With an increased incidence of liver cancer in U.S. children, pediatricians need to understand the most common tumors, pick up on possible signs and know first workup steps. Pediatric hematologist-oncologist Arun A. Rangaswami, MD, offers this guide, including stats to show when hepatoblastoma (the most common childhood liver malignancy) is likely – and when it's not. Learn how UCSF's pediatric experts approach diagnosis, using advanced techniques that inform prognosis, and how an international effort to enhance risk stratification helps clinicians select the best treatment for individual kids. Bonus: Hear about relevant clinical trials currently underway at UCSF.
It's my very great privilege to uh be able to talk with you. Um, today I'm gonna talk about uh our pediatric liver tumor program and also about our pediatric liver center of excellence. Um, so if I'm gonna share my slides. And put it in presenter mode. All right. Um, so, I have no disclosures. And this is the outline of the talk, so I'm gonna start off with a case summary of a patient and, and that patient's clinical course. Then I'm, I'm gonna give an introduction to pediatric liver tumors, um, talk a little bit about the role of the primary care provider um in managing these patients. Then I'm gonna focus on hepatoblastoma, which is the most common uh pediatric liver malignancy in childhood. Um, I will talk a little bit about our, uh, pediatric liver tumor program and then more generally about our pediatric liver center of excellence, um, which, uh, Emily and I can both sort of, uh, do and, and answer any questions. So again, thanks so much for, um, attending and, and for having me. So I'm gonna start off with a, a, a pretty typical case summary. So an 8 month old patient, um, obviously with hepatoblastoma, um, oh sorry, this is the, uh, sorry, I, I put up the wrong case summary. I don't know how I did that. Let's see. Um, apologies for this. Um, but the, the, an 8 month old patient who presents with the right abdominal mass, uh, and a 7 day history of progressive abdominal pain, fever, and fussiness. Um, and it presents to the primary care physician's office, who, uh, primary care physician noted the right abdominal mass. And ordered an ultrasound which demonstrated a large right-sided hepatic mass. Um, the Doppler portion of the ultrasound demonstrated attenuation of the intrapatic portal vein, and the patient was referred to the UCSF emergency department. There again, a right-sided mass was palpated as well as hepatomegaly. Um, at the ultrasound, uh, as mentioned, showed a large hypechoic mass situated in the right lobe of the liver. The labs were significant for a platelet count of 675,000, a hemoglobin of 8, and then tumor markers were significant for an alpha fetoprotein of 1 million. Um, the patient went on to have an MRI scan with a hepatobiliary contrast agent called Eovist, which demonstrated a 10 by 12 by 8 centimeter mass in the right hepatic lobe, um, with complex, uh, free fluid present in the abdomen. And the mass involved quinard segments 56, and 7 with right portal venous involvement. A CT of the chest was negative, and a pretext stage was 3, with annotation factors being 1 P1 for portal vein, R1 for rupture because of the presence of fluid in the abdomen, and the other annotation factors were negative. And I will, I will talk a little bit about what that terminology means, that nomenclature of pretext and annotation factors. CT shows is very large right-sided abdominal mass, and one can sort of notice that there is um rupture of the cortex, or the capsule rather, of the, of the mass. Um, this shows, uh, the mass scene, um, in a coronal view. Um, and an MRI again with EOS shows this large enhancing mass in the right lobe of the liver. The patient underwent an IR guided biopsy, which demonstrated hepatoblastoma with mixed fetal and embryonal histology. Uh, consultation with pediatric surgery, uh, suggested that given the presence of tumor rupture, delayed resection was, uh, preferred over upfront resection. Um, because of the other clinical features of this patient, um, they were deemed low risk, and they started neoadjuvant chemotherapy with a combination of, uh, agents called C5VD which, uh, indicates cisplatinum, 5-fluorouracil, vincristine, and doxorubicin. The patient received 4 cycles of chemotherapy and underwent resection, and then received 2 cycles of adjuvant treatment with um normalization of the AFP uh during that time period. And that patient remains in a continuous uh complete remission at this time. So to turn more generally to pediatric liver tumors, about 2/3 of all liver masses in children are malignant. So when we see a liver mass in a child, the odds are more likely than not that it will be a malignant lesion. Um, however, malignant liver tumors themselves are rare, accounting for only about 1% of all childhood malignancies in the SER database. Um, there are 100 to 150 cases of malignant liver tumors in children each year in the US, and of those, um, 2/3 are hepatoblastoma. When we look at the approximate distribution of pediatric liver masses by diagnosis, again, 43% are hepatoblastoma, um, 23% hepatocellular carcinoma. 