Dr. Rebecka L. Meyers - Surgical Management of Hepatoblastoma: The Good, The Bad, and The Ugly

Right at the top of the hour, why don't we give it a 30 seconds for everybody to get their Wi-Fi settled and get the honor to do so. Good morning. I'm Danielle Cameron, one of the senior fellows and it gives me great pleasure to be able to introduce our visiting professor this morning, Dr. Rebecca Myers. Dr. Myers is an international expert in hepatoglastoma and other pediatric liver tumors with additional clinical expertise and Pectus Hexcavautum and the management of conjoined twins. She served as the chief of the Division of Pediatric Surgery in Utah from 2001 to 2011 and as a recognized leader in the field of pediatric surgery. Dr. Myers was a driving force in establishing the pediatric liver transplant program at primary children's in 1997 and served as the pediatric surgical director of the liver transplant program from 1997 to 2009. She combines her expertise in pediatric liver transplantation with her passion for treating children's cancer with a career focus on the treatment of complex liver tumors in children. She has served as the chair of the National Children's Oncology Group liver committee since 2008 and has led multiple national and international research investigations in the study of liver tumors in children. And that just summarizes her accomplishments within the field of pediatric liver tumors. She has a whole other interest in Pectus Hexcavautum and conjoined twins but I'll keep us focused on liver tumors this morning. There's no doubt that we are lucky to learn from her and our only regret is that it can't be in person. This morning she'll present on the surgical management of the Pato Westoma, the good, the bad, and the ugly. And I'll invite you to join us again this afternoon at 5 p.m. for the annual growth lecture also via Zoom. Welcome Dr. Myers. Good morning to everyone and Danielle, it's nice to meet you and to see old friends. Steve and my very treasured mentor Dr. Bob Canberger. It's a real honor and pleasure to be here. Both of my talks today is your visiting professor going to focus on liver tumors but this morning we're going to take a more discreet slice out of the pie and specifically look at the surgical management of Pato Blastoma. And I have no disclosures. Bob, that's the view from the deck off of the back of the North Rim. And maybe you'll get a rainstorm and a rainbow there. I'll be thinking of you. And while I have no disclosures, I do have a lot of acknowledgments because as we go through this talk, it's important for us all to recognize this isn't my work. This is the work of hundreds of really dedicated people in the collaborative field of Children's Cancer Research and in particular in the field of pediatric liver tumors. I've had the great pleasure to be the driving force behind this international coalition that culminated in the opening of the FIT International trial and that could not have been done without the collaboration cooperation and generous financial support of other groups and dedicated people. I also want to make sure and acknowledge my dear colleague Chris Weldon because we're going to be focusing on surgical management, the contemporary management. Our talk this afternoon in the gross lecture will look at the study that I was personally responsible for the AHA-0731 study which preceded this one is finished and now published. Chris has been one of our surgeon driving forces behind the current FIT study and it's been my great pleasure to develop the guidelines we're going to talk about today in collaboration with him and the other surgeons on the Pediatrics Libertumord Committee. That's the complicated backbone of our FIT International trial. It's an all-encompassing trial of the Padoblastoma and the Padocellular Corsanoma. We don't really have time to get into surgical management of the Padocellular Corsanoma. It would take another hour of its own and so we're going to feature on the Padoblastoma and specifically the four risk treatment groups that define the surgical management because your surgical management depends on which group your risk factors drive you into. These risk factors are the reason really that I'm speaking to you today because this was the work that I focused on within this collaboration for about a decade before we came up with this risk stratification that's now used internationally. When I first started, I'm Bob will remember me trying to get my concept through Science Council to look at liver transplantation for Padoblastoma going back to 2002. Historically the North American surgical staging system was very different than the staging system used by our colleagues in Europe. In Europe they had introduced a radiographic staging system and in North America at that time we still staged people and treated people based on the results of an attempt at a reception that was done for everyone in diagnosis. Our European colleagues introduced the pre-tech system in 2000 with the PSYAPL I study. I'd like to acknowledge Jack Plaschka's as one of my dear and most supportive mentors in the study of liver tumors. He came up with, so they say on a cocktail napkin in his crown, planning for the PSYAPL I study. And by the time I came on the scene in the late 90s, pre-techs Circus IAPL II had evolved into a little bit more refined system. At that time there were still just the four groups defined by the extent of liver tumor involvement at diagnosis and four annotation factors. One for hepatic venous invasion, one for portal venous invasion, extra hepatic and distant metastasis. And my dear friend Dan Erenson looked at this radiographic staging system and wrote a fairly provocative article right when I was getting involved in liver tumors saying pre-techs was diagnosed with a far superior and in terms of its predictive value, very superior to what we were doing in COG. And this prompted me to compare the pre-tech system with what we were doing in COG in our legacy trials back in the 90s and 2000s. And so as we were planning our new study, AHAPO 731, we introduced portions of the pre-tech system to define surgical