Okay, everyone, welcome back. You've come back for part two of this session of Pediatric Liver Cancers from Mechanisms to Treatment. This second section is actually going to focus on novel candidate therapies as well as clinical trials in resistant pediatric liver cancers, as well as highlight some new surgical approaches to challenging pediatric liver tumors. And we're going to really close this session by wrapping up with a very personal story from not only an advocate, but also a parent of a patient diagnosed with hepatoblastoma in HCC. I think for those of us who take care of these high-risk patients, we often don't really understand the goals and expectations that the families have, and so I think that will be very refreshing as we end the program. As before, we will defer all questions for the speakers until the very end. We will have a 20- to 25-minute devoted panel discussion for all of our speakers here. I'm now going to turn it over to our distinguished moderator, Dr. David Kaplan, who will introduce the rest of our speakers. Fantastic. Well, thank you very much for attending this afternoon. Please do make sure you have muted your cell phones in respect for the speakers. Our first speaker today will be Dr. Sanford Simon from Rockefeller University speaking on fibromyalgia or carcinoma, a specific entity with new candidate therapies. Thank you, Dr. Simon. Hi. I'd like to thank the organizers for the invitation and thank all of you for your attention. I'm going to talk about some of our work trying to develop therapeutics for fibromyalgia. I have no financial disclosures, but actually in light of the last statement that you heard, I should mention that I do have a very personal stake in that my daughter has fibromyalgia. So what's known about fibromyalgia is that it's primarily a liver cancer. It mainly affects adolescents and young adults somewhere between five years and 40 years peak detection to 21. It's relatively rare, one in five million in the U.S. It's most usually presented as a large liver tumor with patients having no underlying liver disease not associated with any known risk factors. It goes by a variety of names. I'm not quite sure what the origins are of the different names, but they can be used interchangeably. One note is that it's still coded as a variant of HCC, but I'll show you it has a completely different molecular etiology and pathology and drug response profile. There's no standard of treatment. No systemic chemoimmunotherapies seem to work. It's really the only current management is surgical resection when possible. So it was first identified in 1956 where people saw large enocephalic hepatocyte-like polygonal cells here. They were prominent nucleoli, pale inclusion bodies. These were surrounded by these fibrotic bands or lamellae, which stand in sharp contrast to the adjacent non-transformed tissue. And histopathology is positive for CK7, CD68, but there's no established clear diagnosis with suggestions of many misdiagnoses. When we started working on it, what was not known is whether it's one disease or many, genetically inherited or somatic mutation. So our approach was to collect patient samples that are well-defined as fibromyalar. And we did whole genome analysis, transcriptome analysis, proteomics, and phosphoproteomics. And actually, this is the patient who did the molecular analysis I'm about to tell you about. So from whole genome sequencing, we found that there was very low level of single nucleotide variants anywhere in the DNA. No obvious mutations in any of the known oncogenes. Very low level of structural variants, so no amplifications, indels, inversions. The various callers said there were no deletions, but I'll return to that. In the transcriptome, we compared the transcriptome of the tumor to the adjacent non-transformed tissue. We found over 1,000 transcripts that changed significantly. The pattern of the transcriptome was fairly consistent from patient to patient. It segregated away from the adjacent tissue, so you always saw the tumor was segregated away from the adjacent normal tissue. These changes were completely different from changes seen in other liver tumors. So, for example, when we downloaded the data on hepatocellular carcinoma from the TCGA, pretty much all the hepatocellular carcinoma patients segregated away from the fibromyalar, except for this one I highlighted, who actually turns out to have been misdiagnosed and actually was a fibromyalar patient. We found that there were over a dozen kinases that were upregulated in fibromyalar fairly consistently. For example, Aurora kinase A, the EGF receptor and its whole pathway were upregulated. Percocet, the catalytic subunit of protein kinase A, PAK3. But we saw no mutations in their coding, no mutations in their promoter. So sort of in desperation, we began asking, well, maybe they have alternative splicing going on. Maybe they're using a different exon that are being used. And the way you assess this is that you take all of your RNA reads and you map your RNA reads onto the DNA. So in this case, the DNA is reading from right to left. It's on the negative strand. And you map the reads both in the normal and the tumor. It turns out for all of the oncogenes, everything was normal in the tumor, for all the kinases, with one exception, the catalytic subunit of protein kinase A. When we looked in the tumor, we saw increases in reads at the second, third, fourth exons, increases in reads spanning the exons. Because when you splice two exons together to make the protein, you have reads that span the two. However, we saw no increase of reads here in the first exon. And instead, we saw reads that went upstream about 400,000 base pairs to heat shock protein. And what these results suggested is that we had the normal heat shock protein being made here. We had the normal PRKCA, the catalytic subunit of protein kinase A, which was a mixture of the first exon of the heat shock protein with PRKCA. And when we looked in the tissue and sequenced it, we found that fusion transcript everywhere. When we looked for the protein, if we looked in the adjacent non-transformed tissue, they all had a normal copy of protein kinase A. But in the adjacent tumor, they all had a slower-moving band that we can show was a fusion protein. It was made out of the two together. This was just a correlation. Was this actually driving the tumor? So we used CRISPR-Cas9 to cut the DNA in the livers of mice. And when we did that to form the fusion, we now got tumors that looked to the pathologist like fibromyalgia. And they recapitulated the transcriptome of fibromyalgia. And, in fact, the mice died from the tumor. This doesn't distinguish whether it was actually forming this fusion gene that was driving it, or alternatively, was it the loss of the genes in between when you cut out 400,000 base pairs. So we expressed just this fusion gene by itself, and we found that was sufficient to give us the tumor here in mice. Well, if it was just overexpressing, well, maybe it's the heat shock promoter that's just driving protein kinase A really strong. Maybe that's what's doing it. So what we did is now we just drove PRKCA on its own, but that did not give us any tumors at all. So all of this tells us that this is sufficient to trigger the tumor. All right, so what I've shown you is that fibromyalgia occurs on a genetically clean background. There are very few other mutations, none that are recurrent. There's only one genetic alteration, this 400 kilobase deletion. It encodes a fusion kinase that's sufficient to initiate it. And the transcriptome is different from other tumors. So now the question is how do you proceed therapeutically? To do this, we need test systems. So we tried a few. One was to make organoids from fibromyalgia. And when we made these organoids, we validated them both from the histopathology, but also we validated them. Do they have the continued presence of the fusion oncokinase, the transcript? Do they have the continued presence of the fusion protein there? And then we compared to what extent the transcriptome either increased or decreased for various transcripts and the organoids compared to the adjacent normal. That was one system. The second system was to take tumor samples directly from patients, which we did either by getting a sample from a biopsy at the time of surgery or by doing a needle biopsy and then testing those. And the third approach was to take tumors directly from surgery and implant them in mice and grow patient-derived xenografts. These patient-derived xenografts were validated by a few criteria. One, to what extent did their histopathology recapitulate that of the original tumor? To what extent did they continue to express the fusion oncokinase? To what extent did they continue to express the fusion oncoprotein? And to what extent do different transcripts either increase or decrease here in the patient-derived xenografts compared to the increase or decrease in the tumor? So based on these criteria, we felt comfortable that this was a good model system to go forward with. So our approach was to take these tumors from patient-derived xenografts and either test them directly in the mice when we had something that we thought was really useful or initially for screening, dissociate the cells, separate out the mouse and the tumor cells, and specifically test the human tumor cells for their sensitivity against drugs in vitro. One of the first things we saw is that when we tested drugs that were in use in the clinic, none of them had any effect against these patient-derived xenografts. And we tested a large number of them. First, we did them initially on cells dissociated in vitro. In all cases, we're comparing them. You'll occasionally be able to see a black line here. That's primary human hepatocytes or the adjacent non-transformed tissue. In some cases, we actually went back into the mice where the tumors were growing and tested the drugs there as well. In fact, in this case, serafinib, there's no difference without serafinib whether we test it in vitro or in vivo. This is a small selection of some of the drugs we tested that are in the clinic, and none of them showed any efficacy in vitro or in vivo. So we decided to take a more targeted approach. We had previously shown that a number of different oncogenic pathways were regulating fibromyalgia, the EGF pathway, the Wnt pathway, RRA. So we decided to test each one of these by blocking each one of them. We have systematically blocked all of them, and none of them had any effect on the tumors that were growing in mice nor on the tumors that we've resected from patients. So what are the strategies for fighting fibromyalgia? We could hit the machinery that encodes it. So I mentioned there's a deletion here that results in a fusion oncotranscript. We can block the fusion protein over here. It's a mixture of the two. We can hit the immediate downstream elements activated by it or activate the immune system. So to hit the fusion transcript or hit the fusion protein, we have to know, is it really a valid therapeutic target? The concern is the following. There are a number of cases of cancers where you'll activate, let's say, RAS, you'll initiate a tumor, but the tumor becomes independent of the initiating event. So if you now block RAS, there's no effect. The question is, does DNAJB1 per coca continue to drive fibromyalgia? That's the first question. The second question is, if you knock it down, if you eliminate it, either at the RNA or the protein level, does it just return to being a normal hepatocyte? Which is good. You've stopped the tumor growing, but it's problematic because now you have to continue to