Multimodal Management of Liver Mets: Dr. Rocca (2025)

Betsy Post 0:00
(Video begins mid intro sentence) ….Histotripsy. But when I was speaking with him and preparing for the talk, he had mentioned that he really thinks it’s important for patients to understand not just histotripsy by itself, but all of the different liver directed treatments that are available, so patients can really make wise, informed decisions be part of their care. So I really want to thank him, on behalf of COLONTOWN for being here tonight, and I’m going to turn it over to him in just a second. I want to make sure everyone knows how it’s going to work. So Dr. Rocca is going to speak to us, present to us, give us his wisdom, and if you have questions for him at the end, there will be a time for questions. Please use the chat feature here in Zoom; You just click “chat” and add your question to the chat. The questions will be held to the end of the presentation, and then at the end, when we have time for Q and A, I will read the questions to him, and he will answer those questions. So without further ado, I’m going to turn it over to Dr. Rocca. Again, thank you for being here – we’re so excited to learn from you.

Dr. Juan Rocca 1:09
Thank you so much Betsy for inviting me to speak, and I hope that I can help you figure out different treatment options. I think that you know, here at Cornell, we are a division of surgeons that do liver surgery, liver transplantation, histotripsy. We work hand in hand with our oncologists and interventional radiologists with ablation, our radiation oncologists with radiation. And once a week, we have a meeting, which is called a multi disciplinary tumor board, where we bring our cases, and we have the input of absolutely every physician that is involved in the care of colorectal cancer. I think it’s an amazing meeting, because it really tries to bring the best treatment option for each individual patient. And this is the purpose of this talk today. I think that it’s important to try to clarify – I have no conflicts, – but I just wanted to clarify the purpose of the talk. I think that many of you may know about one or two options that were presented to you, but not all of the options. Maybe you feel you’re being boxed in, the care you’re getting, where you went to get your first consultation about the treatment of your situation. So the main purpose of this talk is to — you geta lot of different treatment options but then, many of you also may know about all the different options, and may be really confused about what is the best option for you, or if you want to know more about the benefits and the risk of each of the treatments or combination of treatments. And finally, I hope in the different situations I’m going to be presenting, I hope that you can relate to those situations, and you can decide what of these options may be working best for you.

Dr. Juan Rocca 3:38
The outline of the presentation has multiple components. First, we’re going to do a quick overview of the treatments that are available for colorectal liver metastasis. This is only metastasis to the liver, which is the main focus. Then we’re going to be discussing what is the gold standard in the treatment of colorectal liver metastasis, which today is a combination of systemic treatments, which is mainly chemotherapy and targeted therapies and surgery. That’s what weconsider the gold standard. From there, we have a lot of data about how that works, and from there, we can move on to other combinations of therapies when surgery is not a good option. For that, we need to discuss, what is resectable disease. That is disease that can be treated with surgery, versus unresectable disease. And then we are also going to be discussing the role of ablation. You’ve probably heard about ablation, different types of ablation, but ablation can be done with microwaves or radio frequency, and this can be used with surgery or can be used for resectable disease, but also can be used on unresectable disease. Then we’re going to go over the role of other local, regional therapies and the different combinations of them. We’re going to discuss the role of liver transplantation. It’s a very strict criteria for liver transplantation, but we’re going to go over that. And finally, we are going to discuss how histotripsy, can contribute to this multimodal management of colorectal liver metastases. It’s a new technology, it’s quite promising in many aspects, and everybody’s embracing it now. We don’t have too much data to really put it against the other treatments, and so it’s important to disclose that. It is promising, it is exciting, I do it quite often, it’s just that sometimes it’s hard to offer something that we don’t have complete proof that it works in the long term. So that’s why I left it for the end.

Dr. Juan Rocca 6:10
Okay, so let’s go with the treatments available for colorectal liver metastasis, starting with what we call the systemic therapies, which today is a mix of different regimes of chemotherapy. All of these sound familiar to you: Folfox, Folfoxiri, Folfiri, Capox; and different targeted therapies like Avastin, Cetuximab, Panitumumab, Pembro. And all these regimens can be combined depending on the different type of mutations that the tumors may have, like the MSI status, the RAS mutations, the BRAF mutations that are of worse prognosis. But now there are more trials and treatments for BRAF mutations, HER 2 mutations as well. The systemic therapies are the backbone of colorectal liver metastasis. In the past, we used to probably use it only in some situations. Now it’s pretty much in every situation. Now for locoregional therapies, I always include surgery as a locoregional therapy, because at the end of the day, when we do liver surgery, even liver transplantation, we are treating the disease in one spot in one region, so it’s a locoregional therapy. So it probably is better to divide it in those locoregional therapies that require an operation, require surgery like resectionwhich is surgery, with or without ablation. We do ablation at the time of an operation, an open operation, a robotic operation. We can do ablation on a laparoscopic operation. We can do ablation together with resection. We’re going to also touch on the role of the Hepatic Arterial Infusion pump and liver transplantation. All these require operations. And then some therapies that do not require an operation is also ablation, which can be done percutaneously with the interventional radiologist. Y-90 radioembolization, which is an injection of material with radioactive activity into the liver, radiation- external radiation and histotripsy.

Dr. Juan Rocca 8:36
So first, the management of colorectal liver metastasis in the last 20 years has improved significantly. The survival of patients who have colorectal liver metastasis improved for three reasons, mainly because we have much better chemotherapy and immunotherapies and different targeted therapies. We have been a lot more aggressive with the surgery that we perform for colorectal liver metastasis, and we also have better locoregional treatments that we’re going to go into in a little bit. But if you look at the last 20 years, the number of operations we’re doing for colorectal liver metastases has increased significantly, and when you divide those patients that made it to surgery versus those that could not have surgery, that’s a striking difference in the survival. So that’s why today, being able to say that we have resectable disease is really very important, because it impacts the prognosis, it impacts the survival and most of the survivors, we’re going to try to put it at the five year mark, which is what most of the papers are usually able to measure or compare survival of different combinations of techniques.

