Rochester Protocol for Liver Transplant in Patients with Metastatic Colon Cancer: Drs. Hernandez & Emamaullee (2026)

[00:00:00] Betsy Post: All right, everyone. So thank you so much for joining us live, or if you are going to be watching the recording, welcome. We are very excited about tonight’s talk. We have, , the COLONTOWN legend, Dr. Hernandez, here from University of Rochester Medical Center.

He’s going to be starting tonight’s presentation on the current status in the Rochester Protocol. So we’re going to learn a lot about transplant generally. Of course, I know some people, of course, are very familiar with it or have transplanted already but there’s something for everyone. And then we are going to introduce Dr.

Emamaullee, which I hope I said your name right. I tried . but, , she is, , in charge of a lot of the research at URMC now, working with Dr. Hernandez on the lab and the research piece. I’m so excited to learn from her and to introduce her to all of our amazing patients and caregivers in COLONTOWN so that she and Dr.

Hernandez can talk about what’s going on, with the research and everything on the horizon. So we can’t wait to learn about that. Of course, we are so excited to have both of them, and their time is so valuable so they’re going to go through the presentation, and then if you do have questions, please feel free to put those in the chat.

We will get to the Q&A at the end of the presentation. And I will say for those of you that sent advance questions, I have sent those to Dr. Hernandez, so he is planning to incorporate a lot of those questions in his presentation.

but if, if we miss one go ahead and remind us at the end or put it in the chat, so we do look forward to the Q&A at the end. So again, everybody’s on mute, and that’s really just so that we don’t have background noise and everyone can really glean a lot from tonight’s presentation. So with that, once again, thanks so much for being here.

And Dr. Hernandez, the floor is yours. Thank you so much for doing this for us.

[00:02:03] Dr. Hernandez-Alejandro: Thank you very much. It’s a pleasure to be with you. Thank you very much, Betsy, for the invitation on behalf of Dr. Emamaullee and myself. , We’re very glad and happy to be here, and hopefully we can bring enthusiasm and points of discussion and alternatives for patients and family members of this area.

Briefly, I just want to mention about Dr. Emamaullee. We are in Rochester extremely grateful and lucky to have her joining our team since early this year. She’s a luminary in the field of research in transplantation. Big things that she does in liver, and also she’s a clinician as well, so she operates as well. She comes to the operating room with us. She does things with us in the operating room, and she has been very involved nowadays in the things that we’re doing with a living donation, with liver transplantation for cancer and those things. So to start here, this is my presentation. This is my slide for disclosure that probably would for you, there’s no – complexity to have those. So, very quick, I’m going to go quick some slides and other ones I’m going to try to answer questions that I think are important for you and some of the questions that Betsy was able to share with me. So colon cancer, very common disease.

The third most common cancer and the second leading cause of cancer-related death. So it’s not a small thing, it is a big thing. And up to 50% of the patients who develop colon cancer will develop at some moment liver metastasis, unfortunately. And this is at the moment of the diagnosis or for some of the patients, even later.

Even if we give chemotherapy around half percent, 50% of the patients. and we can see how, overall in the world it’s increasing these numbers. I wanted to put something more in details in what is happening in our country, in the United States, and I know that some, there are some Canadians, also in this COLONTOWN group.

And overall this has been very stagnant, not increasing the number of the percentage of colon cancer in the population in the United States. However, if we concentrate in the population of between 20 and 50 years old, so those ones who are less than 50 years old, you can see how substantially is increasing the number of diagnosis.

Why is this? The developing countries are having an increased diagnosis of this probably related to our diet. I cannot confirm that, but probably that’s true. Similar things are happening in Canada, unfortunately, so we have many treatments that we have nowadays for patients who develop liver metastasis.

Everybody here knows about chemotherapy and all the biologics. The biologics are not chemotherapy. That’s like bevacizumab, cetuximab, panitumumab, and pembro. These are biologics. These are drugs that are going to help and enhance the chemotherapy and are going to help the chemotherapy to have an action.

And they have been very efficient. They’re specific for some type of colon cancers. Not all the colon cancers are the same. There are some that are more aggressive than other ones, and some of them have some different genetics, and then we can target them with different treatments as well. We have nowadays been able to identify some biomarkers that when there’s some mutations, we can treat them.

A lot of these driven approaches or these targeted therapies are in development, and some of them are on trials. But nowadays we have some specific treatments for BRAF, HER2. I know in BRAF in Australia, they were able to develop this WATER BREAK trial, which was very impressive to see patients with BRAF, that it’s a very aggressive cancer.

Normally we cannot operate on these patients, but they start getting this treatment for BRAF, and these patients survived even two years, which is a lot for patients who have BRAF. So I think things are evolving with treatments that are happening nowadays. And we also have the locoregional approaches, which, locoregional approaches, that means we can do resections.

We, do a lot of resections here at the University of Rochester, ablations of tumors, the famous hepatic artery pump that works very well in some specific situations. The use of Y-90 and histotripsy, that is an area that is under development. At URMC, we have histotripsy. We use it for a few cases, and we have seen very interesting outcomes.

But more of all of these things, they can be used in combination to try to give the patient the best of the best. So now what happens when there’s too many liver metastases? When the liver has too many spots of cancer. So we know that many times we cannot go and do surgery. We cannot do resection.

Why? Because we need to keep the patient with a certain amount of liver so that it’s functional, and if we remove too much liver, the patient won’t survive. The liver is a vital organ, and they need the liver to survive. So the problem of this is that now we can only give chemotherapy to these patients who have, what we call unresectable liver metastases.

