Update Course 2023 - Updates in Pancreatitis

Welcome to the afternoon session of the update course. Uh, I'm Sean Saint Peter. I'm happy to introduce Juan Gurria from Cincinnati. He's gonna be talking about pancreatitis and some of the plaguing pancreatic conditions. Take it away, Will. Thanks, Sean. Um, I hope, uh, everybody's light pace right after lunch is not too elevated. If so, let me know. Um, I'm gonna talk a little bit of, uh, acute pancreatitis, but the hope is to move forward into chronic pancreatitis and talk a little bit of the, uh, surgical options. Um. So, I put, oh, you guys cannot see, but I could, I put this on, on, on purpose because it is very important nowadays to feed the pancreas, even when there's pancreatitis. There's a lot of, you know, remember they, they used to tell you, put the patient NPO, throw him in the ICU and, and fluid his lungs, right? So we don't do that anymore. And there's been A lot of changes, a lot of things in, in the world. There's a lot of people in Europe making tremendous contributions to the field of pancreatitis. Um, our, uh, Pancreas Center for Excellence in Cincinnati Children's is a wonderful team, and you cannot take care of a pancreas without a wonderful team. So, I appreciate their help. I'm only one part of that massive team. Um. So jumping into it, um, we have a 9 year old female with ALL, uh, comes to the ER with acute severe abdominal pain. Um, you get, you get those, those numbers, uh, with the elevated AST, dropping hematocrit, lipase of 9000, um, a little bit tachycardic. Um, that's your CT scan. So, You know, you have a clear uh acute edematous pancreatitis there, uh, not a lot of free fluid in the pelvis, if you ask, there's no signs of bleeding, it's just a bad, bad, bad attack of pancreatitis. We're, so we're a little on the lower side for blood pressure and heart rate is 160 for a nine year old. Uh, it's not advancing. All right. So, the plan is floor, NPO antibiotics, pain control, or ICU with different settings there, bolus x 3, maintenance IV fluids x 3, no antibiotics, pain control, PIQ bolus times 2, IV fluids times 2 of the rate. With antibiotics, pain control, or bolus times 2, main a side fluids 1.5, no antibiotics pain control, or ED and then discharge from ED once they start tolerating PO. What do you think? Who, who has taken care of pancreatitis recently or they all go to medical teams? Surgeries. Yeah, so that's the thing, like if appendicitis was up there, everyone was shouting out their answers. I don't hear much now. Pick you, who would send to the pick you? So I would, cause, yeah, heart, heart rate of 160 and a low blood pressure, who would give antibiotics? Acute pancreatitis. No, no antibiotics. Come on. All right. And what were the other things? Were those the only two main questions? How much fluid, how much fluid we give? 6 L until the all right, let's see. Uh, let's see what people. It's saying out there. All right, there's a lot of different things. Some people will send home from the ED, tachycardia and hypotensive, it's all over the place, um. Some people will give, or divided a group with antibiotics or no antibiotics. I like it. OK. Let's talk about it. So, Doctor Cortal was correct. Um, maintenance in half. So, we're going to the ICU, right? This patient is not humanomically normal, right? Acute pancreatitis could be fatal. If you guys remember, your, uh, adult VA, uh, patients with pancreatitis can get really, really sick, right? So, bolus times 2 is adequate, uh, fluid maintenance.5 once you pass that early phase of acute resuscitation. Remember that pancreatitis is a state of uh hypoxia. You need to re-establish the intravascular flow to the pancreas to prevent hypoxia, necrosis. Atrophic pancreas insufficiency, so you, you have to stop that right away. So early fluoridation, it's, it's the key. However, you cannot be too aggressive with fluids. Now there's no reason to give antibiotics anymore at all for pancreatitis, even in the face of world of necrosis or necrotizing pancreatitis, unless there are signs of sepsis infected pancreatitis, which is a different beast, OK? hypotensive and tachycardic. I, I wouldn't give this patient anti antibiotics, but how do you know that they're not septic because they, because they have a port, right? They have a port, and you're like, maybe it's a port infected now, or maybe it's they're super infected clinical consideration, of course, like if there's, you know, you have ALL, probably good peg peg asparaginase, right? You have, you can put those together and they have a CT scan with pancreatitis and other signs of sepsis, no need for antibiotics now. Uh, uh, my oncology wife will say otherwise and I'll be like the oncologist is gonna let you give this. So if, if the patient, you know, last week was a neutropenic, that's a different story, right? You will consider antibiotics, but get rid of them as soon as that, that is, uh, uh, taken care of. But if there was