Dr. Michael La Quaglia - The Role of the Surgeon in Pediatric Oncology

junior fellow. But Dr. Laquaglia has been at Memorial Sloan gathering and Cornell Medical School since finishing training and really established himself there as one of the prerumative figures in pediatric surgery oncology. And so it's really a pleasure to have Dr. Laquaglia here and look forward to it. Thank you. It is kind of a homecoming here. I still feel like the Chief resident or the junior resident. So I have no disclosures. I was you know what to talk about and so you know we've talked a lot about these kinds of operations and these kinds of tumors. Womestumer and Earl bless some of the big problems in pediatric oncology. I thought it would be more interesting I think. Let's see if I can get this to start. To talk about some things that you don't usually see but that you can see. And things that we have had experience with and are actually working on both from a clinical standpoint and a research standpoint. So I'm going to talk about colorectal carcinoma DSRCT, disemplastics morouncil tumor. The very rare tumor pancreatoblastoma because there's some interesting things there. And we're going to finish up with a tumor called gastrointestinal stromal tumor which is usually seen in adults but has a different and unique genetic form in childhood. So let's jump in. So this is a 14 year old patient that I took care of and you can see that there's a mass in the recto-signoid area here and here. He had presented basically with the vagabondal pain in a long period of a workup with no definitive diagnosis and then he got a CAT scan and showed this lesion. And at diagnosis we found as well if you look at this PET scan very carefully there was regional lymphadenopathy, a regional lymph node involvement. So he presented with metastatic disease right from the get-go. Now these are not colaposis patients and when I speak about colorectal carcinoma in childhood there are a small number that have polyposed that have FAP mutations that's not what we're talking about. They actually do very well. They're usually incidentally found when they have their collectomy. This kid presented De novo and despite nealagium therapy and radiation and a good resection I asked one of my colorectal colleagues to be involved taking out all the lymph nodes, taking out the getting the margins on the pelvis all the way down. He developed this liver metastasis about six months after therapy and that lung metastasis and went on to dive. This is another kid that I took care of. She's eight years old and had an ovarian metastasis from colorectal carcinoma and had pelvic metastasis just like with ovarian cancer with obstruction of the right kidney. So we got kind of interested in this and we first reported this in early 90s in the journal pediatric surgery. There are other case reports but we reported a series of these patients reporting a very poor outcome and a high incidence of signet ring or new sinus carcinoma. We then were able to accumulate about 169 patients. This goes up to 30 years of age but you can see that it's left skewed and but we have patients down to 10 years of age. There's usually there's a very high chance of having a positive family history. These are poorly differentiated in 37% and there's signet ring in 23%. So signet I'll show you a picture of a signet ring right here. So signet ring is a cell that's filled with mucus, new sinus material and the nucleus is pushed to the side. So it looks like a ring, a signet ring you'd wear. The 23% and this has been verified in other studies in a large report from the COG from a seared data is very rare in adult patients. It's less than 5%. So that was one of the first things that we noticed about colorectal cancer in childhood and adolescents. And this is just a poorly differentiated carcinoma which is what you see with what we've seen with is also in a higher percentage. And we started then looking at which is what we could look at, the mismatch repair genes. M-L-H1 is a mismatch repair gene and that's from Vogelstein's work in Johns Hopkins. That's very important in colorectal carcinoma. But really the abnormal staining was only about 17%. So if you remember the stages of colon cancer, it's very dependent on the T stage which is the invasion through the wall of the bowel here and down into the musk into the submucosa. Once it gets into the submucose of course it's exposed to the lymphatics and just sort of the same thing for the rectal staging. This is all AJCC staging from the eighth edition now. So when we look at the 169 patients that we had in our database which included up to 30 years of age, so it's the AYA group, you see that 37% were in the right but if you add the sigmoid, the left and the rectus sigmoid is almost about another half are in the left side as well. If you look at their TNM, most of them are T3 which is of course of concern because they're at risk for metastatic disease and of course when we see that, they're 36% were N2 which is the second nodal echelon away from the primary and 30% were N1. So a high rate of nodal metastasis and 40% had distant perankomal metastasis. So this is like an aggressive colon cancer. It's not like what you see in adult patients where they have the screening colonoscopy and there's a tumor and it's a T2 and it's easily cured with surgery etc. And this just looks at the overall stage distribution. So a lot of them are stage 4 and a lot of them are stage 3. We're able to perform an R0 resection only in about 70% of these