Pancreas Care Updates 2020 - FULL SHOW

OK, hello everyone and all my dear colleagues from around the globe. Welcome to Pancreas Care Updates 2020. Our team from Cincinnati Children's is coming again, and we've been with you through Global Cat MD 4 years ago, and we are here again with more updates as the field in pancreatology is rapidly changing. Our knowledge is rapidly expanding through research that is innovative and driving the field. And our experience is also further growing into how we take care of our patients. We are thrilled, excited to be with you today. While we give you updates, we will be going through your questions live that you send through the talk. And I would like to know if you had questions submitted prior to this event, we did take a lot of those into our slides and contents of today. Let me start with some introductions. I would like to introduce myself first as one of the course co-directors. I'm Doctor Massam Abu El Haija, Associate professor of pediatrics at the University of Cincinnati, and I'm the medical director of the Pancreas Care Center at Cincinnati Children's Hospital Medical Center. Joining me today, my colleague as the co-director of this course, Doctor Jamie Nathan, and he's a pediatric transplant surgeon, associate professor of surgery and pediatrics at the University of Cincinnati, and the surgical director of the Pancreas Care Center. Doctor Nathan, would you like to introduce the rest of the speakers with us today? Thank you, Maisa. I'd be more than happy to. I am very, very proud to Introduce several more very close colleagues in our pancreas Care Center. Uh, to start is uh Doctor Tom Lynn, associate professor at the University of Cincinnati, associate professor of pediatrics. He is a director of, uh, endoscopy, uh, within the Pancreas Care Center and co-director of endoscopy for the division of Gastroenterology, Hepatology and Nutrition. And he has, uh, uh, many, many years of experience as an advanced endoscopist providing ERCP, uh, techniques to our, uh, patients. Next is uh Doctor Andrew Trout. Uh, he, uh, is associate professor uh of uh pediatrics and radiology, uh, and, uh, he directs clinical research in the department of Ray and medical imaging. And as well as director of nuclear medicine in the department of radiology and medical imaging. He has established himself nationally as an expert in pancreas imaging and provides countless hours of support to taking care of our complex patients. And then, of course, is Doctor David Vitale. He is assistant professor in the department of pediatrics at the University of Cincinnati. Uh, he, uh, is extremely active, uh, as well within our pancreas care center. Uh, he too is an advanced endoscopist, uh, providing, uh, ERCP, uh, care to our children. Uh, and in addition to that, providing a very subspecialized endoscopic ultrasound care, uh, to our complicated pancreas patients. Uh, and with that, uh, we will, uh, go to, uh, our first module, uh, and, uh, Those introductions to be Uh, by Doctor Lynn, I believe. For the first module. Great. So for the first module, um, we have, um, as uh Doctor Nathan presented, um, Doctor Maissa Abu Al Haja, uh, will be presenting along with Doctor Andrew Trout and as well as Doctor Vitali for, um, the first session. Thank you, Tom. All right, so let's start our journey with the medical management of chronic pancreatitis. Up to today, we have nothing to disclose. So our overall objectives are to review some definitions, modalities for diagnosis, and then learn the workup of chronic pancreatitis. And then we will review the role of medical management strategies for recurrent and chronic pancreatitis in children. So, it is an insult to the pancreas that leads to the presence of acute inflammatory cells, edema, and necrosis that in some cases may result in organ damage or fibrosis. We are lucky that the majority of the cases are self-limited and um relate lead to one-time case of acute pancreatitis, but at about 30%, you could have recurrence. So as I show in this American gastroenterology slide, an insult takes effect leads to zymogen activation, generation of inflammatory mediators, then further inflammation and ischemia, necrosis and apoptosis in the gland that in a subset could lead to SERS and multi-organ failure. Acute pancreatitis by definition is when the patient has 2 out of the 3 criteria pain that is classic epigastric in origin, lipase or amylase 3 times the upper limit of normal, and then imaging findings. Any 2 out of the 3 would make the diagnosis of acute pancreatitis. Acute recurrent is having more than 1 attack, typically separated by a 1 month free interval, but could be less than 1 month if you had normalization of enzymes and pain-free period. And then acute recurrent could become chronic pancreatitis. Chronic pancreatitis is when typically could be a histologic diagnosis, but due to technical and different reasons why the pancreas is a deep-seated organ, we don't always biopsy and we do not advise to biopsy the pancreas just to make a diagnosis. Um, as we see here in the right, um, image is when you lose those sinner, which are the pinkish, uh, pink structures, and those get replaced by the whitish, which is the fibrosis, and some inflammatory cells in between. Chronic pancreatitis is typically right now an imaging finding, as you will hear from Dr. Trout, but it also requires one of the following three, either the abdominal pain that is consistent with pancreatic origin, evidence of exocrine insufficiency, or endocrine insufficiency. In terms of epidemiology, new cases of acute pancreatitis have an incidence in the United States of 1 in 10,000 cases. Up to a third of them would have recurrent attacks, and chronic pancreatitis in the young population could be up to 2 per 100,000. And as I show in the diagram on the right, the severe chronic pancreatitis cases are the ones that really show on imaging. So for us to advance the field further, we really need biomarkers for early disease. And here I would turn to Dr. Trapp to go over the imaging. So we heard that the diagnosis. of chronic pancreatitis depends on the presence of imaging findings. So I'm gonna focus on that. We don't really have time to talk about all the ins and outs of imaging of pancreatitis. Um, but there is a nice, um, recent publication to this effect that was put out, uh, by both, uh, NASRGA Pancreas Committee and the Society for Pediatric Radiology, Abdominal Imaging Committee that I would point you to. So when we're thinking about chronic pancreatitis, really you're talking about cross-sectional imaging. You're talking about MRI or CT to optimally characterize the findings that we're looking for to make a diagnosis. Ultrasound, while it plays more of a role in acute pancreatitis, in the setting of chronic pancreatitis, it doesn't provide sufficient coverage or detail to really make a good diagnosis, uh, though it does still play a role, um, as it comes to identifying superimposed episodes of acute pancreatitis in a patient with known chronic pancreatitis. Let me go to the next slide, please. So let's talk a little bit about CT and MRI and try to sort of leave you with a few pearls as you're thinking about how to take care of your patients. When it comes to CT of the pancreas, uh, for both chronic and acute pancreatitis, you really always want to be using intravenous contrast material, because that provides us the detail we need when it comes to imaging, not only the pancreatic parenchyma, but also the, the vessels of the pancreas. Now, as far as how many phases to get, this is something that I see, um, sort of vary across institutions. A single phase, portal venous phase is almost always sufficient. You really don't need that non-contrast phase. Calcific pancreatitis is uncommon, if not rare in the pediatric population, and arterial phase imaging is really only needed if you are characterizing masses or you need really good arterial detail. A portal venous phase, as you see in the top pane here, really is adequate to provide us with all the information we need uh to make our diagnosis. Oral contrast really is optional, not required. Um, it can be helpful to separate fluid collections from bowel loops, but in unstable or, or uncomfortable patients, it's really not necessary. And CT really does give us good good parenchymal and, and vessel detail. It gives us OK duct detail, but if you really want to characterize the duct, you're looking at MRI. So let's go to the next slide. So with regard to MRI, there's a bit of a confusion I'm seeing out there where people sort of think of MRCP as a separate exam. The reality is MRCP is just a single sequence, um, or maybe even a couple of sequences. It's part of a broader MRI exam in a patient with pancreatitis. And so, MRIs of the pancreas really always need to include that MRCP sequence, which is a heavily T2 weighted sequence like we're seeing in the top image here. It's important to have some backup T2 weighted sequences to make sure we have um good characterization of the ducts because those 3D MRCP sequences. have a tendency to be um respiratory or motion limited in really young pediatric patients. The other sequence that you really always have to include is the T1-weighted fat saturated sequence shown here on the bottom. And the reason for that is that on these sequences, the pancreas that I'm circling here on a T1-weighted fat saturated sequence is normally gonna be the brightest organ in the abdomen, and loss of that T1 signal is an important finding um for parenchymal changes of chronic pancreatitis. IV contrast depends on what you're looking for. If you want to look um at the vessels or at the time of making a new diagnosis, where autoimmune pancreatitis may be in the diagnosis, IV contrast is gonna help you there. Uh, but in follow-up of patients, it may not be needed. Now, let's talk a little bit about Secretin. We use secrettin a lot here at Children's, and we'll talk some more about that later. But the value of Secretin in our practice really comes, um, and I think in your practice as well will be when you want to look, um, and best characterize a non-dilated pancreatic duct. Um, a very dilated, chronically dilated duct, you might not get a whole lot of benefit from the secretin in terms of duct visibility. But in, in those early cases where you really want to characterize ductal abnormalities, secretin can be helpful in that context. We also use it to assess exocrine function, which we'll talk about a little bit later. An MRI really does provide the best combination of parenchymal and duct detail as it comes to the pancreas, as well as providing good vessel detail with IV contrast. And so this is the cross-sectional test of choice. Go to the next slide. And so here's um an example of pre and post-secretin images. On the top here, a pre-secretin image, and on the bottom, a post-secretin image. And what we can see on these images um is the improved conspicuity of the pancreas divisum here in this patient following secretin administration. And again, this was in a patient with a non-dilated duct, and that's really where Secretin is gonna help uh with your practice. So the next question from one of our attendees is related to, and this goes to Doctor Trout. Um, what's the timeline for doing a CT and acute pancreatitis? Um, more so in a child who presents with an acute abdomen, if you get a CT done too early, is a potential that you might miss acute pancreatitis type of findings. So this is a bit of a nuanced um answer or nuanced question. And it's really important to take the entire clinical picture into perspective here. Um, I think the consensus document that just came out from, from NASpagan and from the Society for Pediatric Radiology does a nice job, um, talking about this. And ultrasound still remains the first line test of choice in the context of acute pancreatitis. That Largely reflects its availability and lack of ionizing radiation. Now, new CTs um are, are much lower in dose than they used to be historically. Um, so you have to be a little bit careful, um, recommending things on the basis of radiation alone. But ultrasound currently is the, the initial test, uh, recommended by, by consensus. However, we know that ultrasound is only moderately sensitive. Um, and so, If you are suspecting acute pancreatitis, you're not able to make a diagnosis with ultrasound, and particularly, if you're looking for complications. That's really where we're using CT is when we need to confirm a diagnosis, um, or when we're concerned about complications, that's when you can leverage CT or MRI, uh, in that context. And typically, again, sort of extrapolating down from the adult data, it's really Several days to at least a week um after initial presentation when people are, are starting to, to get cross-sectional imaging when a patient is perhaps not turning around uh the way you would expect them to. And, and my clinical colleagues may, may want to elaborate more on that. Yeah, I would agree with that, Andrew. I mean, we usually just wait and if they're not turning the corner, you know, and then, in the first kind of few days, then CT is the way to go. Great. Um, so again, last question here is, uh, CT of the abdomen better or is MRI for, is that better type of modality for the diagnosis of chronic pancreatitis, Doctor. So all things being equal, if you were to make me choose, I would choose MRI because you get the best characterization of the duct and the best characterization of the pancreas. However, these two modalities each Have their advantages. CT is fast. MRI takes a long time to do well, right? And so, in a real young kid, you know, you need to consider the balance of, of the need for sedation, uh, versus which of these two modalities you might choose. So both play a role, uh, but if I could pick, I would pick MRI because it really does give you the most complete assessment of both pancreas, parenchyma, and duct. Thank you. Thank you, Andrew. This was very helpful. Um, so, imaging is always part of the workup of chronic pancreatitis, and I'm gonna walk you through how do you also uh look for treatable causes and then the role of genetic testing. This is an early publication from the International Study Group for Pediatric Pancreatitis in Search for a Cure, where there were about 300 patients. Half of them had acute recurrence and half of them had chronic pancreatitis. Genetic causes just by searching for one of the 4 genes being involved was positive in 48% of the ARP patients and. 33% of the CP patients obstructive causes like gallstones, ABPJ, biliary cysts, sphincter of OD dysfunction, um, which is less kind of involved in our cases in pediatrics and in adults now is thought, or annular pancreas, as you see, these causes are all mostly imaging related, so either the cross-sectional image. Or ERCP related diagnosis. Autoimmune pancreatitis could be also part of the picture. Toxic or metabolic causes like medications that could cause pancreatitis, smoking, um, lipidemia, especially hypertriglyceridemia, chronic kidney disease, alcohol use, and passive, passive and active smoking. So these are the list of etiologies. When I see a patient, I go through these one by one to make sure that we have addressed possible treatable etiologies, and one might say genetics does not have a treatable cause, and some of them they do, and CFDR is the classic example, but also finding a genetic cause would help you counsel your patients. Right now there is