Thank you so much for the organizers for the opportunity to speak today. This was a very challenging topic for me because I have no idea actually how to allocate, to do allocation for optimizing long-term outcomes in adults, and I'm sure many of you in the audience actually have better ideas. But I took a lot of creative license with this, and I'm still formulating the ideas. I really look forward to an active panel discussion afterwards for your suggestions on how to refine the plan. Here are my financial disclosures, and so I thought it would be really helpful for us to just remind us about our mandate from the final rule under Section 121.8, Allocation of Organs. It states that equitable allocation of cadaveric organs among potential recipients shall seek to achieve the best use of donated organs, shall be designed to avoid futile transplants, and shall be designed to set priority rankings expressed to the extent possible through objective and measurable medical criteria for patients who are medically suitable to receive transplants, and these rankings shall be ordered from most to least medically urgent. So how do we work within this framework to do what I've been asked to talk about, which is to optimize allocation of organs specifically for the outcome of long-term outcomes? And in order to frame this discussion, I just want to present to you a framework for medical and transplant decision-making, and you may have seen this before, and I know you know this in your head, but hopefully it's helpful to have it in a picture form. I want you to think of three different patients. Let me see if I can get this pointer to work here. Oh, good. It's on the screen. Okay, so here's a patient A, and here's a patient B, and here's a patient C, and the area represented within the borders of the square are what I'd like you to think about as the vulnerabilities of this patient, the vulnerabilities of this individual, these individuals, to have adverse outcomes in response to any medical treatment, but in our case, we're talking about transplant. The patients, however, are differentiated not by what's in the total area, but actually what's represented by the gray box within that area. And so now you have two different ways of representing their vulnerabilities. The first is what's in the white box, which I would call the transplant-responsive area, which John alluded to earlier today, but the gray box is probably the stuff that we really need to pay attention to, and that is what I would call the transplant-nonresponsive vulnerability, and this is the kind of stuff that is not going to go away with a brand new liver. And we can certainly talk a little bit more later about what those factors might be, although I have some ideas. And of course, as you can imagine, we take them to transplant. We get rid of that which is transplant-responsive, but the patient is left with that which is transplant-nonresponsive, and this is what's going to drive their outcomes after liver transplantation. So now think about that first slide, our mandate. As a community, the government has told us that we have these rules by which we must allocate organs. And so the first, we shall seek to achieve the best use of donated organs. One might argue that patient A represents the best use of donated organs because patient A had the best outcomes, right? Had the least, we got rid of the most vulnerabilities because he or she had the most transplant-responsive disease, okay? Now the mandate also told us that we needed to design a system to avoid futile transplants. And I would argue that, well, patient C is a futile transplant because patient C got transplanted with relatively little transplant-responsive disease, and really most of the reason that he or she was sick in the pre-transplant setting was actually because of things that were not going to go away with a new liver. In the simplest of terms, this is the patient who tells you that they have a poor quality of life because they have back pain. You know, that patient has dominated in their head, they have well-compensated cirrhosis and they have severe back pain and they want a liver transplant. Well, that person's not going to have transplant-responsive symptoms, right? Okay, so we have a patient A and a patient C, and I think hopefully now you can better frame this or better picture the types of patients we're talking about, talking about transplanting or not transplanting in order to fulfill the mandate ahead of us and allocate to optimize long-term outcomes. But of course, if we are going to... This is just a framework, this is just a concept, right? But we have to, as a community, make a decision on how to make this happen. We actually have to operationalize this concept, which is much harder to do. And so really, that really comes down to how do we separate these two and how do we fulfill that third mandate that I mentioned, which is to do so through objective and measurable medical criteria, right? So that was the other mandate within the final rule, is that however we decide to decide who patient A is and patient C is, we have to do so objectively, okay? Let's start with the easy one, because I think we figured this out. What are the transplant-responsive factors? Well, we know a lot of them, hepatic encephalopathy, ascites, the Child-Pugh score sort of summarizes them, varices, those things are all going to go away. And we have decided as a community, and I personally think MELD score is the most awesome thing, I wish I had developed it myself, is really measurable and objective. It's very feasible and really does very well capture the patient's pre-transplant vulnerabilities that are going to go away after transplant. I mean, I just love when I look at labs at a patient who just got transplanted last night and the INR the day before was three and today it's 1.1, it's kind of incredible. And so that's like the perfect example of transplant-responsive disease, I wish everybody's vulnerability was like that, right? But in this day and age, and I suspect why we're having this symposium and this talk at all is that I think we're all suspecting, but the data now show that the predictive accuracy of MELD score is decreasing. You can see very clearly in this graph, looking at the C-statistic from MELD score of 2002, this was great work put out by Dr. Abbas at the University of Houston and his team. And then you can see how just perfectly the MELD score is just coming down very consistently, coming down such that more recently the MELD score C-statistic has gone down in the 0.7 range. And there are a lot of explanations, I think we all know those explanations, but it's our patients are totally different than when we originally developed