OK. All right. So, good morning and welcome to Surgery Grand Rounds. This morning, it's our privilege to welcome two distinguished speakers to the podium who are visiting our institution from Cincinnati Children's Hospital, and who are here to discuss some of their groundbreaking work with us on the topic of total pancreatectomy and eyelet autotransplantation. Doctor Jamie Nathan and Doctor Massim Abu Al Haja represent the disciplines of pediatric transplantation and gastroenterology, respectively, and both are collaborators on the work that you'll hear about this morning. Doctor Abdul Hadja completed her MBBS in Jordan at the Jordan Institute of Science and Technology. Subsequently, she joined the University of Iowa as a resident in pediatrics, where she would go on to complete a fellowship in pediatric gastroenterology. She has been on staff at Cincinnati Children's in the Division of Pediatric Gastroenterology since 2012, where she's currently associate professor. And also the medical director of the pancreas Care Center there. Among her many leadership roles, she currently serves as vice chair of the NASPGHAN Pancreas Committee, as well as as a regional director of the National Pancreas Foundation and the current president of the Women Faculty Association at Cincinnati Children's. She maintains active research in biomarkers and progression to chronic pancreatitis alongside her clinical duties. Doctor Jamie Nathan completed his undergraduate in medical school at Yale University prior to joining Duke University where he completed general surgery training. He joined Cincinnati Children's in 2005 as a fellow in pediatric surgery prior to completing a fellowship in transplantation at the University of Cincinnati. At Cincinnati, he holds a number of roles, currently serving as the surgical director of the pancreas Care Center, the kidney transplant program, and the intestinal transplant program, as well as an associate surgical director of the liver transplant program. He maintains active leadership roles in a number of national organizations including serving as the AAP liaison to UNOS, the APSA Cancer Committee, and the Pediatric Task Force of the American Surgery of Transplant Surgeons. His research work is currently funded by the NIHNADDK on the prospect of observational study of total pancreatectomy and islet autotransplantation, as well as intramural funding for the pancreas Care Center, work that we're looking forward to hearing about today. Please join me in welcoming Doctor Nathan and Doctor Abul Hajji to the podium. Thank you for the kind introduction and thank you for having us here and um Um, this is gonna be, as you will hear, uh, a topic where we would split, uh, some of, hi Victor, some of the medical and the surgical parts. Um, so I'll hopefully walk you through, um, the collaborative aspects, and I'll cover the GI portions of what happens before the TPIAT, and then, uh, Jamie would cover the total pancreatectomy and afterwards. So, we will define acute and acute recurrent and chronic pancreatitis together because that has been recently defined um really in the last 5 years and um from the definition, we started understanding the disease better. So the advances in diagnosis and management, and then the surgical options will be covered in the second half of the talk. So in terms of definitions, acute pancreatitis is defined typically as we define it in adults, meaning two out of the three criteria which are the pain that that is consistent with pancreatitis and having amylase or lipase, that is 3 times the upper limit of normal, and image findings of acute pancreatitis. Whenever the patient has 2 out of the 3, then they need the diagnosis of acute pancreatitis. Acute recurrence is more than 1, so at least 2 and separated 1 month apart. Um, it, and it could be less than one month if the patient had normalizations of enzymes and a pain-free interval. And then chronic pancreatitis is not acute recurrent pancreatitis, which is, um, really one of the challenges in advancing this field. When does acute recurrence become chronic and when is the right time for the intervention. In terms of national numbers, um, this is one of the, um, kind of recent, um, epidemiology, if you want to say, dabbling at this problem. We use the CDS, which is the, um, part of the healthcare cost and utilization project, which is most major children's hospitals participates in. And um it surveys years um every three years, so 006, '09 and 2012, and there were, there was a total of almost 28,000 discharged diagnosis of acute pancreatitis as the primary reason for the admission to the children's hospitals. And uh when we split the patient ages into preschool or not really pre in before they enter school age, so less than 5, because we think those are unique patients when they present and they don't always have the full symptoms of belly pain, and then the 5 to 14 and the above 14, which is the typical adolescent into adulthood age, we saw that the number of cases increased as the age increased. In terms of admission trends, um, acute pancreatitis comprised an increasing number, um er when, when the denominator was all pediatric admissions for any different reason. So, every time we looked at this in 006, 09, and 0012, there was an increasing number of Acute pancreatitis admissions nationally, and that really mirrored obesity and chronic pancreatitis in terms of that increasing trend. When we did further multivariate analysis, obesity was not really significant anymore, but chronic pancreatitis, as you may imagine, was. So as more and more patients become chronic, these are the patients that kind of drive the healthcare costs because they are the ones who are needing admissions for the flares. So how does a patient go from acute to acute recurrent to chronic pancreatitis? The natural history is not really fully known. Even in adult studies, that is also a big area for research, um, and certainly, it is an area of research of mine. So at Cincinnati Children's, when I started my, um, Passion of helping, you know, my surgical colleagues develop the center. One of the first things that we started in was starting a registry for all first comers of acute pancreatitis, and I'm very happy that we just started now looking at the numbers and the data because we have about 130 patients with all first attacks that we followed over time. So, Inspire is the international study group of pediatric pancreatitis in Search for the cure, and um Inspire is now comprised, it's a UO1 funded um study led by Dr. Aliya Ojj, who's a mentor of mine in the field when I was in Iowa, and we're part of it, um, and it's really mostly concerned about studying acute recurrent and chronic pancreatitis. So, how do we define chronic pancreatitis? Well, if we have a histology, then that's the best thing, but as you all know, we don't go and biopsy the pancreas for trivial reasons. Um, but if we have a tissue diagnosis, then that's the best of all to say that the patient has chronic pancreatitis. So, the, um, H&E stain of the pancreas on the left is really showing healthy looking pinkish ainar cells, where you see on the one on the left, on the right, there is loss of those assinar cells and then more of the fibrosis and dense fibro inflammatory infiltrate and even the ductal cells become plugged with viscid material that is all changes of chronic pancreatitis. Now we don't have this in most patients because we don't go and biopsy the pancreas. To just look for diagnosis. However, we rely a lot on imaging to diagnose it, and this is In um the inspired consortium, one of the very first efforts that we started with in 2012, we actually defined how we want to diagnose it as pediatricians, relies strictly on imaging criteria, so ductal irregularities, calcifications, atrophy, and the more you have of those criteria, the more specific you are about the diagnosis. It could be on any imaging, CT MRCP or ERCP and EUS, which is also