Benefits of liver transplant in critically ill patients with acute-on-chronic liver failure: Implementation of an urgent living-donor program.

We evaluated the liver transplantation (LT) criteria in acute-on-chronic liver failure (ACLF), incorporating an urgent living-donor LT (LDLT) program. Critically ill patients with a Chronic Liver Failure Consortium (CLIF-C) ACLF score (CLIF-C_ACLF_score) ≥65, previously considered unsuitable for LT, were included to explore the excess mortality threshold of the CLIF-C_ACLF_score (CLIF-C_ACLF_score_threshold). We followed 854 consecutive patients with ACLF (276 ACLF grade 2 and 215 ACLF grade 3) over 10 years among 4432 LT recipients between 2008 and 2019. For advanced ACLF patients without immediate deceased-donor (DD) allocation, an urgent LDLT program was expedited. The CLIF-C_ACLF_score_threshold was determined by the metrics of transplant survival benefit: >60% 1-year and >50% 5-year survival rate. In predicting post-LT mortality, the CLIF-C_ACLF_score outperformed the (model for end-stage liver disease-sodium) MELD-Na and (model for end-stage liver disease) MELD-3.0 scores but was comparable to the Sundaram ACLF-LT-mortality score. A CLIF-C_ACLF_score ≥65 (n = 54) demonstrated posttransplant survival benefits, with 1-year and 5-year survival rates of 66.7% and 50.4% (P < .001), respectively. Novel CLIF-C_ACLF_score_threshold for 1-year and 5-year mortalities was 70 and 69, respectively. A CLIF-C_ACLF_score-based nomogram for predicting survival probabilities, integrating cardiovascular disease, diabetes, and donor type (LDLT vs DDLT), was generated. This study suggests reconsidering the criteria for unsuitable LT with a CLIF-C_ACLF_score ≥65. Implementing a timely salvage LT strategy, and incorporating urgent LDLT, can enhance survival rates.

Transplant benefit-based offering of deceased donor livers in the United Kingdom.

BACKGROUND & AIMS: The National Liver Offering Scheme (NLOS) was introduced in the UK in 2018 to offer livers from deceased donors to patients on the national waiting list based, for most patients, on calculated transplant benefit. Before NLOS, livers were offered to transplant centres by geographic donor zones and, within centres, by estimated recipient need for a transplant. METHODS: UK Transplant Registry data on patient registrations and transplants were analysed to build statistical models for survival on the list (M1) and survival post-transplantation (M2). A separate cohort of registrations - not seen by the models before - was analysed to simulate what liver allocation would have been under M1, M2 and a transplant benefit score (TBS) model (combining both M1 and M2), and to compare these allocations to what had been recorded in the UK Transplant Registry. The number of deaths on the waiting list and patient life years were used to compare the different simulation scenarios and to select the optimal allocation model. Registry data were monitored, pre- and post-NLOS, to understand the performance of the scheme. RESULTS: The TBS was identified as the optimal model to offer donation after brain death (DBD) livers to adult and large paediatric elective recipients. In the first 2 years of NLOS, 68% of DBD livers were offered using the TBS to this type of recipient. Monitoring data indicate that mortality on the waiting list post-NLOS significantly decreased compared with pre-NLOS (p <0.0001), and that patient survival post-listing was significantly greater post- compared to pre-NLOS (p = 0.005). CONCLUSIONS: In the first two years of NLOS offering, waiting list mortality fell while post-transplant survival was not negatively impacted, delivering on the scheme's objectives. IMPACT AND IMPLICATIONS: The National Liver Offering Scheme (NLOS) was introduced in the UK in 2018 to increase transparency of the deceased donor liver offering process, maximise the overall survival of the waiting list population, and improve equity of access to liver transplantation. To our knowledge, it is the first scheme that offers organs based on statistical prediction of transplant benefit: the transplant benefit score. The results are important to the transplant community - from healthcare practitioners to patients - and demonstrate that, in the first two years of NLOS offering, waiting list mortality fell while post-transplant survival was not negatively impacted, thus delivering on the scheme's objectives. The scheme continues to be monitored to ensure that the transplant benefit score remains up-to-date and that signals that suggest the possible disadvantage of some patients are investigated.

Are patients with hepatocellular carcinoma and portal vein tumour thrombosis candidates for liver transplantation?