MELD score. So you can see in the left-hand column, the average liver transplant candidate in 2001, median age 51, now it's much older at 58 and just rising. The proportion of individuals greater than 65 was 7% back when MELD was derived, but now a quarter, one in five, one in four patients who are seeking liver transplantation are over the age of 65. Viral hepatitis is decreasing substantially and going to be gone pretty soon. Alcohol is only rising, right? And then the other etiology of cirrhosis, which we all know of course is NASH, and that's just skyrocketing now as 33%, but is only going to rise especially as viral hepatitis goes down and then the epidemic of obesity just gets worse and worse. The proportion of diabetes, diabetes used to be so unimportant that they didn't even list it back in 2001 in the UNOS criteria, and now of course it's 30% reflecting the fact that so many of our patients now have NASH and even the ones with other liver diseases like PSC and hepatitis B also have diabetes. And then you can tell, you can see it in the kidney dysfunction too, the rates of SLK are going up and seem to be rising. If a picture were worth a thousand words, this is how I would describe it. Before we used to have a ton of these patients with vulnerabilities that were largely transplant responsive and we're now seeing more and more patients who are sort of trending towards areas where they're sort of dominated by transplant non-responsive disease. And so our challenge is how do we measure this, what factors really go into this transplant non-responsive disease if we can find out the factors really, how can we measure it? And I would say here are some of the factors, diabetes, CAD, muscle wasting, muscle dysfunction, even primary lung disease, chronic kidney disease. I would argue that there's some other factors that I personally am really interested in because I think they really impact our patient's outcomes. The apathy, physical inactivity, non-grit. I couldn't, hopefully maybe you guys can tell me what the opposite of grit is, but basically the opposite of grit. The surgeons at my center say, would call it that the patient doesn't have the life force or that patient doesn't have the transplant spirit, right Sandy? I mean, we know that, you know, they don't have the transplant spirit. We know that there's such a strong predictor of outcomes. So I would put that in transplant non-responsive disease because you can better be sure taking them to the OR, cutting their belly open, putting them in the ICU does not get rid of this apathy, does not get rid of their grit or their non-grit. So how do we measure this through objective and measurable medical criteria? I have a proposal and I think why I've been asked to speak here and that is to consider the concept of frailty. In the most traditional, commonly defined term or common definition of frailty, frailty is a state of decreased physiologic reserve and increased vulnerability. Hopefully at this point you guys have heard at least a talk on frailty somewhere, somehow, so you know this definition, so I want to give you something new. This is actually a lesser known definition within, it's very well known in the geriatrics community, maybe lesser known outside of geriatrics. It was put out by Ken Rockwood who is the other founder of frailty, Linda Freed put out the decreased physiologic reserve one, but Ken Rockwood has a whole other camp where he describes frailty as the end manifestation of sub-threshold deficits of multiple physiologic systems. As more deficits accumulate, the greater the susceptibility to adverse outcomes, which I love this definition because that's probably what we need to do, right? You need to sum up the effect of some diabetes, some hypertension, some apathy, because one of those factors in and of itself is probably not enough to dominate the transplant non-responsive factors and to dominate the post-transplant outcomes unless it's very, very severely controlled, but more dangerous, more difficult to assess is the 69-year-old with some diabetes just started on insulin, right? It's when you start combining those factors and you have to figure out, well, how do I sum them up? Do they sum up in total to too much? If I had to portray this in a figure, this is how I would portray the effect of frailty on post-transplant outcomes. Frailty in a sense is essentially describing a patient's physiologic reserve so that a patient with normal physiologic reserve, somebody described as not frail, will experience the transplant surgery, have a transient decrease in their physiologic reserve that will respond really when their liver function perks up and they'll sort of have enough gas in their tank to be able to jumpstart and get on their way after transplant surgery, whereas the patient with already low physiologic reserve, the patient who's coming into the transplant surgery frail, is going to experience a depletion of their transplant surgery as everybody would. Even you and I would actually have at least a couple of days of recovery after surgery, but then it's this period, that depletion of physiologic reserve, that just pulls them into the zone of adverse outcomes. This is the person who is having an extra day of intubation because they had respiratory muscle weakness. This is the person who then gets ventilator-associated pneumonia or gets a DVT or anything that goes wrong, even if they have to have a re-operation for take back for bleeding, if they have any biliary complications, and then, of course, they have acute kidney injury, and then you can't start the tachycardia, and then by the time they've recovered from that, now they're in rejection. It's just one thing after another. And so that's the problem, and that's the impact of frailty on post-transplant outcomes. And so now we have to take all of these factors, and I would propose that perhaps all of these factors that we discussed that might contribute to transplant non-responsive disease and sort of bring them together, and I propose that frailty represents the end manifestation of these sub-threshold deficits, the accumulation of those sub-threshold deficits, and then we can measure it using some objective tools. And just last year, the American Society of Transplantation actually sponsored a consensus statement from a bunch of us actually doing research in this field. It was a super fun experience, and we really did come to a consensus on tools that we recommend to the liver community based on the current evidence available, because there actually are a lot of tools, but we don't need more tools out there. We need the tools to use in our clinical practice, and so we decided on a frailty toolkit that included four tools, the