Dr. Christopher Weldon - A Rare Occurrence

Good morning and welcome. Thank you for coming to Grand Rounds today, and it's an honor to speak to you and to be invited by our senior fellow, Doctor Fallon. Um, today's talk will be entitled A Rare Occurrence. First and foremost, I have no disclosures, but I did attend Bryan's alma mater. Uh, I was asked to do this, uh, 8 days ago because there was no one left to do it, and so, please all apologies in, in advance. Uh, to learn a little bit more about Brian, who you guys probably don't know, that's Brian's hall on the upper left at the University of Notre Dame, and that's his wife's hall on the bottom right. Like probably 30 to 40% of other Notre Dame graduates, he married one. And so, yes, you've heard that figure correctly. It's also pretty telling that up to 3 to 40% of any class is a legacy. I was not, he was. But uh it's a fantastic institution and I presume that whether his children go there or not, his checks will. So, thank you very much again in advance for giving this talk. First and foremost, Happy Liberation Day. Today is gonna be fantastic for all kinds of reasons. This talk is not one of them, but at 4 p.m. this afternoon, we're gonna learn a whole lot and a lot more to celebrate tonight. So, uh, the prologue today is a greater fool. Please remember that, we'll discuss it later. So rare, from rarest, Latin, that which doesn't occur often and therefore of consequence, technically was used in Old English in the 14th century and it described thinly sown in the nature of agriculture. By definition, it implies a comparison, and so therefore, everything is relative. What is rare to 1 may not be rare to another. This, the seed of this talk began when I looked outside of our insular world, because all we do is children, and all we do are treat children and children's diseases. However, the rest of the world does not. And so, therefore, what we take as commonplace, they take as rare, and that goes for everything that we do. Another thing that I've gotten to know and where I come from, um, there's 66 million pounds of strawberries raised every year in the United States, but there's 28 billion pounds of soybeans. So by comparison, strawberry production is quite rare. Furthermore, this is all done by 2 million farmers, which sounds like a very large number, and it is cause it's twice as many physicians, but it's one half the number of accountants. However, the $220 billion. Uh, is only 0.8% of our GDP, which is quite rare in comparison to other things that are there. If you look at the population of the United States, there's 270 million adults, 71 million children, as of the last census. There's 900,000 physicians to care for the adults with 19,000 oncologists, whereas for children, it's 56,000 pediatricians for 3 with 3000 oncologists. 17.9% of our GDP goes to healthcare. So that's $4.9 trillion and all of agriculture, as I just stated, was $228 billion. 1.8% of the GDP goes to children's healthcare. Cancer expenditures in the United States in 2023. We $210 billion whereas pediatric expenses were 12.5. The NCI budget for 2024, supposedly, was $7.8 billion with a 10% increase for 2025, which remains to be seen. The pediatric budget within NCI was 312 million. In the United States, there's 22 million adult cancers diagnosed every single year. Whereas in pediatrics, it's 15,000. The adult number is increasing, the pediatric number is static, hasn't really changed markedly in the last dozen years. Those 2 million cancers in adults produce 6,600,000 deaths every single year. Whereas there's only 1500 deaths in pediatrics, those numbers hold up. The survival rate in children has changed markedly in the last six decades, if not 100 years, and so therefore, some 80% of children now live. But to quantify our numbers, in 10 days, more adults die of cancer than children are diagnosed an entire year in the United States. There are as many small bowel, gallbladder, and anal cancers diagnosed in one year in the United States, and there are pediatric cancers in total. For those of us surgeons going through adult reds, I dare say all of us saw maybe one of these 3, maybe 2, and I doubt all 3. Furthermore, there are more cases of breast cancer and prostate cancer diagnosed in a year in New York City by a factor of 2 than the number of pediatric cancers in total in the United States in a year. Pediatric cancer is rare. What we do is rare. But let's look at statistics. They apply to a population, they don't apply to a person. There's 200,000 liquid tumors a year in the United States and 1.9 million solid tumors. There's 25,000 brain tumors in the various types, and the non-CNS solid tumors, about 1.9 million. The most common varieties are listed below. Pediatrics, quite a bit different. There's only about 14,000 cases of cancer a year in the United States, of which 2/3 are liquid tumors, which you do very little with. So therefore, solid tumors are more rare than liquid tumors. Of the solid tumors, some half are brain tumors versus our adult colleagues, which is a vanishingly small sum. If you look at the non-CNS solid tumors, there's not a single adult tumor that makes it over to a common pediatric tumor. The only one that even comes close would be melanoma, which is 350 cases a year versus 101,000 in adults. So again, what we do is rare. But cancer is the 2nd leading cause of death in children. Trauma is #1 and stays #1 until age 44. There are twice as many cancer deaths a year versus all other anomalies in children in the United States in a year. There are 3 times as many cancer deaths versus cardiac disease in children in a year. And there are 6 times as many cancer deaths as are all from all of infections, especially pneumonias. Although what we do is rare, it's significant. So how did we get here? How did we get this? Disease in check. Well, it really started with yesterday's Children's Oncology Group or COG, which, as we all know, is an acronym, and there's probably 3 or 4 in the room that I actually understand it to a degree, but it took me a lot to figure it out. This was the seminal article on the use of chemotherapy in patients. It was not by Sydney Farber. Sidney Farber, though he utilized it and wrote about it the most, the actual first article was this. It was in 1942, and what it was, it was sponsored by the War