patients. And then here's the rub. This is from our paper back in 1992 which showed a very poor outcome for these patients. And when we look at this, this is overall survival in this more recent cohort. It's really not that much better even with modern neoadrenal radiation and chemotherapy. And the disease free survival is terrible and what this is telling you is that even though there's some survival the patients that have disease are eventually going to succumb to their tumor. And this was this is from St. Jude and this sort of confirms that data. It's both the event free and the overall survival. Whenever you see the event free and the overall survival matching up like this, that's usually bad because there's no salvage from recurrence. And the mucinous, of course, is what we've been interested in. You can see that this is the mucinous patients do worse and there's a high there's a high proportion of mucinous carcinoma in colorectal cancer in these this age group. And again, that's very different than what they see with older patients in their 40s and 50s. And we found no effect either on overall survival or recurrence free survival in terms of the location in the in the colon. No significant effect. And stage, of course, this is again from St. Jude. They show that the stage was important in diagnosis and rather in prognosis. So in our cohort, these are the variables that we looked at. And the so a younger age was worse. Family history was better. Actually, the age of the hereditary non polyposis, non polyposis colorectal carcinoma status was actually better. And of course, increasing stage was worse. Increasing grade was worse. If you had an R. C. Euror Resection, you did somewhat better. Signet ring, however, did not affect this. So it's probably even though there's a high proportion, that signet ring by itself didn't affect it. And maybe other factors, the the undifferentiated cohort and so forth. So what is the role of surgeon in colorectal cancer? Well, I think we and others have defined this problem and put it out there. It happens. We see it. Resection is still the mainstay of cure. So you're the team leader and you have to coordinate with the other services. With that, one patient that I showed you is very important to get medical oncology, both adult and pediatric involved and radiation oncology, to at least give the state of the R treatment. So in addition, I think in collaboration, we have a unique ability to advance the research. So we've looked at mismatch repair genes, but I do think that eventually some kind of next generation genomic sequencing, as I'll talk about this evening, is going to be helpful in trying to understand the differences between colorectal cancer and childhood and in older patients. So that's number one. Another very rare tumor, but it's a problematic tumor is does in plastic small round cell tumor. And this is what it looks like. It's just a big old mental cake, another picture, and another one. This is the sea loop of the duodenum. And you can see the tumors fixed in the sea loop of the duodenum there and difficult to resect. These are just characteristics. You can see that they're young adults, but we have them down to the eight and nine, ten years of age. We take care of actually most of them in the hospital, even the older patients, because we've developed an interest in it. They're mostly male. They mostly present with abdominal pain or a mass or a sightsees. And this is what they look like. Huge abdominal mass, pelvic mass. And you can see that this is a there's tumor in the throughout the abdomen here. A sightsees with a lot of caking of the diaphragm on both sides that can take you six or seven hours to get off. A lot of nodal involvement involved with this, or mental and mesenteric involvement. And this just shows another picture of this sommental cake, which look like this. These actually lift right out and you can take them out way, but then you're left with that disease under the diaphragm. Most of these are characterized by this large pelvic mass, which is often difficult. And you can see there's a nodule overline the bladder here as well. And here's just another, you can see the size of some of these things. And these often require an anterior resection to remove in a diversion and so forth. And they do present with metastases in the liver. I'll show you a little bit more about that later. Pets cans are can be used to follow them. And the pathology, it's desmo plastic. So here's desmo plazia here, this stuff in here, the scar tissue, small round blue cell tumors. And here's the small round blue cells. And that's the name of it. It was described by Juan Rosai and Dr. Gerald in the early in the late 80s, actually. The interesting thing about this tumor is that it stains with keratin, so that's ectoderm, desmins, that's mesoderm. Desmins is usually a marker for rabdo in childhood and neuro-specific inelays, which is endoderm. So it has the three layers. We really don't know what the cell of origin is. This just shows a chromosome spread from one of these tumors and there was always this one. If you look at the 11th chromosome here and the 22nd chromosome here, you can see there's an abnormality, there's a loss in a gain, and these complex abnormalities, which is the old technology, sorry. And so William Gerald that our institution, along with Mark Lodani, was able to figure out that this actually was a translocation in this tumor, which is these translocations are very common in childhood. We see them in, I believe, Elvila, Ravdo, a