And what happens to them in this graph that probably I don’t think it’s difficult to understand. What I will explain to you is this is just showing clearly that 100% of the patients who have unresectable disease and they receive chemotherapy, around five years, only 5 to 10% will be alive. So we need to do something for these patients.

We need to do something, and this is what happened. And you know probably many of you the history, from the group from Norway that it– come and look at these dates, since 2013. So they started doing transplantation in the first decade of this century. They started doing liver transplants for colorectal metastasis, something that was prohibited.

But they took the courage and the interest of doing transplantation for patients who have unresectable disease. Initially, their criteria was very broad. So they were just doing it in some patients who the primary tumor was removed, that they were receiving a couple of months of chemotherapy, and they were responding, and they did a liver transplant.

And look at the difference. This red line is the survival. And at five years, sixty percent of the patients were alive, compared to only five percent of the patients alive at five years. So that’s a huge, huge, huge difference of these patients. However, this gray line represents the recurrence. That means the cancer was coming back.

So cancer was coming back by two years in all the patients, but sixty percent of them were alive. So this opened a lot of conversations, and this is when we started. Later on, it came this to the United States and the University of Rochester with other institutions in Toronto, another one in Cleveland.

We started doing this surgery. Now, the three programs that we started this in the United States and in Canada, we didn’t have access to diseased organs that the way that we normally do liver transplantation, so we started using living donation. Living donation is something that is used in some programs that we use for patients who have disease of the liver, where there is cirrhosis or other diseases that they need a liver transplant.

But it was not a complex thing to go and say, “Okay, we can use the same live donation, living donors for patients with unresectable colorectal metastasis.” So we developed our protocol and this is just a paper in 2022 that we showed just 10 cases, and we were able at that moment to show that patients at three years, practically 80% of them were alive.

Now, a lot of interest started coming from many other programs in North America. This is just to represent, I was able to find some of the literature recently of who has been publishing these things. Toronto published their first seven cases. This is our institution with 23 cases in early 2025.

This is Pittsburgh with 10 cases. WashU in St. Louis, Missouri, with seven cases. Mayo Clinic in Florida, in Jacksonville with 12 cases. So you can see there are a lot of activities that started happening. The vast majority is towards the East Coast, not too much activity in the west coast or in the center, which now is taking place and it’s happening. So a big question was: we are super selecting the patients, right?

And if we are super selecting the patients, some oncologists were mentioning maybe those patients, if they wouldn’t have a transplant if we give chemotherapy only, probably those patients aren’t going to live as long as patients who have a liver transplant. But here I like to put pictures of our fellows and residents that are doing big research, and you will see in the future Matt taking the place of many of us surgeons.

He wants to be a liver transplant surgeon, and he wants to do some pediatrics as well. So Matt, with our group, we did this study where we reviewed in Rochester, twenty patients who were candidates and they received transplantation, and we compared those to thirteen patients who were candidates and they decided not to go for transplantation, and they decided to go and have other alternative treatments.

So they were responding. In that moment, if I would have a liver, I will be able to transplant them. But they decided, “No, I don’t want to go for transplant. I want to go to another institution for resection and ablation and pump or something different.” And you can clearly see here the difference in survival, and this was just a short period of time of follow-up.

But what is more important is in this graph, in this side, you can see how the recurrence, the cancer came back and started moving very quickly in those patients in just one year and a half, eighteen months, that went for other alternative treatments compared to much better outcomes in the patients who received a liver transplant.

And let me tell you, a very important thing that I’m going to show you later is the recurrence, the site of recurrence matters because these patients who have recurrence, it was more in the liver compared to those ones who had transplantation that they didn’t have recurrence in the liver. It was in other places, and those patients live longer. Now, here, this is Dr. Kazu Sasaki, and Luis Ruffolo, who’s at MSK, one of our future surgical oncologists. He’s starting to work with us in just a couple of months. He’s coming to join us from training at MSK. And together with our team, we published this data analyzing all the United States in 2022.

At that moment, there were 15 centers doing liver transplants for colorectal liver metastases. At that moment, there were only 46 cases, and it was very interesting because we saw here that the outcome of patients who receive a living donor compared to those ones who had a deceased organ, the outcome was much better in the patients who received living donor.

Now, we have to be careful with this information because it does not necessarily mean that a living donor is better than the deceased organ. We needed to understand what criteria each center is using. Perhaps the criteria that is used in the patients, that the centers that use a deceased organ, it’s a more aggressive criteria, and that’s the reason that they have a worse outcome.

And it’s very difficult to have that information from the centers or in any registry, but we developed something that I’m going to show you soon. Mariana Chavez, Dr. Chavez, she’s finishing training in Mayo Clinic, Arizona. And guess what? She’s coming to us as well. We’re recruiting a lot of people here.

And Mariana is coming here in August to start working with us as a surgeon, and you will see her here because she’s very interested in transplant oncology. And she published this very recent paper on the number of liver transplants for colorectal metastasis in the United States, including 2025, so this is fresh.

And you can see here that the number of liver transplants per year is increasing substantially and it tripled in the last three years. Last year, there were around 65 or 68 liver transplants for colorectal metastasis in the United States. And you can see the two colors represent living donors in dark, and in light, this is the organ.

So it’s pretty similar here, but initially there was more living donors, and now it’s very similar, both of them. Now, when we analyzed that, we were able to see that the patients in the United States that were transplanted for colorectal liver metastasis, overall, all of them, I’m talking about 153 patients.