13% vascular lesions, 6% mesenchymal hematoma, which are benign, 6% sarcomas, 2% hepatocellular adenomas, again a benign lesion but nevertheless relevant. Um, 2% focal nodular hyperplasia, which again, um, is a benign lesion, and 5% comprising other diagnoses such as malignant rhabdoid tumors of the liver, um, undifferentiated embryonal sarcoma of the liver, and primary biliary tract rhabdomyosarcomas. So in considering a differential diagnosis for a liver tumor, um, the age of the child is very, very important. So early in infancy, we see in the benign tumors, we see hemangioendotheliomas, um. Mesenchyal hematomas and teratomas. Um, hemangioendotheliomas are actually quite, uh, important diagnosis for to recognize because these can cause significant clinical, uh, uh, um, adverse effects. For example, we can see a consumptive coagulopathy called Casabach-Merritt syndrome in large cavernous hemangionotheliomas. We can also see um a high output, uh congestive heart failure. Um, and then interestingly enough, a perineoplastic syndrome that is seen with these lesions is hypothyroidism because they secrete an enzyme that degrades thyroxine. With respect to malignant lesions, again, hepatoblastoma by far is the most common, followed by rhabdoid tumors, yolk sac tumors that are primary tumors of the liver, which are rare, longer Hans cell histiocytosis, and metastatic neuroblastoma. In early childhood, again, we still see hemangiomatheliomas and mesenchymal hamatoma, but now we see more inflammatory myofibroblastic tumors in the benign category. And in the malignant category, we see hepatoblastoma and then rhabdomyosarcoma. Um, later in childhood, uh, you may see an angiomyolipoma as a benign lesion, um, or again hepatocellular adenoma. In the malignant category, you're starting to see more, uh, hepatocellular carcinoma and actually an intermediate entity that has been recently identified, which is called hepatoblastoma with carcinoma features. Um, is, um, the most, uh, likely, um, diagnosis in children over the age of 8 who have a malignant, uh, uh, tumor of the liver. This is a lesion that is, as I said, very recently, um, uh, classified. It hasn't yet entered the formal, uh, classification, so the consensus classification for pediatric liver tumors because it, it really is. Fairly recently identified based on both histopathologic and molecular findings. Uh, and then embryonal sarcomas can occur in this age group as well. As you see, hepatoblastoma is extraordinarily unlikely in this age group. And then in adolescence, um, benign lesions include adenomas, um, and cystadenomas of the biliary tract. Again, hepatocellular carcinoma, more classical hepatocellular carcinoma now, and then fibrolamellar carcinoma, which is a, uh, previously thought to be a variant of hepatocellular carcinoma, which is now, uh, classified, uh, by a pathemnemonic, um, uh, chimeric fusion that identifies it as a distinct entity. One can also see lymphomas in the liver and leiomyosarcomas. So as you can see, the age of diagnosis is extraordinarily important in approaching the differential diagnosis. Um, the clinical presentation of liver tumors, they're usually asymptomatic masses detected by a parent or by the physician. Um, the patient, if they're symptomatic, can present with abdominal pain, weight loss, rarely anorexia, vomiting with more advanced disease. Um, jaundice and liver function abnormalities are rare. They do happen when tumors impinge on the biliary tract, and then of course there are rare entities in um young adults where there's a composite tumor of cholangiocarcinoma and hepatocellular carcinoma that also will present with um jaundice. Um, you can also see jaundice and LFT elevations in the context of fibrolamellar carcinomas, which have a tendency to cause a lot of local regional nodal disease, which in turn can cause um biliary outflow obstruction. Um, if you remember the case I presented had a very high platelet count, um, and that thrombocytosis is due to the production of thrombopoietin by hepatoblastoma. So in a patient who has a liver mass and a very high platelet count, the suspicion for hepatoblastoma should be increased because that is one of the kind of characteristic features. If thrombocytosis is not seen, it doesn't exclude hepatoblastoma, but if it is seen, it strongly points towards hepatoblastoma. And then of course, uh, we see elevations in alpha fetoprotein in 90% of hepatoblastomas. We also see elevations of AFP in hepatocellular carcinoma, although usually not as high as hepatoblastoma. And then in fibrillammellar carcinoma, the AFP is usually normal. AFP elevations can actually be seen in a number of benign conditions. You can see elevation with anything that causes hepatocellular injury, so hemangio endotheliomas and mesenchymal hematoma simply by mass effect can uh elevate AFP. Um, it, it usually is not in the range of hepatoblastoma, which, uh, presents with AFPs of 10,000 all the way to over a million. Um, and so I, you know, I think it's important to also recognize that patients with Beckwith-Wiedemann syndrome, and we'll talk a little bit about this later, um, can have a baseline elevated alpha fetoprotein, and that can be confounding as those patients are also at increased risk for development of hepatoblastoma. So what is the role of primary care providers such as yourself in the management of pediatric liver tumors? Well, of course, the primary care provider is often the very first to detect an asymptomatic abdominal mass, and I will say that I probably about 