Dr. Juan Rocca 10:02
Let’s try to define resectable disease first. So, resectable disease is that, the tumor in the liver, or the tumors in the liver can be removed or treated with liver surgery. The goal of resectable disease is to get to a condition called NED, which is “”no evidence of disease”, because this is associated with the longest survival. If we can bring you to NED, even knowing that the tumor may come back later, each time we bring you to NED we are giving you the best chance of having the longest survival. Now, resectable disease may require systemic therapy before surgery more and more. In the past, we used to discuss that some situations were benefited, first with surgery and then chemotherapy. But now the data is moving more towards trying to do systemic therapy and then surgery in the liver, mostly when you have a higher number of tumors in the liver. Sometimes they require more than one operation. We call this staged hepatectomy, or staged operations, or a combination of an operation with a locoregional treatment afterwards, in order to get you to the NED status, and one of the conditions is that the patient has to be able to go through an invasive procedure and surgery.

Dr. Juan Rocca 11:31
Now, on the other hand, unresectable disease is the opposite of this. The tumors cannot be removed or treated with liver surgery, or we can, but by removing them, we are not going to be able to bring you to NED. We cannot get rid of all the disease, and this is usually conditioned by the number, the size and the location of the liver tumors. Sometimes you have small tumors that are in a poor location inside the liver that require a major operation of the liver. So that’s when other techniques may really be able to bring you closer to resectable. Sometimes due to the condition of the liver, the chemotherapy can be toxic, can give you fatty liver, can give you fibrosis, can give you some scarring on the liver, so the liver may not be able to tolerate a big operation. Sometimes, when we do systemic therapy, it’s a good test of time to understand the biology of that tumor, and if the tumor progresses while on chemotherapy it’s telling us that doing surgery on that liver tumor is probably not going to help too much, so that could be a reason for being unresectable. Technically, we can do the operation, but the biology of the tumor is telling us that it’s not going to help the operation. Sometimes you have disease outside the liver that dictates the survival more than the disease in the liver. And you can have disease outside the liver, for example, in the lungs. The disease in the lungs is quite indolent and easy to manage. The disease in the peritoneum, it’s difficult to make it respond to chemotherapy,…bone disease, etc. So there are different situations which require a multi disciplinary decision about what the best treatment option is. I want to highlight this, because again, in the past, and not long ago, we were discussing if pre-operative, systemic therapy before liver surgery was a good thing to do. And yeah, maybe for a single lesion that came years after removing the colon, and has a slow progression, maybe you can argue that you could do an upfront resection and then do chemotherapy later. But more and more data is coming out that the use of systemic therapy, mostly when you have a bigger number of lesions, is really important in making disease more controllable for surgery, and that improves the recurrence after the surgery.

Dr. Juan Rocca 14:50
So this is a nice study: It’s about 1000 patients that were matched between those that had only chemotherapy versus those that have had chemotherapy and surgery, but they were much based on the size of the tumors and the number of the tumors. And there are different scores that are standard, the CRS score, the TB score, the Game score. These are different scoring systems that we have to assess risk of liver metastasis and the risk of recurrence. And clearly, those that received chemo before the surgery did better in the overall survival, and did better if you look at the recurrence free survival for the first two, three years. The two groups were about the same, but then, after three years, they started spreading again. And those that didn’t receive chemo before surgery had less recurrence free survival than those that received chemo. So I think this is a one of the many studies that now are showing the benefit of having systemic treatment before surgery.

Dr. Juan Rocca 16:06
Now, a few other concepts of surgery in colorectal liver metastasis. First is, we want to resect the tumor with clear margins. That means that we want to cut the liver where there is no tumor, but we also want to leave enough liver volume. Clear margins for colorectal, liver metastasis can be as little as one millimeter. That’s enough, even when a tumor is sitting in a blood vessel near the liver, if we peel it off, that’s enough, too. So it’s not that we need to do a lot of surgery around the tumor. And this is important. The type of surgeries that we usually do, any liver surgery, we can have what we call the West Resection, where we take a little piece where the tumor is sitting. Or we can start taking segments of the liver. The liver has eight segments. And we can take, for example, this will be 25% of the liver. This will be almost a 35-40% of the liver, the left hepatectomy, the extent the left hepatectomy is almost 70% of the liver. We have different sections of the liver. So typically for colorectal liver metastasis, we try to avoid doing anatomical hepatectomies. We try to go around the lesion. The type of surgeries that we usually do for colorectal liver metastasis here in the first column, the Type A, is what we call the parenchyma sparing liver surgery. That means that, knowing that we need to have at least one millimeter of margin, we go around the lesion as many times as we can. Not always we can. Sometimes the lesions are too big, like you can see in the B column. And if the lesions are too big, either we are forced to cut the right side of the liver, for example, and remove maybe 60% of the liver. Or sometimes, if we feel that the rim on the liver is not enough, we might need to do some intermediate steps like what we call portal vein embolization, to deprive blood flow to the site of liver we’re going to remove and let the other side grow before doing the operation. Sometimes we do the two stage liver surgery when we have multiple lesions on both sides, we first do an operation on one side and we remove, for example, here, these two small lesions on the left side. We remove them, we wait for the liver to grow, and then maybe six weeks or eight weeks later, we can go back and remove the entire right side with all the lesions. But these are goals of surgeries with the goal of bringing the patient NED, without evidence of disease.

Dr. Juan Rocca 19:07
And this is the “ALPPS” procedure, which is another two stage procedure where we cut the liver halfway, we don’t cut it all, and we remove the tumors, and that will accelerate the growth of the liver. Instead of in six to eight weeks, we can go back in two weeks and remove the other side of the liver. Again, as you can see, the complexity of these operations increases when you have a bigger size of tumor, or a bigger number of tumors, or both sides of the liver. But these are all techniques that we use to be able to bring the disease to zero, at least with the method that we have today to see disease, which is CT scan and MRI or PET scan.

Dr. Juan Rocca 19:54
Now, why is it important to save as much liver as we can is because when you have multiple tumors, 70% end up coming back at some point. And if our goal is to prolong the survival as much as we can, we need to have enough liver to keep treating that liver. We sometimes do a second surgery in the long term, like two years later, or even a third operation to take care of new lesions that are coming back after a while.

Dr. Juan Rocca 20:37
But then also, it’s important to understand that ablation has a big role here because those patients that – when the tumor comes back, they could have a second operation or an ablation to treat the tumor, they have a better survival in the long term. Those are the ones that we manage to bring to the five year mark. I think it’s important to understand that sometimes patients that have resectable disease have the best prognosis for a five year survival, but many times may require more than one operation, more than one procedure, while still receiving systemic therapy. Okay, this is how we get you there.