Department in World War Two, looking for agents of warfare. They used mustard gas for lethal reasons. In experimentation, a group of doctors who had security clearance and were assigned to Restrictive practices tried to come up with more lethal types of nitrogen mustard compounds. Ethics aside, they used animals to determine lethality. Some died, some didn't. Some developed tumors based off of the mustard compound. They would use those animals again, treat them with a different mustard compound, and lo and behold, some lived, and the tumors went away. So they began to write up that mustard compounds had an apoptotic or cytototic effects that could be used for chemotherapy. They were blackballed from publishing their results until 20 years after the war when they felt there was no longer a security issue. However, one of the lead authors in this work was the first author in this paper, and it was published in 1948, and he went from Yale to Memorial Sloan Kettering and started one of the nascent oncology practices in leukemia. And so he knew this information and he started to use these compounds, and he published this article first. Barber's article came out in the New England Journal of Medicine 3 months later. But this paper was on 5 years' worth of patients demonstrating its effectiveness. That was in 1948. That began a series of clinical trials, and the first clinical trials group in the United States to treat children with cancer was this acronym, which I could not tell you what it is, and so therefore, just remember the letters. They started and 15 other trial groups quickly joined. The issue with pediatrics is there just weren't enough numbers, and there were a great deal of caution about using drugs in adults because they felt there were other options, radiation, etc. However, in children, since there was no other option and lethality was 100%, they decided to explore more. There was no FDA. There was no ethics involved. There's no IRBs. This is what we need to do, so they did it. Single institutions and then joined many. This one group then begat 3 more organizations, Southwest Oncology Group, may we, we may all recognize, and then 2 others. CCSG is the Children's Cancer Study Group, which became the Children's Cancer. Group, which then took up the mantle and for the next 10 to 15 years tried to shepherd in and usher in how we're going to do this and how we're gonna do this well. They begat a series of other groups and they joined together in a factionalized standpoint, such that you had the Children's Cancer Group, and you had the pediac oncology group, which are the two large umbrella organizations, for lack of a better term, they split the country, about 15 centers each. And then there were two offset groups, the essentially rhabdomyosarcoma Study Group or IRSG. And the National Women's Community Study Group, which developed independently, worked independently, although there was a great deal of association between all these groups to get enough patients, and they started to marry to each other early on, at least in combined two studies. Much of this was funded by the federal government through a series of grants. Some was funded locally by institutions or other philanthropic organizations, but the gobbledygook was very difficult to determine what the next best steps were, and there's a lot of wasted money and redundancy. As such, everybody joined together to form the Children's Oncology Group in 2000. They have been essentially uh uh uh denoted to keep everything going by the federal government and so therefore, all children's cancer effectively is done in North America through COG. So, that's Touchdowns Jesus. That's the Affection library of the University of Notre Dame that you can still see from the Notre Dame stadium. Uh, when Brian toured this with his father, who also attended the University of Notre Dame, coming from the great state of Michigan, or 313, the Life of Motown and Bob Seger and the rest of them, that's where they thought he was going to spend most of his time, but what he actually went to was the Rockney gym. Where he uh decided to uh work on his athletic skills as opposed to his academic skills in the library. But nonetheless, Oncology can be coursed through the look of Wilm's tumor. So the turn of the 20th century survival was 0. Though it's quoted as less than 5%, no one can find an article that had shown me that it worked. But by the year 2000, It's up to 90%. So what happened in 100 years? But you can trace oncology's rise through Wilms's tumor survival rise. At the turn of the 20th century and into the first few decades, we had the pandemic effects that were going on from the flu of 1818. The world was at war. We don't technically have a world war, but there's two massive conflicts going on right now with a lot of Children and adults who were killed and other destruction. There are gender equality issues, especially sufferance for women and the ongoing issues that we currently see in our own country. There's geopolitical and socioeconomic disruptions despite Liberation Day upon us. There's technical evolutions in place, but instead of the rise of the industrial revolution, some two decades later, we now have a digital-based economy and the rise of AI. And survival was paramount importance. The first step was William Ladd from here. He published a paper in 1938 where there was no treatments, so he simply operated. He did what he did. He did what we do. He was an oarsman at Harvard, and essentially he approached life in a very straightforward fashion and simply put his head down and he published his personal series that took a survival rate from 0 to nearly 30% with exquisite surgical technique and understanding the anatomy. That's one child that um I was able to secure a picture of documenting the size of the tumor and what took place. But most people weren't talking about what he did and worried about. They were talking about this woman, Pearl S. Buck. She was the first woman to win a Nobel Prize in Literature for The Good Earth, amongst other books, in 1938. The second step, as I like to say, was a lunch conversation between Ladd and Neuhauser here, who decided that local recurrence was a real problem, and you could only do so much during surgery. So, he said, well, let's do radiotherapy. So, I've assumed that they had a cup of