rarely used in pediatrics, but we also incorporate it in our management. Then if the patient has the image findings, they need to have one of the three of the following either the pain that's consistent with a chronic origin of pancreatitis or exocrine or endocrine insufficiency. Up to a third of the patients, or up to 34% after first acute pancreatitis would develop acute recurrent pancreatitis, and this is um children's data from pooled analysis from different studies. In our registry, it's about 20% as they're followed prospectively. Chronic pancreatitis in uh in young population is about 0.5 to 2.7 per 100,000. So it's not an insignificant risk, even if your patient comes in with acute pancreatitis. This is something we use in counseling and we say we're watching for a second attack. Now, the image criteria that we use is really based on late markers. So once you have calcification and gland atrophy, that's really when we've kind of missed the boat on the patient, and the research should be really more focused on the biomarkers for the early disease detection. In terms of management, it's defined into maybe two broad categories. We start by looking up for the etiology because if we find from the list of the most common etiologies one of the treatable causes, then we have served our patients well and we could or may stop the progression of the disease. Examples are hypertriglyceridemic pancreatitis. Um, if, if we find an etiology, then this is kind of half of the work, but most of the time we find ourselves managing the disease and the sequela of the disease because we really have not found a cure. We are staging or understanding which phenotype does this patient have because it's not a one size fits all thing, and then we really manage disease complications in terms of pain, exocrine, and endocrine issues. So by all means, it's a very multidisciplinary approach. This is one of the Inspire kind of, I would say really landmark papers where there was about 300 kids with acute recurrent and chronic pancreatitis, and we looked at those as a cross-sectional analysis at the time of the analysis, what etiologies or risk factors. They have we had half of the patients having acute recurrence and half of them having chronic, and 50% of the acute recurrent had one of the 4 genes that we test for positive, and 73% of the chronic pancreatitis had one of the genes positive, and this is only 4 genes. In terms of obstructive etiologies, about a third had one of the listed obstructive causes divisum, gallstone, pancreatic biliary malunion, cysts, annuolar pancreas, and or SOD, which is more of a debatable condition in kids. Autoimmune pancreatitis, toxic metabolic medications, and alcohol use and smoking was less of a risk factor in children compared to adults. We put a lot of emphasis on genetic assessment. It not only advanced the field in terms of academic knowledge. Families feel so grateful when we let them know that your child has a genetic disease. They kind of know what to expect for the future. They also don't feel the pressure when they are seeking medical attention that this is a stigma of the disease. It's alcohol and smoking. Um, some of the genetic discoveries like the CFDR mutations actually could hold the future for treating the disease with the presence of CFDR modulators and correctors. The first gene that was linked to hereditary pancreatitis was in 1996 by Doctor David Whitcomb, and it was the classic cationic trypsinogen gene. It's an autosomal dominant um inheritance pattern, and you really see it run in families, um. And sometimes not none of them would be tested until you test the child, and then the parents start knowing that they have that gene. Since that time, a lot of the idiopathic pancreatitis cases became known as the as the genetic kind of risk factors. How does this happen? Um, this is also from um Dr. Whitcomb's um work where there's a pathway, whether it's alcohol pathway, trypsin pathway, SNR cell ductal injury, necrosis, or autoimmune, where a first hit takes place by maybe drinking or calcium-driven. And then the genetics play a role in the whether it is a mutation that leads to the loss or gain of function. Then sometimes within that repair there happens another hit where there's continued alcohol, continued smoking, and then continued necrosis and inflammation and macrophage activation that leads to more of the stellate cells and inducing fibrosis, and then you end up with the end stage disease where it's really chronic pancreatitis. We put a lot of focus on the genetics because we're pediatricians, and if you find the inciting factors before all of the rest could come, maybe we could serve our patients better in the future. This is one of the studies that we've done when we first started looking at our patients in the center. What's different about this one and the JAMA paper that I showed you from Inspire, a, it's less number of patients. It's only 50 patients, but we screened everybody for the 4 genes together, and we did not let providers decide. We just said we're going to send these 4 genes together, which are the PRSS1, CTRC, SPINC 1, and CFTR. And from there we found about 68%. Uh, positivity in the chronic pancreatitis, so close to the inspired numbers as well. In the last few years, there's been more and more genes that were known to be associated with the disease, so we needed to keep up and we no longer really send one gene at a time. Even the cost is not justifiable. We send just panels because you could send one or two genes. By the time you're sending your second one, the cost is already approaching $3000 and the panels are probably around that if you ask any lab. There's a lot of commercially available labs, but at Cincinnati Children's, we did diagnose a gene panel just to serve us well, and it's available to everybody, including you guys. So we use next generation sequencing as kind of the most um The most rapidly adopted technology to screen, so the whole gene is sequenced, uh, not just kind of few areas that are known to be associated with that mutation, and we've been finding more of the variants of unknown clinical significance and banking that data to hopefully one day, if there is a or linkage to genotype and phenotype correlation, we could help advance the field. One might ask, why do you custom platform just send the whole exome sequencing? Well, that's another um big black box kind of topic where you could get into issues of what are you going to do with the um interpretation and what could you find about cancer risk and things like that. And then the cost is also higher, um, and there is a risk of lower coverage with the whole exon sequencing. So, for affordability and focused analysis and short time period for report, we really rely on panels. This is our panel, and it uses one of the um most new technologies, it's a MySE sequencing system that um helped us uh through the TRUSSIC. Um, have a custom-designed platform for pancreas, and the, uh, panels are two of them. There's a pancreatitis panel that includes, includes 10 most common genes known to cause hereditary pancreatitis, and then there is one very specific to the gastroenterologist, um, maybe when they're working steatorrhea and failure to thrive for insufficiency panel. Then we look for anatomic causes. So any patient who has a 2nd attack gets a gene testing, and, and we also look for anatomic because from the inspire population, we know that's present in about 1/3 of the patients, and maybe those are the ones where we would refer for an ERCP intervention and we could help the patient by doing a therapeutic intervention. MRCP is really used for um anatomic and ductile abnormalities detection and ERCP is more reserved for the therapies. So chronic pancreatitis management is really to summarize by assessing the extent of the disease. There's an exocrine and endocrine component. There's a nutritional component. Those patients sometimes are suffering from vitamins