management for hepatic blastema. And this was the introduction of the pre-tech system into North American surgical guidelines. Pre-techs 1 and 2 tumors were reflected at diagnosis, 3 and 4 after chemotherapy and high risk after chemotherapy. But still we had four different treatment systems and four different sets of surgical guidelines. COG had their own set, Saipala, Japan and Germany. We're all operating under different risk stratification systems and different surgical guidelines. So if our goal was to do an international study, we need to somehow get everyone on the same page. And that's what this endeavor was. We took eight multi-century trials over the time period from 1981 to 2008 and collected all 1600 patients enrolled on these trials and did an extensive statistical analysis of all the potential risk factors involved to come up with a common system that could be used by all of the multi-center trial groups internationally. Individually, when you look at the different factors, pre-techs was the most discriminatory of all. Pre-techs 1 and 2 tumors actually had very similar prognosis, but were statistically different from the threes and the thores. And so it turns out Dan Erinzen was right. Pre-techs was the most discriminatory factor of all. But in addition to that, AFP turned out to be prognostic. When we looked at several different ways of bunching AFP into categories and groups, these three groups turned out to be statistically significant. We've now learned that the less than 100 group in these older trials is probably a core prognostic factor because several rabid tumors leaked into these old studies because of our incomplete understanding of the importance of I and I-1. But we'll talk about more this afternoon. That's not within the scope of our surgical management to talk. What was surprising in this initial analysis was how important age was, and we did actually a separate and more in-depth analysis of age and found that your age, if you have had a plastrum is almost linearly linked to your prognosis, the older you get, if the worst your prognosis. But the annotation factor also proved to be diagnostic and prognostic, the involvement of the hepatic veins, portal veins, extrophabetic contiguous extension into the diaphragm or stomach, multifocal tumors and preoperative russure. And when you gathered these all up into a multivariable analysis, we came up with these risk trees to help determine risk stratification, which then determines your surgical management, which is dictated by which risk group you fall into. And then as you look at the trees, they're color-coded. People get confused by this. I get a lot of feedback that it's confusing, but it's really quite simple. You're a pretext one when you start, so you're very low risk. Unless you add on other risk factors. So if you happen to be a pretext one and have a metastasis, that automatically bumps you up to high risk and that's by this box's pink, because it's the risk factor that made you high risk. If you're a pretext one and you happen to have a positive annotation factor, it's an annotation factor that bumps you up to high risk, to intermediate risk, and that's why this box is yellow. So the color coding is actually quite simple and easy to follow. One of the problems that we had with the CHS stratification system is that we had used all of the multi-center trial patients that were in existence at the time to create the stratification. So we had no independent data set to validate it. The group at CHLA developed an independent data set that did validate it. Then we've been currently contemporary to this talk, working on a validation data set with the more contemporary trials. Cypel 4, Cypel 6, JPLT2B, and OHPOS 731 were not yet published at the time this risk stratification was developed and introduced. This validation data sets analysis was sponsored by the children grant running the fit study. These results were very recently published, where they're in press right now, but they were very recently presented at our Cypel meeting this spring. You can see over the passage of time, very low risk has stayed pretty similar, low risk, very similar, intermediate risk, pretty similar. But here, over the passage of time, we've made gains in our outcomes with high risk tumors. This is primarily because of the chemotherapy regimen used in Cypel 4 that has been adopted into the new fit study. Now that you understand where all of these groups come from and why we use them, we'll take each group one at a time and look at the surgical management within those groups. Starting with treatment bay, which is very low risk. With a group bay tumor, you have all pretext annotation factors are negative, and there's one or two contiguous free sections of tumor. And importantly, with these surgical guidelines, we don't want people doing extensive receptions that diagnosis. Recommended are either segmentectomy shown here as a left lateral segmentectomy, and you can see it clear and easy margin of resection, or a simple hemie hepatectomy. And when we say simple hemie hepatectomy in the treatment of a low risk tumor, what we mean is we don't want people doing extensive vascular dissections across the boundary of the middle hepatic vein, because retrospective analysis has shown that these are the dissections that lead to positive margins and complications in these early untreated tumors. Group B is in terms of its pretext, the same as group A, except that in group B, we worry about invasion of the vascular tour around the region of the middle hepatic vein. In these tumors, there's either a pushing margin, as you can see, in these CT scans, you can see portal vein here. And the tumor is still clearly a pretext too. It's not going across the sanatomic boundary into the left lobe, but it's pushing this vein. And a resection at this time, at this point in time, is going to involve a fairly extensive dissection of the portal vein, and this is not the kind of dissection we recommend prior to chemotherapy. So with a low risk tumor, as opposed to a very low risk, there's less than a centimeter distance from the middle hepatic vein, the