Dr. Juan Rocca 21:14
This is just a study to show that the difference between doing a measures hepatectomy, like cutting half of the liver, versus doing a parenchymal sparing hepatectomy and ablation to take care of many lesions. And this is an important study that show that when you compare those strategies, they have the same survival, and the patients that have a parenchyma sparing hepatectomy and ablation have less complications than those who have a major hepatectomy, which is important. This is an important number here, back in 2014 only 31% of the cases were being done with parenchymal-sparing surgery and ablation. And that rose to almost 50% in 2022 which is is an important trend. We really use ablation a lot when it comes to colorectal liver metastasis. And this is a study that came out this week, actually another multicenter study that compares the role of ablation or surgery. When you are talking about tumors that are three centimeters or less in size, they have the same outcome. Okay, it’s not inferior to do ablation versus resection. Resection is a gold standard, but now ablation, up to tumors of three centimeters, is equivalent. And this is really important, because sometimes, if we do an operation, we clear your tumor, and in a year or two later, you have a new tumor coming back, you might be able to get away with ablation, without surgery.

Dr. Juan Rocca 23:01
Or if I do an operation and to treat three tumors, and I can safely remove two, but the third one is in a tough spot, or I may require to remove more liver, I can do an ablation of that tumor. That is equivalent, as long as the tumors are three centimeters or less, this is another important thing, as we have a higher number of tumors in the liver, we have less chance of surviving in the long, long term, or a higher size of tumors. This is the liver met survey registry. It’s the largest registry in colorectal liver metastasis. I wanted to show you that these are the things that we always consider for puttingsomeone in the category of being resectable or being unresectable. If sometimes, technically, we can remove all these lesions, but they tend to come back, resectability is not only a matter of a technical surgery, it’s also had to do with the tumor biology and the number, the size, but also how long it takes for that tumor to come back. Sometimes when we do operations and we have what we call the very early recurrence after we do an operation, we get the patient to NED, and then in about three months, we have a new new tumor that is telling us that the biology of the tumor is aggressive, and that usually is associated with the number of lesions that we have, or if there’s any extrahepatic disease, or if there’sany mutation, and it’s sometimes important to the surgery. The outcome after the surgery will tell us a bit more about the biology of that tumor, and that will guide our decisions about what to do next. So, in summary, liver surgery for resectable scenarios, I think it’s always important to understand that surgery always has risk. Liver surgery is always complex, even if we do it small, as small as we can. But you know, it offers really good long term outcomes. 50% can achieve long term survival after a successful resection, always, in my opinion, combined with systemic therapy, and it’s also important to understand that many of these tumors are going to come back in five years-60 to 70%, and that’s why we need to keep treating it as aggressive as we can.

Dr. Juan Rocca 25:44
Now, what happens for those that we consider that we cannot resect, that it’s beyond all these different scenarios that I just showed you where we can do an operation or an ablation? Well, first, I think if you do systemic therapy alone, chemotherapy and now with targeted therapies, the survival at five years is about 20%. But still, it’s important to understand that this is the backbone of the multimodal treatments. Over that backbone of systemic therapy, we can add the benefit of other locoregional therapies that can improve the survival. And those other locoregional treatments can be ablations that a non surgical ablation, percutaneous ablation, Y-90 radioembolization and external radiation. So a brief description of each of these. Ablations can be done with radio frequency or microwaves. We put a needle inside the tumor in the liver, and pretty much we burn the tissue. So that pretty much burns the tumor tissue and the liver tissue that is around with the margin. So the same thing we would do in surgery to make that tumor cells dead. That can increase, maybe 10% more the survival at five years if we combine it with systemic therapy. Now we don’t have a lot of data about Y-90 radioembolization at five years. But yes, we use it when we have tumors that are more than threecentimeters where ablation doesn’t really do a good job. And we inject the tumor inside with radioactive particles, and the tumor slowly gets radiated and becomes non-viable or dies. These injections can be done very focal at the level of the tumor or in different segments. Sometimes for liver transplantation, we use it in the whole liver to keep the tumor at bay until we get to a transplant. I think it’s really an important treatment, and it’s always important to consider.

Dr. Juan Rocca 28:13
And then we have the external radiation or SBRT, which, again, we don’t have long term data. We usually reserve for those patients that cannot receive other treatments. But yes, we do know that it’s able to achieve good local control of the tumor, at least in the first two years when we radiate a tumor in the liver. So I want to bring to the discussion also the role of the hepatic arterial infusion pump, which nowadays is not just that. It’s combined also with systemic therapy, but you’ve probably heard about this usually for unresectable disease, when you have tumors that are on both sides of the liver and multiple tumors. It’s a good method to downstage tumors to decrease the size and the number and sometimes convert them to resectable. So what it does is, because the chemotherapy is usually toxic to the entire system, we give only some specific chemotherapy into the liver, and that first passage into the liver will make the chemotherapy concentrate in the liver only and not give toxicity to the rest of the body. It does have survival benefits, because about 50% of those that receive a hepatic infusion pump may be able to be downstage to the point that they can be converted to surgery.

Dr. Juan Rocca 30:04
When you put it all together, the latest studies the overall five year survival for unresectable disease with the pump is about 50%. But then if you divide into those that responded to the pump and the systemic therapy and were able to have surgery, those had a survival of about 70% at five years. But then the other ones didn’t respond. It’s about 50/50. The other half that did not respond didn’t make it to the five years. But again, these are not only therapies that allow you to downstage treatment, but also to be able to understand the biology of the tumor. And those tumors that respond, they have a shot at having surgery or even transplantation, and those tumors that do not respond, at least we try very aggressive therapy, and if they do not respond, biology wasn’t clear.

Dr. Juan Rocca 31:09
All right, so now liver transplantation. Liver transplantation is the most radical treatment for liver disease from colorectal liver metastasis, and that’s why we call it the ultimate liver correctional treatment. Because what we do is, we take care of some cases of unresectable disease, liver transplant should not be offered to those that have resectable disease, because they have very good survival. But those who have unresectable disease, and they have a five year survival below 50%, below 30% some of them, they could benefit from having a complete removal of the liver, and by removing the entire liver, we’re not only removing the tumors, but also we’re removing the factors that are in that specific liver that allow the tumor to come back. Okay? So that’s the rationale behind it. But of course, for that, you need to be able to have a disease that is well controlled, right? So it’s kind of a long pathway to get to transplant, and many times all these different techniques that I told you beyond surgery, like ablation, like a radioembolization, or Y-90 radiation, or even the hepatic arterial infusion pump, are methods that we use to keep the disease at bay so we can make it to transplant. We use a lot of time, as a test of time, to tell us that the biology of that tumor is manageable to the point that we can do a liver transplant and not have an immediate recurrence, Okay?

