Hi. Hi, good morning, everybody. My name is Doctor Sophia Skar. I'm a surgical research fellow at Cincinnati Children's, and I'm going to be moderating the event today. We're really excited to have you here, and we are going to get started. Can ever screen. Hi, can everyone hear me? OK. Hi, good morning. My name is Doctor Sophia Schermerhorn. I'm a surgical research fellow at Cincinnati Children's, and I'll be moderating the event today. We're excited to have you all here for this, uh, live event on liver tumors, and we're going to get started. If you have any questions, uh, you can put them in the chat, and I will be bringing them up to our specialist that we have here today. So without further ado, we'll get started. OK, we're really excited to have our specialist here from Cincinnati Children's. So we have Doctor Bondo who will be our surgeon. Doctor Ragganathan, who's our pathologist. Doctor Summers, our oncologist. And then Doctor Tobin, our radiologist. And so the plan is to do this like a uh tumor board. So we'll be going through a few cases and again feel free to ask questions as we go along. So we'll start with our first case. We have a 2 year old, uh, patient who came in with to their PCP with fatigue, loss at home, and when they were seen by their primary care, they were a hemoglobin of 8.8. Um, so at that point they referred to the emergency department and they were found to have a part the mask. And their labs showed an AFP of 300,000. So Doctor Tobin, if you're able to just take us through the imaging. Yeah, thank you. Thanks for having me today. Um, so I'm gonna be sharing the imaging. Uh, our initial study that was performed in the emergency department that I'll be sharing today is a CT of the chest, abdomen, and pelvis. Um, and because of the symptoms, um, there was some concern for a lung pathology. So we initially had started, um, with a chest CT and then seeing what was in the abdomen, added on an abdomen and pelvis. On this initial chest CT. Um, there are multiple pulmonary metastases. These are large metastases throughout both lungs. The largest measures up to 3 centimeters in size, and so quite large for, um, a young child. Um, these metastases are throughout all lobes in both lungs. What we saw moving into the abdomen. Um, was this large liver mass. And so that's what led us to do a little bit more imaging, um, of the abdomen. Moving into the abdomen. Um, we did see this large hepatic mass. It's because of the timing of the contrast bolus, it is hard to figure out the margins of this mass, uh, but it's predominantly a right-sided mass. The gallbladder um is to the left of the mass, and so this is all within the um right hepatic lobe. One additional finding that we had identified on this study was fractures. There were multiple fractures. Um, the first one that we saw was of the vertebral body, a mild compression fracture. And then a second fracture um was a rib fracture that's a little bit more subtle. It's this area of sclerosis affecting one of the posterior ribs. The next study that we recommended was MRI and we typically perform MRI as our first-line imaging study for patients with a liver tumor. Um, and so this workup was a bit atypical. Most patients start with an abdominal mass, um, that's identified on physical exam. From there, we recommend an ultrasound to make sure that the mass is arising from the liver or to distinguish it from other types of abdominal masses. That helps us to protocol the MRI the best way possible. Um, for a, once we have identified the, the tumor is arising from the liver. Um, we would recommend an MRI using a hepatobiliary contrast agent. That allows us to better see the um presence of multifocal disease and make sure that we have the ideal assessment of the hepatic vasculature. In this patient, there is again this large right hepatic lobe mass. Um, I tend to start with these T2 weighted images to, to better, um, identify where the tumor is, to make sure I see that a tumor is present, and I get an early sense of the blood vessels. I'll use the post-contrast phases in the um arterial phase, portal venous phase, and delayed phases. To better assess the blood vessels, but this is really what I start with. Um, and on this T2 weighted sequence, I already have a lot of information. I know that there is a large mass. I know it's arising in the right hepatic globe. I do not see multifocal disease, and I am seeing its impact on the vessels. This is the inferior vena cava. Um, with the right hepatic vein, middle hepatic vein, and left hepatic vein all coming around off of it. And I'm seeing tumor extending into the inferior vena cava. Um, so, uh, some active tumor thrombus. Um, more of the arterial phase of imaging. I'm sorry, this is a more of a portal venous phase of imaging. I'm able to see those same things, the right hepatic vein, middle hepatic vein, and left hepatic vein with thrombus having some direct extension. And so this is likely through an accessory right hepatic vein, um, but extending into the inferior vena cava, but not occluding the vessel lumen. Um, and then on the hepatobiliary phase, um, which I'm, I'm showing a more of after treatment at this point, the tumor has decreased in size. With the hepatobiliary phase, we're also able to see, um, the vessels, the bile ducts. Um, and this is after the initiation of therapy again. So we have the tumor has decreased in size. It's confined, uh, mostly to the right posterior section. But it does come up near a branch of the middle hepatic vein, um, with all of these, um, minor branches of the right hepatic vein. Coming down more inferiorly, it gets, um, close to the portal vein and crosses into the right anterior section abutting the gallbladder fossa. Um, at the outset, this was a pretext to tumor. There were venous involvement because of the inferior vena cava and metastatic disease. It has decreased in size at post-text, um, but it's still a post-text 2 tumor. We are not seeing venous involvement anymore. At this point, there are still pulmonary metastases, although they have decreased in size. Um, and that was the last imaging prior to resection. During resection, an intraoperative cholangiogram was performed. The gallbladder was cannulated and contrast injected. Um, this is the common bile duct. Coming to intrahepatic ducts. To the right and to the left. And then with then further resection, the right hepatic lobe has been resected, still injecting the gallbladder to the cystic duct and common bile duct, but now we're just seeing opacification of the left hepatic duct. Doctor Bondok, do you wanna comment on anything else with the intraoperative cholangiogram? Um, no, mostly that during the resection piece of things, um, we, uh, my standard is to shoot an intraoperative cholangiogram. Um, it's not as important for these anatomic resections that are hemihepotectomies, or, but it is important for those, um, that you know, have potentially aberrant biliary anatomy. And which is another, yet another reason why your input is so