portal biopircation, and or the IVC, and or is a pretext three. So what about the margin of resection? Why are we making a big deal about the difference in resection of tumors at diagnosis versus after chemotherapy in our low versus very low risk tumors? Dan Aronson published this article in the European Journal of Cancer just actually a couple years ago, although it represents a collected series of patients over the last 15 years. And in the combined experience of SciPel 2 and 3, which was 430 patients, there were 58 patients who had a positive margin, and five of those had a local relapse, that an EFS of 86%. When Dan compared those with the 371 patients who had a negative margin, 23 had a local relapse, EFS was 86%. Conclusion in the context of cisplatin chemotherapy, the outcome was the same. And he's right, in the context of cisplatin and chemotherapy, the outcome was the same. The problem is, all of these patients in SciPel 2 and 3 were resected after somewhere between four and six cycles of chemotherapy. So this observation and data regarding the margin in SciPel does not apply to patients with upfront resection. If you look at the Japanese data on upfront resection, in their JPL1 and JPL2 series, positive margin had a relapse of 15%, and one death with an EFS of 69%. Compared to an EFS of 88%, in the overall group of pretext 1 and 2 tumors. And rupture carried, particularly poor prognosis, when it was resected at diagnosis with an EFS of 32%. So the margin of surgical resection that is discussed in the SciPel paper is only in the context of preoperative based chemotherapy. If you're resecting a diagnosis, we currently do not have data that says your margin is not important. In COG, we have not published our margin data, and I'm very hopeful that Chris Weldon will do this for us with the addition of the AHAPO731 data. The reason we haven't published it is that it is very suggestive, that it's important, but the numbers are so small, it does not reach statistical significance. When I did this retrospective analysis of pre-treatment factors on our legacy studies back in the 2000s, the Kaplamire curves look very suggestive that a negative margin was predictive of a better prognosis, but when you looked at all of the treatment factors, the log-ray analysis p-value on a positive margin was .08, and that's obviously suggestive that a margin was important, but it was not statistically significant. The reason why is there is a lot of missing data in these retrospective studies, and the numbers are quite small. With better prospective data and better numbers, this analysis needs to be redone. I put this slide here to remind us all that COG works very slowly. This is us, the rhinos prompting them from behind, but this is our statistical support within COG, and it takes a long time to bring these studies to publication. I'm very hopeful that the next generation is going to be able to answer this question for us with our legacy COG data. Moving back to the surgical management. The low-risk studies really separate themselves out into two groups. There's one group, which in the fifth study we call the B1 group, which is going to have a really robust early response to chemotherapy. You see this here in the low-risk treatment strata. B1 means after their first two cycles of chemotherapy, they've shown a really robust, recessed response, and they become receptable. One thing we've observed so far in the fifth study is the approval of the B1 is below target, and in such a review, it appears that this is not really the tumors fault. B1 requires that the surgeon is prepared and ready to resect fairly early in the treatment strategy. What we've seen is that the group B2 is actually accruing above what we would predict. The reason we think, and we don't know this yet, because the data is not released for review, but you're going to resect after two cycles of this chemotherapy. Yeah, we're ready to resect six weeks after diagnosis, and unless the surgeon is getting into the mindset that they're going to be ready to do that resection early, we find a drift into the non-receptible category. I really wanted to dwell on this slide a little bit. Make sure when you get a diagnosis, you talk to the family, talk to the oncologist, and plan optimistically that you're going to resect after two cycles of chemotherapy. Obviously, it's easier to cancel a surgery that becomes impossible than to make arrangements at the last minute. This becomes important because if you do become receptable after two cycles, you're randomized to a fairly significant dose reduction in chemotherapy. This is where the main reduction in chemotherapy in this study is coming from early diagnosis and reduction in post-treatment chemotherapy. Now, if you don't, if you don't, have a good early response to chemotherapy, you go into the B2R, receive a full set of four cycles pre-operatively, and then are resected. We're going to move now from our low and very low risk groups to the intermediate risk group. I want to remind everyone that this used to be high risk tumors in PSYOPAL. This has been a big change for our international colleagues. These tumors are part of why PSYOPAL 4 high risk results were so good because not all of the patients in PSYOPAL 4 were metastatic. Several of them were patients with big bulky tumors with fast-quilling involvements. Those are now intermediate risks. That's these tumors here, either one or no contiguous section for you of tumor and positive annotation factors, one or more, with involvements of hepatic veins, portal veins, contiguous extension usually is the diaphragm, not always. It's sometimes the abdominal wall or stomach, multifocal tumors in rupture. Then just a little caveat that if you happen to be a pre-text for tumor that makes it on to the intermediate risk, you have to be less than three years old because the pre-text for tumors that are older than three do still get pushed to the high risk category. Also, importance to be aware of and read this article because the pre-text definitions were completely redone and overhauled for this international study in parallel with the risk