Dr. Christopher Weldon - Pediatric Surgical Oncological Survivorship

you you you you good morning and welcome thank you for the opportunity to present today to you and I'm going to talk on a subject that's near and dear to my heart and I think it's something that I knew nothing about until I was probably made career and It's really a field that I think deserves more attention nationwide Because I think you'll see shortly the impact of the problem First and foremost, again, thanks so much for your time and attention, and please feel free to interrupt as questions is needed. I have no disclosures of any type, but I do have many disclaimers, and these are really the acknowledgments of the people who have made this possible. Specifically, my colleagues at the St. Jude Cancer Research Center in Memphis and the childhood cancer survivorship study, Dr. Les Robison and Greg Armstrong, who have been instrumental in supporting this effort to allow us to study and produce and publish these reports that will hopefully help generations of children to come. I'd like to especially acknowledge Lisa Diller at the Dana Farber and the Prene Clinic, who introduced me to survivorship issues to begin with. Dr. Schambler and Fishman, who have been instrumental in supporting the entire effort, especially with time and resources. And then my co-conspirators, as I call them, are in Medenti, Brentwile, Andrew Murphy, Brian Diffenbach, and Duncan Ramsey. These are five surgeons who really have pioneered and done the lion's share of the work. I'm not a trained epidemiologist, I'm not a trained statistician, I know very little about methodology. Many of what we talk about in reviewing the data, it takes me a long time to digest it as a trained molecular pharmacologist, this is not something that I have expected to be involved with. But I can safely say it's been one of the most rewarding things I've been able to do. But all this work has really attribute to the people on the screen more so than me. The outline of the talk will be four basic sessions. The first will be the modern model of ecological care. Second part will be reviewing the data that's available. It will then go into what I think is missing and then specific surgical survivorship studies directly. So before I begin, everything has a story and that story has a first chapter, if you would. It was 2011. I was in holding on the third floor. I was about to operate on a child who had a sarcoma in the pelvis, going through the consent, risks, options, benefits, almost had it on auto play if you would. And the father who's an optical engineer at MIT looked up and said, well, what's the risk of a bowel obstruction? What is the actual risk? As a numbers person is somebody who makes a living and studies the optical engineering of space shuttles and instrumentation in space, it was somewhat taken aback. I didn't have a correct answer for him. I didn't have a numbered answer for him. I really, essentially, was going to use data that was old data that was not attributable to his daughter, specifically, especially her age and problem. And that began, essentially, a long journey to where we are now. So what is ecological care today and how did we get here? I'll use Wilms tumor as a model. I don't know why because it's probably the best studied and it truly is a 20th century success story. George Walker at Johns Hopkins published an 1897 report about children who underwent surgery, quote, unquote, for kidney tumors. Granted, we have not gone back to review all of his data to make sure that they're all Wilms tumors or Rabdoid tumors or even if they're Wilms or kidney of origin period. Somebody reported on 145 patients who had four, three-year survivors. The most common surgical operation was a biopsy and so began epidemiological research into survivorship, so to speak. So if you turned to the dawn of the 20th century, roughly in year 1900, a survival rate of less than 5% was expected if your child had a Wilms tumor. And then over the course of 100 years, it became a very curable disease such that by the year 2000 or in 100 years, your survivor rate went from less than 5% to almost 95%, which was a startling number, a startling discovery. And much of it was secondary to serendipity. In reviewing how this happened and each step involved and going back to the original articles, throw away sentences about what stimulated who to do what and when. I think was an amalgamation of hallway conversations, lunchtime conversations, and ideas for people who unfortunately had no their option but to try what they did. And I think serendipity traces its course through all of this, not the least of which was my conversation with the gentleman that day in pre-op holding. The step one was surgery. We're obviously well for, we're well know who William Ladd is. You know what he's accomplished. You know how he accomplished it. We know that he walked our halls and he's a pioneer of our field. At the time with the rise of better periopative care, exquisite surgical technique, and meticulous follow up, single handedly