50% of my patients are referred because of an astute primary care physician who feels a mass. As I mentioned, the differential diagnosis is really dependent on age of diagnosis, clinical and laboratory features such as AFP imaging findings. Tissue diagnosis is the gold standard for all primary hepatic neoplasms. I say this because in prior um treatment eras, um, an elevated AFP in a liver mass would have been sufficient to make a diagnosis of hepatoblastoma. However, we are in now the era of next generation sequencing and molecular phenotyping, and therefore, there's a lot to be gained by both histopathologic examination. Um, of a biopsy as well as running next-gen sequencing such as our UCSF 500, which can identify prognostic variables as well as potential therapeutic targets. Um, initial laboratory evaluation would be a CBCD, um, a complete metabolic panel. Rarely, hepatoblastoma patients like neuroblastoma patients can present with hyperuricemia, um, and they can certainly develop tumor lysis syndrome in the context of chemotherapy. Um, patients, uh, with, uh, hepatoblastoma that are large lesions, um, can sometimes have associated renal insufficiency. Um, and then hepatic function is important to assay. The other reason to look at renal function is because if one is ordering a CT scan with contrast, one needs to understand that the renal function is normal in order to do so. Um, we normally do get coagulation studies, mainly to look at hepatic synthetic function, as I mentioned previously, an AFP. And then, um, at our institution, we do tend to get urine catecholamines, HEEA and VMA because another possibility other than a primary liver tumor would be a metastatic tumor to the liver. And um we know that that happens, for example, in neuroblastoma. Um, it can happen in sarcomas. So, uh, we do order HVA and VMA routinely as part of our workup of these patients. The initial radiologic study of choice, which is what the primary care physician really um orders, is an ultrasound with Doppler. And that is really to assess the abdomen, the mass, of course, but also is there adenopathy? Is there any macrovascular invasion? Um, once the mass is detected, the patient, uh, is usually referred to the emergency department, and we tend to admit these patients for an expedited oncologic workup because we can get, um, for example, an MRI scan arranged much quicker on an inpatient than we can on an outpatient. And then the other important role of the primary care provider, which is a more anticipatory, is in the context of Beckwith-Wedemann syndrome. And I'm sure that you're all familiar with Beckwith-Wedemann syndrome, uh, which is a syndrome that is, uh, a genetic syndrome, um, uh, that, uh, maps to 11P, um, and these patients are at risk for development of hepatoblastoma as well as Wilms tumor. And so they are um getting, you know, ultrasounds frequently as well as AFP measurements, and this is something that our primary care physicians, um, you know, do for us, screen these patients and then refer if they find a concerning lesion. So I'm gonna turn now to hepatoblastoma. Um, hepatoblastoma, as I mentioned previously, is the most common primary liver neoplasm in children under 15 years of age. However, at 1.6 cases per million, it is a rare pediatric tumor. Um, it comprises over 2/3 of all malignant liver tumors in the pediatric AYA population and 90% of all liver tumors in children under 4 years of age. Um, we have noted an increasing incidence annually in the United States and in the European Union. The reason for this is unclear. Um, it may be, uh, linked to, for example, increased use of fertility medications or for, um, our ability to salvage premature infants at earlier and earlier ages, um, and NICU exposures. Um, risk factors for hepatoblastoma are prematurity, and I mean extreme prematurity, um. So that's any patient under 30 weeks. Um, very low birth rate, which is defined in this context as less than 1.5 kg. Parental tobacco exposure, and then potential associations that are yet to be proven, ionizing radiation, such as happens in the NICU when we have babies getting frequent X-rays, erythropoietin, um, for, for infants with acute kidney injury in the NICU. Uh, TPN exposure, and then fertility medications. These are potential associations. They have yet to be shown to reach significance. We have an epidemiology, um, working group within the Liver Tumor Committee and the Children's Oncology Group, and Logan Spector, who is, um, our lead epidemiologist and based at University of Minnesota, Has published a lot of very compelling data about linkages with hepatoblastoma and other congenital conditions and exposures. Historically, 4 international cooperative groups undertook the study and treatment of this disease. Children's Oncology Group here in North America, COPE in the UK and Europe, the GPOH in Germany, and the JPLT. Um, the GPOH no longer exists. The German, uh, Pediatric Oncology and Hematology Group has merged with COPE. And the JPLT has also merged with the Japanese Children's Cancer Group or the JCCG. So both of those are now legacy cooperative groups. However, their trials are continuing to be published as those mergers were fairly recent. And this um is uh data from the SER database 2017 that shows age-adjusted incidence rates for hepatoblastoma shown here in blue and then hepatocellular