factor groups. All of these annotation factors are now commonly defined across all treatments. Categories in all trial groups. For the students and residents, just a few words about how to do a safe liver resection because this is what will sometimes get an experienced people into trouble. It's very important to be methodical. As in everything we do in surgery, you want to have a thorough pre-operative checklist. You want to have conferences with your anesthesia team. Hypothelemic resuscitation in particular is important in liver surgery. You don't want to be pushing a lot of volume during the time when you're losing blood or you'll simply lose more blood and risk air embolism and complications during the resection. And these are all questions every surgeon should ask themselves before embarking on a liver tumor resection. What is the status of the perencoma? Is it fibrotic or serotic? Is this going to get me in trouble postoperatively or during surgery? Is there unexpected multifocal disease? Does the proposed liver remnants have an unanticipated focus of tumor? Is the margin of resection endowed? What is the status of the inflow and outflow to my remnants? Am I sure that I can safely preserve them? Is there any intravascular traumas? And if there has been, do I think it's viable or do I think it's post chemotherapy fibrotic? And perhaps most important to all is the entire team ready for this resection. And as I've watched and done central review of surgical resections over the years, patients that get in trouble virtually always get in trouble for one of these reasons. Somebody wasn't prepared with one of those issues. And if you sit down with your team and make sure you've answered all those questions for yourself and your patient, you're going to have a safe resection. Intraoperative ultrasound will help you answer these questions and it should be a backbone of our technique and current surgery. As you proceed through surgery, you want to again be methodological. You start with your super hepatic kava, you proceed to the retro hepatic kava. You do your hyalurgyzed section, you make sure you have no biliary anomalies. If you do, you do a colangiogram. And if your margins are in question or multi-flocality is in question, hopefully you've made pre-operations to assess those with indesigning green navigation. As you go through your perunctimal dissection here again, you don't want to overresuscitate during the bleeding phase of the operation. It will only make for more bleeding. What's the perunctimal dissection is done is the time to focus on hemostasis. So the tumors out, but now, and this is another thing that will occasionally get teams in trouble. Very helpful and important for the surgeon to go to pathology and assess the margins with pathologists. You can see in this tumor, our margins pretty close right here. We've got a gross negative margin, but it's pretty close. And this is one where I would go back to surgery and take another little piece of liver right here to make absolutely sure that I've done a complete resection. And then of course, to check this for the handoff to the ICU, make sure everyone's on the same page in terms of parameters of resuscitation and target levels for your laboratory values. So with our intermediate risk tumors, we've been talking about tumors that did respond to chemotherapy and became resectable. But what about when the major vessel involvement does not with chemotherapy, where the multifocal disease does not clear? And this is the argument or the discussion I should say that's been going on in a padded blast film, since I became a part of this research. And I am sorry to say we have not solved it. We have more data. But we've really gotten to a position where you can essentially pick your risk. So the arguments in favor of a complex partial resection, if you had excellent neo-adjuvant chemotherapy response, if you have no history of tumor thrombus, if there's no hope of a donor liver, if they were referred late and you simply don't have time to make preparations for transplant, or if there's an increased risk of tumor relapse with transplant immunosuppression, all of those will push you in the direction of a complex resection. Conversely, a transplant will give you a much more reliable complete resection of microscopic disease. There's a decreased risk for a small, precise remnant. There's a significantly decreased risk of postoperative long-term complications. And those are particularly in this partially respected group ischemic colangiopathy, bioliques, and portal hypertension. And there's a decreased risk of global relapse. When we look at the experience that we have analyzed in the AHEPO 731 study, we find that some patients were pushed in the direction of conventional resection, and others in the direction of transplant. There are a couple of things to keep in mind when you look at the results. These patients that were resected at diagnosis in the intermediate risk group did so because their biopsy showed small cell and differentiated histology. And we'll go through that a little bit in this afternoon's talk. This is no longer a reason to be on the intermediate risk stratum. These patients in our future studies will go back to low risk because SCU histology is no longer a risk factor. For our liver transplant patients, you can see we had 33 on this treatment group. And 21 of those were performed on time. We tried really hard in this study to get your transplant done before you started your fifth cycle of chemotherapy. And we succeeded about two-thirds of the time, but still about 12 of our patients are a third are getting transplant after extended and probably unhelpful extended runs of preoptive chemotherapy. The majority of your chemotherapy responses can happen in your first two and four cycles. All of this radiologic literature was centrally reviewed. And when we looked at the fate of vascular involvement, if you had major vascular involvement at diagnosis, it cleared after two cycles in approximately half of the patients. And by four cycles, two-thirds of the patients had cleared. If it hadn't cleared by four cycles, it