Dr. Alex Cuenca - Current Obstacles and Progress in Pediatric Liver Transplant

you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you you level training and transplant surgery at Massachusetts Journal Hospital. He returned to us here at Children's in 2019 to join his staff and in just two years as faculty he secured funding for multiple projects including the ASTS faculty development award and has mentored numerous trainees who have presented at the national podium. Dr. Kwenka has extensive lists of peer-reviewed publications in both surgical and basic science journals clearly epitomizing the surgeon's scientists. We look forward to hearing from him today on the current obstacles and progress in pediatric liver transplant. All right thank you so much for that wonderful introduction let me see if I can get my slides. Everybody see that? Yeah. All right thank you so much for that wonderful introduction it's an honor and a pleasure to present for you today some of our some of the most recent developments and obstacles and liver transplant. Unfortunately I have no disclosures yet but I am working on it. So we'll be broaching a lot of different topics today within liver transplant. We'll talk about where we started and how things have changed. We'll also talk about some of the co-morbidities associated with immunosuppression as well as high-risk donor and recipient groups which will be different than what we typically consider to be high risk groups and adult transplant. We'll also look at the outcomes in our liver transplant recipients with COVID as well as touch on the suggestion by some transplant groups that perhaps we should be moving to transplant first and biliary atregia as opposed to the side and as it's an important part of our transplantation numbers and schema will also discuss changes in liver allocation and policy here in the US and Europe and finally we will end with directions and pine the sky type search that hopefully from a reality soon. If there's any way I could ask everybody to mute just because I'm getting a lot of feedback on my end of the start. All right so as many of you know the first attempt to perform a liver transplant was made by Starsel in 1963. His efforts were not as successful as hope until 1967 when he transplanted a 1.5 year old girl with the Patocelio carcinoma who survived for 13 months before such as the links that coming to her disease. Further refinements and technique and then perfusate solutions allowed for perfio solutions designed to halt or slow the metabolic activity of the organ were made in the 1970s and of course the more significant long-term advances were made in refinements and immunosuppression with the introduction of cyclosporant and then tack in the 90s. So ultimately we've gone from a five year survival about 20% from the early 70s to greater than 80% currently and though living donor transplant has added to our organ pool it still comprises only a minority of liver transplants. Our median graft survival or 50% is about 13 years and has significant and this is significant implications to our patients in particular as are obviously looking at the prospect of multiple transplants down the road. The scientific registry of transplant patients or the SRTR puts out an annual report of outcomes for individual organs every year. The most common indications for pediatric liver transplant remain the same with the line share being colostatic diseases like biliary treasur followed by metabolic disorders and acute liver failure. With regards to deaths while in the waiting list most groups share similar outcomes except those patients that are less than one year old which may be expected. However if they're able to get if we're able to get these patients transplanted they do fairly well and they have five year graft survival at greater than 80% for all groups and patients survival at about 90% of five years. So overall we're doing fairly well. All of these outcomes are excellent and like in kidney transplant they have been fairly stagnant over the last one to two decades so what can we do? Well like most diseases we become experts at managing the acute problems of liver failure and transplantation but ultimately in most cases it's the morbidity of all the other issues surrounding the transplant that are important. Things like immunist oppression, adolescents and medical non-compliance as well as neurocognitive delays in transition and care. Now in some instances we have improved our ability to treat the primary disease we still have a lot of work to be done here and finally there's also a lot of focus and effort on organ shortage in getting all of our patients transplanted in a timely manner. We'll discuss some of these novel their novel concepts at the end. First the best and worst part of all of our advances thus far immunist oppression. While we consider immunosuppression for the pediatric patient we have to consider the differences in physiologic and environmental exposures. Things like metabolism differences, changes in the paddock blood flow that occur over the life of the child, we have to count for changes in growth in body surface area. We're also relying upon responsible adults to administer to administer these medicines and some may not be palatable and ultimately some of these patients may require an NRL2 for placement. In addition surveillance for immune controlled cancers like lymphoma and skin cancers decreases and therefore the incidence of these cancers increase all across the poor. However although no one would argue the necessity of these medications and regimens it's worth revisiting some of the side profile. For induction agents that are being used either as the organ is being sewn in or before, high dose corticosteroids have been associated with impaired wound healing, pancreatitis, gastric ulcers as well as prosposterior reversible in cephalopathy syndrome. We also use Bayes-Lixum avar symulact which is relatively well tolerated but still has side effects albeit less than steroids that we all need to be cognizant of. Following transplant our patients are put on maintenance therapy. These medications include steroids as we talked above which have all of