Thanks for watching. Hello and welcome to Every Possible Angle, a new conversation series where we're going to be delving into the world of transplantation. We're going to be discussing with community members from every part of the field to get a better understanding of what's going on in the space. My name is Michael Tajima and I'm joined here today by my colleague Pratik Patel. Thanks Michael. This is a really exciting time in organ transplantation. We're able to do things that we couldn't do just a year ago and Dr. Ceulemans our guest today is going to be talking about the concept of time shifting. and he's going to talk about how his center is able to use this concept to do some really amazing things. With that, welcome Professor Lawrence Cuelemans of the University of Leuven Hospital in Belgium. We're really excited to have this conversation today. Hello, Michael. Good evening. Hello, Pratik. Good evening. Very nice talking to you, and thank you for the opportunity of the podcast, which is a terrific idea. Thank you for making time. We're We're really excited partly because the Lueven Lung Transplant Program, you're doing some really exciting things right now. An impressive work these days in terms of advancing the research in lung preservation and lung transplantation. But I was wondering if we could start just by you telling us a little bit about your journey in lung transplantation, how you got started, why lung transplantation as a career. So thank you for the introduction. I indeed work as an academic lung transplant surgeon at University Hospitals of Leuven, where I also had the lab of thoracic surgery and lung transplant, which Prati could visit a few months ago. And so I'm really fortunate to work there because we can really take the clinical questions that we encounter in the field of lung transplantation to the lab, to our small animal models, try to study them, and then try to find a solution that can be incorporated in daily clinical practice. because there are so many challenges still in the field of transplantation that need to be answered. In such an exciting field of research, it's really a privilege to work in that field. And one of the questions we had simultaneously with the introduction of the Lunguard technology was about temperature. One of the most interesting findings we made over the last year was mostly about the rewarming ischemia during implantation of a lung during transplantation and how this ischemia, this temperature change affected the lung while it was still not perfused and how also time was critical in the deterioration. of the organ. Absolutely. I think for a long time preservation has been assumed in transplantation. For the last 50 years, it's been a sort of colder is better mentality with transplantation. But your lab's been now paying a lot more attention to... temperatures and the metabolic processes as well as injury going on during the preservation period. I was wondering, maybe you could tell us a little bit about your career. How did you get into lung transplantation? What's been your journey to really get into this space? Thanks for that question Michael. So as a young resident I had the opportunity to practice and work on a PhD in the lab of abdominal transplant surgery in Leuven where I focused mostly on in the field of intestinal transplantation on immunology. It was a very exciting field because the intestine is quite similar to the lung they're both what I call barrier organs. So they are in contact with our environment. And for that, immunology is really an exciting field to study because of the strong innate immune response of these organs. And what I encountered in the field of transplantation was that it was a relatively young field with very exciting questions. What you're actually doing in a transplant is transferring one organ from a person who's not genetically predisposed to be connected to the recipient. and you do something which is biologic, from a biological point of view, doesn't make sense at all. And that's why you're encountered with questions and challenges that are really on the edge, not only of transplantation, but are on the edge of medicine. And what you can see is that trying to push that edge further, trying to push the field, does not only improve the field of transplantation, but improves the whole field of medicine. There are many discoveries in transplantation that find their way later on in the general field of. medicine. So already that aspect made me very passionate and interested. And then the other aspect that it is a young field, and that there's not a real competition between different disciplines and researchers in transplantation. There are so many ongoing questions and challenges, that the competition is not as harsh as for example, in other medical fields like oncology or vascular surgery. And this is more an open field of open interaction and communication. And also that I liked a lot, I must say. I fully agree. I think the international and collaboration across this community has been fantastic. It's been a great experience, at least for me. Yeah. I mean, I think it's interesting you talked about your background as a resident, right? When you're a resident, it's in your formative years, you get exposed to so much in medicine. And it's really interesting that you were drawn specifically to the field of transplantation because it's Essentially less chartered than other parts of medicine Did you have any other interest like besides transplant that you know that you were deciding between and then you ultimately decide to go with transplant? So we were trained in general surgery. That's how our training program in Belgium looks like and then I was I was interested in transplantation mostly from a research perspective and then in thoracic surgery in general. So I was trained as a thoracic surgeon simultaneously because it was especially the organ, the lung that attracted me a lot because of its unique physiological capacities. For example, if you compare it to a kidney, which is more like a filter mechanism or liver, which is more metabolic mechanism, the lung has the unique capacity. of this being a privileged organ with the storage capacity of the oxygen, which is then diffused and then you have that perfusion. And so don't only think as a surgeon, but you think as a physician and as a physiologist and an immunologist at the same time. So I was really attracted, not specifically to a certain profession, but more let's say to an organ. And then everything came together in the field of transplantation. So the real passion is in lung transplantation. I feel like that sort of mentality to be willing to go into a pioneering space, a space that's not fully defined yet, and there's still so many untapped questions, that's got to take a certain mentality. But also I'd imagine it's helpful to be in a place that's very supportive of research and answering those questions that really can take that. And at least Pratik, when you visited Leuven, it sounded like that was really the environment you've cultivated there. Yeah, I have to agree with Michael. When I visited, I remember the experience of the few days. Every single day, we were going between the lab to the clinic. I was observing you go literally between seeing patients to being in the research lab within a matter of a few minutes. But I also saw, frankly, the culture of the younger generation that you were training. They really shared in on that interest and that passion. So. I'm really interested to know if the training model that you have at Leuven, how that came about because I noticed a lot of the trainees were pursuing both an MD and a PhD. Is that something that has organically evolved as a focus for Leuven or is there a certain reason why that exists today? No. So I