The survival was practically 67% at five years. Now, what does this mean when you are at three years, 67%? That is a little bit lower of what the Norway group is showing and what I’m going to show you in the next slide with the group from France, but well, let me show you here.

We divided it and tried to see what’s happening again with the deceased organs and the living donors. There was a little bit of advantage in the living donors, but when it apparently was insignificant, that means that it’s important. But again, we don’t have all the data about the criteria that someone is using, so I want to be cautious with this message.

But seems that perhaps the programs who are using living donor are more cautious in the selection of the patients probably, or perhaps the organ quality is better. Because we need to know and understand that when you are offer a deceased organ, that’s the way that we do transplant, Dr. Emamaullee and myself, every day that we get an offer of a liver transplant. If we have a very sick patient that is in the top of the list, I’m not talking about colorectal metastasis patients who have cirrhosis. Normally, they will get an offer of a very good organ of someone who unfortunately died and the family wants to donate their organs.

That very good organ will come to us because we’re in the top of the list. But if a patient with colorectal metastasis is in the middle or in the bottom of the list – the only way that you can get a very good organ, is with a living donor. Because otherwise you’re going to have a deceased organ who perhaps they don’t want for the top of the patients because it’s not very good quality, and it goes down the ladder until it gets into a patient.

And we can use those pumps that can improve the quality of the organs. We do that, but I think we need to be a little bit cautious and understand the process of, and the outcomes of these organs. Now, I was mentioning to you about the data of France. This is Dr. Renee Adam, where he very clearly showed the better outcome of liver transplant compared to patients who receive chemotherapy.

We knew that, and you know that because you have seen a lot of data. But this is the highest level of evidence. When someone do something that is called randomized controlled trial, that means they have two groups. Both groups are practically identical, extremely similar, both groups. Randomly, half of the group will have liver transplant and half of the group will go only for chemotherapy.

So that is the highest level of evidence, and it’s showing clearly that the transplant patients at five years have a survival around 80% compared to those ones who have chemotherapy that was around 10%. We knew that. I told you that before, but this is just confirming the highest level of evidence.

And if we see the United States were below these, we’re like 67% compared to 80%, and this is at five years, and the US was three years. So there’s something that we have to improve in the US to be able to reach what the Norway and the French group are doing, and this is part of this. So we want to understand why we don’t have in the US, in the country, the excellent results that others have.

So Matt, another of our residents that wants to be a transplant surgeon, has been working on this registry, and these are some of the centers who have been involved who are doing liver transplantation. So as you can see, a lot of concentrated towards the northeast, but we’re getting more people involved, and hopefully they are other programs joining us.

So we have now 22 centers. And now Canadians are joining us, Toronto, Edmonton, and Vancouver, and initially we published something about this, but this is what I want to show you because we have been having very interesting findings that not necessarily the criteria that we have been using, typically like the ones that established in Oslo, are the main ones that we should be selecting patients for this.

We have been able to see that patients who have something that is called in the tumor perineural invasion. So when the pathologist sees in the microscope and the patient’s tumor invades the little nerves around the tumor, that is not a good prognosis factor. So there are more things that we’re doing in our clinical research that we’re learning and understanding more about this and to be able to select patients.

This is perhaps the slide that I wanted to share with you about the title of our topic today about when I mentioned about Rochester criteria, RC’s Rochester criteria. So patients who are within the Rochester criteria that we established, that I will explain in, in few slides, these are the outcomes that we’re having at five years, close to 80%, compared to those ones who are outside the criteria.

This is not only the patients from Rochester. These are all the patients in the United States that we classify. Okay, this is within Rochester criteria, this is outside Rochester criteria. So you can clearly see that the outcome of patients who are outside our criteria, they do unfortunately poorly. So you might be able to ask me, okay, well – but probably those patients survive one or two years, and there’s an advantage of being only on chemotherapy.

And I will say you’re totally right. Maybe there’s an advantage of even if you’re not within criteria to have a transplant. But what do we try to do in Rochester? We will work very hard for the patients who are outside the Rochester criteria to try to get them into the Rochester criteria. We will communicate with our oncologists, with the interventional radiologists.

We will come with ideas and try to improve the response of those tumors to be able to be within our Rochester criteria. And this is what we published in the highest impact factor Journal of Transplantation, which is the American Journal of Transplantation, AJT. This is our criteria. We have shared with many other centers, and what we are very cautious is the Oslo criteria for us, for example, that is what the Norway group established.

They said that if the patient has a CEA below eighty, it’s a good prognosis factor. I believe on that. However, if that’s the only point of the four points that is outside the criteria, they will do the transplant. We are very cautious, and we won’t do it. And also, it’s very important to see if the CEA is going up before the transplant.

That is concerning. There must be some progression of the disease, and we need to delay the transplant, and we need to find out what’s happening, and maybe we have to modify the chemotherapy ’cause the outcome is going to be very different if the CEA is coming down. As well, I think the worst prognosis factor is progression on chemotherapy.

When a patient is having chemotherapy and it’s progressing while on chemotherapy, that’s a bad prognosis factor. And if we do a transplant, we know the outcome is going to be very bad in short period of time. We also use this MTV score. That’s why we use PET scans in our patients, and we were able to see that those ones, we make some metrics there, and we measure the lightening of the tumor, and we call ability.

And then when it’s below a certain level, it has a better prognosis factor, and this is something that we’re using to select our patients. I have shown this picture before of all the activity that’s happening in Rochester. All the green points are referrals of patients that are coming.

