Thanks so much. Now we'll move on to the liver transplantation debrief by Dr. Jacqueline O'Leary. She's professor of medicine at UT Southwestern and chief of hepatology at the Dallas VA Medical Center. Wonderful. Thank you so much. I'm excited to present to you today the liver transplantation debrief. Here at ASLD we had 2,724 total abstracts. I counted 279 of them in the category of liver transplantation, so just over 10%. They were broken down into a variety of categories. The most common were on predictive scores and outcome at 38, disparities at 31, alcohol, biomarkers, HCC in the 20s, cardiac, caregiver resilience, quality of life, immunosuppression and rejection, frailty in the teens, followed by organ allocation, and a variety of other topics, including hepatitis C and hepatitis B, only having 5 abstracts, which was certainly a success compared to maybe even just 10 years ago where that would have dominated my entire discussion. I will disclose that I chose the abstracts to share with you before the oral and poster sessions were available online, so I did do somewhat of my own selection. And there were many more exceptional abstracts that time does not allow me to cover, so I certainly apologize for that up front. And I also want to thank many of the authors who did provide me with the graphs and tables to share with you today. We're going to start with HCC, Comparative Outcomes of Taste versus Tear as Bridging Therapy for HCC in Liver Transplantation by Dr. Ficori and colleagues. They used the retrospective evaluation of the UNOS HCC patients who were upgraded with points from 13 to 22. People who had thermal or external beam XRT were excluded, and then they were propensity score matched, 2,330 people who either received taste or tear. Post-liver transplant 5-year survival was no difference between the groups. However, tear recipients had an increased probability of AFP normalization with an adjusted odds ratio over 2 and an increased probability of complete explant tumor necrosis after adjusted odds ratio of 1.68. Although numbers were small, non-transplant survival in those not receiving a transplant yet was slightly higher in those receiving tear. Second, an impact of pre-liver transplant immune checkpoint inhibitor therapy on downstaging outcomes, a prospective intention to treat analysis from a multicenter U.S. study by Dr. Tabrazian and colleagues. They enrolled consecutive patients with HCC tumor burden meeting the following criteria below at eight centers. UNOS downstaging had 201 patients with a median tumor diameter of 6.4, all comers at 122 patients with a median diameter of 9.4, and the immune checkpoint inhibitor group pre-transplant 64 patients had a median tumor diameter of 5.9. People were excluded if they had a complete response to their first local regional therapy. Of the 64 patients who received immune checkpoint inhibitor therapy, 78 were successfully downstaged, with the month time to downstaging being the lowest at three months in the UNOS downstaging group, intermediate at 4.7 in the all comers, and longest at 7.2 months in the immune checkpoint inhibitor group. The probability of liver transplant was equivalent between those in the UNOS downstaging and all comers, but somewhat lower in those receiving immune checkpoint inhibitors at about 30%. But if patients were transplanted, the post-transplant survival was no different between the groups, although when looking at all the patients, multivariable risk factors for decreased intention to treat survival included CTPB or C compared to A, stable disease versus better response in those who were responders, and if you had fewer local regional therapies, that was worse. Of the immune checkpoint inhibitor group, three-year post-survival was excellent at 94%. The median washout time was 34 days, with interquartile range 13 to 55 days. Three patients had rejection with a washout time of 22, 54, and 57 days. One of those rejections did result in graft loss, and the patient was retransplanted successfully. Three additional patients had HTC recurrence, leading me to conclude that immune checkpoint inhibitor therapy can be considered pre-transplant, and those with local regional therapy isn't enough to achieve downstaging, but be cognizant of the time between treatment and transplant. Turning our attention to donors, the difference in liver transplant outcomes between normothermic and hypothermic machine-perfused livers by Dr. Anoudi and colleagues utilized the UNOS database from January of 16 to April of 24, and they compared machine-perfused organs versus those that had static cold storage, as well as those that were hypothermically perfused versus normothermically perfused. During the time, over 6,900 grafts were analyzed. Only 4.4% were perfused with machine perfusion. The vast majority at 88% normothermic and 6% hypothermic. Machine-perfused organs tended to be older donors at 45 versus 40 and much more likely to be DCDs at 50% versus 9. Recipients also were older at 56 versus 52, cold ischemia time more than double at 13 hours versus 6, and the MELD scores tended to be higher at 24 versus 21. There was no overall one-year graft survival advantage of machine perfusion versus static cold storage, but a trend in the five-year graft survival, despite the deck being slightly stacked against machine-perfused organs, having older donors and much more DCDs. Normothermic versus