vs 23.9% for O), with the lowest median model for end-stage liver disease-sodium (MELD-Na) score (20 vs 25 for A/O). The LT opportunity study revealed that reallocating type A (or A and O) donors originally for AB recipients to A recipients yielded the greatest reduction in disparities in anticipated value per recipient, from 0.19 (before modification) to 0.08. Meanwhile, the survival study showed that ABO-identical LTs reduced disparity the most (3.5% to 2.8%). Sensitivity analysis confirmed these findings were specific to the MELD-Na score < 30 population, indicating current LT allocation may favor certain blood types. Prioritizing ABO-identical LTs for MELD-Na score < 30 recipients could ensure uniform survival outcomes and mitigate disparities.

Hepatocellular Carcinoma: The Evolving Role of Systemic Therapies as a Bridging Treatment to Liver Transplantation.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths. Classically, liver transplantation (LT) can be curative for HCC tumors within the Milan criteria. Bridging strategies to reduce the dropouts from LT waiting lists and/or to downstage patients who are beyond the Milan criteria are widely utilized. We conducted a literature-based review to evaluate the role of systemic therapies as a bridging treatment to liver transplantation (LT) in HCC patients. Tyrosine kinase inhibitors (TKIs) can be used as a systemic bridging therapy to LT in patients with contraindications for locoregional liver-directed therapies. Immune checkpoint inhibitor (ICI) treatment can be utilized either as a monotherapy or as a combination therapy with bevacizumab or TKIs prior to LT. Acute rejection after liver transplantation is a concern in the context of ICI treatment. Thus, a safe ICI washout period before LT and cautious post-LT immunosuppression strategies are required to reduce post-LT rejections and to optimize clinical outcomes. Nevertheless, prospective clinical trials are needed to establish definitive conclusions about the utility of systemic therapy as a bridging modality prior to LT in HCC patients.

Does depressurization of the portal vein before liver transplantation affect the recurrence of HCC? A nested case-control study.

BACKGROUND: Portal hypertension (PHT) has been proven to be closely related to the development of hepatocellular carcinoma (HCC). Whether PHT before liver transplantation (LT) will affect the recurrence of HCC is not clear. METHODS: 110 patients with depressurization of the portal vein (DPV) operations (Transjugular Intrahepatic Portosystemic Shunt-TIPS, surgical portosystemic shunt or/and splenectomy) before LT from a HCC LT cohort, matched with 330 preoperative non-DPV patients; this constituted a nested case-control study. Subgroup analysis was based on the order of DPV before or after the occurrence of HCC. RESULTS: The incidence of acute kidney injury and intra-abdominal bleeding after LT in the DPV group was significantly higher than that in non-DPV group. The 5-year survival rates in the DPV and non-DPV group were 83.4% and 82.7% respectively (P = 0.930). In subgroup analysis, patients in the DPV prior to HCC subgroup may have a lower recurrence rate (4.7% vs.16.8%, P = 0.045) and a higher tumor free survival rate (88.9% vs.74.4%, P = 0.044) after LT under the up-to-date TNMI-II stage, while in TNM III stage, there was no difference for DPV prior to HCC subgroup compared with the DPV after HCC subgroup or the non-DPV group. CONCLUSION: Compared with DPV after HCC, DPV treatment before HCC can reduce the recurrence rate of HCC after early transplantation (TNM I-II). DPV before LT can reduce the recurrence of early HCC.

Exceptional Liver Transplant Indications: Unveiling the Uncommon Landscape.

Liver transplantation represents the definitive intervention for various etiologies of liver failure and encompasses a spectrum of rare indications crucial to understanding the diverse landscape of end-stage liver disease, with significantly improved survival rates over the past three decades. Apart from commonly encountered liver transplant indications such as decompensated cirrhosis and liver cancer, several rare diseases can lead to transplantation. Recognition of these rare indications is essential, providing a lifeline to individuals facing complex liver disorders where conventional treatments fail. Collaborative efforts among healthcare experts lead not only to timely interventions but also to the continuous refinement of transplant protocols. This continued evolution in transplant medicine promises hope for those facing diverse and rare liver diseases, marking a paradigm shift in the landscape of liver disease management.