myosarcoma. They're not the same ones, but we see this kind of, this translocation driven tumor in synovial sarcoma, mixoid liposarcoma, and you can go down the list of tumors. And so we see them. And what they found was that there was a, that the zinc finger from the Wilms tumor gene was translated, was transposed next to the, the Ewing sarcoma gene acted as a driver and that was what was driving the tumor. And this just shows you there are three isotites of that translocation or chimeric product. And they make protein and they do everything. And it's thought in all the tumors in childhood that have these translocations that that's the driver. And if you come to the lecture tonight, I'll show you a little bit more about that, but there are very few other somatic mutations that are consistent, like insertions, deletions, and so forth. So again, one of the reasons I'm showing you this, because I'm assuming there's going to be a lot of young people in the audience, is that this is something that needs work. It's obviously, this is pretty terrible. This is about 180 patients or so that we have. And this is the survival, the overall survival of these patients. So, Jamie Saltsman, when he was working with us, tried to put things together to develop some kind of a staging system. Initial staging system had been reported by the people at MD Anderson. When it was sort of sort of counting the number of lesions and sort of the extended disease and the perineal cavity. And we wanted to see if we could do it without involving surgery, but using the imaging. And so what he did was he went back and analyzed all the images from our cohort of patients and looked at chest liver and abdominal lesions and working with one of our statisticians was able to do this form of an analysis where he looked at what was important and what was most important. And this is all preoperative imaging, not at the time of not involving any surgery. And then he, his conclusion at this point was that any liver lesion or a site where major factors, the change things and in the multivariable model done by our statisticians, that was what came out. So any liver lesion or a site, these are the worst actors. And so he developed a risk score. And you can see that it does stratify reasonably well. The overlap is significant in between these two, I can tell you, if you look at the error bars. But it was a first attempt to try to do a preoperative pre-surgical staging of this tumor to try to see if we could put it into a format that people could talk back and forth about in terms of their extended disease. This is no ascides or liver. This is a site or liver and this is both. And in addition, when we've analyzed this cohort, we have reported since the late 90s that surgery, the bulking surgery actually improves survival. And this just shows you greater than 90% of the section compared to a not. And this is just some of the more recent work that we've done in terms of looking at this and looking at whether there was no surgery versus no gross resection, GTR means gross total resection. I'm trying to figure out what was most important in terms of trying to treat these patients. And so the gross total resection actually was an important factor in this. And so was radiation. So the recommendation we have is to continue to try to debult these tumors as extensive as they are, sort of along the lines of debulking for a variant carcinoma, which has been shown to be effective. And then total abdominal radiation, which is done, this is just the data for that, but this just showed you the, in the multi variable analysis, the resection, what we call gross total resection, are greater than 90% whatever you want to say. But removing most of the tumor and external beam radiation, we recommend, intensity modulated radiation, are still effective in the module. So we, this was done by surgeon. So all this, this was a tumor that was sort of helpless. We received patients routinely once a week that come to us that have been told that this can't be treated and so forth. And we do have some long-term survivors. I have one that graduated from medical school as an EWDF now. So you can, and who had extensive disease like that. And so you can have some cures. I think it's a work in progress. And again, for the young people, it's something that's going to require research and so forth. So we did the initial clinical analysis and work on the staging system. Dr. Hayes Jordan in Texas, I didn't show you that, but she was working with a hot intrapartinial chemotherapy, high-peck on these tumors. I'm not sure that has an effect, but at least an investigation was made. Resection is the mainstay. And I didn't talk about intrapartinial radiomunotherapy, but that's where we're going in terms of further treatment with this tumor. And of course, the molecular genetics developing cell lines. We now have some cell lines. They're very hard to make with this tumor, but there now are some cell lines and there's some patient derives, eagraths to start to do more work. So as being young, most of you, young people in the audience, these are things that are lethal. They don't happen very often when they happen. It's kind of like a major change in life. And I think that there are things that people can think about in terms of working on. So I had a couple of patients with pancreatoblastoma, and this is the form of pancreas cancer that you get when you're a baby. It's an acinor cancer. It's not an endocrine cancer. It usually affects patients between