Karnafsky Performance Status, Activities of Daily Living Scale, a six-minute walk test, and the Liver Frailty Index. We decided on four tools because you need different tools in different settings. You know, these tools have different test performance characteristics, they're administered in a different way, so some are easy and quick and can be administered just in a second, and then others are performance-based instruments, require a little bit more time, require one or two instruments, but it just depends on what you need the frailty instrument to do and what sort of medical decision you're gonna make based on it. And I just wanna point you to, or just inform you that there are actually only two metrics on here, though, within our toolbox, that are truly performance-based and truly objective, and that is the six-minute walk test and the Liver Frailty Index. And so if we're talking about allocating organs, we're going to have to go with an objective performance-based measure, and if we believe this AST toolbox, we're probably gonna have to be sampling from these performance-based metrics, and I would start with these two. And when we start measuring frailty in clinic, in the liver transplant setting, actually in the inpatient setting, too, in patients with cirrhosis awaiting liver transplantation, we find very clearly that frailty is very strongly associated with outcomes in the pre-transplant setting in this population. So frailty is associated with a two-fold increased risk of waitlist mortality, frailty is associated with greater risk of hospitalizations, it's strongly associated with a need for rehabilitation after a hospitalization, as well as 90-day mortality, and it is associated with poor quality of life, as well as development of subsequent disability. So frailty is a very deadly and disabling condition. And so if we know this, if we know that frailty can be measured, and it can capture vulnerability to adverse outcomes, it makes people sick and it makes people die before transplant, a lot of people have taken this idea and said, perfect, meld frailty. And we have this mandate from the final rule that says we need to order our allocation and our rank list from most to least medically urgent. And so they say, well, why don't we just develop a meld frailty and transplant based on that, and then we can save more people on the transplant list. Well, now you guys are probably conditioned based on this framework to know we can't do that, right? Because then we're going to be violating another mandate, which is actually we need to design a system that avoids futile transplants. And so meld frailty is not the solution, and that's why my team at UCSF has not put out meld frailty. There are meld something or other metrics out there, and they cannot be used for the purposes of allocation. There are other ways to use them, but they cannot be used for allocation, in my opinion. Okay. So I think we all have a clinical sense that frailty is transplant non-responsive, so it's going to impact post-transplant outcomes, and there are data to support that. Post... Oh, sorry. I should have said this. I made this wrong. It's pre-transplant frailty is associated with post-transplant outcomes, longer transplant length of stay, a trend toward more time in the ICU. We just put out a paper in liver transplantation that it's associated with higher rates of acute cellular rejection at three months that we did not feel was related to differences in immunosuppression. More readmission days within three months after liver transplantation, and there are early data to suggest a trend toward increased risk of mortality. There are not a ton of data looking at the association between pre-transplant frailty and post-transplant outcomes, but those data are coming, and our multi-center functional assessment and liver transplantation study is hoping, that has nine centers from the United States contributing data, is hoping, fingers crossed, to have data to present to you on that question a little bit later, or actually in one year at this meeting. But the data from geriatrics, I mean, frailty, as I mentioned, is a very well-established geriatrics construct. The data in geriatrics is very strong. There are decades' worth of data dating back to the 1960s that consistently and clearly show that frailty predicts all-cause death. And this is one of the original studies by the mother of frailty, Linda Fried, who found that among 5,000 older adults frailty, you can see frailty in this very nice risk-stratified way, dose-dependent way, really strongly predicts all-cause mortality. In fact, even within a three-year timeframe, older adults, adults over 65, who were frail, you could essentially predict if they were going to live or die within the next three years. I mean, think about that. I mean, to predict all-cause mortality in all patients, in all individuals, just like in your parents. If they're frail, they're going to die within three years, and that's so powerful. And frailty has been applied in so many other chronic diseases, and it continuously always predicts outcomes and all-cause mortality. More recently, there was a systematic review. Actually, we put our patients in this, so there are a couple of patients with cirrhosis in there. But this systematic review of greater than 16,000 patients from 17 cohorts showed that the short physical performance battery, which is a functional measure, it's gait, speed, chair stance, and balance testing, actually predicted all-cause mortality as well. So by functional measures and the Fried frailty criteria, which includes some survey-based instruments, frailty is very predictive of long-term outcomes. So now, hopefully, I've convinced you that frailty can summarize and measure what is in the gray box. And if you believe me, and if you believe this framework that frailty measures these transplant non-responsive factors, and these transplant non-responsive factors are the things that are going to drive long-term outcomes, then come along with me, and I'm going to provide some suggestions. Okay? So, for the patient A, I think patient A, if patient A has an indication for liver transplantation, this patient needs to be transplanted, and we should find a way to transplant them. But we should also make sure that we find a way to maintain their functional status, to make sure that their vulnerabilities pre-transplant really are, really do remain, all about the transplant responsive factors, and that we continue to minimize the chance that this person is going to develop more and more transplant non-responsive factors during their time on the wait list. We can do this by establishing guidelines for standard of care treatments, for preserving muscle