the the significant effects that we discussed above. In addition to growth changes in growth in appearance such as cushioned interfaces, stria and weight gain which as you might imagine may decrease the compliance to our adolescent patients. I will say that many pediatric centers across the US attempt to wean steroids early or minimize steroids compared to adult centers for these reasons but in cases where we are dealing with rejection sometimes we're unable to. Almost all of our patients are on tachylymas which has long-term effects on kidney function, the induction of diabetes, hyperlipidemia, phyresthesia and other neuropathic pain. Excuse me and like all other immunosuppressants, PTLD or post-transparent lymphropliforid disorder. Cycles foreign due to being harder control as well as the added side effects of general hyperplasia and hersotism and it's less used. In addition to these calcinarian inhibitors we sometimes substitute or add m-tore inhibitors like serolimus or a rapamycin. This is done especially in cases where malignancy was the primary indication for transplant as there is thought to be some anti-neoplastic activity. Of course the greatest concern comes, the greatest concern with these inhibitors is the significant effect that these medications have on wound healing and so we try to switch to these patients to attack in the interim if the surgical procedure is being planned to decrease the risk of war wound healing. But there's also additional risks such as oral ulcers, myelusuppression and hyperlipidemia. You may also see anti-metabolites such as MMA for microphenol atmophotel or emurant in our patient lists. The greatest side effect with these medicines tends to be GI distress and marrow suppression. So though we need something many centers of adoptive steroid spheric regimens and have attempted to change the steroid paradigm. This study from Grass which is a single center perspective trial looked at 50 children that were enrolled to either attack and base eliximab group or attack versus steroid group. In the attack and base eliximab group they demonstrated lower three year incidence of rejection and specifically steroid resistant rejection as well as importantly increases in patient growth compared to those that were maintained on tachmonotherapy and attack and malodus steroid therapy. This is important because as everybody is concerned about the risk of rejection and so it was important that they show this. Despite this paper and although it's encouraging most centers feel very uncomfortable with completely removing all steroids from their baseline regimens to do the risk of rejection. Although the data is evolving studies like this Cochrane study suggest above suggest an increase in rejection rates in those regimens not containing steroids so at this point the jury is still out. Some groups have attempted to wean immunosuppression altogether. Sandy Feng's group from the SCSF has looked at this in a prospective multi center trial of 20 parental living donor recipients. The ediology of the primary disease could not be viral hepatitis and patients had to be transplanted for at least 40 years before enrollment. In addition to this biopsies had to be performed and if there was no evidence of rejection of fibrosis they were enrolled. Of 20 patients of 20 patients they identified 12 that were able to be wean completely and were deemed operationally tolerant. Although unclear donor specific antibody was detected in four of 12 of the tolerant patients and seven of eight of the non-tolerant patients. You'll see that this donor specific antibody comes up a lot and is associated at least somewhat with with this with non-tolerance or rejection but it's a little bit unclear as to how that how they this functionally is working. While it is interesting the follow-up for this study was relatively short so they published they recently published a five year follow-up which continued to demonstrate operational tolerance for the original 12. Though there was an increase again in DSA over this time period. There have been multiple other immunosuppression with draws trials over this period since and but they have not been able to exactly replicate these results likely due to the very specific enrollment population such that the living donors were the parents of the recipients which is not always possible in our in our population. Despite this centers continue to wean aggressively and try to limit the long-term exposure in our patients. However we typically use we typically use laboratory values to wean these medication and in this study they examine 157 biopsies from patients with essentially normal trans emanates and GTT. What they found was that in a majority of patients there was some degree of chronic alligraft injury and rejection by a pathologic criteria and analysis of transcriptome pathways that were typically associated with rejection. Again in these in these instances elevated levels of class 2 DSA were associated with this phenotype. So where does this leave us? Well we know that changes in immunosuppression can be made and we and others have created steroid free or steroid avoidant protocols that we think have not dramatically increased the incidence of rejection. However what is disconcerting is that the parameters that we typically use to determine whether or not a patient has rejection may or may not be appropriate and we need to follow we need to develop better assays and biomarkers to follow our patients. Other factors that affect outcomes that are unique to our population are our unique neonatal populations that we use as either recipients or donors. In the mid 1990s column body at all examined outcomes in 13 recipients less than one year of age that received either a whole liver, a living donor segment or a deceased donor segment graph, a deceased left lateral segment graph. In this study there were high rates of complications but perhaps the most striking was the incidence of hepatic artery throbosis. Unfortunately and likely due to the low numbers these were not further separated and segregated into which complications was associated with which graft. Embedded in that in other papers was the sentiment