carcinoma. Um, and what is very interesting to me now is patients in this middle group who we often called either patients with hepatoblastoma or HCC, hepatoblastoma being, you know, older patients, HCC being younger patients, but in fact, as we do more and more molecular, uh, studies of these patients, it appears that that intermediate age group. Um, may be a distinct entity unto itself, this, um, histology I alluded to earlier called hepatoblastoma with carcinoma features. And these are patients that typically have both, um, unusual histology and molecular findings such as mutations in the telomerase, uh, reverse transcriptase promoter, um. ARID-1A, other genomic markers that are seen in hepatocellular carcinoma, but they can also harbor CTNNB1 beta-catenin mutations seen more frequently in hepatoblastoma, and they seem to be some sort of an intermediate diagnosis. Um, intermediate as well in response to treatment and in response and in overall survival and event-free survival. So this is a group that we are very interested in studying in the future. Hepatoblastoma has a median age of diagnosis of 16 months, and only 5% of cases occur in children over 4 years of age. It is more common in males than females, and it's associated, as I mentioned, with extreme prematurity. The relative risk of hepatoblastoma is inversely proportional to birth weight, and in Japan, hepatoblastoma accounts for 58% of all malignancies diagnosed in surviving preemies weighing less than 1 kg at birth. Hepatoblastoma is um associated. With a number of cancer predisposition syndromes and genetic syndromes, foremost among these is Beckwith Wiedemann. Um, which I mentioned earlier, and these are patients for whom, uh, there are defined screening guidelines to promote early detection of, uh, patients with hepatoblastoma or with Wilms tumor. Patients who have a history of familial adenomatous polyposis caused by mutations in the adenomatous polyposis coli gene or APC gene are at increased risk for hepatoblastoma. On patients with hereditary hemorrhagic telangasia caused by mutations of SMAD-4, other overgrowth syndromes such as Prader-Willi syndrome, Soto syndrome, Simpson Globi Bemmel syndrome, and then patients with Williams syndrome or trisomy 18, which um used to be considered uniformly fatal. Uh, genetic syndrome, but these patients with improved supportive care and uh surgical interventions are living longer and now are surviving long enough to get hepatoblastoma. Um, now, other than Beckwith-Weedemann syndrome and familial adenomatous polyposis, um, we do not have screening guidelines for any of these other conditions as of yet. That's mainly because we have to ascertain more accurately what the true incidence of, of hepatoblastoma is in these other diagnoses, which are, are quite rare compared with Beckwith-Weedemann syndrome. Um, and so at the present, we are only really screening. Back with patients and FAP patients for embryonal tumors. Um, and so I just, uh, wanted to talk a little bit about Beckwith-Weedemann syndrome and the defective imprinting at the IGF-2H19 locus on chromosome 11P15, as well as, um, the cause being uniparental disomy, um, where there is, um, you know, a single, uh, chromosome 11 inherited, um, from Uh, rather, two chromosome 11s inherited from one parent, usually the father. Um And turning to FAP, um, there has been a lot of variable estimates of germline ABC mutations in hepatoblastoma. The Germans in 2006 published a fairly high incidence rate of 10%. The group in Cincinnati found a higher incidence with a lower number of patients, but they included variants of uncertain significance. We have an ongoing retrospective study of now over 120 patients. These are patients that are enrolled on this study from Stanford, UCSF, the DFCI, Children's Oakland Huntsman Institute in Utah, as well as in the French database, and we're trying to perform a correlation. Between APC gene mutations and clinical characteristics as well as prognosis. Um, and, and I am the, um, senior PI for that, um, that study. All right. And then the other thing that I wanted to talk a little bit about is the biology of hepatoblastoma. Um, hepatoblastoma, um, classically is associated with acquired mutations in the wind pathway. Typically mutations in beta-catenin, an axon one, but also in APC as we mentioned earlier. Um, typically one sees only one of these wind pathway mutations in any patient. So either betacatenin or axin 1 or APC. Um, there are mutations associated with overexpression of downstream genes like cyclin D1. And then overexpression of wind-related proteins, for which now we have developed um antagonists that are being deployed in early phase clinical trials to see whether these wind-driven tumors such as hepatoblastoma can be um treated by um by reversing the uh the amount of protein in their um blood. Um, and so the role of the wind pathway really is in, um, Patho in, in, in neoplasia and proliferation. So what WIT does is take a normal fetal hepatocyte and when WIT is constitutively um expressed, that fetal hepatocyte transforms into a malignant cell or a hepatoblast. Um, and so, uh, this is of course 90% of what hepatoblastoma patients have beta-catenin mutations or WIT pathway mutations. So historically in terms of staging, there were two approaches. Um, surgical staging, um, which is the children's oncology