hypothermic was also compared, and although the numbers were small in hypothermic, there was no difference between the groups. The one- and five-year graft survivals were also similar, leading me to conclude that machine perfusion is certainly a powerful tool that is being underutilized, probably secondary to cost, and head-to-head studies ideally would occur between the machines so that we can get more information. One of the late breakers today was exciting. Looking at mitochondrial injury during normothermic machine perfusion predicts outcomes after liver transplant, the first analysis of 300 human livers with prospective validation by Dr. Worley and colleagues. This was a single-center evaluation of all end-ischemic normothermic machine-perfused organs at their center, and they used liquid chromatography mass spec to evaluate the mitochondrial flavin mononucleotide in the perfusate as well as the bile during normothermic machine perfusion. They also evaluated histology and compared low-FMN grafts versus high-FMN grafts, looking at fluorescence immunohistochemistry and showed greater mitochondrial dysfunction in the high-FMN grafts. Of the initial cohort of 188 liver transplants in the discovery cohort, 30% were DCDs, four were lost to primary non-function or ischemic cholangiopathy, and three additional grafts had multiple interventions that were needed secondary to non-anastomotic biliary strictures. Recipient livers with perfusates greater than 1 and especially greater than 2 showed increased complication index, graft loss, as well as medical costs within the first six months, and the Yowden index showed an increase for graft complications and loss if it was greater than 1.75. They have been prospectively utilizing this to decline grafts as well, combining the utilization of it in the perfusate as well as the bile with other factors. Turning our attention to immunosuppression, the safety and tolerability of QEL001, an autologous chimeric antigen receptor Treg cell therapy in liver transplantation, a safety cohort in the LIBERATE study, was presented by Alberto Sanchez-Foyo. This is a phase I-IIa single-arm open-label study of QEL001 to induce tolerance and allow the complete discontinuation of immunosuppression post-transplant. However, this evaluation presented here was mostly on safety and early findings. They use a multicentronic lentivirus vector and select patients who have a donor graph that's HLA-A2 positive and the recipient has to be HLA-A2 negative. They ferrese the recipient and then transduce the Tregs that are harvested. They then expand them ex vivo as well as cryopreserve them and then infuse them into patients. This is an ongoing study in two centers in the UK. Patients have to be 18 to 70, have undergone liver transplantation in the last one to five years, and they have a DSMB looking at dose-limiting toxicities and treatment-emergent adverse events. So far, three men have been dosed once after inclusion. There were no dose-limiting toxicities, no SAEs, and no treatment-emergent adverse events considered related to the cells. And serial batches were able to be reproduced without CD8 impurities. They were able to also find the cells within the graphs on protocol liver biopsies, which was exciting, and they are resident among the liver allografts. And specifically, these CAR Tregs represent 15 to 65% of all the Tregs in the donor organs on post-transplant biopsy, highlighting that not all lymphocytes in allografts are bad, and we certainly are excited to hear more about this trial as the weaning begins. Tailoring immunosuppression treatment through follow-up liver biopsy program and pediatric liver transplants was presented by Mercado, Halle, and colleagues. This was a retrospective data collection of follow-up liver biopsies at year 2, 5, 10, and 15, and they had LFTs, TAC level, DSA, and elastography. Almost 200 liver biopsies were evaluated. A quarter of them had an RAI score greater than or equal to 2, and 45 of those patients with an RAI score greater than or equal to 2 had immunosuppression changed. Most had their TAC increased 10%, MMF added, and one steroids added. Of the 45 patients, 31 had a follow-up liver biopsy after that, when the immunosuppression had been changed. 80% had achieved normalization of histology. 15% did show improvement without normalization, and 5% no improvement. Of the other people, 11 had a completely normal liver biopsy and were weaned off all immunosuppression. Six had a follow-up liver biopsy a year later, and it continued to be normal. Three had to reintroduce immunosuppression, two for elevated LFTs, and one for an abnormal protocol liver biopsy. As a result, I conclude, at least, that immunosuppression can be directed with well-evaluated protocol liver biopsy. Outcome models are next, looking at human versus AI, a head-to-head comparison of predictive performance of MELD 3.0 versus the latest machine learning models by Dr. Charu and colleagues, as well as Dr. Kim. This was a UNOS registry evaluation, and they used the trading set that was identical to that where the MELD 3.0 was trained, and a 70% random sample of that data set from January of 16 to December of 18, over 20,000 registrants. The first testing set was the 30% left over, and the second testing set was new registrants from January to December of 19. The primary outcome was 90-day waitlist removal for being too sick or