Unfortunately, we’re not able to transplant all the patients because only around 10 to 12% of the patients who get referred get into transplantation. But what we’re trying to do is to work as much as possible to try to make these patients fill into the criteria with the oncologist group. And these are our very independent results.

These were not including anybody else outside Rochester, and these are all the patients when we have 32, we have done 34. But you can see this is updated survival at three years above close to 90% survival. That is quite impressive to see. And, a lot of the patients will have recurrence, but I think many of the recurrence is in the lungs, and that’s small spots in the lungs, and maybe there’s one or two little spots.

And I believe many of these patients, they already perhaps had those little metastases in the liver when we did the transplant, but we were not aware. And after the transplant start growing, but then we wait for those to be like, I don’t know, three, four, five millimeters. We send it to the thoracic surgeon, they remove them, and the patients do not necessarily have to be back on chemotherapy, and they can be without evidence of disease for many more years.

So that is something very important to see that lung metastases can be treated with surgery. Now, there might be some patients that will have a lot of lung metastases, and that’s a different story, and they might need to go back to chemotherapy. And patients can go to chemotherapy after transplantation. It’s well-tolerated. And now they have a healthy liver that will be able to tolerate chemotherapy again So I think the problem of this is the recurrence because we know recurrence is going to happen in the majority of the patients. And this is the data from Norway, this is the data from France, and this is the data from Rochester.

And then we can see that the recurrence is very similar between the three institutions, and it’s around 25% of our patients that might be cured, or I think they will be cured, depending on how strict we are. But again, when they have recurrence, we can treat it a majority of the time. And we know that if you stay only on chemotherapy, then the outcome is going to be way less. So I already showed you that there’s less common to have in liver transplantation. Recurrence in the liver is very uncommon. When we do resections in the liver in patients who have multiple liver metastases, the most common place that is going to have recurrence is in the liver.

And why is that? Because how do we know that it’s going to come in the liver? So this is a very simple study that is presented in every single conference that I go that we talk about liver transfer for colorectal metastasis. And this was Mariana when she was working with us doing research, and she analyzed these 14 patients and later on more patients, analyzing the CT scans and the MRIs of the patients who went later on to have liver transplantation. And when the liver came out from the surgery, we took it to the pathologist, and we analyzed and tried to find tumors in the liver, and we counted all of them. And 64% of the time we found more tumors even if they were dead, but we found more tumors in the liver compared to the CT scans and MRIs.

What is this telling us? When a patient has many metastases, there’s going to be a lot of metastases that we cannot see. That is why I believe that liver transplantation in patients who have high tumor load and even if we can resect, most likely those patients, they will be better with a liver transplantation.

And also, what are we doing now? And this is another of our residents that wants to be a transplant surgeon. – A lot of people wanted to be a transplant surgeon. This is Abby Losco, and she’s working with this – a lot of people are interested on ctDNA. I’m not working with any of these companies, Signatera and then…..

– But there’s the circulating tumor DNA. So, this is a blood sample. They measure the circulating DNA of the tumor, and we can see if the patient is responding or not. And there’s a lot of data on liver resection. There’s not too much data on liver transplantation, and this is what we’re developing right now.

And Abby was able to show the… – I’m going to explain this to you very quickly. So, those patients who have a negative ctDNA after the transplant, at three years, only 80% have recurrence. Sorry, only, 20% have recurrence compared to those ones who were positive. So, those ones who were positive after transplantation, they will show metastases in some place, whether it’s in the lungs or some other place.

But this is showing us in an early stage, so we can act, we can do imaging and find where it’s coming from, and then attack it, whether the patient needs an ablation, whether it’s in the lungs or other places. But also, it’s telling us that the ctDNA, when it’s negative and it had subsequent negative measurements every three months that is negative or six or seven times, that is telling us that most likely those patients might be cured or not. -Very quick, this is something that I mentioned.

Let me explain to you what this is. I was a big proponent of doing a lot of ALPPS, and I did a lot of ALPPS, and one of the reasons that I moved from Canada to the United States is because in the United States, they were very interested of doing ALPPS. Nobody was doing that. I came to Rochester to start doing ALPPS, but then came liver transplantation.

So I haven’t done ALPPS in a long period of time. I think there’s indication for doing this liver resection that is very aggressive. But here they compare patients with similar characteristics that went from ALPPS with patients who have similar characteristics that went for liver transplantation.

So it seems that those patients who have a liver transplant could get an ALPPS, and vice versa, the patients who have ALPPS could be a candidate for liver transplantation. And you can clearly see here the substantial difference in survival of those ones who have liver transplantation above ALPPS. And similar things happened with a study from France, where they are showing the ALPPS is like something that is called two-stage hepatectomy, and this is the classical two-stage hepatectomy. Now comparing with another group of liver transplantation, again, showing a huge difference in the survival of patients, of advantage who receive liver transplantation compared to those ones who have two-stage hepatectomies.

So, I think this is something that really opened the door of perhaps there’s patients that are going to have a much better outcome. So, what percentage of patients make it to transplant? So if we’re very strict, maybe around 10% of patients. I think with, with the chemotherapies, with all the ablation therapies that we’re having, the local regional therapies, I think that number is going to start getting bigger and bigger.

I think so. I hope we can help our patients, whether for a patient who has multiple liver metastases, multiple, and it’s responding, and perhaps we can do resection. I have to go case by case because probably some of those patients will benefit from transplantation compared to resection because transplantation is going to remove the entire liver.