Dr. Juan Rocca 33:08
So this is the latest study that we have in transplantation. We have some data from the United States. We have data from Norway, which were the pioneers on this more than 10 years ago, but this is the study that came out last year in 2024 and it’s a multicenter study in different countries of Europe. They show that if you tranplant patients with unresected liver metastases under central criteria of the stability of disease and the disease has to be restricted only to the liver. You cannot have peritoneal disease, you cannot have bone disease, you cannot have lung disease. So with that criteria, when they looked at the intention to treat, this is all the patients that were recruited to the trial. The five year survival was 56% for those that received a liver transplant, versus 12% for those that only received chemotherapy. Now, when you start tweaking a little bit the criteria to make it stricter, then the five year survival – that’s what they call the “per protocol” survival – the five year survival went up to 73% when you did liver transplant and chemotherapy, versus 9% for chemotherapy alone. So this is important, because this 73% is beyond what we consider the survival benefit of a liver transplant, which is about 60% at five years. Remember that liver transplant is a standard practice for many other diseases. It started with liver cirrhosis and many other diseases that are not related to cancer or some diseases that are related to liver cancer from primary liver tumors, and they have a high standard of survival. The survival of the liver transplant at five years nowadays is about 80% for most of the indications, and for some cancer indications about 70%. so it’s hard to really start doing liver transplants for colorectal liver metastases if you are going to be having a five year survival that is be below that benchmark of about 60%.

Dr. Juan Rocca 35:38
Now the other thing I wanted to show you about this data is that, as you can see, on the progression-free survival “per protocol”, those that received a liver transplant, with the red dotted line, they did have recurrence. They have a fair amount of recurrence, but by two years, 50% have some sort of recurrence, and we’re going to talk about that. Much of that recurrence could be treated. So if you can treat the recurrence after liver transplant, you have this concept that we have here, is the secondary progression-free survival. That is how you prolong the survival after treating the recurrence. So we’re going to go a little bit deeper into this and talk about the recurrence patterns after liver tranplant, and the difference with the liver surgery. If I do liver surgery for colorectal liver metasteses, the primary site of recurrence will typically be the liver because the liver that I did surgery on still has the conditions for a new tumor, and is harboring microscopic tumor or new tumor to be seeded and grow back and recur. Okay? When we do a liver transplant, not only are we removing the tumor, but we’re removing that liver with those factors, and we’re putting in a different liver that may not have those factors. So the recurrence pattern after liver transplant is not in the liver, it’s mostly in the lungs. And as I told you before, the lung metastases are indolent, usually they take a long time to progress, they are not as life threatening as a metastasis in the liver or the bones, or the brain. So it is important to consider this when we know that some patients have lung metastases after liver transplant, but they can be treated with surgery.

Dr. Juan Rocca 37:51
This is an example that I want to show you. This was done last year in Chicago. I trained in Northwestern Memorial, actually, many years ago, and a young patient that received a liver transplant for colorectal liver metastases was 8 years out from that liver transplant without problems, except for some lung metastases that had recurred and was stable, but they kept coming back after different treatments. So for the first time, it was decided to do a lung transplant for metastases in the lung, 8 years later after a liver transplant. So this is way far from what we consider standard of care, but at least it’s giving us a glimpse of what we could achieve by having a long term survival for unresectable, colorectal liver metastases.

Dr. Juan Rocca 38:52
Of course, we have to be very cautious with all this, and unfortunately, the patients that can be eligible for a liver transplant, the patients with colorectal metastasis, about 1 or 2% of all the patients that are there. So this is an important figure that can give you a sense of all the patients that have colorectal cancer, half of them have colorectal liver metastasis, about 30 to 50% of them have no evidence of extrahepatic disease, which means that we could consider liver transplantation. But you know, 70% of them are technically resectable, so we should resect them. And then there’s the 10% that, if we consider all the selection criteria, may be able to be considered for transplantation. But then, in the end, through the pathway of transplantation, which requires a wait time or requires treatments, requires them to go through a transplant evaluation and to receive an organ transplant from either a live donor, or a diseased donor, only 1 or 2% may be able to receive it. This is encouraging to be able to come with liver transplant, but still, it doesn’t have the scale to impact everyone. This is just to show you the protocol that we have at Weil Cornell for transplantation of colorectal liver metastases. We have a trial that is listed in the clinical trials.gov site. We did transplant five patients, but we did evaluate, (this is a bit old), more than 35 patients. The definition of unresectable is made at the tumor board. We look at the imaging, and we have surgeons, we have oncologist, we have interventional radiologists, and we come up with different strategies to decrease the tumor burden and see if there is a way to resect this patient and make them NED. If we don’t find a way, then that patient, if they only have disease limited to the liver, that patient may be able to go into liver transplantation. For that, we need to have different tests of the lungs, the liver, a PET CT, we usually do six months of chemotherapy, and we have to make sure that the disease remains stable or responds. And then sometimes we have to remove the primary tumor. If the colon tumor was still there, we had to remove it and wait and give another treatment session. And then closer to the transplant, we typically give lobar Y-90 which is this radioembolization to the both sides of the liver, because at some point we need to stop the immunotherapy before the liver transplant, and we need to wait about six to eight weeks for that immunotherapy to go away. We want to have some control in the tumor with with the Y-90. That’s why we usually give it. The product Y-90 is quite toxic to the liver, so we have a little window there to stop the immunotherapy with the effect of the Y-90, and then do the liver transplant.

Dr. Juan Rocca 42:13
This is a summary of the outcomes of different scenarios for colorectal liver metastases. So starting with the easier scenario, single liver metastasis, you can have a five year survival up to 60% with surgery and systemic chemotherapy. If you have multiple liver metastases that are resectable, you have a combination of different treatments and as I told you, you can have survival rates that go between 40 to 50% at five years. If you have multiple liver metastases that are unresectable, your five year survival can go from 10 to 20% if chemo only, up to 30% if you add ablation or chemoembolization or radiation to it. If you have a hepatic arterial infusion pump, your overall survival can stretch to 50% or more. It depends on if you respond to the arterial infusion pump. If you don’t respond, your five year survival won’t get to five years. It’s going to be hard, but you might be able to respond and become eligible to either having surgery or a transplant, for some cases, we do consider patients that are being downstaged with a hepatic infusion pump, we do consider for transplant in some situations, and then liver transplantation, if you make it to liver transplantation again, 1 to 2% only can make it there. You can get up to 75 to 80% of five year survival. It doesn’t have the scale, but yes, it’s very promising for those that can meet the criteria.