like gas or something else on. Correct. That's correct. So, uh, there was a position paper from the North American Society of, uh, Pancreatitis, uh, uh, GI Pathology and Nutrition, um, stating some of the, uh, guideline recommendations. So, when we talk early fluids, better outcomes as a concept. However, how much, so bowls 1010 to 20 per kilo, up to 3 L the 1st 24 hours, even if you can stop it at the 12-hour mark and reassess with urine output and, and, um. And, and vital signs is always better. You cannot uh flow these lungs too much because the outcomes are worse, OK? So, 1.5 to 2 times maintenance, yes, but reassess at 1224 hour mark. Um, there's a lot of uh work being done right now in which type of fluid is the best for for pancreatitis. It's been shown that LR decreases the incidence of uh the inflammatory response and C, C-reactive protein at, at 24 hours. Compared to NS, right, so a lot of people say they're like, well, uh, too much LR, you'll give like acidosis. That's, that, that's not a thing that's out of the, uh, out of the question anymore in the surgical critical care world. Um, if there's, uh, if their albumin is low, uh, please give albumin as well. Any, any questions so far there? Anybody who disagrees? Should this is who here gets called for this at their hospital, or is this go to medics go to peds? You get who, which surgeons get called for acute pancreatitis? Looks like 4 of you. So the rest, I guess, go to pediatrics or we'll we'll be the consulting service, not the, not the, not the primary admitting service. Yeah. You're OK. All right, yeah, so I think surgery should be involved in, in this case of bad pancreatitis, um, as a concept. Um, there was a very, very important, um, uh, uh, um, RCT by, uh, one of our wonderful colleagues from Spain, Enri Enrique de Madaria, wonderful guy, and he, they did a multi-center all over the world trial, they call it the. A full trial to say, to try to see who, um, who's getting too much fluid, basically. So they gave moderate or, or a lot of fluid, uh, clearly, of course, uh, they had to stop the trial on, uh, sooner because the patient's getting too much fluid or getting, uh, organ failure. Uh, how is this not working? Oh, all right. So, they were getting fluid overload, uh, uh, or, um, uh, multi-system organ failure, necrosis, and, and, and they were dying a little bit more. So this is adult data, uh, by the way. I'm gonna skip over this graph because it's just saying the same thing, um, so. Next one. So this is what I was talking about. So, Enrique de Madare in Spain, he's, he's following this with a Waterland trial to see whether in fact ER is better than, than NS. So another multi-center, multi-country RCT, uh, study that is gonna come out, uh, hopefully in a year or two, which is gonna be wonderful. Wow, you really need to hit this guy, huh? I'm just gonna skip over this so we can get into the chronic pancreatitis. Oh really? Is that right? All right. OK. Uh, some, uh, so, to wrap it up from, from, this is from our center, um, acute pancreatitis, aggressive fluid resuscitation, 1st 24 hours, better in the 1st 12, and then reassessed, um, associated with shorter length of stay, less severe complications, less ICU admissions. Now, feed the pancreas as soon as the patient is able to tolerate APO just give in nutrition significantly better compared to TPN or NPO. Let's go, yeah. Yes. You can do any, as long as you feed the, uh, the GI tract it. So we usually prefer to feed the stomach. If you can feed the stomach, feed the stomach. There's another trial from, I think, uh, our, our colleagues in, uh, in, um, Budapest saying NG versus NJ, better to feed the stomach if you can. I feel like we still get into this cycle, like, because I know that data, right, but it feels like we still get into the cycle of you start feeding them by mouth, they puke a couple of times, everybody freaks out, you know, we end up, we go NJ, uh, that doesn't work either. Then we go TPN. That's fine if they cannot tolerate it, it's OK. I mean, but it's like gastroschisis. It's OK to tolerate some, some, some. Vomiting. If you can feed them, that's fine. If you're losing nutrition and you're losing grounds, the patient's gonna have a worse outcome. Their albumin is gonna drop. Inflammatory reaction is gonna be worse. So better to feed if you cannot than NPO or TPN, but outcomes are dramatically better when you feed the gut. And sorry, can you complement it, like have some sort of. In day or some feeding into the stomach but then not to get like bad nutrition, get some MPT like parental nutrition sorry because you like complement with TPN yeah use them you can if if you need. I mean nobody needs TPN the 1st 7 days of acute illness, right? So take that into consideration. Yes sir, can you, can you explain the, uh, normal saline versus LR? I think you, you skipped over a little bit that slide, so I wonder if you can just go into that. Yeah, so it's been shown in, in 11 