never did. And there was no benefit to giving chemotherapy beyond this point. If you weren't resectable by four cycles, you had to make a decision to go one way or the other. Interestingly, there were six patients on this study that were transplanted who did not meet the central review criteria. And those are shown here. It's the unanticipated consequence of encouraging early referral. When the patients were referred at diagnosis to a transplant center without an engaged and thoughtful oncologist imaging and assessment of resectability has to be redone after your chemotherapy or you end up in this group getting a transplant that's not indicated. In the post-Tex2 group, we had two transplants, two conventional resections in the three group. There's an even split between transplants and complex resection. In the pre-Tex4 group, and you can see that a lot of these patients are multifocal, there's clearly a preference for transplant. Now if you decide you're going to go the direction of a complex resection as opposed to a transplant, these are the current techniques that can help you get a safe resection without complications or residual tumor. And we'll look at examples of all three of these techniques, preoperative chemo-embolization, computer-inhance, advanced radiographic imaging, and endoslineine-green navigation surgery. Here's a case to look at the impact of case. Patient presents with IAFP, pre-Tex3 tumor involving all three hepatic veins, retro hepatic vein and caveaportal bioprotation. The lungs are clear, so she's an intermediate risk patient. And you can see that after a new adjuvant chemotherapy, there's been a pretty robust response in the alpha-pepti-approaching that's down to 1800, but the major vascular involvement is still significant. In this patient, we decided to proceed with a preoperative chase. The fourth cycle, a preoperative chemotherapy, we gave the C5B systemically, but gave the docs a ribosin as eluding beads. And we're able to get enough of a tumor kill to make this tumor resectable. She had to win a Mesa Hattectomy with interoperative ultrasound. We actually did find a satellite nodule in segment two, so she was really a pre-Tex4 that was non-anticipated on preoperative imaging. The retro hepatic cavity section almost killed me in this dead, but we were able to get the tumor out, and she did really very well in terms of a cancer cure, but ended up needing a liver transplant six years later because of progressive isochemic colangiopathy and portal hypertension. And this is something you need to anticipate if you do this kind of dissection on the portal bifurcation. As it heals and over time, your liver is likely to respond with progressive fibrosis. The arguments and favor of transplant are a decreased risk of these late-term complications. However, an increased risk of local relapse, so you have to balance those two risks against each other and make your best decision. We have seen an increased use of transplant over the course of the last two decades. If you look at the liver transplant rates back in the 90s, we had none. And on the most recent study, 33, and concomitant are resection rates have gone up, not surprisingly. If your question is how to resect, not if to resect, then your resection rates will go up and they have done so. Our results are very good with late transplantation on this study, the EFS and overall survival of 93% and 100%. But we still have to put all of these outcomes in context. There have been over 40 published liver transplant series for a hepatoblastoma in the last 20 years. And actually, I suspect that number has gone up over the last couple of years. Most of these are single-institution studies or database studies. Overall, survival has ranged from 75 to 100%. And we've learned that it's successful, but we haven't learned a lot about how to make a decision that's informed by long-term outcomes. And because most of these single-institution studies have very low patient numbers, you get variable outcomes. So if you look at this study, the high AFP predicted a poor prognosis, and you know, at this study, a low AFP predicted a poor prognosis. The difference between this study and this study is that obviously they had low patient numbers. And this one had a patient with high AFP that did poorly, and this one had a patient with low AFP that did poorly. And when you have poor patient numbers or low patient numbers, your data is going to be skewed. So we really need to push for our bigger studies. The split study, which came out last year, splits as the pediatric liver transplants organization, is empowered. They had 157 patients, so their data is from a good number of patients. Unfortunately, they don't have any central review for degree of vessel involvement. So we still can't really answer these questions about AFP response to the vessel involvement because there wasn't a central review. They found like we found in the AHEAP study that there is a small but real number of transplants being done for resectable patients. And this is an important problem that we need to solve in our future treatment. We've had studies that show that extreme resection is feasible, but these studies from the group in Chicago, this is Rexibarina and York Pigs, have not done any comparisons with transplant. They've gone all in on extreme resection. And so again, they inform us that extreme resection is feasible, but they don't inform us about the comparison of the two techniques. There have been very few series that actually compare the two techniques head to head. One is ours and COG, which we talked about just a minute ago. And the other is from this group in Tokyo that did a really nice, centrally reviewed match of patients. There were 24 conventional resections, or excuse me, 24 total patients, 12 conventional resections, 12 transplants that are higher relapse rates in their conventional resection patients and concluded that they favor transplant. But it's a very nicely done paper. The problem is the numbers are so small that it's really hard to make lasting conclusions. Greg Chow, who I think most of you know, he's working with our centrally