Dr. Juan Rocca 44:10
So now let’s put this into the right context. I think this is a great picture to tell us what the scale of all this is. Okay, so unresectable here at the bottom, if unresectable are in the 10,000, resectable is about 10% of that, in the 1000s. Okay, so the resectable disease as we define it, that we can do surgery, combined with chemotherapy, maybe with ablation, the tumor comes back, we do surgery again or ablation. That is in the proportion of the 1000 compared to the 10,000 of those that cannot have resection or cannot become NED. Then those that may be considered for liver transplantation are in this grey zone. Yes, they are not resectable, but the burden of disease is not too much, or the biology of the tumor is not too aggressive, like, for example BRAF mutations are not being accepted for liver transplantation because they are too aggressive, but some other RAS mutations are being accepted. And of course, there’s a test of time, etc. So, liver transplantation would be in the 10’s of transplants, okay. So this is just to give scale to, or to give a good context of the different treatment options.

Dr. Juan Rocca 45:45
Okay, now let’s talk about histotripsy now, and I gave you all the data about what the other options can accomplish in terms of survival. Histotripsy, because it’s a new method, and we’ve only been doing it for one year in the United States and in the world, we know we won’t have five year survival data. But how does it work? So first, it’s a non- invasive tumor treatment. It does not require surgery, it does not require a needle to be inserted into the liver. It’s just ultrasound, so in that regard, it’s very novel. It could be compared to external radiation therapy. But external radiation therapy is a lot more toxic. So, what it does is the ultrasound, the shock waves from the ultrasound, induces cavitation, that is, bubbles that expand and collapse so rapidly that it destroys the tissue and the cells, and makes them explode. It’s like an implosion. And that area that is being destroyed turns into what we call a lysate or a liquid, a liquid that only has proteins or different components of the cells, but has no viable cells. Now, the important thing is that these cells that are being mechanically disrupted are cells that are usually either cells like liver cells or tumor cells, but some cells that make blood vessels or bile ducts or scaffolding structures of the liver are not being destroyed because they have high collagen, so that allows the liver to regenerate back in that area. Once that lysate or that fluid is being reabsorbed by the lymphatic system of the liver, the liver will eventually regenerate in that area. This is a little video that you probably saw. But just to give you an idea, how the setup is for histotripsy: We do histotripsy in the intervention radiology suite. Some other centers to it in the operating room, some other centers are doing it in an intervention room that is not specific to anything, but we need to have the patient under general anesthesia. That’s important to understand. So you know patients that have severe heart disease or severe lung disease, some diseases that are not related to the cancer, but you know that they are unsafe for general anesthesia. Those patients cannot qualify for it. But we would put the patient under general anesthesia, and then we use a special water bath that has to be put over the the abdomen in the region of the liver to be able to transmit the ultrasound waves into into the liver. And we use a regular image in ultrasound that is coupled to it so we can see the lesions.

Dr. Juan Rocca 49:05
So this is how the device looks. This is pretty much how we set it up. And then this is a closer view of what happens inside the liver. If this is the tumor, these shock waves start creating these bubbles of implosion and expulsion, and with that, start destroying the cells and creates a bigger bubble. It’s like a chain reaction. And that bigger bubble starts going around. We usually have a very focal targeting of the beam, and we move it in around the the size of a golf ball, if you want, until we create that size. Here you can see what happens when you have this fluid or the lysate. The blood vessels are usually preserved and the lymphatics are usually preserved. So that would allow the liver to regenerate in the coming weeks after the destruction of the tissue.

Dr. Juan Rocca 50:23
This is a representation of once the lymphatic system absorbs the tissue-the lysate, the liver tissue, can grow back into the area. Let’s look at the difference between histotripsy and ablation, because they in some regards are comparable, because histotripsy can be used for lesions that are about three centimeters or less in order to treat the entire lesion. The difference between ablation and histotripsy is that, because ablation pretty much hits the area and cooks the tumor cells on the liver tissue, the regeneration of the liver is not as much. It takes a long time to reabsorb the tissue because it’s pretty much not liquid, it’s solid and it’s is like a burnt tissue instead. You can see the defect there. Here, that beginning is very similar to ablation. But then over time, the normal liver tissue starts growing already, until you have a minimal scar there. So this is one aspect of histotripsy. The other one is that there’re some areas that we can preserve blood vessels and bile ducts after doing histotripsy in areas of the liver.

Dr. Juan Rocca 51:50
The final one that maybe many of you have heard is what we call the abscopal effect, which is an effect that by treating one or two lesions, and by allowing the liver to reabsorb that lysate, with antigens of the tumor that unmasked for the immune system tumor antigens, and allows the immune system to be more active against other tumors that were not treated. That’s a very exciting, exciting effect. However, we don’t see it too often. We see it in about 20% of the cases. And we still don’t have a good way to take which cases are going to have that effect and which cases are not. It’s kind of a hit or miss. But I think it’s important to remark that this is another potential benefit, and I think with more data, we may be able to determine which type of tumors or which type of genetic mutations or what type of liver or location or size can really respond with this immunologic synergistic effect. This is another example of what we do prior to liver transplant for other disease, which is hepatocellular cancer, but hepatocellular cancer is a tumor from liverdisease that we transplant. But many times before transplant, we have to do different treatments of the tumor to keep it at bay. And these are very sick patients, and we are being able to do this treatment now, instead of doing invasive treatments like ablation. We can do histotripsy to reduce the tumors or even knock out that tumor until the patient gets into transplant.