coffee or a lunch and said, yeah, why not? I've got this machine. There's no IRB. Let me just throw the child in it, and we'll figure out dosages and things thereafter. So, he applied radiotherapy. And in the American Academy of Pediatrics conference in 1950, he documented the addition of radiotherapy to everybody who had surgery. And they took a survival rate from call it 30% to nearly 50% with the second modality that was employed. And this was published in 1950, but it was talked about there, but most people were talking about South Pacific, which won the Tony on Broadway as the best play at the time. Step three was chemotherapy. First article was in 1948, but this article in JAMA in 1960 traces his two-decade course of what he did, how he did it, and the serendipitous nature of pitching, picking the one drug off the shelf that actually worked. And if you think about it, it still works, and it's still the backbone. There's a similar serendipitous effect in Houston, where they picked the other agent for Wilms's tumor that worked, worked well, and they've used it to this day. And he published the effects of chemotherapy, what it does, how it does, and how they changed what the compounds might be in the dosage and the regimen. But most people weren't really talking about his work. They were talking about The Sound of Music, which won the Best Oscar in 1966. We really owe what we do in oncology to this group and these two men and their colleagues. Breslow and Beckwith essentially were founding members of the National Women's Tumor Study Group amongst many others. And the pathologists and the statisticians, epidemiologists if you would, were the founding members of the National Women's Tumor Study Group who then figured out that we need to do risk-based therapy. Who needs more therapy, who needs less therapy? How do we trials? How do we have enough numbers? And they pioneered a collective group countrywide to look at a single entity, Wilms tumor, 2nd most common solid tumor in children, 500 cases per year, give or take. At the time it was about 380, but they decided to do a series of studies to determine how the best works. And so, therefore, they started a process with the rhabdomyosarcoma group that essentially was the foundation of all modern oncology. Unfortunately, at that same time, Martin Luther King was killed, and Bobby Kennedy was killed. Martin Luther King was killed on April 4th, 2 days from now in Memphis, Tennessee, and Bobby Kennedy was killed three months later. And unfortunately, the, what we probably should have been talking about, which was cancer, was usurped by public events. And then the last piece of the puzzler with these two physicians who were also parts of the parts of the National W's tumor Study Group to a degree, but D'Anio and Evans, one was a pediatric oncologist, one was a pediatric radiation oncologist from CHP, decided that Wilms tumor survival was not survivorship. They've been in the game already for about 3 decades, and they started to see the effects of their therapies, second malignancies, organic organ dysfunction, and they felt that they could do more. So they started the late effects study group. And it was a single NIH grant, 10 patients, 1 center, and they followed them longitudinally, and they started to attract more and more patients cause they realized they needed results over 5 decades and not just 5 years, like you would in breast or colon cancer. And so, they too not only made survival better, but they could monitor it further and continue it ongoing. And most people didn't read their grant, but they did read Sheeran's work on the Pentagon Papers, The New York Times that won a Pulitzer Prize. So what about today's COG? How did we get here? So the Children's oncology group today. Has a cure rate of about 80%, so 80% or greater of children diagnosed with cancer a year in the United States live, and they live past 5 years and they live longer into adulthood. It spans 4 continents. 80% of children in the United States who have cancer or entered or treated via COG protocols. They have roughly 12,000 patients at any one time, covering 100 trials at 226 institutions, and they do this on a budget of $7.3 million which is at risk. Interestingly enough, 50 patients come from the top 30 centers. That's what cog is. Those are the numbers. This is what it is otherwise. It's for massive divisions or domains that deal with all manner of things. We probably know this one the best are the disease entities, which treat by disease, ALL, AML, bone tumors, CNS tumors, Hodgkin's disease, etc. This is where your clinicians, your practitioners come up with their studies and execute care, and everything else supports it. So what are our statistics again in the United States? Same graph, but let's look at something that's really rare, adrenal cortical carcinoma outlined in the bottom in yellow. Of the nearly 2 million adult solid tumors a year, there's only 200. In pediatrics, of the 5500 solid tumors, there's 25. So by any account in both groups, this is an extremely rare entity. Supported in a study by Koch. Now, this is the Basilica of the Sacred Heart at the University of Notre Dame, where Brian was married to his wife, who's also a Notre Dame graduate, as was 40% of other people. Suffice it to say, in 7 years after college, I went to 19 different weddings at this church of either double Notre Dame graduates or single Notre Dame graduates who wanted to get married. Suffice it to say they bring you back for all kinds of reasons. Oops. This is where he really wanted to get married, which is the Notre Dame stadium, and uh that's it. Now we do night football and that's only started about six years ago. So, Carlos Rodriguez Galindo wrote a study to look at how to treat adrenal cortical carcinoma. Think about that. 25 patients a year, and he wrote a study to try and do that. So this is rare, and this is supported by your dollars. So he came up with this trial, ARAR 0332, which is a groupwide phase 3 trial looking at. Um, adrenal quote unquote carcinoma cancer in children. These were the pioneers, and I thank them very much for their support during this time. And so let's talk about adrenalcoctal carcinoma, which is similar to adults. It's rare and it's aggressive. It's a bimodal age distribution that we probably remember, 1st decade of life