using surgery alone and what might be deemed aggressive operations, he was able to advance cure rates from roughly less than 5% to 25% to 30%. He published his series by him in 1938 in the annals of surgery that documented this, which then revolutionized the field to allow others to proceed likewise. Down the hall was Dr. Newhouser, a radiologist who also did radiotherapy. Dr. Newhouser added radiotherapy because of the risk of local recurrence to the aggressive surgery. And over the next two decades, they took a survival rate in the 20% tiles to the 50% tiles. This would publish an assemble article in pediatrics in 1950 documenting the success of radiotherapy alone. And to that, the studies by Dr. Farber and colleagues, not only here, but also at the predecessor to the MD Anderson Cancer Center, where they then added chemotherapy drugs. They only had two. They used them for leukemia, the Wilmscomer, they used them for everything. His studies were built upon Goodman and Gilman of the Pharmacology textbook fame, who were the first ones to document the successes of using chemotherapy to treat cancers. He published in JAMA in 1966 with the addition of chemotherapy in addition to radiotherapy and surgery in 50 years, they took the survival rate into the 60s. In and around this time, starting in the mid-1950s and extending into the mid-1960s, the NIH wanted coordinated care for the treatment of childhood cancer secondary to its rarity. And as such, a group of experts was convened under the umbrella called the National Wombs Tumor Study Group. It was a forerunner to the renal tumor group in COG. Prior to the Children's Oncology Group, there was two competing pediatric cancer trial groups. There was the Childhood Cancer Study Group, where the CCSG, and then there was a pediatric oncology group. These groups did independent studies, but they gained under one umbrella. The National Wombs Tumor Study Group, however, was interesting in that they took patients just with renal tumors from both groups. It was an amalgamation of surgeons, medical oncologist, geneticists, radiologist, radiation therapists, and the like to try and determine how to cure the disease. For many reports, if we're five-year intervals, they took that survival rate from the mid-60s to really where it was by the dawn of the year 2000 into the 90s. And if you look at what this cancer care meant, it is all about this graft. The graft is not there for you to try and read it. This graft is not there for you to try and interpret it. Sorry. The process that you see before you essentially is the forebearer to how we treat children today. And it's all about risk grouping. So no longer do we treat all children the same. And over time, what they really wanted to develop was what we call risk stratification. The multimodality therapy of cancer started with children. And so did the risk stratification process that now runs through all oncological care. No longer is it just stage of tumor, grade of tumor, but it's a host of both physical and atomical molecular factors that come into play to determine who needs what therapy. And the risk stratification process is really driven by two simple questions. Who needs more and who needs less? Because at the end of the day, we know these treatments have long term effects. However, those long term effects are ill-defined because you don't know because you need time. Unlike adult cancers where we determine five-year intervals are great. And if you're cured at five years, then you can live a nice happy life because you shouldn't recur or your recurrence rates are low. And whatever therapy induced problems realistically at an older age, they're fewer and more easily understood. Whereas with children, we measure treatments over five decades and the effects that they cause. So we really can't talk about survivorship until we talk about survivors. So how do we get this data? What do we really look at? So the data that we use really comes from here, the Children's Oncology Group. This was formed again as an amalgamation of the CCG and the POG. And realistically, it combines disciplines and disease study groups to then run trials, to then determine what is the cure, how do you procure it, and then how do we lessen therapies for the long term risks? These are like any standard study clinical trials, they're three to five years. But the long term data to affect those risks are lost. I think it's a common problem in all pediatrics in that as pediatric providers, we lose track of patients once they hit adulthood and they transition out from seeing their pediatrician. They move across a country, they go to college, they see adult providers, and many of the adult providers have little to no knowledge of pediatric cancers. So though we can get data, is it in the right hands? If you look at the two most common tumors, solid tumors that we see, if you look at neuroblastoma, 80-some odd protocols in the last 20 years through COG, 130 publications, less than five are really there to evaluate if surgery-specific intervention or outcome. Final