Dr. Juan Rocca 53:41
I just wanted to remark the abscopal effect is a systemic immune response that is triggered by the tumor destruction, and it can expose the tumor antigens and that can potentially enhance the immune surveillance. Now this is observed not very frequently, but it’s something that is under investigation, and hopefully we can find a way to make it happen more often. We believe that keeping chemotherapy and immunotherapy while doing histotripsy, can really help synergize the effect of histotripsy. This is just to show you how in one year only, historipsy was embraced by many centers in early state, a total of 28 centers now have it, many here in New York. And this is the number of tumors that were treated in 2024. You can see that colorectal cancer is the majority of them, about 260 cases, neuroendocrine tumors, pancreatic cancer, cholangiocarcinoma. These are all metatsteses in the liver. Cholangiocarcinoma, HCC, which is a primary tumor of the liver, that we do transplants for and other types of tumors. The specialties that do this can be interventional radiology, in some centers radiation oncology does it as well, hepatology or surgery. There are different trials that led to the approval of this technology for treatment of liver tumors. Some initial trials a few years back. – But the trials that really led to the FDA approval was this Hope4Liver trial, which is a multicenter trial in the US and Europe that was able to demonstrate effective treatment once you target and you can go around the tumor and destroy the tumor and the tissue around it. That’s the effectiveness. It didn’t come back within 30 days, which is not long term, but at least within 30 days, and then that it is safe. That there were only a few adverse effects because it’s non- invasive. There were minimal cases of serious adverse events that we call, like infection, like liver failure or death. In those 44 there were a total of three cases only.

Dr. Juan Rocca 54:00
Now this is the important study, the BOOMBOX trial. The BOOMBOX trial is a prospective trial, where we enroll all the patients that are receiving histotripsy, and we follow them up for five years. This is why it’s so important, because we really need to get the five year data to be able to compare to all the existing tools that we have to treat liver tumors. We are participating in this study where we actually enrolled three patients already. And I think it’s it’s important that if you are the receiving histotripsy, you’re very likely going to be enrolled in the BOOMBOX trial, or you may be even enrolled in some other specific trials that are using historipsy in different contexts. For example, in the contexts of certain chemotherapy, certain immunotherapy, or associated to other treatments.

Dr. Juan Rocca 57:21
I have a clinical case that is a transplant case. Just wanted to highlight that there was a woman that had a diagnosis in 2020 and had surgery for the colon in 2021 January, and then had liver metastases and a year later had surgery in the liver in 2022 where they removed different lesions, they removed seven lesions. Okay, so there was resectable, but in the high risk end, and had ablations, then had chemo later, and then five months later, as soon as they stopped the chemo, there were some tumors that came back, they recurred. So she had another surgery in January of 2023 one year later, with resection of three lesions and ablation again, and then was followed by chemotherapy again. And so this is a colorectal cancer operated in 2021 liver surgery. In 2022 liver surgery in 2023, and every time that they stopped the chemotherapy, the tumors were coming back into the liver. The patient was sent to us to discuss different options of treatments. She had no mutations that were of concern for us. And then I just want to show you a little bit, at the top of presentation, the tumors that were active. There was one here, one here, one here, and another here, four liver tumors, and there was an area that was also non-viable of liver. So we did a first intake. We did a PET scan that showed us that the the metabolic volume of the tumors were not that big. A metabolic tumor of almost 90. Best survival is 70 or less, but 90 is quite acceptable. You can see here, 1-2-3-4- 4 tumors, and there was a question of a fifth tumor. In this case, we could say that there’s enough liver. And there are only four tumors, why don’t we go back and resect it again? Yes, but this is when the concept of biology and resectability can come together. Anytime you stop the chemotherapy after resection, the tumor came back, and it was the third recurrence. So, we were a bit skeptical about doing again a resection, and we presented this case at the tumor board. We looked everywhere, the chest, the the bones, and there was no evidence of disease anywhere else. So we presented this as different treatment options. One was to start the chemotherapy of course, to repeat resection and ablation. We could refer her to another center. -We don’t do the hepatic arterial infusion pump, but she could go to receive hepatic arterial push pump, then resection. The problem here was she already had multiple resections. We could include her on the transplant pathway. And so we reinitiated the chemotherapy. And then after three months later, after chemotherapy, she got stable disease, we decided to do a periportal lymphadenectomy to make sure that the lymph nodes around the liver were negative. These were negative, and then we continued again, chemotherapy for another three months, while we gave Y-90 to keep the tumors at bay,after stopping the chemotherapy. And we were able to restage again, we didn’t see any evidence of disease outside the liver. Disease in the liver was better. There was less tumor burden. Here you can see the lymphadenectomy. So after we did a final run of patient, and we find that it was controled liver disease with those four lesions that were smaller, the tumor volume on the PET scan went from 90 to 64, under 70, we considered that she was a good candidate for liver transplantation, and we were able to give a live donor liver transfer from her son. That was in May, and so far, at this point, she has no evidence of disease. So I think this can illustrate all the different therapies that we talk about, except for histotripsy for this case. But we would consider histotripsy in some cases that are going to transplantation, to show you that we always need to find a way to either make someone resectable, or someone that can have aggressive treatments like ablation, like a hepatic artery infusion pump, to see if they can respond and they can become resectable, or they can become transplantable and ultimately prolong the survival more than 50% at five years which is evolved. I’m going to open the floor for questions.

Betsy Post 1:03:16
Thank you so much. I’ve learned a lot. This was great. I think it really talks to all the different treatments and how they can be used together. And a great introduction on histotripsy. I know we appreciate it. So I’m gonna go through some of the questions, we have a question on transplant. Is it always best to have a transplant if one is a candidate for that and not resectable. So I think, sort of looking at that pathway.

Dr. Juan Rocca 1:03:45
I think it’s worth to have an early consultation if the diagnosis is unresectable and no evidence of disease outside the liver, I think it’s worth it to have a consultation. Remember, anytime you go to a transplant center to inquire about transplantation for this, they will put you on a protocol that will require at least one year of wait time from the time you get a diagnosis, and maybe six months after removing the colon and having chemo for about a year, at the very least, to show that you have stable disease. And then we do all this testing to make sure that there’s no disease outside the liver. Many centers do this surgery before the transplant to remove the lymph nodes to make sure that there’s no lymph nodes that are positive around the liver. So it really is a process. So if there is any question about eligibility for transplant, I think it’s important to go to a transplant center that has a protocol for that and inquire.

Betsy Post 1:04:56
We have a question about general anesthesia. So I think it’s obvious that a transplant liver resection are going to be done under general anesthesia. But I think as far as histotripsy, Y-90, the ablation, SBRT, some of those treatments, does a patient have to be under general anesthesia, or how would you handle that?