important during a tumor board case is that if you have these, if you have a, you know, a, a biliary excretion phase, you can be prepared to know that, you know, 25% of the time, perhaps one of the right sectoral ducts comes off the left. And so, you don't want to get too close to, obviously, to the left-sided ductal system and compromise that and, and create a problem. So, Um, I use that as both a pre-resection and a post-resection, um, technique to ensure safe resection of the biliary tree, uh, and then also hopefully prove to myself that I haven't created a bio leak in the resection margin. Um, and this, that's, as you mentioned, that's one of the benefits of the hepatobiliary agent. This is on that delayed hepatobiliary phase. We do see central, um, intrahepatic ducts, as well as the common hepatic duct to the common bile duct. Um, it's a little bit variable about how much excretion we see. Um, we definitely do not see this, the peripheral ducts very well, but centrally, we do, we do see them nicely. After resection, um, there were still pulmonary metastases. These were eventually, uh, gone after as well. Um, and so this is after that liver resection, um, and moving towards lung resections and nodulectomy. I'll transition the, the conversation back, um, to the slides. Thank you, Doctor Tobin. Um, before we go forward talking about this patient specifically, you mentioned that this patient had some pathologic fractures. So I was hoping you all could discuss a little more about some atypical presentations that are concerning for malignancy. Yeah, I'm happy to jump in here, um, as the oncologist representing for our multi our large multidisciplinary team that, uh, really takes care of these patients as a cohesive unit, but you know, rib fractures or, uh, vertebrate vertebral fractures are actually fairly common as a essentially. presentation factor with hepatic tumors in young children, particularly hepatoblastoma. Doctor Tobin and his colleagues have published on this because there are times where we will meet patients, um, as they come down a non-accidenal trauma pathway due to fractures, and their imaging then reveals an abdominal mass that requires further workup. Additionally, we know that, that these fractures will heal as they go through their therapy, and kids um are remarkable in their resilience and tend to be rather unbothered by their fractures once we get their cancer therapy underway. Other things that we look for for atypical presentations that could be related to a hepatic malignancy would be things like precocious puberty. In a Tanner stage one patient, um, so patients that should not have signs of, of secondary sex characteristics developing, that is a sign that, you know, we should consider among many other things, but a, uh, underlying malignancy on the differential. And then, you know, common things being common, most of the time when kids are having vomiting or You know, uh, challenges with feeding, respiratory distress, big bellies, it's often constipation. So we will often meet a patient after they have gone through many pediatrician appointments, which is appropriate. Most kids do not end up having a hepatic malignancy. However, when things are just, just not lining up and kids aren't getting better, that is time for a referral to either the emergency department for urgent care or to a center um that has the ability to assess for, for kind of the next layer of what might be going on in that patient. Thank you so much. And we'll stick with Doctor Summers. I hope she can speak a little bit about the induction therapy for this patient. I would be happy to. So this young man came to us from a, a, a referral center that um we partner with regularly for the care of patients with liver tumors. And basically, we knew from the get-go that this kid would need high-risk therapy due to the presence of um the multiple pulmonary metastases. There are some circumstances where we have a young patient with some questionable concern for pulmonary nodules, but this was a kind of do not pass go moment. We knew these large bulky lesions would clar uh you know, certainly require high-risk therapy. So he was started on treatment per um the Children's Oncology Group study AHEP 1531 Group D. This study is also known as FIT or the Pediatric Hepatic Malignancy International Therapeutic Trial, which is being, um, kind of, it's now close to accrual but being assessed and the data is hopefully gonna, you know, come forward in the next couple of years. Um, as a conjunction between Sciopel in Europe and our Japanese colleagues as well as the Children's Oncology Group to really best answer how we care for children moving forward with liver tumors. So, due to this patient's presentation with metastatic disease, a large burden of disease, a high AFP, Really irregardless of pathology, we know that we are gonna treat him with chemotherapy first to better allow Doctor Bonddock and his team to have successful attempts at resection. So the therapy includes our, um, kind of backbone for pediatric liver tumors, a platinum agent, cisplatin, as well as an anthracycline doxorubicin for which we institutionally will always give um dextrozoxane, the cardiac protectant agent with the doxorubicin. In fairly intensive cycles. And we typically will see um a nice response in AFP if we're gonna have a patient that responds within that first cycle or two, as well as correlation with response on imaging that we obtain um to set the stage for surgical planning. So this patient did very well with his therapy. He had expected complications including need for nutritional support, which I will state almost every young toddler that we meet with a large liver tumor is going to require aggressive nutritional support to best get through the intensive therapy as well as the surgical procedures required. There is excellent data across multiple pediatric cancer types that demonstrate that weight loss or sarcopenia during active cancer therapy is associated with poor outcomes across the boards for all diagnoses. So advanced nutritional support is a key part of the care for these patients to ready them for Doctor Bondo and his team to do their surgical interventions. Kate, in this, in this, um, age group, you know, I think you, you mentioned, this has a very characteristic look to it radiographically and that, you know, the age, the age is, you know, sort of. Predictive of this being hepatoblastoma. What other things will you be thinking about? Let's say the AFP is not as high or the kid is a little older. What other things are you worried about? Yeah, the spectrum of hepatic tumors and um pediatrics moving into the adolescent young adult population would branch towards more hepatocellular carcinoma type presentations and then this hybrid in between hepatocellular neoplasm not otherwise specified, which gives us flavors of both the hepatoblastoma and the more treatment-resistant carcinoma kind of cousin in the same tumor. Additionally, just differential in general, when we