Dr. Tom Jaksic - 20 Years of Interdisciplinary Short Bowel Syndrome Management; Lessons Learned and Future Challenges

agedots. you you you you you you you you you you you you you you you you you you you you you you you you you you Did world It's funny. You can find it. No worries. Sergio Grand Rounds 2019. So right here looks like it's copy. There's your morning on. I'm actually playing an elf today for some Santa Claus. But I'm going to go over to one of the street. It might go. It would be better. Here's your thumb drive back. And I just drive it with the look. With these right here. I'm going to turn it back on. This first slider here. Yes. Turn it on. Go ahead and talk into the microphone. You're good together. Good morning, everyone. Happy December 11th. It's lovely out there. Today's talk is. I'm going to go over to the other side. Good morning, everyone. Happy December 11th. It's lovely out there. Today's talk is. Entiled 20 years of interdisciplinary short bell syndrome management lessons learned and future challenges. And really it's a story of the Center for Advanced and Testual Rehabilitation or Care Program. As you know, the care program. Involves M.D. And we have a very specialties. N.P.s, nurses, dieticians, pharmacists. All working together to provide inpatient and outpatient care for patients with intestinal failure. And along with that, we have a tremendous support from Pathology, Radiology, Transplant, Home PN, Social Work, and Feeding Therapy. So the care idea actually started in 1999. And I know exactly where it started. It was a Tex-Mex restaurant that's still present in Houston. Chris Duggan came down to visit the Children's Nutrition Research Center at Texas Children's. And I was transitioning to Boston Children's from there. We had dinner together as I recall over some fruit flavored drinks and health food. And we had both tried to start some interdisciplinary programs regarding intestinal failure in our respective institutions. We didn't quite get there. And we thought that we could do so in Boston. So this is a red R.Vac who was alive in kicking in 1999. He's a legendary coach of the Boston Selfics. And our starting five, or the five people that started the program were Sharon Collier, Julie Glacias, Kathleen Gura, Chris, myself. And our sixth man was Cliff Low. And this started just as really us wanting to have the people who had intestinal failure to one place where they could get, if you will, one stop shopping. And also we hope to standardize care. We now have a much larger team of very serious-minded individuals. As you can see here, this is Halloween. We have a program with over 325 unique patients that we care for about a third of whom are on the home branch of nutrition. It's very important to stress how important interdisciplinary care is. And I think it's probably something that's generalizable to pediatric surgery in general. And with the advent of the care program, survival improved significantly at Boston Children's. And then this paper written in 2008 by Vierran Modi showed an increase in survival from 70% to 89%. And when we looked at what were the factors responsible for that, there was no single one factor. It's really a multiplicity of things that when brought together and when a bunch of people bring their talents to one problem, that type of survival improvement is seen. And now our long-term survival is greater than 90%. Similar trends have been described in other interdisciplinary programs in the United States and really around the world. As usual with this talk, which I tend to give every few years, we'll go through the definitions, incidents, prognosis, management, nutritional, medical, focusing on surgical management, and focus on new outcome data and remaining challenges that are present for patients with short bowel syndrome. So pediatric intestinal failure, the general definition is intrinsic bowel disease resulting in an inability to sustain growth or fluid electrolyte homeostasis. It involves chronic intestinal pseudo-obstruction, nuphosyl defects, and short bowel syndrome. Short bowel syndrome takes up more than 80% of all patients with pediatric intestinal failure. Chronic intestinal pseudo-obstruction is a terrible and poorly understood compendium of myopathies and neuropathies that really needs one of you to take as their challenge throughout their career and figure it out. Short bowel syndrome is of course that large subset of pediatric intestinal failure that involves actual intestinal loss. In animal studies, it's 80% or greater loss of small intestine, defines intestinal, sorry, short bowel syndrome. There's also now a new term in the literature, which is ultra short bowel syndrome, which may be a way for people to get things published, but actually if you look at it a little more closely, it probably should be defined as those patients have less than 10% of predicted bowel lanes. Our working definition of short bowel syndrome is intestinal loss, leading to dependence on parental nutrition for greater than 90 days. Pediatric intestinal failure is quite a complex disorder. I won't be able to cover everything in this stock. I encourage you to read this review article if you're interested in the New England Journal of Medicine. This really was the work of Chris with me tagging along and the editors and illustrators of the New England Journal of Medicine. But it's a very clear, relatively short discussion of the topic. The incidence of short bowel syndrome is hard to figure out. It's really startling as we take a look at healthcare in the United States that we really don't know the outcomes of almost any disease very clearly, nor do we know its incidence very clearly. In a study that was published in pediatric and Boston Children's participated in, the incidence of short bowel syndrome seems to be somewhere about 7 out of 1,000 live verse for neonates less than 1500 grams. Of course, there are other ideologies of short bowel syndrome that affect older neonates. So let's go through these. First is necroticianic colitis. It's the most common etiology for intestinal failure. And one can see why there is intestinal loss with this disease. We always thought that as we get better and better at saving smaller and smaller babies, the incidence of intestinal failure due to necroticianic colitis will continue to increase. The answer, however, is to what really is happening is more nuanced. This is a study that Sam Han presented at the AAP just