and the 4th decade of life. There's presence of occult lymph node metastases often. There's only 0.2 to 0.3 cases per million children a year in the United States. However, there's a 10-fold greater incidence in two states in southern Brazil because of a cytogenetic anomaly that's heritable. It's a P53 mutation, and so the risk is far greater and the numbers are far greater. So this was a combined study between Brazil and COG. In addition to this genetic predisposition, there's a multiple other unusual cytogenetic signatures that they do believe cause problems, and so multiple genetic missteps are generally labeled as postulated to cause it. The presentation we probably all know, most are hormonally active in children but not adults. Verilization is #1, followed by hypercholesterolemia and or Cushing's disease. A mixed tumor would be the 3rd most common functional problem versus feminization and aldosteronism. There's generally a low biological secretion of these tumor markers initially, and so they can be subtle, and the activity in most people is not quite there. 50% present with abdominal pain and or distention. 60% have advanced disease and large tumors at diagnosis because of the location of the adrenal glands in the back of the abdomen. Metastases are frequent to lymph nodes, liver, lung, and bones. Differentiation between benign and malignant entities is extremely difficult. If you have metastases, you're malignant. If you don't, it's a little unclear exactly what the transition is histopathologically. There's no molecular markers. They've come up with some prognostication scores, however, they haven't been validated, so it's a little unsure. We do know that tumor size, spill, and invasion are noted to be significant in the history of uh in many studies. However, those are legacy studies and predominantly adults. And overall survival in theory is quite good for stage one, but again, you have to call into question whether they're truly malignant versus 23, and 4, which are presented for you, and those are historical numbers. The the trial then essentially tried to figure out who needed what and when, so stage patients were resected and felt to be small or less than 200 centimeters cubed of a volume and normalized hormone levels. Stage two was greater than 200 centimeters. Um, cubed, stage 3 patients were those with residual disease, lymph node mets or inoperable tumors, and stage 4 were essentially those with distant mets at diagnosis, so bone, liver, or lung, not lymph node. This was your schema, and essentially you're broken up into stratums, 3 stratums. Surgery only stratum 1. Certainly surgery only stratum 2 with determining if there was occult lymph node disease, and if there was, they received postoperative adjuvant therapy, and stratum 3 was disease that either was inoperable and or biopsied first and or evidence of metastatic disease or known lymph node disease. They received some combination of chemotherapy, be it induction or postoperatively in an adjuvant fashion, with surgery. Surgery consisted in theory of a radical adrenalectomy. Which is the adrenal gland and all fibro fatty tissue surrounding it. It was proposed that a retroperitoneal lymph node dissection be performed for stage 2 and occult 3 patients to determine what the burden of lymph node disease was. The primary aims of the study are before you, so, outcome for stage one patients with surgery alone, stage 2 with surgery and RPLND that was um denoted what exactly it would be, and then what would be the outcome for metastatic patients treated with miotane, which is an adrenolytic agent, and it's also an insecticide. Secondary aims are before you. What were the feasibility complications of performing an adrenalectomy with an RPLND, toxicity of mitota, evidence of tumor spill and occurrence, presence of occult lymph nodes, outcome in cohorts with known genetic mutations, how to characterize other genetic mutations in addition to known P53 abnormality, and were there any other embryonal markers that they could follow. This is the grotto. Miracles have happened here for the Catholic religion. This is where centuries Brian's parents assumed he was most days. Studying and praying. This is where it actually was, and this is not a church. The results of this trial, which took a long time to get approved, let alone enact, uh, was published in 2021 in the Journal of Clinical Oncology by Doctor Rodriguez Galindo and colleagues documenting the overall, um, success and or findings in the trial. This was the schema, so there were 78 patients enrolled, but only 77 were eligible. This was the breakdown by stage, so 24 and 1, 15 and 2, and then the rest in 3 and 4. Go through the chemotherapy cycles, exactly what happened. Again, this was a breakdown by stage and how it was done, so tumor volume came into play, and essentially, smaller tumors only had surgery first. If you did an upfront resection, had a larger tumor greater than the volume of 200 centimeters cubed, you needed to go back and do a lymph node dissection if you had not done one. Stage 3 patients essentially got surgery either upfront or afterwards with chemotherapy and might attain as did stage 4. Results. So the study ran from 06 to 2013. 77 eligible patients are evaluated. The event fee survival is given as 87, 53, 1981, and 2007, and you can automatically see that there's a problem. Overall survival is 95, 79, 95, and 2016. And so again, you're stage 3 patients, you have a problem. You're stage 2 patients, you may have a problem. And that that was the first sign that we may have an issue with this. On univariate analysis, age, stage, functionality of the tumor and genetic mutations bore significance for prognostication survival, and on multivariate analysis, age and stage were the only two that dropped out. Mitotane use. Was tolerated in less than 30% of the entire cohort. They didn't know how to dose it. The toxicities were significant, not the least of which is essentially an oral agent. The majority of the children were not given a G tube at the time of surgery, and so compliance was horrible. These are the studies of our survival curves, which essentially show you in classic fashion, stage 1 does better, stage 2 does a little bit better, stage 3 and 4 do not. And um for all intents and purposes. We look at both EFS on the left