came back from a fellowship in Zurich in 2019. And I got the responsibility of the lab of thoracic surgery and lung transplant at that time, but there were no PhD students at that time in the lab. So we had to start somehow off scratch with the experience I had. And the experience I had was in fact the template of how I foresee our lab in the future, which means that you do a simultaneous training both in surgery as well as in research. but you have dedicated time for research. And the best way to organize this is to offer to a young motivated colleague an actual PhD. A PhD, you have to see it like a form of education. It's not about the title. It's a form of education where you really develop into a mature independent researcher who can not only ask questions, but also formulate hypotheses, translate it to a certain research model. try to find results and also present them to the audience and write them down in a paper and then mentor them again to another generation. And so in this model, I was raised by my mentor, Professor Jacques Pirenne, who was raised himself in the 90s in the US. And this is the model that he was raised in the US. He brought it to Leuven and this is the model I took over to raise the new generation of... surgeons and transplant surgeons. And I must say that I'm very, very fortunate to have found motivated, passionate young colleagues, because these young colleagues, they are really the driving force of the university. No matter how old the university gets, these people always stay at the same age. We have a university of 600 years old, but the students are still at the same age as 600 years ago. And these are the ones that put the questions forward. These are the ones that challenge you and drive the real research. This is a really stimulating environment. And now our lab has grown up to 28 researchers focusing on intestinal transplantation, multivisual transplantation, lung transplantation, lung volume reduction surgery, fascia transplantation. So it's really a stimulating environment. We have a lot of interaction between different disciplines also. It's not only surgery. basic science, it's pulmonology, it's anesthesiology. All the disciplines together work very closely. Yeah, I feel like that mixing of different disciplines is often where innovation happens. For us, I think that's been very stimulating things, crossing different organs, working in different spaces. Having that mixing of different disciplines is where you find those innovative and interesting ideas. They can really move the field forward. Yeah, no, I agree. I don't know if you know, but Michael has actually a background in mechanical engineering and he worked in aerospace engineering before, you know, joining medical technology. So I couldn't agree with you more. You used to design satellites, but that was a long time ago. Can I ask you, you know, in terms of some of the innovations in the field, how do you see what's going on in the field? One of the areas that I think has been... A lot of interest lately is around preservation, around controlled hypothermia. Can you tell me a little bit, I know Pratik was over doing some research projects with your team. How has temperature become more part of the consciousness of the transplantation process at Leuven? So I think that from the beginning of transplantation and even before, the question and the interest in the fields have always been... quite similar. Already Alexis Carrel, before the first clinical transplant was performed, was developing some kind of machine perfusion together with Charles Lindbergh in order to preserve organs. But we see over the last decade is that the technology is there. If you're background as a mechanical engineer, you will indeed see that we were able as a human race to develop. techniques that were transportable, that could be incorporated in daily life, and that makes these ideas and thoughts that were already there for 50, 60 years, that made them transportable, translated to the actual daily practice. It's not only in medicine that this is happening. This is happening throughout different fields in our daily life. And so also the whole idea about temperature, it's not a new idea. already in the beginning of the 90s in Toronto, in the lab of Joel Cooper, they were doing good, strong research on preservation. And it was taught and hypothesized that the colder you preserve an organ, the better the function of the lung would be after a perfusion. However, to their surprise, when they analyzed several temperatures, they found that by accident, preserving a lung at 10 degrees, outperformed lungs preserved at four degrees. And so a whole line of research early in the nineties, not only in Toronto, but also in Japan, came out to find the ideal temperature of lung preservation, especially for the lung, in contrast to kidney and liver, because the lung is such a privileged organ. It's a privileged organ because it has this unique oxygen storage capacity. And because of this oxygen storage capacity, it has the potential to maintain the aerobic metabolism. and preserve better the cell function during preservation, in contrast to an organ without that oxygen storage. And so, already in the beginning of the 90s, they were convinced that the best temperature to preserve an organ was not on ice, at four, three, two, zero degrees, but slightly higher, which is the concept of what we know now as controlled hypothermic preservation, which is somewhere in range between four and 10 degrees. We do not exactly know yet. what the best temperature might be. And there are some indications in an old paper from Nakamoto, I think in 1993, which showed with a mathematical model that the best temperature is probably between 7.6 and 8.4 degrees. So we still have to do some research to find exactly out what the best temperature is. And so the ideas were there. There was no technology to incorporate them in the clinical practice. And this technology has now... evolved over the last years. Can I ask you, across organs, we're seeing a big impact on temperature, on clinical outcomes, and transplantation, total ischemic times. One of the things that I'm really curious, particularly with lung, that when you're talking about lungs and intestines being barrier organs, with that strong, innate immune response, I think in the early days that Cold Air Better's philosophy was just... heavily driven around a sort of a metabolic thought. I mean, we call it ischemic time. There's this thought of reducing metabolic activity, reduce metabolic injury. But I feel like what the current trends are about reducing any form of injury, potentially freezing injury and kicking off, particularly in lung and intestine, that strong innate immune response to lute, edema, and inflammatory cascades. Where do you how do you see that balance point and these different mechanisms playing in regards to temperature? So I think that indeed what you touch there is a very important aspect and that's ischemia reperfusion injury And of all organs the lung and the intestine are the most vulnerable to this ischemia reperfusion injury Which is nothing more than a cytotoxic storm that is released upon reperfusion of an ischemic organ And what you have to consider is that what is long thought to be the golden standard of preservation and the golden standard of this ischemia time was ice cold preservation. But ice cold preservation means freezing cellar injury with a direct impact on mitochondrial health, mitochondrial swelling and the mitochondria, you have to understand that's the energy safekeeper of the cell, which is completely destroyed. And so this immediate... effect of freezing a cell and really injuring the cell and in the end it ends up in a lot of reactive oxygen and oxidative stress which is released at the moment of hyperfusion will lead to a lot of ischemia hyperfusion injury and especially the lung and the intestine are so vulnerable because of their strong innate immune response and release of cytotoxins at this moment of hyperfusion. That's one important aspect. And we also have to consider in a side note that preserving a lung on ice is not preserving a lung on four degrees. We have shown during the last year in our clinical grade four study, every time a lung came back from a procurement and it was preserved on ice, we took it out of the ice cooler, which is nothing more than a camping box filled with ice, not really an anode. 