dead. And the machine learning models that they employed were random survival forests, gradient-boosted machines, deep hit, and deep serve. Variables included those in MELB 3.0, as well as a variety of other variables, including age, race, ethnicity, ascites, and hepatic encephalopathy. And once again, I thank Dr. Kim and colleagues for sharing this with me, showing how they came to their conclusions, which is that certain variables like accidents or medical errors or complications, we would never want to include in any type of predictive model. Age that can lead to discrimination or subjective variables like ascites and encephalopathy do improve the predictive power with a higher C-index that's statistically significant, but have been chosen not to be included for those reasons. Other variables that don't make a lot of biological sense, like hypernatremia and hyperalbuminemia, do not add to the C-index and shouldn't be included. And when the variables that aren't subjective and cannot lead to discrimination are utilized in other types of models like the random forest plots, the gradient-boosted machines, deep syrup, deep hit, there was no increase in the C-statistic found. Therefore, MELD 3.0 at least is here to stay for now. And the impact of MELD 3.0 on liver allocation more recently was shared with us as a late breaker by Dr. Kwong and colleagues. Today, the OPTN dataset was utilized comparing MELD sodium from January to July 12th of 23 versus MELD 3.0 from July 13th to January of this year. 10,000 new registrants were evaluated and over 9,000 recipients. Women were fortunately more likely to be listed by about 3%, and women were also more likely to be transplanted by almost 5%. Weightless dropout for being too sick or being dead decreased most for women, but also for men, and is now more in line, but still slightly higher for women at 9.1 versus 8.2 for men. MELD at transplant has decreased from 27 to 26 during that overall time, although women remain being transplanted at higher MELDs of average 29 versus 26 or seven for men. And albumin infusions can lead to clinically significant changes in MELD 3.0 scores in patients awaiting transplant by Dr. Aduda and colleagues from the University of Michigan. They retrospectively evaluated 472 listed patients at their single center with over 2,000 MELD calculations. The average MELD score was 20, and they simulated a MELD increase based on an increase in the serum albumin of 0.7 as well as 1.5, and stratified patients based on their MELD score of less than 15, 15 to 18, 19 to 25, and over 26. Not all MELD scores were affected equally, and they were most affected between 15 and 25, and those in that category, if the albumin increased by 0.7, 38% had a decrease in their MELD of 1.6% too. If their albumin increased by 1.5, there was a 30% decrease in 1.13 two points and 2% three points. So we certainly want to keep that in mind, especially if you're transplanting in the low to mid 20s. The Liver Transplant Comorbidity Index, a composite index of ambulatory pre-liver transplant factors to identify patients at increased risk for post-transplant mortality, was presented by Dr. Verna on behalf of Dr. Lai. This was utilizing the Frailty Study, which was a prospective eight-center study of outpatients awaiting deceased donor liver transplant from 12 to 22. They defined liver frailty by liver frailty index closest to transplant, and then utilized a Cox Proportional Hazards Model to develop the score. The goal was to predict simply the three-year post-liver transplant risk for death. They had about 1,500 patients, 20% were frail. The average age was 60, about a third women. Average MELD score, 17. Coronary disease got you six points, frailty five, HCC five, and elevated creatinine three, and diabetes one. Low risk was zero to six, intermediate seven to nine, and high risk 10 to 19. Low risk patients had a three-year mortality, or three-year survival of 89% versus 71 in high-risk patients. ACLF criteria and alcohol-associated hepatitis, certainly significant implications for liver transplant by Dr. Diaz and colleagues. This was a multi-center prospective study of consecutively admitted patients with severe alcohol hepatitis. From 15 to 22, at 24 centers in eight countries, almost 650 patients, pretty young at 50, mostly men, median MELD 25, almost half had steroids, very few transplanted at 2.2%. A third did not have easel-cliff ACLF, two-thirds did, with 10% grade one, 19% grade two, and 38% grade three. And in multivariable analysis controlling for age, BMI, MELD, only ACLF grade three by easel-cliff increased the hazards ratio for death. And those patients had a very high mortality at only a 28% survival. Turning our attention to disparities, liver transplant disparities in listing to death ratio and mortality from 99 to 2001 was presented by Dr. Zhao from Dr. Rosenblatt's group. They utilized the CDC Wonder database to analyze cirrhosis and HTC deaths and then cross-referenced it to the UNOS liver transplant data set. They analyzed people between ages 25 to 64 and their primary outcome was listing to death ratio, although they did analyze the annual percentage change. During the time period, over half a million people died and importantly, the deaths per year doubled. The average percent change was 3.3, but the greatest change occurred in women and Hispanics. During the same time period, 200,000 and change