group's historical approach, um, looked at extent of resection. So a stage 1 completely resected, a stage 2 resected with microscopic residual disease. A stage 3 is a patient who has gross residual disease, including involvement of local regional lymph nodes, and an inability or and or an inability to resect the primary tumor and stage 4 distant metastatic disease. More recently, however, our European colleagues developed a more sophisticated staging system called pretext or pre-treatment extent of disease. Um, this was developed by the Syop Group, um, in Europe, and it's based on the number of liver sectors, not segments, sectors. So if you look at the, uh, liver in an AP, uh, dimension and divide that liver into 4 equal sections, um, this is based on the number of contiguous sections that are involved. Um, we look at the degree of extrapatic extension and whether metastatic disease is present. And these are characteristics that help to determine resectability, although this is really ultimately determined by the surgeon, um, because we do not want surgeons to operate outside of their comfort zone on patients like this, um, because, for example, a, uh, rupture of a tumor that could have been shrunk with neoadjuvant chemotherapy. Um, is a, a, a significant complication and, uh, a risk category for patients. Um, the Europeans developed pretext staging as well, um, out of an interest in, in giving preoperative chemotherapy in a more, um, individualized fashion based on extent of disease. Um, multivariate analysis in the Cyopel 1, chemotherapy trial, uh, showed that pretext staging, uh, was the only predictor of overall survival, um, and we believe that it was because pretext staging is a surrogate for resectability and possibly biology. And um the other thing that was predictive of event-free survival was um uh the presence or absence of metastatic disease. And so, this is where a group called SHIC that I chair comes in. SHIC stands for the Childhood Hepatic Tumor International Collaboration. And sheikh is a uh um a attempt to unify the language of uh risk stratification and harmonize it among the different national cooperative groups. So as I, as I show here, historically North America used the Evans staging or the Cog staging, and Saipel used the pretext staging system. So the traditional Evans staging we've already been through. The Cyopello staging system, um, is actually, and this is the historic, uh, staging system because there was a modification on the staging system published in 2018, but that modification is somewhat controversial, so I'm gonna discuss the historic staging system. Um, so again, pretext stands for pre-treatment extent of disease. We now are looking at post-text or post-treatment extent of disease to see whether post-text correlates with outcome. Um, patients can be pretext 123, or 4 based on how many sections of the liver are involved. Here are the 4 equally divided sections of the liver. And then there are these annotation factors. Um, and this is what I alluded to earlier in the case presentation. So in patients who have ingrowth in the vena cava or all three hepatic veins, we call those patients V positive. Um, in, in growth in the right and left portal vein or at the bifurcation, we call P positive, E stands for contiguous extrahepatic tumor, F for multifocal tumor, um, R for preoperative tumor rupture. C for caudate lobe involvement. The caudate lobe sits here. It's, it's actually um the quinard segment one of the uh uh liver. And because it is so closely associated with the vasculature, um, caudate lobe involvement in and of itself can increase um the potential necessity of using transplant as the local control measure rather than resection because Um, only about 25% of patients who have caudate lobe involvement can be resected. The majority of those patients require transplant. N stands for lymph node involvement and M for distant metastatic disease. So you can see that this is a much more nuanced way of approaching tumors of the liver, looking at both local extent of disease and also macrovascular involvement and also metastatic disease in a unified system. So, going back to Sheikh, Sheikh is the largest database extent in a pediatric rare tumor. Um, it comprises 1,605 patients, um, drawn from four historical cooperative groups and eight clinical trials. And actually, recently, this database has now increased to 2200 patients because we recently added um data from more contemporary trials that have been published. Um, then the, um, original, uh, database was formed of 8 clinical trials. These were the German HP 8999 trials, INT 0098 from the US, uh, POG 9645 from the US, JPLT 1 and 2 from Japan, and Saipol 2 and 3 from uh Europe. And what we did was we we pooled all of this data. Using a common set of prognostic risk factors that were agreed upon by consensus, we performed a univariate analysis, and then we performed a statistical methodology called backwards elimination, um, to perform a multivariate analysis um within these 4, actually 5 backbone groups. Um, which are backbone 1, pretext 1 and 2, backbone 2, pretext 3, backbone 3, pretext 4, backbone 4, metastatic disease, and backbone 5, AFP under 100 as a um putative negative prognostic marker historically. We also looked at age, um, as a prognostic factor, and this is one of the most, um, I think, important, uh, um, discoveries