Well, good morning, everyone. Welcome to our session, Innovation in Transplantation. I want to invite our program chair, Dr. Goldberg, to have a seat on the panel. And thank you for the opportunity. My name is Pratima Sharma. I am the vice chair for liver transplant and surgery SAIG. And we have Dr. Somaya Abulishi. She is one of our at-large member. We have an all-star lineup. And I want to invite our first speaker, Dr. Tector. Dr. Tector is a professor of surgery at University of Miami. And he has done some seminal work in xenotransplantation. We are so delighted to have him here. Thank you, Dr. Tector. It's your turn. Thank you. I'd like to thank the organizers for inviting us to talk about this. Okay. Great. Thank you. All right. So, I've got a lot of slides, so I'm going to move it. That's my disclosure. So, in 2015, Jose Estrada, in coming out of my lab, described a triple knockout pig that has three key enzymes, glycan enzymes, that produce xenoantigens deleted, and that is the alpha-1,3-galactosyl epitope. There's the SDA antigen, which is made by the beta-4-galant 2-transferase, and then there's N-glycolylaluminic acid, which is made by the semahydroxylase enzyme. So, when that was deleted, the exciting thing about it was, you know, people have antibodies against pigs. And so, when we draw blood from a person and we run a PBMC cross-match in a wild-type pig, they're all genetically identical, but they have a very large amount of IgG, significant amount of IgM, that's going to be hyperacutely rejected. If you knock out gal, you can see that this is a better cross-match, but it's still quite positive, and that person's going to reject it with kidney, for instance, in about six days. The semah gal cross-match is much better. It's better than a chimpanzee cross-match, so that's exciting, but it's still reasonably positive. However, for this particular patient, when you knock out all three glycans, that's a negative cross-match, and you would not expect to have early antibody-mediated rejection. On the bottom here, we looked at 44 patients, IgG is on the X-axis, IgM is on the Y. You want your dot to fall somewhere in here. You can see that for the wild-type, nobody has a negative cross-match. The gal knockout, they're getting in the range. Semah gal, it's improving, and for the triple, it's better. So it's fully 30 percent of people have no detectable antibodies to these pigs, so that you wouldn't expect them to have AMR. So with that in mind, we started to evaluate pig kidneys in non-human primates, and we have been able, over the last bunch of years, with relatively simple genetics. We now have more than 28 animals out over a year, 16 using this particular very simple gene modification combination, the gal knockout with the CD55 transgene. And then we did T-cell depletion, some B-cell, one-shot of B-cell depletion, and then cell sub-steroids and an anti-CD154 antibody. This animal here went out one day short of five years with a pig kidney, and half of the animals are out over a year. That's important because if you look at it now, we're getting in the 70 to 72 percent range go out a year. Eighty percent of non-human primates receiving a renal allograft go a year, so we're close to allograft survival. Because of that survival, and because of some of the stuff done in Germany and at the University of Maryland in the non-human primate model, because of that, the University of Maryland initiated a clinical compassionate use program, and they transplanted two people with end-stage cardiac disease that were not going to be receiving an allograft, and they received pig hearts from pigs that were genetically engineered for the three glycan enzymes that we talked about, and they also had six additional human transgenes. One was immunosuppressed with an anti-CD40 antibody. One was immunosuppressed with an anti-CD154. Both patients died less than two months from antibody-mediated rejection, which signals the need for much, much better cross-matching, which we've spent the last 10 years doing. So our initial foray into the liver xenograft space was in 1994 when I was in surgical training at McGill in Montreal, and so we hooked five people up to pig livers long enough to keep them alive for transplant. This is one such patient. She had ex vivo circulation. That's the pig liver. That's her three weeks after the perfusion and a subsequent liver transplant. That's her probably 20 years later. She's in her early 80s now. So when we looked at these five livers and evaluated them, it was interesting. They had what appears to be a lot of steatosis, which is actually not steatosis. We misidentified that, and they had a lot of neutrophils, which is consistent with an antibody-mediated injury. They had a lot of IgM on the surface of the endothelium, and so that prompted us to start an in vivo program. So we put dog livers into pigs. It's a weird model, but that's what we did. And so the cause of death was an immediate exsanguination from thrombocytopenic coagulopathy, and you can see here that within five minutes, all of the platelets are gone. It was not because of venous bypass, and it's not something that happens in a kidney xenograft. When we looked at the coagulopathy, they had fibrinogen levels that were consistent with the ability to clot throughout. Their PT did not drop, and their coagulation factor levels were consistent. So this was not due to coagulation dysfunction. So we evaluated platelet function using sonoclot analysis. So this is a piston, and you put blood in a cup, and then you measure the resistance to flow. And as fibrin polymerizes, you get resistance to the probe moving, and then the platelets start to aggregate, and so that it contracts a little bit, and that's this peak here. And then this peak here is when the platelets contract because it pulls the clot off of the piston and off of the wall so that it can move easier again. So when you look at it in this model, a pig-to-pig liver allograft, the platelet function was normal. Veno venous bypass, it was relatively intact. They were heparinized a little bit. You can see in a xenograft, they had no platelet function for liver xenograft, completely absent. This is a renal xenograft with veno venous bypass. Just eliminate those variables, and the platelet function was normal. So now I'm going to draw your attention to the world experience with non-human primates. The only thing I really want you to get out of this diagram or graph is that the survival is measured in hours, okay? So the longest here was 10 days. I think the longest survivor now has been somewhere around 29 days, so we're still a ways away. This is work from Birch and Exer and working with David Cooper, then at the University of Pittsburgh, and they transplanted gal knockout with CD46 transgenic pig livers into baboons, and I want to point your attention to the cause of death in the animals. Most of the animals was bleeding in the abdomen, bleeding in the lungs and abdomen, bleeding, bleeding, bleeding. And if you look at the platelets count, it drops down to almost zero very quickly, and it stays there for more than 10 days. So we wanted to look at the pig liver and see what antibodies did, so we took pig liver endothelial cells, wild type, and put human serum on them and then looked at them with a confocal scope. This blue is the nucleus, and you can see that the IgM is bound up in kind of looks like some kind of compartmentalizing inside the cell, and if you blow this up in a big deal, the other thing is you'll see that IgG is also internalized. So the next thing we did is we evaluated platelets in the absence of antibody, or so we thought, so we isolated the platelets, we washed them, we made sure there was no antibody in the effluent, and then we put a CFSE green label, and then we ran them through a perfusion circuit in a pig liver. And what you can see is within 15 minutes, all the platelets were gone again, whereas the pig was different. And if you want to look at the pathology, you're going to see that at time zero, there is no vacuolization, but here at 15 minutes, you start to see vacuolization. It is not steatosis, and you need to think about that when you're doing allografts, when you're looking at donor liver biopsies, but at 30 minutes, it increases, but by 60 minutes, you can see that it's starting to clear up, and by 120, it's gone. And so you can see that there are platelet fragments, platelets in the endothelial cells, and you can see these big water vacuoles, okay, so that's what these are. So we wanted to trace the course of these platelets going through the liver, so we did some confocal microscopy, and you can see that this is a pre-perfusion biopsy, so this is CD31, which outlines the sinusoidal endothelium. LAMP1 is lysosome-associated membrane protein, which is important in endocytosis, and the platelets are green. At 15 minutes, you can see the green platelets are starting to become yellow because red and green makes yellow, and that means that they're becoming intimately involved with the endothelial membrane, and you can see over time that dissipates, and you can start to see the hepatocytes becoming brown as these get cleared all the way through. So that, you're watching how platelets get pushed through the liver in this situation. So then we wanted to look and say, okay, are they actually endocytosed? So we, again, put CFSC-labeled platelets on liver sinusoidal endothelial cells, and then did confocal microscopy, and when you look at these shots, you say, gosh, that could just be sitting on top. So we did what's called Z-stacks, and those are like CT scans for cells, so it takes multiple cuts. And this is the important picture right here, is see, you can see that there's the endothelial cell membrane, and the platelet is actually underneath it, and it's intimately associated with LAMP1, which indicates it's phagocytosed. Meanwhile, the rest of the world was looking at this. They were doing gal-mock-out pig livers. This is from Parseidography at Mass General, and putting them into baboons. And they did, the immunosuppression is not that relevant. They used a lot of coagulation factors. Nova-7 was the big one, and you can see here that the platelet count drops to almost zero and stays there for 10 days. Now the longest survivor they were able to get was about 29 days, but their pigs were dying, their recipients were dying from coagulation problems. They have like carotid artery thrombosis, portal vein thrombosis, and so they were actually dying from the treatment to try and prevent this. Jim Markman at the Massachusetts General Hospital then started trying to deplete antibodies in the recipient before they got the transplant, and so they would take the baboon and they would perfuse their blood through kidneys, pig livers, or lungs. And what you see here is they died from early liver failure with coagulopathy. So antibody removal did not improve survival, so that left us a little bit confused. Greg Martens in my lab then at the University of Alabama Birmingham at the time said to me, hey, I think there's probably antibody inside the platelets. And so the question becomes, do