one and eight years of age. If it's cystic congenital, it's associated with Beckwith-Wedeman. There's a male predominance, and it is also predominant in nations. And it's very, very rare. It's less than one in one million in Europe, and it constitutes 0.5% of exocrine tumors of the pancreas. So this is just a, it's always good to do some history sometimes. So this is Becker in 1957 called an infantile carcinoma of the pancreas. And the histologic histopathologic description was made in 1971, and then the word pancreatoblastoma was coined in 1977. So this is the equivalent of Hepato-Blastoma in the pancreas in terms of embryonal tumors that occur in those, in those forgot areas. And this just shows you the papers that were published in those things. And it's not even on this list of this distribution of tumors. You can see the hepatic tumors are very small, but it's in this other. So very rare. We did a meta-analysis of this, and we go Danzer, who is with us for a couple of years, worked on this along with others. And the median age was four years, and it went from prenatal up to 22.4 years. We've seen older patients with it, let's see. And the site of origin and the pancreas, most of them are in the head, but they can be distributed throughout the whole pancreas. So we had to do whipples, we've done distal pancreatuctamase. This is just what they look like. They can have cystic components to them when you take them out. These fibrous bands, the ductule structures, and these squamoid corpuscles are characteristic of the, you can see in the squamoid corpuscle up here, are characteristic of the histology of the tumor. They stay with C-A and AFP, and AFP can be used as a marker for these tumors as it can be with hepatoid blastoma in childhood. We've tried to do a lot of molecular work on this. We do, you have a foundation medicine up here at the Broad Institute, but we do a form of that that is sort of the similar thing, and we don't really find anything that's very consistent, except there are somatic mutations in beta-cateenin in the wind pathway. So that's where it's at right now. Again, this is another tumor that will require more work in terms of research and so forth. You can see that hypervescularity in the head of the pancreas on ultrasound, if you can actually see that, but I think it's pretty clear you can see a big tumor in the in the tail of the pancreas here, and you can see something here in the snowstorm. This is tumor extending up into the liver with a nodal disease, and tumor extending over. And I had the, I resected one of these, and this young girl was a young baby at the time was, I think, four when I resected it, we did a wipple, we did a lymph node dissection, we cleaned it out, she had chemo or alpha-approaching, it was down to ZIP, and we watched her for four or five years, and she recurred after that with hepatic metastasis like this. They're pet avid, so you can use pet scans to see them. Just another case. And the procedures that are done are kind of evenly distributed, it just depends on where it is in the pancreas. We don't usually recommend a nucleation for this, I guess if it were very small, it's possible. Again, as I mentioned, the alpha-feet of protein can be used, it's not usually as high as you see with hepatoblastoma, but you can use it to follow the patient, so this is chemo-started, resection, and you can see that it drops, so you can follow the alpha-feet of protein and be nervous if it starts to rise again and so forth. So this is a meta-analysis, this is looking at about 150 papers from the literature, and trying to get data we have about, I think, 12 of these are ours, but these are from the literature search that was done, and it's really the first attempt to try to get a Kaplan-Mire curve, because there aren't any that we could find in the literature for pancreato-blastoma. And one of the things you notice is that it's not even as good as hepatoblastoma, which is usually up here somewhere, and so that's one problem, and lymph node involvement, which is what happened with my kid that I had the recurrence five years later, is a big problem. So again, this is surgeons and working to try to understand what's going on. Obviously, this is not an epidemiologic problem in the continental United States. On the other hand, we see these kids in a place like this, you're going to see them too, and trying to understand what's going on with them and so forth is extremely important. And distant metastases, or also, as you might imagine, important diagnosis and in-art prognosis, and the margin status is also important. One of the things that I learned from this is that there's a form of this that's congenital that people are born with this, and maybe I heard Dr. Adzick present a case of this once at one of the meetings, but they actually do very well. So if you have congenital, pericardial, bless, don't be too much better than the non-congenital form. It's the same disease, so again, it asks the question, I mean, we can't be very happy with this, so it asks the question, you know, what's the difference between this and this? So this is just a summary of the analysis that we did, and the nodes and the margin and the metastatics, the M status were important. Size was an important day of p at diagnosis and so forth, was not important, gender was not important. And then if you did, in a, put it into a Cox model, it's the nodal involvement, and the margin seemed to be the most important, the metastatic disease fell out. I think it's because the