and micronutrient deficiencies. Use pancreatic enzyme replacement supplementation following the CF guidelines, and we also supplement the vitamins if they are exocrine sufficient. And then the ERCP and surgical management is really for anatomic issues, obstructive issues, and treating the chronic pain. In terms of pain management, um, our pain team has a pain physician and a psychologist and a nursing and social worker because the pain affects the physical and emotional and social well-being of these children and sometimes the whole family. Um, the physicians do medications and interventional management. The psychologist really focuses on coping and cognitive behavioral therapy, even right upfront, even when we think that the patient needs a total pancreatectomy down the line. These are very important. Therapies to install early on and then nursing helps with all of the above, and there are socioeconomic barriers with these patients because the chronicity of the disease could make them lose work or school time and then that becomes a whole burden on the society and the family. In terms of assessing the function, we really use it to detect is this early chronic pancreatitis, or if it's evident and they're already losing weight and their fecal elastase is low, then we might not need these tests. But maybe these tests also could be early biomarkers of the disease to help us understand it better. Um, you will see in these two graphs, and I'm not going to go into the details, endoscopic versus dreiling, and dreiling is one of the earliest in the 1950s where there was a double lumen and it's fluoroscopy guided, and one suctions the fluid from the stomach and the other one suctions the fluid from the duodenum, which is the pancreatic fluid, and it would go over an hour to assess the bicarb content and then they would help decide if the patient is exocrine insufficient or sufficient. There were a few studies, and these are two of them, that showed that endoscopic function testing is as good as drying in healthy subjects as well as chronic pancreatitis, and really over the last Maybe 3 decades, dreiling has fallen out of favor from almost all institutions. This is our protocol for the pancreatic function testing, and it's really more maybe something for the gastroenterologist to know, but it's really an EGD and we add to it a couple of samples to collect pancreatic fluid. And this is it, just kind of shooting from the ampula of water and then we collect it using a catheter and then we send 3 ampules, but 2 is enough, 5 and 10 minutes into the induction of the pancreatic stimulation, and then we use them for analysis of the enzymes. So you could either measure bicarbs in children, we measure enzymes, and there is cutoffs and for trypsin amylase and lipase and chemotrypsin, and as long as the patient is above the cutoff like this patient, then we say they have sufficient function. But then you could get a patient, and this is a real patient where if you see their amylase and lipase, they're across the board below, and this is a patient that might not be having the full blown diarrhea and failure to thrive, but that's really the beginning of the loss of function, and they really could be helped by pancreatic enzyme supplementation. Um, we have established some curves, so the blue curves are what is normal function and the red curves are kind of what is an abnormal function for um the four of these enzymes. And we've also looked at about 500 samples and we saw that there is an enzyme maturation process with age, so we have to be very careful when interpreting this in children under the age of 2. Something I'm very excited about is the use of MRCP in detecting pancreatic function. We have partnered um in our center with one of the lead radiologists, Dr. Andrew Trout, who's really taken an interest in this. So, it took him two years to develop the protocol, and then validate the protocol. Then we started to do it in chronic pancreatitics, and then the National Pancreas Foundation helped fund us to do it in healthy controls, and now we're going to have standards against which we could compare the diseased population. But basically, as you see here, you give, um, you get the scan, um, the scanned images pre-secretin and then post-secretin, and there's an area of interest that measures the total fluid volume in the intestine. And when we had two reviewers read the volumes, there was great correlation when they were both blinded. So it does have the ability to be reproduced between radiologists, which is very important for objectivity. This is a normal pancreatic function testing, so the images on the upper part are before applying the signal thresholding, and this is the same image pre-secretin after we apply the signal fluid intensity. Um, postsecretin, you see a robust increase in the fluid in the whole intestine, and then this is after the fluid signal intensity is applied. So the area of interest multiplied by the slight thickness gives you a volume measurement, and this is a patient who secreted 119 mL. So this is a normal volume over the course of the test. It's about a 10 minute test, and this is a patient that secreted 9 mLs, so this patient is insufficient. So this is holding future for our patients that they might not need even endoscopic function testing and just get that from a one kind of image that assesses anatomy as well as fluid production. In terms of ERCP, um, as you all know, um leaders in the field are Doctor Victor Fox, and, you know, one of the very first pediatric gastroenterologists to take this on and help us advance the field, really started in the early 70s, where it was more kind of in um described to um cannulate them and pull out ladder. It is, um, had kind of started as a diagnostic modality and shifted more um to be a therapeutic modality, especially in our kids. There are indications for ERCP of benign pancreatic disease and acute recurrent pancreatitis, gallstone pancreatitis, congenital anomalies like the Devi, the SOD. Again, it's a debatable condition, and especially in children or even in adults, and then, Sometimes in pancreatitis of unknown etiology. Chronic pancreatitis, definitely there's a role for ERCP where there is ductal calculi, and they need to be cleaned up or sweeped, and then there's stricturing of the disease as a sequela from the chronic inflammation and fibrosis. Pancreatic trauma, when there is a, a duct um leak or a gap or um a laceration that happens um as an abdominal injury, then there is a role for ERCP as a therapeutic as well, and then in pseudocyst drainage transpapillary. This is a patient who has PRSS1 with a PD stone where the ERCP um would help, and then this is a patient who had a long stricture in the pancreatic head um with this PINC one mutation, and this pancreatic duct um in the head of the pancreas was uh successfully opened by an ERCP intervention. Endoscopic ultrasound provides high resolution imaging of the pancreatic parenchyma. It's underutilized, I think, in pediatrics, but I think the future is bright. We're learning more and more about diagnostic and therapeutic capabilities from the adult studies and applying them to pediatrics. It does have a role in the pediatric disease and there is limited data on safety and efficacy, but this is a list of diagnostic and possible therapeutic interventions. The one that we really have needed to incorporate are the cyst gastrotrostomy or duodenostomy when you have a walled-off necrosis, and it's part of the step-up therapy when you have a complicated acute pancreatitis. In terms of chronic pancreatitis, the Rosemont criteria was built on EUS criteria. So the more criteria you have of hypeechoic fossa and parenchymal globularity, and these are all listed in the table, the more specific you could be about chronic pancreatitis, and it would correlate better with histology. The typical cutoff we use is 5 or more criteria to say if this is a definite chronic pancreatitis. So