by Sheikh. We, uh, actually determined that age appears to be a continuous adverse prognostic variable in hepatoblastoma. So increasing age inversely affects the hazard ratio um for metastatic disease and annotation factor positivity. What I mean by that is that when you become old enough, like over the age of 11, It doesn't matter whether you're non-metastatic or metastatic, your outcomes are very poor, regardless. And this shows that effect of increasing age, abrogating the effect of metastatic disease, which you see here. So, here are the pretext um and uh sorry, the chic stratification uh algorithms or trees as we call them, and um the, this is what we use to stratify patients to treatment to this day. Um, and then, We are no longer using AFP under 100 because the SHIC database was analyzed and what we found is when you take out all the patients who had wrong diagnoses, so for example, rhabdoid tumors who have normal AFPs, that low AFP in and of itself was not an adverse prognostic factor in typical hepatoblastoma. So what about local control of hepatoblastoma? Well, hepatoblastoma is a surgical disease and complete surgical resection is necessary for cure. Only 40-50% of primary tumors are resectable at the time of diagnosis, and the goal is a lobectomy with a clear margin for pretext 1 in 2 patients. And then pretext 3 and 4 patients should really be biopsied at diagnosis with an early referral to a transplantation center such as here at UCSF. Um, for consideration of either liver transplantation or a complex or extended liver resections, which really should be done by, um, centers where transplantation um allows for greater surgical expertise to conduct these types of operations. Um, cisplatinum-based chemotherapy regimens generally make about 50% of unresectable tumors resectable, so that, that's good news. Chemotherapy, when administered neoadjuvantly, um, does help to shrink tumors and make them resectable, but that leaves about 25% of tumors that may require advanced surgical approaches, including transplant or orthotopic liver transplant. Um, and then there is some evidence that the Cyopel chemotherapy regimens, which are cisplatin intensive, may actually be superior to the COG regimens in terms of rendering resectability, and this is under active study currently. Also, for patients who have pulmonary metastatic disease, hepatoblastoma is the one type of metastatic childhood cancer for which a liver transplant can be allocated. Hepatocellular carcinoma is not in that category, at least not yet. Um, and so, however, they do need to have, um, resolution of their metastatic disease either by resection, if they don't disappear with chemotherapy, or if they have an excellent chemotherapy response and a negative CT scan, that is also adequate for proceeding with liver transplantation. In terms of chemotherapy, um, the mainstay is multimodal therapy with, um, cisplatin-based pre and post-operative chemotherapy. The children's oncology group, as I mentioned earlier, uses a regimen called C5V or C5VD in um standard risk or intermediate risk or high-risk patients. Cisplatin Saipel used Pla-Doh, cisplatinum and doxorubicin in high-risk patients, and cisplatin monotherapy in low and standard-risk patients. The Germans used IFOS and cisplatinum and found a higher incidence of second malignant neoplasms, and the Japanese used epirubicin and cisplatin, and they also found an increased risk of second malignant neoplasms. Um, salvage therapy with vincristine and irinotecan is effective as are other salvage regimens like carboplatin and entoicide, which tends to be my go to actually based on German data that's been published recently. The utility of radiotherapy in hepatoblastoma is principally confined to the treatment of extra hepatic nodal disease, especially, for example, a patient who has jaundice that limits administration of chemotherapeutic agents like vincristine or doxorubicin. You can use radiotherapy to relieve the, the point of obstruction and allow the bilirubin to return into a range where you can deliver um appropriate chemotherapy. And then I was um the PI, the USPI of a Cyopel trial that looked at um amaphostine, um, I'm sorry, that looked at sodium thiosulfate to reduce odotoxicity in children receiving cisplatin-based chemotherapy, and we found an almost 50% reduction in uh odotoxicity in patients receiving um uh cisplatin-based chemotherapy. Um, this was in standard risk patients. The COG trial looked at amaphosphine as an odoprotectant and unfortunately, amaphosphine did not bear out to be protective, but sodium thiosulfate does. And so that was published actually in the New England Journal of Medicine. So, this very complicated scheme is how we treat hepatoblastoma currently. This is the AHEP 1531 COG nomenclature or the FIT, the Pediatric Hepatic International Tumor Trial. This trial recently closed in January of this year. Um, it was a trial conducted across, um, North America, Europe, Japan. Um, Australia, New Zealand, and, um, Asian sites such as India, Hong Kong, and Singapore, which enrolled patients under the Japanese umbrella. It was the first international trial for a uh pediatric liver tumor, and it was really quite a successful experiment in our ability to To study a relatively rare disease by leveraging the numbers of patients available through international