that perhaps whole livers had fewer complications than split livers and that led many groups to not consider split graphs for their patients. A bias that still exists today. But several groups have looked at more contemporary outcomes and the data is more encouraging. Dory Seggebs group at Hopkins has done a lot of work with data mining in particular has looked at this trend and as you can see from a more contemporary cohort of patients compared to a prior cohort of patients so those patients from 2010 and 2015 versus those from 2002 and 2009 have we've essentially improved outcomes with split liver and whole liver deceased donor graphs to the point where they're equivalent compared to the prior cohort. We and others have also looked at the effect of small donor size on recipient outcomes. In this study by the side they examined recipient outcomes from donors less than 20 kilograms and stratified them into four groups. They found that with the smaller donors less than 10 kilograms they had twice the rate of hepatic artery thumbosis and worse graft survival. In our study we analyzed 127 liver transplant recipients that were performed between 2002 and 2016 and found similar things. Specifically Dr. Vickili found that those patients less than 25 kilograms that received whole liver is at significantly higher rates of HAT or hepatic artery thumbosis. In addition Dr. Vickili found that those patients that were less than 25 kilograms but that also had a lower donor recipient ratios also had higher rates of hepatic artery thumbosis. This essentially states that when a donor is the same size or smaller than our donor is the same size or smaller than our smallest recipients they have a higher rate of hepatic artery thumbosis. Therefore we carefully consider accepting whole livers from infant donors as our outcomes traditionally have shown that they have been worse than split livers. As we've optimized many aspects of our post liver settings, most post liver transplant care, how of our patients fear to the pandemic the respect to COVID outcomes. As our patients are immunist or press there are obviously concerns in previous reports of the beginning of the pandemic had some estimates of mortality and adult solid organ transplant patients at over 25%. This study by GOSIDOL is probably one of the largest series from the US looking at all solid organ transplant patients and their outcomes and demonstrate what we have seen on our own practice which is that although some require hospitalization they are in fact not as critically ill as you might expect. In fact in this series none of their hospitalized patients required any supplemental oxygen. In another study looking just that either patients with native liver disease versus those with status post liver transplant. As you might expect most of the liver transplant patients did actually quite well following COVID infection. In fact risk factors for more severe clinical presentation those patients that required pick you admission or supplemental oxygen slash mechanical ventilation was associated with actually native liver disease obesity and no immunosuppression use. This certainly fits with what we currently understand about the path of physiology of the viral illness as well as the physiologic effect of some modalities of treatment. Since our outcomes in pediatric transplant have improved we should be considering the liver transplant as a primary therapy for certain diseases such as biliaria trisia. Well certainly biliaria trisia remains the most common indication for liver transplants in our population and despite our best efforts our outcomes with respect to biliaria trisia are somewhat stagnant and so groups of us is there a better way. This study led by a Vanderbilt USC transplant group identified patients by an administrative or California administrative database and examined outcomes following the SI or biliar interdrainage versus primary liver transplant as well as outcomes of primary liver transplant versus salvage liver transplant which would be considered to be post-cissile. Interestingly they show that primary liver transplant seems better than either primary cussi or salvage liver transplant. So based on this study should we be considering liver transplant as a primary therapy at BA? Well we don't think so. In fact our group and others have questioned the data. Dr. Kim and Elisophon from our group published this critique in hepatology with several concerns about the data and study conclusions. The most significant of which was that it was incomplete as it suggested that 40% of the BA patients did not have any intervention before five years old and 50% of infants in the administrative database didn't have a beside. Both of these prescriptions are very important because we know that the natural history of biliaria trisia is that it is lethal by age five and considering that the SI is the gold standard how is it possible that 50% of the patients in the database did not have a biliaria teric procedure. Needless to say this did not change our practice. So what other novel concepts for liver transplant have been introduced in the last decade or released in the last five or seven years? One concept was a proposal that we've discussed in the US but have not implemented is potentially evaluating every liver every liver donor as a potential split. This was done in Italy and published in 2019 in the American Journal Transplantation. All liver donors between 18 and 50 were anatomically able to be split were offered to a non-status one pediatric recipient. Once a pediatric recipient was found an adult counterpart was then matched for the other part of the graft. There was no difference in graft survival in the pre and post periods of this implementation and pediatric waitlist time seemed to decrease from seven to four months. In addition pediatric wait adult and pediatric waitlist mortality both decreased by 50 and 40% respectively. Since 2018 the new US policy is based on distance as opposed to arbitrary regions. Recipients within 500 miles of the donor hospital are offered the organ first which then proceeds to a national allocation if a suitable match is not found. This is dramatically