I'm just going to finish with a case. This is a real case that came to us as an outpatient 9-year-old with a hereditary pancreatitis. She just came for chronic pancreatitis and chronic pain management. Had really multiple hospitalizations over the last 4 years prior. She was on almost daily opioid requirements, really not drug seeking because her mom would keep the medicine from her, but that kid would be crippled in pain and would really perk up, do her homework and do great with opioid management. She um was found to have a significant pain the day we saw her in the pancreas clinic that prompted us to do lipase and amylase, and her lipase was in the 1,000s. When we did the CT scan on her imaging because her mom said even her belly looks swollen, she had massive ascites in her abdomen, so we admitted her for further workup, and at that time we did a peritoneal tap, which is not surprising. And it was high in amylase. The ERCPU that was done showed a site of leak where you see my arrow is, so that was too far to be bridged, but helped her some, um, by putting a stent there to drain that kind of fluid collection that she had. She required multiple taps to the extent eventually because we're working her up to a surgery that we just needed to place a peritoneal drain. Um, to let her belly just become dry and less hostile for undergoing such a big surgery. She needed multiple fluid requirements, nutrition, pain management. She was hospitalized over 6 months, and we could not send her home. So from clinic to Cincinnati Children's Hospital and just stayed until she really got her surgery, and I We want to tell you that this is a patient who underwent multiple ERCPs at her home hospital and could not really improve afterwards. She developed another pancreatic pseudocyst up in her chest um as a surprise on the kind of the week before her surgery date, so we had to even push her surgery further and go ahead and drain that collection. But um, With the complexity of her disease from a medical and, and really multidisciplinary team, IR helped with her management. The surgeons were at the bedside with the GI doctors, and when she had a GI bleed and wanted to to die one day, it was coming from hemorrhaging from her pancreas. After she was very fully stabilized, um, I mean, I hope that we would all think at this point that when all medical and endoscopic interventions fail, that surgical interventions are really needed for these patients. So, um, again, I would like to stress that for now, it's really reserved for when maximum medical therapies and endoscopic approaches fail to relieve the pain or address the specific complications of the disease that surgical procedures are considered. So thank you for your time and I'll give the podium to James. I'd like to start by thanking you for the privilege to uh come to present what we've learned about the pancreas and about TPIAT and we'll cover in this 30 minutes the surgical details regarding TPIAT. But I'll start, of course, generally speaking with indications, and we know that from adult literature, up to about 50% of patients who have chronic pancreatitis eventually require an operation. Classic indications are, of course, obstruction of the bile duct or duodenum, uh, pseudocysts that can't be managed endoscopically, suspicion of malignancy, of course, is much less common compared to the adult population, but in fact, the most common indication is in fact debilitating pain that fails to respond to medical and endoscopic approaches. The question about timing of surgery remains, and it is clear from a number of studies that the watch and wait approach really does not result in a significant number of patients that burn out and resolve their pain. This in fact is a Dutch pancreatitis study group cohort study looking at 266 patients that underwent pancreatic resections or drainage and drain or drainage operations for pain relief in chronic pancreatitis. Uh, and the attempt here was to determine what are the risk factors associated with pain relief. Uh, and as you can see here, shorter duration of pain, no significant preoperative opioid use, and limited endoscopic, uh, treatments were the, uh, uh, risk factors that were most associated with pain relief. So this again begs the question, should we be intervening earlier? From the perspective of how do, how do we approach uh surgical options in general, uh, we have to obviously look at the anatomy and the morphology of disease, and we all see, we all know, especially in this room, what we mean by large duct disease. Uh, in the, particularly in the adult population, less so in the pediatric population, uh, we do see patients with an inflammatory head mass, uh, the so-called pacemaker, uh, of disease that can be addressed locally. And then very rarely, we might see some distal stricture causing very focal disease in the tail of the pancreas that might be amenable to a distal, uh, uh, pancreatectomy. Uh, from the perspective of large duct disease, as you all know in this room, uh, modified pusteau has been the classic approach. Simple remal, uh, preservation is, uh, uh, reasonable. There's low complication rate, and it does result in short-term pain relief in about three-quarters of patients. But over the longer term, pain relief uh does not continue and in fact, this is likely due to continued inflammation in the head of the pancreas or incomplete ductal decompression in the first place. And so this is a little bit more limited in terms of uh when we apply this now. Uh, certainly isolated PD dilation without the presence of an inflammatory head mass and without a genetic risk factor is typically the way we approach the Pusteau application. The Whipple procedure, as you know, of course, uh, will resect the inflammatory head mass, but of course, the bile duct and the alimentary tract need reconstruction. It does result in pain relief in a, a good proportion of patients, uh, but there is a high percentage of late endocrine and exocrine insufficiency in over 50% and less commonly utilized in the pediatric population. The duty and preserving pancreatic head resections, uh, more popular in Europe, and especially in Germany, uh, is a combination of drainage and partial resection. And again, it addresses the inflammatory head mass and does decompress the pancreatic duct with preservation of the bile duct and GI continuity. Uh, there is a good response, pain relief in 80 to 90% of patients, and lesser, uh, rates of exocrine and endocrine insufficiency. So the challenge, of course, is that conventional surgeries can result in initial pain relief, but up to 50% of patients do have recurrence of pain over the long term. And so failure of a conventional operation is an indication for a total pancreatectomy with eyelet autotransplantation. Uh, and of course, debilitating pain from chronic pancreatitis or acute recurrent pancreatitis without a conventional surgical option. So you see here, absence of an inflammatory head mass, absence of a focal, uh, uh, tail disease, absence of a large duct. is the population that we particularly are talking about. And in fact, in our experience, uh this is a predominant, uh, the predominant morphology that we see uh in the hereditary pancreatitis cohort. So the first DPIT was performed in the late 80s. Uh and again, the primary, primary goal is relieving the incapacitating pain and impaired quality of life. We are commonly walking around the hospital and the question always is how's the transplant patient? How's the transplant patient? Uh but really, the number one goal always is to relieve impaired quality of life or incapacitating pain. And of course, the secondary goal is to preserve beta cell mass and secretory capacity of insulin and, and glucagon. This, uh, as you know, uh, does, uh, involve a multidisciplinary team. Uh, early on, surgery, GI, endocrine, genetics, and radiology uh play significant roles. We obviously have to confirm the diagnosis of pancreatitis. Is