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.

Liver transplantation and hepatocellular carcinoma 2023: a narrative review of management and outcomes.

BACKGROUND AND OBJECTIVE: Hepatocellular carcinoma (HCC) is a leading cause of morbidity and mortality in the United States. For certain patients, liver transplantation (LT) may be curative. The determination of which patients would benefit most from transplant and have the lowest risk of post-transplant recurrence has evolved as technology and treatments have expanded. We aim to review epidemiological changes in the HCC landscape, selection criteria for transplant, organ allocation, bridge therapies and post-transplant recurrence, and identify points for palliative care involvement. METHODS: Literature review was performed using PubMed MeSH searches in addition to reference list review. Additional information was retrieved from government regulatory and procurement organizations. KEY CONTENT AND FINDINGS: Metabolic and alcohol-associated liver diseases have surpassed hepatitis C as the leading causes of LT over the last decade, and have also risen as the underlying conditions seen in patients with HCC requiring LT. The United Network for Organ Sharing (UNOS) coordinates organ allocation, which includes disease severity, waitlist time, blood type, and distance from donor hospital. It has progressed to incorporate treatment response and alpha-fetoprotein into its listing criteria for patients with HCC, in addition to the well-established Milan Criteria (MC, one tumor <5 cm, ≤3 tumors ≤3 cm). Therapies to bridge patients until LT include locoregional therapies as well as immunotherapy. Dropout on the waitlist is seen up to 20% either due to decompensation or progression of disease. Recurrence of HCC post-transplant remains challenging. Given this, current guidelines recommend early palliative care involvement regardless of transplant listing status for both symptom management and advance care planning. CONCLUSIONS: For patients with HCC with favorable tumor biology, LT can be curative. However, given the symptom burden while awaiting LT and the notable number of patients who are unable to receive a transplant, early palliative care is critical in appropriate management of HCC.

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.

Use of machine learning models for identification of predictors of survival and tumour recurrence in liver transplant recipients with hepatocellular carcinoma.

Background: Hepatocellular carcinoma (HCC) is one of the leading indications for liver transplantation (LT) however, selection criteria remain controversial. We aimed to identify survival factors and predictors for tumour recurrence using machine learning (ML) methods. We also compared ML models to the Cox regression model. Methods: Thirty pretransplant donor and recipient general and tumour specific parameters were analysed from 170 patients who underwent orthotopic liver transplantation for HCC between March 2013 and December 2019 at the University Hospital Merkur, Zagreb. Survival rates were calculated using the Kaplan-Meier method and multivariate analysis was performed using the Cox proportional hazards regression model. Data was also processed through Coxnet (a regularized Cox regression model), Random Survival Forest (RSF), Survival Support Vector Machine (SVM) and Survival Gradient Boosting models, which included pre-processing, variable selection, imputation of missing data, training and cross-validation of the models. The cross-validated concordance index (CI) was used as an evaluation metric and to determine the best performing model. Results: Kaplan-Meier curves for 5-year survival time showed survival probability of 80% for recipient survival and 82% for graft survival. The 5-year HCC recurrence was observed in 19% of patients. The best predictive accuracy was observed in the RSF model with CI of 0.72, followed by the Survival SVM model (CI 0.70). Overall ML models outperform the Cox regression model with respect to their limitations. Random Forest analysis provided several relevant outcome predictors: alpha fetoprotein (AFP), donor C-reactive protein (CRP), recipient age and neutrophil to lymphocyte ratio (NLR). Cox multivariate analysis showed similarities with RSF models in identifying detrimental variables. Some variables such as donor age and number of transarterial chemoembolization treatments (TACE) were pointed out, but these were not influential in our RSF model. Conclusions: Using ML methods in addition to classical statistical analysis, it is possible to develop sufficient prognostic models, which, compared to established risk scores, could help us quantify survival probability and make changes in organ utilization.

Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.