plenty of genetic testing available. The one we utilize is here housed in Cincinnati Children's utilizes the 10 genes that I have here. This is the link to the test, so it will be saved in your slides. And this is the requisition which collects the data needed when we do this test, and this test has a 28 day turnaround time which is also needed to promptly manage your patient. So the methodology that is used is one of the most kind of technologically advanced ones. So this test is performed by enriching the coding regions and the flanking. Um, intronic and the untranslated regions within the genes known, and in here we're talking about the 10 genes, and we also look in the areas in the promoter and deep intronic regions of the genes specified, and then those will undergo next generation sequencing. With more than 50x coverage at every targeted base, and then all the pathogenic and novel variants, as well as the variants of unknown clinical significance, will be confirmed by Singer sequencing, which is the classic method to confirm any next generation sequencing. Why do we report unknown, um, uh, variants of unknown clinical significance? Because as we manage more and more of these cases, one might say, I only want the pathogenic, but in the pancreatic disease as an evolving field, what's variant of unknown clinical significance today might be with more studies, pathogenic or likely pathogenic later. So you as the clinician, you need to know this information so we give it back to the uh clinicians. Any regions less than 50x will be filled by uh Sanger sequencing, and I have to say here PRSS1, which is the classic cationic trypsinogen gene that is stomal dominant, is always done by Sanger due to the high homology. Precision medicine in general is really, and I show here a uh um a publication from the Cincinnati Children's Organoid um um Center, and it was showing that from a single cell you can grow a 3D um or 3D3 organs liver, bile duct, and the pancreas something. Really beautiful and shows that how you could approach the disease treatment and the prevention, taking into account the variabilities in the genes and the environment and the lifestyle of each person. This is the way that medicine is evolving. So through understanding the genetics and the mechanisms, you could really help personalize the therapy for each patient. So I'm gonna give you um examples of genetic testing and how it was helpful and change the outcome. So this case, um, series is actually was done by Dr. Vitale early on in 2018 when our center saw three siblings. Those three siblings were found to be heterozygous for a PINC1 mutation that is known, the PE PN34S. That's one that everybody knows, but it also had a. Novel mutation that was not reported previously. So when there were double heads for these, all the three siblings showed similar um presentation in terms of the age of onset of the disease, as well as you see in the three images on the bottom, how they had some pseudocyst or cystic lesion in the head of the pancreas. So could really your pancreatitis phenotype be predicted on a shared genotype? I do think so, and this is one of the examples that um I'm happy to share with you. Another case is that I saw this patient who's a 14 year old and now she's probably in her mid-twenties and she's been healthy when she presented initially had idiopathic acute recurrent pancreatitis. So I say idiopathic with uh quotations because why would a patient who does not smoke or drink alcohol in pediatric. have pancreatitis, and she did not have anatomic abnormalities or any of the list of causes that I showed you. A limited gene panel for 4 genes was negative. She kept having recurrent admissions with lipase elevations, sometimes showing an imaging, sometimes not. So people started calling her that she has functional pain disorder and started treating her for that. When the 10 gene panel became available, she was tested and she was shown to be positive for one of the variants in the CPA1 gene. And we came to find that that variant was never reported before. So, do you believe it? Do you not believe it? Two years later, her brother had his first pancreatitis attack and then had more attacks. Would you test this brother? Of course I did, and he had the same finding. Then the mother, who was diabetic since she was in her 20s and not type 1 diabetes, by the way, had asked her doctor to check why is her pain so severe in her belly when she was diagnosed with gastroenteritis, and then they found that her lipase is in the 3000 range. So this genetic testing was life changing, not just for the patient, but for her family as well. I, I hear show how we published it because we um through that found the family tree and tested all of them, and the mom had the genetic phenotype. She passed it off to all her offsprings, and one of them actually did not show pancreatitis, but all her um. Um, offsprings carried that mutation. And then we did the functional studies in the lab, and it was shown that it leads to pancreatitis through a misfolding pathway. Uh, regarding genetic testing and, and the concept of, uh, ramifications of genetic testing. So, uh, what role, uh, does genetic counseling play prior to proceeding with genetic testing, just because of the potential for downstream. Uh, ramifications in the context of risk of pancreatic cancer, etc. other implications for family members. Talk to us a little bit about that. That's a great question. If we want to follow best practices, genetic testing should only be ordered as directed by a genetic counselor, so, In fact, sitting with a patient and and telling them upfront what the implications of having or not having a genetic abnormality is gonna hold to their future, their medical insurance, their offspring, and so on, and then have the patient decide if they want that genetic testing sent or not. Um, what we've done at Cincinnati Children's is that we've partnered with the genetic counselors very closely, and we have a model where we always approach the family and offer them that first and if they say no, we're very comfortable by you telling us, and as pancreatologists we develop this expertise through working with the genetic counselors, then sometimes we buy. that, but that's again, it should be offered for every genetic testing and actually in some institutions, MDs are not allowed to order the genetic testing. Last but not the least, and not to make this about reimbursement, if the genetic counselor is not ordering the test, some, um, institutions cannot be reimbursed for it. So it does have a huge role from multiple aspects. So, now we're going to talk about exocrine pancreatic insufficiency, and I would like to turn it to Dr. Vitale to cover that topic for you because that's very important in the workup of chronic pancreatitis. Sure, thank you. So what is exocrine pancreatic insufficiency? It's a that's characterized by reduction or deficiency of uh exocrine pancreatic enzyme activity and bicarbonate in the lumen of the intestines below what is required to digest food, um, which can lead to madigestion and malabsorption. Uh, so, there's two types of pancreatic function testing, indirect PFTs, uh, which you're familiar with, measure the consequences of pancreatic insufficiency, whereas direct pancreatic function testing involves stimulation of the pancreas through administration of secretagogues such as cholecystokinin or um secretin, after which we analyze the duodenal fluid to look at pancreatic secretory content. And the indirect PFTs are generally screening tests, whereas those direct pancreatic function testing is generally confirmation of exocrine pancreatic insufficiency. So these are some examples of the indirect PFTs and you're familiar with these, uh, um, you know, fecal elastase is used frequently, fecal cymotrypsin, fecal fat collection for 72 hours, which is very difficult and obviously pretty unrealistic for most patients, uh, breath tests or serum trypsinogen. Uh, fecal elastase, generally accepted values that are less than 100 is consistent with severe pancreatic insufficiency. Uh, levels 100 to 200 are indeterminate and then values greater than 200 are normal. Uh, you have to remember that this does fluctuate through the first year of life. So an initial value of fecal elastase in a younger patient can be very different from a value that they get at 1 year of age or even 2 years of age if you check it down the road. So this is an example of a classic double lumen, uh, drying tube test. And uh this is what has been done in the past. And uh as you see here on your left, there are both gastric and duodenal fluid aspirates that are collected after secretin stimulation and these are collected via nasogastric and nasoduodenal tube. It over about 45 to 60 minutes. And on your top right there, you see that that both volume and bicarbonate secretion are measured in the duodenal fluid. It's a very sensitive and specific test. Unfortunately, it's unpleasant. It's time consuming. Fluoroscopy is needed for placement of the tubes, and in most institutions, it's really not readily available. So in the early 2000s, endoscopic pancreatic function testing started, and this was the initial. The way that this was approached was to aspirate gastric and duodenal fluid, collect a baseline duodenal fluid sample, and then stimulate with either CCK or secretin and collect a duodenal aspirate over 60 minutes. And this is still done in some institutions, as you can see. Uh, with both of these charts, both the lipase concentration on your left there and the peak bicarbonate concentration on your right, when stimulated with CCK or secrettin were similar to the drying tube methods when looking at both healthy subjects and patients with chronic pancreatitis. So our protocol here at Cincinnati Children's involves an IV bolus of either secrettin or CCK at zero time point prior to any collection of fluid. And then we collect 3 duodenal aspirates and, and we fill syringes at 5-minute intervals after the CCK or secrettin administration. And we really use whichever one is available um uniformly here. So, uh, we then collect duodenal fluid aspirates and we use a 543 tapered catheter to do this, and we point of care pH test each sample to assure that there's no gastric fluid contamination. And then we transfer the aspirates to Eppendorf tubes and then place them on ice to ship to our reference laboratory in Buffalo, and we test for trypsin, amylase, lipase, and chimotrypsin along with the total protein level. So this is an example of what we see when we go to collect the pancreatic fluids. And you can see this sort of Coca-Cola colored fluid here, a combination of pancreatic and biliary secretions, and there's our 543 catheter going in to collect the fluid from this pool. So this is an article that was published from our institution in 2016 looking at these endoscopic pancreatic function curves using our methods. And you can see from the blue bars there, those are healthy patients. And then the red bars, they're really, we see a peak of the enzyme concentrations at uh at 5 minutes and then they generally tend to down trend when we get our 10 and 15 minute samples. We also looked at age in this study and the pancreatic function testing showed that the enzymes do mature with age. So, the younger patients have lower levels and then as you increase in age, these, these do mature. Uh, one thing to note is that any kind of pancreatic function testing that you do can be abnormal if it's checked around the time of acute pancreatitis. Uh, so either indirect or direct methods, we generally try not to put too much stock into those results that you get within about 6 to 8 weeks of an episode of pancreatitis, and try to measure those a little bit later, because they can temporarily be abnormal and then normalize during an acute episode. Uh, enzyme activity does mature over the 1st 2 to 3 years of age. So something to really keep in mind when interpreting these results. And as you can see, these are all invasive measures. So we do need a non-invasive functional tests of exocrine pancreatic sufficiency. And Dr. Trout is going to tell you in a few moments here about some up and coming imaging testing. In terms of characterizing the parenchyma and the pancreatic duct. Um, and then we've talked about, uh, invasive ways, um, to go about measuring, uh, exocrine pancreatic function. Uh, so you could allow my clinical colleagues to put an endoscope down you and sample your, uh, enteric fluids. Alternatively, um, we are working on some new approaches, uh, that utilize, uh, MRI which we're already performing to make the diagnosis. And by administering The same secretagogues, though for MRI we, we use secretin to both both capitalize on the duct dilatation as well as to get the secretory effect. We don't do the CCK. We can characterize how much fluid is actually secreted uh in response to that secretagogue. So here's um an example of a patient, a normal patient, uh, with pre and post-secretin images. These are identical fat saturated T2 weighted or fluid sensitive sequences pre and post-secretin, pre on the left, post-secretin on the right. And you can see that in response to the secretin, there's a filling of the duodenum, and then as well as increased fluid within jejunal loops in the left upper quadrant. And it's these changes that we're looking for to measure an adequate response uh to secretin. Can you go to the next slide, please? Um, and the advantage of this is we're already performing the imaging for making the clinical diagnosis, and here we can combine this and get a non-invasive measure, um, of, uh, exocrine function. And so on that last case, we saw that the duodenum filled nicely and it spilled over into the jejunum. Here's a patient that started with fluid already in the stomach in the duodenum, and you see that following secretin, really the only fluid secretion is a small amount. Over here in the jejunum. We don't see marked filling of, of bowel loops and, and spilling over into um other jejunal loops. And this is actually uh qualitatively uh inadequate secretory function in response to the secretritagogue. Now, we can grade this qualitatively according to the Matos criteria, which actually doesn't work all that well in children, um, because we typically see much more fluid filling into the jejunum. Or we can go about this in a more quantitative measure, which is where we're going here at Cincinnati Children's. If we can go to the next slide. And essentially, what we are able to do is that by utilizing image segmentation, where essentially we quantify the fluid um pixels on the pre and post-secretin images, and then subtract the two to basically figure out how much fluid volume was secreted in response to that secretin, we can compare that to values that we have previously defined in a normal population. So I point you to this publication here, um, that, uh, will provide you with the normative ranges that we were able to generate based on a population of 50 healthy children. And the quantile regression curves here, this red lower line here um is the 5th percentile value. That's this red lower line here. That's the 5th percentile value below which we would not expect um a healthy patient to fall. So we're using this now um to try and be more quantitative about our measures of decreased exocrine function. Thank you, Andrew. I still, as a um gastroenterologist and an endoscopist cannot resist if I am doing an endoscopy for a