platelets have internalized antibodies that could tether the platelet to the sinusoidal endothelial cell and result in phagocytosis? And the answer to that we're going to show you a little bit. So platelets do contain IgG and IgM and alpha granules. IgG, in fact, is the second most abundant protein in an alpha granule. IgM is also present. And so the platelet may come loaded with its own internal endothelial tethering mechanism. This activation could lead to extrusion of alpha granules and anti-pig antibodies could be present on the platelet surface in the absence of serum antibodies. And so the mechanism doesn't require serum antibodies, and so it could explain how removal and absorption studies did not work to alter the thrombocytopenia. So when we looked at human platelets, CD62 is a marker for endosomes and alpha granules. And so you can see that there's a lot of CD62, there's a lot of IgG inside a human platelet. And when you merge them, they co-localize, and you can tell because it changes color. If you look at IgM, the story is the same. You see the CD62, there's a lot of M, and they change color. This is electron microscopy showing a number of platelets. This is a large view of one platelet. That's an alpha granule. That's an alpha granule. You can see all these alpha granules. That's just a larger shot. When we immunolabeled antibody, human antibody, and put it in the media with the platelets, they got internalized into alpha granules. You can just see that with the yellow arrows. So then we took the platelets, and we wanted to say, okay, with Western blotting, can we show that there's IgG, and we did. And then when we activated the platelets, there was more, and we did the same thing for IgM. When we took those eluted antibodies and put them on glycan arrays, you can see that there was no binding to blood group H, which they should not be. That's our negative control. But they had a lot of antibody to the gal epitope. They had a lot of antibody to N-glycolylaluminic acid, which is a SEMA product, and they had significant antibody to the beta-4-gal-NT2 transferase product. So then we took endothelial cells and made sure wild type and triple knockouts, and we can show you that these are endothelial cells. They both have CD31. Then we looked for gal. The knockout does not have any gal. The wild type does. Then we looked for new 5GC, the SEMA product. The wild type had it. The knockout did not. And then finally, we looked for the DBA lectin, which shows the beta-4-gal-NT2. That was also devoid. And you can see with three different platelet preparations that there was more binding to the wild type than the triple knockout. So that's a big improvement. When we looked at the – we isolated the platelets with – and looked for – on endothelial cells, you can see that IgG and IgM is definitely inside of the platelets. So we looked for ex vivo support for this theory using gene-edited livers, and so we went back to the same model where we take the liver and perfuse it with platelets. And what I'm going to draw your attention to here is the wild type livers at 50 minutes have less than 10 percent of the platelets they started with. The gal knockout, there's still probably too much antigen left, so that there wasn't a big difference. But when you knocked out two, the gal and SEMA, you can see that that improved significantly. So it's likely that thrombocytopenia occurs as part of antibody-mediated rejection. So what are our next steps? So we're evaluating triple knockout pig livers in the ex vivo setting, demonstrating that phagocytosis is greatly reduced by perfusion through the triple knockout liver. We're setting up a xenoantigen deletion pig livers in a non-human primate transplant model so that we can do long-term evaluation of thrombocytopenia, and metabolic evaluation of the pig liver in a preclinical setting can now be started. We're developing testing immunosuppressive strategies, and it's a clear opportunity to identify the next barrier. In addition, we're setting up a human decedent model where we're going to put triple knockout pig livers in and develop preclinical in vivo human data, again, to evaluate thrombocytopenia and coagulopathy in a clinical model. We'll also be able to evaluate the clinical hemodynamics, and we can provide a short duration, four to seven days. If that's successful hemodynamically, we ought to be able to use that as a IND for a bridge to liver xenograft, and it's an opportunity, again, to identify the next barrier. So planning for this is going to be critical. There are many details. If you don't pay attention to them, you're not going to have a successful outcome. And the other thing that's really important is I think you need to adhere to all the principles that you've developed in the experimental lab. So blood banking is going to be critical. I don't think you're going to be able to do a liver transplant without any blood products, not on a chronic basis. So we have to quit making the same mistakes. In 1970, Dr. Starzl described a series of chimpanzee livers, and in this particular case he was trying to get a great cross match, and so they did a lot of immunologic studies, and they had to give the kid a lot of transfusions, and that made the cross match terrible in that the child died in less than 24 hours because of AMR, and he described that. But unfortunately, in 1984, when Leonard Bailey did Baby Faye, they had a medication error, and they gave IV cyclosporine, they gave it IV push instead of over 24 hours. So to combat that, they gave exchange transfusions, and that gave all of the new 5Gc antibody that babies don't have, and so that resulted in graft loss. Leonard McKauk, in 1993, published in 1995, put a pig liver into a 26-year-old woman dying from autoimmune hepatitis, and he put it in heterotopically. They perfused her blood with pig kidneys, and you can see it dropped the antibody levels precipitously, but they kept giving FFP, and you can see that he kept repleting the antibody levels, the xenoreactive. And with each successive unit of FFP, when they put the serum on pig endothelial cells, you can see that the viability of the endothelial cells dropped. So we have to quit doing that. Unfortunately, in 2022, when they did the first cardiac xenograft, they gave the patient IVIG for hypogammaglobulinemia, and again, triggered antibody-mediated rejection. So we have to quit making those mistakes. Now I'm going to give brief attention to surgical and perioperative considerations. So we've done a series of pig livers that we've put into human torsos, just to work out the technical procedure. And the pig liver is much flatter than the human liver, because the pig stands, so the liver hangs right off the vena cava. So you're going to need to use a liver from a donor that's about 50 to 70 percent the size of the recipient. That's going to be an important consideration. Another important consideration is because the liver is very flat, it drops its temperature very, very quickly when you put it in ice, and this is data from Paragonix that Jake Miles provided for me, it's nice enough to do. And so you can see that at 12 hours, this liver, using infrared thermal imaging analysis, is basically frozen, and it's going to have a burn injury, and so that's very bad, so you don't want to have that. So as a result, we're going to use a Paragonix liver guard for transport to prevent cold thermal injury during the transport. And this is just saying, so we looked at it specifically. This is one of the torsos. It's going to be relatively straightforward to do this piggyback on the left and middle hepatic vein. So which patients does it make sense to enter the clinic? I think that's going to be the next really important consideration. We're going to target patients with acute and chronic liver failure, grade two and three. If you think about the ACL, acute and chronic liver failure grade three, those patients have a greater weightless mortality at 14 days than a status 1A patient, but if you look at their survival post-transplant, it's in the 80s or high 80s now, and that continues to improve. Their long-term survival is quite decent, and so that's where we're going to start. As far as putting these graphs into patients with acute and chronic liver failure, I think it's going to be critically important to be very, very strict about your adherence to your selection criteria to be successful. If you look at the transplant for acute and chronic liver failure model score, if you have a score greater than two, you have an 8% one-year post-transplant survival. We're going to steer away from those and focus more on those with a TAM score of less than or equal to two who have more than an 84% one-year post-transplant survival. The other thing to consider is that patients with MELD scores less than 35 have limited access to transplant through the current allocation schema. And the other problem is MELD sodium significantly underestimates the risk for mortality or delisting in patients with lower MELD score with acute on chronic liver failure. So in conclusion, thrombocytopenia and liver xenotransplantation is the result of anti-pig antibodies that are inside of platelets binding to antigens on the pig liver sinusoidal endothelium. Xenoantigen deletion is a strategy that will eliminate this barrier, and it's something that we should continue to pursue. Triple knockout pig livers, if they eliminate this thrombocytopenia in our decedent model, then we should be able to use the pig liver as a bridge to allotransplant as a way to introduce this to the clinic. Patients with ACLF and lower MELD scores, i.e. less than 30, may be ideal candidates for an initial bridge trial. And the development of non-anti-pig antibody-containing blood products is going to be a critical element of developing and implementing clinical liver xenotransplantation. So with that, I want to thank the people in my lab that have done so much work, particularly Jose Estrada, who's the DVM PhD, who's made all these pigs. I want to thank the University of Miami, Meccano Therapeutics, which is the biotech company we spun out of our lab in Indianapolis that's going to support the clinical trial, Cytotherix is the barrier facility we're using to raise our clinical-grade pigs, and I certainly want to thank Paragonix, and I certainly want to thank Andrew Adams at the University of Minnesota for all the work they've done. Thank you. Thank you, Dr. Tector, it was a great presentation. Thank you, Dr. Tector, appreciate it. Our next speaker is Dr. Allison Kwong. Oh, I want to say that we will save the questions until the end of the presentations, I apologize. So the panel discussion and the Q&A will be at the end of the presentations. Our next speaker is Dr. Allison Kwong. Dr. Kwong is a transplant hepatologist at Stanford University. Her clinical and research interests include cirrhosis, portal hypertension, and outcomes before and after liver transplantation. Dr. Kwong, the floor is yours. Thank you. Thank you. Oh, it doesn't, it shows up there, okay, all right, so, am I, is that, is it coming? Yeah. Ah, okay. All right, I have nothing to disclose