treat the patient with a drug, allowing time for mutational escape. Or, in fact, do the cells die when you knock it down? So we initially tried to identify sRNA or shRNA that would hit the fusion transcript. We tiled across the junction, initially expressing the fusion transcript in HUS7 cells, and we identified a few of these shRNA and sRNA that were very effective at knocking down the DNAJB1 per coca but not affecting either of the two parental genes. We then went into fibromyalgia cells and showed that when we induced them, they can knock down the chimera, the DNAJB1 per coca, with no effect on the parental genes. So then what we did is we implanted these into the fibromyalgia tumors in such a way we can induce them with doxycycline. And what we did is we let the tumors start growing, and then we induced the shRNA. And so in these here, which either didn't have the shRNA or we didn't induce, the tumors continued to grow. But if you look down here in red, and we'll sort of enlarge it here, if we allowed the tumor to start growing but then induced the shRNA, in fact, the tumors not only stopped growing, they regressed away. And the few cells that are left here are cells that we can show were not transduced and did not have the shRNA. So this shows that, one, the chimeric transcript does need to continue to drive fibromyalgia, but, two, there's an oncogene addiction. If you get rid of it, the tumor cells die. This is very specific to fibromyalgia in that if we induce this shRNA in a hepatocellular carcinoma cell line, there's no effect. Or actually, in this case, we took an HTC cell line and we put into it this chimera that drives fibromyalgia, DNA J1 percocca, and, again, activated the shRNA, but these cells have not been selected to be oncogenically addicted to it. And, in fact, when you activate it, we can eliminate this chimeric protein, but there's no effect on tumor growth. So for a number of these approaches, we now have success in the lab. We can show success in mice. The problem is these are all new agents. It's going to take time for them to be able to be in the clinic, and people are ill now. So the question is what can be brought into the clinic now? So the approach we took is let's look at drug repurposing. We took our PDX lines, we dissociated the cells, and we screened them against 5,000 drugs. Initially, we screened them against six independently-derived PDXs and compared them against primary human hepatocytes. And it came up with a series of hits here. We're going to zoom in. And some of them were surprising. This is the effect against the fibromyalgia cells compared to the adjacent normal. There are ones that hit marks with chromatin, arenotecin, a topo-1 inhibitor, things that affect cell death pathways. So we tried combining them. So if you have the tumor growing in mice, if you just give arenotecin, you see it stops the growth, although it doesn't regress. If you combine arenotecin with nividoclax, one of those top hits that blocks BCLXL and BCL2, you can see it starts actually regressing back down. But there are two problems. First of all, these are tumors that were selected for growth in mice. It took nine months for them to grow. Maybe we only subselected a small number of cells that grew well in mice. Maybe it's not representative of the patient tumor. And also, nividoclax has adverse effects on platelets. So to address the first question, is it representative of tumors in patients, we started getting cells directly from patient resections and screened them. And as you can see here, some of the patients were sensitive to panobinostat, some highly sensitive. Some were sensitive to arenotecin, some highly sensitive. So they were recapitulating what we had. We would recapitulate the synergism we saw with blocking the anti-apoptotic pathways. So we're going to take this sample from a patient that was one of the least sensitive ones to arenotecin, SN38. And what we did is we incubated with increasing concentrations of nividoclax to block BCLXL and BCL2. And you can see we drove sensitivity down to single-digit nanomole against arenotecin. Now, the problem is nividoclax has adverse effect on platelets. So we worked with a group that's made of ProTac that works against nividoclax, but it does it by targeting E3 ligase, a desubiquitination that's not found in platelets. And we can show this eliminates the BCLXL in our fibromyalar tumors. It doesn't have any adverse effect on platelets over time. Now, if you look at the growth of the tumors in mice just on their own, if we treat them with arenotecin, here you see the population, here's individual mice, arenotecin gives you stable disease. But now if we combine the two of them together, blocking BCLXL and arenotecin, you can see here what looks to me as a non-oncologist as complete regression. So the current status is the DT2216 is currently in testing as a monotherapy for other purposes. We took records from the patient medical registry, and we found three patients who had received arenotecin sort of as an action of last resort, and all three of them had very similar results to what we had in mice. So now we're trying to develop arenotecin and DT216 is sort of an investigational drug for fibromyalar. So why does arenotecin work? It's a TOPA1 inhibitor. It should only work against rapidly growing tumor cells. So arenotecin is made to an active metabolite SN38, which enters the liver cells. Normally in liver cells, there's a group of enzymes that will add a sugar group on it, which is now involved in transporting it out of the cells. It turns out this novel oncokinase we found actually downregulates these quite significantly. So, in fact, the SN38 builds up inside of the cells, which is what makes them sensitive. So in conclusion, this is a tumor that is a somatic mutation. It's a result of a dysregulation protein kinase A. I told you about hundreds of patients who have this deletion, which fuses these two together. It's sufficient to create it. There are some variations. There are three patients who are missing a regulatory subunit for PKA. There are a few patients that have a different first exon fused in. In the Zuckman-Rossi lab, they found mutations in BAP1, which activates protein kinase A, and makes a tumor that looks a bit like fibromyalar. Drugs currently in use in the clinic on fibromyalar have no effect. If you try precision medicine, drugs that hit the oncogenes just have no effect. But from doing a functional screen, we've identified a number of things that show efficacy against fibromyalar on dissociated tumors in mice, on tumors directly from patients, tumors growing in mice, and tumors right in patients. And the efficacy of these drugs can be understood from understanding the biology of the tumor. So I want to thank those who gave us support, funding agencies, both private agencies, who are absolutely essential for kickstarting the work. A variety of individuals have given a lot of support to the work. The members of my lab have completely switched directions to come working on this. And above all, I want to thank the fibromyalar patients. They've really been the vanguard. They've provided tissue samples, blood samples. They've recruited other patients, funding. They've actually been working in the lab, and I owe everything to them. Thank you. Thank you, Dr. Simon. And again, we're going to take questions at the end. Our next speaker is Dr. Greg Chow from Cincinnati Children's, who's going to speak on novel surgical approaches to improve pediatric liver tumor care. Good afternoon. It's a privilege to be here. It's also very hard to follow a talk by Dr. Simon because he's doing things at the precision level, and I'm about to talk to you about something that's a little more blunt, which is surgical options for treating tumors here. But in the next little bit of time here, I'm going to try to give you some thoughts about, you know, the evolution of some of the surgical approaches to more hepatoblastoma focused on, although I do have a slide of a patient who has a pedocellular carcinoma, a fibromyalar. So slides. All right, great. All right, so and to say these are novel surgical procedures, to say liver transplantation is a novel procedure, it really isn't. But then we will touch on one thing towards the end that is a little more innovative that's going on in the field here. So just a couple disclosures. I'm one of the principal investigators for the current international pediatric liver tumor trial in North America. It's called AHIP 1531. I also am working right now with Stryker on the usage of endocyanin green in the pediatric population. So, you know, again, as an overview, we're going to talk about hepatoblastoma. We're going to talk about the role of liver transplantation for locally advanced tumors. That's pretext three and four tumors. We're going to talk a little bit about the management of patients who present with metastatic disease as it ties to transplantation. And then I'm going to touch on ICG here. And so, again, Dr. Simon was talking about fibromyalar HCC, but most common malignant pediatric tumor is hepatoblastoma. Its incidence is rising. It's estimated now it's between 250 and 300 cases a year. And it's thought to be because of the prematurity of kids who are actually surviving the neonatal course and actually developing hepatoblastoma. And there's been huge changes in the treatment algorithm over the last 30 years, where survival back in the 1980s and 90s was pretty limited to now we expect to get 80 to 90 percent of the patients through their course. And so from a standpoint of the trial, when we were working on this international trial, we were trying to develop a collaborative approach between North America and our European colleagues. And in North America, surgeons were oftentimes first asked to address the disease process. And in so doing, definitive resection at diagnosis was often offered as the first intervention. In contrast, our European colleagues focused more on neoadjuvant chemotherapy. It's not only applied to hepatoblastoma, but it's applied to multiple other pediatric tumors. And then after a response or lack thereof, conventional resection or transplant could be offered. But the most crucial intervention to achieve long-term survival in a patient with hepatoblastoma is a resection. There are case reports of patients who've been cured with chemotherapy alone, but otherwise a resection is going to be necessary. Unfortunately, about 50 to 60 percent of the tumors at diagnosis are not resectable, and therein is where the challenge really arose. And this is typically because of the location of the tumors and its relationship to blood vessels, and most importantly, the hepatic veins and the portal vein. And so that's really what governed potential outcomes in the past. And this is where neoadjuvant chemotherapy has evolved pretty dramatically over these last 30 years, to now we can see a significant response. And subsequently, after that chemotherapy, a resection, be it conventional or a transplant, could be offered. And that's one of the, you know, fundamental approaches to this process where a resection is going to have to be achieved. Now, one of the other challenges that we faced when we discussed liver tumors on a kind of an international scope was how to categorize disease. In North America, different surgical teams might have different comfort zones offering a surgical resection. And so in so doing, trying to compare patients amongst different centers and different study groups was difficult. So our European colleagues actually recognized this, and they, back in the 1990s, early 90s, devised a radiographic basis for how to stage tumors. And