pancreas patient to resist getting a pancreas fluid sample. They wanna know if they're still making enough exocrine enzymes or not. And also that helps delineate if they are insufficient, um, down the line, how do you prove that they have pancreatitis or not, because then they might not elevate their lipase or amylase, um. Endocrine testing, and as a non-endocrinologist, we all as pancreatologists have to become savvy into how do you diagnose and when do you refer. So as a classic indication, even if your patients are asymptomatic, we advise that yearly the patients should be tested by hemoglobin A1C, fasting insulin, fasting glucose levels, and maybe even if you have the capacity of mixed meal tolerance testing. I show here a cross-sectional analysis of um our patients that were 52 of them um tested with any test available that I mentioned, and 13 out of the 52, so 25% were diagnosed with either pre-diabetes or diabetes. Um, 15% were after the first attack of pancreatitis, about a half after a second attack, and 38% were after classic CP. What is the ideal diabetes testing? We believe, similar to the CF related population, it would be by mixed meal tolerance test. And here I show how we do it at Cincinnati Children's, but basically it is a fasting, uh, glucose level and then you give a boost stimulant, which is a, a, a replacement of a meal, and then you measure their, um, insulin, glucose, and C-peptides at every 30 minutes up to 2 hours. It does show um it, it, um, help, help, um, in diagnosing and even management in that detecting impaired fasting glucose, impaired glucose tolerance, and CFRD and even in diabetes mellis in general. Complications of CP, we need to monitor and treat the sequela of CP, which are, as we mentioned, exocrine problems, diabetes problems, growth in macro micronutrient deficiencies, gastroparesis, small bowel bacterial overgrowth, vascular complications. strictures or ductal diseases, or even the risk of pancreatic carcinoma. And this publication came out of the Pancreas Committee as a position paper just last month. So I encourage you to go back to it because it does cover all the medical management aspects. This is a pancreas passport that NASAGAN Pancreas Committee published as well, and it helps when you send your patients to different ERs to kind of put a brief summary on how you want them to be managed. So, in general, what is CP management medically? You assess the extent of the disease and you stage it in terms of exocrine and endocrine problems. You also assess the nutrition and treat the nutritional problems. In terms of uh pancreatic enzyme replacement therapy, we follow the CF Foundation guidelines, and we reserve ERCP and surgical, as you will hear in later sessions to treat the anatomic problems or obstruction or the chronic pain. Pain management is really the main reasons patients seek us out because pain affects their physical, emotional, and social well-being. Unfortunately, despite multiple trials, there is no single medical or dietary intervention that could prevent recurrent episodes or treat pain effectively in chronic pancreatitis. We generally say low fat diet is not needed. Pancreatic enzymes are not needed if your patient doesn't have exocrine insufficiency, antioxidant cocktail, steroids, leukotriene antagonists, or somatostatins are not helpful, as shown in trials. But what we know is that if you approach it like other chronic pain conditions, that CBT, physical therapy are going to be effective in treating that. And again, this publication does show how you could approach pain systematically from level 1 pain to level 2 to level 3. So in conclusion, we have made some advancements. There's a lot more to be made in the medical therapy of CP patients. We have included a wider understanding for screening for risks and complications to minimize the pain and suffering of the patients. And there isn't a single medical therapy that has been shown to slow the progression of the disease. However, a comprehensive multidisciplinary team approach would be critical to ensure the optimal outcomes. So thank you for listening, and here I would conclude our slides. And turn to the moderators. That's great. Thank you. Next, a couple questions regarding fat. One about fat going in and one about fat coming out. So I'm gonna combine the questions. So, with regard to uh no fat diets, um, any role in CP, uh, pancreatitis related to hypertriglyceridemia. So that's the fat going in question. Regarding fat coming out, what about the role of spot fecal fat estimation? David, do you wanna take both? Sure. So, so Dr. Hedge is a true expert on this, and she's published regarding nutrition and fat intake with chronic pancreatitis. So we, we don't limit fat intake in our patients. Um, you know, I think that there's been in pediatric patients and studies such as Dr. Hadja's study looking at progression and And patients with chronic pancreatitis and fat intake, and it does not affect their disease course. And so we generally do not limit that fat intake. Now, that being said, um, if I have a patient in clinic that is telling me, I have pain when I eat fatty foods or I have pain with this, you know, then I, then I do actually have them sort of limit things um anecdotally. Um, from a hypertriglyceridemia standpoint, yes, those patients certainly need to be on a low fat diet. Um, any patient that has pancreatitis, which can be quite severe with hypertriglyceridemia, uh, we do limit their fat intake. Um, from a standpoint of the spot fecal fat, I don't put any stock in this at all. Um, so it's, it's, uh, you know, a random fat test. The reason that we collect when when we actually do a fecal fat test over 72 hours is because there's so much variability with each stool, with how much fat you're having. The diet affects this very much too. And so generally when you're doing a 72 hour test, you want to make sure that they maintain a certain level of fat intake each day to normalize the test. So the spot fecal fat, as far as, you know, looking at pancreatic insufficiency, I put no stock in that at all. Yeah, I would agree with that. And I think also for the hypertriglyceridemia, we have a few patients. It's really a severe course once they go into an attack. So It's not only limiting their fat intake during the admission, it's even this, that's their chronic management as an outpatient, the hyper and thank you for the person who asked that question because that's very important. It's actually a low fat diet for the rest of their life because most of these patients, they do have a genetic problem that leads to the hypertriglyceridemia. So you cannot treat that easily, and then they actually get put on medical therapy with. Some combinations of niacin and other treatments by the lipid clinic, usually a lipid expert to help lower that and keep it below 500 to prevent recurrent attacks. Great. So, uh, the last two questions. One is related to the use and utility of celiac plexus block for pain relief in chronic pancreatitis. So the celiac plexus block, as far as we know, has not been shown to be effective, and all I can say is that we need more studies. And I'm not sure how we would do more studies on such an invasive procedure. Would you do a placebo controlled? I mean, that's, that's gonna be the ethical dilemma with celiac plexus block and also it's operator dependent. So depending on who's doing it and how they're injecting, um, could be done by US as well or interventional methods, um, so all of that has to be standardized. I, I might comment additionally, you know, that, that is a challenge. I mean, we're often asked about celi plexus blocks in the context of pain management for CP. Uh, and the data, uh, you know, for CP is, is, uh, is not good. Uh, and, you know, first, you know, we've evolved from utilizing radiologic, uh, guidance, uh, to using EU US guidance, uh, from a safety perspective. Uh, and the reality is in pediatrics, you know, there's not a whole heck of a lot of folks out there that are comfortable doing EUS in the first place. So, it has not progressed substantially in the pediatric realm, but even if you look at the adult studies, there's barely a 50% um uh efficacy with, with regard to celiac plexus block for, for pain, for CP. Uh, and the fact of the matter is it's transient, uh, it will require repeated um interventions, uh, and, uh, it, it is, it is not something that, um, has, uh, really, uh, remained as a central opportunity for management and CP. So, we have come to the conclusion of module one. and we appreciate all of the very important questions, uh, and please keep them coming. Uh, we will integrate them into the discussions. Uh, any questions that may be relevant going forward that have been asked, you know, we'll try to integrate questions that have already been asked. Um, and I see, see some coming through here that we'll be addressing in the next couple of modules. Um, so thanks very much. And I think we're having a five-minute break. Is that right? Yes. Thank you, everyone. Hello everyone. Welcome to module two of this course. And next we will be covering the role of ERCP and EUS endoscopic ultrasound in chronic pancreatitis patients. I would like to welcome our next two speakers, Doctor Tom Lin and Doctor uh David Vitale. Great. Thank you, doctor. I will hija. So we're gonna jump in right into things. So our objective slide hopefully with the attendees um they are able to get a better understanding and appreciation of the, uh, the benefits of both ERCP as, as well as endoscopic ultrasound but also having an understanding of some limitations there might be as it applies to, uh, utilizing it in children for chronic pancreatitis. So to start off with, um, some of you may well be familiar that, uh, the NASS began or the North American Society for Pediatric Gastroenterology just earlier this year put out a position paper related to um the specific roles of EUS and ERCP for chronic pancreatitis in children. And so what's important, uh, as it relates to our particular presentation is that our, our own center Currently as well as historically does um um practice these particular uh position paper uh guidelines um and suggestions from an endoscopic standpoint and so we're, we're in line with uh the societal position paper that was published. So, ERCP in children, um, as you might suspect, uh, it continues to be the gold standard for pancreatic duct imaging in, in kids, um, and that's no different from, uh, how it's applied for adults. Um, it does also continue to be reserved for therapeutic interventions, but there can be some exceptions to the rule where ERCP for diagnostic purposes, though less frequently might be indicated and one such indication is for pancreatic trauma. Um, but the vast majority of times it is still reserved for therapeutic intervent interventions. Um, as it relates to age limitations, um, from our perspective and then our center, there is no age limitation in performing ERCP. So even the youngest of patients who might need an ERCP for various indications whether it be biliary or pancreatic indications, even as young as a neonates doing a successful and, and safe ERCP is possible with the appropriate equipment, um, and the appropriate accessories which do exist. Um, from an altered surgical anatomy, um, this is no longer considered a significant limitation as it relates to performing ERCP ERCP successfully in kids. Part of the reason for that is with the advent of enteroscopy or more specifically balloon enteroscopy, this has bridged that gap, um, where altered surgical anatomy, including such as, um, R and Y anatomy no longer is a significant obstacle. Um, so the other thing that's important to recognize that um though MRCP has made significant leaps and bounds as Doctor Trao has presented before in regards to um uh the Uh, resolution and the ability to pick up um various abnormalities, um, for diagnostic purposes, there are still continued limitations in MRCP and what we've learned from the literature as well as from our own center is that there can be certain false negative rates for MRCP, specifically pancreatic duct stones as well as chronic pancreatitis findings, um, depending on the severity and perhaps The size of the particular stones might be overlooked by MRCP and perhaps it may be even related to the size of the patient. Um, and then other, um, other times that uh anomalous pancreatic biliary junction or APBJ might be also overlooked, um, on MRCP and thus because of that, um, there may be some, um, some benefits of, uh, proceeding with an ERCP, um, for that purpose. So as it relates to ERCP limitations and I kind of hinted to that this before, um, as we know ERCP and, and what we're capable of visualizing is really just continues to be limited to the pancreatic duct itself. So looking or visualizing, visualizing the parenchyma is no longer, is not capable from an ERCP standpoint. Um, the other thing to, to consider and understand is that, um, from our own personal experience at our center, um, ERCP in children for chronic pancreatitis and pancreatic indications is more technically difficult and complex in kids compared to performing similar procedures on adults and they go, again that goes back to our personal experience at our center which um we do get um many referrals from across the country. Um, the, the other thing that, that's important to understand and recognize as it relates to ERCP limitations that, that though an ERCP can be technically successful in regards to perhaps removing, removal of obstructive, um, pancreatic duct stones or perhaps effectively treating a stricture, it may yet still fail to adequately alleviate the patient's clinical symptoms and so there can be some limitations in how effective clinically an ERCP might be. The other important factor to, uh, to consider is the risk factors associated with the ERCP, um, that are very similar to adults. And so the, the greatest risk factor as we know and understand is developing post ERCP pancreatitis from the intervention that someone undergoes when undergoing an ERCP. From larger pediatric cohort studies, um, that rate of post ERCP pancreatitis has been, um, published as 3 to 11%, which is very equivalent to what's been published on the adult side. As it relates to other risk factors, they're much, much less frequent, um, including perforation, bleeding, and infection, infection from ERCP. So all those are either 1% or less than 1% of the time in, in, uh, pediatric, uh, studies and so relatively infrequent and so above anything else, still it continues to be pancreatitis that's the greatest risk factor. Other factors to consider clearly when deciding on whether or not an ERCP is the appropriate thing to do is, is understanding the uh exposure to ionized radiation from the fluoroscopy component of ERCP and um nowadays the standard of care for performing ERCP in children is utilizing general anesthesia and so the anesthesia-related risk factors are important to factor into uh this decision-making for proceeding with an ERCP or not. So moving on to therapy, therapeutic ERCP we'll cover um uh several of these topics and then again hopefully uh allow the, the attendees to get a better understanding of what we do. So from a pancreatic duct stenting standpoint, um, there are things that are helpful for, for perhaps the non-ERCP ERCPs to understand. So as it relates to the stents that we utilize, the vast majority of the time they are plastic stents, um, but there