tumors, greater than 40 protocols, 52 publications, 17 looking at surgery-specific outcome. So at the end of the day, we have the data on the cure, and we have data on trying to survive, but we don't have the data on the survivors. And that's where this really comes into play, because COG, their website is curesearch.org. They focus on sustaining life, but the problem is we also need to know what it means to live, because our results are measured over five decades. And so who studies the living? This was an interesting journey that we had to figure out, so what was the missing data? How do we go from a survival rate of less than 5% to a survival rate of 95% in 100 years? But then what do we know that the child who is treated in 1960 is doing in the year 2000? What are the health concerns? The doses of radiation, and the scatter radiation? What's his risk of second malignancies? Hypertension from the lost kidney, etc. How do we advise them to live their life to the fullest in the best? This is an index patient treated here who had a large renal tumor that you can see outlined here. This was the Thoracobdombalm decision that was proposed to do the surgery. This was her pretreatment chest x-ray, documenting extensive pleural disease. Two years after therapy, this is her chest x-ray. He responded remarkably well to the intervention. Unfortunately, I don't have a chest x-ray from 2007, so I can't tell you if the child is alive, nor can I tell you what is wrong with the child currently based off of the therapies administered five decades before. So therefore, when we think about survivorship, and I think about back to the question that was posed to me in the pre-opipal holding, what is the risk of a bowel obstruction? That is something that we should be able to answer. We have decades worth of survival data, but we don't have data on survivors to answer simple questions about health risks, health needs, health interventions, and what we can do to educate them as a population to seek their own care or to have family help them seek the appropriate care and when. And this all comes down to the concept of what is the cost of cure and how can we optimize and maximize their life's journey. So survivorship is really broken up into this. The definitions, the problem, the initial catalyst that started the field, as I like to say, the fission chain reaction, the self-sustaining reaction, where the product of the reaction feeds itself and allows it to continue. So the definition of survivorship through the NCI, as published in 2014, is the chronic physical end-or-scikosocial side effects, which can be severe to be able to be sometimes permanent, present years to decades later, that are caused by the therapies administered during treatment as a child. This, as you can see, was really not picked up until 2014. So though we know a lot about surviving, we know very little about how it's defined until almost 50 to 60 years later. So what's the epidemiological definition? What is the scope of the problem? Well all comers, pediatric cancer survival rates, border on 80%. So think about that. All cancers, all comers, 80% live. That means they're predicted greater than 400,000 childhood cancer survivors who are currently adults in the United States. That's one out of 450 adults in the year 2020. 75% of whom will have at least one chronic condition by the age of 40, for which they need to seek chronic medical care for and need interventions, medical, surgical, psychological, or otherwise. Of the 75% that have at least one chronic condition, 40% are deemed life threatening, where they need intensive care at least once a year. That's an increase in medication, addition of another medication, or even a procedure. Resulting an increased healthcare cost measured in the billions over those that don't have a diagnosis or a history of a childhood cancer. So the problem is extensive and is measured in epidemiological terms that in many respects are somewhat startling if you think about it. So what was a catalyst for this? Two physicians at CHOP, two bed rocks of the National Wombs to Mercedi group when it started in the late 60s were Dandianjo and Audrey Evans. One was a radiation oncologist, one was a pediatric oncologist. They decided to start a late effects study group as part or an offshoot of the National Wombs to Mercedi group. They wanted to know so that they could educate the child and the parent what was the cost of cure? What did they need to look for when the child was 18, 28, 38, 48, etc. They started with a single steditor, theirs. They then quickly expanded to 10 centers under an NIH-funded mechanism. They had five simple determinants that they wanted to look follow. Second, malignant neoplasms, not recurrence and progression of the primary womb swimmer, but others induced by the therapy, radiation induced sarcomas, chemotherapy induced leukemias, etc. They wanted to look at infertility. They wanted to look at the rate of reproduction. They quickly deduced that was going to be an overarching need for their population. They wanted to