of our Europe colleagues, uh, study that LR has better outcomes as a concept in terms of inflammatory response. Compared to the, the normal saline. Now, it's been followed now with this, uh, uh, water, water land, uh, multi-country, uh, RCT specifically looking in which volume or which product is better, LR or NS. So there's gonna be an, a clear hopefully a better answer, uh, in the near future. So, let's jump into this 1. Um, 7-year-old with acute recurrent pancreatitis, um, abdominal pain, has a diagnosis of, uh, ARP referred to you with an ERCP showing a stricture in the head of the pancreas and a dilated duct distally. We've seen this multiple times, um, has had 7 ERCPs and a stent in the past. So this is the ERCP, um, by the way, we rarely, rarely see this in children. Um, the inflammatory head mass that we see in adults is not usually the case for children. Uh, we deal with minimal dog change disease, small dogs, usually not dilated dogs in, in, in pediatric population. So, we have a clear, you know, um, stricture in the area of the head of the pancreas and a dilated duct distal and you see clearly the branches going into the parenchyma. So, you do an MRCP to evaluate for chronic changes, to call it chronic pancreatitis instead of acute recurrent, uh, you repeat an ERCP balloon, balloon, dilate, and put another stent. Get an MRCP, obtain genetics, um, admit and plan for a ray procedure. Um, if you guess anybody remembers what's a freight procedure. What do you guys think? Um, get more imaging. Um, obtain genetics. Children don't get pancreatitis, uh, wrong diagnosis. Definitely genetics. OK, so I would say C. Anybody else? All right, let's talk about it. Yeah, let's see what, what people are thinking out there. Why, Mira One, no, so there are the chronic pancreatitis patients have, there are a number of genetic markers associated with chronic pancreatic pancreatitis, PRSS1, etc. and those things play a role in how you figure out what you might do and also understanding genetic risk to others in the family. So anyone with pancreatitis. Chronic chronic pancreatitis, not an acute flare-up. What if it's an acute flare-up? So I think an individual, one will know better than me, but an individual episode of acute pancreatitis, no. But recurrent acute pancreatitis, yes. So that's, that's exactly it's interesting to see this, uh, very divided, um. MRC so the main is repeat ERCP. So keep doing it. We're 7 ERCPs in, and we're just gonna keep going. Um, OK. Yeah, the question is, when do you stop, right? You don't wanna see children having 1517 ERCPs, and then, you know, every time you get an, an ERCP you have a risk of getting post ERCP pancreatitis. It's low, right? But it's still a risk, and you lose eyelet cells with every attack. So we're losing cells down the road. Now, ERCP does not change the eyelid yield that you're gonna get transplanted, but if you get pancreatitis, you lose cells. So, yes, key point in pediatric pancreatitis and children get pancreatitis. We have a running list of 800 patients right now in Cin Children's. Uh, we get over 100 referrals every year for TPIT. We only offer it for 2025 per year because not everybody's a candidate, but, uh, genetics is key. Even we're moving a little bit forward more into Even first attack, if it's an acute, bad, horrible pancreatitis, they're gonna get a genetic analysis because we have the most common one. So the most common cause of pancreatitis in children is, is, is medicine induced. The most common risk factor for pancreatitis in children is, is genetic factors. So one, I yes, sorry, finish your sentence. Sorry, yeah, I know, I was gonna say PRSS one is the most common one, which is a trypsinogen activator. It activates trypsin inside the pancreas. So, you get auto-attacked by pancreatitis. It's the most aggressive one. There's CTRC, CFTR, um, you know, CPA1. There's a whole bunch of mutations that we now know. We, our gene, gene panel in Cincinnati runs 10 different genetic, um, Uh, uh, uh, um, uh, markers, uh, and then we're catching all the patients that are having genetic mutations. So, that's how we're changing the approach to pediatric pancreatitis, chronic pan pancreatitis treatment because of the genetic factors, right? If you see that ERCP in an adult, That patient is probably most likely gonna get a Fry procedure. Pistol, remember, was the filet open the duct, dilate the duct, run wide, and drain it, right? This, this patient, if it was an adult, most likely is gonna get a, both a drainage procedure and a resection procedure, which is a fry. You core out the head, but you drain the entire duct, not in children with a genetic problem, because up to 50% of those children are gonna keep getting pancreatitis despite you opening the duct and draining it. So what's gonna happen next in 4 years? Oh, I have acute flares again, and then you send half of your, the top of your pancreas to the trash, right now you have that patient that has the