collaboration. So, just to summarize, Pediatric hepatoblastoma is a rare pediatric tumor with all the inherent challenges that that means in studying it. The four major cooperative groups that have studied hepatoblastoma I've mentioned, and there were variable approaches to staging and treatment, which were harmonized through the CHI uniform risk stratification system. So I'd like to turn a little bit to the UCSF pediatric liver tumor program. Um, and our liver tumor program, um, you know, uh, treats children to young adults with a variety of diagnoses including hepatoblastoma, HCC, hepatoblastoma with carcinoma features, fibrillammellar carcinoma, undifferentiated embryonal sarcoma of the liver, rhabdoid tumor, and cholangiocarcinoma. Um, we are, uh, employing a number of strategies to improve outcomes. We are leading, uh, a, a national pediatric, international pediatric liver tumor board. Um, we have international research collaborations, as I mentioned, leadership in clinical trials, um, as well as I should mention Emily's role in, uh, leadership in, uh, approaches to immunosuppression in the con uh in the transplant context. We're defining a better clinical and biological risk factors and trying to identify molecular targets. Um, ours is a multidisciplinary team which includes hepatobiliary transplant surgeons, um, hepatologists, oncologists, radiologists, interventional radiologists, pathologists, um, and molecular pathologists in genomics. Uh, our faculty have leadership positions in the Cog Liver Tumor Committee, the AF 1531 Study Committee, the CIOP, uh, uh, consortium, the SHIC Consortium, as I mentioned. We are participating in a, uh, development of a pilot trial for fibrolamellar carcinoma, and as well, we're participating in a pilot trial for high-risk hepatoblastoma, both of which, uh, have been drafted and submitted to the CRG Science Council for consideration. We are participating in a relapsed refractory hepatoblastoma registry. Um, uh, Emily has, you know, has leadership in UNOS and the Starzal Network. And then we participate in the Pediatric Surgical Oncology Research Consortium. We have a monthly International Multi-Center Liver Tumor Board, which I'll talk a little bit more about uh later. We have integration with the pediatric hereditary cancer clinic, which I lead with our molecular tumor board and our early phase uh um program. And, uh, And um, And of course integration with the UCSF Liver Center and ongoing research collaborations such as risk factors and hepatoblastoma and HCC through CHIC. Incidence of de novo germline APC mutations in the multi-institutional trial, genomic profiling of pediatric liver malignancies in a collaboration with the Sweet Cordero Lab, and then, uh, both Doctor uh Bruce Wang and Amer Nigigal have laboratories that are looking at single-cell sequencing of hepatoblastoma, while Doctor Sweet Cordero's laboratory really looks at bulk sequencing of those tumors. We have a number of um trials open, uh, phase 2 trial of immune checkpoint inhibitors, pembrolizumab and relapse and refractory hepatocellular carcinoma and HCNNOS that is open and accruing, a phase two trial of cisplatin rechallenge with sodium thiosulfate, um, for odor protection in patients with relapse and refractory solid tumors that are sensitive to cisplatin. This of course is, uh, extends beyond hepatoblastoma. And this is pending site committee review at our institution. And then we recently opened and treated our first patient with an industry-sponsored trial of an AFP specific CART agent in children and adolescents with relapse and refractory hepatocellular neoplasms. And, and actually, um, uh, this is, uh, for any patient with a high AFP secreting tumor, meaning an AFP greater than 100. That patient, as long as they have the correct HLA type HLAA2, uh, uh, that patient will be eligible for enrollment in this trial. The UCSF Multi Center International Hepatobiliary Tumor Board is a monthly forum with participation by an international panel of experts, um, spanning all of the disciplines listed there. Um, many of our panelists are members of the COG Liver Committee, CIPEL or the Japanese group. Um, it provides consultations to clinicians managing these rare and challenging diagnoses. Um, I say it lasts 60 minutes, it, it now typically goes to 75 minutes. Um, we have an average of 3 cases per tumor board and a max of 4 cases, and it, on occasion when we have the time, we incorporate a 15-minute didactic lecture focused on clinical and basic science research or new clinical trials that are available. The goals are to really provide access to global expertise um in managing challenging cases, to update clinicians on developments in risk stratification and treatment approaches, uh, and to advertise available early phase clinical trials for eligible patients. Um, we have considered patient confidential confidentiality and autonomy. Uh, we have a secure platform for PHI. We have integration of global expertise in pediatric liver tumors. Uh, we are supporting enrollment in cooperative group trials, uh, a user-friendly interface, and a quick turnaround and case review, and we do have the capacity for expedited reviews. And anybody, uh, any physician is welcome to, to participate. Um, you don't have to be a pediatric oncologist. If you're a primary care physician, you have a, you're