have a patient, uh, a young patient with a liver tumor, we think about hepatic sarcomas, although they're less common in this toddler age group, particularly with a markedly elevated AFP. Um, we don't tend to see metastatic disease patterns with these large bulky, um, liver tumors, but it, it's something we would certainly be considering. And then there are some benign liver masses that can be rather impressive on presentation. Although, uh, radiographically, it's, it's, you know, um, Doctor Tobin and colleagues are able to distinguish this better. So things like hemangiomas, adenomas, and, um, Other benign processes would still fall into our differential bucket when we first meet a patient. The pulmonary metastasis for this child, as well as the size of his primary tumor, helped us narrow down very quickly in conjunction with the elevated AFP, but there are certainly many other things that can kind of masquerade in the hepatoblastoma arena. Uh, from the initial imaging, we would have, we would not have much of a differential in this patient. Um, with, uh, a young child, pulmonary metastasis, and a large liver mass, this is hepatolastoma, 99.9% of the time. And the other stuff is just super rare, so not, not worth the general differential discussion. Um, it, it comes out on the biopsy or because AFP doesn't make sense or other things. For just a large liver mass in a young child, the other thing that I would add would be mesenchymal hematoma as a benign lesion, that should be more of a cystic tumor or have larger cysts within it, but that can be variable. Um, and, uh, but I would not expect lung metastasis. All right. Thank you. Doctor Bonda, are you able to share a bit more about the surgical uh care of this patient? Yeah, I think, you know, what I mentioned, what I alluded to earlier is certainly the communication with um Doctor Tobin, Doctor Summers, and Doctor Rangganathan is critical here. And, you know, there's also data in certainly in pediatrics about the approach of a tumor board as it Pertains to the success and the long-term outcomes of patients whose cases are presented at a tumor board style multidisciplinary um conference. And I most certainly need that to know, especially in this case, where we knew that there was um cable thrombus encroaching into the IVC um in order for me to not only plan the primary resection, But to, um, to address the cable thrombus, which can be almost like a needle in a haystack in a lot of ways. And so, after, you know, we, the timing of the surgical therapy is typically after the 3 induction blocks of Cyopel 4. In order to get the maximal um effect um of the tumor shrinkage to make it resectable. In this scenario, it was pretext 2 to begin with, but also, you saw that gigantic caval thrombus, which in that scenario, if that didn't respond after maximal neoadjuvant therapy, then you would be talking about involving your cardiothoracic surgery. Uh, friends to go into the cava or even go through the diaphragm into the atrium to fetch that if it was, if it remained the way it was. And so, we need to know that as we sequence the imaging through therapy. There's, there is also some data to suggest that you get the maximal bang for your buck after the first. Um, block or cycle of C5VD in, in intermediate risk patients or the first block after of Cyopel 4, you typically won't get as much shrinkage or contraction of the tumor after your subsequent blocks. So that's something to be mindful of as you continue to serially uh image the patients, but also to time your surgery. So, in this scenario, we got through the, the 1st 3 induction blocks. We knew that this was pretext 2, limited to the right hemilir, so that was gonna dictate a right hemihepatectomy, but then also we knew in the operating room, we were gonna go have to go find this tumor, thrombus, which was residual. And so, one thing we do routinely for any liver tumor, but is most sensitive in hepatoblastoma, which we published on is use, is the use of endocyanine green, which is a fluorophore. Um, that, um, can be elicited and, and glow like you're kind of seeing here, uh, in this image in the gall that's the gallbladder, and this is actually post resection to assess the margin of the liver. Now, one of the failings of, and you need specialized equipment to do this, um, that most visualization companies, uh, offer, um, and you can do this thoracoscopically, laparoscopically, or A lot of the companies also have open detectors. And so what I'm trying to do here is look for any residual tumor, knowing that one of ICG's kind of limitations is that it's not specific, it's highly sensitive. So it can help you find. Uh, multifocal disease, and we've published on this. Alex has helped me go through many, many chest CTs to go backwards and look and see, and we found that they're in a very small handful of cases, about 15% of at least lung resections, that sometimes we'll find things that we didn't see even with high resolution uh axial imaging. But in this scenario, we're looking for margin status, um, which we demonstrate that there's nothing left and Ranga will talk about margin status. Um, the next set of slides here or the next images here, Sophia, we're trying to look for the cable thrombus, which we couldn't find cause you can actually see tumor through vessel walls with ICG. But in this case, we didn't find it and Doctor Ranga will tell you why we didn't find it with ICG in a, in a, in a little bit here. But you can also use other techniques like intraoperative ultrasound, which we actually did for this because we needed to get isolated. of the, uh, of the vena cava, there you can see it with the clamp, this metal clamp, because you can't just open the vena cava and hope for the best. You have to isolate that area from the rest of the flow or take out the flow of the vena cava, which can, you know, which affects the, the patient's preload, certainly. Uh, but we were able to find this little tiny mass, isolate the vena cava, make a venotomy, and then, uh, extract this piece of tissue. And then, unfortunately, due to the size of the venotomy to extract this, we ended up using a little bit of bovine pericardium to reconstruct the vena cava wall and the patient needed to be anticoagulated for that after surgery. So, uh, I think at this point, we might turn it over to Doctor Ranga to show some pathology. This is just showing, I'm sorry. You're good. This is just showing you the other possibilities of their other, the software and the detector can show you very high resolution imaging, which is the left side, uh, I'm sorry, the right side of your screen, where you eliminate everything else except the ICG. So if you only have faint. ICG fluorescence, you can see it much better when everything else is dark. And then the, the panel on the top left is, I call it the weather map. It's the it's the intensification. Um, um. View where the red, and you can, you can't see it behind the photo, but the, the panel shows very high intensity is red, and then a decreasing