and OS on the right and determine what our results are. But the real question for us as surgeons is, what about an RPLND? The surgical implications for this disease are critical, because without surgery, there is no cure. And you want complete extirpation of all disease, tumor, lymph nodes, etc. You can also do aggressive metastasectomies if needed, especially depending on the organ and the quantity of disease. Spill is significant, so technique does matter. Occult lymph node disease is known, is, is known to happen, but its occurrence is unknown and its rate is as well. The adrenal gland is extremely difficult from an anatomical fashion because it has 3 different arterial inflows, at least in the normal state, and in the abnormal state, you'll probably have more. The venous outflow is varied. Though we do know where it should be, it's not always the case. Lymphatic drainage is robust and unpredictable. Furthermore, undocumented, and the lymph node status role of a retroperitoneal lymph node dissection and prognosis are unknown. The literature is rife with examples saying do it, don't do it, where to do it, how to do it. There's no uniformity in Europe, there's no uniformity in the United States, there's no uniformity anywhere. And I bet anyone could find a paper to justify what they do. So this study tried to make the playing field level for children. Our surgery-related aims are pretty simple. You have a stage 1 tumor less than 200 g, complete extirpation. You have a stage 2 tumor greater than 200 g, complete extirpation with an RPLND to determine occult disease. The study was set up such that if it wasn't done at the time of the initial operation and the tumor proved to be too big, they want you to go back and try and convince the family to go through a retroperitoneal lymph node dissection to see what would happen. That was a failing. That was probably not a good way to do it. Furthermore, they wanted a feasibility and complications of a retroperative lymph node dissection. However, they never defined exactly which lymph node basins were appropriate for the adrenal. We'll get into exactly what that means in a second, but nonetheless, what was espoused was not necessarily what the community wanted to do or did. They also looked at the documented frequency in consequence of tumor spill, and then what was a lymph occult lymph node disease rates. So the lymph node dissection as described was an intralateral classic retroperitoneal lymph node dissection for all stage 2 to 4 patients undergoing operations. Especially in stage 2 where you had occult disease and larger tumors. The anatomical boundaries provided were based upon the drainage of the adrenal glands and indirectly upon the glands blood supply. So therefore, it was a stepwise involvement and you wanted to identify all metastatic deposits. These are your retroperitoneal lymph nodes, and these are their basins. And therefore, the templates were based off our anatomical understanding of the retroperitoneal lymph nodes were. The lymphatic midline of the body is the aorta, it's not the spine. So therefore, left-sided and right-sided tumors, what you would consider to have a lymph node basin, are not the same. So the template outlined in green would be for what you would want to do to determine occult lymph node positivity in a classic retroperitoneal lymph node dissection template for a left-sided tumor. Everything to the left of the aorta and the interradal cable groove extending down to the bifurcation. On the right side, again, it's different, but the lymphatic midline is the aortic midline, so therefore you really need to get over through the inner cable groove to determine lymph node positivity. That's quite an undertaking for presumably a very treatable, straightforward adrenal tumor, regardless of size, especially if it can be done laparoscopically. So, the surgical data really want to know was there an adequate retroperitoneal lymph node dissection. Was there a tumor spill, and what are the data to really answers #1 and 2? In these studies, everyone does a case reporting form. OK. That's filled out generally by a research associate who goes through all the data, to document everything. Milligrams of meters squared of anthracycline delivered, type of chemotherapy, metronomic fashion, when the X-ray was done, when the CT was done, what the findings were, what the procedures were, etc. and generally they're very simple yes-no questions that can be been put into a data cruncher, some type of program. So the case reporting form simply asked was an RPLNE done, yes or no. Presumably based off of the templates prescribed by the protocol. Pathology reports were delivered. With the pathology specimen to look at all the cytogenetic data, but they were used not for reporting data, they were used for their own. Aims. No operative notes were provided and we had to go get permission to use both the pathology reports and the operative notes, but at least the pathology reports had to be submitted. We just need permission to use them. The operative reports, we need permission to use them, and then we had to go get them. So, retrospectively, starting in 2019 or 2017, we had to write to all centers to try and get operative notes. These are the data. So the stage 2 patients, of which there were 1512 had a case report form that stated that an RPLND was done. Only one patient had pathological confirmation that an adequate number of lymph nodes were actually taken. And by operative reports, only 3 documented the regions of the lymph nodes that were sampled and or taken. In stage 3 patients of the 24 patients, 17. Had known advanced disease locally, and they had the correct or they had a CRF documenting that one was done when 100% should have been done. We had 4 that had an adequate number of lymph nodes retrieved for classic known expected numbers of the lymph nodes from an RPLND which should be somewhere between 3 to 4 dozen. And in the by the operative note, only 4 of 8 that could be acquired actually documented what basins they did. So suffice it to say, We had inaccurate CRFs. We need adequate number of lymph nodes retrieved and delivered on pathology. And our operative reports did not help us. So, our only conclusions are the CRFs, the majority of stage 2 patients had an RPLND. However, per the operative notes, they did