this is called the pretreatment extent of disease. And in so doing, they actually started to categorize patients into subgroups in which we could then have a common language as to how to approach these patients. And there's four stages. It's really dependent upon the anatomy of the liver. For surgeons, we always kind of have that as part of our backbone. But for some of our colleagues who are a little less focused on liver resections, we break the liver up into four sections of the liver. It's based off caudate cunode segments, where there's a left lateral section, a left medial section here, a right anterior, and a right posterior. And a tumor that is located in just one section of the liver is going to be considered a pretex-1 tumor. In other words, you have three contiguous sectors that are free. A pretex-2 is two contiguous sectors free. Pretex-1 is three. There's only one section of the liver that's free. And a pretex-4 has tumor in all components. On top of it, you have annotation factors that help you kind of gauge the degree of the vascular involvement, be it hepatic veins or portal vein, but then also caudate, extropathic disease, and metastatic disease. The point of bringing this up is this categorization allowed us to start to compare across groups how patients were going to do. So that was one important thing. And the other important thing as it really occurred over the last 20 years is the integration of liver transplantation for hepatoblastoma. Because about 20% of the tumors are not going to respond to chemotherapy to the point that they can be resected by conventional surgery. And so this is where transplantation has been integrated into the process. And this, of course, is an example of a patient who has a pretty impressive tumor, basically encompassing most of his upper abdomen here. And then, of course, another indication is patients with multifocality. So this is the tumors here and here in terms of it. And so, again, the indications for liver transplantation have really evolved, and this is just kind of a laundry list of outcome studies dating back into the early 90s where at the beginning parts of that period of time, outcomes following transplantation weren't so great. But then a series of single center studies came about in which the outcomes were a little more favorable to now both in UNOS and in the split pediatric studies, the outcomes are in the 80% range following liver transplantation. It's still not as good as biliary atresia. It's not as good as the cholestatic diseases. But if you think about it from the other side, these kids, if they don't get a transplant, are not going to survive. And so, again, from a standpoint of outcomes, we kind of look at it in that fashion. And it's become integrated into all of our treatment regimens in a way so that hepatoblastoma is actually tracked by UNOS as a subgroup in terms of outcomes. And here, again, you can see the cholestatic disorders are up here, but then the hepatoblastoma is in the 80, 85% range in terms of survival. And so it's an integral part of the process. And the current recommendations for transplant is multifocal pretex-4s or a large solitary pretex-4 and unifocal pretex-3s. And so, again, one of the other things that happened during this evolution was a trial that was run by COG called AHEP0731 in which the surgical team came up with recommendations for how to approach these patients. And the idea behind that was in the past, patients might get a resection at diagnosis, but then they might also get a series of chemotherapy treatments before they were actually determined as to resection or transplant. And sometimes teams would go to really extensive amounts. So the goal was to actually refer these patients into centers with expertise to do resections at earlier points in times or make the assessment for it and to get them on to transplant if it became necessary. And so how did that impact the outcomes? So this is one of the study main results that just got published this year by Howard Katzenstein. It was a study for the intermediate risk group in which these are patients with pretex-3 and 4 tumors that were not amenable to resection at diagnosis. And you can actually see that the event-free survival was up to 85 or 89% and overall survival was 94%. So it was a home run in the sense of patients actually getting chemotherapy, going on to resection or transplant and having really great outcomes. So that seems like a great thing, but then when we started to do the analysis and these studies are just starting to come to fruition here now, when they looked at the surgical guidelines, which was to get these patients into a center at a timely fashion, it was successful. But then when we actually looked at the patients who got transplanted, there were 33 patients in the study who got transplanted out of 104 or out of about 120, of which nine patients had smaller tumors, post-tex-2 and post-tex-3. So that's after cycles of chemotherapy, who upon a central review, which we contributed to in terms of a post hoc central review of all the imaging, were potentially resectable. And so the benefits of getting these patients into centers with more expertise was there in terms of improving survival, but we were actually offering transplant a little bit more frequently to patients who potentially didn't need it. And this is actually also a study from the SPLIT group in which they combined 144 patients in the SPLIT registry. Julia Boester, who's in the audience here, did a lot of work to get this paper done. But when we went back and looked at the patients who actually got transplanted, again, similar to the AHEP prospectively collected data, from a retrospective standpoint, there were 20-odd patients who actually got transplanted who were potentially resectable. So the point of that was transplantation was integrated into the care algorithm in an effective fashion, but the end result was patients who might not need transplanted actually could end up getting transplanted because depending on how that center approaches patients, they ran into that challenge. And here's a case that arose from our center, which was that diagnosis, this patient had a pretty impressive tumor, a pre-tex-3, the portal vein was completely distorted so it was difficult to see. But with chemotherapy, that patient's tumor shrunk substantially. So at diagnosis, this patient was likely to be referred to a center with expertise to do liver transplantation or resection. But then over time, subsequently after four cycles of chemo, this patient became amenable to a straightforward conventional resection. So the point of that is about 60% of tumors that are advanced at diagnosis will respond to chemotherapy in a way that they downstage and they don't require transplantation. And so this is where, as people are focused on liver disease, if you're running a transplant program, you want to be sensitive to that balance because a patient who might've come into your system who was being assessed for transplant may actually respond to chemotherapy significantly. And so this is the challenge that we now face, which is who's the right candidate to consider for liver transplantations? And it really does start with the characteristics and the burden of disease at diagnosis, but then it translates or subsequent decision-making is based off the tumor biology and the treatment efficacy from a response. And of course, as we all know, the consequences of utilizing transplantation are lifelong immunosuppression and it's utilizing a scarce resource. So what does that translate to in terms of a diagnosis and initial phase treatment? We don't want to transplant patients excessively, but then we have other patients just who represent the exact opposite, which is patients who present with metastatic disease, which oftentimes cause teams to be cautious. So again, I'll use a case that we had in our institution where a patient presented with a pretext for disease, portal vein tumor, multifocality, metastatic disease. So you can see the multifocality here, this giant tumor here, the portal vein was thrombosed. And of course she had giant metastatic lesions. And so we knew this patient was going to face a challenging course, but transplant was in all likelihood going to become necessary. So as we were devising the current trial, one of the studies had come out just a few years before as we were working on, it was a CYOPEL4 study. And it was a pilot study of phase two trial in which they looked at 39 patients with metastatic disease, where they had 70 patients overall in the study. It was pretext three and four disease patients. But when we looked at the patient's metastatic disease, there were 20 patients who had metastatic disease that completely cleared with chemotherapy. In contrast, there were 19 who didn't with that first induction phase of chemotherapy, and the outcome differences were pretty dramatic. And so with that, we ended up devising this in terms of the liver of the current trial. I'm actually presenting these slides because one of my own hepatologists was saying, you know, you guys oftentimes, I would just defer to you and Dr. Geller, one of the other oncologists, who's the other PI for this study as to how to decide things. But I thought it might be helpful for the audience to see the thought process behind the oncologist and surgeons who are getting the patients to decide upon transplantation. And so this is the actual surgical treatment schema for patients who present with metastatic disease. And this is a CYPEL4 regimen, where there's three blocks of intense induction chemotherapy. It's dose-intense cisplatinum with doxorubicin intermixed, followed by a consolidation regimen after resection has ideally been achieved. And so what we ended up doing is there's a group of patients whose METs clear with induction chemotherapy. So the patients get these three blocks of chemotherapy, and if they actually clear their disease, this is, we broke this up into two different pathways for teams to kind of pay attention to. Scenario one is patients who are gonna go on to a conventional resection. So their metastatic disease clears, they get a conventional resection, they end up getting three blocks of consolidation chemotherapy, and ideally they have a favorable outcome. In contrast, if patients who require liver transplant, they get referred to a transplant center during this induction phase, or if it's your own center, then you're ideally getting the patient listed for transplant around this period, and then they're getting their transplant someplace during the consolidation regimen, and they end up ideally validating the outcome from CYPEL4 in terms of favorable outcomes. In contrast, this was a much more complicated schema for people to first kind of reconcile here. But this is for patients who do not clear their metastatic disease with chemotherapy. And this is where these patients then are integrated in where they get pulmonary metastectomies, surgical resection of remnant disease, and then an extended block of chemotherapy on the backside, a consolidation regimen during which you can complete your metastectomies and ideally offer liver transplantation. And what we're trying to do is improve on those outcomes in those patients who did not clear disease. So just as a case in point, this was that patient here who after two blocks of the induction chemotherapy still had a pretty giant MET, had metastatic disease, multifocality, and was still gonna require transplant. So we actually offered resection a little bit earlier here to clear that patient. This was that disease burden. And so this was the actual clinical course just to kind of lay