expanded the catchment area for larger cities like Boston and New York and has dramatically increased dramatically increased the number in certain other landlock cities with sicker patients such as Cincinnati and was ultimately the subject of several lawsuits because several centers were could extrapolate out that their numbers would decrease and they did but ultimately this was found to be the most appropriate strategy for liver allocation. Regardless pediatric patients are still given priority in right or first refusal in every tier of allocation. So I didn't discuss the difficulties with adolescents and transitioning them to adult practices and neuro cognitive outcomes and socioeconomic analyses mainly because I didn't feel that I could do those topics enough justice in this time frame. Suffice it to say that these interventions are arena's that are critical for the success of our patients and our pediatric transplant center. They certainly deserve their own hour or three to discuss all of their advances and proposed interventions but maybe for next time. And now for something completely different. So just to revisit we discussed many of the important concepts and morbidity of flicking our patients as well as some changes to induction and maintenance protocols that are being trialed. What other novel strategies are on the horizon to improve our immunosuppressive regimens or achieve alligraft tolerance and what are we doing to address the organ shortage aside from policy changes. So we know that very few developments in new immunosuppressive medications have been found and this may be limiting our ability to improve alligraft and patient survival. It also may be related to or at least affecting the flat line of this curve here that has started over the last decade with regards to the six to five year survival. One option may be in the arena of cell therapies which may offer long term alamine suppression without the administration of toxic immunosuppressive drugs. One of the cellular therapies that's being developed here in Boston and that's being also collaborated with my research mentor Dr. Markman. Has been in the development of patient expanded T regulatory T cells. This group is isolated peripheral blood and expanded allogeneity right T regulatory T cells for immunotransplant patients in the presence of bilatusep which is a CTA fusion protein. This protein essentially blocks the simulator blockade and expands energetic T cells. If you look here you can get the T-reg population to expand by twofold which then can be used as a donor lymphocyte infusion to prevent rejection and potentially induce peripheral tolerance. These studies are currently in phase one and two clinical trials and other groups are developing chimeric antigen receptor T-regs or CAR T-regs which would then suppress alamine responses. This is piggybacked onto the new concept of CAR T cells which are being used to tumors. Other efforts have been focused on B regulatory cells due to their purported ability to secrete immune inhibitory factors and control T regulatory responses. Similarly myeloid derived suppressor cells or MDSCs have also been shown to have alamine suppressor capability and is one of the major foci of my research efforts. These cells in particular or all as similar to all innate cells seem to coordinate a lot of responses including T-regs and B-regs and so would be essential in potentially generating a tolerogenic response. In fact if you're interested and I know you are I will be giving another grand round about this and other translational concepts in it. Another area of research and something that I work with while I was at the general doing my transplant fellowship is in improving longevity of procured livers and in the rehabilitation of livered for donation. With regards to cold storage which is currently what we use some of the limitations are related to cell membrane loss of cell membrane potentials, electrolyte hemostate homeostasis, incomplete suppression of metabolic activity and an inability to provide energy substrates while in storage. This graph represents a classic experiment from Roy Calming, one of the pioneers in transplant and surgery a transplant surgery in research in which it demonstrates a significant almost complete loss of ATP by about 12 hours. This data has been extrapolated to human livers and is one of the reasons why some centers consider 12 hours to be the relative limit in terms of max cold ischemia time. Aside from limitations of cold storage why do we typically why do we sometimes discard organs? Well the reason for discarding organs is many but some of them are reversible and some of them are some of them are reversible and some of them are what we consider to be irreversible at this time point. Things like fibrosis malignancy, cirrhosis, the age of the donor and reversible causes being like a schematic injury and those injuries that occur after donation, effort, cardiac death, long storage time, partially crosses in stiotosis. So in an effort to improve these factors X, V, V, V, V, V, and normal thermic perfusion therapy was developed. These machines as such as the one that's pictured here provide either pulsatile or non-pulsatile oxygenated blood flow in addition to an energy substrate as well as bile salts. You can assay for the function of the liver through cable outflow with one of these cannulas to look for the metabolism of lactate as well as markers of liver and drink. In addition, a separate cannula is placed into the bile duct as one of the metrics for liver function on this machine as bile peruption. The development of these machines could theoretically render currently used organs better safely extend the preservation period and potentially allow for elective transplantation, allow for organs to be currently that are currently being discarded or recovered to be used and to even to discriminate those organs which will not function well from those that well. This was actually examined in a relatively recent nature paper from a UK group from Peter Friend. This was a prospective randomized control study which looked at either 120 livers that were procured and then subsequently placed on this