mass, for liver transplant candidates, we can sort of require that. And then we can measure it, too. We need to start assessing frailty at baseline, at evaluation, and we need to continue to assess frailty longitudinally, because it's so important for us to know that information and for us to provide the message to patients that this is important to us and important to outcomes, and important for their ability to get to transplant. Patient C. So, patient C, we already said, sort of falls into that futile area, but let's just try, let's try to prehabilitate. I think that for, you know, depending on the circumstance, depending on how long it's been going on, if this is their first encounter, they just had a hospitalization, you know, if there are things we can remove, like alcohol, or cure their hep C, or something like that, we should try to prehabilitate and eliminate any factors that are making them decompensated, okay? But I think we've all had many experiences in which we just know that that's not going to happen, that's not realistic, and we should use this framework to be honest with ourselves and honest with our patients and say, you know what, it's just, it's not going to happen. There's just no way that I can, that I see us in a place where when you're ready for transplant, when your MELD score is high enough that you're actually going to be suitable for transplant, that we're going to have minimized these transplant non-responsive factors, and we should really be aggressive and initiate palliative care principles early on in the process so that we can reduce suffering for the patient and the family members. But I've been ignoring a patient this entire time, you might have noticed, and that is patient B. Patient B is the most interesting, and I think the one I'm really still trying to formulate in my head about what to do. So patient B, the obvious first answer is we have to try to prehabilitate them, okay? We have to, just like patient A, who we're going to maintain, we have to develop more aggressive programs and nutritional support, physical therapy, hopefully therapeutics in the future, in order to try to bring these patients, reduce their transplant non-responsive factors to become a patient A. Patient B, if you have decided you're a center that can afford to transplant patient Bs with intermediate outcomes, I think we should avoid transplant-related factors that are going to exacerbate their transplant non-responsive disease. This patient may not be able to tolerate a DCD. This patient, there are certain livers that are going to be fine, like hep C. This is the person who needs a hep C-positive liver, right, because that's not going to result in early graft dysfunction. But I think some of the other technical, the other kinds of livers, like high cold ischemia time livers, DCD livers, ones that might prolong the time of surgery, for example, different surgical techniques that might preserve kidney function, this is the time when you got to bring them out for the patient B, okay? And then, but, I think if you're a center that can afford intermediate outcomes, this may be the person we have to think about, how do we accelerate transplant for this patient? Because they're the most vulnerable to become a patient C, to getting kicked off the list. They sort of have this most, and they also, they sort of stand the most to lose, right, as well as stand to gain. So this is when we bring out the whole concept of survival benefit. My only difficulty with this is that, well, I have lots of difficulties with this, but one difficulty with this is that if we have decided that we need a metric to measure this transplant non-responsive disease, and it's going to be performance-based, I don't want to create a system in which we encourage anybody to not do their best on functional measures or to answer questions or surveys as if they were frail. If we're going to implement this construct of frailty in allocation or in our evaluation in any way, it must always be implemented in a way that inspires and motivates best performance, okay? The best thing that I ever hear, because we're doing liver frailty index in all of our transplant patients at every clinic encounter, the best thing is when a patient comes to me the next visit and they say, hey, Dr. Lai, I've been working on my chair stand so I can beat your test. And that's the best thing ever. I want them to gain the test to be good, right? And so they're super, so I know they're going to be super strong and fit for transplant, but I also know they got the transplant spirit. So for two reasons, I think that the system can be created to motivate improvement as well as help patients truly get better. So I'm just wondering, though, if we can implement a system in which we actually test response to therapy. So we want to see if this patient has any resilience, any reserve left. Can we try to prehabilitate them? And if they can prehabilitate just a little bit to suggest they have some resilience, do have actually truly transplant responsive disease, then can we then accelerate those people to transplant? So that's sort of where I landed on, to get a transplant, a patient B to transplant and accelerate them. And this may be the place where we as a community have to work to develop a system to identify those candidates who are going to benefit the most from accelerated transplant. And those people we have to prioritize and allocate organs to so that we can achieve the best outcome after liver transplantation. Now I may have lost some of you on this, because at this point now it's like, oh my God, now I have to measure frailty at baseline, and then I have to measure frailty again, and now I have to send them to prehab, and now I have to go into nutrition, and then I have to measure frailty again, and then I have to know the cut point at which they change, and then now I have to wait for a transplant. Okay, I got a little confusing, totally, but I'm just going to play a little word association to see if you recognize something. We're doing this with other diseases. I mean, I had to go to the HCC practice guidelines review today just so I could refresh my memory on how we're transplanting HCC patients. I mean, we have already done this for another disease state. You can go into, you can be in the UCSF criteria, and then now we do six-month wait and wait, and then you can't have an AFP above this, and you can have four or five nodules, but none greater than this, no recurrence after three months. We do tons of measurements all the time. We have to continually justify them to UNOS and the review board, right? And so actually what I am proposing is no different than downstaging. It is just downstaging applied to