reviewed imaging, both from the COG-0731 study, and in the future with our imaging from the FIT study, to try and come up with new and or more informed recommendations for a decision of complex resection versus transplants. But I'll take you through the one, um, central review that has been done, and this was done as part of FIT by Steve Wehrman and York Fuchs in Tumonchin. The children grant, which is this grant that's running our FIT study, got money to look at me this advanced radiographic imaging. And if those of you, or haven't used this before, it's really very elegant, um, computer enhanced imaging of the liver segments. This is a paper that Steve Wehrman published a few years back showing the variations in liver anatomy and liver segmentectomy. You can see that simply basing your surgical decisions on number of segments involved is not taking account into account the fact that some livers have really big right lobes and really little left lobes, and some livers are just the opposite. And so with advanced preoperative planning, you can make very detailed predictions of your remnant liver volumes. And using this imaging on the FIT study, we've done a central review of 34 patients, potentially unresectable cases. Our goal was much higher than that, and we're still working on this analysis. What we found in this central review panel of imaging is that the post-ex staging was important for pretext most of the time. That Meevis was helpful in making a decision about transplant versus resection. Again, most of the time, but not all the time. And when the central reviewers were asked, why did they recommend transplant versus resection? 37% of the time, it was because they were worried about a small remnant, 25% of the time they were worried about increased risk of vascular dissection and or vascular involvement. How can we leverage the use of indesigning green to make some of these complex decisions? And this case is really illustrative of that. This little boy presented with pretty extensive tumor thrombus. You can see this in the portal bifurcation, and the thrombus is extending out into the right portal vein. The majority of liver burden is left lobe and right medial lobe. So if he's going to be resected, somehow we have to be able to save the blood flow to his right post-serial section. The other complicating factor in this little boy is that there's some evidence of some tumor outside of the dominant tumor, multifocal disease at the junction of 6 and 7. What we found after chemotherapy in this little boy is that the thrombus receded. Here's bifurcation right here and the thrombus is still there, but it's not going out into the right portal. And that multifocal disease cleared. And he had just extensive metastatic disease that had cleared radiographically. And we were headed for transplant, we thought with him. But when we did a thoracoscopic biopsy with ICG, we found actually avid areas that we could not see with our CT scans and looking at those under the microscope, there were microscopic foci of bio-timer in the lungs. So we decided to try and do a conventional resection and found ICG very helpful. This is the left portal vein. We've opened the bifurcation and you can see the thrombus inside the left portal vein is completely non-ICG avid. That gives us the assurance that there's no viable tumor here. You can see that our ICG is well lit in the main tumor itself. And this gave us the reassurance we needed that we were probably safe to do a portal reconstruction and not a transplant. But most importantly was the multifocal disease. This is that area over in 6 and 7. It had radiographically cleared. But at the time of surgery we find that it's microscopically still present. And sure, enough, you couldn't see these with the naked eye. They turned bright green and on pathology, there was still microscopic disease here. So ICG, as we go into the future with these complex resections, can be very helpful in making some of these resection decisions. Whereas ICG is particularly helpful with high risk tumors. And when we're talking about high risk tumors and transplant, the question that always comes up and no one knows the answer to and we still don't know this answer is what is the risk of relapse if you transplant somebody who comes in with pulmonary metastatic disease? This is a meta-analysis. I did a published literature 10 years ago. So this is old data. And I simply put it up there to compare with our data from the new study. This would be a really nice paper for some young investigator to write, to update this meta-analysis because there's a lot more data out there than there was when I did this the first time. But essentially the numbers are this. There's 32 patients that have been transplanted that come in with pulmonary metastatic disease. About a third of them are going to relapse in the lung, but not all of those patients are going to die of disease. And 60% long-term survival, 36% die of disease. And again, this is 10-year-old data. If we compare that to our contemporary data from 0731, there's a couple of changes that have happened. One is we're using surgery to clear metastatic disease a lot more commonly. You can see here that six of these seven patients were cleared surgically. And even though our relapse rate is actually higher, our overall survivor is better. And that's I think because of just more aggressive attempts at chemotherapy. ICG navigation surgery is going to impact this data. This is data from just the last two years in a recent review done by Isahiyama looking at ICG for liver or excuse me for ICG navigation surgery of pulmonary metastasis. The problem with ICG is this false positive rate. ICG will light up chronic inflammation and you get a lot of false positives with this technique and that has yet to be worked out as a technical detail. This is Tomorohishiki from Tokyo really pushing the envelope with ICG. He recently published this case. 100 pulmonary nodules resected with ICG. This is really pushing the envelope. I'm not sure that that is in terms of cancer behavior going to be a long-term winner. But this is what's technically