except, oh, yes, I have financial disclosures. I am on the, wrapping up a term on the OPTN Liver and Intestinal Committee, so, which is a very volunteer position, but a lot of this data comes from my experience on the committee over the past few years. I am also a transplant hepatologist, not a surgeon, and in the United States, so a lot of the data also will describe the U.S. experience. And specifically, I am also a hepatologist in California, which I also speak from, from that experience, which I, is not representative, necessarily, of the entire United States. We'll go through recent updates to the OPTN allocation distribution policy and the evolving landscape of liver transplant and what that means for future directions for U.S. liver allocation policy in the next few years. This is the root of the problem, that demand outpaces supply. We're doing, the red line is transplants. We are doing more and more transplants every year, but there's still a huge gap between the number of transplants and the size of the waiting list, and we continue to add more patients, more new registrations as well. So that creates tension between, well, these ethical principles, but also a lot of different people who have different ideas of how an allocation system should be designed, the basic principles, balance, utility, and equity, so, you know, optimizing medical benefit, quality of life, but also trying to give patients fair access, and that is, can be defined in several ways, or targeted in several ways, giving everyone equal opportunity, trying to prioritize the worst off, or those that are the closest to death. Variatings is related to trying to give everyone the same life opportunity for the same life milestones, so that's how pediatric priority comes in, and for livers, we don't do very much first come, first serve. So the system we have now prioritizes those who are the sickest, so urgency-based, those are closest to death, and that happens to be also the people who have the greatest medical benefit in terms of years of life. No allocation talk is complete without mentioning the final rule, but it's written into law that the system's supposed to provide equitable access based on sound medical judgment to achieve the best use of donated organs. You've all heard these terms, to avoid wasting organs, to promote patient access, and promote the efficient management of organ placement. No system, I think, can do this all at once, but should try its best to fulfill these terms. That's how the system we have now exists, so it's an urgency-based system, it's really driven by, or the rankings are driven by the MELD score, with some updates over the years, and then exceptions for patients who still need liver transplant, but don't have chronic liver disease. And then also, the distribution policies have evolved as well, so how far these organs can travel with regional, national sharing, and now acuity circles. So we'll go through these most recent policy changes, and what that means for the current state of liver transplantation, and beyond, which here is continuous distribution. So we've all lived, or many of us have lived through, this is what we live through now, is acuity circle-based distribution. You might remember donation service areas, that's where these colors show different median MELDs at transplant, and the idea was to make this a little bit more even, so now we live in concentric circles with around the donor hospital, 150, 250, and 500 nautical miles by decreasing MELD bands. So this was intended to try to make the unit of distribution more regular, and less arbitrary, and even out the median MELDs, so people weren't going, for example, from California to Tennessee for their transplants. What was the effect? Well, the effect was, it wasn't, a lot of this was intended, so broader sharing, reduced geographic variation, we saw decreases in the variance in the median MELD at transplant by DSA, state, and region. The overall median MELD actually was projected to increase, but actually stayed the same around at 28 for adults, and dropped for pediatrics because of increases in pediatric donor priority, and there were more transplants and fewer waiting list deaths, so this was all intended, and also, secondary effect was more, which we knew would happen, but not kind of to what extent, was longer travel times and decreased efficiency in the system, so that's reflected in the median sequence number of these organs going at sequence 5 in the pre-Acuity Circle era to sequence, median sequence number of 9, just reflecting and more offers, more work, more burden on the system for specific, particularly, OPOs and surgeons. This is the most recent policy change that just took effect a few months ago, so updates to MELD, these are the MELD equations, MELD 3.0 adds sex, albumin, and some interaction terms, as well as updating the coefficients, so the equation's a bit more complex, but the idea is that it outperforms MELD sodium in predicting wait list mortality, and importantly, the discrimination, so how patients are ranked on the waiting list in terms of their medical urgency or risk for death, it's felt to be more accurate for the current population of patients with liver disease, and importantly, corrects the sex disparities, so I always show these slides so you can see that the women have just, since the implementation of MELD, have had a lower transplant rate compared to men, and because of that, they have excess or higher wait list mortality, and this is multifactorial, but a part of it is the creatinine term and the MELD score, and that underestimates renal dysfunction or mortality risk when women have renal dysfunction. There's also issues with height and body size, which we'll get to, but they have a smaller donor pool and are waiting longer for size-appropriate donors, and that's part of the problem as well, but MELD 3.0 is intended to kind of fix this problem. You can see under MELD Sodium, these are SRTR simulations or LSAM simulations that under MELD Sodium, men in blue have a higher transplant rate than the women who are in red, but MELD 3.0 is predicted to equalize this and improve equity in the system, particularly for women who've been disadvantaged. So we'll see the effects. I think early data show this is working, but we'll see kind of the full impact and what we're living in now, but we'll see it in the next few months, too. So at the same time, PELD was updated for the first time in 20 years. It's a more complex equation, but the addition was creatinine to the PELD score and as well as a factor for age-adjusted mortality to bring them kind of on the same level as adults with the MELD score, and so the effect of this is also to better predict mortality for the children and perhaps maybe that they wouldn't use so much of the exceptions. So that brings us to the exception point system. There's still a not significant number of candidates and transplants with diagnoses that aren't reflected by the MELD score, which is built for patients with end-stage liver disease. So it's still about 30 to 40 percent of the pediatric waiting list and 15 to 20 percent of the adult waiting list. The system changed or the shift from regional review boards to NLRB in 2019, but the other big change at that time was that things were pegged to medium MELD at transplant. So that brought overall lowered the number of exceptions by transplants that were doing with exception by lowering their wait list priority. HCC, at least for adults, is still the most common exception. I've listed the policy-approved exceptions kind of by decreasing prevalence here. So there are pathways for these patients to be transplanted, and the committee's been working iteratively over the past few years on updating guidance for other diagnoses to better reflect their mortality. So polycystic liver disease gets median MELD now. A provision for DCD ischemic cholangiopathy in recipients of DCD livers get median MELD. And then the most recent update has been that the liver and intestine committee felt they needed more priority, or the liver and intestine community felt like they needed more priority. So they actually are recommended to get median MELD plus six. So these are all updates in the past few years to the guidance, which still needs to be reviewed by the NLRB, but there are recommendations for scores. And just a preview of what's coming up in the winter cycle is that actually there are proposals, and this might be a bit crazy, but there are proposals to give priority for intrapathic cholangiocarcinomas and colorectal liver metastases. So that's coming up within the next year for comment. So what does that bring us now? Transplant in November 2023. We're doing more transplants. Still the majority is deceased donor. There's growth in DCD, machine perfusion we'll hear about. And we're seeing excellent survival. This is 89 percent at three years, and obviously even better at one year. As a hepatologist, alcohol, or this, I always show these trends because this is the most, I think, important or consequential thing for our practice, is that this runaway pink line for listings and transplants is alcohol, and that's really changing our day-to-day practice. So we're already seeing the effects of this in allocation and transplant, and we'll have to deal with this soon. And I think the hardest thing to address is just, and this is an ongoing issue, is ongoing geographic disparity and trying to make an allocation policy that works for all the different corners of the United States. So these are projections from the old DSA system, I think from 2018, where there was a lot of variation in the median meld at transplant, and the projection was that it would become a nice sea of blue where the median meld would be around 29 to 31 for everybody. This is what actually happened. The color scale's a bit different, but it's not all blue. So this is two years before and after acuity circles, and there's still a lot of variation in their pockets of green and purple still. So just taking donors from one place to another or rearranging the donors didn't necessarily fix the problem. So why did this happen? I mean, we see longer travel times, more cost, more logistics, maybe affecting utilization. There were differences in center practices that are happening, and so the high meld patients or centers doing more in high meld areas are, if you look at it, listing more patients with high meld, which, as hepatologists know, a lot of them are alcohol, more use of marginal organs in areas with lower median meld, so you could see that centers were changing their practice or being more aggressive or adapting to the allocation system by becoming more either aggressive or using more marginal organs. So that wasn't necessarily modeled or predictable in simulation. So there's a lot of things that contribute to the variance in median meld at transplant. You know, waiting list populations are different, center practices, OPOs, so even neighboring areas might have different median melds, and so it's we see more clearly that it's not all about the variance in the median meld at transplant and that we need to pay