2023, but still this is the current practice. It came out and we immediately took a surface temperature and because it was a lung, we were able to introduce a very small probe into the lumen, Brunkio lumen of the lower lobes. And what we found out was that ice and immediately measuring temperature afterwards resulted in temperature of around zero to one degrees. And we know that zero to one degrees has a severe impact on cellular injury. So Dr. Ceulemans, that's really fascinating kind of what your team is seeing when lungs are preserved on ice. You mentioned when they come out of ice storage that they're not four degrees, that they're closer to zero essentially. Can you just share about how exactly the lungs are packaged when we talk about ice storage? Because there is some variation across the community where some teams put ice within the bags and some people don't put that ice in the bags. I think we have to consider that the standard mode of preservation has been ice over the last 30, 40 years. Any form of ice, mostly in a classic camping box filled with liters and liters of ice, which is really not slushy ice, but there's really ice that you find on the North Pole. And so what I think is that we should abandon ice completely. And I say this with... a bit of an adagio, leaving the ice age behind. We're really leaving the ice age behind now. It's time to leave it behind and to go for a more controlled way of preserving and maintaining the temperature that is surrounding the lung. What we have done over the past 30 years in Leuven is the camping box filled with ice, and then you have these lungs. We pack them individually, inflated, and we pack them classically in three bags. We have an inner bag which is filled with preservation solution at an ice cold temperature. And then you have a second bag where you have some ice cold water. Sometimes they pour in some ice and then you have a third bag just to keep the sterility to hand over the organ after the preservation. And so what we are doing now is shifting towards the device of the LUNGguard Paragonix where you have this. this cooler with a certain temperature maintained at around six degrees. And we fill it again with two individually packed lungs, which means six bags in total. And we pour around two liters of preservation solution in total. Well, not two liters of preservation solution. We have one liter of preservation solution per lung and then one liter of... cold water around that preservation solution. So in total, we have around four liters of water or preservation solution together with the lens in the cooling box. Absolutely, and I'm curious, how has this been used and implemented in your clinical practice? I know we've worked together on the GRAPHEL study and the measurements of cold temperature opposed to ice, but you've also started to implement controlled hypothermia as part of... your practice. How has that indication been used? Where have you implemented that? So it was a bit of serendipity, again, all the things in research happened with serendipity. So what we found out, I think now already two years ago when we did retrospective analysis of our Leuven series, we found out that actual implantation time of lung, which means the moment when the lung is deflected and exposed to warmer temperatures up to the body temperature, that we could see that the longer you need to implant an organ, and in fact it was the lung, the more PGD the organ developed afterwards. So we knew and we understood that there was a link between timing, temperature, and ischemia and perfusion injury. And so we set up a study, which is called the Grateful Study, and we wanted in the first phase to assess... to which temperatures and which timings the lungs are exposed during the implantation. And to do that, we didn't only focus on implantation, but we wanted to visualize the whole process of ex vivo preservation, starting from the donor until the reperfusion. We've even taken biopsies of the brain one hour after reperfusion. So we set up a whole clinical protocol for that. And exactly at that moment... We were approached by the company with the introduction of the LUNGguard You had the studies from Toronto and Vienna coming out with their preservation bridging the night. And so everything came together and we decided after the first initial phase of feasibility to switch the entire system in Leuven and to really stop transplanting at night. In the first phase, we sat together. We've all involved partners in the physiology, or management, nursing staff. And we decided that if we would have a clamping of a lung after 10 o'clock in the evening, we would start the transplant at 7 o'clock in the morning. And then already quite soon after the first few cases, you have these cases coming up between 7 or 8 in the evening and 10 and 10. And what were you going to do? Because last time it was so nice to sleep. and he had no PGD at time 72, so could we not shift a little? And what you see now, and this happens, I must say retrospectively, seen quite natural. And in a period of only a few months, we started 1st of January 2023, we are now beginning of November, and now we have shifted towards when there is a clamping after six or seven in the evening, like they do in Toronto, then we keep the lungs stored. in the office of the nurse locked in the OR and we start in the morning between seven and eight with a fresh team and it went quite natural. In the beginning of course everyone had to be convinced and it was important to have everyone's input because we could not compromise the outcome for our patients so we were lucky that we had that we had this research already performed by other international teams and we could stand on these first initial feasibilities and safety trials and then we had also the luck that we were doing this clinical research and that we were keeping a record of all our cases to a very detailed level. And it's always good when you start changing your... your program or the way you handle things that you record what you're doing. And so these two came together at the beginning of the year. And from then on, it flew quite natural. I mean, I think those synergies just happen sometimes in times of evolution of new technologies. And I think it should be underscored. One of the things you said that the intentional extension of ischemic time, you know, would have been quite provocative, quite counterintuitive historically, but it sounds like your experience has been strong. You're doing that now as routine clinical practice, it sounds like. And purpose-wise, when we talk to different institutions around this concept of sort of time shifting, of shifting the times, the institutions use it for different ends and different purposes. Pratik, you've spoken to... institutions around the world about this. Yeah, you know, we speak to lung transplant programs on a weekly basis, and the interest to shift the timing of the procedure for transplantation is widespread. Every program is thinking about it. I think what's really interesting about Lueven is that, you know, what I understand is that indication, you know, can sometimes be from a time perspective, but