intensity scale, so you can kind of gauge what is, how, how, um how much fluorescence is being given off by the ice, the whatever you're assessing for. About this one, Sophia, so yeah, we can go with Doctor, perfect. Good morning, everyone. Um, so, Next slide, please. So it's interesting that in this case, at least retrospectively we reviewed because this biopsy was done outside. So there was a biopsy that was done and we make it a point to confirm the diagnosis every single time when we get a subsequent surgery or when the patient gets referred to us just to make sure that we are seeing exactly what the outside pathologist has also seen, so. This was a very small tissue fragment, just one of these pieces, so the biopsy was very small despite the fact that the tumor itself is so huge. But again, there are always a lot of restrictions when biopsies are being done in different centers, and we perfectly understand that not every time we can get perfectly multiple cores of tissue. Uh, I just want to highlight at this time that I know that the default was to see a liver mass and imaging and to start treatment, but the FIT trial, the AHP 1531 and the FIT trial actually mandated liver biopsy for diagnosis of the lesion before we start treatment. So, uh, the current protocol till it got close, the requirement was that you have to do a biopsy to confirm the diagnosis that it is hepatoblastoma. And I'll come to that a little later as to why that becomes significant uh to know the histology of the tumor before you start the treatment. Next slide, please. So at the time of surgery, this is how we approach it. We get the entire, the hepatectomy specimen, hemiheicectomy specimen over here, and we in pathology have an amazing group of pathology assistants on the grossing bench that actually meticulously slice the liver in the plane and of imaging and basically lay it out and then take a picture of everything. And once we select the piece which has the maximum, so here you can actually see that the tumor is this large mass uh that is present, you know, pretty much occupying this whole portion of the liver. Now this is post treatment, so you can understand that that post treatment there's always an element of shrinkage, but what we're looking for is we're looking for the margins. We're making sure that we ink it black as you see in this first slice at the top left. And then we sly slice it and then we go ahead and map this as in the right sided image basically so that we can go back if there is any place where there is an abnormal looking histology, we could go back and reevaluate it and we know exactly in which slide that particular area is represented so we can do additional stains or molecular testing on that so. NGS testing has become an integral part though we still, uh, you know, because the biopsies get done up front outside somewhere and come to us as a referral, we may not always have necessary tissue to do the NGS, but we have really found it to be helpful in our internal cases where we sort of have set the process of doing uh NGS testing locally in our institution. So next slide please. So this is what the tumor looked like on resection, and you can see here pretty much all you're seeing is these pools of blood and some inflammatory cells in between. So this tumor actually showed a great chemotherapy response and the resection specimen actually showed very, very little viable tumor that was present in here. So this was actually a very good outcome for this patient. In the sense that the liver tumor responded completely and resection showed almost greater than 90% of the tumor was dead and all it showed was these pools of blood and very little of viable tumor cells that were scattered here and there in pockets in between all. This dead responsive tissue. So again, this is one reason why we say that tumor response, as Alex mentioned, tumor response is maximum in the initial stages of chemotherapy, because once chemotherapy begins and the tumor gets replaced by these pools of blood as well as fibrous tissue. There's nothing for the chemotherapy to kill. It's now all this tissue that's going to keep staying on, and then the size doesn't decrease much further beyond a certain point. So I think that's an important lesson to understand in the surgical decision that once chemotherapy effect takes place, the tumors may not change much in size beyond a certain point. Next slide, please. Sorry, the next one. I think this patient also had multiple bilateral lungs that were removed surgically subsequently, and there was really no viable tumor at any of the nodules. So we saw all those multiple pulmonary tumors, but they all responded beautifully, just like a primary tumor. So this was among the better outcomes in a way that you can see in terms of tumor response to chemotherapy. OK. Thank you. I'm done with the first case. Yeah. Thank you. And Doctor Summers, can you talk a little bit about the adjuvant therapy? Absolutely. So, you know, this is one of the, the tricky points that often comes up um when we're discussing with families is, you know, we're, we're telling the great result that we had a beautiful treatment response, um, but we need to get more chemotherapy and do more surgeries. So what we typically do for patients that are off study until we have the uh maturation and publication of data from Um, the FIT trial is for patients that have had a successful primary tumor resection, which is always our first surgical goal whenever possible. We will then proceed with kind of alternating chemotherapy consolidation cycles with uh carboplatin, so a cousin of cisplatin that is somewhat better tolerated and less intensive late effects, as well as continued anthracycline with doxorubicin. So the goal would be whenever possible, we like to allow the patient to recover and our recovery time is rather quick post the, uh, liver resection. Give a cycle of carbodx and then plan to head back to the operating room for uh clearance of lung lesions, which we typically do in a staged procedure. So one side and then the other will follow, following the next cycle. When we can achieve this schedule, um, we know we can kind of give our intended 3 courses of consolidation chemotherapy without needing to extend further cycles and still allow for nice time for surgical recovery, um, moving forward. But I think particularly of note in a patient like this child where we have known vascular invasion, known metastatic disease, you know, continuing chemotherapy despite a beautiful response and despite the fact that we know that we will have, um, You know, our biggest chemo effect earlier on, we still give chemo to try to weed out any remaining cells that are circulating that are remain active. So, you know, making sure that we stick to the path of our full intended chemotherapy treatment and fold in our surgical sequencing is another thing that really um requires the multidisciplinary collaboration on each one of these patients. And we have a question from the audience. Um, so