attention to center practices, OPO performance, and it may not be realistic to try to get everyone at the exact same median meld. The other thing about the circles is that, yes, maybe the borders are more regular than DSAs, is that a lot of us live in areas where half the circle is in the ocean. These are 250 and 500 nautical miles around my center, but I feel worse for Seattle and San Diego and Florida, which don't have any eligible donors in most of their circles. So this is a problem, a different kind of problem that also needs to be, you know, circled. The circles are not the same everywhere. So I'm glad I think the community is paying more attention. Equity is written into the final rule, but so it's been there, but I think we're still starting to try to figure out and understand where those levers should be that we can actually improve equity in the system. You know, I think everyone understands, you know, everyone should have equal opportunity to transplant, but who should get those boosted, who should get that boosted, and how we're going to do it is still kind of up in the air, and what we have seen is that it's not just about the variation in the median meld, but there's also differences in the waiting list and the donors that also need attention. And that a lot of our data also comes from, we can capture from listing to transplant, but a lot of it happens at the population level, and then even making it to the doorstep of transplant centers and getting referred, and then on the list, there's already, here you can see this map from showing the listing to liver-related deaths, and you can see the geographic disparity starts a lot earlier. And just, I like subway maps, this is from the SRTR, but just that you can see there's a lot of stakeholders and that a lot of places that patients can fall through, but also that any policy will have a lot of different kind of unintended and unintended effects. So this is the UNOS plan to try to improve the allocation system for all organs, so this is how UNOS feels this is going to fix the problem or improve the allocation system. So different buckets for various attributes, medical urgency, patient access, efficiency, and that together can become a score that can be used to rank patients on the waiting list. And so this is what it would look like, so instead of the table, kind of the tables we have now is that you would assign different points and weights for these attributes and that it would add up to a score that would, and that's how the match run would look. And what points, what attributes that would be and what points, how many points people would get is what we've been working on. So we're kind of in this middle area of building the framework and about to do the modeling. Lung has already gone ahead with implementation and kidney is a little bit ahead of us and heart is a little behind us. So all the organ systems are going through this. The liver committee has identified some attributes or these attributes that will that they want to put into the liver allocation system into this framework. So MELD is still going to be there, status 1A, status 1B, pediatrics, a lot of things we talked about but it will also give us a chance to add in attributes like height, body surface or height or body surface area, maybe try to encourage split living donation or split liver donation and then really drill down or focus on what efficiency metrics are important or to optimize for. So hopefully some of you participated in this community exercise to understand what there were several hundred responses but it looks like at least, you know, medical urgency is important to us and so MELD or something like it will be very highly weighted still. So it's still going to be a MELD or urgency-driven system. Pediatrics also will preserve its really high priority, biologically difficult to match was also important, that's kind of the height angle or body surface area angle. And then distance is still important, you know, a very nearby candidate but kind of on the lower end. So this will help, this helps the community kind of decide what the weights, what starting weights we should use to put into the system. This is one solution to the circle problem that's proposed so population density circles so everyone gets a kind of different, there's no more, you know, 150, 250, 500, everyone gets a different size circle depending on, you know, what their underlying population would be. So that's just one proposal that we could do or will do so for some people that might be welcome to use that acuity, that the current acuity circles will change. So this still needs to be modeled but it's one proposal to fix the system. I will move more quickly about, so I think I have to mention survival benefit-based allocation. This comes back around every year but whether post-transplant survival should explicitly be in the system, MELD, you know, fortunately actually represents a lot of the transplant benefit but maybe there's some kind of variation in the post-transplant survival that should be accounted for. Why would we include it? There are a lot of reasons to do it, you know, organ allocations, it maximizes utility, other organs do do it but then the committee kind of got stuck trying to figure out, you know, how it would be measured, what is the right threshold. We were looking at models that said, you know, 10 year, 50 percent survival which other people thought was actually pretty good so no one could really decide, you know, what was futile and then five and 10 year survival is harder to predict so then what about one year but then there's already a lot of focus on one year outcomes in our system and that wasn't clear what that would add necessarily to the current system so the final, this was a lot of pros and cons and back and forth. It's not going to be in the first version of continuous distribution but I'm pretty sure that it's probably not the last we're going to hear about it. So this slide originally said this is going to happen in 2025 and kind of maybe 2026 at this rate. The largest weight will still be medical urgency and we'll still have the priorities we already set out in the current system but it kind of gives us the opportunity to add in areas where we can improve equity and efficiency like flying versus driving or trying to place marginal organs without having to go down like 100 people down the match run. This is all occurring in the context, yeah, this is all occurring in the context of the NASEM report which was kind of critical about the current transplant system and how we could improve donation and efficiency and decrease non-use and variation in the system. So there is kind of stuff going on in the background that I would direct any questions to Dr. Goldberg about but this all may be very different next year and I cannot predict the future but that the contract which has been held by UNOS to manage the OPTN may be broken up or very different in the next few years. So I hope I've shown you, you know, that the allocation system is complex. There are utility and equity principles to consider and then also that the field of liver disease is just changing so rapidly that it requires us to kind of be very flexible with how the allocation policy serves everyone equally or equitably at least. You know, I think that's demonstrated by the growth in alcohol-related liver disease. We're having talks about how turleypressin affects our transplant practice and we'll hear from Angie about machine perfusion. Continuous distribution is the plan to, you know, and hopefully a more flexible system to add variables to improve the system in terms of equity and efficiency but everything I said about continuous distribution might go out the window next year but regardless whatever system we have, we'll have to contend with these same issues. Thank you. Thank you, Allison. Our next speaker is Dr. Angie Wall. Dr. Wall is an abdominal transplant surgeon and bioethicist at Baylor, Scott & White Transplant Institute in Dallas, Texas. Her clinical research interests include transplant policy, ethics, ethical and clinical questions in uterus transplantation. Dr. Wall. I think we should, because I think this, because I think then you're like, oh, mine? Yeah, okay, perfect. Sorry, I don't need a standing stool for this. I usually do an EOR. All right, so what I'm going to talk about is how marginal organs and machine perfusion are the, provide the greatest potential for near-term growth in liver transplantation today. I don't have any disclosures. We've talked about the increase in deceased donation in the U.S. already but what I want to point out in this slide is that we've been growing year over year in terms of deceased donation and the biggest driver of growth right now in deceased donation is donation after circulatory death. And if we look at liver transplantation, you can see that with growing the number of donors, we're growing the number of liver transplants but we're also growing the number of waiting, of patients on the waiting list and so we've stagnated in terms of the number of patients who are staying on the waiting list for liver transplantation. And if you just kind of do back of the envelope math, we're short about 3,000 livers per year. If we just want to kind of have a steady state and maybe even, maybe even start to bring down the number of patients who are staying on the waiting list. So, one of the issues is that we're not using all the donors that are out there and the characteristics of non-utilized donors are donation after circulatory death, older donors, fatty livers and logistically complex livers, livers that are going to end up having a long cold ischemic time. And I just want to draw your attention to this graph that a lot of people look at. This is from 2019 from the SRTR and what you can see is that livers recovered for transplant and not transplanted by DBD versus DCD status. In this, you can see less than 10% of DBD livers that are pulled for transplant are not used but over 30% or right around 30% of DCDs that are pulled with the intention to transplant are not used. But what I'm going to show you is that this is only the tip of the iceberg in terms of our non-utilization of transplants. So, if you look at all the donors in the United States, so the green line is all of the brain dead donors in the United States and the blue line is all of the livers that are used from these donors. Year over year, you can see that about 80% of brain dead donors have a liver that is used for transplantation. DCD donors are that yellow line. So, you can see the yellow line is going up and up but the gap, the number of livers, the green line is the number of livers being used from DCD donors. That line is going nowhere. We're using 27% of livers from DCD donors. The blue line is living donors just so that you all can get a sense. We do about 500, 600 a year. That line isn't going up very fast. But where I would say the biggest potential and the biggest gap is that we're using one in four livers from DCD donors. And what that means is that as we're growing the donor pool with DCD donors, it takes four