organox metropomp which is a version of this non-etharmic perfusion pump versus 100 livers that were procured in place in statical storage or standard of care. What they found was very interesting in that the primary endpoint was PKSD and they found that it was significantly lower in these organox pump groups. As you can see from these numbers it's almost half of what it is the pump number the pump livers have ASTs that are half approximately half of what they are with the standard of care. In addition to this secondary outcomes such as discard rates, primary and unfunction, post reprefusion syndrome and as well as early aligraft dysfunction were also looked at which were all found to be significantly better in the pump livers. So their conclusion was that normal thermothomic machine pump livers are safe and may decrease fairly aligraft dysfunction. So other user friendly platforms since this time have been developed but some of the applications that are being proposed thus far are the possibility for liver regeneration and growth of a viable graph. Eschemia free procurement whereby cannulas are inserted into the aorta, portal vein and kava prior to cardiac death so the liver can then be placed on a pump after all the cannulas have been placed and you can have an eschemia free reprefusion. Sorry, eschemia free procurement. The opportunity to perform ex-evil resections or the ability even to split on pump and this has been published as a proof of concept. In addition as one of the major reasons for this advance is to potentially rehabilitate marginal livers there's also a great possibility to administer or treat graph sex vivo with defadding cocktails for stiotosis or other medical interventions. Finally a significantly less important but attractive reason may be to turn a liver transplant into an elected case for at least the recipient surgeon. Another area of active research is to expand on the donor pool. Sorry another active area of research to expand the donor pool is in the development of porcines unigrafts. We've come a long way in terms of development of genetically modified pigs starting with the deletion of the polysaccharide alpha gal. It's prevent hypercube rejection of the graft to the modification of innate immune proteins to decrease rejection. In addition attempts have been made to generate porcine grafts that express some primate clotting factors such as case and to express some primate clotting factors. At this point the case center is still being used to supplement to provide clotting factors in all of these preclinical models. Finally one of the other benefits of the normal thermo-machine is the potential to test these zina grafts X-Vivo to see which of these genetic permutations may be successful in a human model or a primate model in general. However you may recall a recent article where a porcine kidney was transplanted into a brain dead recipient for 54 hours. This kidney made urine and had no signs of rejection and were identified but in the no signs of rejection were identified. While this is promising for kidneys again one of the major barriers for the liver zina graft transplantation is the inability to generate primate specific clotting factors. Obviously without clotting factors the zina graft transplant recipients do not survive. So in conclusion we've discussed many things related to the developments in liver transplant. Changes that immunosuppressive regimens have and can be made. However cellular therapies offer the promise to further modify these regimens or potentially remove them all together. In addition infant recipients and donors were associated with an increase in surgical complications and worse patient graft patient and graft survival. However contemporary data suggests that these outcomes have improved significantly likely related to more comfort with split lever techniques and better parian postoperative care. Further COVID specific outcomes are excellent for pediatric solid organ transplant recipients and only a minority require hospitalization or respiratory intervention. In addition despite the suggestion by some liver transplant groups that the primary surgical therapy for biliratrizio should be transplant the gassai is still our goal standard. In addition although some European countries have adopted a mandatory split policy such as the UK there's not been a similar traction here for such a policy that there may be in the future. And finally there are many new developments on the horizon and transplant research and so the next 10 years should prove to be an exciting time. I would just like to finish by thanking all of my colleagues in the pediatric transplant center from our social workers and case managers to our NPs that have a topologist and of course I would like to thank my partners and clinical mentor instructors Kim and Vikeely and with that I'd like to take any questions. Alex that was really terrific I think you're going to win awards for speed record triple people tail over the time that's pointing out really spectacular work and I think it was terrific for the faculty across much of the institution to see one incredible background training education you've had with the 16 or 17 sets of boards and it had a incredible sort of golden touch seems like everything you submit for funding gets accepted and the recognition of the search and scientists institution is really being buttressed by your efforts at this early stage in your career. I know that that how we came is kind of doing our our cry-cold training mandatory training for the New Yorkers and able to comment. I have a question about transplant as a medical industry you commented a little bit about some other countries in this country medicine is you know free trade pretty unregulated but if there's anything that is regulated it's it's the transplant industry because the access to organ is controlled by an essentially quasi-governmental organization and they're contract with Congress but it's not like like other countries where where there can be deemed this will be the transplant center for this region or for the entire nation that you taught us about new options for graph delegation for increasing the number