metastatic disease and the nodes kind of go together, so it kind of falls out of the model. They're co-linear, just what my colleagues tell me. So what's the role of the surgeon? Well, you're going to be involved with diagnosing this and trying to, you know, understanding looking at the scans with the radiologists, you're going to maybe be considering a biopsy or perhaps an upfront resection. You're going to have to think of the diagnosis and realize that neo-adjuvant chemotherapy is used for these tumors. You can use the alpha-feta protein. You may be responsible for a secondary resection after chemotherapy and for metastectomy and removing tumors, we remove tumors from the liver for that young girl, I told you about. And there's no, I mean, we found that beta-cateenin is involved with this tumor, and so doing research to try to understand what's going on, it's also involved with hepatoblastoma, some of you may know. So involving in the research. So I put Chris up here, because he did a lot of the work and is the first author on a paper, but my final talk here is on gastrointestinal stromal tumors. So this is just, this is a very rare tumor that we used to see and really nobody knew much about. And so you would see this tumor that would be primary to the stomach most of the time in kids. And you would resect it and then it would come back in the nodes on the perennial surfaces. And in fact, one of the things that made me very concerned about how we were managing this tumor is that I laparoscoped a kid who was sent to me from, I think, Michigan to to resect nodes that were metastatic after a gastrectomy and I laparoscoped her and there was a tumor down in her in the cul-de-sac and the pelvis. And so I started to think to myself, this is, resection is probably not going to help this. And on the other hand, that kid is still alive today. And that was, I think, almost 20 years ago, she lives in the Midwest. So Lee Helman from the NIH got together a bunch of people who had some interest in this. And we've been meeting, initially, was twice a year, but with a cutbacks in funding. So now, once a year, we're meeting down at the NCI and trying and seeing patients, actually seeing patients doing genetic testing, examining the patients, talking to the families and looking at their course. And so the results of this analysis actually is the first elucidation of the clinical role in treating these patients. And surgeons were very involved with this. So this is, this is Santiago Ramoni Cajal who did the silver staining on these nerves in the myontary ganglion and the nerves that he described in the myontary ganglion are thought to be the nerves of origin of gastrointestinal stromal tumor, although I think there's some controversy about that right now. And again, these are just the nerves there in the wall of the bowel. And it's very, this is relatively much more common patients over 21 years of age or over 40 years of age. And is one of the most common sarcomas that's reported, it's reported as a sarcoma in adult series of sarcoma. And usually they're in the small bowel, but most of the time when we see start in the stomach, you can see this large tumor here. And an extra, this is a soft tissue nodulogen into that tumor. They can have these nodules in the lung. And this is part of what's called carnice triad. And there's another simpler, there's another, another, a, a diad that goes along with this. But what this implies is there's an STH, there's a, well, I'll tell you about that in a minute. But what you have with carnice triad is a just a gastrointestinal stromal tumor. These are not met. I actually biopsy one of these and it's pure cartilage. It's an endchondroma. And then you can get these paragonal illnesses. It's important to know about paragonal illnesses because they can close hypertension and strokes and so forth. So this is a patient with carnice triad who had a gist and this lesion turned out to be a piece of cartilage. They are pet positive, so they can be, pet can be used, although we don't recommend that at present. And then, this is how they look like. They're large and intraluminal tumors. They're covered with new coza. So a mucosal biopsy will get you a normal gastric mucosa. You have to actually stick an edel inside the tumor and get into the get in beneath the mucosa into the stroma to try to get the diagnosis, which is feasible. And again, they show up in the stomach a lot, another case, and just some more. You can see that there's blood here and there's been bleeding from this ulcer here. And again, another ulcerated tumor. Gastrointestinal hemorrhages is one of the most common presentations. This shows you they're very stromal tumors when you cut them. They're within the wall of the stomach. They're not mucosal. You can't do a mucosal resection. And so here's the rub. These kids, what we found in this clinic and what's been published, I think, in Lansing, on collagen now, is that they have mutations in succinyldehydrogenase gene, which I think was described by Krebs a long time ago. But so there are abnormalities of these four components of the succinyldehydrogenase gene that cause the tumor. And that's in contra-distinction to the kit abnormality. I think you could see it on that slide that I showed that is seen in older patients that have it. So these are, this is a famous in England Journal study. Dr. Dmitri is at the farber here. And this just shows you the response to Gleevec Matinib of these tumors. Oral and Matinib had more effect on this huge tumor than