It’s going to remove those cancer cells that are in the liver, compared to liver resection where we know that the patient’s going to have recurrence in the liver. And if you have recurrence in the liver, the outcome is worse. Then, what are the advantages or disadvantages of living donor versus deceased donor?

I will have to say, at this moment, we cannot confirm that one organ is better than other one, as long as the deceased organ is a good quality organ, right? I think we have to be able to understand more about this, and we are working, – our team is working on doing some research on this area. What are the percentage of recurrence?

I would say that the vast majority of the patients who have a liver transplant will have recurrence. But again, it comes in the lungs or in other places. Sometimes it can come in a single organ that can be resected, like the adrenal glands, and that is something that could be resected and the patient will not necessarily need to go back to chemotherapy.

If it comes in the liver, then we can do ablation, we can do resections of the transplanted liver, and the patient can have a good outcome as well. So those were some of the questions that Betsy shared with me. …Yes, there are some centers that have different criteria, so unfortunately… And those criterias are important because there might be someone who… in the United States, the problem is that each hospital can regulate their own criterias. And unfortunately, I wish we could have something like in France or Norway that we have the same criteria. But they might be giving opportunity for other patients to have a transplant compared to other ones who are more strict, but we know what’s going to happen with the outcome.

I think the objective of a program should be to do whatever is possible to make their patients to be within a good criteria, and with that, I want to conclude and let Dr. Emamaullee to give her perspective on the research. Liver transplantation in the US has shown to be a benefit. Overall survival is favorable. I think improved standardization and centralized criteria may help to improve regional outcomes. Living donation, well-selected deceased organs can achieve favorable outcomes. More longer data is needed. And I will stop here and let Dr. Emamaullee to have her presentation.

Is that okay, , Betsy?

[00:36:46] Betsy Post: That was perfect. Thank you so much.

[00:36:48] Dr. Hernandez-Alejandro: All right. Juliet

[00:36:58] Dr. Emammaullee: All right, so, thank you again for having me. I just joined the team here in January, and so I’m going to present to you how my research team has approached difficult clinical problems and working towards precision biomarkers and liquid biopsies for management of transplant patients, and how we’re going to apply that in our patient population we see here as part of the Rochester Protocol.

I’ll talk about how my lab approaches these clinical decision-making challenges, and I’m going to share with you the story that we’ve developed over the last eight or nine years about rejection in transplant patients as a kind of methodological approach for tackling these clinical problems, and how that might translate to this patient population.

So, I came to transplant after going to graduate school to study transplant immunology and do my PhD. And this here on the left shows you photographically the history of transplantation and transplant tolerance where we started with the very first successful transplant – was a living donor between two identical twins, a kidney transplant.

The patient survived for eight years with no immunosuppression, and his brother, as the living donor, survived to be in his 70’s. And this is a clinical goal: is where we can do transplants without the need for immunosuppression. In fact, what happens is that despite receiving immunosuppression, our patients get rejection episodes, and generally, the younger you are, the more likely you are to have a rejection episode.

And these are not subtle and they can impact the long-term results in our patients. And so, these rejection episodes are really hard to diagnose, treat, and monitor, and it’s a major driver of morbidity and complications in our transplant patients, and it’s not just limited to liver. This is an editorial that was written by a woman who had a heart transplant when she was young.

She developed chronic rejection. She was re-transplanted, and she had to have high-dose immunosuppression from her immune system reacting to that transplant. And as a consequence, she got a lung cancer and died from lung cancer. She talks in this editorial about her experience with this area of transplant not really evolving through the course of her care.

So, when I came out of fellowship and I took a job in Los Angeles, I was tasked with building on our very large volume pediatric liver transplant program and developing a research program. And for those of you that aren’t familiar, children who need liver transplants, about half of them are born with problems in their bile ducts, and about half the kids we transplant are under the age of two.

And so they’re small like this. They have severe complications from their liver disease, and we really need that transplant to last throughout their lifetime. I know Dr. Hernandez just talked about all of our traditional transplant metrics, things like one year and three year and five year, when you’re talking about a small child, I want that transplant to last 20 years, 30 years.

And so, the problem is, is that we have to give them a lot of immunosuppression, and I just told you that the younger you are, the more likely you are to have rejection episodes. And so we want to prevent rejection and have the best long-term results, but we have a lot of side effects with infections, the risk of cancer, injury to the kidneys.

And in children, it can really impact their growth and their development being on these drugs at a high dose. And so we looked at our experience at our center, one of the largest volume centers in the country. We surpassed 500 transplants a few years ago, and we started doing biopsies as part of our management plan after transplant that are called surveillance biopsies.

So these are at a specific time point rather than when we think that there’s something going on. And the protocol we implemented in 2016 was if they had a stable graft with good lab numbers at five years intervals, we would do a surveillance biopsy, or a year after they had a proven rejection episode.

And in this study, which was led by Brittany Rocque, one of our Rochester residents who’s going to start her transplant fellowship at Columbia in a couple of months here, we looked at over 800 biopsies, and since that time we’ve looked at over 1,000 biopsies in our patients. And what we do, is this approach, is we get a core needle biopsy, and a pathologist looks at these little areas that are circled and scores visually how much of these purple immune cells they see around the structures of what we call the portal triad, the blood supply tree that’s within the liver, and scores the degree of rejection.

And what we saw is that the liver labs that we routinely check on our lab tests for patients, , whenever we want to look for liver problems, whether it’s in transplant patients or not, they don’t correlate with whether or not there’s biopsy, proven rejection, whether we get a biopsy because we think there’s rejection or whether we’re doing a surveillance biopsy.