frailty. I don't yet have the metrics for you. It's not yet ready for implementation, but if we as a community can agree that this is sort of the way that we want to start to move our system towards allocation for optimizing long-term outcomes, then we can work, we as a community, the researchers who do frailty research, we can work on developing these cut points. We can work on developing the metrics for liver transplantation. And it requires us, though, first, as a community, before those data are available, before those cut points are available, I need you to start doing measurements. I need you to assess transplant non-responsive in all your liver transplant candidates using standardized, objective, I would argue performance-based criteria in a longitudinal fashion. This is what people were doing for HCC years before we did this, you know, years before we implemented the HCC downstaging protocol. And so we have to actually decide we're going to measure it before we can develop the cut points. And I would argue that we could really accelerate the pace of this research if we could get frailty metrics, performance-based frailty metrics, integrated into large cohorts, particularly the UNOS registry, so that in one or two years, we could have a huge database to start studying to identify where is that sweet spot for transplantation, where is the patient B, and how did patient B change, and what is that, you know, that delta of change at which point is the right time to transplant to achieve the best outcome. So in summary, the current allocation scheme prioritizes patients based on medical urgency that incorporates only transplant responsive factors. Optimizing allocation for long-term outcomes after liver transplantation must consider the impact of transplant non-responsive factors on long-term outcomes. Accelerating the pace to identify thresholds for transplant non-responsive metrics, such as frailty, to optimize long-term outcomes requires systematic and longitudinal data collection in large multi-center or even national cohorts. Thank you. Thank you all so much. I'd like to welcome the speakers from the first section for a panel discussion. I'm really happy as they walk up here, I just wanted to say I'm really happy that we've been able to talk about both of these populations, both the adult population and the pediatric population, but especially as I was listening to Jennifer's talk about transplant responsive factors and unresponsive factors and comorbidities, to think about the population really as a single population. You know, if we put our pediatric patients into that group of responsive versus non-responsive and some of those variables, where do they play out if we look at this population as a whole? I'd like to go ahead and open the floor for questions and comments. Great. Josh Levitsky from Northwestern. I just, first of all, want to congratulate both of you, both very eloquent, fantastic talks, just very open and honest about things, I think is a great way to help lead this, you know, talk about this now in the panel, because some of the things I just wanted to kind of, I was thinking about particularly with Jen's talk, two things. One is the last point that you made about maybe having some type of downstage or maybe it's upstaging, kind of an improvement, right? I think that, I think just, you know, having taken care of a lot of these patients, I think you have time, maybe have some time to wait to have that type of protocol in people who are low-meld. And so people who are higher-meld who are kind of frail and you're struggling with trying to improve them, it just seems really challenging to even get to a point where you can upstage them. And then you're, so I think it's a little different than HCC where they're not really at constant risk of dying while in this waiting period. Maybe in the low-meld you, your prediction of death three months is pretty low that they're gonna, it's likely that they're gonna be alive, but the higher-meld. So I think that's where it may be a little different than HCC. I like the concept a lot, I just think that, and I have one other comment about the frailty stuff. I just wanted to see what your perspective on that is. So I think that's a really fair point, I get that a lot, like, you know, it's great if you have time to prehabilitate for sure. And I would agree, you know, a meld of 40 who's frail, you don't have, you're not sending home trying to prehabilitate them, it's super, super fair. I think this is a system problem in terms of the recognition of frailty. Right now we're not systematically measuring frailty, and so it, we need to just, we need to start slowly by making sure that frailty gets acknowledged at the very beginning. I kind of liken it to ascites. Nowadays many people outside of transplant centers know that, or primary care doctors know if you have the first onset of ascites, then you start referring to a specialist, right? And so I would love to have that same, and so it's actually, yes, we all get a fair number of refractory ascites on first, you know, coming to a hepatologist as their first presentation, but actually more often than not, we're starting to see them earlier, their first episode of ascites when they're still on diuretics, and not waiting until they get a refractory. So I'd love to see that with frailty, that we, if we start and we say, we're starting to allocate organs based on frailty, or that, you know, that's important, then we can affect the upstream process where primary care doctors, referring doctors are starting to say, well, now I have to measure frailty, and I have to start referring them much sooner in the process, when they have just mild ascites and mild frailty rather than refractory. But you're totally right, it's definitely a problem with the protocol. So you're sort of taking the clear box and avoiding the patient going to the little black box in there from the beginning. That's right. From the very beginning, that would be the vision. You're right, early on, when we first implement this concept, it will be very difficult for the patients whose initial presentation, you know, they're super frail, but the reality is we turn down people all the time on their first admission, because they're too sick for transplant, right? So that might just be what we have to do. So second comment, Jen, was just about, I mean, you wrote a great paper on the pre- to post-transplant frailty, and I remember from your paper, I think we wrote the editorial on it, that there is a certain percentage of our robust, so your clear box, become like kind of pre-frail or frail afterwards. So how do we use that for allocation? Is that just a matter of just a DCD? They don't do well, they're, you