look at organ hypoplasia. They treat children from their young and their bodily immature and atomically and physiologically. And as such, their organs become stunted. What does that produce for insufficiency later? Lone, liver, kidney, heart, lung, etc. They wanted to define toxicities and they used this to define those toxicities and when they might arise. And one thing that they had not predicted, but then came to the fore very quickly, is genetic underpinnings of these diseases. Because some were linked. And it was really the starting of the genetic predisposition of cancer and cancer syndromes. So that was an unexpected byproduct. Serendipity, if you would, to start an entire new field. So if this was the catalyst, what spurred them to do it? If you read one of their seminal papers, it was extremely interesting to know that they figured that we treat children at a very young age. More often than not, they don't remember any of their therapy, let alone specifics about it. Surgery, radiation, chemotherapy. None of these details are there. Furthermore, their parents don't either. Their parents suffer from post-traumatic stress disorder. The parents end up going one year, two years worth of therapy and all the stressors that go with life and other children at home. And when the child is 10 years out from therapy, they can barely remember what the child had as well. They'll see the physical scar. But more often than not, they can't remember specifics. This is also in the time of paper charting. Nothing was necessarily kept at the institution. So even if they wanted to go back, record keeping was not adequate. They know that therapies induce cognitive dysfunction in the child themselves, such that even if they could remember, it is very likely that they would have cognitive disability later such that they couldn't even recall. They know that their therapies induce psychosocial impairments, which also restricted their ability to care from the cells and to maintain ongoing dedicated care to prevent problems that would rise later on. They know and identify in the United States that medical care is disjointed. Children grow up. They go to college in different parts of the countries that then work in other parts of the country. They don't take their medical records with them and at the time it was paper charts. So there's no way to carry it on a thumb drive or to have it on the cloud. And now it's extremely difficult to maintain health care in all your records. There is insurance concerns. This is a pre-existing condition. Would it be covered in by whom? Many families they found never reported that the child had a cancer when they started a job so that they would get insurance because there is concern that it was as a pre-existing condition, nothing stemming from that cancer would be covered at all. And then they needed to have these specific care plans. The child who is AML has a totally different set of problems than the child who has a Williams tumor or a brain tumor or a sarcoma. And as such they recognize early on that survivorship is more than just one problem. It's a disease-specific care plan that will then be interacted or have other interactions along the way that will also modify it. And then we get to the vision chain reaction. This is the health-sustaining reaction that has carried us forward for the last 30 years. Les Rebusin is an epidemiologist at the University of Minnesota. He has had an interest in psychosocial issues in cancer patients, in pediatrics, and has sent you, has been the bedrock of his career since. In 1992 he applied for institutional and state funding to look at a cohort of cancer survivors, the University of Minnesota, through the prior 30 years. He went back, extracted the charts, names, and then developed a survey to send to these children to document what their current state of health was in 1992. This study was in the basis for an ongoing NCI-funded mission since 1994. It started out as a single R award and has grown considerably, which we'll go through. We call it the Childhood Cancer Survivorship Study. Initially, he run out of the University of Minnesota for the first decade and then moved to St. Jude. It is now funded by a eight-figure U-grant that has been renewed every five years for the last 20 years. And they have currently 55 active R mechanism types grants as well, looking at specific proposals. They look at all tumors, and children save liver and germ cell tumors. Those were left off out of a cost-reason, a cost basis. They looked at the tumors, they took the most common ones, and unfortunately the incidence and the rarity of those made it such that they had to be cut. So all the data we will show, none of it pertains to liver and germ. They started recruiting member centers and principal investigators at those centers from across the country. We have 32 member centers now of which Dr. Diller is our PI, and Dana Farber was one of the first six founding centers. They have six working groups dedicated to specific, overarching, ongoing, known problems. Second neoplasms, chronic