can be few situations. that um we can uh appropriately utilize fully covered metal stents within the pancreatic duct, um, whether it be plastic or metal, they are all considered temporary stents and so at the current time, there is no consideration for a permanent stent within the pancreatic duct. As it relates to the plastic stents, they are made or, uh, made of primarily flexible plastic polymers. Um, they are radio opaque and so if there's a need to assess whether or not a stent has spontaneously passed, they will be very, um, apparent on a standard KUB. Um, the vast majority of plastic stents that are produced out there by the various vendors are considered MR conditional. So if there is an indwelling stent or if there's a consideration for a child needing an MRCP or an MRI study. Um, for pancreas indications for, or for some other type of indication and there's um, um, an indwelling pancreatic duct stent, it's important for your radiologist to understand that, um, and before doing the study so they can protocolize the, the study appropriately, um, so, uh, they can, so it can be done safely. As it relates to stent duration, and this is a, a frequent question that we get, um, what's the duration and, and, uh, and length that a stent should remain within the pancreatic duct. And so the answer to that really depends on what your original indication was for placing the stent. And so, um, we'll touch upon that in a second, but, um, that varies from having a plastic stent in there for 4 weeks and other times a little bit longer duration depending on what you're treating. If there's a need to perform serial stenting because of a, a, um, uh, a ductal pancreatic duct stricture that requires more than one session of ERCP, question is, well, how often is, is safe and appropriate to perform those serial ERCPs? And I think the general understanding and the acceptance um out there both on the pediatric and the adult side is, is to perform serial stenting for. For pancreatic duct strictures for a maximum of one year and if those strictures proved to be continued recalcitrant beyond one year, then, um, considering what the other interventions thereafter rather than continuing to perform ERCP serially for, for greater than one year. So the, the approach thereafter would be um discussing options with your, your local surgeon. So indications for stenting on the vast majority of times when it's, um, uh, performed for a either a biliary or pancreatic indication in the ERCP is, um, there is a prophylaxis of placing a pancreatic duct stent into the pancreatic duct that will spontaneously pass for the purpose of reducing your, your risk of post ERCP pancreatitis. And so that approach in children has not changed from what's been documented in, in adults, um, to as well in regards to the indication of placing prophylactic pancreatic stents. Other indications for pancreatic duct stenting, they include, uh, stricture therapy, as I hinted before, stone therapy if there are, uh, inability to remove all the stones in under one clinical session for an ERCP and other times if there's a duct leak or duct disruption, even in the context of chronic pancreatitis, having a pancreatic duct stent, um, that's therapeutic, um, there temporarily can be of benefit. So, um, pancreatic duct stenting, um, um, here's an example of a child with, uh, an older teen with, with, uh, complete pancreativism. Um, this child also had underlying liver disease that was felt to be unrelated to their underlying, um, pancreas disease, but, um, an MRCP documented that they had a high suspicion for complete pancreas disease. Um, this patient also had negative genetics prior to deciding to go forward with their ERCP. And so at the time of the ERCP with cannulation of their minor papilla and into the dorsal pancreatic duct, confirmed that they indeed had complete pancreas division, but we, what we also see here at the time of the ERCP is a grossly dilated beaded pancreatic duct with two focal strictures within the, the main pancreatic duct that the next step would be to see if, if they're effective enough to treat endoscopically and so what we Do at that time is placing a dilating a balloon, dilating balloon across those two scriptures, um, breaking those, uh, those scars, scar fibers that have developed because of the, the chronic pancreatitis, and thereafter placing a therapeutic pancreatic duct stent with the hopes that ultimately when the decision is to leave out your, your stents, um, you will have effectively treated, um, the, the strictures effectively. Um, of note in this picture, this, this is actually, uh, also showing on the same patients, um. Uh, required an NJ endoscopic NJ placement, so that's the other, um, tubing that you see there in that, in that picture. So how about pancreatic duct stones and so they come in different sizes and shapes and so fortunately from a pediatric side for children who have chronic pancreatitis, the vast majority of them are um soft and non-calcified and so readily, easily removed um from the duct with standard endoscopic therapies. And so, um, oftentimes we either utilize, uh, a basket or more commonly we utilize a retrieval balloon. To remove and extract those obstructive stones within the main pancreatic duct and, and again most of the time, uh, they are, it's effective, uh, in the pediatric patient population. But what about those stones that are a little bit more, uh, stubborn per se and then maybe indeed we, we do come across some stones that are, or have some calcified components and so Lithotripsy is also available within our pediatric pediatric population for ERCP. So there's different approaches that we have. We have mechanical lithotripsy using a basket that can, that can, um, fragment those particular stones and then other options are utilizing electrohydraulic lithotripsy or even laser therapy under direct visualization, um, to break up those stones and be able to extract them more effectively. Um, SWL, um, is one of those things that is available and capable of, of, um, approaching pancreatic duct stones in a different manner. Um, as you know, the, uh, as our audience knows, SWAL is typically reserved for, um, kidney stones, um, but there has been application of utilizing SWLL for pancreatic duct stones, um, using it safely both in the adult population as well as on the pediatric population. So here's an example of a child who came to us. They were less than 10 years of age, um, and, uh, had an MRCP already before even coming to our center for a second opinion with um clear findings of introductal filling defects suspicious, suspicious for introductal stones within their pancreatic duct and again this is our, our initial MRCP images. So we, at the time of ERCP. We see a very similar findings that we saw on MRCP perhaps maybe a little bit more of a, a greater stone burden than was apparent on the MRCP. And so our next approach from that standpoint is performing a, a pancreas, pancreatic sphincterotomy and then the balloon extraction of the, the obstructing stones that we see here from an endoscopic standpoint and alleviating that obstruction, uh, aspect of, of those stones. So pancreatic duct disruption and leak, um, as our audience members know, the most often scenario, the most common scenario that we see that is in an acute setting where a child has blunt abdominal trauma and granted our, our discussion today is related to chronic pancreatitis. So there can be situations and we've seen, um, unfortunately, uh, uh, a number of Patients ourselves who have chronic pancreatitis or present or, or had issues related to necrotizing pancreatitis who develop pancreatic disruptions or leaks and so ERCP at times can be helpful in those situations. And so here's one child, again, uh, a younger child less than 10 years of age. Who, um, had recurrent episodes of pancreatitis, had findings by MRCP of chronic pancreatitis, and also had imaging findings suggestive of, um, a pancreatic duct leak with, uh, a, uh, collection of fluid outside of the pancreas. Um, and so at the time of ERCP indeed we confirmed that the child had a pancreatic duct. leak, we see here that um uh there's extravasation of contrast outside of the normal course of the main pancreatic duct. And so what we would want to do in that situation is placing a stent which we ended up doing, leaving that there for anywhere from 4 to 8 weeks and then subsequently repeating someone's ERCP and so in this situation, the same child had a successful resolution and healing of that, uh, extravasation of the, of the, the contrast that we saw initially, um, but unfortunately had a Uh, continued findings of chronic pancreatitis within their pancreatic duct as we see from this repeat ERCP. So pancreatoscopy, um, so this is one of the, uh, the, the newer modalities that's available to the, the therapeutic endoscopist. And so when I spoke about before, um, utilizing electrohydraulic lithotripsy or laser therapy to, um, treat introductal stones that were untreatable from the standard approach from an ERCP. This is a single operator pancreato pancreas, pancreoscope that is a 10-French scope, uh, which is considered a mother-daughter scope that goes within. The ERCP scope channel, um, it goes through the adult ERCP channel, um, and is, and you actually pass the, the D scope within the duct of the of the uh the main pancreatic duct, and there's various interventions that you can perform at the time they related to irrigation, visual. Realizing how the, the duct looks within the duct itself. Um, biopsies can be be performed if there were considerations for an abnormal, um, uh, mass within the duct. And then as I hinted and, and suggested before, lithotripsy under direct visualization can be done utilizing this new technology. Um, so, uh, a few slides on pancreas divism, and I, and I think this is important to address because of how frequent we're seeing it, especially in our center. And so as we know, pancreas divisum is the most common congenital anomaly of the pancreas. Um, it's known to be a risk factor for acute recurrent pancreatitis as well as chronic pancreatitis and within the, within the general healthy population, it's been identified to be, um, uh, to have a prevalence of 7%. Um. Uh, Doctor Haija had mentioned before about an international study group um that our center is a part of, um, looking at acute recurrent and chronic pancreatitis in children and from that, um, that international study group, um, one of the publications identified a prevalence of pancreativism of 15% within that, that particular cohort. And so what's the role of your CP with, uh, with possible minor, uh, sphincterotomy for individuals who are identified as having pancreastovisa. So what we understand and recognize from the adult studies, there can be a favorable clinical response to minor papilla sphincterotomy at the time of ERCP. But how does that apply and is that applicable to children? And so from our own center, we've been able to identify our, our larger patient population with pancreas divisum of nearly 2/3 of those patients who underwent therapeutic ERCP, um, they developed, uh, or had a clinical positive response with either symptom improvement or complete symptom resolution from minor papilla sphincterotomy and so there is a, um, a potential role for ERCP in kids with pancreas disease but a lot of questions still remain. And so fortunately, currently there is an adult um uh blinded um random randomized sham control trial um called the Sharp trial related to specifically Pancres DeVM. And uh the idea of studying um minor pylo sphincterotomy and determining whether it's, there is true utility to it or not. And so this is an active study that's um undergoing recruitment on the adult side but there is a very similar study, um, on the pediatric side that is in the early stages of developing, um, and, uh, going forward that will also be randomized and hopefully answer some of the outstanding questions that we have related to Pancreas disease. So lastly, um, I think it was important to actually address briefly address, um, the, uh, the existence of multi-drug resistant organisms and as our viewers or our, as our attendings um have have an understanding within the past year or two, there's been a greater concern about MDRO MDRO infection risks and most often this applies to ERCP and whether or not, um, patients who are undergoing ERCP are at elevated risk for developing these highly drug resistant organisms or superbugs as they might be referred to as, um, and what's the overall risk. Unfortunately, I think the, the Uh, the vendors have listened to the, these particular concerns and recognized that this is something that's important to address and so what multiple vendors have, have developed recently and that's currently available and has received FDA clearance for its commercial use is either a disposable cap, uh, duodenoscope for performing ERCP to reduce that risk of, um, contamination and passing on. A, uh, drug resistant, uh, organism to the next patient who needs, uh, an ERCP despite, um, appropriate cleaning and, and sterilization of the scope and other vendors have introduced a single-use fully disposable duodenoscope to perform ERRCP that completely eliminates the potential for passing on these particular, um, resistant organisms to, to our patients who are vulnerable. So in summary, um, ERCP in children can be safely and effectively performed for various disorders including chronic pancreatitis and, um, and the complications are, are readily, um, uh, similar to adults and not any higher. Yeah, thank you. Uh, the first question I would like to ask the radiologist in the group, Doctor Trout, can you comment on the accuracy of MRI in detecting or diagnosing or ruling out, um, pancreatic duct strictures? So this is kind of a complicated question. It depends a little bit on your, your definition of, of stricture. Um, but both MRI and ERCP play roles in this. ERCP really is the reference standard still. Um, Secretin, uh, can help improve the caliber of the duct and increase visualization of strictures. MRI is getting quite good at this, um, but You know, the degree, the ability to image the duct under distention with ERCP really provides a degree of characterization that we can't get yet with uh non-invasive imaging. So, MRI is very good, but if there remains a question, and obviously, anytime you need to do a therapy, you are gonna still be going to ERCP. Great. Great. Thanks, Andrew. So, a couple of technical questions here. One for ERCP, one regarding EUS. So there's a lot of, there are a lot of questions regarding age and weight limitations, and, uh, for example, for ERCP, youngest size that we can do an ERCP in, are there um size-related, uh, stents, so, size of the child or size of the duct, so different size stents and how Does that play in? And then also regarding EUS similar types of questions, um, about, uh, age and weight, uh, minimums for scoping for EU US and for interventions via EUS. So, I wonder, you guys might, you, Tom and David, you might want to split those up. Yeah, so from an ERCP standpoint, I spoke about this before about no, no type of limitations on being able to perform both diagnostic as well as therapeutic ERCP. Um, are there specific, um, stents or other type of equipment that's, that's, um, manufactured specifically for, um, kids in pediatrics? Unfortunately not, um, but, um, there are, um, accessories as well as stents that are small enough to be