out the description of how the different combinations of surgery, both metastectomy and transplant was necessary. So the patient had the CYPEL4 induction regimen, had a very favorable response from an AFP standpoint. We explored her right chest, and I'm gonna show you what we used in a second here with ICG. I'm gonna run out of time here, but I'll show some of those slides real quick. Then the patient went on to receive the third block of chemotherapy, and then we went into her left chest, and she still had disease burden. So she got another block of chemotherapy. We went back into the right chest to make sure there was nothing left. There was still a lesion that was positive, but we were able to clear it. And at that point in time, we called her a surgical cleared of metastatic disease. We went ahead and listed that on patient for transplant. We took her to the OR with a graft after the second cycle of consolidation regimen, and we opened and we found the changes that were suspicious for peritoneal, for tumor rupture at diagnosis. So we actually had to biopsy those lesions. We backed away from the transplant. The lesions turned out to be negative. We relisted the patient, and she got transplanted after the third block of chemotherapy, I mean, the third block of the consolidation regimen, then went on to, had a very routine recovery from her transplant, and then went on for VI maintenance, and her AFP normalized. Two years later, that patient relapsed. We cleared a lung met. Another year, a few months later, she relapsed again. We cleared that. She got another cycle of chemotherapy, six cycles of chemotherapy, and she's now 42 months out from transplant. So this is the surgical approach to a very complicated patient, but she's alive here today and able to go to school. So all of that translates to a combination of both surgery and chemotherapy, and an effort to try to get these patients to a remission. But in the end, this is all going to go back to tumor biology, because all the stuff that Dr. Simon was showing in terms of the elegant work that he was showing from a treatment standpoint, we actually have to do the same thing for a pateblastoma. Because what we know is patients who have favorable responses to chemotherapy with a drop in AFP, radiographic imaging, those patients are going to do well if they get conventional surgery or if they get a transplant. But patients who do not, those are the more challenging patients that we still have to reconcile moving forward. And just in the last few seconds here, I'm just going to flash through some things here. The trial is open now. We're up to, these are the 440 patients who are enrolled from North America. All across the study, both Europe and Japan, we're up to 900 patients. The study is coming to an end, of which one of the integral parts of that study is to do molecular profiling of all these tumors in a way so that ideally, in a few years, we'll be able to present to an audience like this strategies that are as innovative as what Dr. Simon was showing just a second ago. And the very last thing is, because we were going to talk a little bit about, because the request was for some novel surgical approaches, transplant's not exactly novel, but one of the things that has been integrated into the treatment armamentarium for people who are taking care of pateblastoma is endocyanin green. Endocyanin green is an agent that's been around since the 50s. It was first developed to assess liver function after treatment, but it's an agent that can be given. It's very well-tolerated. It has very little risk from a standpoint of allergic reactions. But one of the nice things is it's taken up by hepatocytes and then excreted in the biliary system. And so one of the things you can do with this is there's detection devices have been developed. I give credit to our Japanese colleagues because they're the first ones who recognized its role in liver tumors. But what you can actually do is you give endocyanin green, and then you have this ability, this is a striker equipment, but this is where they actually superimpose the imaging appearance or the acquisition of the fluorescence as to where nodules are. And so this is actually being utilized to try to improve the clearance of patients with disease. So this is a patient who had a metastectomy here. We would have seen this grossly with a surgical procedure, but with ICG you see it lit up that much easier to find it. It's been particularly helpful in patients with miliary disease, where we actually have cleared patients with between 30 and 40 lung mets with this process where we're not actually even seeing or feeling them, but we can actually detect them with ICG. This is an example of a patient with a fibromyalgia ACC in which also took up the agent here. And you can see there is multifocality in the liver, but also there was lesions on the diaphragm and into the mediastinum. By having ICG, we were actually able to resect all of the additional disease that we may not have seen grossly. We were actually also able to do a celiac node dissection to identify additional disease, which we generally will do for fibromyalgias, but this was targeted with the ICG. And then when we were done, we're able to look at the cut surface for any kind of remnant ICG detection. And right now I'm just using the green superimposed value, but the actual detection is a black and white, and you can actually see white spots if there's remnant disease. And so we actually first used some of this technology on a patient with relapsed hepatoblastoma who was having a rising AFP and we couldn't find a source. So we actually, he had been biopsied through his chest early on in his course. And so after his AFP had hit 200, we went into his chest and we found a lesion here that I think I would have seen no matter what. But then interestingly, when we scanned his chest in his pericardial fat pad, he had two additional ICG Abbott spots, which were actually hepatoblastoma. And so again, this patient who is a relapse is now seven years out from this process in remission. And so again, it's a technology that has been integrated into the treatment process. And I'm just gonna skip through these things here and finish since I'm way over time. So anyways, it's a privilege to be here and I will turn it over to Dr. O'Neill. Thank you, Dr. Yao. Our next speaker is Allison O'Neill from Harvard. Dr. O'Neill will be presenting clinical trials in resistant liver cancer. Remind me what I need to do to. Sandy did it for me. I'm sorry. Okay, great. So hi everybody, it's a pleasure to be here today and thank you for the opportunity to present on this topic, clinical trials in resistant pediatric liver cancers. My disclosures are as follows. So I'll talk a little bit about relapse and resistance in both hepatoblastoma and hepatocellular carcinoma. You heard from Greg that both are very, very rare diseases in the pediatric population. Hepatoblastoma occurring at roughly 200 to 300 cases a year. Hepatocellular carcinoma of the conventional subtype that looks under the microscope a little bit more like we see in adults, occurs about 50 to 75 cases a year in the US and I'm talking US stats. Very rare diseases as we know. And the bulk of what we know about relapse and resistance is in hepatoblastoma as opposed to HCC. But we also know is that the outcomes for HCC are so unbelievably poor when patients present with advanced disease. In truth, they're very difficult to cure. Many of you may be familiar with this hybrid entity, hepatocellular neoplasm not otherwise specified that Kalyani mentioned in the last session. This is really a hybrid entity between the two. Tends to occur in older patients, often greater than eight years of age. Tends to have entities of morphology of both hepatoblastoma and HCC and or a hybrid morphology in the cells. But those patients also tend to do quite poorly. They may respond to chemotherapy up front but ultimately disease tends to return and it's truly biology driven and different from what we see in hepatoblastoma. So what then do we know about incidence? Well, the incidence is all over the map, as you can see. If you look at publications, it's noted anywhere from six to 50%. There are probably two major publications that outline this best. And what we know is that incidence largely depends upon risk categorization and diagnosis. If you look at the European literature, there's one article that encompasses treatment of patients on SaPEL one through three, three separate trials and about a cohort of 600 patients total. About 10% of those relapsed or progressed, 52% achieved remission, but you can see that the EFS and OS is quite poor regardless. If you look at COG-A-HEPO731, that's the Children's Oncology Group trial that Greg referenced that preceded the one currently running. You can also see that the incidence of relapse or progression tracks fairly closely with the stage or the burden of disease or the resectability of patients up front. So the lower risk patients had a lower rate of relapse or progression and obviously that tracked up as you got to the higher risk patients. That also tracks in terms of outcome. So needless to say, successive salvage is fairly poor, particularly for the higher risk kids. And if we're talking about HCNNOS or HCC, the salvage is extraordinarily poor if we can even get them into a first remission. So what are prerequisites for cure? Well, of course, eradication of all disease sites and that undoubtedly requires a combination of systemic therapy and local control. The majority of patients see cisplatin up front. It's our backbone therapy, it's the best drug we have. And we know it's very efficacious for hepatoblastoma. A fraction of patients with higher risk disease of diagnosis also have already seen doxorubicin. So we're walking into relapse with patients who have already seen two of our best drugs. So what's available in the literature with regards to therapies that work? Well, there's a decent amount of literature on doxorubicin for patients who haven't previously received it, of course. So if they've mostly gotten cisplatin monotherapy, use of doxorubicin in the relapse setting is very efficacious. And you've seen documented response rates up to a third. Cisplatin for patients who have received a low cumulative dose in the past or who have been minimally affected by endorgan damage, i.e. ototoxicity or renal toxicity, are candidates for cisplatin reintroduction. And we found that for patients who previously responded, they do tend to respond again. But of course, you're dealing with endorgan damage and cumulative toxicity as the dose increases. And again, these aren't always used alone. They're often used in combination with other agents. There have been a few other successes that you can see here, ifosfamide being one, traditionally given in combination with carboplatin etoposide. Carboplatin, in a European publication, cited a 50% durable remission. And I think many of us have found great success when utilizing carboplatin in combination with etoposide. And then the topoisomerase category has been quite successful. I think we have the most data on arenatequin as a single agent or in combination with other therapies. You heard from Greg that, you know, folks use vincristine arenatequin as maintenance therapy in relapse patients. And we know it works. But it tends to work in the patients that have maybe a solitary lung nodule that you can resect. It doesn't work for the bulk recurrent patients or those that progress through upfront therapy. There have been a lot of disappointments. So I'll call your attention to these two papers. The first is listed here, published in 