Dr. Juan Rocca 1:05:15
Yeah, that’s a great question. Any surgical procedure, of course, is under general anesthesia. Ablation – it depends on the center for percutaneous ablation. Some centers do it with sedation only, depending on the location. Some centers prefer to do it with anesthesia because they have a better control on the movements of the patient. With histotripsy it’s the same thing. Histotripsy requires anesthesia because when you target the lesion and you treat it, the respiratory movement has to be predictable. So with anesthesia, we can control the movement of the of lungs and how the liver moves, and we can decrease the amplitude of the movement to the minimum to try to stay in the area and not burn. For example, when we’re doing it, histotripsy or ablation, but mostly with histotripsy we don’t want that area to move too much, because maybe then the ultrasound beam can go into the colon or to the stomach or to the duodenum, to areas that are not liver, and can damage those areas. So that’s why it requires general anesthesia. Now, if we find a way to do a less invasive treatment, like with ventilation that doesn’t require general anthesthesia, that’s in discussion. But so far to my knowledge, none of the centers that do histotripsy are avoiding general anesthesia. Everyone is using general anesthesia so far. For radioembolization you might not need general anesthesia. That’s sedation only. For radiation, you don’t need anything.

Betsy Post 1:07:14
Is it logical to pursue partial histotripsy with the intent of down staging before other therapies such as SBRT or Y-90? In other words, is it logical to target one part of a tumor with histotripsy and then use another therapy to finish the areas that were not treated? For example, in cases where Y-90 or SBRT would not get all of the tumor alone or would be too risky?

Dr. Juan Rocca 1:07:42
Yes. So that’s a very important question, and this highlights the role of multimodal treatments, right? Yes, histotripsy can be done for what we call complete treatment or partial treatment. So if histotripsy can be done, let’s say, the liver has three tumors. The three tumors are under three centimeters, and they’re in spots that are safe to burn around the tumor or burn. Just do the histotripsy to lysate the tissues, so that will be a complete treatment. There were three lesions, the three lesions were completely treated with the histotripsy. That’s a complete treatment. Okay. Now, for most of the cases, we do histotripsy in situations that we have more tumor burden, multiple lesions, different sizes. And what we do is we try to do a stage histotripsy. We treat two or three tumors at a time. And sometimes, for example, if there’s a tumor that is five centimeters, we may treat three centimeters once, and then come back and treat the remainder two centimeters and to try to clear the entire tumor. Or sometimes we have multiple tumors. Some of them, we can target them with histotripsy, but some others may be in a difficult location for histotripsy, either because it’s close to the colon, close to the stomach, or high up, or surrounded by lung, and it’s hard to get the ultrasound beam to get there. So sometimes we use combined modalities of histotripsy with ablation or histotripsy with radiemobilization in order to treat all the tumors that are in the liver.

Betsy Post 1:09:39
Thank you. Could you provide your thoughts on getting a hepatic pump with replaced right hepatic artery abnormality?

Dr. Juan Rocca 1:09:50
Yeah, so the the arterial anatomy is an issue, and the eligibility of the hepatic infusion pump depends on different variations. But the problem would be, when you’re trying to inject, the catheter of the pump has to be in an artery that’s only to the liver and not anywhere else. So many times when you do this procedure, I don’t do this procedure, but Memorial Sloan is located across the street. They do it, and so they are very detailed about the different branches of the arteries where the catheter is to make sure that that chemotherapy goes only into the liver and doesn’t go into the stomach or into the pancreas, into the duodenum. Many times, when you have a right replaced hepatic artery it may be very difficult to control the flow, or can even reflux. And that could be a contraindication. That’s right. So if you were turned down because of having a right replaced hepatic artery, this could be a contraindication, yes.

Betsy Post 1:11:11
For tumors that are under three centimeters, is radiation equally as effective as ablation? I think you talked a little bit to that, but I did want to ask you that.

Dr. Juan Rocca 1:11:23
Yes. So this is the COLLISION study. The study that I showed was a multi center study in Europe. The research came out with the final results. Actually, the study was stopped earlier. So the study was designed as a non inferiority trial. This is the gold standard, was resection for tumors less than three centimeters. And they started comparing ablation for those same tumors, same size, and they couldn’t see any significant difference. They recruited 300 patients, 150 and 150, pretty much. And they stopped it early because there was no difference in the outcome. So this validates ablation as an equal treatment to resection for tumors under three centimeters. Of course, the devil is in the details, and that doesn’t mean that in your specific case, you should have an ablation, another resection. That depends on the location of the tumor. Sometimes the access with the ablation, sometimes we do it with surgery, but sometimes percutaneously, it’s not as easy to access every tumor in the liver than with a surgical ablation, or sometimes a resection makes more sense. No, that depends on the specifics of the case.

Betsy Post 1:12:49
Thank you. And this is from a patient that actually had the histotripsy procedure done to three lesions in the liver. The patients had two CT scans since the histotripsy, and is just wondering, other than comparing the size of tumors of those treated lesions on the CT scans, how would the patient know if histotripsy-induced abscopal effect has taken place?

Dr. Juan Rocca 1:13:17
Yeah, so far the way to tell is with imaging. This could be MRI or a CT scan that has contrast. And with that between two to four weeks after the procedure, you could see the abscopal effect is, if you got treated three tumors, but there are three tumors that were not treated. You should see a rim enhancement in the tumors that were not treated, like there’s some inflammatory activity around the tumors. If you do it early, maybe two weeks later, and if you do it later, like four weeks later, if that already happened, you should see a reduction in the size of the non-treated tumors. The only way to document abscopal effects nowadays is, like we did mention so far.

Betsy Post 1:14:13
Can you comment on the HAI pump for patients after resection to help prevent recurrence, so, when a patient would get a pump to help prevent recurrence. I think you did comment some on that, but I just wanted to ask that.

Dr. Juan Rocca 1:14:27
So the pump has benefits. It’s an aggressive therapy. It’s like two stage hepatectomy or even liver transplantation. These are aggressive therapies, and it has benefits, but also has some drawbacks or toxicities. The benefit is if you respond to the pump and you can downstage the tumors to make them resectable, which 50% can respond? Good news. You’re in a good spot if you respond and you can have resection. For example, the chances of recurrence is a lot less after using the hepatic arterial infusion pump. So not only it can reduce the burden of disease and make it resectable, but also it will prolong the amount of the recurrence-free survival. Okay, so that’s important. On the other hand, sustained treatment with the pump can lead to liver toxicity, and in some cases, can lead to some irreversible liver damage on the bile ducts. It is reported to be 1 to 3% but when it happens, it’s a real deal. So as part of an aggressive treatment that can be very effective, it’s always important to discuss the potential risks of having liver injury or having to interrupt the treatment because there’s liver toxicity. Not every patient can continue the treatment, and sometimes it has to be interrupted. The management of the pumps requires a multidisciplinary team that is not only the surgeon, but it’s very specific oncologists that know how to manage the dosing in order to manage the toxicity in the liver and to try to mitigate the potential injuries to the liver.