mutation that they're, they're trypsin activated. What's, how do you mediate that? Is there medication or is there another path that you can do to Wonderful question. No, no, there's no, unfortunately we don't have that just yet. That's why I still have a job. But, uh, I hope, I hope some one day we have, you know. Before you move on to that question in more detail, if you're gonna, I just have a question about medications. Yes, um, the very first podcast we ever did was with Wit. And, uh, appendicitis, and you talked about using ceftriaxone and Flagyl. And so we switched. But a lot of people complain that that causes pancreatitis or gallstones. Is that not true? Have you not seen that? Yeah, we, we see with a, there's like a list of 100 different medications that can cause it. Like Lasix can cause pancreatitis, steroids can cause pancreatitis. But what, um, I get it, but we're using that like water now. And so is that the wrong medicine to be using? We, it's hard to, we, I don't think we've seen recently from ceftriaxone or an antibiotic one, no, because that was the complaint we got, Tim. Yeah, um, I, I would do a fewte on this kid. What's the downside of that? So, excellent, excellent, uh, uh, question. If there's a generic mutation, let's say there's a PRSA1 mutation, right? For a pistol, you have to like get the top of, the top half of the pancreas out to open the duct, right? Um, you, you throw uh some eyelet cells to the trash. Um, this patient most likely is gonna keep getting pancreatitis despite you draining the duct. The, the parenchyma is gonna keep getting attacked by the mutation. So, you're temporizing um the attack by draining the duct, uh, but you're not fixing the problem. Uh, these patients keep getting recurrent attacks, so, um. To, to offer like a partial conventional surgery, we, we, we divide into conventional surgeries for pancreas versus TPIET. Getting a conventional surgery for that will be doing half the job you could potentially offer as a solution. Remember, um, TPIT, which is total pancreatectomy with eyelid autotransplantation. Uh, the main indication is, is for pain, chronic debilitating pain for children that are losing their lives. They don't go to school anymore, they're withdrawn. They're, they, they don't play soccer anymore. There's no more ballerina dancers, right? So, chronic debilitating pain, uh, second is to try to give them back their beta cells to prevent diabetes. So, um, but yeah, that's why we don't offer a puso or a conventional surgery for this type of patient. Yes sir. So I know the scenario pretty much points towards, OK, maybe recurrent or chronic pancreatitis, but after how many do you feel like, OK, this is what we're dealing with? 2, BRCPs, 3, when do you start thinking, considering that this might be a problem? That's a great question. We don't have a set number of ERCPs, but Um, uh, back to the point, like, if, if you keep getting pancreatitis, you're losing time on that, right? The, the pancreas, we have 34 years old with like very atrophic pancreas, um, and the, their eyelid cells, you can offer them back are, are low. So, uh, there's no set limit on that. The sooner the referral, the better for an evaluation. We don't offer. Uh, to take care of the pancreas unless you've maximize medical and endoscopic management. If there's no other options and your endoscopic guy tells you, you know what, there's nothing for me to balloon dilate, open, drain, or anything. There's been a stent. Even with the stent, the patient keeps getting pancreatitis. There's no reason to keep going with ERCPs. So, uh, just to give a brief description on, on, on, on imaging, um, we use endoscopic ultrasound. My GI colleague, Doctor Vitale, uh, is an expert on this, and, and, uh, and you can confirm diagnosis. Um, an ultrasound, CT scan is image imaging of choice once they come. MRCP is the best non-invasive study for pancreas by far, uh, with different, uh, uh, T2 sequences. Um, um, they're great. And ERCP, of course, is more therapeutic than diagnostic. Um, So, remember, patients with chronic pancreatitis are, are always uh uh having micro and macronutrient deficiencies, so we need to pay a lot of attention to this. That's why, uh, we, our GI colleagues are, are, you know, they are the experts on this, and, and they work really hard on, on, on having them support, uh, their nutrition with the, these patients sometimes need pancreatic enzyme replacement therapy and they should be on, right? Um, you lose first your exocrine and then your endocrine function, so you need to keep screening for it. Um. So, what happens when there's a big collection that they call you, uh, there's a, there's a big collection wall of necrosis. Should we touch it or not, you know? Once the, the wall is mature in 4 to 6 weeks, uh, if there's symptoms, drain it. If there's no symptoms, don't drain it. If the patient's not, not having gastric outlet obstruction or pain, There's no need to drain