2012. And the second was a follow-up study in 2019, both published by Angela Tribolotario and Jim Fusner, who have done an exceptional amount of work looking through all of the literature for relapse therapies. Among the unfortunate disappointments, methotrexate, docetaxel, oxaloplatin. Folks have tried high-dose chemotherapy with stem cell rescue. The literature is very varied. People get the utilization of upfront kind of chemotherapy or high-dose chemotherapy prior to stem cell rescue is very variable. But overall, it doesn't seem to be that efficacious. Radiotherapy and interventional modalities, while seemingly successful, have been published in really small cohorts. So it's a little hard to derive patterns for which they should be used. But we know that they work. The question is, can they work for a patient with metastatic disease? They're local control modalities, and we need to depend on both local control and systemic therapy in most cases. And then targeted therapies. Hepatoblastoma patients have been enrolled here and there on clinical trials for pediatric patients. The definition of relapse or refractory disease varies substantially between these trials. Often the trials exclude children less than a year of age. And of course, hepatoblastoma occurs in a young age group. A lot of the drugs do not have liquid formularies. So young kids can't take them. And then we noticed limited enrollments for whatever reason. And maybe it's because we're prioritizing chemotherapeutic modalities, and we never get to the point of having end organ function enough to enroll on a clinical trial. The largest enrolling trials have looked at oxaloplatin and 6-etuximab, which is an IGF-1R inhibitor. Neither yielded appreciable responses. And they each enrolled about 10 patients with relapse or refractory hepatoblastoma apiece. So then where do we go from here? And born from this frustration and the lack of literature is the Relieve Registry, which I'll talk you through briefly. Greg had mentioned AHEP 1531, which is the FIT trial currently running through Children's Oncology Group. We went through an exercise to say, if we're gonna enroll these number of patients on each of the strata, and we know generally what we think their EFS will be, how many patients might we predict would recur? And it turns out quite a bit. And you can of course see what predictions are higher for the higher risk patients based on historical outcomes. And hopefully we're doing better with this trial, but these are based on historical data. And then of course, in the HCC category, we anticipate a lot recurring. But we said to ourselves, how can we collect data now to better inform what we should propose for these patients going forward? So born from that was the Relieve Registry. And the global PI is Mark Ansari, who's a pediatric hematologist oncologist out of Geneva, Switzerland. This is designed to have scientific chairs in each of the continents to collect data from over 50 institutions spanning four continents, all to get granular data on relapse, refractory, pateblastoma, or patecellular carcinoma. The dots kind of indicate the clusters of sites that are most engaged currently, but we're always looking for additional sites to get involved. This will be the largest cohort of patients granted retrospective collection of data, but I think we'll be able to derive meaningful outcomes, or I hope we will, to inform the next trial. In the U.S., we operationalized collection of that data in something called the Liver Tumors Research Consortium. It was founded between myself and Jim Geller from Cincinnati, and our goal here was really to house retrospective and prospective data. We piloted the relief, the collection of relief registry data retrospectively, and our goal independently is to run prospective registries, Jim for relapsed hepatoblastoma and myself for pediatric HCC in concert with the Broad Institute up in Boston, and really to support subspecialty projects going forward. We recognize these are rare diseases and we have to work together, and our goal here was to kind of unify efforts within the U.S. So now that you have this background, let's pivot next to novel therapies, and I wanted to talk about them in terms of three large categories, chemotherapy, targeted agents, and immunotherapeutics. I'll start with chemotherapeutics, and I'm going to walk you through what trials are available or are soon to be available. The first is kind of contingent on the fact that for some patients, cisplatin reintroduction works. And the question is, is it a factor of, quote-unquote, cisplatin insufficiency, and I think that was a phrase coined by Jim Geller from Cincinnati. But the thought is, you know, are there patients in whom more cisplatin can work? So this trial intends to enroll patients to receive additional cisplatin monotherapy if they previously were cisplatin responsive, and or to receive cisplatin in combination with HDAC inhibition, the combination of which is perceived to perhaps increase the efficacy of cisplatin for patients who were previously cisplatin unresponsive. As I mentioned, Jim Geller is the PI from Cincinnati. The participating sites are Cincinnati, UCSF, and Dana-Farber. This is pending activation. And one interesting addition is that the trial intends to include use of sodium thiosulfate, so an odor protectant that essentially is a cisplatin chelator that, as many of you may know, has been studied in the context of standard risk of hepatoblastoma and was the focus of a publication in New England Journal for those patients that were treated on a CyA-PLUS trial. It hasn't yet been studied in the relapse setting. It hasn't been studied adequately in the high-risk setting, but this certainly will lend some more information to tell us whether we can further protect hearing in the context of giving more cisplatin. When we pivot to targeted agents, I want to talk briefly about tegavivant. This drug binds TBL1. So you heard in the prior session that beta-catenin is a driving factor in over 90 percent of these tumors. Nuclear beta-catenin typically binds TBL1. This protects beta-catenin from ubiquitination and degradation, such that it can drive transcription in these tumors. Tegavivant binds TBL1, thereby freeing beta-catenin and allowing it to get degraded. So in theory, it should work well for beta-catenin-driven tumors. This trial is the PI for this trial is Sarah Whittle out of Texas Children's, and the participating sites are through Children's Oncology Group, through the PEPCTN network. It's enrolling not only hepatoblastoma, but diseases that are reliant upon beta-catenin outside of liver. But thankfully, liver kind of is front and center in terms of this trial, and hopefully we can learn more about these patients that do enroll. In the category of targeted agents, I wanted to touch briefly on Allerin 6924. This is a dual MDM2-MDMX inhibitor. MDM2-MDMX typically binds to wild-type P53 and kind of interferes with its function. This Allerin compound is a staple peptide that's permeable and binds to MDM2-MDMX, and then effectively releases wild-type P53, which can better protect the cells and allow the cells to protect themselves from DNA damage. The reason that I bring this up is there is some preclinical data generated by Sanjeev Vesdevadin's lab in Texas Children's that shows that higher-risk hepatoblastoma tumors are dependent on this pathway. So they, too, are getting enrolled and have a cohort on this trial. This trial is PI'd by Dave Schulman from Dana-Farber. You can see the participating sites, and it, too, is open and enrolling. And what about future targets? Well, we know that NFE2L2, that we know that mutations in NFE2L2 have been associated with an increased risk for metastasis, vascular invasion, adverse prognostic signatures, and just adverse prognosis in general. It's also linked to expression of NQ01, but it's not currently targetable, unfortunately. We know that TIRR promoter mutations tend to appear in HCNNOS tumors and also in PD hepatocellular carcinoma tumors, again, not perfectly targetable. And RAS mutations, ARID1A mutations, there are a host of others that are creeping up in genomic signatures for patients that don't tend to respond upfront to therapy in the way we'd expect them to, but we don't perfectly have a means by which to target them, but perhaps in the future. And I'll pivot in the last few minutes to immunotherapeutics. I had mentioned, of course, the beta-catenin pathway, but GPC3 is a protein that complexes with THWNT and then, in doing so, kind of supports the beta-catenin pathway in both hepatoblastomas and hepatocellular carcinomas. Thankfully, GPC3 is not expressed in healthy liver cells, so it is pretty specific to tumor cells. And so there have been a number of groups looking to target GPC3, and I'll walk you through the trials that exist here as well. So codratuzumab is an anti-GPC3 antibody. The goal here is to enroll patients who are GPC3-dependent or express GPC3, which include other tumors like germ cell tumors, Wilms tumor, rhabdomyosarcoma, but of course also liver. MycRT is from Memorial Sloan-Kettering as a PI. The participating sites you can see here, and this, too, is open and enrolling. Pivoting even further to cellular therapeutics, Andres Hexi and the group of Texas Children's have been working on CAR-Ts targeting GPC3 for some time. Their first generation CAR-T was not armored, it was simply a singular target, and then they moved on to their second phase trial, which is now open and enrolling, which is an interleukin-15-armored GPC3 chimeric antigen receptor expressed in T cells targeting GPC3. This is a single site because it's kind of a niche entity. Their lab really created these CARs, and so patients do need to travel to receive therapy here. But he certainly has shown some promising results thus far, and I think now it's balancing promise with toxicity. This has been open and enrolling for some time, and he's really done incredible work down there in Texas. I recently had the opportunity to launch a trial with Eureka Therapeutics, and this is a TCR mimic that is targeting AFP-bound HLA-E2 using GPC3 as a costimulatory domain. So many of you may be familiar with AFP. It's a protein that's secreted in the bloodstream by all hepatoblastomas and about two-thirds of pediatric HCCs, and certainly HCNNOS patients. So the goal here was to target AFP, as you may know, is an internal protein, so we need to kind of wait for a portion of the protein or a peptide to be bound to HLA-E2 and present it on the cell surface such that a targeted antibody can reach it. Oops, sorry. And so the goal here is to utilize that AFP-bound peptide with GPC3 as a costimulatory domain. This trial is enrolling hepatoblastoma, HCNNOS, and hepatocellular carcinoma patients who are in relapse or progression. Currently we're single-site, but our goal is to expand to additional sites once we're at the expansion phase and once we have a dose. And in the last minute, relapse to hepatocellular carcinoma, I mentioned that everything I've discussed thus far predominantly centered on hepatoblastoma, for which we have so much more data, and because HCC is so rare, it's been difficult to really understand the genomics that drive these tumors and the disease characteristics. The fact that they're now enrolled on the COG trial, the international COG trial, means we're going to learn a tremendous amount more from these patients. And by HCC, what I'm talking about now is conventional HCC. But this paper came out in 2018 by Viola Wieda, and she looked through every single targeted agent that had been utilized at the time for adult patients that could potentially