not, and per the pathology reports, they did not. And we know that because you should retrieve a standard number of lymph nodes. Go back to all of adult training with breast cancer. You can't do an X-ray lymph node dissection and give them 3 lymph nodes. You need a minimum of 30. So therefore, if you're doing an RMPLND, you need a minimum of at least 30, if not 40, lymph nodes to say that you did one adequately to assess all the basins. So therefore, we really can't assess an RPLND in this context. And so the study from some respects is a failure, and that is significant, but why? First and foremost, it espoused a second surgery. So imagine you're a parent, child has adrenal mass, bad things are going on, you're not happy. There's no way you're gonna be happy. You have surgery, and they come out and tell you your tumor is 205 g. 252 g 311 g. And we didn't do what the protocol said we do, so now we have to go back and do a retroperitoneal lymph node dissection on this child. Of the 15 eligible cases, only 1 family agreed to do that. And to be honest with you, I can't blame them. The incorrect RPLND template was prescribed by the protocol. Most RPLNDs, if it's adequate, should have 40 lymph nodes retrieved. Our median number was 4. So, the majority did not have it. Only one got up to the mid-20s, which in theory you could count, because you want to get as close to 30 as possible, but 28 is a hell of a lot more than 4. Though none of them met our classic historical number of lymph node standard. So, let's think about that. So, if a right-sided RPLND is outlined in green and what was espoused by the protocol, going again over to the aortic midline, those are the basins that kind of need to be sampled. But we know that an adrenal lymph node dissection is not a retroperitoneal lymph node dissection. So the basins that actually needed to be sampled are actually outlined in red. And not as significant and not as great. Furthermore, there's a litany of papers documenting the number of lymph nodes that need to be sampled or the quote unquote dissection should be on the order of about 6. So people did do the correct operation, just not the one espoused by the COG protocol. And then that created a lot of problems. For a left-sided lesion, it's the same thing. The classic template is on the left, but what probably would be best understood by today's standards is on the right, or your lymph node basins in purple, the ones that really need to be sampled. And you really are looking for 6 lymph nodes at best. So, we unfortunately wrote a protocol that was not going to be successful or helpful based off of many factors, not the least of which is our definition was wrong. Furthermore, it's imperative in doing these cases. Words matter, precision matters. So even if we didn't have X, Y, and Z, if it was documented, then we could say nothing was there, they did what they had to, but the majority of op notes that we tried to recollect. Were incomplete, inaccurate, or had significant missing data, and as such, even though we tried to collect them, we could not really interpret the majority of them. The solution really is looking at what are we gonna do for the next study, which is ongoing. Obviously, we're gonna publish a failed result, but it hasn't been the first one to come through COG. 33 years ago, they published a study on the use of laparoscopic surgery in, or minimally invasive surgery in children with cancer, and they tried to have a protocol for it, a combined POGCCG study that didn't quite work out well. And so that will essentially be a roadmap to get this reported. We'll publish these results, we'll highlight the results and the errors, and obviously we'll learn. So, um, since Brian's joining us, this will be in his office, cause it's in his home right now and his wife can't wait to get rid of it. Um, so let's go back to the epilogue, or a prologue of the Greater Fool. So what is a greater fool? So, it's actually an economic term, and I'll let you read this quote because it probably describes it best. I think the last two sentences are the most important thing, especially in today's day and age, where the greater fool is someone with a perfect blend of self-delusion and ego to think he can succeed where others have failed. This whole country, the United States, was made by greater fools. So it was oncology. Thank you very much. Questions? Wow. Well, I think a lot of us, as I mentioned last night, we're I've been pondering what the title of the talk was going to imply. And uh there's a lot of lessons here. It's a reminder to me always when Dr. Weldon speaks that I need to have a You used to be a dictionary thesaurus. Now I can just like um look up all the words and, and it's a little electronic uh dictionary, uh, because there's always verbs, I don't, and the second lesson I think is, um. Even if it takes 8, it takes 8 months. We knew that Chris was get, get back at Brian. Um, It's hard to, in light of your last quote, which I think you're implying something, it's hard to not look at the environment of what's going on. In this country in the world right now. Uh, in the last 24 hours, even exacerbating the risk to study of biomedical science, medicine. Um, When you show the statistics of adult versus pediatric. And what's rare. It used to be that kids were of greater value, right? So, I was doing quick math before exercise, turning like dollars per child, dollars per cure, um, and then get far enough before the slides turn because there's too many zeros in my calculator. Um. Are the modern economists going to say, Why, why are we, why are we allowing the government to fund a study for 25 children a year? And Are they wrong? No, and I think that's the real problem. I mean, if you think about it, you know, if the budget. To be frank, for COG is only $7.8 million a year. And Even if it was $7 million a year for 70 years. You know, they have $490 million that took a survival rate of Rome's tumor from zero. To 90% in a century. And Regardless of everything else that comes out about of that. I dare say that if we could pull all the Wilms tumor survivors out there, they probably added a hell of a lot more to the economy cumulatively than $490 million over 70 years. And their progeny will as well. So That's just one small number, and if you look at the rest of it. Think about the