In this debate, the authors consider whether patients with hepatocellular carcinoma (HCC) and portal vein tumour thrombosis are candidates for liver transplantation (LT). The argument for LT in this context is based on the premise that, following successful downstaging treatment, LT confers a much greater clinical benefit in terms of survival outcomes than the available alternative (palliative systemic therapy). A major argument against relates to limitations in the quality of evidence for LT in this setting - in relation to study design, as well as heterogeneity in patient characteristics and downstaging protocols. While acknowledging the superior outcomes offered by LT for patients with portal vein tumour thrombosis, the counterargument is that expected survival in such patients is still below accepted thresholds for LT and, indeed, the levels achieved for other patients who receive transplants beyond the Milan criteria. Based on the available evidence, it seems too early for consensus guidelines to recommend such an approach, however, it is hoped that with higher quality evidence and standardised downstaging protocols, LT may soon be more widely indicated, including for this population with high unmet clinical need.

Mitigating selection bias in organ allocation models.

BACKGROUND: The lung allocation system in the U.S. prioritizes lung transplant candidates based on estimated pre- and post-transplant survival via the Lung Allocation Scores (LAS). However, these models do not account for selection bias, which results from individuals being removed from the waitlist due to receipt of transplant, as well as transplanted individuals necessarily having survived long enough to receive a transplant. Such selection biases lead to inaccurate predictions. METHODS: We used a weighted estimation strategy to account for selection bias in the pre- and post-transplant models used to calculate the LAS. We then created a modified LAS using these weights, and compared its performance to that of the existing LAS via time-dependent receiver operating characteristic (ROC) curves, calibration curves, and Bland-Altman plots. RESULTS: The modified LAS exhibited better discrimination and calibration than the existing LAS, and led to changes in patient prioritization. CONCLUSIONS: Our approach to addressing selection bias is intuitive and can be applied to any organ allocation system that prioritizes patients based on estimated pre- and post-transplant survival. This work is especially relevant to current efforts to ensure more equitable distribution of organs.

Liver transplantation for secondary liver tumours: The difficult balance between survival and recurrence.

Assessing the balance between survival and recurrence after transplantation for secondary liver tumours should be based on the type of cancer in question. For neuroendocrine liver metastases, high recurrence rates are clearly related to reduced long-term survival. For colorectal liver metastases, experience to date indicates that pulmonary recurrence alone has a modest impact on survival outcomes. Further studies focusing on this group of patients will be important for the development of this field of transplant oncology. Liver transplantation for secondary liver tumours should be implemented in accordance with stringent transplant criteria and preferably in the context of prospective trials. Expansion of the donor pool by utilising extended criteria donors and partial liver transplantation could be considered for this indication.

The trials and tribulations of liver allocation.

Allocation policies are necessary to ensure a fair distribution of a scarce resource. The goal of any liver transplant allocation policy is to achieve the best possible outcomes for the waiting list population, irrespective of the indication for transplant, whilst maximizing organ utilization. Organ allocation for liver transplantation has evolved from simple centre-based approaches driven by local issues, to complex, evidence-based algorithm prioritizing according to need. Despite the rapid evolution of allocation policies, there remain a number of challenges and new approaches are required to ensure transparency and equity on the decision-making process and the best possible outcomes for patients on the waiting list. New ways of modelling, together with novel outcome criteria, will be required to enable a dynamic adaptability of the allocation policies to the ever changing demographics of the donor population and the changing landscape of indications for transplantation.

Who is too healthy and who is too sick for liver transplantation: external validation of prognostic scores and survival-benefit estimation.

OBJECTIVE: Thresholds for when a patient should be considered too healthy or too sick to undergo liver transplantation (LT) have been pursued, but have undergone little external validation and may differ between centers and countries. MATERIAL AND METHODS: We investigated the ability of the Model for End-stage Liver Disease (MELD), D-MELD, Donor Risk Index (DRI) and Balance of Risk (BAR) scores to predict 1-year graft survival, and determined the 1-year survival-benefit of LT, compared with conservative management, according to MELD score and graft quality among 538 adult LT recipients with underlying chronic non-malignant liver disease. RESULTS: One-year graft survival rates showed small, but statistically significant variation according to MELD (p = 0.002) and D-MELD score (p = 0.04), and among LTs after year 2000 also according to BAR score (p = 0.01), but not according to DRI. Diagnostic accuracy of these scores was poor; area under the curve was 0.50-0.65 depending on the score. A 1-year survival-benefit of LT emerged at MELD scores ≥15, but also at lower MELD scores when using high-quality grafts (DRI <1.075). CONCLUSIONS: The performance of various prognostic scores in the Finnish setting was poor. Careful clinical evaluation is imperative when deciding on the timing of LT in the course of chronic liver disease.

Timing and benefit of liver transplantation in acute liver failure.