do you all do lung biopsy of those lesions before you move to resection? We would not, um, I mean, but as, as Alex was saying, you know, 99.9% here is hepatoblastoma and the, you know, knowing that. Um, hematogenous metastases to the lungs as the primary site. So we are simply make, um, the assumption that with the biopsy, with biopsy proven in this scenario by Doctor Ranga or the team who referred the patient, we would assume that those are also patoblastoma and, you know, based on a, a good amount of data. Um, published by the COG, by Syopel, um, that we know how to sequence this exactly as Doctor Summers was talking about. In this one, the patient has obvious metastatic disease, and it's not a question. Would it, would, in a smaller lesion where it may be questionable, would you do it differently if that would upstage for therapy purposes? How do you feel about that one, Kate? That's a tough one. Yeah, it would really, really have to be case-dependent. Um, you know, it's rather uncommon if we're going to have pulmonary disease to have one tiny little nodule that we think is metastatic disease. Um, so it's us, it's not a clinical scenario that comes up often. We usually have some good clues that this is going to be metastatic disease. And, um, It would be a, it would be a conversation. It would definitely need to be a conversation. The other hard part about biopsying is if it's a tiny, tiny lesion and we biopsy, we can't ensure that we got the entire lesion out either, and that can make it much more challenging for um Alex and colleagues to go back in and try to clear that spot if biopsy determines that it was in fact disease. And the pretext criteria have some strict definitions for what is a metastatic disease. Um, and so that's more than 2 nodules greater than 3 millimeters in diameter or 1 nodule greater than 5 millimeters in diameter. Those are tiny numbers, um, in an, in, uh, in adults practice. Those are very small nodules that you might not pay attention to, but in young children, those are fairly large nodules. And a clarification from the audience, so after they undergo that induction chemotherapy, there's no biopsy to check for viability before going back for a metacystectomy. No. And in fact, even if we, we know the disease needs to be cleared from the body, and our best pathway to cure, and this is what kind of changed the overall survival for hepatoblastoma patients over the past several decades, is the combination of chemotherapy And surgical clearance of known disease. So even in a patient such as this where we know the first side of the chest had no viable tumor, we still go back and clear the other side of the chest, um, because that is our best pathway to long-term disease control and maintenance of remission. And that's exactly what we did here, Sophia, as you're showing is this is um the, the majority of the, the, the right side of his disease was um more significant after uh induction therapy. So, we typically, as Doctor Summers said, like to stage it because it's, it can be quite a bit for, to ask a child to recover from what may need to end up being bilateral thoracotomies or open surgery, but a lot of these patients will do well with isolated thoracoscopy. And here you can kind of see, as Doctor Ranga mentioned to you that the, the viability of uh the lung resection was not, they're all, the vast majority of them are all dead. And so, you can kind of see the hint of uh fluorescence green here with this thoracoscope. But really, there were other masses we could see with the naked eye that weren't fluorescent. And so, it's interesting that ICG correlates with, can correlate with the viability of these lesions. And here we are just stapling them off, so you can just use a surgical stapler despite the chest of a two year old being quite a small space. You can maneuver your way around it and isolate the metastases to gain a margin, so that Doctor Ranga doesn't get mad at me for getting too close. I think we already discussed um about clearing both sides of the chest. So for the sake of time, um, are there any questions about this case from the audience? Feel free to, um, comment. We do have one question that I'm going to say in the next case, um, so I see it and I will bring it up for the next case. Um, so moving forward to the second case, we have a 9 month old patient, um, who is an ex-3 34 weeker, and they had a little more complicated prenatal history, so they were found to have anhydramus on 20 weeks' anatomy scan. And this was due to bilateral multicystic dysplastic kidneys. Um, and they ended up undergoing intrauterine infusions, um, 6 times. And then after they were born, um, they have hyperplastic lungs. They were intubating delivery room and underwent a period of high frequency oscillatory vailation, um, and eventually were acted. Um But due to those um bilateral um multicystic kidneys, they ended up requiring hemodialysis originally that was then transitioned to your peritoneal dialysis on day of like 16. And so they were transferred to an outside hospital, um, but then returned back to CCHMC for, um, hypoxic respiratory failure several months later, um, with their dysfunction of their peritoneal, um, dialysis catheter due to a large hernia, and that's when they presented to our team here. So they ended up doing a CT venogram to assess the grade vessels, um, and I'll let Doctor and talk a little more about what they found. Great, thank you. Um, so for this patient, we had been screening, um, performing ultrasound for quite a while before that CT venogram that was just mentioned. Um, so we had a lot of imaging that included the liver. This is one of the studies prior to the CT venogram, um, by several months. And on this one, the liver looks abnormal. It has a coarsened architecture. Um, but there were no masses. Then we have the CT venogram several months later. Um, on this study, um, moving into the liver, there are hepatic lesions. There's at least this one that's a large one. It has a heterogeneous appearance. It's mostly hypodense compared to the background liver, but it's tough to tease out. There's also this hyper dense lesion or component more anteriorly. Moving more inferiorly, there is a suggestion of additional lesions, but they're really hard to tease out. And then we get down to the kidneys and the kidneys look like they're full of cysts. This is not a typical look for multicystic dysplastic kidney. It's um more common look of a other type of celiopathy or, or abnormal um Uh, abnormal kidneys. Multiccystic dysplastic kidneys are often smaller than this and not as cystic. Um, these all look more fluid density. Because of the renal replacement therapy, the ribs have this bulbous appearance, um, almost like rickets. These were not fractures though, compared to the last case. Um, and because this patient had chronic kidney disease, also had lung disease that was related. Patients, um, with hepatblastoma are frequently born prematurely. Um, this patient, because of renal failure, had, um, challenges