lost productivity of the lack of investment in all that we do, and I just know the NCI. I'm not talking about the entire NIH. There's a lot of other people in this room that know a hell of a lot more about other institutes than than I do. But all of the funding, all of the issue is threatened. And you have to ask yourself, is the short term gain worth the long term loss? I personally, I don't think so. Is there a redundancy of the problem? No question. But I dare say that, you know, the model that was done and invested here. Um, really serves worldwide, cause what I did not get into, which is now commonplace in pediatric cancer, it's no longer a single cooperative group. It's not just now North America trials. There's all different tumor types joining worldwide to look at disease, to even get bigger studies. The germ cell tumor group does North American trials and now foreign trials through a consortium called MAGIC. The liver tumor group does North American trials with their Japanese and European colleagues, and it's fit. Neuroblastoma has their group. The womb tumor group is going to have their group. And so, I think it's of paramount importance that this is a global investment and a global understanding, and much of it is threatened by politics. Forget about our today's day and age. When Brexit, when Britain left the EU that threw administratively at least. Execution of these studies into peril. Because the data reporting center was in Britain, who no longer had a treaty with Europe. And the treaty with the United States was null and void because it was with Europe. And so therefore, you have to ask yourself the politics come into play because now they can't share data by rote law. And it's clear that Adults do not Do this as much as we do, but we do, we have to out of necessity because they're rare, but I absolutely positively think that the loss of funding will be critical. Answer is just one part of it. Anyone can get up here and talk about what they know for institutes, and it's gonna be the same thing, unfortunately. And that's even the non NIH people, that's NSF and all the other DOE DOD and everything else. Chris, that was a great summary of the initial treatments for uh pediatric oncology. It's interesting that. The When they were doing this study secretly at Yale to look at antidotes to um. The uh. Chemical warfare that the Axis powers had used during World War One, they started coming up with, um, identifying the, really the effect of the initial agents, and one of the things they found was that the soldiers that died from nitrogen mustard had essentially ablation of the lymphocytes in their lymph nodes, um, and some smart mind decided, well, maybe that means that would be good for treating. Leukemias that that are proliferated lymphocytes and it went from there. So I think it's not inappropriate to say that one of the few good things that came out of World War II was really modern oncology, which is sort of the most recent of the medical specialties to come, come to light. And I think the other thing he pointed out was early on there were not the uh IRB restrictions and such for obtaining treatment and, and having looked at some of the Children's charts on patients that Dr. Farber treated with Jimmy Fund 3, which became known as ectomin I said D, as you say, uh, there was really no documentation of what discussion the parents had, um, so, and I think you focused on, on sort of the, the challenges with surgical protocols and the, uh, you mentioned in passing really the failed study and looking at the role of. Uh, laparoscopy and thoracoscopy and, and oncology, and we're currently struggling with a study looking at that in patients with osteosarcoma. And, and it all comes down to the lack of equipoise, and if studies are proposed where there is an equipoise, not only amongst the providers, but amongst the, the families and the oncologists, you're never gonna be able to get adequate enrollment, but uh, Other studies have done better than that one. So, congratulations on a great summary. Yeah, I really appreciate the, the talk and not sure how much about Brian was true, uh, versus fabricated, but we'll find out someday. Um, one of the things that's always bothered me a little bit about, uh, COG studies and, um, I, I think the treatment of pediatric cancer in general is it, there's What you would do if you knew exactly what you were dealing with, and then there's where you start from in the real world, and where you start from in the real world. Relating it to the adrenal uh study is you have imaging or some symptoms, as you described, related to hormonal excess. And you have a tumor. And, um, probably upwards of 95% or more of kids, that's going to be a benign tumor, all comers, if, if you didn't think about symptoms and, and, uh, hormonal influences, and how that might change your calculus. So, it's really nice to say like, if this is an ACC we would just do an RPLND, we would do it open, we would do all this stuff, but that's not the real world. I know there's probably not an answer, and this is a very catch-22 kind of a a scenario, uh, where you would do one thing, uh, given your information, but you would do another, uh, if you could predict the future and what you were dealing with. Can we do a better job in COG with our trial design in terms of incorporating that scenario as opposed to Only starting from the point at which we know the diagnosis. I think so. Um You know, Not to use a local example, I'm gonna use a non-local example. So, for those of you who don't know, What is the key admission factor to be seen at MD Anderson? Anyone shout it out. First and foremost, what do you have to have known to be senior? Bingo. You need a diagnosis to be seen. At MD Anderson. So whether the tumor needed to be violated or not, whether the tumor needed to be X, Y, and Z or not, you have to have a pathology report. Always have. That was one of the tenants of the institution. Because the family was misdiagnosed because they didn't have a pathology report, so one of the major philanthropic donors insisted, and that was put in their bylaws. I think the one thing I've come to realize more than anything else is that I'm not too sure that's the most important thing. And our colleagues in Europe and SIO are not perfect, neither are we. They traditionally never