managing a patient with a liver tumor and would like to, you know, have that patient considered, we're always happy to do that. Um, current participation spans a number of sites across the United States, Germany, uh, and Europe, Canada, Mexico, Brazil, New Zealand, Japan, Hong Kong, Vietnam, India, and the United Arab Emirates. And the sites that I've highlighted and read denote, um, centers that serve, uh, uh, uh, enriched rural, minority, uh, indigenous or resource challenged populations. We have been selected as the site of the next International Pediatric Liver Tumor Symposium in spring of 2025. Previously, this was hosted at Texas Children's, Cincinnati Children's, and most recently Boston Children's. The symposium is biannual, um, and its centers considered to have expertise in the management of pediatric liver cancer. The duration is 2 to 3 days of scientific sessions with concurrent poster and abstract sessions, and 1 day of patient family advocacy forum. Uh, usually we have 100 to 120 individuals attending from across the world, representing a variety of, um, specialties. Referring local oncologists are invited and covered, and of course, if there are any pediatricians who are interested in this area, you would be more than welcome to join. I'll pivot now to our pediatric liver Center of Excellence, which uh expands beyond uh liver tumors into other conditions um associated with pathologies of liver and children and adolescents and young adults. We have multiple missions, caring, healing, teaching, and discovery, and um. And, and these are reflected by, for example, you know, clinical consultations that we provide or advanced fellowships in oncology and transplant and, uh, you know, hepatology and interventional radiology, and by uh our research endeavors, both in terms of clinical trials, discovery through the sequencing efforts of our uh of our scientists and looking at things like health outcomes and disparities. Uh, and so, uh, we try to do multiple, uh, missions, uh, that support the UCSF mission. Um, in 2017, we came together to launch the pediatric Liver Center, and I don't know, Emily, would you like to sort of, uh, take over to talk about this? Sure. If that's OK, can you guys hear me OK? Yep. OK, um, I, this has been a really exciting effort for us, um, you know, to, to really work together and try to make sure that When a child is recognized to have some sort of liver disorder by their primary pediatrician or somewhere else, that the experience for the, the child and the family and the referring doctors is really seamless, that you can access sort of whoever in our you need as the sort of workup evolves. Um, and so it has been a really exciting opportunity for Arun and I and several of our other specialists to work together to really try to create a medical home for every child diagnosed with the liver disorders. So that we can really both offer and, and deploy our team of experts in a really comprehensive and equitable way to provide services for families, um, as well as providing a great platform for us to do things like advancing research, um, in, in a lot of different areas related to pediatric liver conditions so that we can increase children's opportunities for long-term recovery and health, not just the UCSS but in a, a broader community as well. Um, this is what our clinical team looks like as you kind of saw 3 stages on the last slide. We are really excited to have a team of folks from a lot of different specialties that includes Arun, as you see here, Emmer, who's one of our pediatric surgeons, um, and me as the co-directors. Um, from our different specialties as well as radiology, transplant, surgery, um, interventional radiology, radiology, and folks really on both sides of the bay so that, um, kids and families can access this kind of care wherever it's most convenient for them. Um, this is a list of conditions treated in a little bit about how we work together on all of them. But again, I think the important thing here is that our goal is to be sort of, uh, to have a relatively seamless point of entry for the child and the family as well as the referring doctor. So that if you have something happen where you identify a liver mass on an ultrasound from a PCP. Um, that you can be referred into CSF in the liver center and if Arun is the right person for you because it's hepatoblastoma, then you get hooked up with his team. But if he, you know, finds that it actually is something smaller and a non-malignant mass that, um, it's a very like easy sort of transition over to my team, maybe in conjunction with the interventional radiologist or even the surgeon. So we try to take on a lot of that work in terms of who does the family need to access to really get the best care, um, behind the scenes so that from a family perspective and from your perspective as a referring provider that it's really easy and, I mean, I mean, um, you know, doesn't require sort of separate going to different folks and trying to figure out where we need to be. So this is, I think, just a, um, a longer, again, list of, of all the things we do, which is essentially anything that has to do with the liver. It's done with the blood vessels in and out of the liver, the bile ducts, um, you know, all the way through obviously to the liver transplant team that I help lead as well for those kids who need it.