feasible. They use synapse, Vincent software and resected 64 lesions on the left and then waited excuse me on the right and then waited and did the remainder on the other side. They published this case with one and a half years of survival personal communication. This patient has since passed away. But that is what's technically feasible and if we can leverage that to help us in patients that we really think have a chance for a long-term survival, it will be a technique we use increasingly in the future. That's what an ICG-avignaudial looks like at the time of blood resection. And these are the ones that sometimes are really hard to judge. They're almost positive. Sometimes you'll find microscopic post-eye of timber. Like in the case I showed you, sometimes you'll find chronic inflammation and that's simply just as good as the technique is right now. We don't have a better way of determining. I want to finish with the concept of long-term outcomes because in my old I've been doing this for 25 years. Look back at liver surgery. I think this is really the place where we could use some more data and some more work because our patients are having long-term outcomes that aren't being captured by our overall survival rates. There's a eight month old boy with pretext for tumor and multiple metastases. You can see after two cycles of chemotherapy, tumors responding really well to the chemotherapy. But still has significant multi-focal disease with all four sectors involved. We had scheduled him for a living-related liver transplant after his four cycle of chemotherapy. But our pre-transplants Chessi Tscan actually showed a new nodule. So he said, no stop. He's got a progressive disease. We went in and we biopsyed this and low and behold it was not cancer but aspergillus, which is something that you're going to see on these aggressive chemotherapy regimens. His transplant was canceled. He was put on anti-fungal therapy. Chessi T was repeated. He got in his fungal disease and his lungs cleared and he ultimately went on to get a chateverect transplant, which went smoothly. And his early outcomes were very successful, unaventful. We all high five clap hands. This is a success, right? And one year follow-up is a happy little boy with an AFP of nine. And at four year follow-up, he's still completely churred. AFP is still nine. One of our transplant complications post-transplanting. They're for proliferative disease. He's been on treatment for that. And at five year follow-up, he gets a secondary malignancy. AMML has been reported increasingly with our sci-of-health for chemotherapy regimen. The Japanese have a actually a big series of this from their JPL2 study and it's particularly AMML. He almost died on ECMO at Christmas this year, but but didn't made it through his fever and neutropenia. Ultimately went on to get a successful bone marrow transplant for his AMML. He got, I would say, the worst case of graft versus host disease I've ever seen. And ended up with profound hearing loss, secondary malignancy, and graft versus host disease, bad diabetes, bad hypertension, chronic rejection of his transplant liver and growth retardation. He's still a chair. So if you look at our statistics, he's overall survival, EF-S, 100%. But this list of complications in my mind is not 100% survival. That's a bad list. And at 13 year follow-up, he died of sepsis and complications of this graft versus host disease. So we can share these patients with aggressive surgery, but I think in the process of hearing that we need to be increasingly mindful of these long-term complications, which at present we don't have a really good solution for except that I think that we're becoming increasingly cognizant of them and need to be mindful of how to prevent them and how to make more sophisticated decisions of who we can respect without these long-term complications. So with that kind of sobering note, I'll say thank you. And especially thank you for having me. Bob, this is Delicat Arch. This is where you're headed. Next month, and we would like to welcome you to Utah, and I would like to thank you for welcome to me to Boston. And I'd be happy to take any questions. Thanks. Well, Rebecca, I'd really like to start by thanking you. I think everybody can see that you are truly an international expert in liver tumors, and specifically with the sportings talk of Padawala Stoma, we'd better be to join us for the annual gross lectures at the Section A, with Dr. Myers, we're going to be on liver tumors in children with large. Dr. Myers is known as one of the most humble, selfless mentors and experts surgeons, and you can see by her presentation that she takes credit for for nothing in this credit to the international collaborations. But in fact, she is in a drying force behind much of this. So we thank you for your leadership. We thank you for your long-term perspective. You close by being honest about the fact that we haven't solved it all yet, and despite the numbers, and it's really the children's overall health that that meets so much. So thank you for your leadership and your integrity. And when we open up for questions. I remember Betha, some make him. How are you? I see you. Oh, hi, I'm good. Thank you. Thanks for the great talk, and I also appreciate your leadership over the years in this field. I, you know, as you know, we have a multi-disciplinary group here. We talk about all the receivers together. The Chris Walton, Leo Neal and others. And it's always interesting to see how sort of the history of all this explains in such detail as you just did. One of the questions I've always had is this question of receptability. And as you know, receptability is that I have to be holder. And sometimes you get referred patients who are deemed unresetable. You feel like you can recept them. And I can always, I've always been concerned about all the studies around this because it's very subjective. It sounds like Greg is trying to pursue this current study. But I guess one question is how, how do you deal with this in studies? How do you deal with this in these studies? And also has there been an effort to share how we all do