able to, um, be utilized successfully for our smaller pediatric patients that are typically reserved for, uh, adult patients. So from an EU US standpoint, um, the, the scopes that we have that are made for GI, uh, endoscopic ultrasound, the limit is 15 kg about, you know, you get much smaller than that, you really risk an upper esophageal perforation when you're inserting the scope. Now, there, there is an endobronchial, um, echo endoscope that can be used um in smaller patients. It's about 6.5 millimeters, but it really can only be used for diagnostic purposes. You are able to do um fine needle aspirate from that, uh, even up to a 19 gauge fine needle aspirate, which I've done in a few small patients. Um, you know, there's some question about the utility of it when you're just doing a diagnostic endoscopic ultrasound in a smaller kid when transabdominal ultrasound can can work well. But if you need to obtain tissue, that that's certainly a possibility. Um, to use that smaller echo endoscope. There's also a probe that you can put through from a diagnostic standpoint through an upper endoscope, a small mini probe that you can use as well um to get nice ultrasound, radial ultrasound images. And then as far as intervention goes, um, from a standpoint of like a cyst gastrostomy, etc. those limitations are really 15 kg for the US guided interventions. Now I have done some patients with forward viewing endoscope intervention. With collaboration with our interventional radiology colleagues, providing transabdominal ultrasound for a view of this at the same time, but that gets a little more complex, you know, and you're not really using endoscopic ultrasound for that. Um, so that, that's a little more rare for us to do, but we can do it. I would like to turn this to David to cover the endoscopic ultrasound now and we'll try to catch up with the questions cause as uh the audience might see it will be some of it is included in the talks as well, David. Great. Thank you. Um, so, uh, endoscopy, what about endoscopic ultrasound and pediatric chronic pancreatitis? So just a brief introduction here. These are the types of, uh, endoscopic ultrasound, uh, scopes that we use. So, um, on the right side here is a linear scope. You can see a small balloon here. Um, this gives us a 180 degree view of um the rankyma. And then this is a radial scope, which gives us sort of a 360 degree view. much as you might see with a CT image. Uh, so just a brief introduction to echogenicity, which we'll be talking about. Um, anechoic lesions are generally cysts, gallbladder, vessels, anything with fluid in it essentially. Um, hypoechoic things we think about neoplasms, when it's hypoechoic relative to adjacent tissue and then hypo hyperechoic lesions are lipomas and stones, and those sometimes shadow as well. So you just see here what we're looking at uh when we go in and do these endoscopic ultrasounds. So this is a linear view with our scope here. We have a 180 degree view. And then this is a radial view, um, which shows us looking at the gallbladder and then actually just some air around here. But you do see you get a nice 360 degree view. Our radial scope is really just a diagnostic scope, um, to be able to look and see. We are not able to take biopsies with that. Uh, from a standpoint of indications, uh, and for endoscopic ultrasound and pediatric pancreatitis, uh, from a diagnostic standpoint, we can do this for suspected, uh, cholodocholithiasis or cholelithiasis, um, acute pancreatitis or recurrent or chronic pancreatitis of uncertain etiology, uh, to look at or um aspirate fluid from cystic pancreatic lesions, uh, suspected autoimmune pancreatitis, the visum or pancreatic masses. And then from a therapeutic standpoint, uh, With symptomatic walled off necrosis or pseudocysts, we can approach with cyst gastrostomy or cyst duodenostomy. And as we discussed before, celiac plexus neurolysis, and then biliary or pancreatic access after failed ERCP. So this is just to show, this is a 19 or 2018 comprehensive review of the literature. There have only been 19 publications since 1993, 630 procedures with a low complication rate, but this is just to show you that there really has not been much done in the way of pediatric endoscopic ultrasound and it's a, it's a burgeoning field. Um, from a safety perspective, uh, diagnostic uh at uh US is quite safe. It has uh perforation rates very similar to to standard upper endoscopy. Same thing with bacteremia. You do increase your risk of pancreatitis a bit uh when you biopsy the pancreas. And also there is a bit of a risk of bleeding after biopsy as well. Um, from a therapeutic standpoint, it's obviously much higher risk. So these patients that are getting cyst gastrostomy, cystoodeostomies, or rendezvous procedures have higher risks of both bleeding, infection, and perforation. Uh, so this is, uh, what Doctor Linn referenced earlier, the role of, um, pediatric, uh, pancreatitis, the role of the US, um, and this was published recently as an expert opinion. Um, this is just a quick summary of what was published and from an US standpoint, abdominal pain without a suggestive pancreatic pathology, its use is discouraged. Uh, appropriately trained advanced endoscopists with experience in pediatrics are preferred when doing EU US in pediatric patients. And then standard equipment. Patients less than 15 kg can be used and otherwise requires alternative equipment. So we've sometimes used an endobronchial scope with ultrasound capability in the smaller patients, which is about 6.5 millimeters. The adult-based chronic pancreatitis criteria, including the Rosemont and conventional criteria, can really only be used as support and guide interpretation in pediatric patients. Uh, some of the other guidelines recommend that contrast enhanced US and elastography, both. Further investigation before widespread use in pediatrics. Chronic pancreatitis associated fluid collections should be considered for watchful waiting if the patients are doing well. And then when intervention is required, EU US is really preferred to surgical and open interventions and even percutaneous interventions as well. And the US is very safe for diagnosis of chronic pancreatitis just as a diagnostic tool. And obviously the risks increase when any therapeutic interventions are performed. So, um, from a standpoint of diagnostic US looking for chronic pancreatitis, you see here, um, the Rosemont criteria, which are widely accepted and used in the adult world. Uh, you know, we do extrapolate this for our pediatric patients. This is not for you to look at in great detail, um, but just know that combining some of these major and minor features that we find can either have us have findings that are consistent, suggestive or indeterminate for chronic pancreatitis or even normal as well. Um, this is obviously an expert opinion. It's made for adults and it's very subjective. Uh, it's, and it's user dependent. Um, so while it's a nice tool and a good expert opinion, um, it is just that. So this is just looking at a patient with a normal pancreas, what we see on endoscopic ultrasound. Uh, generally, we see this sort of homogeneous tissue. Uh, we don't see any hyperchoic lesions here. Uh, and then we're going to play a video here, um, that looks at a patient that had actually a normal MRI on the pancreas, and you're going to see, uh, we did an endos. endoscopic ultrasound on this patient that had some intermittent episodes of pancreatitis and you actually see some lobularity come into view here, um, some hypoechogenic stranding, uh, and then also some hypoechogenic fossa. Um, so this patient sort of was in the indeterminate category for chronic pancreatitis, uh, but obviously quite different than what we saw with the completely normal MRI for this patient. So following this, we are looking to look here at a 7 year old who has chronic pancreatitis, and you're going to see a marked difference. I'm going to play the video right now. We're going to see a marked difference in what we see here. So we're looking at the tail of the pancreas initially towards the top of your screen there and you're going to see the duct come into view. The duct is quite ecstatic. It has some hypoechogenic margins and subsequently you're going to see here some debris uh within the duct, uh, indicative of stone disease within the duct there. Um, so Uh, this is a patient with chronic pancreatitis. So here's a case where we utilized endoscopic ultrasound. It's a 15-year-old female who had episodic severe epigastric pain every 2 weeks, uh, for over about 6 months or so and had a completely normal workup. So normal MRCP, normal lipase and amylase, uh, normal LFTs, and a normal transdominal abdominal ultrasound twice. Um, all done at our institution. And, and she presented again with pain and this time some elevated LFTs, um, that were mild. Uh, she had a repeat transabdominal ultrasound during her admission and was found to have a completely normal common bile duct, uh, without any evidence of cholodocholithiasis and a normal gallbladder. So we, um, went to EU US and, uh, because of the nature of her pain and concern for biliary colics, So here you're going to see us labeling the common bile duct, which looked very nice, about 2 millimeters there. And then we looked at the gallbladder and found this 5 millimeter hypeechoic shadowing stone within the gallbladder that was missed on 3 abdominal ultrasounds on cross-sectional imaging. So we do know that this is more sensitive for microlithiasis in the gallbladder and also for cholodocholithiasis and even MRI. So changing gears a little bit to pancreatic fluid collections, um, I think the most important thing is to know how we define these from a standpoint of acute fluid collections or acute necrotic collections. Those are a time course of less than 4 weeks. Um, whereas when we start talking about a pseudocyst or walled off necrosis that we might intervene on if needed, and the patient is symptomatic, uh, we're looking at a time course of greater than 4 weeks and that they have an encapsulated wall. So the mainstay of therapy for those patients with fluid collections is observation. Even large pseudocysts and Waldoff necrosis can often resolve with time. If the patient's minimally symptomatic, you can monitor them on oral nasal enteral feeding if they're doing well. Now, when do we have to go in and drain? So here's a second case, and Dr. Trout here is going to present this image for you. So this is really where, you know, the collaboration between radiology and, and our clinical colleagues is important because it's critically important that we all use the same language as David was referring to, as we're describing um the different forms of pancreatitis and the fluid collections we're seeing, because this has implications for management. So what we see here um in this 8 year old is we see Complete absence of enhancement of a large portion of the pancreas, uh, with fluid, uh, that is contiguous with this, um, area of absence enhancement and extending into the periccolic gutter on the left. So this is necrotizing pancreatitis with an acute, um, and likely peripancreatitis with an acute necrotic collection. Again, no degree of organization at this point in time. So now we move on to about 6 weeks later without any intervention, the patient was on TPM because he could not tolerate nasoenteral feeds. And what we see in this um CT image at this point, relatively similar plane at this point, coronally oriented, the fluid collection is now more well defined. And, and David laid out the criteria for defining um organized collections versus um early collections. And, and there is a time course of 4 weeks, but even more important than that, is the presence of organization or the presence of an investing wall like we see around this, um, the edge of this, because that defines uh when it's possible for our endoscopy colleagues to go in and intervene on this, on these patients. So this is now a walled-off necrosis and we see, uh, that it is abutting the dilated pancreatic duct. So this patient was quite symptomatic. Um, so what do we do if, if drainage is required? This patient's having pain, can't tolerate nasoenteral feeds, and now we've got a walled-off uh collection. So, uh, we approached this with endoscopic ultrasound and do a transgastric or transduodenal drainage. This has been shown in plenty of studies now to have lower complication rates. The length of stay is decreased when you compare it to surgical or percutaneous intervention. And if necrostectomy does become required in these patients, then endoscopic is generally preferred. Um, so this patient went on to develop this finding, uh, which Dr. Trout will show you, uh, in just a moment here. So not only when we're sort of, when we're making these diagnoses and helping um our clinical colleagues decide when to intervene based on the degree of organization of collection, but we need to be looking for other important findings that impact that. One of the most common things that we see in the context of pancreatitis is occlusion or partial occlusion of the splenic vein that can result in varices, uh, that might get in the way of an endoscopic intervention. Or even more concerning are findings like this, where we see a focus, um, a round focus of enhancement that is similar to blood pool. Um, if you, uh, were to do arterial phase imaging, this would enhance, uh, like, uh, the artery, uh, and is consistent with a, uh, pseudoaneurysm. And, and our colleagues need to be aware of this as they plan their interventions. So after this was discovered, the patient underwent a coiling of that coil embolization of that pseudoaneurysm, and here you see us going in and looking at the collection. There's some debris. Maybe after we, you know, looked at the entire lesion, there's about 10% of debris and then the rest was fluid. And in the top of your screen on the video there you see some hypeechoic content, which is actually the coils from the embolization. So you're going to see here again at the top of your screen our our stent going in. This is a metal lumin opposing metal stent. Uh, and we're going to deploy the distal flange in just a moment here. You do get a little bit of artifact from those coils, um, but we deploy the distal flange and then, uh, you're going to see us change to an endoscopic view from ultrasound to see the proximal flange of this lumin opposing metal stent deployed. And we're draining this through the, through the gastric wall. Uh, so just a moment here, you're going to see this, uh, stent deploy. And once we've deployed the, uh, the distal flange of the stent, uh, we provide tension to assure that the stent does not actually deploy all the way into the cyst. And so we're pulling, you can see that distal flange there, and then we're going to pull tension and switch to an endoscopic view. And once we switch to that endoscopic view, We're able to deploy the proximal flange of the stent. And then once we do this, uh, we get a nice drainage from the cyst. And these stents generally we leave in for about 3 to 4 weeks at a time. So, um, Pancreatic fluid collections from an endoscopic drainage standpoint, walled off necrosis, even after that index procedure where we do cyst gastrostomy or cystoodenostomy, they often resolve with time. Uh, patients with any worsening clinical symptoms after placement of lumen opposing metal stent or even sometimes we'll place a plastic double pigtail