disease conditions, cancer control and prevention, genetics and genetic underpinning, including a biorepository and looking at specific genetic factors detailing chronic conditions. Psychology and psychosocial, epidemiology and biostatistics. They have five support centers across the country, including a biorepository, a radiation dosimetry, component, and others. It is quite the undertaking. On this, they essentially extract data for three decades worth of cancer survivors treated between 1970 and 1999, broken up into two cohorts, each separated by 15 years. So it was 1970 to 85, and then 86 to 99. They use extracted data from a validated survey with an active 90% ongoing participation rate, which is startling. They have nine primary surveys and 20 ancillary surveys over the last 30 years. They follow 25,000 survivors actively and 5,000 match siblings so that they can take away any concern about the causal effects of where the child grew up, etc. They publish over 400 manuscripts. It's a very simple process to get involved, and their website is there for anyone who's interested. So what do they do? I'm going to walk through two studies of theirs quickly just to show you what they can do. This seminar report came out in 2006 that really showed what's the risk, what's the burden of the chronic health conditions and adult survivors of childhood cancer. So if you look at a relative risk of severe grade three or life threatening grade four health conditions among cancer survivors is compared with siblings. We'll look at some very simple things. Major joint replacement separate from the inertia therapy. If you look at survivor services, the sibling, your relative risk of needing a joint replacement is 54. Conjustred heart rate 15 second, malignant theoplasms 15 dysfunction or cognitive dysfunction 10% etc. So realistically the burden is there across every organ system across everything. Survivors are impacted to a grade degree out to 30 years. And then if you look at broken down by tumors, type, you look at total survivors, the rate of any grade complication condition is in the blue and the severe and life threatening are in the red. Regardless of the tumor type, survivors versus siblings have worse any condition and disabling conditions as well. And we can see across Hodgkin's non Hodgkin's Wilms, Neuroblastoma, soft tissue circumus etc. So the cost of cure is great and it rises decade over decade. But doesn't matter when you are treated, another seminal paper that showed demonstrating the effect of time. So if you look for death from any cause, 15 tumors of year mortality occurs. If you are treated in the 70s, you realistically got more therapy than if you were treated later, most likely because of risk stratification. We learned who needed more and who needed less. So decade over decade, if you are treated earlier, your mortality risk was greater. And that death was from recurrence and progression in addition to most importantly health related causes. So we know that the cost of cure is great and they need ongoing active care almost immediately after they are cured. So we became involved at this time and we started to look at is there a surgical outcome of the 400 publications through the CCSS, 82% of the cohort received surgery but there are only 24 publications that had addressed a surgical topic directly before we got involved. So over 25 years, 400 publications only 24 had a surgical hypothesis. So can we use it to evaluate surgical conditions? Is there any data there? So what are the surgical survivorship studies? The first one that we looked at was to answer the question is what is the risk of a bowel obstruction? I had no idea how to answer that. At the time that we were doing the operation, actually two days later, Lisa Diller gave a report on survivorship, serendipity. So I go from preop holding on Monday, not knowing the answer to listening to Lisa Diller on Wednesday and then Aaron and I speaking thereafter about, hey, I think we can answer this question. Aaron went through the website and they had a specific question looking at the late effects that would involve intestinal obstruction requiring surgery in one of the surveys. So that led to this report five years later. I'll walk you through this one study and then I'll go through others. So essentially our populationization was the childhood cancer survivorship study participants, diagnosed with cancer before the age of 21, between 1970 and 84, 26 institutions at the time. Those were the number of survivors and those are the number of siblings. Our inclusion criteria was survivors of childhood cancer and the siblings of the survivors were randomly selected. Our exclusion criteria was death within five years of cancer diagnosis. These are outcomes and our statistical analysis about how those outcomes were achieved. Our results. So we looked at survivors with and without abdominal tumors. This is the breakdown by tumor type. A lot of our anatomical definition was able to be extracted to know that our bone tumors were really of the axial