be repurposed towards pediatrics. We now know that in the adult world, checkpoint inhibition with VEGF inhibition is really the mainstay of therapy. But unfortunately, as came up in the last session, checkpoint inhibition hasn't been widely adopted in pediatrics because of the low somatic mutation rates and the fact that patients don't traditionally respond. So the question is, is there a pocket for PDHCC that may respond better? Because these tumors are much more genomically dysregulated. They have a higher mutational burden. And in keeping, we have enrolled we've started enrolling patients, actually it's been quite a while, COVID kind of interrupted enrollments, but we have an open and enrolling checkpoint inhibitor trial in pediatric HC and NOS and HCC, with again multiple participating sites. The armored CAR-T that I mentioned that Andras Heksy's group has been working on, likewise is available for HCC patients as is the AFP targeted TCR mimic. And you heard from Sandy Simon, a fantastic talk regarding fibromyalgia carcinoma. I think this one slide that I aim to incorporate is really to say that we know it's a unique entity. It's not conventional HCC. We are enrolling those patients on the current FIT trial for upfront care. They are eligible to enroll in the checkpoint inhibitor trial for relapse care. And there are a number of other trials that are enrolling a vaccine targeting the Chimera plus dual checkpoint inhibition by Mark Yautrin and Johns Hopkins, 5-FU interferon plus or minus checkpoint inhibition by Dr. Lee at Texas at MD Anderson. And our goal is really to try and push through a pilot design through COG and the PEPCTN group, such that we can recognize this rare disease, and then we can work together in a collaborative network, because that's what we really need to do to engage as many sites as possible, given that these patients are so rarely diagnosed. And they're diagnosed throughout the U.S. They can't all go to one place. And so the hope is that as we continue to organize COG to recognize even rarer disease subsets and perhaps kind of organize ourselves around their study that we'll be able to enroll more patients and learn more. So my takeaways are as follows. As you can gather, a collaborative approach is really, really warranted. I mean, these are rare tumors. It's really the only way we can study them, learn from them, and make progress. I think the registries will be informative. I think deep dive genomic profiling these tumors at diagnosis and at relapse is necessary. Drug screens, I mean, you heard from Sandy up front, are exceptional in terms of high throughput analyses. We depend a little bit on the in vitro and in vivo models, and that's challenging in hepatoblastoma in particular and conventional HCC. But we've also established clinical trial networks. You notice that the enrolling sites, it's the same sites. So we've really managed to kind of target sites throughout the U.S. that can enroll patients to hopefully increase the efficiency with which we study new agents. And of course, the FIT trial, the AHIP 1531 COG trial, will likely be informative in terms of patient characteristics for HCC relapse patterns. Can it set the stage for the second international trial, which we hope to proceed with as a successor trial? I hope so, such that we can make more progress here. So I wanted to thank all of the consortia with whom we collaborate on a regular basis, my own institution, patients and families, and my colleagues. Thanks so much. Thank you, Dr. O'Neill. Our final speaker in this session is Julie Chessel, who will be talking about pediatric liver cancer from a patient advocate perspective, and the title, Patient Advocacy, Expectations from Patients and Families. Thank you. Well, thank you. Thank you so much. It's really amazing to be here with you all. And as you know, I'm a parent of a hepatoblastoma and HCC survivor. So I want to thank Dr. Leung and the AASLD for having this voice here. It's really important to have that patient perspective, the parental perspective, especially when you're looking at clinical trials, when you're looking at novel therapies. It's really important. So I want to introduce myself. As I said, I'm Julie. And I just want to start with this quote, faith is the ability to see the invisible, believe in the incredible. And that is what enables believers to receive what the masses think is impossible. So you all are our faith. You doing all of your research and your trials and having that clinical aspect is really what gives us hope and belief. So there I am in a gown at one of my gallows that I've been to. So I speak all over. I'm a mindset coach. And I'm also one of my biggest roles, not only of a mom, but I'm a nurse. And that brings a little bit different perspective to the game. I'm 23 years as a nurse. And I have been on the surgical floors. I've been in the operating room. And recently, for the last 12 years, I am a team leader in a maternity labor and delivery and NICU unit. So these are my boys. This is Rhett, Brock, and Carter. So Carter's 18. He's in college. Brocker is my cancer boy. And then this is my youngest. I also have a website called Warrior Mama. So I'm kind of known as Warrior Mama. But as parents or as moms, we all are warriors. For our kids who have cancer, their parents are warriors as well as the kids. So I want to draw your attention to this slide. So what does time mean to you? What would time mean to a parent whose child is diagnosed with cancer? So it could be maybe for you a certain event. Maybe it's a specific day of the week. Maybe it's a moment in time. Maybe it's an experience or a memory. But for a parent with a child who has cancer, time is everything. You remember that time when your child was told they have cancer. You remember that time when they started chemotherapy. You remember the date. You remember if they had surgery and how it went. So time is really important to parents. And that's what you do. You give us time. You give us, hopefully, as much time as we can. Okay, so this is going to be a little unconventional. What I want everyone to do, if you can, is just look at that stairwell. Hold it in your mind for a little while, okay? Look at that. And now I want you all to close your eyes, but keep that picture of that stairwell. So this long, seemingly endless staircase is what having a child with cancer is like. It all starts at the bottom of the stairs, with your ears ringing from the echo of the words, your child has cancer. It bounces off the walls of that narrow staircase, and the echo hits you. Then you climb. Your climb begins. Looking up from that first step, it's a dizzy, unbalanced feeling. How will we ever get to the top? You look down at your child, and you do what any parent would do. You hold their hand, and up you climb. With all the adrenaline surging through you, you make that fight-or-flight response to tear the beast down that we call cancer that's attacking your baby. The first flight of stairs, meh, maybe isn't so bad. Or at least you don't have time to really stop and notice. You must keep climbing, and that's all you can do. There is no time to stop and rest. There's not a time limit on this upward journey, and you're not willing to find out what the cost of stopping may be. Now you're many stories up in that stairwell. At this point, reality is setting in. You now take more notice that you are not alone on this climb. There are other children and parents making the same climb as you. They're holding their loved one close, just like you. Some are a few steps ahead, or maybe behind you. Some are stories above you, while others are just making that first step. No matter how strong you are, you're tired, physically and mentally drained. There are no elevators to get to the top, so up you climb. There's hope at the top. The promise that if you can just get them up there, they may live. There's no stopping either. Once you start that climb, if you ever want to get to the top, you don't stop. So that means those tired legs attached to the hand you've been grasping onto need help. That's when you encourage them to keep climbing. Through the tears, through the screams of their tired little bodies, you keep putting one foot in front of the other. At some point, you take notice of the amount of people on this climb, or passing you on the way back down. You may not let your mind wander to the time when that will be you, or could be you and your child. It hits you like a punch in the gut. Some of them are walking down, alone. Their arms are empty. You hold your child closer. You kiss them and hug their fragile and frail little body, and hope that you can get them to the top before they wither away in front of your eyes. The worst part of all this, even if you can get them all the way to the top, there's no promise that it's the end. That they will ever have to do this climb again. That you will have to climb with them. And that stairwell is full. It's full of exhausted patients on every level. It echoes with the sound of both pain and joy, and it's not a guaranteed one-time climb. Some will make it to the top, only to be told halfway back down that they need to start climbing again. This is what having a child with cancer is like. A steady stream of support people and patients moving in both directions. It's a congested stairwell in a tall, dark, very old building, with all these families climbing every hour of every day. And no one on the outside of the brick and mortar walls sees you, unless they happen to pass by one of the very few windows along the way. Okay, you can open your eyes. You know, as parents, we all are parents here, we guilt ourselves, right? Oh, they didn't get good marks, or oh, I didn't pick up the right bag of chips, as Brock would say. But as a cancer parent, we say to ourselves, how did I miss this? As a clinician, how did I not see this? I'm supposed to be the one that picks up on these things. I'm the parent, their protector. When my middle son, Brock, was diagnosed with Pretex-4 with metastases, we mandated a theme within our little family and broached it very matter-of-fact. We said cancer eats negativity and hates positivity. We broached this every day. And this is how our mindset changed. Brock ultimately had multiple rounds of failed chemotherapy, and then transplant. But I'm happy to say that he's still with us and in remission. So let's talk about mindset. So mindset can be defined as a set of beliefs that determines one's actions, attitude, and mental strength. This is what Brock wrote on his whiteboard at SickKids in Toronto, so I'm from Canada. This is what he wrote and didn't have any preemptive. I found this as I came back into his room. So my goal is to set a new record for fastest time out of the hospital after a transplant. I, Brock, will be out of the hospital on Saturday morning. He had his transplant on a Wednesday morning. And nobody can stop me. Number seven, hashtag strong, cancer-free, cancer survivor, and then he swore a little bit there. Nobody can beat me. So when Brock was diagnosed, he was actually playing AAA hockey. So that is the highest level of hockey that you can get in Canada. And when I saw him that day getting into the shower and he was so skinny, he had just signed his contract. And we thought we were going into the family doctor's office for maybe some protein shakes, maybe a dietician consult. He was a picky eater, a boy. He was 12 years old. But what we came out with was Hepato and HCC. So communication was really vital for Brock. As a patient and for parents, to allow as much honesty and truth into playing with decisions. This fundamentally was the only control Brock had. When