the pain from the pancreas. Advanced endoscopic approaches may be, uh, uh, applied in select settings. From the endocrine uh perspective, uh, is there any evidence of prediabetes or diabetes? Uh, are there islet autoantibodies? We do assess beta cell mass with mixed meal testing. Obviously, from a surgical perspective, we are looking at morphology, anatomy of diseases or existing liver disease, portal vein uh issues. The pain physician and pain psychologist, as you've already heard, play significant roles, of course, and social work and nutritionists play significant roles in terms of optimization. And really when we're heading down toward the possibility of a TPIAT, hematology and infectious disease are also teams that are involved in the multidisciplinary approach, obviously to look for any bleeding or prothrombotic issues and of course from the perspective of vaccination and opsy prophylaxis because splenectomy is performed with this operation. From the perspective of diagnostic considerations, you heard about this from my sum a bit already, uh, but really we follow the inspire criteria. Which is findings of CP on any imaging modality inclusive of EUS with greater than or equal to 5 Rosemont criteria or uh in the context of uh fewer criteria by EUS, the presence of 4 criteria and either exocrine or endocrine insufficiency. What are the overall criteria for TPIT again, making the diagnosis in our hands, pain and debilitation for greater than or equal to 6 months with either chronic opioid dependence or impaired quality of life that we define by frequent hospitalizations and school absences, failure of other interventions, absence of reversible cause, no psychologic or psychosocial or physiologic contraindication. And these patients have to know that they are willing to accept the risk of lifelong diabetes because uh there is a high likelihood that this will occur. Uh, and from the IAT perspective, uh, we want to assure no C-peptide negative diabetes. Surgical considerations, uh, in this room, I do not have to go into very significantly. Uh, but again, we want to assess, uh, has there been, uh, are there any local complications that are active? And again, the presence of ongoing pseudocyst does make things a little bit challenging. We do look at liver volume, particularly for the smaller children, and so we have a liver volume cutoff of 400 mLs. From the perspective of accepting the islets, is there any underlying steatosis or fibrosis that we need to work up? And of course, is it portal vein patent? And importantly, what's the hepatic arterial anatomy? So is there a replaced right hepatic artery that in this particular patient actually traversed through the head of the pancreas, which makes things a little bit more challenging. So we do uh uh preserve the pylorus and preserve D1 in our hands, uh, in our institution. Uh, we do perform a splenectomy from the perspective of technical reasons, rather than trying to preserve the vessels and thereby lead to potential islet ischemia during the course of the operation. Gallbladder comes out, appendix comes out, and we do place a GJ tube from the perspective of managing the postoperative uh delayed gastric emptying that we see in this patient population. All kids get a central venous catheter, arterial cannula that we utilize for frequent glucose monitoring, uh, post-op in the ICU, midline laparotomy, and we do, of course, encounter adhesions, etc. We do maintain the blood supply, the GDA, the splenic, um, uh, artery, as well, uh, as a portal of venous outflow until the very time we're taking the pancreas out. Uh, this is the field with a resection SMV portal vein. We do leave a little splenic vein stump for eyelet infusion. Obviously, the goal of the eyelet isolation is to just disrupt the exocrine tissue to release relatively pure eyelets. This is not a completely pure uh isolation, uh, but we want a small enough tissue volume to safely infuse into the portal vein, and this is performed by modifications of the Recordia technique, which is a combination of mechanical dispersion as well as collagease and neutral protease digestion. That pellet at the end of the 4-hour isolation is assessed for count, viability, and a toxin. During that isolation, uh, this is our reconstruction. We reconstruct with a Rouen Yi hepaticogeninostomy, uh, as well as a Ron Yi duodenojeinostomy, uh, and both pylorus preservation and the Roan Yi-duodeno jeinnostomy is, uh, with hopes of reducing, uh, bile reflux. We do infuse the eyelids via the splenic vein stump. We heparize, of course, to mitigate risk of portal vein thrombosis. We measure portal vein pressures as well. We do know that from the literature that there is a tenfold increase in the risk of portal vein thrombosis if the change in pressure from start to finish. To max is greater than 25 centimeters of water pressure. And if that occurs, or if we have substantially high pressures, we'll pause, wait for auto regulation, and then continue to infuse the islets. And if we run into issues whereby the portal pressure remains very elevated, we'll place those eyelets in the peritoneal cavity or some secondary site. Our postoperative care, we obviously monitor for portal vein thrombosis. We heparinize as well. We utilize the Dexedrine infusion, which does have antiplatelet effects. Uh, it does have an effect in animal studies to reduce the instant blood mediated inflammatory response. And so we do utilize that for 48 hours. Blood glucoses are very tightly controlled. Uh, obviously, antibiotics, advancing tube feeds, and then transitioning over the course of the, uh, 56 days in the ICU, uh, to, uh, full, uh, insulin pump therapy from an intravenous infusion of insulin. Uh, we do, uh, typically, uh, now, uh, spend less time in the surgical ward, go directly from the ICU to endocrine where they, uh, undergo, uh, all of their pump teaching, education, GJ, uh, tube education, etc. Surgical complications. Um, typically, uh, we have a balance between bleeding and portal vein thrombosis. Uh, Obviously, anything that we sew together, uh, can leak, as you all know. Every patient gets a systemic inflammatory response that, uh, if it persists over the course of, uh, uh, a week, we'll go ahead and scan and look at there, and see if there's a, uh, fluid collection to drain. Uh, and patients do get significant delayed gastric emptying which lasts for several weeks. Uh, we do keep our patients locally for, uh, several weeks, uh, to manage the ongoing nutritional, uh, vitamin and, uh, weaning of insulin and uh opioid needs. Uh, from a nutritional management perspective, obviously, uh, PERTS is a, a significant, uh, management criterion and our GI colleagues help to manage that. Uh, and of course, as you already heard, uh, all of the fat-soluble vitamins and folate, iron and vitamin B12 need to be managed as well. Gastroparesis, dysmotility in upwards of 36 to 45%. Uh, we do utilize a, um, a vari variation of, uh, cyproheptadine or sometimes metoclopramide, sometimes erythro amoxicillin, uh, but often it really is a tincture of time and over the course of the first several weeks, this delayed gastric emptying does improve. On rare occasion, we've gone ahead and done a pyloric dilation and uh Botox injection by EGD. Uh, there is a preponderance of GI symptoms that continue after this operation. Uh, and one study from Johns Hopkins, uh, demonstrated up to 30 to 80% of patients complaining of diarrhea, constipation, weight loss, uh, that may not be necessarily related to inadequate PER dosing as they, uh, uh, demonstrated, but rather to perhaps altered neurohormonal regulation or chronic opioid use that might contribute to these, uh, GI symptoms. From the endocrine management perspective, uh, our endocrine team, uh, is also a large team, and we have a lead endocrinologist, a team of diabetes educators, as well as dietitians, uh, in the diabetes center and social workers. We know that the eyelets undergo a