stents. at an index procedure if it's purely a pseudocyst. Uh, we need to do a step-up approach. Uh, so those patients that are not doing well, um, from an overall standpoint, endoscopic drainage is very successful in these patients. It's 90% technically successful. There is 10 to 15% morbidity, which we discussed before, 70 to 80% of patients have resolution. Of their collections and then about 10 to 15% have recurrence. Um, so this is a third case to go over here briefly, um, of, of a patient with Walddof necrosis who's 9 years old and presented to us. So just quickly here, that last case we showed you um was a CT case where we saw the um progression from the episode of necrotizing pancreatitis to development of the organized collection. This is a single, uh, MRI image, T2 weighted, highlighting the fluid-filled structures, non-fat saturated. And what we see on this MRI image is this fluid collection. along the greater curvature of the stomach that is replacing a good portion of the pancreas, and we see the collection here. And what we noticed about that collection is it has a thick investing wall, so it is organized, uh, it is a walled-off necrotic collection, and we see all this debris, um, internally within the collection here that reflects the necrotic material. MRI and ultrasound are much better at characterizing the content of these fluid collections than CT is. CT can give a false sense of simplicity, uh, to these collections, uh, but, um, in a patient with necrotizing pancreatitis, these are gonna be nec necrotic collections until proven otherwise. So this patient underwent a similar placement of aluminum opposing metal stent. It was placed, the patient was discharged home. You also see a double pigtail plastic stent through the lambs here, and that is generally placed to prevent this opposite cyst wall from collapsing onto the aluminum opposing metal stent and growing into the stent, which can make removal difficult or even dangerous for the patient. The patient was placed on nas. Adrenal feeds. A two-week follow-up, uh, we did a CT, um, and you can actually see here that there is some debris within the stent, um, and the cyst has not collapsed completely. The patient started spiking fevers. So we, uh, next stepped up our therapy. So this is a video of an endoscopic necrosectomy. So you can see our double pigtail stent here. We're going to drive towards the cyst gastrostomy site, uh, the scope, and then you actually at some point a little bit of pus coming out of this, um, and know that that that area did get infected and clogged with some debris. Um, and so with this step-up therapy, we go ahead and do an endoscopic necrostectomy. Um, so this is about, uh, after working 15 to 20 minutes, pulling some debris out, and then we're going to get a nice big necrotic chunk of pancreas to come out here, that was clogging that stent. And uh generally, I will, um, uh, irrigate this with some dilute hydrogen peroxide, uh, when we're doing this type of procedure to try to break up any of the remaining necrosis within the walled-off necrotic cyst. Um, we'll, we'll drive into the actual cyst with the scope as well and, uh, and debride some of the necrosis. We use, uh, you know, a variety of instruments, including this rattooth forceps you see here, sometimes a snare, sometimes a basket. etc. whatever is needed. It's important to be very mindful of any vessels and things like that. So this is about a week later, uh, and you see that things look much, much better here. Um, the cyst has really collapsed well. There's a lot of nice granulation tissue there. Uh, and we were able to remove this lumen opposing metal stent and then go on and place a double pigtail that'll stay there for several months while the patient continues to heal. And this patient did quite well. Uh, so in summary, endoscopic ultrasound in children is an expanding. field that allows for a lesser invasive approach for diagnosing and treating pancreatic disease, uh, including pancreatic chronic pancreatitis and its complications. I do think it's interesting that there are a couple of questions that came at the end about the role of surgical versus endoscopic management when it comes to necrotizing pancreatitis, necrotic collections. When do you consider surgical necrosectomy versus do we call the EU US. And what cases would we kind of involve? I know the surgical section is coming up next, but this is very relevant multidisciplinary related um questions. So maybe I'll have Jamie and David maybe comment on that together. Like, when would you say, David to Jamie, this is clearly your patient, I'm not going to attend. Yeah, it's actually fairly uncommon for us to do that if it's accessible via the gastric or the duodenal lumen. You know, if I have a good window and I feel like I can do a cyst gastrostomy or a cysduodenostomy, this is the way I'm going to approach it every time, you know, obviously we have to get in, we have to make sure we have an appropriate window, it's safe, etc. but once we can do that, you know, I I do feel like that's really the first line of therapy. Uh, now, you do obviously have to explain all those risks and benefits to the family because it is relatively risky compared to the other endoscopic procedures that we do. Um, but I think there's been, uh, you know, good literature in the adult world, uh, that shows that starting with endoscopic therapy is really the way to go. Um, and if it's far away from those lumens, I think, uh, you know, I can probably attest to this a little bit more. We oftentimes are thinking more about a percutaneous drain placement than actually open surgical debridement or laparoscopic surgical debridement, but Jamie can answer that a little more. Yeah, I mean, I can tell you that the last time, um, you know, I did a uh an open necrostectomy was during general surgery training about 2025 years ago. Uh, you know, things have gone, come a long way with regard to advances in, uh, less invasive approaches, specifically EUS, um, you know, even in the context, I, I, I, it's been really uncommon, even in the context of finding collections that, you know, you can't quite even reach from the lumen to do an EUS. I mean, we've, we've, it's rare now that we have encountered a patient where we've had to even do a percutaneous approach. Let alone a surgical approach, uh, you know, an open or laparoscopic surgical approach. There are a number of techniques, uh, with regard to minimally invasive, uh, surgical approaches. Uh, one is, uh, that has come into favor, uh, is sort of a video, uh, videoscopic approach through the retroperitoneum to really limit the complications of an open abdomen, uh, that we, uh, managed, you know, two decades ago, uh, um, and, uh, but, but even so, extraordinarily uncommon now. Yeah, I think it's important to say too that, you know, pediatric patients are different, right? So that, you know, there are multiple adult patients that I've taken care of where we require multi gateway technique from an endoscopic ultrasound perspective or a combined endoscopic ultrasound approach with cyst gastrostomy and percutaneous drains in the adult world because of how sick they get with their necrotizing pancreatitis. We get patients that are very Very sick from a pediatric standpoint, but I feel that we really have to step up the therapy quite frequently less in our pediatric patients. Now there's no data on this. This is just anecdotal, but I think that's an important point to make that, you know, if somebody's watching this and saying, oh, what are they doing? You know, they're never putting percutaneous drains in, never doing this. Our patients tend to do really well once we drain them internally. Sounds great. So on this positive note, we are gonna end module two, but the positive note is that maybe EU US is gonna put surgery out of practice when it comes to necrostectomy. So, so it's a great job everyone. We will give a 5 minute break and then reconvene with module number 3. Thank you. All right, so we're gonna be starting our 3rd module here. Uh, we'll be presented by Doctor Lynn, Doctor Nathan, Doctor Abu Al Haja on, uh, total pancreatectomy with eyelet autotransplantation in children. Great. So objectives, um, So, um, from this, uh, surgical, uh, module we're gonna identify the options and decision-making approach for surgical management and of debilitating pancreatitis in children. Um, also plan on summarizing the techniques and complications of TPIATO total pancreatectomy in kids and then finally to analyze the outcome and future directions of total pancreatectomy in children too as well. So we'll start this module off with uh a case demonstration that'll lead into our, our overall discussion. So this was a 14-year-old female referred from Texas as a second opinion for our, our pancreas care center for essentially a pre-TPIT assessment. Um, so she has a history of a lifetime, um, occurrence of recurrent pancreatitis episodes, um, on a very, very frequent basis. Um, genetic testing identified her to be having a, a heterozygous spin one mutation. Um, she presented to us as a second opinion with daily abdominal pain requiring frequent use of tramadol, um, as well as ketorolac. Pain severity and frequency resulted in, um, significant impact on her daily life including the need for homeschooling as well as the disruption in her normal daily activities including her play activities. So prior therapeutic ERCP interventions, unfortunately, were not of clinical benefit in this situation. Thanks, Tom. So, what I'd like to talk about first is just the concepts of an operation for chronic pancreatitis. Uh, the reality is that well over 50% of patients with chronic pancreatitis eventually require some type of operation. Classic indications are obstruction of the bile duct or duodenal obstruction, uh, the presence of pseudocysts that cannot be managed endoscopically, as you just heard about from, uh, David in the last session. Susp suspicion of malignancy, that's a much uh less common indication for an operation in children with chronic pancreatitis compared to adults. But really what remains the most common indication for an operation in chronic pancreatitis is debilitating pain. Pain that fails to respond to medical and endoscopic uh treatment options. So, what is the approach to surgery in general? Preoperative assessment of the anatomy and morphology of disease is critical, and really that's what helps to determine the most appropriate surgical procedure, uh, as well as in part, uh, uh, underlying risk factors, and we'll get into that. There's really no surgical uh procedure, uh, in and of itself that can be recommended to every single patient, of course, with chronic pancreatitis. And so, when we talk about anatomy and morphology of a disease, you know, the classic, uh, findings, uh, related to the duct are quote unquote large duct disease. So you have a, a large dilated main pancreatic duct over the course of the, uh, gland from head to tail, uh, and classically, historically, this has been addressed with a surgical drainage operation or a modified puste. Um, I will note that, uh, uh, nowadays, um, Pousteau is really falling out of favor as a surgical drainage procedure, uh, and being replaced by a Fry procedure, uh, which, uh, adds some additional coring out of the head of the pancreas, and that's, uh, that's really been, uh, what has occurred over the last several years with regard to surgical drainage procedures. Uh, inflammatory head masses. So, uh, patients may present with an inflammatory head mass, uh, in that head of the pancreas, that is termed the pacemaker of disease. Uh, and the concept is, is resection of that inflammatory head mass, whether it's by the standard classic Whipple pancreatic oduodenectomy, or by the newer approaches, the duodenum preserving pancreatic head resections, the bagger, the burn in the fry, uh, those components or those operations really now are Especially in children, uh, being considered, uh, more readily than a Whipple procedure for a patient that has a dominant pancreatic head mass. Uh, the reality is, is that these findings, the large dilated duct or the pancreatic, uh, head mass, are generally speaking fairly uncommon in the pediatric patient with chronic pancreatitis, as opposed to the adult population, where these anatomic findings make these considerations, uh, a potential reality. Uh, and then, of course, you might have just a focal disease in the tail of the pancreas with a, a focal stricture way out, uh, distally, and you might consider simply a distal pancreatectomy. Now, conventional operations, as I've just described, uh, for CP do result in initial pain relief in a number of patients, but honestly, pain recurs in approximately 50% of patients over the long term, and we have to recognize that this is an issue. And so, the failure of a prior conventional operation, uh, is an indication for total pancreatectomy with autotransplant. And as well, debilitating chronic pancreatitis or acute recurrent pancreatitis without a conventional surgical option. They don't have the head mass, they don't have a large dilated duct, um, and they are termed small duct disease, which is the preponderance of CP in children. Those patients directly may be considered for TPIAT. So, TPIT was first performed in the late 1980s at Minnesota, and it's it's extremely important to recognize that the primary goal is to relieve the pain and debilitation and impaired quality of life. That is the primary goal. It's not to preserve or save eyelets, uh, for, uh, um, in terms of viability concerns, etc. It is to relieve the pain. Pain and the debilitation. The goal of the islet auto-transplant component is, of course, to preserve beta cell mass and frankly, alpha cell mass as well, uh, to really, uh, make glycemic control, uh, more straightforward than if you did not provide the islet, uh, auto-transplant component of the operation. Now, this, uh, obviously takes a significant, uh, um, commitment from a number of different disciplines, as you can see on the slide, uh, certainly, uh, surgery, gastroenterology, endocrinology. Endocrine obviously plays an important component in, uh, understanding the underlying, uh, uh, glycemic control as a starter. Uh, is there type one diabetes present, etc. Um, genetics, as, as we all know, plays a role. Are there genetic risk factors. Um, and it is very clear that, uh, children with genetic risk factors, uh, tend to fail conventional surgeries, uh, more, more often than those without genetic risk factors. And so, we're, so even if you have a, a child that has Um, a big dilated duct. Um, we now are more reticent to, uh, offer a surgical drainage procedure rather than a TPIT because those outcomes, uh, clearly are not as good in those with genetic risk factors. Obviously, we need a radiologist like Doctor Trout, the fine Doctor Trout to help us, uh, with vascular anatomy, liver volumes, etc. and then pain physicians, pain psychologists, uh, because there's significant need for Improving, uh, coping, uh, in these children who are chronically ill. Uh, social work, nutritionists, uh, nurses in all of the realms, uh, of course, are critically important. Uh, and then, of course, if we're really heading toward a TPIT, uh, since it does involve a splenectomy, uh, we talk about, uh, vaccinations for, uh, overwhelming post splenectomy infection, prophylaxis, and then does the patient have an underlying bleeding or clotting tendency. I'm not going to