sometimes it can be for another indication, clinical consideration. Can you share with us a little bit about what... What are some of those examples where you might shift the transplant timing beyond just the cross clamp? That's a very important topic and I'm happy that you raised that because for me it's far beyond night bridging. What I call it is introducing flexibility without compromising the outcome. So we have to safeguard the outcome. We're doing it now for a year. We didn't see any adverse effects so far. So we are quite confident. And also with the... With the data coming up from the registry and other centers, we are quite confident that we don't compromise the outcome. But this introducing flexibility has several aspects. First of all, you have the avoidance of the nocturnal transplant and trying to shift it during the day, which have several advantages. Maybe we can come back to them later. And then you have the concept of logistical limitations, which also impacts the... you're in a direct way your lung transplant. For example, today, right now, we have a case going on of controlled hypothermic preservation because of the fact that we had a difficult oncological multidisciplinary case planned this morning, and we had limited to our capacity. So we had to choose between the transplants on the one hand, which is always an emergency for patients waiting for one, two years. And then you have these patients with a complex oncological... problem that needs to be electively planned. And so it's always a very difficult choice between them. And what I mean with introducing flexibility is that we don't have to make that choice these days. This morning we performed, my colleagues performed the case of the difficult oncological surgical procedure and we could easily shift towards this afternoon, three o'clock, four o'clock in the afternoon, with the transplantation which was procured this morning. between eight and 10 in another hospital. And so in only one year ago, probably we would have the clots, this lung effort, just because we had no capacity of performing the transplant or we had to postpone this difficult to plan multidisciplinary oncological case. Yeah, and so this just gives a lot of flexibility. And with this flexibility, you also see that there are less arguments between. different caretakers. You can imagine that if someone has to cancel their program and everything that is related to that, and you have someone who really wants to push the lung transplant program, that this might lead to some difficulties within the hospital, but sometimes also within a department. And I'm happy that with this controlled hypothermic storage, we increase our flexibility to take care of all patients in the best possible way. That's the second part of flexibility. And then the third part of flexibility, and I think that's also a very important one, is that we see that the quality of available organs is really declining rapidly. We don't see the same quality lungs anymore as we did 20 years ago. Luckily, we have less trauma with young people, but what we face now are people who have been smoking. or people who have been admitted to the hospital for two, three weeks with a lung exposed to ventilator-associated pneumonia or injury, patients who have been exposed to other detrimental factors during their life. A lot of comorbidities. Age is also an important factor. And so you have this, what we call extended criteria, organs more and more, together with a higher rate of DCD. organs. And so what I think is really important for these organs, that you limit your ischemic injury as much as possible. And you can do that in two ways. Either you further limit the time of ischemia, which is already now try to be around six to eight hours, if you have to squeeze it further, that will become a logistical nightmare. And you also decrease, especially in North America and other regions of the world, you decrease the... transport time a lot and these logistical issues or you find a preservation mode which just Decreases the cellular injury that is performed to this already very sensitive organs and I think that's a third one and Therefore I would like to refer to two recent case. I think we did now a month ago Where I had it was a Sunday afternoon if I recall well critique where I had an offer from from a suitable 94-year-old donor. It's probably the oldest lung donor ever recorded in the world. And I called Pratik and I said, listen, this organ has been exposed for almost a century to our environment. We just have to preserve it in the best possible way to make it a success. And we agreed to put it in the LUNGguard Although it was not for an extended preservation, it was just to create the most optimal environment for that lung. I mean, that's absolutely incredible. I mean, these lungs started their journey on this planet long before lung transplantation even existed as a discipline, and now they're starting a new life and a new patient. How's the recipient doing? The recipient is excellent. He went home after, I think, two to three weeks. Wow. He had not been, seen any complication, and he's doing very well. I'm looking forward to his pulmonary function at three months, and we will present this case at the ISHLT Symposium. Yeah. I mean, it's literally a different generation that the lungs have now gone into, right? Where they were originally. I think it was really fascinating how you just covered the three kind of areas, how you think about what controlled hypothermic preservation allows you to do. And as you were talking, I couldn't help but think what this allows you to do is really make sure you get the right donor organ at the right time with the right team to the right recipient. And that's quite... quite fascinating and I think like you said, 20, 30 years ago this was not even possible. So I have to ask when you go out and do these procurements, you have other team members there too, right? For other organs. What's been their experience? What is some of their feedback or reaction to now the lung team being able to kind of schedule their procedures? The lunging team was always a bit lagging behind, because they were coming in sooner than, for example, the heart. They were leaving later. They had to rush to the hospital, transplant. Mainly the kidney team is already reclining from doing a nocturnal transplant for many years. And so all of a sudden, this lung transplant team takes a big leap and they see that we're going to sleep. There's another team in the morning taking care of these organs. And so of course they're interested to see if the same technology could extend their preservation times as well. I think for kidney it's not a major issue because we have learned with this machine perfusion technologies that we can keep also marginal organs for extended preservation times. But I think especially for the liver, they are very interested to see if the same would happen as well because the whole logistical challenge of putting an organ. on the machine where you try to maintain it hypothermic, normothermic, perfused for a longer time, it's also a logistical nightmare. And what they see now is that we come back to Leuven, it's also in a device, but we put the device unguarded in a locked room and we track the temperature on our phones and the whole team goes to sleep. And that's a big difference with the logistical challenge of keeping an organ perfused. there's always someone who needs to be there to safeguard the organs and see that nothing happens. That's a major difference. So also other organs are interested. And I must say that the experience with the heart team and the heart registry that we have with this higher temperature really is a lightning example for the other organs. How this preservation technology not only