significant insult, mechanical, osmotic, and hypoxic stresses. Their vasculature obviously is disrupted, and of course they're not going to resume function for several weeks until neovascularization has occurred. And during this time, we are managing the glucoses very closely due to the fact that high levels of glucose systemically will obviously create a significant risk for apoptosis and beta cell death. We do utilize continuous glucose monitoring to help with close regulation of the blood glucoses. So you see here, uh, Clark error grid analysis on the left and surveillance error grid analysis on the right, uh, and we demonstrated in our ICU setting that the continuous glucose monitoring approach does lead to a low risk of hypoglycemic, hypoglycemic episodes. Uh, and so we do utilize that and all patients go out on a CGM. I did mention uh hyperglycemia and avoidance of hyperglycemia, and there are a number of animal studies that have certainly demonstrated in sysy genetic mouse models that we do face beta cell death and loss of eyelets uh with the presence of elevated glucose levels. Our endocrine, uh, management, uh, is, uh, uh, very, very, uh, um, In depth, I should say, these glucose data are sent routinely from our patients directly to our endocrinologists. We do monitor our fasting blood glucose C-peptides, hemoglobin A1cs at 3-month intervals, as well as eyelet function in general with area under the curve of C-peptides with mixed meal testing. And for the most part, we go ahead and Wean over time as this data is coming back to our endocrinologists with general rules of fasting, of most blood glucoses uh less than a fasting of 126, postprandial, less than 180, and hemoglobin A1C of less than or equal to 6.5. We have a significant uh education from the perspective of uh foods to avoid, uh, and so high glycemic index of foods. Uh, we tend to, um, Uh, try to get families, uh, to, uh, avoid. Although frankly, so many of these families are so happy that these children are eating finally after a significant, uh, time where they cannot eat, uh, that's, uh, our, our patients are often, uh, um, really indulging, so to speak, and that does make some management of, uh, insulin, uh, uh, challenging. Our pain management team, you already heard about. Uh, there's very early introduction from the perspective of, uh, assessing the needs, education from the perspective of what therapies are available, uh, and introducing, of course, uh, cognitive behavioral therapy, uh, to deal with the psychosocial, uh, or the psychological implications of chronic disease. Step-up approach, uh, is, of course, uh, a, uh, management approach that we take. NSAIDs and acetaminophen, uh, are utilized early on in our, uh, experience. Opioids are limited, uh, and we do actually try to limit, uh, opioids to some degree even going into a TPIAT. And our pain management team does introduce neuropathic pain medications because in fact, we do see significant central sensitization in this patient population. And so really we have loss of descending inhibitory control mechanisms. We have increased responsiveness of central pain transmitting neurons due to this chronic pain, so that you end up, of course, with pain that's no longer coupled to the actual peripheral stimuli. So you have Hyperalgesia, you have allodynia, and in this patient population, this, this is a cohort that may not necessarily have a good outcome after TPIAT because we've essentially missed the boat and removing the pancreas will not address the central sensitization. And so this does play a role in what we are trying to study from the perspective of defining which patients may or may not respond as well. So what are the outcomes? And so this is the largest series from the Minnesota group with 75 patients, and you see on the left prevalence of opioid use dramatically reduced over the first several months, sustained, and and again, a decreased prevalence of pancreatic pain as well. Improvement of lost school days, of course, is not surprising. And from an eyelet to functioning glycemic control perspective in children, younger children tend to achieve insulin independence more so than the older children. Uh, although longer-term outcomes are clearly needed in this realm, we do know that insulin independence, uh, is correlated with eyelid equivalent per kilogram, uh, transplanted with the, with the highest insulin independence, uh, in the greater than 5000 eyelet equivalent per kilogram, uh, group. The youngest patients have also been studied. This is 17 children under 8 years old. Uh, again, all had very good pain relief by 1 year of age and, uh, free of opioids by a meeting of 68 days, and greater than 80% achieved a period of. Insulin independence, uh, but certainly longer-term follow-up, uh, are needed in this realm. Why do children do better? Uh, this is, there are a number of, uh, hypotheses. Uh, younger children do have lower insulin, uh, demands. So is there a better metabolic milieu? Uh, is there, uh, the opportunity for rep replicatory capacity of the beta cells? Uh, this has been demonstrated in autopsy studies that the youngest, uh, of our population do have a higher capacity to, for beta cells to replicate, and this may play a role. Uh, and there's also been some thought that there may be some eyelet neogenesis that occurs, uh, in response to injury and severe pancreatitis, uh, and that this may also play a role because we are, of course, uh, transplanting, not just eyelets, but there is some exocrine tissue. It's not a pure, uh, um, isolation, and there, of course, stem cells as well. A number of studies, retrospective, predominantly have demonstrated that there's a relationship between yield of islets uh and uh the uh atrophy and calcification, so the, the degree of radiologic findings from the perspective of chronic pancreatitis. There's also a correlation. Between fibrosis and atrophy and also between duration of symptoms and islet yield as well. So, uh, clearly we're thinking about how do these findings play a role in patient selection and timing of TPIT. We also know that ductal drainage procedures and resections, of course, reduce eyelet yield and the probability of insulin independence. And so we do really think very carefully about who we might uh offer these operations to. Uh, and, uh, patients that have a, uh, a, a field defect, those with uh genetic risk factors or those that we really are nervous about offering uh a ductal drainage procedure. This is our experience. Uh, 24 patients since April 2015. The vast majority do have genetic risk factors, 87%, pancreas division present in about a third, uh, very high eyelet yields. And as you see, the weaning of opioids does occur very early on. Uh, and, uh, up to 50% of patients that had an eyelet yield of over 5000 per kilogram are independent at 12 months with several more patients requiring just a whiff of insulin. I, uh, the, uh, TPIT does, of course, alleviate the need for TPN. We had patients that were requiring a TPN pre-op that by 90 days post-op or off. And again, the percentage of, uh, on opioids does reduce substantially by 90 days. Uh, though the weaning process, uh, because of the long-term need for chronic opioids in a number of patients does occur over many months. So where are we going? And I'll finish up with, uh, some of the, uh, The details of uh research uh in the field. Uh, so, what are the gaps that we need to assess? So how do we predict who will have an optimal, uh, pain outcome, optimal, uh, outcome from the perspective of health-related quality of life after TPIT? This is an RO1 funded multi-center consortium of nine centers that we are part of that will be accruing hopefully 450 patients. And so really trying to define what patient characteristics, what disease characteristics are associated with the most favorable outcomes and pain and health-related quality of life outcomes, and what characteristics are most associated with the glycemic outcomes that