The case for using emergency liver transplantation in acute liver failure was made two decades ago by a series of single centre experiences. The development of models identifying a poor prognosis assisted the selection of patients for liver transplantation but none of these delivers both high sensitivity and specificity for prediction of death. Enhanced sensitivity favours the individual patient while enhanced specificity targets the pool of organs available at those who will derive greatest benefit. The non-transplant survival rates have improved considerably for certain cohorts of patients and these prognostic models have not been adjusted to reflect these changes. The presumption of transplant benefit can no longer be taken as established in paracetamol-related acute liver failure and a policy review is appropriate. In other scenarios, such as seronegative hepatitis and the phenotype of sub-acute liver failure, spontaneous survival rates remain low and the basis for liver transplantation remains sound. Outcomes after liver transplantation are improving but are not yet comparable to elective transplantation. The understanding of factors associated with failure after liver transplantation is improving but accurate definition of futility has not yet been attained.

Analysis of transplant urgency and benefit via multiple imputation.

Missing (censored) death times for lung candidates in urgent need of transplant are a signpost of success for allocation policy makers. However, statisticians analyzing these data must properly account for dependent censoring as the sickest patients are removed from the waitlist. Multiple imputation allows the creation of complete data sets that can be used for a variety of standard analyses in this setting. We propose an approach to multiply impute lung candidate outcomes that incorporates (i) time-varying factors predicting removal from the waitlist and (ii) estimates of transplant urgency via restricted mean models. The measures of transplant urgency and benefit for individual patient profiles are discussed in the context of lung allocation score modeling in the USA. Marginal survival estimates in the event that a transplant does not occur are also provided. Simulations suggest that the proposed imputation method gives attractive results when compared with existing methods.

Multidisciplinary Treatment of Hepatocellular Carcinoma in 2023: Italian practice Treatment Guidelines of the Italian Association for the Study of the Liver (AISF), Italian Association of Medical Oncology (AIOM), Italian Association of Hepato-Bilio-Pancreatic Surgery (AICEP), Italian Association of Hospital Gastroenterologists (AIGO), Italian Association of Radiology and Clinical Oncology (AIRO), Italian Society of Pathological Anatomy and Diagnostic Cytology (SIAPeC-IAP), Italian Society of Surgery (SIC), Italian Society of Gastroenterology (SIGE), Italian Society of Medical and Interventional Radiology (SIRM), Italian Organ Transplant Society (SITO), and Association of Patients with Hepatitis and Liver Disease (EpaC) - Part I - Surgical treatments.

Worldwide, hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death. The remarkable improvements in treating HCC achieved in the last years have increased the complexity of HCC management. Following the need to have updated guidelines on the multidisciplinary treatment management of HCC, the Italian Scientific Societies involved in the management of this cancer have promoted the drafting of a new dedicated document. This document was drawn up according to the GRADE methodology needed to produce guidelines based on evidence. Here is presented the first part of guidelines, focused on the multidisciplinary tumor board of experts and surgical treatments of HCC.

External Validation of the United Kingdom Transplant Benefit Score in Australia and New Zealand.

Introduction: In Australia and New Zealand, liver allocation is needs based (based on model for end-stage liver disease score). An alternative allocation system is a transplant benefit-based model. Transplant benefit is quantified by complex waitlist and transplant survival prediction models. Research Questions: To validate the UK transplant benefit score in an Australia and New Zealand population. Design: This study analyzed data on listings and transplants for chronic liver disease between 2009 and 2018, using the Australia and New Zealand Liver and Intestinal Transplant Registry. Excluded were variant syndromes, hepatocellular cancer, urgent listings, pediatric, living donor, and multi-organ listings and transplants. UK transplant benefit waitlist and transplant benefit score were calculated for listings and transplants, respectively. Outcomes were time to waitlist death and time to transplant failure. Calibration and discrimination were assessed with Kaplan-Meier analysis and C-statistics. Results: There were differences in the UK and Australia and New Zealand listing, transplant, and donor populations including older recipient age, higher recipient and donor body mass index, and higher incidence of hepatitis C in the Australia and New Zealand population. Waitlist scores were calculated for 2241 patients and transplant scores were calculated for 1755 patients. The waitlist model C-statistic at 5 years was 0.70 and the transplant model C-statistic was 0.56, with poor calibration of both models. Conclusion: The UK transplant benefit score model performed poorly, suggesting that UK benefit-based allocation would not improve overall outcomes in Australia and New Zealand. Generalizability of survival prediction models was limited by differences in transplant populations and practices.