better safeguards and gives you more flexibility, but that it also actually improves the condition. Well, not improve, but in comparison to the standard storage of IH, how the short and long-term outcome or improved. Absolutely. Can I ask, I mean, coming back to the, on the one hand, I think your points two and three in terms of the use of the technology to create that flexibility. you know, that potentially makes more organs available to more patients, which is just remarkable, you know, because you have the right teams available. You can coordinate these challenges where you in the past may have had to turn things down. But I also, you touched on a couple times the idea of avoiding nighttime procedures. I have to imagine one of the things about transplant is that it's such an intensive field that in the middle of the night, all of a sudden you have to leave you have to cancel your cases. The burden and burnout that is faced by teams is a real thing. Can you tell me a little bit, I think the idea of avoiding nighttime's procedures is not to be underestimated, its impact on a program. Yeah, so I think that it is indeed true that for a long time the transplant surgeon or transplant physician has been seen as someone who has been in the hospital for a long time. doesn't like to sleep or likes to work during the night, during the day, staying up for 36 hours. I can tell you it's not true. We also like to sleep. And I must say, just from my own perspective, how my life has changed after the introduction of this controlled hypothermic preservation. When you do a night transplanted complex case at Sunday night, going to the... Monday morning where you have your elective case plans, your whole week is ruined. Yeah, yeah. And it's just better from my own perspective to have regular sleep. That's just my own perspective. No disagreement there. But I think it's important to consider in avoiding nocturnal transplants that there are different benefits. But they're mostly related to what I call human factors. You take care of the... patient that that's one factor and then maybe the patient will in the end benefit from the fact that the organ is better preserved but that's one aspect that we touched already. The other aspect is the aspect on the quality for the human factors of the transplant team. First of all I think that reducing time pressure on the young colleagues who are going out for procurement and who have to decide in a remote hospital without not always a lot of experience if they should accept the organ or not, knowing that if they accept it, they have to assist the transplant the whole night and then do a whole day shift. So they are always in some subjective bias that if they accept the organ, they inflict their own night rest. And so you take away that pressure. and you shift it just to a very objective decision for them. Should I avoid this organ? Is the quality of his organ good enough for the patient who needs, who needs these transplants? And that's one important aspect. You improve the objectivity. That's one thing that should not be overlooked. The other thing is of course, the fitness of the team. I think when you have a fit team, you reduce the likelihood of errors, no matter how you see it. And I, I read that there are. conflicting literature on that, especially in the field of transplantation, where another systematic loop showed analyzing more than 300,000 patients who had either yes or no a nigh transplant, that there was not a real impact on short or long term outcome. However, most of these analyses have been done for kidney and there can be several biases in this research. But if you compare it to general surgery or trauma surgery or whatever, you You just see that the fitter the team is, the less you have a reduction of errors. And the more expertise, especially in the field of transplantation, you gain during the daytime, especially for Leuven, for example. I can tell you that our philosophy is to do a transplant without extracorporeal life support, but if we need it, it needs to be there. And then the cardiac surgeons have to come over. If they have to come over at two o'clock at night. from home to put a patient urgently on ECMO, or if they have to come over from a nearby OR during the day, that makes a big difference. So just the whole, and also regarding the anesthesiologist, during the day we have a specialized thoracic anesthesiology team there, which is not always the case during the night. So they're just more expertise. And all these factors. will result in also less burnout. There has been a very interesting cross-sectional anonymous survey of the American College of Surgeons who captured, I think, around 8,000 surgeons. And they are important in association of burnouts and this increased career satisfaction with nighttime surgery. And there was a significantly higher proportion of surgeons. who said that they would not consider surgery as a profession again. So I think avoiding this nighttime surgery will also increase the attractivity of the profession and the retention of the transplant personnel. So there are many things to take into account, which are mostly human. That's a very powerful data point. I think, you know, before COVID, the idea of a CEO of a hospital paying attention to burnout was not a major topic, but... I think we're hearing that across the board in terms of staffing challenges, burnout challenges. Not only it sounds like you're getting the best, most specialized people that you can arrange during the day, but for the program sustainability to retain young talent, to keep them in the profession, there's a huge investment of time and effort to get a professional to the point that they're a transplant attending or any of the specialized support staff. And to lose that because of burnout is got to be a huge program costs that suddenly have that gap and have to retrain Someone new to fill those roles. I would assume That's absolutely true Michael and also I Must say from my own perspective. I raised a young family. I have three small children I have a newborn this year Just being able to sleep and be there for them in the weekend and not be tired the whole weekend and do things together with them that increases your quality of life as well. And it has a positive feedback loop in both directions, I think. It's really not to be underestimated. Because these young professionals, they also have young families, and then they are forced to work two, three times a week at night, and then it also leads at home to difficult situations, I can imagine. So it's better to have that in a good balance. The fact that you could, in addition to losing sleep from the newborn and then also have to lose sleep for staying up all night for cases, I can imagine that's gotta be brutal. I mean, it's striking to me when you think about professions outside of medicine, right? Especially professions which require a lot of high cognitive ability and focus. I can't really think of any other profession which is expected to not sleep for 36 hours and then perform at that high level, right? you think about pilots, you think about other really high-intensity sports, people get good sleep. But when it comes to surgery, like you mentioned, it's almost kind of, you know, historically something that people have to deal with. Yeah, I agree on that. And I think we have to evolve more towards these controlled systems, like aviation, where we just safeguard not only the patients, but also the one who executes the procedure. Can I just briefly go back to the 94-year-old donor that you mentioned? I think what was interesting was, you know, you've done research and published from the Lueven team about how donor age is potentially something that we should reconsider as a risk factor. What was particularly interesting