with lung function as well. So we often see patients with, with this type of, um, poor lungs or bronchopulmonary dysplasia type lungs, um, that can make it difficult to identify nodules. We did not think there were any nodules at the time of diagnosis. After the um CT the same day we performed ultrasound, there are multiple hepatic lesions again, some of them are more hypoechoic, others are more hypeechoic. Um, and these were solid with internal vascularity. The next study that we performed was an MRI. Um, again, my approach is usually to start with Two-weighted images. On the Two-weighted images, there are multiple hepatic metastasis or multiple hepatic lesions. Um, they do have slightly different imaging characteristics, but most of them are, um, are similar. And then we see multiple cysts in both kidneys. With the multi-phase post-contrast imaging, there was no vascular involvement. The portal vein is open and the hepatic veins were all open. And then on the hepatobiliary phase of imaging, we can see the extent of multiple lesions. Um, they are in each section of the liver. Um, so this is a pretext for multifocal tumor. There is involvement of the caudate, and so this is also a caudate positive annotation factor. I can pass along the baton to um for the further discussion. Thank you. Can we share my screen here? OK, so, um, again, this patient is a little more complex than the last patient we talked about. So, as I mentioned, the PD catheter wasn't working, they were then transitioned to hemodialysis and were listed for simultaneous liver and kidney transplant. Um, and Doctor Summers, maybe you can talk about the neoadjuvant therapy for this patient and how you, um, took into account their greater, more complex medical history. Yeah, thanks, Sophia. I think, you know, even taking a, a further step back and looking at the big picture of a medically fragile or complex patient with a new oncologic diagnosis, the care and um kind of thought behind how we can manage these children has, has evolved. And I think um there are a couple of reasons for that, you know, first and foremost, more kids that have very complex medical histories are surviving past the neonatal phase. And so we are learning which conditions and which predispositions might give rise to, to oncologic risk. Um, so it's not that this is, this is a new phenomenon. I think, you know, our medical technology and ability to do things like renal, um, replacement therapies are allowing kids to have longer lives where we can uncover more things that they might face, um, further down the road. So, you know, our traditional predispositions, um, we think about Beckwith-Wedemann syndrome, some of the other hemihypertrophy syndromes, trisomy 18, which certainly falls into the category of patients that previously had extraordinarily poor neonatal outcomes, but now, Um, are sometimes able to be able to support it, uh, supported through early life, as well as known, um, autosomal recessive poly polycystic kidney disease, extreme prematurity. These things are all known, um, risk factors for developing hepatoblastoma. But what we've kind of uncovered working through our institutional experience here is, it's not just the autosomal recessive, uh, polycystic Kidney disease children. It's really end-stage renal disease early in life. We are noting an increased incidence of hepatblastoma patients. And You know, the, the challenges there is cisplatin's primary toxicity. It's our best drug for these tumors. The primary toxicity is um renal, and so we can really cause chronic kidney disease. But it also means that we are fully dependent on a renal system of some sort to, uh, process and excrete platinum. So when we are faced with having to treat a patient on dialysis, we actually have some great experience treating patients both on chemo and peritoneal dialysis with platinum and able to kind of support appropriate infusions without the typical mandated hyperhydration. And use um advanced pharmacokinetic and pharmacodynamic modeling systems to be able to understand a patient's individual platinum clearance curve. So I think this is a population we are learning so much more about because we are given the opportunity to treat more children than we have in previous years. Thank you, Doctor Summers, and that actually um goes into a question from the audience pretty well. Somebody asked about antenatal diagnosis of glioblastoma. Um, can you speak at all to that? Yeah, so, um, we, you know, our, we typically see kids more in the toddler range, so, you know, moving towards that first and the 2nd year of life. However, these patients that are more predisposed can develop as early as immediate, you know, if not congenital immediately. Um, post-delivery. So for a known predisposition patient, we will start a screening protocol with ultrasound as well as, um, alpha fetoprotein levels, taking into account that alpha-feetoprotein has a very different range of normal values in early, in those first months of life. So we, um, sometimes an early presentation of hepatoblastoma is gonna cue a genetic workup where we discover things that we didn't previously know about the child. OK, thank you. So we already spoke a little bit about this. So I'm gonna move on for the sake of time. So Doctor Gonda, can you talk about this patient's transplant? Yeah, so I think one thing to remember is there, there is data to suggest, and we kind of alluded to it in the previous, um, case, how are we gonna anticipate the patient's surgical control for cure. And if, if Alex showed me this MRI of pretext for multifocal disease, I'm gonna tell you right off the bat this patient's a trans is gonna have to have a transplant. So even in the outside of the context of changing the cisplatin monotherapy, you know, having lung mets, this is a patient who would be referred early to our transplant, our liver transplant program to be evaluated because again, The way typical deceased donor liver transplant works, you can't snap your fingers necessarily unless you have a living donor to transplant the patient. And again, timing of therapy, of neoadjuvant chemotherapy with definitive surgical resection is, is incredibly key. So, but the added complexity of this case, as Doctor Tobin showed you those horrible kidneys and the kid's been, had in utero kidney failure. Um, and been sustained with renal replacement therapy since birth is a combined liver, kidney, uh, transplant, which in a two year old, 1-year-old is incredibly complicated. And in this scenario, what we ended up doing for this patient was an on-block, liver and kidney bilateral kidney transplant from a size-matched donor. Now, obviously, in liver transplant, in deceased donor liver transplant, or even living donor liver transplant, you take a bigger piece, you take, you section off a piece of an adult's liver or an older person's liver, and you can sometimes use the kidney. So there are options here. This was what we happen to do for this patient. Um, and we're able to get