The positive impact of the COVID 19 pandemic on organ utilisation in liver transplantation.

Background: As the world recovers from the aftermath of devastating waves of an outbreak, the ongoing Coronavirus disease 2019 pandemic has presented a unique perspective to the transplantation community of ''organ utilisation'' in liver transplantation, a poorly defined term and ongoing hurdle in this field. To this end, we report the key metrics of transplantation activity from a high-volume liver transplantation centre in the United Kingdom over the past two years. Methods: Between March 2019 and February 2021, details of donor liver offers received by our centre from National Health Service Blood & Transplant, and of transplantation were reviewed. Differences in the activity before and after the outbreak of the pandemic, including short term post-transplant survival, have been reported. Results: The pandemic year at our centre witnessed a higher utilisation of Donation after Cardiac Death livers (80.4% vs. 58.3%, p = 0.016) with preserved United Kingdom donor liver indices and median donor age (2.12 vs. 2.02, p = 0.638; 55 vs. 57 years, p = 0.541) when compared to the pre-pandemic year. The 1- year patient survival rates for recipients in both the periods were comparable. The pandemic year, that was associated with increased utilisation of Donation after Cardiac Death livers, had an ischaemic cholangiopathy rate of 6%. Conclusions: The pressures imposed by the pandemic led to increased utilisation of specific donor livers to meet patient needs and minimise the risk of death on the waiting list, with apparently preserved early post-transplant survival. Optimum organ utilisation is a balancing act between risk and benefit for the potential recipient, and technologies like machine perfusion may allow surgeons to increase utilisation without compromising patient outcomes.

Clinical impact of a modified lung allocation score that mitigates selection bias.

BACKGROUND: The Lung Allocation Score (LAS) is used in the U.S. to prioritize lung transplant candidates. Selection bias, induced by dependent censoring of waitlisted candidates and prediction of posttransplant survival among surviving, transplanted patients only, is only partially addressed by the LAS. Recently, a modified LAS (mLAS) was designed to mitigate such bias. Here, we estimate the clinical impact of replacing the LAS with the mLAS. METHODS: We considered lung transplant candidates waitlisted during 2016 and 2017. LAS and mLAS scores were computed for each registrant at each observed organ offer date; individuals were ranked accordingly. Patient characteristics associated with better priority under the mLAS were investigated via logistic regression and generalized linear mixed models. We also determined whether differences in rank were explained more by changes in predicted pre- or posttransplant survival. Simulations examined how 1-year waitlist, posttransplant, and overall survival might change under the mLAS. RESULTS: Diagnosis group, 6-minute walk distance, continuous mechanical ventilation, functional status, and age demonstrated the highest impact on differential allocation. Differences in rank were explained more by changes in predicted pretransplant survival than changes in predicted posttransplant survival, suggesting that selection bias has more impact on estimates of waitlist urgency. Simulations suggest that for every 1000 waitlisted individuals, 12.8 (interquartile range: 5.2-24.3) fewer waitlist deaths per year would occur under the mLAS, without compromising posttransplant and overall survival. CONCLUSIONS: Implementing a mLAS that mitigates selection bias into clinical practice can lead to important differences in allocation and possibly modest improvement in waitlist survival.

Colon Rectal Liver Metastases: The Role of the Liver Transplantation in the Era of the Transplant Oncology and Precision Medicine.

The development of liver metastases in colon rectal cancer has a strong impact on the overall survival (OS) of the patient, with a 5-year survival rate of 5% with palliative treatment. Surgical resection combined with pharmacological treatment can achieve a 5-year OS rate of 31-58%. However, in only 20% of patients with colon rectal liver metastases (CRLMs), liver resection is feasible. In highly selected patients, recent trials and studies proved that liver transplantation (LT) for non-resectable CRLM is a surgical option with an excellent long-term OS. The paper aims to review the indications and outcome of LT for CRLMs, with a special focus on immunosuppressive therapy and the management of local and extrahepatic recurrence after LT.

Liver Transplantation for T2 Hepatocellular Carcinoma during the COVID-19 Pandemic: A Novel Model Balancing Individual Benefit against Healthcare Resources.