of recipients for organ preservation with exfee of a profusion. I wonder if you if you think that the ultimate distribution of organs and survival graph survival patients survival would be enhanced if and this is a big if if in this country we could use those techniques to to restrict your graphically home meant the centers there were going to be instead of having four liver transplant centers in one metropolitan area if there were one or two per large region of the country knowing that there would be less time pressure for you know for the transportation and the plantation of the work. Well thanks for that question I think that in general as we've shown with other procedures the more experience and the more concentrated the experience is the better the outcomes and if we had we do currently have several centers or several regions that have procurement centers whereby the patient who's or the donor that has been selected goes to the center and then as the procurement surgeon goes and procures that organ and whatever way they feel necessary and then those you know essentially they have all of the resources there to do what they need to do. I will say that traveling to to many of these different hospitals with variable equipment you know and variable levels of expertise of people in the room can make it challenging with regards and potentially affect the outcome of the graph during the procurement and so having sort of a centralized mechanism or place where you can perform these procurements is definitely would be desirable but also would unfortunately I think the reason there's a lot of resistance to that is that it does provide a significant amount of income for the given hospitals and and potentially transplant surgeons to be the center for the procurement or to go and procure the organ itself. The the normathrmic perfusion device is here this is something that the FDA approved and I know that we're currently the you know sort of the experimental aspects of it are looking at rehabbing or a donation after cardiac death livers and seeing how far they can push the limits and because in most centers what they would require so the donation after cardiac death is different from the standard disease brain dead allocate procurement in that the disease after cardiac death procurement happens in patients that essentially are not brain dead but are essentially medically terminal and so support is withdrawn and we go and procure the liver after a period of acysdally. If that period of acysdally happens significantly and there's a significant amount of ischemia what we've fought is about 30 minutes in most cases 30 minutes we don't typically procure the liver and so in those cases a lot of times what is being looked at is whether or not that's actually accurate number one and number two if we can procure that liver take that liver out and put it on the machine to rehabilitate it and get it oxygenated blood quicker as opposed to just putting it on ice that is definitely being trialed here and that will probably expand the donor pool significantly in New England. So and if we had a centralized area where those machines could be set up and the technicians could come to as opposed to going all over New England again that would facilitate that aspect of it but you know and one of the things that I had talked to Dr. Markman about as well as our group is the potential for you know I want to one of the at least for a junior faculty member who's who's who's procuring is for when you're doing this split the cardiac surgeons and the rest of the surgeons are waiting on you typically to take the organ out and one of the benefits of this may be that you could take you could procure the liver in a rapid manner from the body put it on the machine and then subsequently split it on the machine as opposed to you know splitting it in in in sight to and everybody waiting so but yeah it's it'd be an interesting concept to try to get that done here but I will say that there's a lot of resistance based on financial issues as with so many things in America yeah I would also like to comment on the extraordinary results we've had over the decades really as a pre-standing children's hospital which is is tested not only to the to the surgical prowess but also to the team nature of this sport and between anesthesia nursing um hepatology it's really extraordinary what what's been accomplished here and I see Scott Elsoff from hepatology joining us and he and his hepatology team deserve an enormous amount of credit for all of those medications that Alex rolls off his tongue so eloquently but I think our hepatologist had a lot to do with with helping and choosing some of these medications I don't know Scott if you'd like to comment oh no uh yeah I mean it definitely has been a team sport as you say and it's really you know a huge effort with with our entire team so it's obviously been a pleasure to work with these surgeons and you're right the anesthesia teams that these patients come out with almost elective surgical cases estimated and going going to the ICU instead of being intubated for days in an ICU and that's really changed I think dramatically I missed the first part of Alex's but I think you know cash has shown that uh you know most of our our transplants are really coming out of the OR estimated which is a huge difference and we're getting patients to the regular floors quickly and then our whole team would join in and uh and take care of the patient so that's great I think cash right is hand up to the Steve yeah I don't I don't see him on here oh wait is he so long yeah he's there okay I'm great yeah I'm sorry my question now Alex Alex great talk and yeah that was fantastic he covered covered a lot of topics obviously there's a lot to be uh covered here and certainly I look forward to your talk in April but you know what I wanted to ask you which you started talking about is being able to do the splits on the normal thermic pumps um and you know obviously we we have never done it you have experience with that at MGH you guys were putting these lyrus on pumps um do you think it'll be feasible to be able to do the splits on the pumps I think so I you know