about this case was not only is it potentially the oldest donor, but it was also a donation after circulatory death lung, if I remember correctly. Can you talk to us a little bit about... both of those risk factors and at least historically been risk factors and how the team came to the point where they felt comfortable with this type of donor long. So that's a very important topic, Pratik, and that's what I call with our experience in extended criteria donation, which has grown over two decades. In Belgium and in Europe, we don't face the same kind of donor as you face in North America. What we face is the 50 to 60 year olds who might have been smoking with comorbidities. And in most of the cases, in many cases, which in the end becomes a donation of the circulatory debt or DCD. Our program alone accounts in 40% of cases, it accounts for DCD. And what has been shown, not only by us, but by the whole international community, and there's a very strong paper from IAZHLT on that. is that there is no difference in outcome regarding DCD lung versus donation after brain death lung. And that is different than, for example, in comparison to kidney or liver, where you see a more detrimental outcome with DCD. The reason probably is that lungs are quite unique and privileged because they have this oxygen storage and they are less prone to... to this first warm ischemia. As long as they are ventilated, a lung is somehow protected. So regarding DCD, we have built a very strong experience and we are not afraid, and we do not consider anymore the DCD lung as an additional risk factor, as it is used to be in the North America, or as it used to be in more than a decade to go at our own center. So we're very confident with accepting A good DCD might even be sometimes better than the DBD, who has been ventilated for two weeks. And then last year, indeed, we were able to show for the first time that in our retrospective series in Leuven, we performed a propensity-matched analysis of all donors that were transplanted beyond the age of 70 years. And we compared them to donors. under 70 years. And I think we had a comparison of a median age of 74 years versus 54. So a difference, a significant difference of 20 years between these two groups. All other parameters were the same. And we have seen this in this propensity matched analysis that there was no difference in short, neither in the long term out. What we did observe was that we were more selective if we chose or accepted an older older donor. So I think calendar age should be interpreted as a relative risk factor. But the most important is to look at the actual biological age of the donor. What are the comorbidities? How has he or she lived? Has he been smoking? What's the BMI? And to have a good understanding of how marginal that organ is in this extended criteria donor. is more important than focusing on calendar, which I can tell you this 94 year old donor was still living on his own, doing activities, riding a bike. And just this tells you that this whole body has a younger biological age than some of the organs that we see at 49 or 50 years old. And based on this experience with this 94 year old donor, we're setting up a whole research line on the impact of age on donation and transplantation. And one of the new PhD students will start on this next year. So there's some truth to when people say age is just a number, at least when it comes to donor lungs. That's really fascinating and the fact that you guys have now kicked off an entire research focus on that. Absolutely. I'm curious, actually, has your team gotten aggressive towards... evaluating more and more extended criteria or marginal organs. How have you viewed different technologies? You said you've used controlled hypothermia. Do you also use EVLP towards that? Is that part of your strategy towards extended criteria? So we have been involved in Leuven in the clinical practice of ex-fever lung perfusion. At the moment of the... start of the clinical trials, we were involved in the INSPIRE trial, in the EXPEN trial, which was assessing donor organs with the OCS technology, which was normotermic, perfusion and ventilation with whole blood. And what we have learned not only from these trials, but also from the Viena trial, etc., was that despite the logistical challenges that were performed, there was no impact. to be seen on PGD on its own, on primary graft dysfunction. And so the real indication, I think, that remains for ex-fever lung perfusion currently is assessing questionable donor lungs. And this is how EVLP technology is used throughout the world, especially for DCD lungs. However, in Leuven, as I explained, we have built a very strong experience with DCD, and so we don't feel the need to assess these lungs with ex-fever lung perfusion. We assess them based on the criteria we have from the donor and our own experience, and we also look at how the recipient is. And so we don't use it in that field anymore. I think what we have also... experience over the past is that some of these lungs which might be transplantable get edematous on the machine, which is normal because they go through the first phase of ischemia reperfusion, but then it's just more challenging to transplant an edematous lung with less exposure, leading to more surgical complications. And so it might be more... understandable to let that ischemia hyperfusion injury to have that cytotoxic storm after actual hyperfusion in the in the patient and because then you can you can handle this with better ventilation strategies or the use of ECMO postoperatively but you don't lose that organ and you don't make the transplant as complex as this so I think I think EVLP is still there and we are using EVLP again in the near future. One of my colleagues is leading that project and we will use it probably in research setting as well for questionable donor links. We will not use it anymore to extend preservation like we have done in the past. I recall a case that we published in the American Journal of Transplantation. where we did a combined liver lung transplantation. And we were forced due to the nature of the disease of the patient to transplant the liver first. So we kept the lung on the machine for almost 12 hours to transplant it then afterwards in the recipient. Looking at it back now, it seems quite strange to do it because with such lung preservation times on the machine, you might actually damage the lung, we have learned. And nowadays for these cases we would always use the strategy of controlled hypothermic storage. So I think there's no indication for EVIP anymore in controlled preservation, but where I see the real indication is where I see real indication is in the allograft treatment and modulation. I call it ATM. The money is in the ATM. That's where you have to use it. And also Toronto has been leading that path. showing that with genetic modification, that's actually what we're doing right now in the lab, we are genetically modifying red lungs when they are on the EVLP. And this out-of-body ex-fever modification just has so many potential advantages that I see a transition to the clinics in the future. Yeah, you know, it's really interesting. The ex-fever lung perfusion approaches are quite interesting. And I... And if I remember correctly, a lot of those trials happened before controlled hypothermic storage was even a preservation option, right? So all those control groups that X-View and perfusion technologies were studying was against ice storage. So to me, that's really interesting, you know, that basically teams have now made a leap from ice storage beyond EVLP, for the most part, to controlled hypothermic storage. I think one of the things you touched on, I think, that is interesting, and I think, again, this is sort of that crossing