are favorable. We will try to address what is the optimal timing of TPIT. Is TPIT cost effective, and then there will be a subgroup in which quantitative sensory testing will be performed to try to demonstrate whether or not central sensitization does impact the failure of pain resolution. What about predicting, uh, glycemic outcomes? Uh, and so there are a number of models that have been proposed uh to attempt to predict glycemic outcomes preoperatively. Uh, this is one formula, the homeostatic model assessment of beta cell function or homo beta, uh, which, uh, utilizes uh fasting blood glucose and insulin values, uh, to, uh, um, Attempt to correlate with uh predicting uh insulin independence postoperatively and in fact, in this small study, there was a higher uh ROC area under the curve than islet yield, in fact, in predicting insulin independence. What about assessing eyelets and eyelet function? It's not just about the numbers, we know that. Uh, and so there are a number of studies that are looking at oxygen consumption rates, uh, as a matter of predicting uh insulin independence just to add that, that quality assessment, uh, into consideration rather than just eyelet quantity, which is really what we have in 2018. What are the biomarkers that might predict islet damage? And so microRNA 375 is an islet-specific regulator of insulin secretion, and there has been evidence that there, the lower release into the systemic circulation and during isolation does correlate with a better glycemic control post DPIT as defined by hemoglobin A1Cs and lower insulin requirements. There's also a lot of work being done to study the instant blood mediated inflammatory response and what are alternative sites of implantation. The liver, of course, has been considered the most physiologic site for implantation of the eyelets, but we do know that there's substantial loss of eyelets, up to about 50% due to the instant blood mediated inflammatory response. And so, in fact, the peritoneum, intramuscular injections, subcutaneous sites have been Uh, assessed, uh, and in fact, there's some evidence that patients who have undergone TPIT that had a proportion of uh their eyelets placed into the peritoneal cavity rather than just all, uh, in the liver do have, in fact, an improved glucagon response to hypoglycemia. And so there may be a role in the future for placing some of the islets, uh, in a site other than the liver. Ongoing clinical trials. There are a number of them. Obviously, many of them are aimed to optimize and engraftment and function. Uh, and in fact, alpha-1 antitrypsin use, uh, TNF alpha inhibition as anti-inflammatory approaches, uh, are being studied, uh, ILA receptor inhibition as well to improve engraftment. And what about efficacy of other sites, intramuscular site, uh, for, uh, autotransplantation. I'll finish with just a word about mesenchymal stem cell co-transplantation and again with the goal of improving engraftment and long-term glycemic control. This was just a very small pilot out of MUSC that looked at co-transplanting autologous bone marrow derived mesenchymal stem cells during the eyelet arter transplant. Just a handful of patients demonstrated, of course, fortunately no adverse events related to the stem cell infusion. Uh, there was some evidence of lower mean fasting blood glucoses at 6 and 12 months. Unfortunately, in this small cohort, no difference in hemoglobin A1cs or C-peptide levels. Uh, and so this is in fact continuing to be an area of study, uh, with the thought that engraftment of eyelets, uh, needs to be addressed and optimized and whether this is an effective immune modulation with mesenchymal stem cells or improved angiogenesis is certainly not, not clear. So just to conclude, We know that in appropriately selected patients, TPIT does achieve durable pain relief and improved quality of life with manageable glycemic control. Uh, we do certainly present that comprehensive multidisciplinary team is critical to ensure optimal outcomes, and we need a lot of research in this field, you know, how do we predict the optimal pain outcomes? How do we predict improvement in health-related quality of life? How do we build predictive models for failure of weaning of opioids? Uh, and of course, optimization of engraftment function and durability, uh, are, are critical as well. So with that, I will finish with just looks like a couple of minutes. We're happy to take any questions. And Abu and Doctor Abu Hajad, I certainly wanna thank you for bringing this forward to us. It's obviously a very complex group of, of patients with which you're, you're dealing. I have a couple of questions, and I'm sure there'll be more from the audience. So, as far as the pain, The suggestion, excuse me, that you presented is that the longer the kids have the pain, the less likely they're gonna get weaned off narcotics. So the question one is, is this leading you to want to intercede in the patient's Earlier so that you have better control of, of the pain. Second deals with the Obviously the issue of Of diabetes, recurrent diabetes. You mentioned that there's this acute response to the To the eyelets when they're infused in the liver, which was obviously new information to me today. Is there anything that can be done to, to prevent that with using anti-inflammatory agents at the same time that you're, uh, infusing the eyelets? And what has been your experience with the longevity of having insulin-free Period for the kids between when they recover the eyelet function and, and then over time. So with regard to uh pain outcomes, uh, this is obviously very tricky, uh, and, um, uh, the, um, specific timing uh is yet to be defined. And so when, when is the best time to, uh, to intercede? Uh, you know, we know that prolonged opioids, the development of central sensitization, uh, and again, introducing the ability to define central sensitization, uh, with quantitative sensory testing may help predict when you're beyond the point of, uh, improvement, uh, following the operation. Uh. So, we do take, especially in the context of a um genetic risk factor, we take a bit of an earlier approach uh to offering the operation, uh, such that uh we do not want patients to be on everyday uh opioids. Many of them come to us, unfortunately, already on everyday opioids. Uh, but certainly from the, in the context of how do we define what is the most appropriate time. Uh, we have to take that into, um, in context of what else can we offer and are there other endoscopic approaches? Have we maximized the medical therapies? Many patients come to us, uh, really from the, uh, uh, community of uh GI physicians without having, um, approached medical and endoscopic approaches substantially. Others have come to us with 50 endoscopies and, uh, ERCPs and stenting. Uh, so we, in general, have taken an earlier approach, particularly in that patient population that has hereditary, uh, pancreatitis. From the perspective of longevity, so our experience is certainly, uh, is, uh, about 2.5, or 3 years old. Uh, we, what we have learned are these beta cells, um, uh, are, um, uh, um, Not very consistent, so, so to speak, uh, and, you know, why are they not consistent? And, and so, for example, we have patients that have been, that come off of insulin. We assess their uh their follow-up over the course of uh A1Cs and mixed meal tolerance testing, uh, and we see a, uh, an increase in their A1C. So they're back on a little bit of insulin. Uh, and it's, it's really, you know, how do you predict, um, how the eyelets will work. Uh, it's, um, very, very, uh, patient-dependent, and it's a, uh, we're not there, uh, to be able, we're not there yet to be able to really say. Uh, that, you know, these eyelets will work for 5 years. These eyelets will work for 10 years. Uh, we know that the long-term, uh, durability of uh eyelet, uh, function, uh, has been demonstrated in the pediatric population for as long as 10 or 20 years, um, but that's in