all the doxarubicin in the world. But it doesn't work in our cohort of patients. None of the tyrosine kinase inhibitors works on these tumors very well. And that's what we found from our clinic that we did at NCI. So Krebs was able to, one of the things, let me go step back for a minute. One of the problems with this is that we get called all the time about, I've got a kid with a gist. It's a big one. And I see a couple of other things in there. And I'm doing a laparoscopic total gastrectomy tomorrow. Is that the right thing? And it's like, it's not. And the reason is that total gastrectomy is something that's done with the idea that you're going to affect the cure that you couldn't otherwise do. Okay. You're not going to affect the cure in these patients. We could, we knew that from our experience. And it's also very debilitating. Total gastrectomy when you're 14 years or 16 years of age can be very debilitating. So we tried to get at this, what's the role of surgery and STH deficient gastrointestinal stromal tumor, which is the kind you see in kids. And even in some adults. And so we took 76 patients out of the database that had adequate data. A lot of these kids are females. And the other demographics are seen here. Most of them were gastric and only 17 percent were in the small bowel. And 63 percent of these presented with localized disease. So they started with localized disease. And the problem is that you start with localized disease and you take it out and you think everything's going to be fine. And then five years later they have pertinial involvement. 12 percent had spread to lymph nodes. It diagnosis in 26 percent had metastases, perencomal metastases. And the tumor size was seven centimeters. And some of these kids were treated with the matinee. But as we said, it doesn't really affect it very much. It just shows that some of these tumors can be quite large. The median was around here. Seven. So this just repeats the liver, peritoneum, and lymph nodes were involved with these percentages. And again, to reiterate, the adults have a C-Kit mutation. The kids have a high rate of SDH deficiency. There are a few other things in there. But this is really the main driver. And they don't respond well to tyrosine kinase inhibitors. But this is the overall survival. So I just told you there are a whole bunch of patients there that had peritoneal disease, liver disease. This is the overall survival. So if you see this, if you see this with thyroid, carcinoma, and kids, if you see this in this tumor, you have to think to yourself that whatever you're doing has to be first of all not to not causing too many problems, not associated with high morbidity. And it should be sort of something that you've thought about and is very directed in terms of the problem because this is the event-free survival. And there are no deaths. There's I think one death now from a very long-standing patient. But even though they have a long survival, they continue to have disease. And they live with the disease almost symbiotically. And this was something that was not appreciated. So we've had kids that have had eight-operate laparotomies. Every time they saw something on a PET scan, they go back and operate on it. So knowing that the survival is close to 100% and that the event-free survival is close to 0%. It sort of makes you think about what you're doing with interventions in terms of this disease. And clearly we need more research on it. This is just showing metastatic versus non-metastatic. And as you expect, this is event-free survival now. So this means that somebody had a recurrence or some other event, but most of them are recurrences. Okay? So they're still alive, but somebody found a new lesion. And that's what this means. So if you started with metastases, then you had a higher chance of having an event sooner than if you didn't start with metastases. But your survival is still 100%. And my tautic rate is something that the pathologists at the Brigham have been very interested in. I'm blocking on its name right now, but the bottom line is that the mytotic rate is something that is looked at, especially with adults. It doesn't seem to be all that important with kids, although there is some effect. And then you can do a, there's a risk stratification that's again done by Dr. Fletcher at the Brigham here. And you can look at these data and it's stratified as well for event-free survival or recurrence, but not death. The surgical margin didn't have much effect, although I guess they cross, but we really didn't see much of an effect. I mean, everybody was relapsing, and then I think is shown in this slide where you can see that if you had a primary section, you still relapsed. If you had a seconder section, you relapsed sooner and it goes on. So what we showed was the futility of trying to take these out in an aggressive fashion. In other words, we're not carrying this disease. This disease is disseminated early. Often the tumors are perforating through the wall of the stomach and they're disseminating early. They're going through the peritoneal cavity, and they're not amenable to a surgical approach. And this is just some of the, this is just the Cox model, which really didn't show any role for R0, you know, major role for R0 section and so many other parameters. We didn't see any benefit to total gastrectomy either. So what we recommend, these patients present with gastrointestinal bleeding most of the time, a lot of the time. And so we recommend resecting that lesion, resecting that