Brock was first diagnosed, the transition into the introduction of his newfound world was delivered in a manner that was calm and portrayed a level that he understood. To most of all of us healthcare professionals, the term we often hear is we're dumbing it down or use your words like a lay person. There was always dialogue about his interests to ease his mind and initiate that really formidable bond with his oncologist and team. That carried so much weight with him. And if you can remember that as clinicians, just take a little piece of what you know about those kids and integrate it into their clinic visit or to say, hello, so-and-so is playing hockey or what do you like today? That carries so much weight with patients. As a patient, making the effort to let them make choices about their bodies is instrumental. Not all the time would Brock get his way or his choice in the matter, but it was validating that communication. As a patient and allows children to be a participant in their own care. Patient-centered communication is vital not only for the medical team, but for all of us involved, whether that may be the patient themselves or the parent that is accompanying their child. When I think of patient-centered care, three components come to mind, not only as a parent, but as a practicing healthcare professional. The first element is critical in eliciting an understanding of patients' perspectives, which may include their concerns, expectations, needs, and certainly feelings. The second is it needs to be understood between all partners that they have their own cultural context, their own unique psychosocial issues. This information also falls to the patient to communicate their beliefs and limitations. The third important component is to have a shared understanding of the patient's problems and treatments so that they can coordinate and adhere to treatment. So communication is key. Although not all patients are 100% satisfied, but whether it's factors related to wait times, how the patient is feeling that day, outside stressors, relaying information in patient-centered mindness allows all participants to have a positive session. Eye contact is really important. Listening attentively is key, and nonverbal cues lead to great communication and understanding. Sometimes it's as simple as keeping information uncomplicated, but being specific. And repetition is key to maintaining understanding for that parent, for that patient who is so stressed they only hear certain things. Minimize that jargon and always before the visit has ended, please make sure that you have understood what the patient's needs are for that day. So using some of these techniques for positive communication can lead to overall health outcomes, whether it's lower blood pressure, whether it's physiological measures, it's improved health. It means that the patient doesn't have as much stress when they come in. A more accurate diagnosis that promotes adherence to treatment is key as well. As we all know, the diagnosis of hepatoblastoma is rare and if my research is correct, which I have seen on this panel today, fewer than 250 children are diagnosed this year. When engaging in conversations with parents internationally, here's some things that they said. Patients' priorities, they want to feel supported. They want their voices heard when high quality clinical care is available. As I said previously, the stairwell analogy. Emotional support is key, not only for the patient, the parent, but don't forget about the siblings. They have now been taken, their parents, out of the environment and their parents are having to deal with other things. So sibling support is very important. Long-term mental health issues are a huge priority. Whether a child is fortunate enough to have a resectable tumor or the transplant, families want to see more resources and teaching on long-term psychological impacts. Quality of life of treatment and post-surgery is vital to ensuring that future medical care can be minimized when all parties involved feel validated and heard. Families would like to see more of a multidisciplinary approach, whether it includes social workers, dieticians, oncologists, hepatologists, ID, whoever it may be. That's important too. Now I've had the crazy absolute privilege to be involved with the AACR and from my experience I'm so pleased to hear that there's being done more research in the solid tumor area. There's my liver. So Dr. Teo, I didn't know that you were gonna be on the panel today. So it's actually a very, it's a privilege. I'm so sorry that, but I think you look very handsome there. So as you know, Dr. Gregg has had this FIT trial going on since 2017 at Cincinnati and having access to that cutting-edge genetic testing, participation in these trials, these new exciting solid tumor trials is, allows family to have hope and an outlet to advocate for their children. Now in Canada we don't actually have an option to do genetic testing right away and that is something I would like to see changed in Canada. I know it's bigger in the U.S. but if you're involving these patients and families, a really important thing is when the clinical trial is done, circle back to these families and let them know what the outcomes are. It's great to be involved in a clinical trial, right? Your child's taking extra blood here, an extra scan there, but parents often don't hear what the end result of those clinical trials are. So please circle back to that. So at the present time, the standard of care as we know is the cisplatin, doxorubicin, and broccad carboplatin. Treatment with preoperative chemotherapy is shown to benefit some children and some children not. So this cocktail, all I heard as a parent is, one will destroy the heart, one will destroy the kidneys, and one will destroy hearing. They may not remember the names of these but they do remember destroy, could lead to. So multiple parents, as Dr. Allison said, multiple parents question the lack of the thiosulfate. For survivors of hepatoblastoma, the most common lasting treatment is hearing loss. So why isn't not being used? Maybe that's something we can talk to our parents about because as you know, Dr. Google is a big thing. They start researching, they find out things. So having those conversations up front is really key. Standardization of care across the board is imperative too for patients receiving care. Parents all want teams working together whether it's day or night. Some parents actually said that all they want for their child is to live, live obviously, but we can't fix this. But single patient rooms, private rooms, we can't fix those in the hospitals, but that was an emerging theme too. And that was actually one of Brock's biggest issues, is that he was either in a ward room or he was in a semi, and he never wanted anybody to see him with no hair. So if you can minimize that stress as you're going into it, there's lots of families that said that they would prefer a private room while their children's going in for that induction of chemotherapy. Another big one, and I know I'm over time here, but this is really, really key as Brock is 16. Transition and aftercare. Very, very much anxiety around that for the future. What will it look like? How often will we have scans, blood work, and preparation for a brand new doctor, a brand new center in the adult world? That's very stressful for parents and for the teenagers themselves. Scan anxiety is real. Have you, I'm sure you've heard about scan anxiety as parents, right? But reach out to having those milestones, the five-year mark. I, as I said to Dr. Leung today, that is my comfort blanket. When we're not doing those scans every three, six, eight months, it's like somebody's ripped a bandage off. That was how I knew that there was no evidence of disease. So how can we have parents lessen anxiety? Could we do scans once a year? Could we do scans every six months? Maybe it's tailored to the individual, but that's something that is really important because parents wait for that other shoe to drop. As I say to Brock all the time, come here, let me look at that bruise. Mom, I'm fine, I'm fine, I'm 16. It just was a hockey bruise or a baseball bruise. But for parents, it could mean a relapse. So people all around the world are facing that gut-wrenching moment when you hear your child has cancer, your loved one has cancer. So how can we here collaborate together? Let's start the conversation of how we can include parents, include patients into clinical trials, into amazing conferences like this because it's so important. Let's be the change that we want to see in the world. Thank you. Thank you, Julie. That was very moving and we really appreciate it. We are now open for questions. A short comment and then a question for the rest of the panelists. First, Julie, thank you very much for sharing that. Thank you for your strength. And actually, as also the parent of a child with liver cancer, I want to thank all of you out there who are working on liver pathologies and liver cancer. Thank you for everything you do. And now a question for the panel. I didn't mean to give the impression in my talk that, you know, therapy was, you know, really chemical or immunotherapy was the only way to go. I actually think that a combination of surgery and therapy, in fact, particularly fibromyalgia, I think surgery should be used for the bulk of the tumor. And then my hope is that any of the therapies we or others are developing will help sort of clean up the micro metastases. But the perspective I'd like to hear both from, you know, the surgeons on the panel and the oncologists is, do you think that it should be surgery first and then therapeutics, therapeutics, then surgery? Does it depend upon the tumor? Do you go back and forth? What kind of guidance would you offer? I'm happy to start. I think we all recognize that we want to capitalize on a surgically resectable tumor when possible. I mean, I think I'm saying that as an oncologist. So I think we are somewhat pigeonholed when we're studying earlier phase therapies whereby we have to know they work, right? So there are circumstances in which we have to deliver therapy to see whether the tumor shrinks, to understand whether the drugs are efficacious. But that's often in the relapsed refractory setting where patients' tumors have already recurred despite standard of care treatment. So I think knowing the role surgery plays, knowing the importance of it, particularly for higher-risk tumors that might not respond to systemic therapies as well, fibromyalgia included. I'm a huge advocate of resecting a tumor when possible and then thinking about adjuvant therapy on the back end. Yeah, I mean, I 100% agree. Surgery is central to the ability to achieve a durable cure. But the challenge, of course, and this is where transplant has been integrated in, is those tumors that are not amenable to conventional surgery at diagnosis. And then trying to figure out the balance of integrating transplant into, you know, paradigms. The challenge with fibromyalgia and HCC, and the standard HCC, is we have a diagnosis or disease process in pediatrics that is presumed to be similar to that of adults. And so then there's adult criteria that have been established that then make transplant options even more challenging. And so, you know, we all have cases where we've offered transplant to patients who had HCCs that were far beyond Milan, UCSF, any of the criteria, and have them as durable survivors. And so that's where, but then you get into all the other challenges of outcomes when you're taking on those higher-risk patients, and it just gets so complicated quickly. And therein is where it