donors for every one liver transplant. We have to figure out a way to use these livers or a different way to use these livers for these donors. So, I would argue that not all marginal livers are the same. This is a busy slide from JAMA, but the green line just points out that a DCD liver that's put in in less than six hours has a fantastic odds ratio for survival, .68, whereas a fatty liver that's put into a patient on hemodialysis has a pretty bad outcome, 2.26. And so, what we consider marginal and how we conceptualize risk is kind of, we need to do a better job of thinking about risk and thinking about what's marginal and what's not. And if we could just use 40% of the DCD livers, we would have 500 extra donors. That's more than the number of living donors that we have at baseline. If we got up to 85%, we would almost be at that point of starting to clear the list. We would be up 85% to 90%. You're getting above 3,000 livers. And where the orange line is, is if we could do a little bit better with DBD donation, we would be able to even push the envelope further. So, what I'm going to talk about is how we get from where we are with the state of donation that we have to actual liver utilization. So, this is why we don't use DCDs. Number one, historically, they are associated with primary non-function, 16% primary non-function in the 1990s. That's terrifying. But note that in the 2000s, DCD grafts got down to the same level of primary non-function as DBD grafts. And that was without any fancy technology. Same issue is biliary strictures. So, this is an early study of the biliary strictures. And you can see that DBD grafts are associated with high rates of biliary strictures, or at least were in the 1990s. But if you look at the 2010s from big centers who did a lot of DCDs, the ischemic cholangiopathy rate is less than, it's in the 2% to 5% range. It's very low. But we historically are uncomfortable with DCDs because of concern for primary non-function and concern for ischemic cholangiopathy. And the reason that these improved was procurement technique, minimization of cold time, and donor recipient matching. We didn't do anything fancy. We just got better at what we were doing with DCD donation. But we have to figure out a way, even with doing that and even with getting great outcomes, we're still only using 27% of DCD donors. And so, we have to do something different. And what I would argue is we need something that brings all the utilization, all of our users of DCD organs from the lowest quality users, meaning the lowest volume users to the highest volume users, way up to where we are with DBD donation. The only way we can do that is with disruptive technology. So what we have with disruptive technology is we need something that ensures organ quality. We need something that improves recipient outcomes, that increases utilization, that's widely accessible, and that's financially viable. And so, I'm going to argue that our baseline should be something easy. And that, to me, is normothermic regional perfusion. So this is postmortem in situ oxygenated perfusion to the organs intended for transplantation. And I'm going to talk a little bit about abdominal NRP, which is abdominal cavity only. That's where we perfuse the liver, kidneys, pancreas. And the way that NRP works in a very simple surgeon-minded description is that it separates warm ischemia at donor warm ischemia time from donor cold ischemia time, and it allows for some level of rehabilitation of the organs during that separation between the two times. This is from Amelia Hesheimer's group, and it just describes the physiologic impact. But basically, what NRP does is it stops the depletion of your ATP, and then it also blocks the creation of xanthine and hypoxanthine, which are what end up with the oxygen-free radicals in the recipient and what contribute to your ischemia reperfusion injury. And so what NRP allows you to do is to stimulate cellular repair prior to graft recovery, and then you don't have the same ischemia reperfusion injury in your recipient. And what it does from a quality and understanding standpoint is that it allows you to do a ton of assessment of the liver while you're in situ. So what we do when we do an NRP donor, we check labs every 10 minutes. We look for the pH to correct, for the bicarb to correct. We look for the lactate to downtrend. We can do a pre-cross-clamp biopsy, so if the liver looks at all fatty or if we're worried about fibrosis, we can take a biopsy and we're not on the clock for cold time. We do a perfused visual, so it's just like when you do a standard brain-dead donor. You can see and feel how the liver looks, and you get a similar assessment with NRP and then obviously a post-flush visual just to confirm that everything looks good. If we look at the outcomes in Europe and in Spain where they've been doing this forever, you can see that the outcomes are fantastic. There are lower rates of early allograft dysfunction of hepatic artery thrombosis, lower rates of biliary complications. Note that the ischemic biliary injuries are 1% versus 9%. Retransplantation rates are lower. Graft losses and patient deaths are lower. NRP really changes your ability to assess the organ, but it should also change our confidence in using these organs and our confidence in the outcomes of these patients. The other thing that NRP does is it increases our ability to utilize organs, and this is where I think we have that potential for increasing our donor pool. This is a UK experience where they started with organs that are offered, organs that were accepted, retrieved, and then transplanted. What you can see is that the black line is donation after brain death, and they have about 80%, which is what we see in the United States. The NRP being used resulted in 63% utilization from offer to utilization, but without NRP, it's a 34% utilization rate of livers from DCD donors. There's a substantial difference in the ability to utilize these livers. If you look at that in the United States, it's the same thing. This is a study of only thoracoabdominal NRP donors from the Florida group. What you can see here is that, again, reflective of the United States experience, 80% of DBD donors are used for transplantation, and if you look at the DCDs that were done with NRP, it's almost 70%, 65%, and then without TANRP, you're down in the 20% again. A 65% utilization rate means that we would add 1,600 liver grafts a year if we did nothing, if we didn't even lift a finger to change the number of donors. What it would also mean is if we did continue increasing the number of donors, for every three additional donors, we would be doing two additional liver transplants instead of one additional liver transplant for every four deceased donors that we add to our list. Now, NRP doesn't fix everything. It allows us to get better assessment, and it allows us to have a better graft quality for what I would consider decently standard DCD grafts. But we will need, if we really want to push that envelope, I think we also need to use machine perfusion, XI2 machine perfusion, and this is a poster from Washington University where they're using XI2 normothermic machine perfusion to rescue livers. And they're taking livers that would not be transplanted by anybody. They're putting them on the machine and using the machine to assess and potentially rehabilitate these livers. And so if you start at the baseline of NRP and then you have a liver that you're not sure is going to be usable for one reason or another, for a DCD, you can use machine perfusion to increase the opportunity to transplant some of these still considered marginal livers. And so what I would say is if we reimagine transplant and we talk about where our near-term potential is, it's in machine perfusion. It's an in situ and XI2 machine perfusion. The donors are already there. I think that if we could have a nationwide NRP standard procurement technique for DCD transplantation, we would increase utilization substantially. We need to be able to use XI2 machine perfusion for fatty livers, older livers, longer cold ischemia time so those livers can travel further. And then in order to do this right, we need national guidelines. We need training programs so that surgeons can learn how to use NRP, which honestly is not particularly complicated, but it is a little bit different than a standard procurement technique. And I think that the final thing is that we need to default to a yes mentality, where when you get a liver offer, it's not there's 10 reasons to not use it. It's how am I going to make this work? So with that, thank you. Thank you, Dr. Wall, for the excellent presentation. Our next speaker is Dr. Nadia Jonassent. Dr. Jonassent is a transplant hepatologist at the University of Pittsburgh, where she is currently serving as interim chief of GI. Her interests include health disparities, access, and healthcare delivery. She will be speaking about the near and future opportunities for living donor liver transplant. Dr. Jonassent, the floor is yours. Thank you so much. So, I have been given the task to really talk about what are the potentials for near growth in living donor liver transplantation. I just want to speak to the fact that next year is going to be the 35-year anniversary of living donor liver transplantation in the United States, which was done for the first time in 1980-89 at the University of Chicago, where Alyssa Smith, who had BA, received a left lobe from her mother. The patient is pictured on the left-hand side of the screen with her child by report is off immunosuppression, and her mother was quoted as saying, once you've given someone a piece of your heart, it's easy to throw in a little bit of liver. So, just thinking about how far that we've come. Living donor transplant volumes have grown, but I think growth is profoundly slow, and here you can kind of see the growth over a period of time, and I think people have spoken to this in the previous talks. What we know is that the total number of liver transplants since 1988 through 2023 is somewhere in the 190,000 range in the United States, but only 4 percent of those are living donor liver transplants. So, you can see here in the small graph that I put here is that in 2021, there were just over 8,200 deceased donors in the United States and only 492 living donors, and in 2022, we only had a 2.8 percent growth in the deceased donor population and a 4.6 percent growth in the living donor population. I think it's safe to say that the real controversy in living donor liver transplantation is donor safety, and the question is really, is this a programmatic issue in regards to donor safety or society's stomach for the death of someone who's putting themselves at risk for other people in order to save a life? The Trotter Group actually looked at the risk of intervention, and I think it's easy to say that the risk of the intervention will never be zero. There's no way that you're going to undertake this very, very complex surgical procedure and have zero deaths in donors, and when Trotter looked at about 4,600 patients who had undergone donation across Europe