Betsy Post 1:16:36
In your opinion, how many times can you perform resection and targeted therapies on the liver before you would consider that transplant path would be the best path forward.

Dr. Juan Rocca 1:16:49
Yes, well, the clinical example I showed you was two times resected, and the third time that it recurred, we decided to do a liver transplant. It depends on the presentation. If someone presents with unresectable disease, but in that gray zone that is unresectable, but the size of the tumor is no more than five centimeters, there can be multiple tumors. The metabolic volume on the PET scan is not high. It’s not more than 90. Of course, that kind of patient has to be on chemotherapy. So if they are stable on chemotherapy, or responding on chemotherapy, and we see that there are more than six seven lesions, it could be considered for trouble, because we know that resecting six or seven lesions with surgery, the chances of recurrence is very high. And the long term survivors are showing one of the curves, of resection, chemotherapy, of seven or more lesions, the five year survival is about 25%. So some cases that present like they could be considered for transplant from the get-go based on how they present, in the number of lesions, the number and the type of mutations we would consider transplantation up front. But clearly resectable cases with low risk of recurrence, or a lower risk for recurrence, we would resect first.

Betsy Post 1:18:38
Does Weill Cornell have different criteria for transplant than Columbia?

Dr. Juan Rocca 1:18:45
Not too different. But Columbia just started doing this. I think that they just listed a patient so they’re trying to use the more recent criteria from the transplant trial. We have our own criteria. Our trial has been around since 2021, and we evaluated 35 patients. We transplanted five. So we actually work together. We are under New York Presbyterian we are two different universities, or two different types of faculty under the same hospital system. We work on two protocols together, and we are actually working on a common protocol based on our experience with transplantation and their experience.

Betsy Post 1:19:39
Does the liver regenerate in areas where you receive Y-90?

Dr. Juan Rocca 1:19:44
Not so much. No. The areas that were not affected by Y-90 will regenerate. But the liver areas that receive Y-90 will not. It depends on the doses of Y-90. They are very variable. It depends on some mapping studies to make sure there’s no — dosage chance into the lungs, depending the goal of the of the Y-90 if it is to destroy a specific area of the liver or to give lobar Y-90 like before transplant, to kind of keep the tumor at bay. But lobar Y-90 is very toxic too. So sometimes, if we give the lobar Y-90 too early before transplant, we may have some liver failure. So I think it’s important to understand, at the timing of the transplant, if you have a live donor, it’s a lot easier to really have a good timing and be able to to schedule the Y-90 3 months before transplant, knowing that at that time, if the liver has failure, it can be rescued with a transplant. When you go into the disease donor wait-list, and it’s more unpredictable when the transplant is going to happen so that we can run into liver decompensation or liver failure from the lobar Y-90 that was already beaten up by the chemotherapy too and prior resections, etc.

Betsy Post 1:21:15
Is histotripsy an option for patients with the BRAF mutation, and then, as well, a RAS mutation, such as NRAS or KRAS?

Dr. Juan Rocca 1:21:25
Yes, there’s no contraindication based on mutations for histotripsy. The limitations on histotripsy are certain size of tumors or certain locations where, we may not be able to clean the entire tumor from the liver. But if there’s no other therapy available,I think histotripsy is totally indicated, yeah.

Betsy Post 1:21:55
I just want to make sure.

Dr. Juan Rocca 1:21:56
We do histotripsy in patients that we would not be doing any other therapy because they have disease. We know that the liver disease is the one that really dictates survival. Many patients that present to us with liver metastases, but they have lung metastases, bone metastases, and they are generally doing well, and the liver disease is threatening their survival we do histotripsy on those patients.

Betsy Post 1:22:30
Is it possible if you have a tumor right next to the IVC?

Dr. Juan Rocca 1:22:35
With what technique?

Betsy Post 1:22:37
With histotripsy, sorry.

Dr. Juan Rocca 1:22:39
Yes, yes, the IVC is a big vessel, same as the hepatic veins. We usually anticoagulate for that, because even if the vessel is preserved, the skeleton of the vessel is preserved at the endothelium, which is the the cellular lining that is very delicate on the blood vessels. That one gets destroyed, but the structure remains. So the endothelial lining gets repopulated very quickly. But to prevent clotting, we give anticoagulation. So for the hepatic veins and the IVC, the venacava, it is safe to do it with anticoagulation. For the portal vein,t hough, it’s a bit trickier because the portal vein is a different type of flow. Sometimes despite anticoagulation, we can have clotting on the portal vein. And that’s something you have to be careful about. So lesions are very close to the center of the liver, where there’s a lot of portal branches, we try to avoid them.

Betsy Post 1:23:55
And I apologize if I missed this one. We just have a couple questions left. One is, what is the largest size that can be treated with histotripsy?

Dr. Juan Rocca 1:24:05
In different sessions, you can treat larger lesions. It all depends on the location. And sometimes large lesions, you may be able to access with the ultrasound being an area of the lesion, but the other area is too high, there’s too much lung that doesn’t let you deliver energy. But by six centimeter lesion, if there’s no other good option to treat it, I would try histotripsy. Now we should consider, usually, for lesions that size, we also consider Y-90 because Y-90 is very effective at reducing large size lesions if they are not resectable.

Betsy Post 1:24:47
Let’s see. I think all the liver-related questions are pretty good. I think we’ve got some people saying they’re going to make an appointment with you. I think you had your email on that prior slide, that last slide, so I just want to make sure that as part of the recording, everyone can see that. So if you do have questions specific to your case especially, and you want to seek a consult, this is the email with follow up questions, I feel like we got everything we could.

Dr. Juan Rocca 1:25:25
I’m not very reliable with emails. Some days I’m in the operating room all day, and I get many patients that send me emails. I think it’s probably better to leave an office number, because at least someone can be more accountable for replying, but yes, I can send the office number, and we have a free assistant that usually take all the calls.

Betsy Post 1:25:55
Perfect. If you send that to me, I’ll make sure that everyone gets it. And I appreciate that. I appreciate all of your time. You’ve spent an hour and a half with us tonight, late in the evening, and we are so appreciative. I learned a lot. This was great. I know that the patients and families here tonight got a lot out of this, and I just can’t thank you enough. So thank you so much, and there’s a lot of thank yous in the chat.