belabor this slide. These are diagnostic considerations. Obviously, we need objective criteria to be met for the diagnosis of CP and you could see those on the slide. I won't go through them. You've heard about them already in the prior two talks. What are the criteria for consideration of a TPIT in general? So, again, objective diagnostic criteria must be met for CP or ARP with pain and debilitation that has lasted for at least 6 months. And how do we define pain and debilitation? Well, either chronic opioid dependence, um, or, um, patient doesn't need to be on chronic opioids, but simply they have impaired quality of life because of frequent hospitalizations. Hospitalizations every month or 2, continuously, um, school absences, uh, etc. So, uh, either of these criteria, they have to have failed medical, uh, and endoscopic interventions maximally. Absence of a reversible cause of pancreatitis. Obviously, we have to ensure that there are no psychosocial or physiologic contraindications. Uh, and frankly, uh, patients need to, uh, recognize, and, uh, patients and families, they need to recognize that there is a risk of lifelong diabetes, uh, with this operation. And I'll, we'll get into the outcomes later in the talk. Uh, and we, uh, certainly want to assess that beta cell function, uh, upfront. Uh, and if we're talking about a type one diabetic with a, a nose, uh, C-peptide response to a mixed meal test, uh, we have to think about really, are we gonna auto transplant those islets. So, preoperative considerations again, bleeding, clotting disorders, nutritional status needs to be optimized, immunizations up to date, other comorbidities addressed, um, any, uh, presence of local issues, prior pancreatic, uh, operations, presence of pseudocysts, and liver volume. We do have a minimum of 400 cc's for the small child, and so, um, uh, and to accept the eyelet auto transplant, and so we do have, uh, um, 3D reconstructions to assess that. Uh, liver volume in the smallest of children, the 2 year olds and the 3-year-olds, to make sure we've reached that threshold before proceeding with the TPIT. Is there any underlying fibrosis present, critically important, uh, patency of vessels. So what does the procedure entail? Obviously, total pancreatectomy, partial duodenectomy, we do preserve the pylorus and D1. Uh, as I mentioned, for technical reasons, we perform a splenectomy, uh, as well. We remove the gallbladder, we remove the appendix, and we do place a gastrodugeneral feeding tube for early postoperative feeding distally in the GI tract. What is the goal of the eyelet isolation? Obviously, the goal of that component of the operation is to digest the pancreas, remove, disrupt as much exocrine tissue as we possibly can, to release a relatively pure eyelet, um, uh, solution, uh, in as small a tissue volume as possible, uh, because this does relate to risk of, uh, complications such as portal vein thrombosis, when you have a very significantly high tissue volume, you're infusing it to the portal venous system. Uh, and this process of eyelet isolation is a combination of mechanical digestion, as well as enzymatic digestion, uh, termed the recording method. It takes about 3 or 4 hours, 4, 4.5 hours, and we assess that pellet for account and viability, uh, thereafter, uh, prior to infusing. During that, uh, eyelid isolation, we are reconstructing the bile duct with a rune Y, uh, biliary enteric anastomosis, uh, and then as well, reconstructing the, the alimentary side of things with another rune Y duodenojuginostomy. When those eyelets come back to us, we do infuse them via a small splenic vein, uh, stump that we've left, uh, uh, versus direct puncture of the portal vein. Uh, as I mentioned, with significant tissue volume, those portal pressures, uh, will increase substantially and may increase the risk of portal vein thrombosis. So, we do heparinize, we do measure portal pressures, uh, every 5 minutes during the infusion. And when we have a very significantly high pressure change of greater than 25 centimeters of water pressure, that actually is associated with a 10-fold increased risk of portal vein thrombosis. If those pressures rise in the portal venous system substantially, we pause the infusion, we allow auto regulation to occur, uh, and we usually can keep going and keep infusing eyelets. If those portal vein pressures remain elevated, we put those eyelets in the secondary site, very often the peritoneal cavity. What do we do postoperatively? Uh, for monitoring in the PICU, we obviously surveil for, uh, uh, evidence of thrombus in the portal vein system with the Doppler ultrasound. We continue anticoagulation as well as some anti-inflammatory approaches to decrease the, uh, instant blood mediated inflammatory reaction of the eyelid that's caused by the eyelid infusion. Uh, and then critically important is, uh, managing blood glucoses, and we keep blood glucoses very tight, uh, for in the ICU as well as in the early postoperative period, over the course of several weeks to months, as those islets engraft, because hyperglycemia is very detrimental to the islets. Uh, we utilize continuous glucose monitoring as well as an additional tool. Uh, antibiotics, of course, uh, are, are maintained, uh, for several days because of, uh, the, the point that these eyelets, uh, are often coming out of a, uh, infected, uh, uh, pancreas or, um, a contaminated pancreas because of prior ERCPs and stenting. Uh, we advance feeds early on in the first several days after, uh, operation, and by the end of, uh, one week in the ICU we're at full feeds, and we transition out of the ICU. Uh, to, um, uh, uh, the endocrine floor on the surgical surface, where patients are then transitioned to an insulin pump. Pain management cannot be overstated. Uh, every patient has a very unique and individualized, uh, pain management, uh, plan. So, on the floor, uh, over those, uh, generally speaking, 7 to 10 days, uh, there's a lot of teaching that goes on, diabetes and insulin education, uh, feeding tube education, enteral pump teaching, continuous glucose monitor teaching. Um, to speak just briefly about surgical complications, it's a big operation. There's no question. Uh, it is a balance between bleeding and clotting. Both risks are generally speaking quite low, uh, but, uh, they are important considerations. Probably one of the larger more common things we encounter is wound infections, uh, perhaps, um, bowel obstruction related to adhesions, uh, do occur, um, uh, but are somewhat unpredictable. Um, and there's a small risk of anything we sew together can leak, whether it's the bile duct or the GI anastomosis. Uh, I will say in our experience, we've never had an enteric or bile duct leak, uh, in any of our patients. Every patient does get a systemic inflammatory response syndrome that lasts for several days to even upwards of a week. Uh, and really, every patient has some degree of delayed gastric emptying, uh, and hence the need for downstream feeds via the J portion of the GJ tube. And then on rare occasion, we encounter anastomotic ulcers, some gastritis, uh, down the line in the postoperative uh time frame. Our patients get discharged locally after 2, 2.5 weeks, and they stay locally in our Ronald McDonald house for several weeks. We have very routine follow-up, uh, in that first year, as well as thereafter. And there are a number of components that need to be managed, uh, in the postoperative time frame as outpatient, and I'll transition to Doctor Haija to discuss that component. Great. So moving on to outpatient management, we uh have developed protocols to make things very regimented. And in general, the theme is that you continue to advance feeds via the J tube. Um, we use polymeric or partially hydrolyzed formula, no preference there. By all means, the patients have exocrine insufficiency, so they need pancreatic enzyme replacement therapy with the tube feeds as well as with the PO ad lib regimen. We do use the, uh, parts to match fat content, body weight, or even adjust it based on the symptoms, diarrhea or oily stool or, um, their weight gain. Um, while we allow the window for PO feeds and PO intake, um, more by weaning the J tube feeds, we see in the immediate weeks post-op that there's more oral intake and less J-tube dependency, and they really do great, and the young ones sometimes they could be weaned off J-tube feeds as soon as 2 to 3 weeks post-operation, but of course the patients will have more prolonged need for the J tube feeds and we keep them on those longer. Um, we watch for ongoing needs for nutrition that is balanced, diversified in the caloric, um, sources, and then, um, we monitor for fat-soluble vitamin deficiencies, mainly ADEK, um, and then folate iron because of the resection of the small bowel portion, um, which is in the duodenum and vitamin B12, which has been reported in pancreatic insufficiency in general. Uh, long-term monitoring is needed for their, um, nutritional, um, needs. Next slide, please. So in terms of GI symptoms, the gastroparesis and dysmotility has been reported in chronic pancreatitis patients, but also post total pancreatectomy autotransplantation. These papers have looked at um the need for prokinetics, um, and, and we've noticed that too, that they need, um, for their gastroparesis prokinetics early postoperatively. So we use cyproheptadine, methclopramide, erythromycin, amoxicillin, and then we. When the gastric emptying goes back to normal. Sometimes in extreme cases we have needed pyloric dilation and uh Botox injection by EGD. Other GI symptoms are also reported, um, despite the perfect PER dosing, those patients sometimes do have ciatora problems, um, or diarrhea or constipation. So you tailor the management according to the symptoms, and sometimes it's related to the post-operative. Opioid use. Next slide please. In terms of the fat soluble vitamin deficiency, as we know, it comes with a condition of exocrine pancreatic insufficiency. So we monitor for those every 6 months, but also if we replete one of the vitamins, then we monitor for that 3 months after the depletion. We do have protocols for that as well, so that we don't uh miss subtle vitamin deficiencies that could be very, very important for. Red cell functioning or bone health and so on. For folate and iron monitoring, it's the same thing, and then the same is for vitamin B12 monitoring. So folate, iron, and vitamin B12 don't get supplemented, but they are per routine, but they are supplemented according to the deficiency or the need. The fat soluble vitamin deficiencies, every patient is on those. Next slide. So bone disease is prevalent. Um, we didn't know that until more and more reports have come up, and it's been shown in the study that osteopenia was present in 45% and osteoporosis was present in 10% in a chronic pancreatitis population from the Netherlands. Next slide. Endocrine management is key and in the endocrine team as we um advance the feeds or wean the feeds that has direct implication on insulin needs. We work with a group of endocrinologists, the MD provider, as well as diabetes educators, um, and then dietitians and social workers to maintain that. Next. So the insulin infusions, as you heard from Doctor Nathan start as early as the eyelet transplantation, and that's monitored very closely throughout their inpatient stay but also throughout their outpatient, um, because the initial phase is very important to ensure eyelet rest and engraftment. Um, we also know that the islets do not resume the full function immediately, so their nutrients and, um, oxygen diffusion, it, it doesn't occur until weeks to months later. So the tight glucose control is very, very important to prevent from toxic hyperglycemia, so that's why we keep it within range. Next. We utilize the continuous glucose monitoring following the TPIAT because that has been shown that it's very closely correlating with the um finger sticks and the accuracy of the serum blood glucose as we show in the first figure on the left, is that 88% of the time in the study we have shown that the the um. Continuous glucose monitoring had a time matched pair values in the zone A, which is the desirable agreement, and we showed the same thing in the um in the figure on the right. So, and right now we have different uh continuous glucose monitoring, so um the, there's a newer version that's on the market and we are using that as well. Next, please. So we wanna avoid hyperglycemia because it does have an implication of it's through animal studies or even from human-related data that if they run into hyperglycemia, it could induce beta cell toxicity and those eyelets could die and not function or engraft on the long term. So we monitor the blood glucose, um, and we have the data sent to the team at frequent intervals, and having continuous glucose monitoring would make the download of the data and the transfer very easily and seamless. And then they make active changes in the basal or bolus dosing. The usual theme is that we wean the exogenous insulin as the eyelets are waking up and functioning, and we know that through the patients running into lower glucose and needing lower oxygen. Exogenous insulin supplementation. We do also perform, uh, mixed meal testing at 36, and 9, and 12 months, 18 months, and then yearly after to kind of help us guide that therapy. The majority of the blood glucoses have to be within range, and when we mean insulin over time, we want to see that the fasting blood glucose is less than 126 and that the postprandial is less than 180 and that the hemoglobin A1C is less than 6.5%. And education is a big part of what we do. So, um, through handouts to the patients, they are educated of what is a, a lower glycemic index compared to the yellow and the red zones as you see here that have higher glycemic index. So it's not just much about what is the amount of carbs that they eat, but also the type of the carbs that they consume that could help protect those eyelids. In terms of pain management, and we covered that initially through the medical management, it continues to be important post TPIT because the goal of these patients have been on opioids for months or years leading to the surgery, so everybody's desired outcome is to get them off that dependency or the need for opioids. So really it's that they under. Go by pain team assessment by the physician, medication management, as well as intervention is needed. A psychologist is always paired with a team and it helps with coping and functional and emotional impact assessment, um, the role of anxiety and depression, and then the cognitive behavioral therapy as part of it, and then nursing helps with all of the above. Again, education to and expectations for them to meet the goals and then with pain management is also um education regarding available therapies and the rationale. CBT is a huge, it's really pain-focused and it helps those patients get off medications and assess for the Comorbidities or maybe the hurdles that could prevent them from achieving those goals. And then we use integrative medicine therapies through our pain team as needed for the patients and those could be presented as part of the therapy like acupuncture, yoga, massage, and, and other uh um terms. So it's really a latter approach. NSAIDs and Iminofe has a role, opioids, there's a consent or maybe a contract between the physician and the um patient, and then there's a risk assessment form. It's very regulated, especially