sampled, never biopsied, and never did a lot of things upfront. They used biomarkers, and they played the odds. So in kidney cancers, everybody had a Whelms tumor, even they knew that that was discordant on the actual pathology results, some percentage of the time, 8, 1214, depending on the number and the type of tumor. But we know. And we have learned that knowing good care up front and delivering good care up front doesn't start with the operation of the diagnosis pathology report. It starts with the preparation. How many children have we seen that on a CT scan of the abdomen had a single tumor in one kidney, when in fact, if you had an MRI or an ultrasound, there were bilateral disease, at which point they would be treated totally differently. And so, I think when you look at the broad swords of both radiation therapy and chemotherapy of any type. You're treating everything, and if you go up and down on your dose and your milligrams per meter square and this type of, you know, things, that's a very large field, that's a very large, um, systemic delivery, even with radiotherapy. Surgery is much smaller, OK, it's much different, and we all know that. And so therefore, they take the rules. Of essentially radiation therapy and chemotherapy in many respects, and they throw them onto or add them onto the surgeons as an underpinning. And it just never made a lot of sense, because though 2/3 of cancers are liquid and will never need surgery. And half of all solid tumors left are brain tumors that we'll never see and get a lot of radiotherapy, and I don't know if anyone's ever seen their neurop protocols, but they're rather interesting. As far as what they are, and they're a lot different than what I think our solid tumors are. I think preparation is the most important thing and adequate diagnosis, and so to take a step back. If we're going to engender these protocols, I really think surgery in and of itself needs to be seen not so much from a systemic standpoint, but really a more focused standpoint. And so, therefore, its application. I think there has to be a lot more gray and less black and white. Because if you look at this protocol, you didn't do that template that for all intents and purposes should have been for a testicular tumor. You didn't do it. We know that's not the case. We know the majority of surgeons did the right operation is dictated by the disease, not dictated by the protocol, but it's a failed protocol, and the statistician says we can't evaluate it that way. Because the majority of patients had the correct number of lymph nodes taken, regardless of any other factor, they had the correct number of lymph nodes taken, but I can't evaluate that way. Cause it said to do an RPLND and they should have gotten 40 lymph nodes. So, we're missing valuable information that I hate to say it, I can't publish. Because I probably could answer, what does a lymph node dissection mean, or at least answer it better, but I'm not allowed to say it. Uh, Chris, great, and you, as always, you bring us into, to new realms. I just had a very specific uh question about your data. One, it looked like the results in, in stage 2 versus stage 3 were kind of flipped in, in some of those domains. Uh, uh, is that true? And if so, how would you explain that? So, that was the first clue that stage 2 and stage 3 patients were, uh, inadequately, uh, surveyed and had inadequate treatments. Stage 1, no question was done right. Stage 4, it's metastatic, no question, it's a bad problem, and they learned all they needed to about mitata. But stage 2 and 3, and what it means, especially because stage 3 numbers were better than stage 2 numbers. Essentially told us that both stage 2 and stage 3 were inadequately diagnosed and received inadequate therapies. And so, therefore, it calls into question not so much the validity of 1 and 4, but the validity of 2 and 3, which essentially is lymph node disease. And occult disease versus non-occult disease and what do you do with it? And so, It's a failed study again, but at least we had the first one. I hope we have another one. I, I can't, I can't resist Chris, uh, with the, um, couple of minutes we have left, given your, um, Uh, historical mastery and, uh, your encyclopedic knowledge of cancer in the current era, the evolution of time, you mentioned some great cancer hospitals. You've got the Dan-Farber Cancstitute, um, on your slide here. Um, and given the evolution of what is happening in Boston with the Dan-Farber Cancer Institute. I'm, I'm guessing that some people here don't know the history of how the Dana-Farber Institute was created. You mentioned a little bit about, about Farber's background here at Children's. I wonder if you can give a, uh, a 45 2nd summary of, of how the Dana-Farber Cancer Institute was, was, was created here in Boston. Um, short version, yeah. So, um, to be frank, I, I probably don't have it perfectly, but, uh, as you all know, the, uh, departments of hematology and oncology are separate. Hematology is housed at Boston Children's Hospital. And the department of oncology is not. It's housed at a completely separate institute. Dana was a philanthropic benefactor whose relative had cancer treated by Sydney Farber at some point along the way, and I don't know the exact uh deal. But his use of the agent was not looked upon favorably. And he had significant um uh apprehension and arguments with the powers that be, such that his research and work, I believe, was being impeded, for lack of a better term. Um, and again, I don't know all the details. As such, um, he felt it was, uh, imperative that he leave Children's if this was going to continue, and this work was to continue and go to a different institution, such that he didn't have overarching people trying to affect it. So, they went across the street and set up. The clinic, and I probably don't have all the details correct, but I think that's quickly summarize it, and to this day it's still there. And now they, now they want need a hospital again and they're gonna have one. Yeah, it's come full circle. Well, I think we can all appreciate, um, you know, and, and, uh, uh, as always, encyclopedic, uh, knowledge and history of, of this, and, and, uh, thank you for bringing this, uh, um, not surprisingly unusual perspective to us, uh, with surprise. So thanks. Thank you very much.