this. Um, it will, it will self-resolve, uh, and, of course, there's no need for antibiotics. There's a higher risk of getting pancreatic cancer from chronic pancreatitis, uh, up to thirteenfold. Uh, it's important to mention. We talked about the rest. Let's jump into the, the other one. Oh. OK, we have a 5-year-old, chronic pancreatitis, debilitating abdominal pain, multiple hospital admission admissions in the last 2 years, fell behind on milestones, Dilaudid 3 times per week. MRCP, uh, I don't know if there's a picture, but, um, chronic, chronic changes, um, uh, uh, minimal, uh, duct change disease, but has appears as one mutation, has had 5 ERCPs and a stent in the past with no improvement. So now what? So as I described, a Fry procedure is draining the, uh, the duct like a pusto but coring out the head as well, and with a ruined Y limb, a classical modified pusto, uh, to drain the, the duct, uh, TPIAT or a whipple procedure. Tim. Learned now that I do a TPIT. Anybody wants to do a whipple? Cora and get rid of the head. All right. 53% are doing TPIT. Some people are doing a whipple. Remember, there is a mutation, right? So if you, most of the pancreatic parenchyma is in the head and the onsonate process. If you get rid of that head, And there's a pancreatic, uh, uh, PRSS one mutation, this kid is gonna get acute or, or, or, um recurrent attacks. So you're just throwing some eyelid cells to the trash. Uh, There you go. So, up to 50% of patients with chronic pancreatitis will eventually require surgery, and we used to like break it down like that for a large duct and small duct. However, genetics have changed the world of how we approach uh uh pediatric uh uh chronic pancreatitis treatment. And, you know, I was telling, uh, um, Um, uh, uh, taught here earlier, like, we, we get over 100 referrals for, uh, TPIT evaluation per year, but we only do 2025. Not everybody is, is a candidate for, they need support. They need social support, right? We, our team requires, I'm just a part of it, uh, right? Surgery, massive GI, uh, pancreatologists, experts, social worker, geneticists, psych. Psych is massive, right? Uh, pain control, um, um. Uh, uh, uh, uh, the social workers, uh, are, are phenomenal at this. Um, some, some families ask us like, so you're gonna get rid of the pain, right? 100%, and you cannot say that, right? People that have chronic pain, their bodies, their brains learn how to be in pain, right? They can function in pain. That's called hyperalgesia and central sensitization. So, when you take the, the, the organ part out, you maybe 90% of the pain is gone, but you cannot promise them that 10 that 10% is gonna linger for a little bit. We need behavioral therapy for that. And there's more and more research coming uh uh on, on that cause it's very important cause, you know, they still have the phantom pain, which is a sensitization, um, you're not gonna cure that right away. Uh, remember, this is, uh, just for debilitating chronic pancreatitis, all right? Um. Let's keep going on this. So, again, the goal is to bring this kid back to their life, right? There's a, a 5 year old should not be in the hospital every 6 weeks in ICU admissions and not being played, not being able to dance or play soccer, right? So, they're incapacitated. These kids are like totally withdrawn. They dropped their milestones dramatically, so it's important to bring, bring them back to their society. And as a secondary goal, is to try to prevent the brittle diabetes that happens once your pancreas is out. All patients have enzyme replacement therapy, of course, you cannot, we cannot provide that service um just yet, but if you don't give the beta cells back, You know, they're gonna become diabetic. So, um, we use like a, there's an eyelid cell equivalent per kilogram of body weight that we use as a marker of prognosis. Uh, when we have 5000, around 5000, there's a good chance they, they, they will be, um, insulin independence. There's a lot of factors that play into insulin independence, uh, on the, on the, on the, on the, um, outcomes of this surgery, but right now, 50% chance, if you hit 5000, 50% chance you're not gonna require insulin. 20% chance you will require a, a, a small dose of insulin. The other 30% are still diabetics. So we need to tell the families, they're, I'm exchanging potentially disease for a disease, right? Chronic pancreatitis for potential diabetes. Want to explain what your day looks like when you do one of these operations. When does it start and then what happens when you send off the, the, the pancreas, and then when you get it back, how do you put it back in? That's a great question. My day starts the, the night before as I start going through the case. It's a long day. It's a long day. I reviewed this case in my head, uh, 30 times before I go in. Um, it's taking about, um, average. 