recently. And if you do a little back of the envelope, a calculation represents a study of over half a million very low birth weight neonates born in the U.S. It's a grade of 90 percent of all very low birth weight neonates born during that time. And this represents one of a long series of studies that we've done with the Vermont Oxford network and trying to figure out neonatal disease and specifically those diseases that contribute to intestinal failure. This is neck incidence in the United States and each one of these lines represents a different region. And you can see that neck incidence, even though we are saving smaller and smaller babies, is actually declining. I'll get a chance to talk to you about this and other bond findings in a grand rounds in 2002. But just let's look at this in terms of what it means for intestinal failure. What might surmise is that we're going to have less and less patients with neckerizing anorocolytis. However, the other thing that this study demonstrated is that mortality of medical mac is decreasing as is the mortality of surgical mac. So in fact, there are two contradicting trends, if you will, and it's likely that neckerizing anorocolytis will continue to be by far and away our most common cause of intestinal failure. The other interesting thing about neckerizing anorocolytis is that patients with neckerizing anorocolytis have the best prognosis regarding the ability to attain full-antial nutrition. And that's when standardized for a small bowel length. One of the reasons for this, maybe, that these children are premature, hence they have a capacity to adapt perhaps better than full-term neonates. If one looks even at our data or data from consortiums, this trend is born out. And more remarkably, a lot of patients that have very trivial amounts of bowel actually can mean from PN who have neckerizing anorocolytis. And we think it's because those babies actually have good bowel, you know, they're resected to the point where there is a good bowel in general. It's important to try to avoid the term nectotalus in a recent paper looking at kids with ultra short bowel syndrome. It's clear that children with his littlest 10 to 20 centimeters a small bowel can mean from parental nutrition. It's important to also look at their larger outcomes in terms of neurologic outcome, etc. But just the fact they have not very much bowel does not mean that they should necessarily be let go. And as the people in our intestinal failure program can tell you, we have several patients with nectotalus that are alive and well. And certainly one of them I can recall is fully off-ferential nutrition. The next common cause is gastroskeesis. Gastroskeesis, as you know, is an abdominal wall defect that affects neonates who are slightly premature. In a large Vermont Oxford study that we did in the United States, the survival now of patients with gastroskeesis is 98%. But the nutritional morbidity is high. The median time to full-antro nutrition is 37 days. Some children, even with a full complement of intestine or near full complement of intestine, end up having intestinal failure throughout their lives. So gastroskeesis is a combination defect. There's foreshortened intestines sometimes with atreasia, but also an intrinsic motility disorder. The next most common cause are intestinal atreasias. This is a type 3B atreasia. You can see the apple peel defect distally. Surprisingly, type 3B patients do incredibly well if you didn't ask them most of them. And they often require in fact no specific supplementation because they still have a terminal ilium once they mature. There are things with intestinal treason where you have almost no distal intestine and you have hugely dilated bowel. What has been reported and shown and something that was envisioned when the step operation was designed is you can actually step that proximal bowel and an estimose to the distal small bowel without losing a substantive surface area. And we'll talk a little bit more about the step operation later in the talk. Intestinal atreasia has a median time to full entrial nutrition. That's for genus olio atreasia, which are intra, if you will, intra-udorine vascular accidents where there are wedges of bowel loss of about 17 days. One of the first successful treatments for intestinal failure, or at least series that reported successful treatments, was by Luther Lonscheno from this institution. The interesting new finding is that although type 3 and type 4 atreasias are the ones that are associated with intestinal loss and they are the ones that we focus on, type 4 atreasias also have a very interesting subset, which may be associated with TTC7 amutations. Type 4 atreasias, as you recall, have multiple atreasias throughout. And those with TTC7 amutations also have an ecosophriability, malabsorption and skids. The first real survivors of this set of diseases were reported, or they were reported in abstract form, but actually occurred in this hospital. And one of whom received multi-bisterile transplant and is doing quite well. But the moral of the story is if you have a type 4 atreasia, always look at their panel that they've had in terms of what the immune deficiency they may have, that the usual panel that's obtained with neonates. And see if they could have skids, because if you operate on these children without correcting their immune deficiency, they will die. Neonates with short bowel syndrome in fact, in general, seem to exhibit immune deficiency when we take a look at Massachusetts data of babies that seem to be true. Why that so is a little obscure, but it could be related to the production of arginine, which is an immunomodulator. And that production is decreased in patients with intestinal failure. Next major cause is mid-gut volulose. And that is a devistating disease due to malrutation, where you lose the whole of the mid-gut. The treatment is unwinding the twisting of the bowel. Then going back perhaps through a second look operation to try to conserve as much in testing as possible and then doing a primary and estomosis to reestablish bowel continuity. These are some very interesting outcomes from our program. And one thing that I never anticipated is that children with mid-gut volulose lose their whole mid-gut can be weaned from parental nutrition. And this describes a series of patients that we have who had volulose on a medium of one day. They had 9% predicted bowel length. They were managed in the care program. 