from the standpoint of you know especially this transmetics device which I partial to only from the standpoint that I this was the device that I used the most when I was at MGH um it gives you a nice output and you know if you're you can theoretically it's it's dramatically it would be dramatically blitter but although somewhere in between doing an incitee split versus you know a backtable split because you can see where the you know bleeding occurs or potentially even biolique and take care of those things I do think it's feasible I just think that you know part of the part of the resistance into our application has been uh in in some of the costs and the technical aspects of you know you need to take a separate perfusion group or the perfusion group that we have at at uh new England Oregon Bank has to be trained to use the machine and help during that process because things have to be added to the machine as as the the liver is on pump but um you know if you could split if you could take it out split it at the donor hospital one part one uh and then one group gets the the right triceg and we would get the left lateral segment uh or or whatever the permutation I mean I think that would be amazing but I mean the tricky part would be to maintain both uh segments on right yeah otherwise you could take it out you split it and then you put it in you know normal cold um you know static uh preservation then doesn't make a difference the question really is can we maintain it on pump yeah and I and I think that um I think the answer that question is yes as long as we develop uh different canulas for the right triceg I'm obviously for us it's a little different since we're taking the entire silia patch uh for our group um but you know it would be similar for developing a different portal canula for us um to be able to do that but I mean it did you know I definitely think it's possible it just needs to be developed right thank you sick us a job Alex yes Alex uh chef burns um I just wanted to acknowledge and uh follow scots comments um I'm old enough to have seen now several generations of our liver transplant and what you HB and cash have done is uh simply extraordinary it it uh it's a privilege to take care of these patients and as scots said they come up excavated and uh you know they're really doing so well that it's not difficult to care for them in the ICU because they transition so so quickly um I wonder if you could give us a preview of your April grad rounds are we on the threshold of kinder gentler immunotherapy or is this going to be um you know an incremental improvement as it has been over the last several decades yeah thank you for that question entrepreneurs I think that that's a great question I will say that what I'm working on is probably years away compared to what uh uh Eva Geinen and and and Jim Markman have been working on with the T-regs and I know that those are definitely um uh you know sort of wrapping up the first stages of the clinical trials and and potentially are being advanced but um you know I don't I don't see what I'm I would like to think that what I'm doing is not incremental and that what I what I would propose is that uh one of the reasons why I'm looking at these sort of cell different innate immune effector cell populations is because I I did from from prior research I don't I don't typically believe that there's one magic bullet that can control everything but if you delete this thing or this gene or focus on this one um that sort of end effector cell that you'll be able to to uh solve what the issue is um and so T-regs for a lot of people or for a lot of groups are the end effector cell in this setting and so what my thought process is is how about we take a step back and look at um the innate immune effector cell which can coordinate all these responses and even the bone marrow to see how we can manipulate the bone marrow to potentially produce a aminous oppressive milieu um to to provide some amount of immunus opp uh an immunus oppressive environment that uh can be tailored to what what the different transplant recipient needs uh what I what I'm what I'd focus on with my uh work is that um can you give essentially uh substance that typically causes inflammation in one setting but then causes immunosuppression in another and then essentially hone that or hone the bone marrow response to the immunus oppressive so that you can now come with your living donor transplant or or whatever um uh post and uh provide uh decreased amounts of these immunosuppressive medications which as as I've sort of stated are terrible are terrible for our patients long term but maybe not short term. Scott's laughing but it's true. Aaron. Hey Alex uh great talk thank you um I'm wondering you mentioned briefly about the ability to test the livers and how well they're going to function uh potentially on these um on this external pump. What kind of functional assays are are out there are there ones we developed to to sort of say hey this liver is going to work great when we plug it in. Yeah that's a that's a great question um so it's specifically designed to look at the outflow and the um you know standard liver injury markers such as astl t ggt um over the course of time it's on the pump um and see sort of this decrease after the pump after the liver gets reprefused and then use these uh sort of conditioned livers as as uh as the the graphs um I will say that you know during the time that we we did this um in addition to those those markers we also looked at bile production and lactate metabolism and uh in particular I'll recall that there was one liver that was definitely marginal that we that everybody every other center had turned down that we thought oh it's a youngish donor but um there was the concern that the patient had been on uh you know support a significant amount of support and so when we took the liver out and put it on the machine we noticed that in contrast to the other livers in a given timeframes a three to four hours there was no decrease or decrement in lactate there was no bile production and so we think that maybe what we found was a liver that may have led to primary non function uh and maybe