over of disciplines. One of the things we're hearing from physicians in the NRP space, particularly on heart, is that when you have the full complement of the physiology of the body, the recovery of the organ, that the impact on the organ is really different than just sort of replacing blood and circulating in isolation. So I think that's a fascinating sort of aspect to it. Yeah. And just to build off of that, Dr.... I also know that your team, at one point, if I'm not mistaken, did NRP, at least the heart team did, right? And your team feels pretty comfortable taking donor lungs from NRP cases. Can you share a little bit more about that? Because I know that's also a really hot topic in the U.S., whether donor lungs from an NRP case are viable for transplantation. So I think indeed NRP has been performed in Leuven and we have transplanted some lungs with NRP with good results. I was involved in these cases as well. The benefit for the lung itself was that you could do the actual assessments of the donor lungs after the body was recirculated. And so what I remember, what I recall from these cases is that I actually drew some blood gases from the pulmonary veins in situ. after the heart was beating again. So you could assess, which was therefore never possible in a DCD setting, and therefore you had to use the machine to do a proper assessment. What I think is really critical in NRP, besides the ethical challenges that we are still facing, but they are working on that. There are studies currently being performed to assess the fact if the reperfusion leads to brain reperfusion or not. But... except for that, besides that, I think it's important to consider that the lung transplant programs were not hampered or limited by the driving force of the cardiac physicians and surgeons to accept hearts instead of lungs. And I think as a lung transplant community, we have to safeguard the fact that DCD lungs allocated in regards to the use of NRP. What I understood from North American colleagues was that in the first analysis of the UNOS data, it seemed that with the implementation of NRP, there was a relative decrease of the use of suitable lungs. I think overall NRP is really dramatically increase the possibility of heart transplantation. But yeah, we really have to have to develop international protocols that safeguard lungs. One of these is that you have to take into account that we need to monitor that is recirculation does not harm the lung. One of the most important aspects is that I think is the, is the, to avoid an overflow of the lung and that you need to vent the lungs properly during NRP. And we're working on that. Also with the European Society of Thoracic Surgery, this year coming up in Barcelona, we will have a special session dedicated to that. That's fantastic. A special session on NRP to really look into that issue. I think that's definitely called for at this time. I want to come back to something you had mentioned a little bit earlier. So it sounds like the historic timeframes that you'd use for cold ischemic times might have been on the order of six to eight hours. With controlled hypothermia, how long are you going? What is acceptable to your team? for a lung to maintain a cold ischemia time? That's a very good question, Michael. I can tell you that the longest preservation we did now was 22 hours and two minutes. 22 hours. It was 22 hours, it was not preservation, the whole thing, it's what I call ischemia time. Ischemia time, cross-glam to cross-glam? With the preservation over 18 or 20 hours. in the lung guard. And so I must say at the end of the procedure, the reason to do it was first, it was bridging the night. Second, it was a very complex case. So we needed a lot of specialty during the day. And then it was also very complex case in regard to the explant of the lungs. And so just the whole surgery took a lot of time to do it steadily. And then... After these 22 hours, the language was reprefused. And I must say it was really very, very compliant. What you sometimes have when you have an organ preserved on ice for such a long time that it just, it's really cold. It's like taking a steak out of the fridge. It's cold and hard. And it just isn't compliant. This one was really elastic and compliant. And so that made us very confident to indeed. routinely use this extended preservation. And I think we have now gathered, we have sent an abstract for the IHLT next year, gathering I think almost 15 cases of extended preservation, which means is ischemia times beyond 15 hours. And in not a single one of them, we have seen PGD grade three at 72 hours. So I think for us, this is not a problem to extend preservation for that long. I think probably the limits with this technology, if I look back to the old literature, is probably around 24 hours. And I say this because what you see with this controlled hypothermic preservation, controlled hypothermic preservation is avoiding freezing injury, but at the same time keeping an equilibrium between the aerobic metabolism that is performed and the oxygen consumption. And probably after 24 hours, a lot of this oxygen has been consumed. You don't know this for sure. This is based on literature from more than almost 30 years ago, where they did experiments and measured oxygen saturations over time. But I think probably around 24 hours is the current limit. If you find a way to replace the oxygen, we might even further extend that. And I refer you also to a paper of Toronto where they did the PIC experiments and kept the lungs viable for three days. So what I think you have to imagine, it's more like in a very naive way maybe, but this mitochondria, you have to keep them viable. And these are the batteries of your cells and you have to refuel them after a while. So what they did was... They had this pig lungs, they were preserved, then they were refueled before hours of EVLP, then preserved again, refueled again. And so by doing this, you can extend the preservation for a longer time. In the liver now, they can preserve livers for up to seven days. And if you get into that time limits, and I think it's possible, I never say something is not possible. I think it should be possible over time. then you get a situation where you might think about focusing more on trying to create tolerance in your recipient. Because that gives you the opportunity to take donor cells, I think about donor regulatory T cells, expand them out of the body that requires time and give them to the recipient before you actually transplant the organ. And so over time, since the beginning of transplantation, there have been developed so many protocols to trying to reduce the need for immunosuppression after transplantation by making the whole transplant procedure more proteo-lerogenic. It always requires time. And if you can buy time with extended preservation, you can focus on the really whole scale of transplantation, which is creating tolerance. That's fascinating. That's fascinating. I was speaking with a laboratory researcher who's been in profusing organs for a long time. And he says this analogy of it's like if you introduced two dogs in a fight, they will never get along ever again. If you can introduce them as friends, they'll be best friends forever. And this is sort of to what he was saying about getting in organs in a state that will lead to the best outcomes. doing so in a way that you can create time, that you can extend the flexibility and the coordination of everything you need to do to pull off this incredible procedure. It's truly amazing. Dr. Ceulemans, one of the things you mentioned, which is really interesting, was about the use of oxygen over the preservation period. That's actually another interest for us from a research perspective. We recently got a new technology cleared by the