But about one out of every five kids would have evidence of biopsy, proven rejection with normal labs. So as a consequence of all this, what we showed is this blue line here. If you have a surveillance biopsy, you have the best long-term result. You can see twenty years here, and we think that’s because we can treat those rejections that we didn’t detect otherwise when we do a biopsy.

Plus, if their biopsy is really clean, we can back off on the immunosuppression a little bit, and it means we’re following these patients really closely. But what does this actually look like? So, in our patient population, we generally get lab draws because we have to measure drug levels first thing in the morning when they come to clinic, so they have to be there for 7:00 AM.

They get their blood test. Uh-oh, they see us in clinic, and something is wrong with their labs, and so then we have to admit them to the hospital and plan for a biopsy. So that’s day number one, completely gone. If they’re school age, they’re out of school. One of their parents is with them. This is very disruptive.

Then we make them so they can’t eat or drink at midnight. They have to wait all day to undergo a biopsy procedure, and it requires sedation because they have to stick a needle into their liver under image guidance. We get that result. We take that tissue, it gets processed, and then the next day we get a biopsy result, and if there’s evidence of rejection or something going on, we start to treat it.

So, 1,000 biopsies I told you about, those kids went through this entire process. If they have to get treated, you’re suddenly in the hospital for a week. So this is really disruptive But I just told you it results in the best outcomes. So ultimately, the way we take care of patients, whether they’re children or adults, has not changed in my lifetime.

We measure liver labs, which don’t really match the biopsy. We do this biopsy and read it in a way that hasn’t changed in decades. And then when we diagnose a rejection, we actually generally use two different drugs, steroids or a drug, an immunotherapy called Thymoglobulin, which is just a very non-specific, very powerful drug that depletes your immune system.

And none of this has changed. And so what we’re working towards is instead of getting that needle biopsy which gives us the best information, can we develop a small blood test that matches that biopsy, is quick, and less uncomfortable, and gives me results on the same day? That’s what we’re working towards in my research group.

So how do we do that? Well, we have these new techniques called personalized or precision medicines. We can use them for prevention, we can use them for diagnosis, and we can use them to help guide our treatment. And so there’s many new technologies. I won’t go into a lot of the detail. But we first started off saying, “Can we actually figure out what’s happening inside the tissue in these patients?”

This will help us understand which immune cells are causing the most injury. Can we de-identify specific immune populations that predict clinical outcomes? Can we predict a response to treatment? And ultimately, can we find cells that we want to target with an immunotherapy? I’m sure that many people on this call are familiar with things like immune checkpoint inhibitors, BRAF inhibitors.

Those are called immunotherapies. And if we know exactly what cells are causing the most damage here, we could develop new drug targets so that we have new options rather than steroids or thymoglobulin. And so these are many of the new techniques that have come over the last decade. They require really complex, technical analysis strategies, things you hear about on the news like AI and big data.

It requires that expertise which my team has in order to work with these data sets so instead of a biopsy like this that I showed you, this shows rejection in a liver transplant patient. We can use these markers to color and identify different immune cell markers, and then we can turn this into a single cell data set and identify many of the different cells inside this.

And this is just a clinical biopsy specimen. We didn’t do anything fancy with this. This was taken as part of a routine biopsy for clinical diagnostic purposes. We can go back and look at those specimens. And so with our computational algorithms, we can identify these little islands of immune cells.

You see these little purple islands, these little green islands, and then compare them to clinical outcomes and determine that this pink island of immune cells is very strongly associated with T-cell mediator rejection, which is acute rejection, and disappears during chronic rejection. And so this can help us understand should we, instead of using these very nonspecific drugs, target these cell types that we see in the tissue that are specific for the disease process we’re studying.

And in fact, we think that these drugs that are called PD-1 agonists, for example, it’s the exact opposite of immune checkpoint inhibitor, may help the immune system get turned off when it’s causing a lot of inflammation from rejection. But back to this story. Can we detect biomarkers in the blood?

Can we detect response to treatment, which we have no way of doing right now? Can we ultimately eliminate that biopsy? So we’ve been using something called plasma proteomics. It’s a very sophisticated and sensitive assay that uses a tiny amount of blood. When I say 60 microliters, that volume is about the same as an eraser on a yellow pencil.

So that’s how much blood we need to do this assay. It can measure very, very uniquely over 10,000 proteins in the plasma, which is about 50% of all the proteins generated in human. It’s the most sensitive assay. It has a low false negative rate, which means that it very rarely misses a specific protein.

And, there’s 10,000 biomarkers in this assay. If we do some unique, AI-generated modeling of these data, we can pull out the ones that correlate most closely with our disease that we’re studying, and that’s called a SOMA test. And so if you can get that down to 100 or 50 or 20 protein biomarkers, that bespoke custom assay can be used clinically.

And there are already examples of this, not in liver disease, but in other diseases. So it’s something that once we figure out that fingerprint or signature, we can push forward into the clinical setting pretty quickly. And ultimately, this has the capacity to be run inside a hospital setting with a 12-hour turnaround time.

And so that means we could do that lab test at clinic, – before clinic at 7:00 in the morning, and we might have a result by dinner time saying, “We think it’s very likely you have a rejection. We’re going to start treating it tonight.” So it would completely compress that imeline. And lastly, for biomarker discovery, the pediatric space that I’m bet in is ideal because most of these children only have a single medical problem rather than underlying diabetes or hypertension or other problems that can make interpretation of the results a little bit more complicated.