a liver that we would not have been uh optimal optimal for our our recipient and so we ended up declining that liver ultimately afterwards and looking uh with pathology you know uh what what if anything was wrong with a liver and there was a significant amount of ischemia and statois is associated with that liver and so with regards to you know saving a patient from getting a terrible graph because that's obviously not what we want we think I mean at least these these these machines offers the ability or some insight into how that graph would function inside the patient I don't know if that answers your question or if that yeah yeah that's great thank you other questions or comments from Alex Bill Sparks, Amanda Svita um just with respect to the survivability being so great I can only imagine economic impact on these families and then also the developmental concerns related to the child with education and societal impact what type of networking it goes on with respect to ensuring that these families can can manage the financial issues and uh the developmental issues are the child kind of child get back to the key level of care? well thanks Dr. Sparks I uh I think the answer to that question is essentially uh we hope is yes um I'm just you know so I the last time I gave this presentation I went over a little bit and so that's why I took out so many slides um just give me a second here um so there have been several studies that have looked at this and have shown that with the increased survival of graphs that the patient focuses shifted to these longer term type metrics but you know the incidence or the the presence of colostasis or you know critically ill critical illness definitely affects how these kids do in the in the future and so there have been several studies this one in particular from Wayman back in back in 1997 which did that biliary treasurer patients even status post-transplant by several years were up to one standard deviation below the mean infant development there were other studies looking like such as this one from our studies of pediatric liver transplantation cohort which was a study of 144 patients that basically identified them and uh at about uh kindergarten age and then followed them out for about uh 36 months and showed that every metric either IQ or vocal scores or or verb sorry verbal scores were essentially lower than our expected normal distribution suggesting a significant impact on uh on on of again liver liver disease and critical illness on their overall development so some of the things that they sort of looked at and they thought were responsible for it that they had you know correlations for uh and increased odds ratios for where I under show of stirring critical during the uh the post transplant period is cephalopathy delirium pre transplant creatinine and renal optimization and post post transplant uh renal failure and also so as you might expect such an economic index of family structure uh I end steroid avoidance and withdrawal so against steroids ears its head so what we do is I mean obviously we have fantastic case managers and social workers we and and and psychologists working that work with our kids uh we try to intervene as early as possible and make sure that they're placed in the right track I don't know Scott if you if you know what our current metrics are or what are what measurements of what our car kids how our kids are doing um but I'm you know I know that we do a significant amount of work in the post transplant period with these children I think the general theme is you know if you look from the outside now you can't see who had a transplant who didn't have a transplant you know in the age of to crawl a misverse cyclosporin where you could tell who is the transplant patient um and I think the most important part is really you know they're physically usually fine they're doing their activities but I think you need to take a deeper dive in terms of some of their neuropsychiatric uh abilities and whether they're functioning at the level they should be functioning at uh during school so that's something we're definitely cognizant of and from a financial standpoint most of these families have you know maybe their primary insurance plus mass health or are there Medicaid equivalent backup for uh prescriptions and all of those we sometimes need assistance programs that some of the companies are willing to help out and and uh cover costs but usually usually the families are able to cover most of these and with some assistance as well you pretty well how you would come up with your diplomatic I can trust in a little trouble with feedbacks on not sure that this is going to come too very well but uh you know one of the decisions that they can buy in that first spot that I was watching is my goodness it's actually taking this to me here in the best area you're looking to choose hard to hear you right here you're right all right I think he was going to make a congratulate uh congratulatory comment did not just the surgeons but to the entire to the entire team um and and he was there in the days that Jeff was talking about when these patients came out of the OR cold, queridopathic bleeding and invaded and unnarcotics for a week sometimes longer I certainly remember those days well when I was a fellow um my my my chief here uh it's a long time ago um we did 11 liver transplants that year um and they all died one left in uh and now that's a rarity and uh yeah these patients come up there in the ICU for uh literally hours sometimes uh with without central lines and without to uh without much narcotic and uh often without having to transuse and that's a testament not just at a surgical skill of the team but also to the extraordinary preparation and anesthetic gendersing management this is important to this particular ground round since uh many of the people on the screen participate in the care any other comments well if done Alex I think we all uh appreciate the the comprehensiveness of your of your work I do do it for you to your next uh scientific presentation um I started being writing down the dates so they'll be here uh and thank you all for uh your comments I think um thank you