people were listed for transplant. There was an annual percentage increase in transplant per year with the greatest increase also happening in women and Hispanics. But unfortunately, we want the listing to death ratio to be going up and the listing to death ratio, despite advances in improved access and increased donor organs, continues to go down. So this really highlights how significant we are, at least in the US, having real severe problems with increasing death from liver disease and not enough access to transplant for everyone. And the current burden and geographical disparities in liver mortality and access to transplant was continued by Nick Rinella and colleagues, similarly using the CDC Wonder data set, evaluating liver-related mortality and cross-referencing it from the UNOS data set from 2018 to 21. The crude rate of liver-related mortality was 28.1 per 100,000 in 21, which represented a 20% increase over 18. There was marked variation by state by up to fourfold with Utah being the lowest and New Mexico being the highest. And liver-related deaths per transplant also had considerable variation at 7.2 in the lowest quintile and 21.5 in the highest quintile. States with the highest liver-related mortality had lower median household income and the highest percentage of people living below the poverty line. But paradoxically, the rates of liver transplant are actually lowest in residents of states with the highest liver-related mortality. Geographic disparities in liver transplant waitlist outcomes for critically ill candidates, the impact of population density amid the acuity circle in the United States presented by Dr. Tanaka and colleagues utilize the UNOS data set only looking at deceased donor transplants from June of 13 to May of 23. And they separately analyzed high-meld patients defined as greater than or equal to 37 and the population density in 150-mile radius around them versus ALF patients and the population density 500 miles around them. They analyzed the data pre-acuity circle and post-acuity circle. With high-meld, there are almost 4,000 patients in the pre-acuity and almost 1,400 ALF patients, post-acuity high-meld 2,300 and almost 900 ALF patients. The population density did not affect outcomes in ALF patients. However, the lowest tertile of population density increased waitlist mortality in the high-meld patients with an adjusted odds ratio of 1.68. And for every one unit increase in log-transformed population density, this reduced waitlist mortality by 15%. Turning our attention to metabolic disease, which has been a lot of this conference, the impact of GLP-1 agonists on metabolic health in liver transplant recipients was presented by Dr. Spengler and colleagues. This was a retrospective evaluation of 76 liver transplant patients with diabetes and they propensity score matched people with by age, gender, ethnicity, MASH etiology, and immunosuppression based on whether they were being treated for their diabetes with a GLP-1 agonist or insulin. Weight increased in the group who was receiving insulin versus decreased in the group taking GLP-1s. And on Fibroscan, CAP was high in those on insulin and much lower in those on GLP-1s. The immunotransferases also decreased in the GLP-1 group from 36 to 31 and increased in the insulin group from 29 to 50. And last but not least, sleep disturbance is associated with frailty, impaired physical function, fatigue, anxiety, and depression in liver transplant recipients, results of the LiveCOG Cohort Study by Dr. Kim from Marina Serper's group. This is a prospective study called the LiveCOG Cohort Study from four US liver transplant programs. At 90 days post-transplant, the patients wear a wrist actigraphy for eight days to measure their time in bed, sleep duration, and sleep efficiency. I'm guessing all of you have had short sleep duration during this AASLD at less than six hours, but probably your sleep efficiency has been better than 80%. Subjective sleep disturbance defined by PROMIS sleep disturbance T-score of greater than 55 was also analyzed, and frailty was defined by the LFI at greater than or equal to four and a half. 99 patients were evaluated, the median age 57, a third of them women. The average time patients spent in the bed was seven hours, 85% sleep efficiency, 57% had short sleep duration, and 26% short sleep, poor sleep efficiency. Subjective sleep disturbance was reported by 45%. Objective sleep measures of poor sleep efficiency were correlated with frailty even after adjustment, and subjective sleep measures being poor were correlated with poor physical function, fatigue, anxiety, and depression. So in conclusion, at this year's AASLD, 279 of the abstracts covered a myriad of liver transplant topics. Disparities in liver transplant still exist, but fortunately MELD 3.0 has taken an important step in the right direction. Outcome models continue to improve, immunosuppression personalization is certainly a worthy goal which we must continue to study and strive toward, and machine perfusion continues to be an exciting area of exploration. But ultimately, liver transplantation remains an unfinished product that requires continued investigation and advancement, and I certainly know that you all are just as excited to hear the next advances as I am. Thank you so much. Thank you.

liver transplantation

disparities

biomarkers

immunosuppression

machine perfusion

MELD 3.0