So we have a study that we hope to be publishing soon where we followed patients prospectively, about 100 patients over the last five or six years, and we measured all sorts of aspects of their tissue, their blood at different time points, and then we performed a variety of these different assays and ultimately, we have approximately 40 protein biomarkers in the blood that can tell us in a single blood sample if rejection is present or not, no rejection versus a T-cell-mediated rejection.

It can differentiate different types of rejection, whether it’s driven by B-cells or T- cells, and it can tell you if they’re having a response to treatment. And so we think this has the potential to be a dynamic blood test that we could use, throughout the hospitalization. So we diagnose the rejection, we start treating it, and then we can look for a protein signature that matches response to treatment.

And this could be our new way of customizing how we take care of our patients. So all of this data over several years has resulted in us having a very detailed, multi-dimensional understanding of what rejection looks like in our patients at the tissue level and in the blood, and how these biomarkers relate to both the tissue injury and the immune system.

And these– some of these protein biomarkers in the blood are also known drug targets, so this is another strategy for developing new therapy. So since I’ve been recruited here, I will say we’ve applied this same systematic approach to several pediatric liver diseases. We have projects in acute liver failure, in biliary atresia, in some congenital heart disease patients who have liver disease.

And so we have a pipeline for this kind of work. So since I came to Rochester, we think about these clinical challenges, and a lot of these were covered by Dr. Hernandez. So first of all, who will benefit from transplant? We want to know, as early as possible in the course of somebody’s colorectal cancer if transplant’s going to be the right decision for them.

And right now, we have a very, very select criteria, and as Dr. Hernandez said, only about ten percent of patients ultimately come to transplant. So what I’m wanting to know, and, as part of our research, is there some feature in that index resection that we can identify that tells us this patient is going to benefit from transplant, and we know that now versus a year from now?

First of all. Secondly, how long do we need to wait before we move forward with transplant? Do we need to wait for a year? Could we have a biomarker panel that says these are the patients with this signature who will be stable and have a low risk of recurrence, for example, and we should move forward quicker?

And lastly, as mentioned, patients get recurrence post-transplant. Sometimes that happens in the lungs, sometimes that happens in other parts of the body. Can we identify in the explant, for example, in the tissue specimens, features that are associated with risk of recurrence, with a very precise signature, and whether that will help us risk-stratify those patients and optimize their care after transplant.

And really, the goal is to select the right patients at the right time for the best outcomes, and to give this option to as many patients as possible. So, as an example, one of the ways we did this in acute liver failure is we used machine learning techniques to develop and validate a scoring system, a tool to help us determine how quickly kids should be referred to a transplant center and be evaluated for transplant called the CHLA Acute Liver Failure Score.

We were able to do this using common admission labs. We made a very easy-to-interpret score, and we made an app to deploy that for clinicians to use and we determined that a score over 30 predicts a lower chance of survival without transplant. And so that means if a kid comes in with their admission labs that meet this criteria, you can rapidly move them to a transplant center, and the transplant center then can move forward with listing them and then make a decision, on a daily basis whether transplant is the right option, and that will help kids get offers earlier.

And so I think as a starting point, we’ve already started to say, are there any of these features like Dr. Hernandez spoke about, about the histologic features, the imaging features, some of the labs, the number of tumors. Can we start to model this and maybe make a score that could help us further refine the Rochester Protocol?

But ultimately, we’re going to work within this biomarker infrastructure that has already been being built by Dr. Hernandez before I came along with my expertise in this space, and look back at these samples collected from clinical standard of care from either their primary resection if we could get that, and if patients are not from our center and had them done elsewhere, there is a way for patients to access these blocks and have them sent for research after the fact. And so we’re going to facilitate that. We’re going to apply our spatial biology, is what it’s called, correlate that with blood samples, and then begin to look at prediction.

And obviously it’s going to take us some time to generate enough samples to get there, but I’m pretty confident that it’s going to give us some insights and maybe even some therapeutic targets for these patients. At the same time, as he mentioned, we’re incorporating circulating tumor cell-free DNA assays, the Signatera assay, that helps us identify patients that are at risk of recurrence much earlier in their course.

And so that’s part of our entire multi-omic strategy for advancing the care of patients in this population. So I know that’s a lot to digest, but ultimately what we do is called systems biology, and this is precision biomarker research. And I personally believe that this is rapidly advancing our ability to personalize diagnosis, treatment, and monitoring for complex diseases, particularly in surgical and transplant patients and that any of the patients who come into our program, as part of the Rochester Protocol, will have the opportunity to participate in our exciting research program, and this will become part of our capacity to refine and expand the criteria to guide our transplant decision-making. So, I’m really grateful for the support.

It’s, been exciting to join this team, and I’m happy to try to answer questions if people have them.

[00:55:13] Betsy Post: I’m trying to see where the chat is and if we have any questions. You guys did such a good job, I don’t know. Let me look in the Q&A. I don’t see any questions, actually. Not sure if anyone sees the Q&A where they can ask questions or if there are any questions, but I don’t see any.

Any questions? If anyone does have questions, let me know. You can raise your hand if you can’t find the Q&A.

[00:55:46] Dr. Hernandez-Alejandro: I think there’s another question, , Betsy, if, if you give me a minute here just to-

[00:55:52] Betsy Post: Sure …

[00:55:53] Dr. Hernandez-Alejandro: Someone was mentioning, and this is some of the questions that you provided me yesterday that I skipped saying, – If there’s recurrence after transplantation, right?