liver sessions because I think in fact we probably all do it differently based on where we were trained. And we are somewhat siloed in surgery. So you get trained by your mentors. I was trained in this by Bob Shambler at Criville High. And we don't get out there much. And we talk about things at meetings. But in fact, I've never come out to see how you do with the liver session. I've never seen how Greg does liver session. We talk about it, but we actually don't really teach each other. I wonder if there's been an effort to do that. Because of the variability of what we all think is receptable. Whereas it's the, of course, given your knowledge in this field, it's the big question, right? How do we make this decision? And at the end of the day, each individual surgeon makes it, as you said, with their own set of preconceived notions and their own patients in mind, right? We're all trying to do the best thing for the patient in front of us. And you see people come to really different conclusions about what that may or may not be. I think the thing that we can do in our research studies is try as hard as we can to centrally review the imaging so that when we talk about long-term outcomes, we're really talking within an informed way about what the extent of tumor was going into the surgery. And that's why I could probably back up here to answer your question in an elegant way to say, I don't know. Because this is where we are today. I'll get there just a second. So bear with me. That's where we are, right? So those are all centrally reviewed tumors. And this was really good, central review. I mean, we know that these are matched tumors based on their degree of ascolar involvement. I think pretty much they're good consensus that when you have these extensive tumors that involve the entire liver, transplant your best way to go. And we also know from that case, I showed you at the end, because we've all had one that had a bad long-term outcome that we really like to resect if we can. And the question is, how do we make this decision? And there is no elegant way of I know that I know of making that decision without asking yourself these questions. And sitting down in front of the family and in front of the oncologists and saying, here's my problem, which camp does this kid fit into the best? Because not not everybody is going to be a transplant and not everyone is going to be a a resection. There are a couple things that we can do to push people into this conventional resection group if possible. One is, have your resection done at Boston Children's, right? Have your resection done by a really competent surgeon, because that's going to bring a bunch of these patients out of the transplant group and into the conventional resection group. And at the end of the day, above and beyond, going to a really sophisticated team with all the best tools, I think the only other thing that we can do is simply try and resect when we can knowing that transplant is a viable alternative. In the short term, it's highly successful. It comes with a lot of long-term baggage. That's the best I can do to answer that question. I wish I had a needer answer. I know that Greg is working on a much more sophisticated algorithm. And we'll get there someday, but it's never going to be a black and white question. It's always going to be a judgment call. And if that judgment can be made by the most experienced person you can find and trust, the more confident you're going to have in that judgment. I would trust you to make that judgment for me. But I wouldn't trust anybody. So that would be my answer to how we can make that decision. Thank you for that answer. Rebecca, this is Bob. So a wonderful presentation. And I think it's a great compilation of all the way and know when it's learned over the last decade or so about treating a hepatoblastoma. And I think it also highlights the importance of multidisciplinary trials and studies with which you've been one of the leaders worldwide for the last many years. Only by cohorting large numbers of patients can we really address many of the issues and questions you've tried to educate us on today. So congratulations on all your efforts and all the knowledge we've gained under your leadership. Like Mars, I'm just like to ask, I'm an anesthesiologist, so I'm not aware of many of the surgical issues, but along a clinical trial design issues, I'm just wondering it would seem logical with some of these cases to have an adaptive trial randomization strategy because of the nature of the disease and the numbers about. Is that part of the plans here? So that is really a great question. Next time you see Ali O'Neill in the hallway, grabber, because that's what she's doing right now, is planning an adaptive trial that we call the Fit2 trial, which is in its planning processes as we speak. Something we'll be able to talk about a little bit more this afternoon in the growth sector or some of the advances that have been made in biology. And when you take the the biologic markers, together with alpha-femial protein response to therapy and recessed response and responsive vascular involvement, all of those are adaptive changes that are occurring with our chemotherapy, and that's our goal for the next trial is to design a trial that takes those early responses into account. And the person in charge of that is actually Dr. O'Neill. Well, Rebecca, we're over the hour and we have lots of things for you to educate our teams on today. We could probably go on for a long time here, but we want to thank you for this. This is a little bit of an enticement for our Fit2 attend the growth lecture this afternoon at five. Everybody should have the link. If not, please let us know and we'll make sure that you're going to attend. We look forward to all of the dept activities in your participation in our educational conferences today. And thank you once again. We definitely had some some beautiful social events plan for you and you can take a range check anytime you can. I'll be thinking of you while I have my coffee. You're in my thoughts. Thank you also much. And we'll see you in an hour. Bye. Thank you.