is a multidisciplinary process, and we as a community need to advocate for these patients, just as Jessa was saying here, that if we can advocate for these patients in a way that opens up the option to do more things, that's really the ultimate way to give these kids a durable chance. Maybe I have a question for the panel also. It seems that in pediatric liver tumors there is a spectrum of different tumors, in fact, and that are reaching from the very early onset of hepatoblastoma, that is completely different from the late onset of hepatoblastoma, and from the tumors that are supposed to be undetermined, but I believe also that we can classify them using molecular diagnosis, and then for freebrew MRR and so on. And it seems that the response to chemotherapy declined according to the age of the patients globally, and that could be refined by the molecular classification or subtypes. But what is your comment on that? I mean, the sensitivity to chemotherapy that is so important for hepatoblastomas, and we can rescue some patients from a very advanced disease, whereas for other tumors it's really primary resistance to chemotherapy that cure. So what we have to learn from that, and what are your comments for the future clinical trial, because we have not a lot of time and not a lot of patients to treat and to organize with a clinical trial. I was very impressed by that with the clinical trials that you are currently setting up. I'm happy to start. It's a perfect point, right? And I think we're evolving to understand that these tumors seem to be on somewhat of a spectrum, and that when they occur in younger children it's potentially influenced by the developmental stage of the liver and or the immune kind of development of the child. There's probably an intersection of all those things, and I know some folks are doing work on that. And then as the child ages, seemingly the tumor develops additional genomic insults and more aggressive features, and I agree, tends to act more like HCC on that end. And curiously, we keep saying HCC, but HCC in kids is so very different from HCC in adults. Only about 20% of HCC tumors in kids arise in the context of cirrhosis. The rest are de novo in a totally normal liver. But despite that, they do respond slightly better to chemo than an adult HCC, but you're right, still not perfectly. So I think, slash, hope that we're getting closer to understanding the ends of the spectrum. Maybe not the nuanced in between, and my dream would be that for a successor trial we'd be able to better characterize the extremes of the spectrum and perhaps intervene on the extremes to recognize earlier the resistant patients or the patients unlikely to respond, and to recognize the patients that have very genomically silent tumors that may not require all the cisplatin we're giving. And if we can impact the extremes, we can set the stage for better understanding the intermediaries. But that is what you're driving at is exactly one of the primary, you know, most important outputs from FIT. Yes, we'll understand treatment options a little bit better. We're trying to figure out different ways to integrate surgery. But one of the drivers of the trial was to do the biology. And this is where we need people like you and other teams focused on this disease. The whole goal was to establish a large registry of data in terms of patients who had molecular profiling. And so for the, across the three consortiums, they, all of the teams who are contributing from a biology standpoint, are profiling the tumors according to the same technology. So it's a nanostring and additional testing that's being done so that interested future researchers will take that information and explore different components of the process so that they advance the field in ways that we never might have thought of right now. And so from a trial standpoint, that was one of the most fundamental components that brought all the consortiums together because no individual consortium can study or has the patient population to study, you know, 200, right now there's 290 patients enrolled in the high risk arm. So that's more patients than has ever even done in some of the single trials. You know, trials for all of hepatoblastoma, yet we have 290 patients in that arm, we have 250 patients in the intermediate risk arm. And so the molecular analysis of those patients, which really plays a really important role in terms of trying to get it to actually happen, is one of those things that will hopefully change the paradigm. Unfortunately, not in the current generation, but in future generation, future trials, and that's really one of the outputs that are critical. Simon? Maybe it's more homogenous subtype for fibromyalgia, but what is your comments on that for the future? I mean, in terms of how it fits in on the spectrum? I think Dr. O'Neill pointed out that there's, in fact, these different developmental stages may be important development, not only for the liver and the types of liver cells, but also for the immune cells. And we're just beginning to learn, you know, what exactly is going on. So, for example, we recently found a cholangiocarcinoma that by all characters, histopathology was cholangio, except it had the same fusion gene that we found in fibromyalgia. And when we took the cells from the patient, we screened them against drugs, they responded exactly like fibromyalgia. When we actually looked at the transcriptome, much to my shock, even though it was cholangio. So, there may be a spectrum, but despite there being a spectrum, I think we can start categorizing them. And I think there's the hope to categorize them enough that we can actually be able to target therapeutics that work for them. So, we don't understand the full spectrum of the players that Dr. O'Neill referred to, but I think we are getting a handle on them, and there is hope for having a handle in the near future. Thank you, Julie. Any comments on that? I mean, also the story of your son was very, very important. So, any comments on the continuum of different disease and how we can assess the prognosis of the patients and fight against poor prognosis? Yeah, I think really for, as a parent, I was just talking to the amazing pathologist that we heard from earlier. Transplant wasn't in our wheelhouse. We were diagnosed with cancer, the chemo was going to work, and that was it. We knew we might have a resection. So, I think really like being open and honest about all of the stages or what could possibly be happening is really important for parents to kind of hear. I know it's overwhelming, but to change our mindset into a transplant arena is daunting, right? And as most people say, oh, aren't you so glad that you're done with cancer? You're never done. You're never done, right? So, having the cancer arm and the transplant arm, I think if parents could hear this is what could happen, you know, pretext four, you're looking at this, this, and this. We were never told that. It was pretext four with metastases, here's the cocktail of the three chemos, and away you go. We were not offered genetic testing or sequencing or anything like that. Now, that could be because we're in Canada and we just don't do that, which I'm going to change. But I think just being really open and honest about your pretext one, this is what it's going to look like. Your pretext four, this is what it's going to- so it's not such a slap, a big slap, when you're talking about transplant. Do we have time for another question? Okay, thanks everyone. That was an incredible panel. Question for Dr. O'Neill and Dr. Tiao. Does the FIT trial as it stands, does it exclude recurrence and specifically salvage transplant? And if so, how are we going to better understand, given conflicting data, the true risk of that? Because as we've kind of postulated before, that maybe plays a role in some patients undergoing transplant. Initially, that could have been potentially resectable. It is one of the more frustrating parts of participating in a structured trial that is sponsored by some, you know, an organization like COG, where they aren't willing to allow us to include relapsed patients in the study. And this, again, is where that relive registry really was evolved from, because Saipel faces that same issue. They're trying to run a clean prospective trial, and then if you have a relapse, those patients are not going to get chemotherapy on trial. The physicians are going to treat the patients as necessary. Surgeons are going to intervene as necessary. But we aren't able to track the outcomes in a way that can be truly informative for the group. And that's where, you know, all of Ali and Jim and Mark's work is so central to the future, because families, you know, it's hard enough to survive the first course, and then when you deal with that additional, you know, just horrifying idea that you might have to deal with again, it's daunting. And I think the only thing I'll add is it's interesting, right, because the existing data is probably somewhat marred by our inability to adequately control disease in the context of relapse. And I think we're getting better and better at recognizing that maybe cisplatin reintroduction works, or there are other agents out there that work. So I think moving into a rescue transplant in a better state of systemic disease control may be a different ballgame in terms of robo-allocum. So I imagine the two will evolve together, and we'll kind of collect data in parallel that's meaningful. Hi, amazing talks. Carlos Luque from Argentina. This question goes to Dr. Teo. It's a surgical question. Have you considered at some point some other surgical alternative to the transplant, the ex-situ resection, knowing that the same team has transplant skills and hepatobiliary surgery skills? That's a great question, and there are other alternatives like ALPS to kind of try to generate more parenchymal liver residual so that the patients can tolerate the resection. So there's a lot of alternatives that we didn't touch on here, but teams are exploring things. People have done ex vivo resections and then re-implanted the organ, the remnant organ. The point there, though, is if you're at that degree, it's most likely because the patient had metastatic disease that was not controllable, because we do know that transplant is an effective alternative and has improved outcomes in a way that is favorable. And so that's where you kind of balance, and perhaps the community has swung a little bit too far to transplant at this stage, because there are patients who should not be transplanted who are getting transplanted, but then there are the challenge for the people who are very committed to the field is to try to figure out for those patients who might be amenable to more aggressive resection how to balance those risks, because having done a pretty aggressive resection and nearly had a patient need to be transplanted for immediate salvage, it is a pretty scary course to induce. Thank you very much. I think that now we have to close the session. I would like to really thank you, all of you, for your participation, the questions, and et cetera, but for sure ASLD to having given us the opportunity to set up this session. I think it was really fruitful, and I am sure you will fight the disease all together, and we need to have a multidisciplinary communication, exchange in data, and it is exactly what we are doing today, but also in our daily life for research. So thank you very much. Thank you.

pediatric liver cancer

relapse

resistance

systemic therapy

local control

Cisplatin

doxorubicin

ifosfamide

carboplatin

new therapies

clinical trials

immunotherapy

targeted therapy