with the epidemic and. Um, that's opioid epidemic all over the country. And then, um, we subs our pain team uses pain medications that could be opioid sparing, uh, like amitriptyline after they um um obtain an EKG or gabapentin even to try to wean the opioids. They get follow-up in the pain clinic until they are weaned off all pain meds. So if the patient is on any pain meds at all of these intervals, they see the pain medica uh, the pain doctors as well, as well as the pain psychologist. Physical therapy is very important because these patients sometimes are deconditioned and they need that, uh, structured physical activity as part of their rehab, and then they may resume integrative medicine techniques as desired. Hematology, we've seen thrombocytosis as part of this, and the platelet counts could rise to more, even 1 million, more than what you see in splenectomy cases that could be in sickle cell disease patients, for instance. And our hypothesis, and we've been working on this as an area of research, um, that the increased thromboweidin that is generated by the liver could be a mechanism driving this. Next slide. This is from an earlier publication that we showed that the thromboplatin level in red rise preceding the thrombocytosis that happens in these patients. But sometimes, um, we also could predict when these patients, as their TPO levels decrease, how long would they be dependent on the medication that we use to lower the platelet counts, which is the uh hydroxyurea. Next slide. This is a care map that we have uh made available for our patients as part of their anticipation and planning. It's available on our websites and easily accessible. They want to see what is expected during each visit that they have. So, I will pick back up and move on to outcomes. So, what do children who have undergone uh TBIT uh expect uh in their postoperative course? So, this is a study, um, that was early in our experience. On our 1st 20 patients, um, we're now up to doing about 20 patients per year, um, where we really looked at early outcomes in the 1st 90 days after TPIT, uh, for, uh, patients with chronic, children with chronic, uh, or acute recurrent pancreatitis. And, um, as you can see here, even within 90 days, this is opioid use, and so you can see a dramatic decrease, a significant decrease, even after the 1st 90 days, um, in terms of weaning of uh patients' opioid needs. Um, as you can see, it's a long-term process, though. Many of these patients come into us having been on chronic opioids for over 1 year, it's sometimes several years, and uh that just speaks to the need for, uh, patients in terms of weaning, uh, the opioids over an extended period of time after TPIT. Um, a little bit different than adults, uh, something unique in children, um, with chronic pancreatitis is nutritional challenges. Um, we have a very, have had a substantial, uh, component, uh, cohort of patients who have required TPN, who have required enteral nutritional supplementation or combination. Uh, prior to TPIT, and you could see by 90 days post-op, uh, we, uh, have gotten a, a dramatic improvement in terms of, uh, how we are providing, uh, nutrition to these children, uh, and, in fact, getting patients off of, uh, TPN, uh, who required it prior to TPIAT. Insulin requirements, while you've already heard, um, during this talk that, you know, the, those islets uh take uh weeks to months to really, um, start to function, uh, and they can be unpredictable. Uh, and that being said, Even in this study, we found that by 90 days after surgery, there was a decrease in, uh, insulin, number of units per kilogram of body weight per day required, um, by, uh, from the perspective of exogenous supplementation. And this is quality of life outcomes. So, uh, for kids under 12, uh SF 10 is the tool that we utilize for patients over 12, the SF 36, uh, and you can see even by 90 days after surgery, there are improvements in physical health scores in the SF 10 and SF 36, uh, as well as a, a significant improvement in the total SF 36 score. So, even by 90 days, we are seeing improvements in quality of life after TPIT in children. This study, uh, is from a few years ago, um, that highlights some longer term, uh, outcomes in the pediatric population. Uh, and you can see here, uh, on the left is a reduction in opioid use. Uh, and you could see that decrease in uh occurs pretty quickly over the 1st 6 months or so. And, and that is, um, a sustained effect, uh, over time. But you can also see that there are a percentage of patients that, uh, really, uh, continue on opioids. And so, the question always is, is, you know, are we offering a TPIT too late after patients have already gotten to the point where they have central sensitization. Uh, sort of that, uh, uh, a phantom type, uh, um, issue with reprogramming of sensory neurons, and so you've, uh, missed the opportunity to really help these patients. And likewise on the right is pancreatitis pain. You could see a dramatic improvement within the 1st 6 to 12 months, uh, and again, that is also, uh, uh, sustained over time. Improvement in lost school days, uh, is, um, uh, clearly, uh, we see as patients are feeling much better, they get back to school uh routinely. What about eyelet function and glycemic control? Uh, you can see here on the left, this is insulin independence rates, uh, broken down in age groups. So, you see the dark line is, uh, children between 13 and 19, and the dotted line is children that are younger, under 12. And you can see that they're that younger children are more likely to achieve insulin independence. You can see at 12 months in this study. Uh, a rate of about 30 or 35% in older children, uh, and, but in younger children under 12, you see that rate approach 50 to 60% at one year, and you could see insulin independence rates, uh, or insulin independence, uh, is also, uh, sustainable over time, as you can see on the right. This is insulin independence, uh, over time. Now, insulin independence is largely associated or can be predicted by the number of eyelid equivalents per kilogram body weight that we, uh, that are isolated out of that pancreas at the time of operation. Uh, and you can see here, uh, that, uh, eyelid equivalence is essentially eyelet mass that we standardize to the size of a medium-sized eyelid, 150 microns. And you can see insulin independence rates at 3 years uh increase as you have a greater number of eyelets, uh, eyelet equivalents per kilogram body weight that have been auto-transplanted. Now, uh, very importantly, and I already highlighted this, uh, in a prior slide, uh, this is a study looking at kids even younger, those under 8, most of which, again, had genetic risk factors, very high eyelet equivalent per kilogram, uh, uh yield, uh, over 6000, the median. You can see that all of these patients had pain relief by 1 year and were free of opioids by a meeting of 68 days. And you could see that over 80% of kids under 8 achieved at least a period of insulin independence. Uh, and when you can compare, uh, overall independence at most recent follow-up, uh, that was 64% were insulin independent compared to kids over 9, where it was only 41%. But the reality is, is that we do need longer term follow-up for insulin outcomes. Why do younger children do better with regard to insulin, uh, independence? Uh, it is perceived, basically, uh, one factor is that younger kids have a better metabolic milieu for engraftment, perhaps, and they have lower insulin demands. Um, but there are also another couple of hypotheses, which is that beta cells from the pancreas of a young child, uh, have a higher capacity to replicate. And so, you know, are these beta cells actually replicating after they engraft, uh, and providing a greater opportunity. For, uh, insulin independence, or are there other sources of islet neogenesis, such as, uh, components that are of ductal origin or stem cells, uh, that are getting auto-transplanted, that might also be a source, uh, contributing to insulin independence. Now, as I mentioned already, insulin independence correlates with number of eyelet equivalents per kilogram body weight transplanted. We know from a number of retrospective studies that there's a relationship between eyelet yield and imaging. So, more substantial atrophy, more substantial ductal dilation correlates with lower eyelet yield. Uh, increased fibrosis on final histopathology correlates with lower eyelet yield. Duration of symptoms, longer duration of symptoms correlates with lower eyelet yield. So really, we have to start to consider what is the role of or of these factors in the um in the care of a chronic pancreatitis patient in regards to patient selection and timing of offering TPIT. And we certainly know that ductal drainage procedures such as a puste, as well as resections, particularly distal resections, distal pancreatectomies, reduce eyelet yield and decrease the probability of insulin independence if a patient then needs to head to a TPIAT or completion pancreatectomy. Uh, and so we really have to be cautious about, uh, um, what we are offering, the types of operations we're offering in patients, particularly with genetic risk factors, who tend to fail these conventional operations. So, where are we going, just to finish up, there are a number of gaps in this field, Obviously, predictive modeling, uh, you know, how do we, uh, determine or predict who will have the optimal pain quality of life outcomes after TPIT. Post is a multi-center consortium, of which we are one center that is enrolling patients to really try to determine what are the patient and disease characteristics that are Associated with the most favorable outcomes in health-related quality of life and pain, uh, relief, uh, and also, uh, with regard to insulin independence. Uh, also, a component of this study is, uh, to assess whether TPIT is cost-effective. Does central sensitization impact pain resolution? All of these we're hoping to answer with this study that is currently in progress continuing to enroll patients. What about other gaps? So, eyelet assessment, how do we assess functional quality at the time of Of eyelet isolation. So, work being done on determining whether oxygen consumption rates can predict eyelet, uh, quality at the time of isolation. Are there biomarkers such as microRNAs that may predict eyelet damage and thereby be predictors of poor outcomes after uh TPIAT? Uh, and then what about other sites, uh, for for implantation of the eyelets? So, as I mentioned, placing these eyelets in the liver, it makes the most physiologic sense, but it does induce a substantial instant blood mediated inflammatory response and local eyelet injury as they are trying to engraft. So, other, other sites that we need to be considering, peritoneum, intramuscular, subcutaneous sites. Uh, other sites such as this is one of our patients where we used Omentum and basically created an omental envelope for, uh, auto-transplantation of these, uh, of a number of these islets. And of course, clinical trials are critically important to move this field forward. How do we optimize and uh engraftment and function, uh, and assess uh alternative sites, uh, for auto-transplantation. So, in conclusion, in appropriately selected children, TPIT does achieve durable pain relief and improves quality of life with manageable glycemic control. Uh, we really stress the importance of a comprehensive multidisciplinary team approach to ensure optimal outcomes, and we need more research in this field, research regarding management of pain to develop predictive modeling, uh, as well as, uh, optimizing eyelid engraftment function and durability, as well as biomarkers. So, with that, uh, I'll finish and happy to take, uh, questions. Great. Thank you. Thank you very much, Jamie, uh, and my son and Tom. Um, so, uh, uh, just one, we have only a couple of minutes here for questions. So I'll just be brief. Uh, but one question about the durability of violets you just recently brought up. So, so how do you answer that, you know, when we don't have that sort of very long-term data when families ask those kind of questions? Yeah, so, um, critically important, and, and, and, um, I, we, we always stress, um, it is, we cannot predict, we cannot predict, uh, if that patient, uh looking them in the face in the clinic, whether that patient is gonna come off of insulin or not. It would, it would be disingenuous to try to predict that or to try to promise that, I should say. Uh, we obviously want to try to predict. Um, and, and so, the reality is, is that the data that we have, um, there is attrition. We know that from adult data, uh, adult patients that have gone through TPIT. You look at the 10-year data now, that, that has been published, uh, and in that study, Um, it's predominantly adults, very few children in that, and so I didn't bring it up. But there is attrition, and so rates over time at 10 years dropped from about 30 to 30 early, um, low 30s% of insulin independence, um, to down to about the low 20s. Uh, so, there is, there is attrition. But can we say, if you're insulin independent today, are you gonna lose that independence at 5 years, 10 years, etc. Very, very hard to predict and promise. Sure. And then, and then one other question, uh, regarding patients who may, may have some genetic cause of their pancreatitis, uh, who have previously undergone another surgical intervention. Are there, uh, prior surgeries that may exclude them from being able to undergo a TPIT? And how do you, uh, how do you, um, uh, speak with families about that and other providers? Right. So very important. And this is why, um, you know, we, we have just finished submitting a paper. Uh, regarding, uh, surgical approaches for chronic pancreatitis, conventional NTPIT, and really tried to lay out an algorithm algorithm for how, how we counsel how we we believe we should be counseling patients. You know, that's the little data that we have does certainly does suggest that patients with genetic risk factors tend to not do well from a pain and debilitation improvement after a conventional, a non-TPIT operation. Uh, and so, uh, we are very reticent to offer those operations. Now, having had one of those operations, does that limit the ability to offer a completion TPIT? Um, um, no, it does not, it, it's not a contraindication. Uh, it might make this operation a little bit more lengthy because of additional scar, um. But we are definitely upfront with the concept that if you've had, if that patient has had a surgical drainage procedure, for example, a pusteau or a distal pancreatectomy, you can absolutely predict that those patients, um, will have a lower eyelet yield, and that's the reality that that families have to recognize. Um, but I will tell you, you know, have we had teenagers that have had a pusteau that had a really, really marginal eyelet yield that came off of insulin? We have, of course. OK, great questions and session. Um, I do think we did reach our time mark, um, to finish. Thank you, um, for all the speakers, uh, for Global Cat MD for hosting us. This has been really fantastic. Hopefully all the people who attended, um, our colleagues, uh, we will take the questions that we couldn't get to as well here and try to address those in emails. Thank you for providing your emails and reach out. Um, for any collaboration or help needed with your patient care. Thank you, everyone. Have a great evening, afternoon, night, wherever you are in the world. Thank you.