him through, uh, both kidney and liver transplant. So, but again, with transplant being the key piece of surgical resection for those patients who have multifocal disease or who have locally advanced intermediate risk disease who you don't think you'll be able to You know, if it's invading both portal veins, although it spares one side of the liver, these are all the kids you have to refer early and work with your multidisciplinary team to get them staged appropriately, but also ready for transplant. Um, so, that being said, I, it's, you know, we have a handful of these patients, uh, because we have this, we have a fetal surgery program who a lot of these patients would not have survived past the postnatal period. But at the, at the expense of time, I want Doctor Ranga to weigh in also on these patients and this patient's pathology. So on this case, I guess this was a little unusual specimen. It was, I mean this was something that I had to pull up from my files, so to say, but I did manage to find the girls' images of the surge of the surgery of both the kidney as well as the liver. So the left hand picture actually is of the kidneys when they were cut open and basically you can see that they have varying size scar cysts, and the kidney tissue itself, parenchyma around the cyst pretty much doesn't exist, so it's sort of a very scarred. Uh, parenchyma, which would be more keeping with, uh, multicystic dysplasia. So despite the radiology saying that looking big, it happens sometimes with some of these multicystic dysplasias that the kidney doesn't shrink to that level because the cyst size themselves are quite big, and that could be because of, uh, most common causes are usually lower urinary tract obstruction that results in. And the multicystic dysplasia. So this one was an example of multicystic dysplasia. The cysts in both autosomal dominant and autosomal recessive, have a more specific pattern of arrangements which makes it more, uh, you know, doesn't show the degree of fibrosis that you see associated with the multicystic dysplasia because it's not an inflammatory process in that scenario. So the liver transplant on the other hand was very interesting that while the patient had multifocal tumor, you can see a lot of those tumor sizes actually had shrunken a lot. So you have all these slices that we cut through the liver, but the tumor slices which are labeled with those green labels, they basically are small. nodules that are seen post chemotherapy. So there was a much more extensive sampling that was done in this just to see whether there was a tumor that was viable or not. And for the most part, a lot of those sections did show dead tumor, and there were occasional focal areas with some live tumor. So next slide please. So I think the, the point was this was still called, there was a lot of bone in this case, and that was why it was called as a mixed hepatoblastoma, but a lot of those nodules were because of chemotherapy effect with a lot of bony tissue that was left behind, and the chemotherapy response was difficult to assess because each of the nodules were different, but overall it seemed to be much better than 50% response, which I Usually associate with a better chemotherapy response and hopefully better outcome. So the pathology on these details of the histology, I could not generate because of the fact that the slides were very old and faded. So this was a little bit of a unique case, so there was not too many cases to duplicate this, and I did not want to. Uh, bring slides from another case, but I do, I have shared a presentation that basically highlights the pathology of hepatoblastomas and pediatric HCCs as a, you know, review article which you can probably refer to for the different histologic categories. The important thing that we assess in these tumors is basically the response because this patient has had therapy and of course, uh, there would be continuing management on these patients which probably Doctor Soms can. Uh, comment on after that. And before we move forward, um, just a question for Doctor Bonddock. So if this patient had had pulmonary meds, um, what would your strategy have been for trying to get this patient to transplant? It's somewhat similar to um what we discussed with management, what, what Kate mentioned about management of pulmonary meds after. We try to sequence them in between. Cycles of chemo. So let's say Alex showed me a pretext for patient, we've referred early for liver transplant evaluation, thinking that we were going to optimally transplant the patient after the 3rd block of Cyopel 4. So we're way in advance, but in order to make the patient transplantable, you cannot have extra hepatic disease, because remember, you have a huge induction of immunosuppression. To get the patient to accept a liver from another human being. So what we'll try to do is we'll stage the blocks and then in between the blocks, we will do chest surgery to resect lung metastases, to clear the chest, so that once we get approval from the whole liver transplant team to list a patient for transplant, because that's a condition of it. That once we get through that third block of Cyopel 4 high-risk therapy, or whatever the induction therapy is, 6 cycles of C5VD potentially, we would go, we would be ready to, you know, have all that done so that we could immediately list the patient, activate the patient so that our wait time accrues. So, another sort of Thing to mention here in the United States when you're on the deceased donor list, a child with hepatoblastoma automatically gets status 1B categorization, which is the second highest stratum for organ allocation. So not only do children get priority because of their age, but also based on the severity of their disease. And remember that a patient with hepatoblastoma, less so than a hepatocellular carcinoma. Typically does not have underlying liver disease, which usually is, are the criteria, or at least the measures of how high you will ascend on the uh liver transplant waitlist. So, it, it's all timing, it's all working with the team you see here to get the patient to the right spot in a, in the right, in the right amount of time. And Alex, just to add to that, typically, as um part of the requirements for moving forward with the transplant listing process is, you know, um, an offer of some sort of systemic therapy that I can give the patients while we're potentially waiting for, um, sometimes an extended period of time for an appropriate organ offer. And this is where, um, uh, regimens that are less intensive like vincristine rinotecan can come into play. But part of the planning and why we like to be so aggressive with our surgical timing is we don't, if we have to extend therapy due to organ offers, we certainly don't wanna extend it due to our lack of ability to get the patient to the OR when they need to be. So I think the, the kind of level of organization that comes in from just a Um, more administrative side of caring for liver tumor patients, uh, really