8 to 10 hours. The, uh, you start at 7:30, we, you know, put all the necessary lines, central line, arterial line. Um, taking out the pancreas is the, the most problematic part, as you can imagine, it's cemented back there in the retroperitoneum, um, uh, with neovascularization, collateralization, some patients have thrombosis in the portal vein or in the splenic vein, so you deal with those collaterals as you go in. Um, the pancreas comes out, usually, you know, let's 334 hours, right? And then we send, we have a, um, uh, in-house facility for the eyelid isolation in Cincinnati Children's. We have one of the experts, world experts, uh, from Pittsburgh working with us now, um, doing the eyelid isolation. The pancreas goes out to the lab, and as they're trying to get the eyelid cells back, I started the reconstruction. So the GI tract and the patobiliary, um, you know, it's, it's a run wide, it goes up to the, to the, um, hepatic, uh, duct, and then you do the intestinal uh, um, a reconstruction just like that. I think it's up there, is it up there? Yeah. That's how we do it. We take the pancreas, the spleen comes with, um, you see the bile duct there in, in green, and we do a room-wide reconstruction. Uh, we do pyloris preserving, um, uh, resection. We inject pyloric Botox, which has, uh, shown to improve outcomes in gastroparesis that all pancreatitis patients have gastroparesis. Uh, R Y deals with that gastroparesis as well. So, we inject Botox in the pylorus, um, and that's what we do reconstruction. That takes about, you know, I said, 2 hours or so. Sometimes we have to wait a little bit, um, uh, for the cells. The cells isolation takes 4 hours, 4.5 hours. Um, they come back and we inject them right there in the portal vein, um, inside the liver. They, they find a home. Yes, that's a good question. Splenectomy, we do routine splenectomy, um, except for very special cases. Uh, but the, the thing is, 22 reasons. Um, one, they share blood supply, right? The pancreas and the spleen. The, the, the back of the pancreas, it comes where the splenic vessels come. It's supplying tiny branches throughout the entire body until the pancreas. So, can you do it? Yes, you can resect the pancreas, leaving the spleen, but Every time you start cutting these tiny vessels, you're having ischemia time. So you're losing eyelid cells. There's 4 points where you can lose eyelid cells. One, recurrent pancreatitis, dying pancreas. 2, during the dissection, right? Ischemia time, necrosis kills the eyelid cells. Um, 3, During the processing and putting the cells back, a lot of cells die. And 4, in the acute post-op period, you have to manage their glucose for them. If you put them under stress, the cells die. Everybody's on insulin in the ICU. I want the cells to be like just chilling, not doing any work until they implant and find new vessels from the liver to survive. So if you take another hour to dissect the, the spleen out, uh, you lose cells. It's not worth it. All right, thanks, Juan. That's fantastic. Any closing thoughts before we move on to the next session? Closing thoughts or questions because I know this is, you know, this is one of those things that, um, is newer, newer. We don't, it's again one of those things that is not at a lot of centers. So again, is it new? Is it, is it not scaling at the rate we think? But, uh, yeah, so quick question, Juan. So where do the cells eventually implant? In the, in the end, uh, end branches of the portal vein inside the liver, yeah, they live in the liver, uh, there's a, a lot of, uh, uh, uh, publications in extrahepatic, uh, reimplantation of the eyelid cells. They don't work as well. Only they, you know, for, for hypoglycemia, there's a good glucagon reaction when they're extrahepatic compared to intrahepatic. Um, however, the best site for them is the liver. We've done it in the omentum, for example, create a pocket in the omentum in the retroperitoneum injection in the rectus muscle, um, as well, just like the parathyroid kind of thing, um, um. And in the submucosal of the stomach, but it's a, they bring a bag of like 200 mL, so it's a decent amount of volume. So it's better to put it in a portal vein. There's risk for portal vein thrombosis is very low, less than 1%, but it can happen, so we monitor the portal pressure as we, as we're injecting. I'm skip the commercial because there's questions. Oh, I'm gonna skip the commercial because there's questions going and so we'll just get set up. So we'll just go right into it. Thanks. Uh, Katie, just, I've never seen this. So quick technical question, do you take the duodenum when you take the pancreas, or you just shave it off the duodenum? No, no, we take the duodenum right at D1 post pyloric. We take for the same reason. You could sur duodenum, but the shared blood supply is hard, so you disconnect the, the bile duct and the duodenum, yeah. Would anyone, I look at Tim's face. Would anyone consider starting this program? We got 2. All right, 34 early referral is key. Yeah, great. Thank you guys. Awesome one. Thank you so much. Yeah, thanks.