know, they have post-transplant outcomes, or do you think that there is a concern there, and what should we be doing up front or right after transplant? I don't think it's a concern in the sense that it's, that we should not transplant, we should not have transplanted those patients. I personally believe that was a surgical, you know, it was a surgical complication or some complication that wouldn't have been avoided. What I do know, if that patient had started off frail pre-transplant, they would have been dead, probably, right? And that actually being robust allows a patient to tolerate whatever unknown random surgical factor is gonna come along, whatever random infection or complication is gonna come along. Because they got better later. Yeah, those patients actually don't, when their frailty, or when their robustness worsens after transplant, they don't bother me, I don't see them as a, oh my God, we should never have transplanted them. I think of it as, thank God, they were robust to start, so they could have withstood that complication. I do think that, at some point, we need to start talking about early post-transplant rehab. Absolutely. You know, immediately coming in. I'd love to develop a program where, literally, day one, you're starting to do, like, you know, leg lifts and stuff like that. And we need to design a system in which we initiate leg lifts and tacrolimus at the same time. Right. Thanks. Dr. Spade, I have a number of comments and questions for you. So, to quote Pogo, who looked in the mirror and said that the enemy is us, I wonder what the responsibility of the pediatric community is to try to address these things. For example, you had implied that the PELD score is a relatively poor indicator of weightless mortality. But a paper I think you're very familiar with demonstrated the C-statistic for PELD is currently .84, which, as Dr. Lai demonstrated, is much better than MELD, yet we seem comfortable with MELD. The PELD score does good to rank children against other children. What it doesn't do is make equivalent the risk of mortality between children and adults. So I think that if children had priority, I think the PELD would work fine to rank them, although there are some groups for which the PELD doesn't work as well, and I think that's where we get to that pie chart of what the wide variation of some of the indications for transplants would be. But I think you would agree it's become a nuclear arms race in terms of listing kids with exceptions. You know, we're up to 75%. And you can't justify that with a PELD score, C-statistic of .84. Right, but I think that the reason for that is that children aren't competing with other children. Children are, in fact, competing with adults for the organs that they need. And a recent publication demonstrated that transplantation for hepatoblastoma does not yield better results in surgery and chemotherapy, yet it's given 1B priority. That's very, I mean, I think that's something that we, there are certain pockets of the pediatric transplant community that feel very strongly about what we should be doing about those hepatoblastoma patients, and we really wanna make an effort to, they're not the same as our chronic liver disease 1B patients who are very, very sick at the time of transplant. So I completely agree with you in that, but that applies to a very, very small proportion of children that we're transplanting. The other thing you mentioned that the current state of allocation underserves pediatric population, but acuity circles, if it does go into place, which hopefully it will in the next three days, the one population that's gonna significantly benefit from acuity circles is gonna be pediatrics. That's absolutely true, and I think that the willingness of the wider transplant community, wider liver transplant community to address the concerns of children in that particular conversation was really helpful, and I think what's really booing is being in these conversations together and seeing the perspective of all these different groups as far as how much responsibility do we have as practitioners and as stewards to do the right thing by all patients for all society. And kind of my last two points are similar, but as you know, there's a proposal out right now to try to encourage splitting, and for those of us who are really old who've been in this field for a long time, this will be the fourth proposal that's going out there to try to incentivize splitting, and I have no belief that it's gonna make any difference whatsoever, and I completely agree with you that that is the way to really optimally serve the pediatric population. And it really comes to my other point, and so why, why is it the lady behind me? There she goes, yeah. She moved on. But why are they so successful in the UK? Because they're very comfortable with splitting, and there's enormous trust among the surgeons that doesn't exist in this country. We have a surgeon on the panel who can give his estimate as to how many programs out of the 130 we have in the country now are comfortable with splitting, but I would offer it's probably 30 or 40 at most, and that's, I think, the biggest problem is you've got so many programs that are uncomfortable with splitting that that is why it's very difficult to just incentivize it rather than mandating it. If you try to mandate it, all of a sudden you've got 90 programs that are screaming about it, and it really brings up to my last and I think most important point, and that is what should be a pediatric liver transplant program, in other words, if you can't offer splitting live donor as well as whole organ, do you think you have any benefit calling yourself a pediatric transplant program and listing pediatric candidates? I think that we have demonstrated that better outcomes come from programs that can do every type of transplant. That includes, I think, if you can do a living donor transplant, you can basically do everything else, and I think that is a controversial thing. It leads to your other question, which is that we dwarf every other liver transplant program in the world, and I think coming to a consensus among 1,000 people is harder than coming to a consensus among 10. And I did have one question for Jen. So what do you think is the best frailty test? I think I know the answer to that question, but what about the FREED test, for example? Yeah, so I would argue for the liver frailty index, but one might argue that I'm extremely biased. Although we are using it in the UCSF for every patient, and I think that we agree that it's very useful. The FREED frailty test is problematic because it has two components that are, it has this component of exhaustion where you ask how many