Or, and this is something common because also after resection, which recurrence is quite often? If there is recurrence, the way that is handled, about how it can be managed. So it’s, it’s a little bit different when you have recurrence after resection and when you have recurrence after transplantation.

Overall, the majority of the time, the recurrence after resection is going to be in the liver. Patients might need to go back to chemotherapy plus some ablation therapy or re-resection that we call it, so going again for resection, and then what is the outcome of that? It kind of reduces the overall survival, but if we are able to resect that metastasis or two metastases, the patient might do well.

But most likely, it’s going to come back at some moment. Now, some of the patients who have liver resection and they have recurrence, that is another group of patients that could, I want to be cautious, could benefit from liver transplantation as well. It’s not only all the patients who haven’t gone for resection.

It could be patients who have a lot of liver disease, that they are responding to chemotherapy, and they get the opportunity of getting a transplant, but it also could be patients who went for resection, and they have recurrence in the liver, that there’s no evidence of disease outside the liver.

And then they could also be patients that are going to be going for transplantation. But I think what is very important here as well for the message for the team members of COLONTOWN is having good communication between the group of surgeons and the medical oncologist is imperative. And not…

Unfortunately, not everybody’s able to have that in transplant centers and oncology physicians. There’s not a lot of good communication sometimes there. We have the opportunity of transplanting a lot of patients who are outside from New York State here, and we keep that communication as much as possible to be able to have a multidisciplinary team approach because recurrence matters and the way that it’s treated when our patients have one or two lung metastases, I talk to the oncologist and say, “Don’t worry. Don’t give chemo. Just wait. Just wait. Let’s wait, two or three months. Let’s get those getting bigger.” And then we send it to the thoracic surgeon. Or in anticipation, we talk to the thoracic surgeon, they see the patient, and then these get resected, and they don’t necessarily go back to chemo. So that is something that counts, that it’s of a lot of value knowing about the disease and also having those conversations and communication with the other teams.

[00:59:28] Betsy Post: Great. Thank you. Does anyone have any questions? You can raise your hand if you want to come off of mute and ask a question, or you can put it in the Q&A

I see a question. Any new immunosuppressive drugs coming out that can replace Tacro?

[00:59:50] Dr. Emammaullee: Yeah. The problem with immunosuppression drugs, the short answer is not particularly, and it’s because the trial designed to bring in new drugs into transplant is completely different from how we do new drugs in cancer.

Because in the cancer space, when they trial new drugs, the patients are facing mortality from their cancer, and so the criteria are a little different. In transplant, they compare new drugs to the standard of care, which is Tacro. And in the trial design, there’s generally so much less rejection overall because they run the drugs really at a stringent level, that it’s called a non-inferiority design.

It’s really hard for companies to justify developing a new drug because there’s not a big difference that’s observed. So that’s really stagnated the development of new immunosuppression drugs over the last 20 years or so, and so my idea for myself in this area of research, is to devise a study where we actually enroll patients at the time of a rejection and trial new drugs specifically to treat rejection.

And as we enroll and do new drugs that actually work against rejection, they can be repurposed to do standard immunosuppression in patients because they’ll have an indication in transplant, if that makes sense. So it’s just going to take us time to do that. , but it’s been a real problem because so many patients have issues with Tacro

[01:01:14] Betsy Post: Thank you. And — do you have any follow-up questions on that?

Thank you. Thanks, — And I will have to say something about, Dr. Emammaullee, her science is pretty advanced, as you can see, what she showed here and what she has been working for many years with immunosuppression with pediatric patients. But, the way that she’s thinking is incorporating all this knowledge that she has and experience, and bringing into the transplant oncology and the cancer perspective is what we’re doing nowadays, and this is what our future, our goals and the areas that we’re working on, here at the University of Rochester with her identifying, … I think it will be amazing to be able to identify those patients who do not necessarily… I believe that not necessarily every patient needs to wait for one year to go in for transplant. Maybe in an early stage we can identify that patient that, okay, we won’t not necessarily have to wait one year.

Maybe they can go and have resection of their primary tumor, and if they are responding, they can go for transplantation in an early stage. I think only with people with talent in the research and knowing the correct questions and knowing and understanding how to answer those question is…

questions like Dr. Emammaulee, we’re going to be able to provide information to patients and have better outcomes.

What I would say is, what’s stagnated this area of research for so long is because we don’t have good animal models for these clinical problems. And generally what we could do with a teeny bit of tissue or blood in the past was very little, and so we were just stuck.

But we can get so much meaningful information from these samples, and these ones that were… after you have an operation and they take your sample out, they preserve it, and the hospitals keep it for decades, believe it or not. And so we can access those and study them and generate a big population of knowledge to try to really develop a new way of thinking about these problems altogether.

Betsy Post:

All right.

Well, thank you both so much for your time and efforts for us this evening. Thanks to everyone that joined us live, and for everyone that will watch the recording. We really appreciate it. I know I learned a ton, so thank you so much, and have a wonderful rest of your evening.

Well, a pleasure to be here, and thank you for the invitation and happy to answer questions in the future if there, if people has more questions, Betsy.

[01:04:20] Dr. Emammaullee: Same. Yeah.

[01:04:21] Betsy Post: Thank you.

[01:04:23] Dr. Hernandez-Alejandro: Goodbye.

[01:04:23] Dr. Emammaullee: Bye.

[01:04:24] Betsy Post: Bye