a very small pen. So many of these patients, um, do come off. Uh, some of them go on intermittently and they come off again. Uh, and it's, uh, it's a very hard thing to, to predict. From the perspective of altering the inflammatory response, uh, there are a couple of studies, uh, that we, um, we have not yet participated in. They're, uh, in the adult population, uh, but certainly an open, uh, study looking at, um, TNF, uh, alpha inhibition. Uh, there's an open study looking at, uh, uh, use of alpha-1 antitrypsin to try to mitigate some of these, uh, responses. Uh, I didn't even get into, I didn't have time to kind of get into some of the, uh, uh, other, um, effects that we see, uh, in response to the eyelet infusion. And so, we also see a very dramatic increase in platelets, a very significant thrombocytosis, uh, that is likely mediated again by, uh, mechanisms, uh, via, uh, hepatocyte inflammation and what we've studied, and I didn't present the data due to lack of time. Uh, but we've started to look at thrombopoietin produced by hepatocytes, uh, that we have found is dramatically increased, uh, in the, uh, uh, blood of patients that have undergone an eyelet auto transplant, and this is, uh, preceded a very dramatic increase in platelet counts, uh, to over a million. So something that you would see well beyond what you'd expect from simple splenectomy. Uh, and so, uh, we've introduced, um, uh, use of hydroxyurea to try to mitigate any potential, uh, platelet effect, uh, that might, uh, Um, reduce our long-term, uh, eyelet, uh, viability. So the field is wide open. Um, you know, there are a number of clinical studies that, um, are again open in adults, uh, but certainly there's much to be done. Additional questions, Doctor Jennings. I just have a, a technical question. We do lots of um Jujunal interpositions for esophageal replacement, and one thing we noticed is if we do an end to end anastomosis, we have the usual issues with maybe some strictures or something. We're doing an end to side, we get these diverticula from the end from the side anastomosis from the stapled end that over time enlarges and becomes a problem. And I noticed that when you do your biliary loop and you do your do your your um duodenal replacement. Uh, that you're also doing endocy anastomosis. I'm just curious, do you have any problems over time, or do you track it? Do you even look to see if you get a bulbous dilation and stagnation and problems? So we have not, uh, we have not seen that. Um, we have had a, uh, one patient that developed an anastomotic ulcer, uh, and, uh, has been, um, on a PPI and, uh, therapy with, uh, sucralfate and uh PPI. Uh, we have not found necessarily, of course, we haven't been doing upper GIs and we haven't had patients come back with the symptoms, uh, to suggest a diverticulum, uh, but certainly an important point to consider. Uh, thank you both very much for coming and, and presenting this work to us. A couple of questions. One is, uh, is previous surgery a contraindication to, to, uh, total pancreatectomy? And if not, uh, any idea of your eye when you compare the eyelet, uh, yields, uh, in, uh, previous surgery versus not? Yeah. So certainly not a contraindication, uh, and, um, uh. Ultimately, again, you know, with the number one goal being relief of pain and improved quality of life, you know, if we have a patient that comes to us, uh, having had a puste or having had a distal pancreatectomy, um, we are, we would not consider that a contraindication. Uh, if that patient is still suffering and still, uh, meeting our criteria in terms of, uh, opioid use, uh, and or, uh, terrible quality of life, uh, then that's a patient that we would offer the operation. Uh, we do know that there is a reduction of about 50% in terms of eyelet yield, 5050, 50% in patients that have have had either a distal resection or a pistil. Um, and part of that, um, is related to the eyelid isolation technique and so, uh, injection of the duct is not possible when you file open the duct and so you'd have a similar issue with the FRI procedure as well. One other question, and that is, do you prioritize your genetic mutations? That is, uh, if, if a child has a PRSS-1, is that, uh, are you more likely to, to move ahead to the total pancreatectomy? So based on the data that we have had out of Pittsburgh, we certainly consider PRSS-1 1 of the, one of the worst actors, and particularly in the context of potential risk down the line of adenocarcinoma. Obviously, that's something that we wouldn't see for many decades. Uh, but we have a bit of a lower threshold in the context of, uh, PRSS one mutation. Doctor Fels. Very nice uh review, both of you. Uh, is there any regulatory requirements such as FDA oversight or a like for an institution to perform eyelet or transplantation? If not, there is any, is there any national standard for quality control? Very excellent questions. Uh, so there is, um, FDA oversight for allo transplantation. Uh, currently, there is not for autotransplantation. Uh, and in fact, uh, Quality Metrics, uh, that's one of the, um, Uh, that's one of the things that we struggle with as a community of, uh, institutions doing TPIATs. There is a lot of variation in terms of the, uh, percentage of the various collageases, the degree of temperature changes, um, how long do you, um, allow the, um, uh, the actual digestion to occur? Is it 30 to 40 minutes? Is it 15 to 20 minutes? And it varies from institution to institution. And that's a struggle that we have. Ultimately, that's where the field has to go. There has to be quality assessments so that we can maximize outcomes, but right now we struggle with that because there are so many variables in terms of the isolation. It's hard to keep me quiet longer than 30 minutes, but um, it's, I want to comment on the regulatory aspects, um, you know, while it's a transplant, but not really like under any regulations like the UNOS regulations, we just came back from a, a chronic pancreatitis or TPIT symposium, and it happens once every 4 years and it was um hosted by MUSC in Charleston. And really, there's a great need and call for that because you could see amongst the audience that A lot of um the centers that are thinking about it, you could hear that there is some noise, oh, we can do this, and we should do this, and if you have a major center that has been doing this and worked their criteria and refined their criteria, do you really put an overall regulatory aspect to say, well, if this center turns this patient down because they're not a candidate, I really fear that they will go to another center and have it done. There is soft call where people just would do it for softer reasons, and it's not a light operation that we never take lightly. So maybe there should be a call and a need and it came from that conference, so that's still in the works and people's minds. Um, in terms of hereditary and, and how we take that into account, we still do not know in terms of which genes are the highest risk for um diabetes progression over time or exocrine insufficiency over time or even cancer risk. But from the PRSS1, which is the most studied gene, there's a very nice uh work by the French group. They have thousands of patients that actually the risk of cancer, I don't know if they published it yet, but by the age of 50, it's 40%. So that's not an insignificant risk when you see Um, and NAS 2 is almost very similar numbers, which is the national American kind of cohort of chronic pancreatitis. So by after the age of 50, it's not an insignificant risk with being the fastest killing cancer, not a good way to screen for it. Um, the ones who have pistoles or whipples and still have their pancreas and have that genetic mutation, it's just something that they still worry about in the back of their minds. Any final questions? If not, thanks so much for your very informative and excellent presentation. You
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