and the United States, he found that possibly or definitively nine donor deaths were secondary and were caused by donation hepatectomy, and this put the risk of donor hepatectomy about 0.2 percent. There's been some suggestion that this risk is probably somewhere near 0.5 percent because of the underestimation of the risk of donor hepatectomy because we don't nationally widely share donor deaths throughout the United States. The question for me, and I think that this is more of a provocative question, is is there any good comparison for the risk associated with this surgery? And I think there's not a great comparison, but I think if we thought about do we ever put a healthy person through a surgery that they don't need, and are we okay with the likelihood of death from that procedure? The most common elective abdominal surgery in the United States is cholecystectomy, and there's about 1.2 million cholecystectomies per year. If we presume that 95 percent of those cholecystectomies are indicated, which I think is a gross overestimation of the number of those surgeries that are actually indicated, we're talking about 60,000 unwarranted surgical procedures in presumably a good percentage of which are unhealthy individuals. If we then go on to presume that the risk of that surgery is a 1 in 10,000 risk of death, we are talking about six deaths per year of a healthy person undergoing an elective surgery in the United States. And the question is, I think, from a societal standpoint, do we have the stomach for that? It's clear that we send people for this surgery quite often, and I think that, you know, as I was thinking about being provocative in this sense, this is probably the closest thing I could come up with in regards to an analogy for what we should be able to stomach in regards to living donor transplantation and the death of a donor or morbidity associated with donation. So I just want to take an opportunity to talk about the extension of donor criteria and also talk about the extension of recipient criteria, and then get back to how we kind of address the growth of living donor transplantation in the United States. So there are multiple ways. We wrote a paper out of the University of Pittsburgh, multiple ways to increase the donor pool that have been explored. And I'm not going to have the time to talk about all of these things, but the things that have certainly been considered are accepting donors with increased hepatic steatosis, decreased graft recipient weight ratio, and there are some people who suggest that you could push the graft recipient rate ratio all the way down to 0.6 if you make sure that you can modulate portal flow, less stringent donor age limits, which I will speak about, ABO incompatibility, altruistic donation, and what I won't talk about also is dual graft because I think using two suboptimal grafts to save one life when I don't think we already have the stomach of putting even one donor at risk is probably not applicable here. So let me first talk about donor age. So I think you can see on the right side of your screen that I think we're pretty comfortable at the, when we start to talk about spouses and siblings giving, that 30 to 50 year range in age for donors is something that we're very, very comfortable with because we have fully, fully plotted out in the research that donor age does portend the prognosis of the recipient, right? But where we're less comfortable, I think, are at the extreme. So when we talk about the very young, which I think we would say would be less than 18, what we would consider an adult in the United States, and then people who are slightly older, so those over the age of 50, what I'll say here is Cabuto did a beautiful job at looking at this data, and what we can see here, what you can see, appreciate here on the far right side of your screen, is that one, if you do well, if the recipient does well after one year, they're going to continue to do well despite the age of their donor. But I think concentrate on B, which is really this idea of what do we do with those people who want to donate who are in between the age of 50 to 60, which has really been the pushing of the envelope in regards to donor criteria. And what you can see here is that for that age group, there's an overlap in the curve, right? So what we're saying here is that overall, recipient outcomes in between those who have a donor age of 50 to 60 are not significantly changed. I will say as a part of this, I think as part of this data, we at the University of Pittsburgh have actually increased our donor criteria from age 55 to age 60, so I think there is movement to start to understand this, and I think we all have a sense that physiologic and chronologic age are not the same, so really taking this at face value. The other part of this is really the other extreme, which is the young. So this is from Toronto, and I think this was done in the early 2000s, maybe around 2011, when a 17-year-old boy wanted to donate to his mother, and the thought was, do we allow someone under the age of 18 to donate? I think what we can agree on, if many of us are parents, is that the maturity amongst teens is dramatically different, and the age of 18 is slightly arbitrary. What we do know in the United States is that we do allow 16-year-olds to get into a two-ton vehicle and put multiple people at risk for death, maybe through driving, at least within the first year, and we also know that the likelihood of a motor vehicle accident at age 16 is 1.5 times higher than that at 18, so we really have made some societal decisions about what we feel like maturity is, and in this particular case, the University of Toronto had decided, based on this case, that they would start to consider age 16 a reasonable time for consideration for donation, and again, each person would be considered specifically based on their own merit and their level of maturity. So I'm going to move on to ABO-incompatible donation, which I think is important, because this is something that comes up and something that we do do at the University of Pittsburgh and is done throughout the world, mainly in the East. This is really an alternative to paired donation, so rather than you coming and saying, I'm an A and I want to donate to a B and someone else is an AB pair, and swapping, this would be the idea that the recipient would get preconditioning to accept someone outside of their ABO group. The issue with ABO-incompatible donation really is the fear of humoral and antibody-mediated rejection, and we heard about antibody-mediated rejection quite a bit in the xenotransplantation case. There are thought to be antigens expressed on the vascular epithelium and the bile ducts that put people at risk for hyperacute rejection and biliary complications. Initially historically, splenectomy, plasmapheresis, and immunosuppression was trialed, but unfortunately did not change the pretty bad outcomes that we had after ABO-incompatible donation. But the addition of rituximab really revolutionized, and preconditioning of the recipient with rituximab really did revolutionize. And I'm going to show you some data from Yadav that suggests that ABO-incompatible transplantation in the setting of rituximab survival is on par with ABO-incompatible transplantation. So when we look at ABO-incompatible donors, and sorry, I'm getting older here, so I have to take off my glasses to see up close. Okay, sounds great. So hepatic artery stenosis, antibody-mediated rejection, overall biliary complications, strictures, and hospital stays are slightly increased when we talk about ABO-incompatible transplantation. But when we look at one-year, three-year, and five-year survival, we really see that ABO-incompatible and compatible transplantation are on par with one another. I'm going to move quickly to altruistic donation, or anonymous donation as some programs call it. And we know that this makes people feel good. The Toronto experience from 2005 to 2017 suggests that in 50 people that were anonymous donors, the median age of 38, 50% women, 70% learned about these opportunities through social media and were thought to have personal traits associated with agreeableness and conscientiousness. The median stay was very reasonable at six days, and the recipient survival amongst adults and children were 91 and 98% respectively with no deaths. Let me briefly just talk about, since Dr. Goldberg has given me four minutes, the extension of recipient criteria in regards to living donation. So there are also some considerations in regards to this pool, and I think the issue of sicker than meld comes up pretty often. People who are suffering from resistant or refractory ascites or suffering from recurrent bleed. And I think as we begin to very, very strongly consider TIPS as destination therapy, as we would the LVAD in cardiology, that population is going to be less of an issue. But we did, it was touched on, this idea of metastatic colorectal cancer, HCC outside of Milan or San Francisco, intrapathic cholangiocarcinoma, and then I think a conversation about severe alcoholic hepatitis is something that I will say for another time. So this is an area that we would call transplant oncology when we talk about it, and I think there's three vital studies that, oh, sorry, two vital studies that were done in metastatic colorectal, and I'll review them quickly here. So SECA-1 was a trial done in 2013, 21 patients, broadened exclusion criteria, meaning that METs had to be confined to the liver, the primary tumor had to be out, and you had to have received at least six weeks of chemotherapy. This was not standardized chemotherapy, and this, I believe, was before the Thor-Furanox time period. The results from this study were a one-year survival of 95 percent, a three-year survival of 68, and a five-year survival of 60 percent. And the significant prognosticators, retrospectively, was a tumor volume less than 5.5, a primary surgery at least two years out from your primary resection, which I think essentially is selecting for biology of the tumor and no progression on chemotherapy. The second trial was done by the same group, which is SECA-2, and what you had to do in this trial, have in this trial, was at least a 10 percent response to chemotherapy and be at least one year out from your primary resection of your tumor. The one-year survival was 100 percent, three-year survival 83 percent, and five-year survival of 83 percent. Remember that in metastatic colorectal cancer, there is some assumption that people will go on to recur, but most of the time, those recurrences happen in the lung, where people think that you can have surgical resection. And the overall survival after the time of relapse, which is a median of typically about six months, survival at one year, 100 percent, and two and four years at 73 percent. I just mentioned the Fong criteria here on the side, and if you have zero to two of these, more likely to have better survival than if you have three to four. In regards to intraepatic cholangio, I want to briefly go over this. This was done by a group that looked at the overall survival on the left-hand side is