skeleton. These were a comparison of those with abdominal tumors to not by age, sex, race and the year they were diagnosed. This were the abdominal tumor versus not abdominal tumors by the number of surgeries at the time of treatment, chemotherapy, yes, no and then graded radiation. How much by desial? If we then look comparing those with abdominal pelvic tumors to not versus siblings and we see the late risk of intestinal obstruction requiring surgery, so intestinal obstruction requiring surgery, iOS, we then can see that when this happens and when the time of diagnosis was. So if we take the data at its most simple, what is the risk of late intestinal obstruction was about 6% to 30 years. If you had an abdominal tumor. If you did not, it was 1% and in siblings it was 0.3%. So we could answer the question now. His daughter's risk of surgery from intestinal obstruction was gone to the young order about 6% and this is the best that we had. Unfortunately, she was going to have radiotherapy and that made the risk worse. Such that if you had abdominal pelvic tumor with radiotherapy, your risk jumped to 7.1% over the same time period. Whereas those who had a tumor without radiotherapy had dropped and if you didn't have an abdominal pelvic tumor with or without radiotherapy, it was even lower. So what was the impact of our intestinal obstruction? An unhidden finding if you would is that the mortality rate was 80% higher than others. So not only did we tell them the risk, but it was a significant mortal risk as well. Whether that, because they presented late, didn't have the education, we couldn't glean that. But that is the importance of the survivorship study because that is something that they need to be full warned. But again, the child who had surgery 30 years ago, who's going to warn them? Who's going to know? That is where we really need to focus on education. So we know that childhood cancer survivors with a abdominal tumor is 6% developed in test blood obstruction, requiring surgery at 35 years from diagnosis. And that risk extends for decades beyond and mandates ongoing surveillance and education. So I think answering one simple question posed by a parent really made it such that survivorship studies would be worthwhile. This lens led to further studies looking at what is the risk of infection related mortality from the splenia? Majority of Hodgkin's patients underwent a staging laparotomy if we all remember the term very few of us have done it in the 70s and 80s even in the early 90s. What is the real risk of infection related mortality from being a splenic? What are the data? Their poor, the atrama, hematologic disorders or in this condition? This gave us a better answer. For those that were unexposed, your risk of infection related mortality was quite low as comparison to those who had splenic radiation and those who had a splenectomy. So the cumulative incidence could finally be determined. Interestingly enough, you became a splenic with enough radiation and what the story bore out and what we were not expecting is the risk and the role of radiation inducing a splenia with an increased cumulative incidence of late infection related mortality in the survivors as well. So it wasn't just those that had surgery and loss their splenia. It was those that had radiation to almost any degree but essentially greater than 20 grade. We're also an increased risk of infection related mortality. Again, these data are used to educate. We then move on to other studies. What's the long-term risk of venous thromboembolism? Again, demonstrating an increased cumulative incidence in both male and female survivors but female survivors are more impacted than their equivalent siblings. Using a forest plot, looking at the standard usual suspects for atrace for venous thromboembolism, we see what the relative rates would be looking at gender, ethnicity, degree of radiotherapy exposure, specific hemotherapy agents used, body mass index, and an adjoining second malignancy. So again, data that can be used to educate. What about late onset and erectile disease? This is a different psychosocial impact that we determined. And it's primarily related to the institution of radiotherapy. If they get significant radiotherapy, they're more affected, giving a cumulative incidence of late anorectal disease with treatment RT to the pelvis and as such that significantly impacts quality of life by almost any measure looked at. And again, education and understanding of the problem to help treat it is key. What about coldostectomy? Again, higher rates in both male and female survivors over their equivalent siblings with the liquid tumors having a greater cumulative incidence than lymphomas or solid tumors. Again, providing the option for education to the cohort to make sure that they understand what to look for and when. These were risk factors also associated with it. Again, many other usual suspects. Finally, on late onset of kidney failure. One of the most pressing questions we're always asked dealing with Wilms tumors and children who lose kidneys by