ulcerated tumor, and reconstructing the bowel, or if there's perforation or if there's obstruction, or if there's an increase in size that's reaching the limits of resection. It's getting so big, it might be worried about it. Pain is always an iffy thing. But this is something that we're able to do through the NIH as surgeons for a very rare tumor that really nobody knew anything about. And some people were operating on every time they saw something, some people were giving ducts, rubissons, some people were giving tyrosine kinase inhibitors. And the bottom line is that by putting this together and working with the group collaboratively down there, we're able to show that these really is what we should be doing with these kinds of tumors nowadays. So I brought you through a sort of a list of things that are sort of been sort of pet interests of mine over the years. They're very rare, but as you can see, they're very problematic in different ways. I'm hoping that by showing you this data, and if you want us, we can talk about it later, that some of you will become interested in this kind of material and oncology and in research and try to look at these. And again, thanks. It's a great honor to be here at Children's and to sort of come back, still feel like the chief resident though. Dr. Lacroix, I'd like to thank you for accepting our invitation to be the gross lecture we're honored by your presence. I think what you've presented this morning, it's really the paradigm of what's needed in pediatric oncology, and that's intensive involvement of the surgeons with the studies. And it's interesting, I'm thinking, as you went through, the approach is diametrically opposed between the just tumors and the dismal plastic small-around cell tumors as far as what the surgeons should be doing. And if we don't have surgeons involved in the studies who knows what the oncologist are coming up, going to come up with for their recommendations. I think they need guidance. I mean, we're in a meeting. There's a young investigators meeting at American Society for Pediatric Immatology on College on Friday. And it's, there are a lot of people in the oncology world that are also interested in colorectal cancer, which is what we were talking about. But they have, they really need to understand the nuts and bolts of that, and also how the involvement of the surgeon can help with that. So they're all about the work, genetic work at the NCI and so forth, but not really in terms of the clinical what's to be done clinically, how to describe the cohorts, the identity, the differences between the two cohorts in terms of that whole thing of signet ring just never is striking. It was striking to my colorectal colleagues when I showed them the data. It was such a high percentage of patients who had signet ring and use in this carcinoma. It's been borne out by all the studies so far. There's something there. There's something that's there and I think we bring a, as surgeons, we bring an insight into it and sort of bring them down to reality a little bit in terms of, you know, what's important. Also, I think as surgeon, one of the things I did tell them was that that not everybody should do these things because they were saying, well, we have very good surgeons, and I'm sure they do, but are they going to get all the lymph nodes? There's data that you have to take at least nine, but, you know, preferably 40 lymph nodes when you're a sick colon cancer. There's data that shows you have to be on the end of pelvic fascia and when you're a sick rectal cancer, you have to know when to do neoadjuvant chemotherapy and radiation therapy. So, again, a very rare tumor, but the surgeons really need to be involved from the ground to the ground up. I think as young people, I think some of you hopefully will and also will be involved in the research aspects of this and we can talk about that later. Questions, Dr. Laquagli. Thank you, Professor Laquagli, for your worldwide teaching about cancer. Oh, just one concern. How do you have the chance to perform a transplant, a minimum, minimum invasive surgery, inpatient with TUT1, T2 rectal cancer in other sense? We've not had any T1 or T2 rectal, and they're all extensive. And that's what I tried, you know, the more than almost two thirds or T3 in the Cotinial HoCoA. A professional. Well, thanks, Professor. Such an enlightening talk. You know, we're facing, in our, especially if you had to surgery, this question of regionalization of complex care, rare things seen commonly, you can make progress. These are ultra rare, where you're talking about. You're showing an entire career of decades, small numbers and the total incidence in the country of the world is, is, is minuscule. You've attracted these cases because you're you and the institution that you're at. How do you view the ability to really understand and make progress in these ultra rare things? Should there be a way in our society that, I think there is a way. You always get these cases. Yeah, I think there is a way, Steve. I think that, you know, there's a big push in the Children's Oncology Group and in Pediatric Oncology. And again, I was at this meeting in New Orleans on Friday about this. And they're very interested in the adult and young, adolescent and young adult cohort. And I think we do better job with them. We certainly do a better job with them with you, in Sarcoma and with some of the, most of the other Sarcoma. So I mean, if you have a 23 year old that has you in Sarcoma, you much better off on a pediatric