The COVID-19 pandemic caused temporary drops in the supply of organs for transplantation, leading to renewed debate about whether T2 hepatocellular carcinoma (HCC) patients should receive priority during these times. The aim of this study was to provide a quantitative model to aid decision-making in liver transplantation for T2 HCC. We proposed a novel ethical framework where the individual transplant benefit for a T2 HCC patient should outweigh the harm to others on the waiting list, determining a "net benefit", to define appropriate organ allocation. This ethical framework was then translated into a quantitative Markov model including Italian averages for waiting list characteristics, donor resources, mortality, and transplant rates obtained from a national prospective database (n = 8567 patients). The net benefit of transplantation in a T2 HCC patient in a usual situation varied from 0 life months with a model for end-stage liver disease (MELD) score of 15, to 34 life months with a MELD score of 40, while it progressively decreased with acute organ shortage during a pandemic (i.e., with a 50% decrease in organs, the net benefit varied from 0 life months with MELD 30, to 12 life months with MELD 40). Our study supports the continuation of transplantation for T2 HCC patients during crises such as COVID-19; however, the focus needs to be on those T2 HCC patients with the highest net survival benefit.

A 2020 update on liver transplant for hepatocellular carcinoma.

INTRODUCTION: Hepatocellular carcinoma is the most frequent liver tumor and is associated with chronic liver disease in 90% of cases. In selected cases, liver transplantation represents an effective therapy with excellent overall survival. AREA COVERED: Since the introduction of Milan criteria in 1996, numerous alternative selection systems to LT for HCC patients have been proposed. Debate remains about how best to select HCC patients for transplant and how to prioritize them on the waiting list. EXPERT OPINION: The selection of the best scoring system to propose in the context of LT for HCC is far to be identified. In this review, we analyze and categorize the various selection systems, assessing their roles in the different decisional phases.

Liver and kidney function in refractory heart failure: The narrow gate to achieve post-transplant survival.

Substantial evidence is underscoring the importance of a combined assessment of liver and kidney function in patients with refractory heart failure, to stratify early post- heart transplant risk: multi-organ dysfunction, while identifying sickest patients on the list is also associated with a high risk of post transplant complications. In this issue of the Journal, Dr. Lebray provides an analysis of combined kidney and liver function patients undergoing heart transplant, identifying potential boundaries for futility of transplantation, because of excessive post-operative risk. Further development of this concept may help to design prioritisation algorithms allocating the organ to HT candidates not only based on the risk of dying on the waiting list, but also on the chances to survive after transplant.

Selection of patients with hepatocellular cancer: a difficult balancing between equity, utility, and benefit.

Although liver transplantation (LT) represents the gold-standard strategy for hepatocellular cancer (HCC), its use is circumscribed by several factors like donor shortage, perioperative complications, or competition with other candidates without HCC. Moreover, different alternative approaches like resection or loco-regional therapies may be attempted in selected cases. The best option for the treatment of an HCC patient is a complex decision, involving several ethical principles including: equity (horizontal equity and vertical equity or urgency), and utility. These principles influence the different phases of the patient selection process for LT: inscription in the waiting list (WL), deciding upon patient priority and drop-out before LT, allocating the liver donor to the best matched recipient. The best end-point for describing the principle of utility is the "transplant benefit" (TB). This concept expresses the survival gain obtained comparing LT with the best alternative therapies (i.e., difference between life years obtained with and without LT). The TB used with a mid-term time horizon (post-transplant 5-10 years), has the intrinsic potential to reach the dignity of an independent LT selection principle. Thus, the present review investigates the role of organ allocation using a TB model with the intent to introduce equity among patients transplanted having HCC or non-tumoral diseases.

Effect of the lung allocation score on lung transplantation in the United States.

BACKGROUND: On May 4, 2005, the system for allocation of deceased donor lungs for transplant in the United States changed from allocation based on waiting time to allocation based on the lung allocation score (LAS). We sought to determine the effect of the LAS on lung transplantation in the United States. METHODS: Organ Procurement and Transplantation Network data on listed and transplanted patients were analyzed for 5 calendar years before implementation of the LAS (2000-2004), and compared with data from 6 calendar years after implementation (2006-2011). Counts were compared between eras using the Wilcoxon rank sum test. The rates of transplant increase within each era were compared using an F-test. Survival rates computed using the Kaplan-Meier method were compared using the log-rank test. RESULTS: After introduction of the LAS, waitlist deaths decreased significantly, from 500/year to 300/year; the number of lung transplants increased, with double the annual increase in rate of lung transplants, despite no increase in donors; the distribution of recipient diagnoses changed dramatically, with significantly more patients with fibrotic lung disease receiving transplants; age of recipients increased significantly; and 1-year survival had a small but significant increase. CONCLUSIONS: Allocating lungs for transplant based on urgency and benefit instead of waiting time was associated with fewer waitlist deaths, more transplants performed, and a change in distribution of recipient diagnoses to patients more likely to die on the waiting list.