impacts their outcome and their overall late-term or long-term, uh, toxicities from therapy. One question we have for the audience was about exome or genome sequencing, and I thought that could also lead into talking about um synthesis since we haven't had time to talk about that. Sure, I think, uh, so one of the important things that we have realized is that to categorize the liver tumors correctly, especially in the pediatric age group, and to really recognize the entity that we have called provisional so far because of lack of data that we had based on the previous consensus classification, the hepatocellular neoplasm NOS category. We realized that we need to do molecular studies on these to basically identify what is the event that is going on and driving the tumor. Normally hepatoblastomas, the conventional hepatoblastoma, is sort of genomically quiet. Basically it has a very low mutation burden, very little mutation events, and invariably has either a point mutation or a small deletion in the exon 3 of the CTNNB1 gene. As compared to that, when we come to the hepatocellular neoplasm NOS category, we see a lot more genomic instability, activity, a lot more chromosomal gains and losses, more similar to what we see in hepatocellular carcinomas in adults sometimes, but they are all characterized by the CTNNB1 deletion, and many of them tend to have large deletions in the CTNN. B1 gene and some of them even skip the exon 3 completely so they have exon 2 joined to exon 4 and the entire exon 3 disappear, disappearing, and this sort of reflects on the beta ketenin immunoistic chemistry that we use in these cases. The beta keten in immunoistic chemistry is frequently very weak positive, or even negative in many of the cells, and that sort of is a. Flash that together with a very pleomorphic appearance of the tumor cells, a lot more heterogeneity in the tumor cells, a macrotrabecular arrangement of the tumor cells that resemble the HCC, all these are clue to the diagnosis of HCNNOS, uh, and the reason we call it HCNNOS, which was decided in the FIT trial, was that to treat these patients have definitely a hepatoblastoma. Component and in fact many of the biopsies are called hepatoblastomas and it's only at the time of resection we see the hepatocellular carcinoma-like areas and I think the point is that because there is a hepatolastoma in there, it is possible to target them as a high risk hepatoblastoma therapy to shrink the tumors and make it amenable to surgery in most cases. It may not be 100% of the time. But at least there is some reduction in the size in response to the chemo hepatolastoma areas dying, and then you can go and take out the tumor and even if the tumor remaining shows hepatocellular carstoma-like areas, at least it was surgically removed and the burden on the patient is decreased. Obviously, the FIT trial will give us a little bit more concrete data on some of these patients that have been treated prospectively with the Group D chemotherapy as well as surgery following that, and we may have a better idea on the outcome on these patients as we collect the data, which is not available at present. And to address the, the exome, um, so every patient that comes to us, um, in oncology with a new cancer diagnosis is meeting with our genetic counseling, um, oncology team. So we have learned over the years that we just We don't know. We don't know what we don't know, and kids are not supposed to develop tumors. These are, you know, by, uh, driven by different processes than adult cancer. So every child will get the opportunity for complete genetic testing, including watershed testing if something is identified. And then we utilize our in-house next-generation sequencing test in Z-Seek, which has rapid and um thorough analysis with an excellent turnaround time, and a panel that was developed in conjunction with um Doctor Ranga and then Doctor So McElroy, who's our molecular pathologist, as well as us on the oncology side to ensure that we are capturing all kind of targets of interest in pediatric oncology. Alex, I wanted to ask you too, as a setup question for you cause I know what your interests are in and, in AI and, and what you know from radiology. But do you think, you know, you showed us that, especially that first tumor, how heterogeneous it is. Will you ever get to the point where you can predict what's inside of that tumor? Uh, we hope to. Um, and so there's a field in radiology called radiomics. Um, you might hear it as radio genomics or radio something else. But radiomics, the goal is to say, can, from the pixels, can the phenotype predict the genotype or predict the outcomes or predict the histology. We've done some early work on this with hepatoblastoma. Um, it is not yet published, but that, what we've been able to see is that we're able to predict, um, pure fetal histology, for example, with a relatively high degree of certainty. The area under the receiver operating curve for that, um, that specific histologic diagnosis is about 0.85. Um, and that's meaningful because if, if we can get to that point, those patients are cured with resection alone. They don't need chemotherapy. Um. That's early data that needs to be validated on, on future work. Um, we've also shown that artificial intelligence can segment tumors very accurately at the level of an expert. That, that work has been published within the last month. All right. And Doctor Vando, a question from the audience about robotics. So, are you using robotics? Is anybody using a robotics at Cincinnati for these, either for the primary tumor resection or for the metastatectomy? We haven't yet. Um, typically, these patients come to us around somewhere in the vicinity of 10 to 1510 to 17 kg. Um, so we've talked a lot about it, um, because as a lot of the audience clearly is asking. Um, there's a lot of adult robotic liver surgery, both on the, you know, living donor side, but resection for cancer. I do, two of my partners are doing neuroblastoma resections, uh, robotically down to about 12 to 15 kg. So, um, but one of my partners and I have discussed operationalizing, um, the, using the surgical robot, the intuitive robot to, um, It's the one we have, we happen to have, um, operationalizing it for complex liver surgery is certainly, but again, like anything else in an emerging technology like Doctor Tobin was talking to you, you have to validate it. So you have to find the right case that you think you could do and stage it in such a way that the learning curve is not such that you harm your patients, try, you know, just for the sake of improving um technology. Or saying you can do something. All right. I think we've gone through most of the questions from our audience, and I think we're at our hour. Um, I have one more slide. I just wanna thank everybody for being here and sharing your expertise. I think that was a really, um, dynamic discussion. And, um, if there's any further questions, people can post them, um, and you can also post them to our social media.