all comers, so in the 29 patients that they looked at for intraepatic cholangio, pretty horrible survival when you look out five years. But if you go to the B level and you separate those people with what this trial calls early, very early intraepatic cholangiocarcinoma with cholangiocarcinoma less than two centimeters, then those people have a survival on par with what we would expect from regular transplantation. Lastly, just to talk about the extended criteria in living donor in HCC, there is an extremely exhaustive list in the east of people extending the criteria for donation for HCC, including partial thrombosis from actually tumor thrombus, and very, very aggressive extension for HCC criteria. So we've exhaustively listed those on the side here, but just something to think about. Lastly, I just want to talk about patients are not going to go it alone. And the Dory Segev Group at Hopkins initially published a paper back in August of 2020 talking about the Champions Program when they looked at trying to address the racial disparity of living donor kidney transplantation. And what they found is if you can advocate for the patient, you can train the patient, educate the patient, and walk them along the process, which they call the Champion Program, this really leads to a significant increase in referral for donation. So they found in this study that through the Living Donor Champion Program that they established, people were six times more likely to have someone come forward as a donor for living donor kidney for them. And as a result of that, we went forward with the Pittsburgh Champion Program. And you can see here, again, all of the things that I've talked about previously in my slides, public awareness, social media, TV and radio, and town hall meetings. I've gotten a couple of calls over the years in regards to my transplant friend saying, why is there a University of Pittsburgh commercial playing in the lobby of our clinic in Florida or Louisiana? And I think that that's really the media, TV, and radio pitch, but also allowing people to use social media and the things that we have available to us in society to advocate for themselves. The Champion Program is based on the fact that the patient is not the person advocating for donation, but they have someone, a loved one, a friend, a family, who is the major mouthpiece advocating for donation for that person. So it's really, really important. And as you can see here, I've demonstrated the data from the University of Pittsburgh. The red bar is living donation at the University of Pittsburgh. And we were doing, in 2012, just over 10 transplants, and in 2020, did just over 90. Thank you. Thank you. We had great four talks, and now we are open for panel discussion. We're going to extend the panel discussion until 10.10, because we have the room for the business meeting afterwards. Dr. Goldberg has a question. For Dr. Ran, so we all want to, obviously, innovate, but one of the things that comes up a lot that we didn't have time to talk about for everyone is that we have this sort of the SRTR report cards and PSC that sort of holds us back, because you want to innovate for LDLT. You want to start pig trials. And humans, you get bad outcomes, you're scared of the UNOS jail. As we're all hopeful for new sort of OBTN leadership, how do you think innovation should be incorporated into report cards? Should there be research carve-outs or ways that you can innovate but not get dinged if things don't work out well? I'm curious what people's thoughts are, because I think there's a lot of potential. You're asking me? Everyone. All of you. Are you all going to add an extra five minutes for Dave Goldberg's question? I think that if we are going to innovate, I think we are going to have to have some idea of what we're going to do about those, because I think people are fearful of innovation in the setting of getting dinged, right? How we carve that out, I'm not sure, because you also don't want people living on the edge in regards to what they're doing, and if you carve out too much, then you're doing a lot of experimentation. What are the guardrails there? So I think that there's probably a sweet spot there. I don't know if it's a carve-out, but it may be some permissive understanding of if you do, you know, if there's this much plus or minus in regards to mortality, we're willing to do that, because to all of the speaker's points, we need this, because people are dying. And the truth is that those small deaths on our list are not comparable to the amount that we're having on all of our wait lists cumulatively. Dr. Rann. Thank you, and I'd like to thank all of the speakers. Those talks were so informative and thought-provoking, and I have a question that pertains to the xenotransplantation. I loved what I saw. It was really fascinating. However, due to these problems of organ shortage, I'm not sure that extending the ICU time of a person in acute on chronic liver failure is going to help us much. It's just probably going to mean more people will be in the ICU for longer while they die waiting for their organ. So my question is, when are we going to have pig livers that a person can receive and have for a long term? So I agree with your sentiments. What I would say is you got to figure a way to introduce it at some point. I think because of all the questions about metabolic complexity, which I think are actually going to be overblown, but I think because of that, I think you have to start asking the question in the relevant model sooner rather than later. So I'm not, I think if it's going to work short-term, I think it's going to work long-term very quickly. So, I think that's a much faster way to introduce it. Does that cover it to some extent or no? Yeah, keep at it. Please introduce yourself. Yeah, Joseph Redman, Intermountain Transplant at Salt Lake. Also on the idea of xenotransplantation, interested in the field, not an expert, but heard that a large challenge in making pig livers work is the porcine, the PIRV viruses, porcine retroviruses, and curious if you see that as a barrier in making this work. No. So, it's a good question. So, the FDA has, so PIRV, porcine endodontic retrovirus, it is, it has never infected a pig that we can tell. It has never caused disease in a human being, despite all of our exposure to pigs. It's sensitive to two classes of retroviral drugs. To get PIRV into a human cell, they've been unable to do it except for transformed cells, and you have to have a recombination event between PIRV-A and PIRV-C. Eleven percent of pigs are born without PIRV-C, so we are going with a PIRV-C negative pig, and the FDA has been very, very comfortable with that as far as going forward. You can also knock them all out. I think, you know, eGenesis has done that. I think probably in 2013, we knocked out 59 of the 62 copies. We stopped because, quite frankly, it's a lot of genetic engineering. It's okay, but the FDA is a little bit concerned about how much genetic engineering you do, so we backed off from that. Not just infecting humans, but is it antigenic, part of the rejection? Not that we can tell. Very interesting. I'm from the University of Toronto. Also coming to the xenotransplant, I mean, in allotransplantation, the liver is not the most sensitive organ for antibody-mediated rejection compared to kidney, heart, or lung. So why do we see these effects with the platelets, which we see even in other xenotransplants, so strongly in xenoliver? Question one. Question two, where are we with regrowing human livers in pigs, in FAH pigs or others? Sure. Sure. So as far as antibody-mediated rejection, quite frankly, it's probably worse for the other organs because it chokes off the blood supply and they go down. The only thing is it's dramatic because these bleed to death. But if you look at ABO-incompatible liver transplantation, those, they bleed like crazy as well, but it eventually peters out. And I think it's because it's largely IgM, because they're all glycan antibodies, and those get exhausted after about two months. So I think that's why that is, and I think it's no different than what you would see in an ABO-incompatible liver transplant. But let's say xenoheart or xenokidneys, they don't have the same steep drop with all the bleeding. No. It's because the endothelial cell internalizes the platelets so that they're removed from the circulation. So then you start bleeding from all your suture lines. We didn't recognize this problem when we did the pig liver perfusions because we had cannulas in the vessels and we tied them so there were no suture lines for them to bleed from. So that's what the challenge is, is it bleeds from all your suture lines. What was your second question? Regrowing human liver cell pigs and FHH pigs. Gastroplasticity complementation, it's really, really interesting. What I will tell you is we were really interested in it, and we were able to make pigs that would die at 30 days of gestation because they didn't form a liver. And the problem is cell homing. So you can't control where the human cells go. And so we made these pigs all green so that if the cells were clear, we knew that they were human. Thirty percent of the brain in these fetuses at 30 days was clear human cells. So quite frankly, I considered that potentially a field ender, so I stopped doing it. But the other problem with blastocyst complementation is you have to produce one pig for one person. And so it's going to scale up, it's going to be hard. I'm not saying impossible, right? If you give the human mind enough time and money, we've been able to figure out just about everything. So I'm sure there's someone on this planet that's going to do that, but it's not going to be me. And FHH knockout pigs, would you repopulate just with normal human hepatocytes? Yes, so that work is going on. There's some very promising results. And so I think, you know, again, that's a time and money problem. You just have to give them enough time, and I think they're going to get to that point. Thank you. I have a question about NRP and organ care system. We have seen really great results, and also it is good for, you know, you can pump these livers and you can schedule your OR time. My question is about the cost, like how are we going to incorporate that cost into the contracting, and most of the cost is built by, is, you know, eaten up by the institution right now. But what are your thoughts about that? Yeah, so a couple of things. So number one, the reason that I think NRP should be the baseline is cost as part of it. So for us right now, when we do an NRP, when we go out for an NRP, the disposables for the machine cost $500. The cannulas each cost $250, and we don't open them unless the donor expires. We open the disposables, so if the donor doesn't expire, we've invested $500. If the donor does expire and we use straight cannulas in a clamp, it costs $1,000. If we add a balloon occlusion, that adds another $400. So you're looking at between $500 and $1,500 in terms of the materials. And then for our team, we have two perfusionists who come out with us, so we pay them time and a half call pay for