either medical therapies or surgical therapies is, well, what's the rate of renal failure? So these are data that my PhD mentor would say are back of the room data. You don't need to read anything else on the slide and I've purposely left it small. The red line is the survivors, the blue line are siblings. It's pretty clear that no matter how you look at it, the cumulative incidence of late onset of kidney failure is far greater in the survivors and it is in siblings and it rises decade over decade. And this is borne out such that we then can see it by tumor type. And if everyone notices Wilms tumor and this was a British publication, so we had to spell tumors so much differently, it's highest in Wilms tumor but you also see it in other suspects, neuroblastoma, sarcomas, etc. This is broken down by nephrectomy status, anthocycline dose administered. I foster my dose, splatnam dose and then radiotherapy, all demonstrating other factors that will increase renal dysfunction over time. So these studies are part of what we do and have done for the last seven years. We meet every Tuesday night, we've got six more studies ongoing but we sat down and Brian Diffenbach one day posed, well what is the real burden of surgery period? There's papers out of the CCSS on the burden of chemotherapy as a methodology or as a treatment modality. There's papers on the overarching rate of risk of problems from radiotherapy but there is no paper on the burden of surgery and what surgery happens or how often into what degree. So we then pose a query, can we document and the study is what will show you? Can we document what is the burden of late surgical problems, all comers? So in 2016, 2015, we queried about our ability to get better granular surgical data. Again posed by Brian Diffenbach, spearheaded by Brandt and we all participated. We then created through their platform in the cloud and access data sheets such that we could then extract data to become more granular about what is the late burden of surgical problems. So we undertook a coding project of treatment related surgical procedures for the expanded cohort from 1996 to 1999. We physically started to extract the data in 2016 and spend a year building the website and the forum. It's now completed, it's completed in 2019 but it's been validated, verified, cleaned, et cetera. We reviewed over 15,000 patient records and extracted some 26,000 procedures looking at what they had done and when. So we looked at 25,000 childhood cancer survivors, 5,000 siblings diagnosed for the age of 21 from 70 to 1999. A primary outcome was undergoing any self-reported late major surgical intervention greater than five years after the cancer diagnosis through this coding project. All available procedures were recorded and the ages which they had it. We looked at treatment exposures and then we began to formulate what is the 35 year cumulative burden of late surgical intervention by mean cumulative count. We then also looked at rate ratios associated with undergoing late surgical interventions among survivors and siblings estimated by a piecewise exponent model controlling for the following. So what's our demographic data? This is broken down by sex, race, healthcare status. If we look at our characteristics for survivors versus siblings, we break it down by disease. We then can look at our treatment characteristics of childhood cancers by decade of diagnosis. So our largest percentage was 80 to 89, small in both the 70s and 90s. We look at their age of diagnosis. We then look at the treatment variables. Surgery as treatment for a primary cancer, 6,000 did not have any. 13,000 had a single or two operations only. 4,500 of their abouts had greater than three operations. Those that had chemotherapy versus not. Those that had radiotherapy or not and to where it was. We then looked at the occurrence of late surgical procedures greater than five years in survivors versus siblings and documented that just under 12,000 survivors self-reported that they'd had at least a single surgical procedure five years after the cancer diagnosis versus only 2,000 siblings. And that the number of procedures, 5,000 had 1,2702, 2,700 had 3 to 5 and an unfortunate 760 had reported six procedures or more five years after their cancer diagnosis. And those numbers are juxtaposed to their siblings on the right. So obviously a much higher burden. So if you do a 40 year mean cumulative count of the late surgical procedures, we can obviously see that survivors have a much higher burden of undergoing this late surgical procedure than their siblings, markedly so. These can be broken up by disease as well with Hodgkin's patients in the green having the highest cumulative burden versus ALL in the black as the lowest, but none are spared. If we go from a liquid timbers to the solid timbers, we can see that the sarcomas, uins, osteo and soft tissue have the highest cumulative burden, not necessarily unexpected secondary to the intensity of the therapy and knowing that bone tumors frequently require form many more procedures during