days in the last seven days have you felt exhausted? And that's such a nonspecific. My answer would be fine. Right, and so everybody is frail. And I don't know that the answer to that indicates that you're gonna have bad outcomes after transplant. It also is a scale from zero to five, so it's very hard to assess longitudinal change. And if you already start off at one because you're exhausted, are you really gonna get to zero? Can we prehabilitate you to zero? So it's unresponsive to change. There are survey-based instruments that can truly be gained. And it's a non-flexible instrument. So we actually, in our multicenter cohort, have stopped using FREED altogether because I don't think it's very practical in clinical practice. Hi, I enjoyed all the talks. I'm Liz Rand from Children's Hospital of Philadelphia. I'd like to ask a question that I think is gonna be very controversial and unpleasant. But what I'm wondering is how can we as a transplant community limit giving transplants to people who shouldn't be getting them? So for example, if I hear about a preteen child with a metabolic disease who's nonverbal but can play with his iPad and received a deceased donor liver and kidney transplant for treatment of the metabolic disease, I'm sure there must be adults who are analogous who maybe have some significant cognitive injury. And I would say this child maybe, in the one that I'm just describing, would fit with that large black box that a lot of what's the matter with him can't be solved by transplant. And it makes me wonder what is the purpose of some of the transplants that we're doing? And it may not be a huge number of transplants, but is that something that we as a transplant community need to address our own responsibility for doing transplants in people who in some very basic way cannot benefit? And I think they would be very different types of patients, adults and pediatrics, but I wonder what Jen and Evelyn would say about that. Yeah, and I have the same question. It was really fascinating what you were talking about and hearing you talk about how frailty could predict post-transplant outcomes being poor and the other transplant non-responsive things like, I mean, what other things would you consider transplant non-responsive things? Does alcoholic hepatitis consider? Sorry, what was that? Alcoholic wasn't on there at all. Right, right. Or. It's a huge thing and I think we're doing way too many transplant problems possibly with people who can't benefit because they have profound problems. Or addiction. I mean, I think that's the other thing. I guess you bring up a really good point. So I clearly simplified this and made everything that wouldn't respond to transplant into frailty that predict poor outcomes. But I guess I would challenge you on just trying to determine did that child's cognitive dysfunction, will that impact their outcomes after transplant? No, they're not gonna go back to playing on sports and running Apple, but are they going, is that going to affect the. I'm talking about permanent cognitive injury that occurred prior to transplant from something that's not addressable by the transplant itself. So in metabolic diseases of childhood, they've had perhaps brain injury due to high ammonia levels or what have you. Yes. And so they might, their bilirubin might not be high, but they're not gonna have these metabolic crises anymore. But the damage is already done. And there are probably adults that have some similar analogous thing. I can't think of what they would be. I guess the question we need to ask is, do we feel that that cognitive impairment, is that going to impact their post transplant outcomes? Is that person gonna get, live shorter time? Is that gonna impact their graft dysfunction? Because if the parent, who's the caregiver, feels that that kid is going to live, feels that that kid is still gonna live a good life and enjoy their life, I would say that I wouldn't put that into the gray box of it would not impact them having a poor outcome. That would be maybe not an outcome that you or I would want for ourselves. But if the caregiver feels like that's what I want, I want this person to live another 20 years in this state, then I feel like that I wouldn't put into this gray box. I guess I wonder whether we as a transplant community should have an opinion about that beyond just the parent. I mean, it's very painful. But I just, I kind of think that we, the transplant community, maybe have a responsibility to address that in a larger way. I see a little bit more of an assumption of that responsibility within the pediatric community than I have in general in the adulthoods. Hi, sorry, I'm Noel Georges. I'm from Texas Children's Hospital. I also have kind of a controversial question that almost piggybacks off of Dr. Rands. We had a couple teens that were listed after suicide attempts and prior suicide attempts and overdosing. And I just wanted to know the panel's thoughts on that being a transplant non-responsive factor, whether or not you think that is, and how you think that kind of plays into allocation. It just, I mean, I think we should, for sure, transplant these kids. But I know it causes a lot of angst among the caregivers and the nurses. And I just wanted to see what you thought about that. We had a case like this a few years ago where we decided not to relist somebody who had a recurrent suicide attempt. I don't know, and I think it's not generalized or set into policy across the country, and certainly not for pediatrics. And I would hazard not for adults either. Yeah, we would do, we see this all the time too. And if we believe it's transplant non-responsive, we won't list them. If we believe it was a one-time attempt, same with that this is the argument that's going on with alcohol. If you believe it's a one-time attempt, this was the first, they just had an impulsive behavior. But we believe that there's enough support in place. We've never seen this behavior again. And there's a reasonable chance that actually, obviously the suicide, that was not responsive to transplant but will go away after transplant. Just because we'll provide them with support, we will transplant them. So I think it's just a matter of if you think that it will affect their outcomes after transplant. Just one quick comment there too, is that the brain development, there's emerging data on brain development that a teenager really who has an episode like that, doesn't really, they're not, once again, fully formed. And I think that that's a really critical point as we make judgments on teenage behavior. We should look in the mirror, as Jack suggested, and remember when we were at that age and what we did. So it's a little bit different. Hi, it's