whatever number of hours, which at the end of the day is not a huge amount of money compared to what we pay overall for an organ. So the baseline cost of the organ acquisition charge for a liver is somewhere between $50,000 and $70,000 depending on OPO, and so an extra couple thousand is not really a huge difference. And that's why I think that that as a baseline technology makes a lot more sense because it is, compared to the others, it's very cost effective. If you look at the cartridge cost for back-to-base, it's about $38,000 for the organox cartridge, and you have to pay somebody to watch that machine, and so for us, it would be the same investment in perfusion, time and a half call pay for whatever amount of time. And then for transmedics, the cartridge itself, I think, costs about $80,000, and then you're adding the team activation cost, which is around $20,000, and whatever the transportation cost, which is usually, you know, if you're looking at a charter flight, it's between $10,000 and $20,000. And so you start to add up a lot of money, especially for the X-site 2 machine perfusion. And if you look at contribution margin for livers, it's going down. At least in our center, the contribution margin per liver is going down. And so the only technology out of all of them, if you didn't have, if you can't figure out an additional way to get compensated, the only one that actually keeps you within still having a positive contribution margin is NRP. Thanks, Chris. Yes. Didier Samuel, France, for Dr. Textor, regarding xenotransplantation, I think the point is that you did a huge work to decrease the risk of rejection, thrombocytopenia, path transmission. However, the liver is producing animal proteins in the recipient, and so I don't see any hope to have a long-term use of xenoliver in a human. So if you use it as a bridge, I think you should consider to have a specific program to put the patient with a pig liver on an emergent liver program to be transplanted in a relatively short time period. And this is, I think this is what should be done. I mean, if you want to do this as a bridge and to have a success. That's very sobering. What I would say to you is this, is so far people have talked about species incompatibilities. They have not panned out. I'll give you an example. People will tell you that pig erythropoietin does not work in non-human primates or people. But, you know, we had a monkey go one day short of five years never seeing EPO. None of those animals that I showed you ever received any EPO. So I mean, that's, here's the problem. There's what we think, and then there's what we can prove. In clinical medicine, what we think matters a great deal. But for experimental medicine, it matters a little bit less. And so what I will say is as these proteins get tested so far, if you're really looking at it, it ends up that they end up working out okay. So I'm actually quite optimistic that it'll work. I guess that's why I still try to do it. But I think we just have to generate the data to answer that question. Yes, but I mean, this is why the liver is different from a kid and from a herd because it's producing most of the proteins. So I mean, this, I mean, the biology of the pig is different from the biology of the human. So for a short-term period, it is probably compatible with life and certainly compatible with life. But for a long-term period, it is really an open question. Thank you. Hello. Gautam Reddy, Chicago. This is a question for Dr. Wall. Can you comment on the ethical implications of NRPs, specifically around ACPs? Yeah. Sort of, you know. This could be a very long talk, but what I'll say is there are a couple of things. So one, NRP is not all one thing. And I think that that's one thing that we've been so focused on. So there's abdominal NRP and there's thoracobedominal NRP. And what I will tell you is that the ethical concerns about NRP are really focused on thoracobedominal. And if you look at the overall picture of every, you know, kind of the bigger picture of DCD donation, only about 5% of DCD donors are cardiac donors. And so even if you have significant ethical concerns about thoracobedominal NRP and you focus only on abdominal, which is, we do mostly abdominal just because we have extended our criteria and we only perfuse the abdominal cavity. You eliminate a lot of the concerns with restarting the heart as well as with collateral circulation from the thoracic cavity to the brain. So that's number one, is that I think that when you start to have discussions about ethical concerns, you really have to bring out what it is that the OPO or the donor hospital or whomever, what those concerns are. As a baseline, there are kind of two camps of concern. So one, in thoracobedominal NRP, what happens is that you clamp the aortic arch vessels before you start perfusion and then the heart restarts inside of the body. And so when the heart restarts inside of the body, there are some bioethicists who say that alone negates the circulatory definition of death. And so that is one concern that really comes down to what organ you believe means that somebody is alive or dead. And there are people who believe that the heart beating means that you're alive in the absence of brain activity. Number two is the idea of if you start perfusion in the body and then you clamp, or if you start perfusion in the body after having clamped vessels going to the brain, is this an act of commission where you are causing a brain death? Well, at the end of the day, the person is already dead by our criteria, by legal criteria and medical standards. And so there's a lot of debate about if that has changed. I don't believe it changes, but there are individuals who believe that brain death is the only and common pathway of death. And so there's a debate about if the brain is dead enough at the time of NRP donation. I will say it's the exact same time that you do DCD donation. And so if you have a problem with the characterization of where the brain is in terms of function at the time of procurement for NRP, you would also have to have that same concern with DCD. And we don't have that with a standard DCD. And then the third thing is, are we adequately maintaining perfusion only to the organs that you're interested in for transplantation? That is something that is actually very much solvable in terms of being able to show, to be able to study the level of the amount of flow that may happen through collateral circulation. There's studies out of NYU and out of Spain that show that with thoracodominal NRP, there is no flow to the brain. And so if that's your only concern, or is the procedure adequate, that is the most solvable of the ethical concerns. And right now, at least the small amount of data that we have is very, I think it's very convincing that there's not adequate flow, meaning there's no function. Thank you. I have a question for Dr. Kwong. So in 2002, when MEL was implemented, it was supposed to be objective and easy to explain and based on the labs. And we have come a long way from MEL sodium to MEL 3.0, which again has albumin, which was initially thought would be difficult because patients are getting albumin. So we can still explain the MEL score, but my question is, how are we going to explain the continuous distribution score? Because when the patient comes to you, they ask you, where do I stand on the list? What is my score is, and how it's going to all work? I know it's in the development, but I just wanted to see what's the thought process behind this. I mean, I think we are already stacking things on top of in this system. So I mean, I think we say that we have, it's all about the MEL, and that's what's controllable for the patient. But there is also, we're stacking pediatrics and status one, and like all these other things. And so, I mean, continuous distribution in some ways is going to be, is more flexible. But yes, it's going to be hard to tell people where they show up on the match run, or you're top of our lists, or that's going to go away a little bit. But the benefits, at least right now, are felt to outweigh that. And hopefully with enough education, and kind of the system will end up being hopefully more transparent and not less. All right, we have one more question. Hi. Bashar Al-Fateha from Baylor, Dallas. So I have a question for Dr. Wohl. When we look at the studies of the NRP and the NMP, one of the major drawbacks, one of the major problems is that they use different definitions to what constitutes the graft viability. So some of them has used, for instance, lactate clearance, bile flow, glucose metabolism, different rates of flow for the hepatic artery and the portal flow. You've mentioned the three simple things, like the biopsy and the viability, the gross inspection of the liver. Is this the time to maybe come up with a standardized criteria that is readily available at the bedside to even improve the utilization of these livers? Yeah, so, I mean, I think you have to, in the way that we do organ procurement in the United States, which means you go to any hospital in any place, anywhere, you have to be, you have to have something that's easy and that you can, and that's portable, right? And so for us, what that means is we bring two ISTAT devices with us, and any hospital is going to have pathology. And then we bring our own, we bring our own circuit. But with the ISTATs, the ISTAT with a lactate cartridge, you can get your pH, your bicarb, you can get, and you can get lactate. And if your pH normalizes, if your bicarb normalizes, and if your lactate begins clearing or at least stays stable, that's enough for me to know that that liver is going to function because it's functioning within the donor. Now what's, what we don't do, we don't, we look at if the, you know, we cut the bile duct at some point, and if the liver's making bile, like that's another thing that's useful, I guess. But we don't do bile salt analysis. We don't do any of that because that's really hard to do, and it's really hard to do on the road. We also don't have a piccolo device, so we don't check AST and ALT, which is something that is done in some of the European centers. But I have done a few at our own center where we sent a CMP and then got it back like two days later. And, you know, like we didn't use it for analysis, but the enzymes were normal, and so I just, I don't find value in adding a bunch of extra noise when what we have right now seems to be working very well. I mean, we've done 42 NRP liver transplants, and we've had no primary non-function, and we actually haven't had an ischemic cholangiopathy yet. We'll have it at some point, but, you know, I mean, I think that, I think that you can get a great assessment with very minimal tools. Any other questions? All right. Well, thank you so much to all the speakers and participants.

Machine perfusion

Marginal livers

Real-time assessment

Liver quality

Preservation time

Cellular function

Transplantation

Organ supply-demand gap

Non-standard livers

Normothermic regional perfusion

Graft viability assessment

Xenotransplantation

Advancements in liver transplantation