therapy than not. But again, no single solid tumor is spared. So if we look at adjusted rate ratios for late procedures by subtype and selected procedures in childhood cancer survivors' relatives, the siblings, let's look at some comas ones. You're six times more likely to have a mastectomy versus your sibling. Your rate is sixth greater for coronary artery bypass, 13 for a valve, VP shunt, etc. So again, the burden is great and this helps us measure it. If we look at the adjusted rate ratios for late procedures by subtype as well, looking again in other areas, cataracts, male reproductive, limb operations, the rate ratios are greater. So this report, still in its infancy, will hopefully lead to a seminal publication that brand is spearheading, documenting that survivors of childhood cancer undergo major surgical procedures in a much higher rate, that the risk of requiring late surgical interventions varies based on diagnosis and treatment exposures and the exposure to prior surgery and radiotherapy being associated with an increased rate of late surgical interventions. These findings, again, have not been reported and shed new light on the impact of childhood cancer treatments can have for survivors highlighting the elevated burden and the high cost of the surgical procedures that they undergo greater than five years from treatment. So in conclusion, I think it's just as critical that we continually investigate the living as it is to procure life. And I think we have an obligation to do so. We have an obligation to inform the patients, the families and the medical community at large what it means to survive cancer as a child and how to best provide education for them such that going forward they can take command of their own health care and hopefully prevent many of these problems. I want to thank you very much for the opportunity to speak and I'd be happy to take any questions. Of course, that was spectacular, no surprise to anybody that you would give such a comprehensive review of a topic that is so crucial. We all go through our education and training in medicine learning about a five-year survival rates. Of course, in childhood, five years is just the beginning and if you survive, you survive with this burden that you and your colleagues around the country are so nicely describing. It's interesting. I was personally touched by your comments about kids still remember, the parents don't remember. There's no records. My cousin's son had a bone marrow transplant, a radiation therapy in bone marrow transplant when he was a teenager and he's now in his 40s and last year he had a massive MI. Of course, he's in a different institution than he's been. He didn't know much other than he had radiation. There were no records from when he was a child and the adult providers are looking at this young adult like you should be vigorous and you're almost on the ECMO and they didn't know anything about radiation and do his coronary artery disease. Which you document here is well established to be a very significant life for it. But although the numbers you show are common, the providers who deal with adults in the routine medical setting, it's not common for them to see many of these conditions. Even ball destruction, all general surgeons deal ball destruction. Ball destruction is a different disease. It's really crucial that this knowledge is gathered, perpetuated and that people focus on dealing with these patients as you say for life. Really spectacular and the mentorship that you've demonstrated with our and Brent and the rest and the collaboration with the medical oncologist is really a paradigm for how we address problems bigger than any one of us can do in our career. I'm sure those are the questions. I want to apologize for the ABS background. I was trying to get that off beforehand and somehow I got stuck. So I didn't want to give everybody PTSD. Sorry about that. We're glad you're serving the community. Questions for Chris? Before you came on, we were informed that you threatened the fellows that you wouldn't speak if they introduced you. So they didn't. But everybody of course, you need an introduction to the crown and everybody understands the New York commitment to this field and the betterment of our institution in our department is pretty two minutes of work to answer. And the long term effects is much due to your efforts. And of course, his legacy coming down from Dr. Schambert who saw the wisdom of bringing you on to carry on in his image. He's still there at your side. This shows the benefit. I remember when Dr. Henry used to show that picture of that child with the work of Gungal in Cigin Dr. Schambert showing it. And now you're showing it. And you're probably going to do so as well. Thank you very much. Appreciate it. Questions? You've overwhelmed everybody. This is Zoom deal. They might be afraid you're going to ask them a question for Borge from your background. Sorry. Well, thank you for everybody for joining us. Thank you, Chris, for Patrick Rattock and we'll approach you back in Boston. Thanks so much.