Jeff McCorn from Sydney. And I'd just like to bring an Australian perspective to the pediatric aspect of splitting, which is, so we're in the UK camp in the sense that we split a lot. And one of the things that we've done, I mean, presumably all transplant programs have to somehow have a monthly audit of what they did in the last month. Surely that must be present in every transplant unit. Is that correct, isn't it? It's present but not required, right? Yeah, but it's best practice and somehow best practice needs to be in place with auditing as well as how good you do the surgery. So one of the things that our national bodies require us to audit is our allocations. So we go over our allocations each month so that it's known that Jeff McCorn didn't allocate a liver to his favorite patient because I've got to explain to Jack Lake why I did that because his favorite patient didn't get transplanted. So we have an audit system for that. But one of the things we audit is if there's a splittable liver, why wasn't it split? And the people who made the decision not to split have to answer to the rest of the transplant unit every month about why they didn't split. And that's part of our audit system. So I would sort of try to, at a national level, to suggest that your bodies ask people, units, to put that into their audit system. What are the consequences? I mean, other than being kind of publicly. Apart from shame. Apart from shame, right. Because we've tried that. It's not working. Shame's okay, particularly if it's repetitive. As Jack said, this has been tried many times in the U.S. and it's just not working. And hopefully, when the new allocation system goes on, as alluded to before, it's really addressing the organ-shortening pediatric liver recipients. And hopefully that argument will go away in a short period of time. But again, it's hopefully. Because it is, as John put it in his slides, there are very different goals in a transplant. One of which is to avoid disease progression, which is not any different in adult patients. And the second goal is to avoid complications and technical complexity, which is a little different than the adult population. So most of us here who do both adult and pediatric transplants, surgeons face this on a regular basis. When you're offered a 17-year-old liver coming from a donor 100 kilograms to a four-year-old biliary atresia kid, do you split that and accept the complications that come with it? Or do you just wait for the next size-appropriate donor? So if there are any pearls on that, I'm happy to receive it. It's a little hard. But hopefully the new allocation system will address that if it's ever implemented. So the one thing to comment on is the allocation system in the states. The prioritization is very highly regulated. Allocation is highly regulated. In the final rule, they talk about the autonomy of the center. The acceptance of organs is not highly regulated. And this is a distinction that's in the final rule. And I think that a lot of the comments that we're talking about is organ acceptance behavior and the decision on splitting or not, which falls within the framework of this. So it's a complex system. People have competing demands within the system. And I think it's very different from a national system that we're talking about, some of the other countries we're talking about too. Can I ask one more question? We have time for one more. Yeah, one more question. Sure. This is the first time for me to attend this meeting. Thank you so much, our speakers. I wonder you, for the first time, as this lady point out, the operation length affected the long-term result, the operation time during the liver transplantation. This is really, really first time. Nobody make any judgment on surgeon's skills. We know the long-term outcome from liver transplantation depends on three major factors. One is liver quality. Second is the surgeon's skills. If a surgeon can make the shorter and haptic phase, that must be good, you know? Nobody never mention surgeon. Always we're trying to do tiny things, tiny things, tiny things. We should have a system to measure the surgeon, how good skill they are. This is the first time you mentioned the operation length affect the liver transplantation outcome. You know, how can you in your system or every hospital can have access to the what patient, how long they survive related to the haptic phase, how long time. Some one can do within 20 minutes, another one can do one hour. The huge difference. The body response during the, because the whole circulation up to here is stopped. The haptic, the pressure, the whole system circulation, tremendous difference. Nobody never mention, you know, always. It's a fantastic point. Actually, my mentor, Sandy, tells me this all the time. She said, you're not measuring what's in that black box. She's like, where's the black box, which is what happens in the OR. And it's so true, it does make a huge difference. And I think this is a huge unmet need, I think, for any budding researchers looking for an area to research. Like, we need ways to quantify this. We need, you know, it's more than just minutes in the OR. Right, it's gotta be, we've gotta be able to get through anesthesia records or, you know, it's more than just number of transfusions. I don't think that actually matters that much. You know, there's gotta be some way to be able to measure and quantify in an objective way. And developing those metrics would be so key to better understanding what happens after transplant. Thanks for bringing that up. Yeah, and exactly, it does predict outcome, predicts that ideal outcome, predicts all those surgical complications. And I think that the charges to our colleagues who are in transplant surgery about how do we standardize and regulate those things, what Dr. Lake talked about of who should be doing pediatric liver transplants. It really should be anybody who is experienced in living donor transplants. Another short question for you, you know. In China, all children, if they need liver transplantation, parents urgently, you know, to donate to the organ. What happened here? They just, you know, I feel the children still on waiting list. No, that's absolutely a great point about the uptake of living donation of technical variant availability to children across the country. Children have different access to expertise across the country because of the standardization of practices here. Thank you. We should move on to the next section. Thank all the speakers for excellent presentations.

organ allocation

long-term outcomes

adult organ allocation

equitable allocation

medical criteria

frailty

post-transplant outcomes

performance-based metrics

surgeon skill