FDA, not yet CE marked, The goal is to maintain inflation pressure of donor lungs between the site of donation to the site of transplantation. These pressures can vary based on how the lungs are packaged, but also during the transport period, they actually, we've seen that the pressure goes down. And with that, the oxygen level also goes down. So one of the benefits that I'd love to talk to you more is how this type of preservation could potentially retain the oxygen concentration that you talked about and how we could extend preservation. So I'm curious since we're on that topic from a from a inflation standpoint, you know, we've talked a lot about temperature Inflation as a parameter of preservation. What are your thoughts on that the importance of focusing on that? So where I see this going is that we're going towards the technology where you try to control as many parameters as possible. And the first logical parameter was temperature because you can do that quite easily with current technology. There are two other parameters which are crucial in lung preservation and that is pressure. And pressure is related to volume. The physical law of Boyle and Marriott is just correlated. So pressure is volume. And then you have oxygen. I think that there is a that there is of course a correlation between volume and oxygen. But what I'm really talking about is oxygen consumption. You start after inflation of a length, you can have your two or 50 percent. Otherwise, if you start too high, you have too much oxidative radicals, free oxidative radicals. So you start around 50 percent and you try to maintain that oxygen because it is consumed by the cells. What you do with lung that is transported over the air and where the pressure and volume shifts, because you transport your organ at different heights, is that the oxygen is still consumed in the same way and the number of oxygen particles just diffuses over the volume with which the lung is inflated. But what you actually have to measure is how many oxygen particles are present in that lung. And is there a way? to maintain that oxygen level in the lung over time. That's still something else than maintaining pressure, I think, because if you're able to maintain pressure with the bar guard, which by the way, I'm really looking forward to use myself in Belgium, I think, then if you can maintain the pressure, then the next step would be trying to maintain the oxygen. Yeah, one of the things that we're hypothesizing is that the partial pressure of oxygen is actually higher. So, as O2 is being used up, the inflation pressure is actually going down. And so, the system would actually reintroduce room air oxygen and bring the pressure up, but also the concentration back up. But we can talk about that a little bit more, too, to get your thoughts on. Yeah. And it would be interesting because it's about finding the right... oxygen concentration you need for optimal lung preservation. It's the same question as you had with the temperature. What is optimal temperature? And here the question is, what is the optimal oxygen concentration? I recall some other old literature where I've seen that the first two hours with an oxygen concentration of 50% is more detrimental than an oxygen concentration of 21%. So it could be that the optimal oxygen concentration is somewhere in between. And that will be crucial if you want to further extend the preservation of these organs. Yep. So that's a topic for another day that I'm happy to have with you. This will continue, this discussion. Yep. All right. Well, I'd really like to thank you for making time. We're incredibly thrilled to have you here today. I thought it was a great discussion. Thank you for making the time. I want to take a moment. What do you think in terms of... major initiatives or important areas that we should highlight to the community before we go. That is our top of mind to you and to your program. I think that the community should consider that transplantation in general is a very unique field and that we face more and more challenges by a very limited organ donor pool. It's very hard to find quality organs and I think the whole community should realize that every one of us is a potential donor. And we should consider that... at the moment when we're able to, after we pass away, that we are able to donate. And it's important not to have some general policies around it, but just discuss it with your family, with your friends. What is your wish at the moment that you would become a potential donor? That is just discussed upfront. And this on itself might... have a positive impact on the potential donor pool. We're developing so many complex strategies like xenotransplant, developing CRISPR modified pigs just to increase the potential donor pool. And we all walk around with potential organs, which we shouldn't take to heaven when we can still use them here. I think that's extraordinarily well said. There's such a... rich resource pool here that is so critical to help more patients and that we truly do have to make the most out of every potential donor out there and find every strategy possible. But it's something that we all need to take internally to our own lives of the way we're going to play a role in this whole ecosystem. Thank you. That's been a fantastic discussion. I really, really do appreciate it. I'd like to ask you sort of in terms of initiatives and topics going on in the community. Are there any other areas you'd like to highlight before we go? Thank you, Michael, for that. I indeed would like to highlight a special event that's coming up, and that's the annual European Society of Thoracic Surgery Conference coming up from 26 to 28 of May 2024. It is the... Health in Barcelona, the European Society of Thoracic Surgery is in fact the largest community of thoracic surgeons worldwide and I was appointed last year as chair of the committee of transplantation. And so what we really pushed forward this year was to have more transplant related sessions. And I am happy to announce and to advertise that we will have transplant related sessions every day. The first day is a Sunday. We will have a specific topic. on basic science and how lungs can be generally modified while being on ex vivo lung perfusion. On Monday I can tell you that we will have two transplant sessions of which one is really focused entirely about the impact of normotermic regional perfusion on lung transplantation which is a very hot topic and which will be chaired by Shafke Shafshi from Toronto and Konrad Herznecker from Vienna. And then I'm really proud to announce that on Tuesday morning, we will have a sunrise symposium organized together with the European Society of Organ Transplantation and together with Irene Beyo. I will share that session, which is completely centered around the topic of hypothermic storage, highlighting a state of the art on the protective mechanisms of controlled hypothermic storage and a pro-com debate on the logisticus in... avoiding nocturnal transplantation. So we're really looking forward. We will advertise this throughout the year. And I call every physician related to lung transplantation to come to that event and share their thoughts with us. Thank you. Thank you very much. Thank you. That sounds like a fantastic agenda. We'll hopefully see you there in May. And anyone out there, we hope you all join Professor Ceulemans's and the group in Barcelona. Thank you so much, Dr. Collins. Really appreciate you making the time today. And thank you everyone for listening. Wherever you are, we appreciate you joining for this episode. If you enjoyed this, we're just getting started. We're gonna be putting out more episodes. So stay tuned, follow us on social media for the latest news, or visit us at paragonics.com. Thank you very much.