you know, a good multi-disciplinary pediatric floor than you are on a, than you are in the, in the community certainly, but even in academic institutions. And this is going to be a big push in oncology in Pediatric Oncology going forward. I mean, there's a lot of interest in trying to gain these patients. And your guys are going to be the ones. Obviously, they're going to inherit some of that and be involved with some of that. This, this meeting again was a meeting about the adolescent and young adults. Once you do that, then the numbers go up a little bit. But also, you know, it's, we can say, well, this is not, these are rare. And so, you know, why, you know, it's like the NIH, you know, it's not breast or colon or prostate. We're not going to fund the research. But, you know, it happens. And that's what we're all about. And so, there are ways, you know, ways to do it. So, I don't think everybody here will be a pancreatic, less known expert. But maybe somebody will get interested in the beta-cateenin aspects of it. Look up the data here at Boston Children's Hospital. Maybe at some point through the COG, somebody's going to do a meta-analysis and bring all the data together from the institutions, not just from the literature. Maybe somebody's going to do some work in the laboratory and compare it, you know, do some deep sequencing of the tumor, get fresh tumor, and do some deep sequencing compared to Hepatoblastoma. So, you have the same sub beta-cateenin when issues are there. I mean, that's what we do. I mean, I think we're, if we, as pediatric surgeons, I think we need to be, you know, positive about that. We can't just be, it's like, we're not going to see it or it's the DRG's or it's the numbers. What are we going to do about it? And, you know, I'll show tonight how we had 15 cases of a tumor that nobody knew anything about. And we found the driver gene, sort of on a shoe string. We found the driver gene that is now opening up the field of the research. So, number one, the AYA, number two, this is really what we should be about. Now, are you going to spend your whole life doing this, since doing pediatric, probably not? But could you go to the COG and be a leader and do analysis and try to get some scientists involved and try to get something going in terms of some kind of a program project or something like that? You know, that's what we should do. I think. Well, Michael, very proud of a junior fellow. Goodness. What a career. And, you know, the thing that I'm struck with, as I listen to you this morning is, is where you really epitomize translational research. That you're a doctor's doctor, you're a kid's surgeon, you're there for the families in these difficult situations, these difficult problems. And in addition to that, you use that information then to foster better therapy for them. And the way you've done that is really to collaborate with not only other surgeons, and on occasion, it's the adult surgeons that you'll tap into it, but other investigators across the street at the Rockefeller, I mean, it's a it's a tremendous career of accomplishment. Well, thanks for you. But that's I think we all do that, right? I mean, we've all, you know, Professor here has done that. All of you, all my colleagues, my, so I just want to publicly thank you for all the support over the years. I started with the NH NCI work with this and a new very little. I didn't know where to go when I first got there and didn't even know anything else about the topic, but you really mentored me through the whole project and you certainly didn't have to do that. And I want to publicly thank you for everything. You took the time to teach me statistics. You took the time to help me fill in data. You took the time to review drafts. You took phone calls at midnight. You took phone calls at 5 a.m. You took phone calls all day and night. And I wouldn't be here without you. So it's an important thing to do, Kristen. Thank you for being involved with it. But again, it epitomizes what you can do. I mean, we had this data and I think we've defined what the role of a surgeon should be in this particular tumor. It's published in a high impact journals in JCO. So I think that this is what you can do if people work together and and and propose what Steve was saying. It's a rare tumor. How many just do you see? I mean, we follow, I think I follow six or eight of them in our institution. But the bottom line is that we were able to pull together and and the genetics and so forth. We're also, but that's different, but we pulled together a paper that got published in JCO that defines what surgery should be for STH deficient just at least the present. Okay. And that's something that I think is very worthwhile. That's telling the surgeons in the world now you don't do total gastrectomy. You don't go in and try to take a big margin and so on and so forth. You you take out the tumor, you only operate for, you know, symptomatology. It just kind of echo what you answered Dr. Fisherman's question. I mean, we were able to do this because we leveraged multiple institutions, the sizes of our institutions, the intellectual firepower behind those and the sub specialization that we do to push the field forward. And I think that's what are at the more obligation is to to our feet. That's what we do. So we're supposed to I'd say think about that's what we're supposed to do. I would welcome everybody to join us for the Robert E. Gross lecture 10 night at five o'clock by Dr. Laquagui. Thank you so much. Thank you. Being Tom