7 of 12 who did not have concomitant gastroschesis mean fully from parental nutrition. It took a very long time, a medium of 718 days. Interestingly, 0 out of 6 of those who have both gastroschesis and mid-gut volulose weaned. With these patients, beware of de-lactic acidosis. They lack a barrier between their colon and their small bowel. They have dilated small bowel. You do add up patient usually. And de-lactic acidosis is a real problem. And how do you figure out whether someone has de-lactic acidosis? If they're older, they'll present with neuro-cognitive issues. They'll become confused. If they're younger, you'll see a non-NIN-capacidosis that you can't explain based on renal or other reasons. So you may ask, how in the world can patients with so little bowel possibly wean? Obviously there's bowel adaptation, but it's a relatively limited process. And as a biochemist, I always look at various sides of the equation. And you have to look at the demand side of the equation. And what you can see here, and this is something we've published in 2017, the requirements per kilo of protein and calories in children drop almost exponentially. The yellow line shows protein requirements dropping. And the red line shows chloric requirements dropping. And those of you who have or have had little children know that they're a little crazy. So there's sort of this little plateau of high requirements where they're going through that stage and then that drops. If this hypothesis correct, then what we should see is a weaning pattern, the frumpian that is quite symmetric to this demand curve. And these are some data that Sam, as the first author and Jamie has the second author want to prize with that the Canadian Association of Pediatric Surgeons. And this represents how our patients wean off parental nutrition. And you can see that the curve is almost symmetric to that demand curve. And further what you can notice is that weaning continues along through life. So the old axiom that if you don't wean by X amount of time, you'll never wean is inaccurate. It's just as ones requirements drop. Perhaps as one adaptation improves a little bit, you will wean from the end. And here we have patients weaning from 10 to 12 years of age. The 70% probability of weaning from parental nutrition at 10 years is sorry at 10 years. There's a 70% probability of weaning from parental nutrition if you take a look at all of our patients in a malignant. Of course, those patients at any time period who are on parental nutrition have a greater burden of disease with higher end hospital stay, etc. So how little intestine do you need to attain an antroletonomy? That's a moving target. So in 2001 when a paper was published from here, it was around 35 centimeters of small bowel. Now it's probably around 20 centimeters of small bowel. 20 centimeters of small bowel is a 50% chance that you will wean from parental nutrition eventually. And that's a compendium of various studies around the world. What if you don't have a way to measure the intestine? Is there some other predictor? Another predictor is serum citralline. Citralline is an amino acid that's made in watermelon and look rined. Watermelon is citrallis vulgaris, hence the name citralline. It's not called that in the whole foods, it's watermelon. And but in humans citralline is made by the intestinal necosa. And what you can see here is if one plots the citralline level versus the ability to take antralline take, although it is significant as a linear regression. It's in fact a step function. And you can see here that once the serum citralline starts going above 10 micromole per liter, then the ability to wean from parental nutrition is great. Unfortunately, the converse also is true in patients who are fed and the serum citralline stays below 10 micromole per liter. They tend not to wean from parental nutrition. What is the treatment for short bowel syndrome? Well, the treatment is actually antralline nutrition and getting these patients on natural nutrition. It eliminates the risk of hepatic injury. And because we tend to remove their central lines, it actually greatly reduces their risk of septic complications and death. How do we attain that nutritionally? Well, nutritional therapy still really needs to be defined better for these patients. But what we have found is that breast milk and animal formula are both associated with improved outcomes, probably for different reasons. Breast milk is bioengineered, if you will, for the human gut and is remains the best form of nutrition for any baby. We do need to supplement it in babies who are premature, elemental formulas. They have a distinct advantage in that there are monomeric amino acid formulas. And when we look at our patients, quite a few of them have immune problems in terms of allergies. And it takes eight amino acids to trigger an allergy. If you have a monomeric formula, you tend to avoid that. So that's helpful. We follow growth curves carefully. Chris and I always discuss function tests for our patients, how well our patients absorbing. The best way to tell in 2019 is to take a look at the growth curves. If you're feeding a patient and they're getting PN and they're weight percentiles, they're going higher than their growth percentiles, which are genetically predetermined, then you know you have absorption, then you can weep PN. And that's in a nutshell, how we do it. We avoid and treat oral aversion. That's a big problem with patients with short bowel syndrome. Metabolic bone disease is a big problem with our patients. We simply can't get enough calcium and phosphate into a PN solution. And these patients tend to be inactive. They have problems. We follow that very closely, weight bearing exercise and adequate calcium and vitamin D long term are the best treatments we have. After age 16 and girls usually in 18 and boys usually our ability to accrue new bones, new bone strength is limited. Then it's just a holding proposition. Overfeeding is a bad idea in our patients. And there's a lot of interesting things here. This particular graph is just her own data of C13 CO2 infusions and looking at CO2 production in patients. What you see is that as you feed more and more calories, there's more and more CO2 produced. The reason is that we as humans store all our excess energy as fat and data oxidation generates carbon dioxide. So what this is telling you is the more you feed patients, the more likely you're going to put them in respiratory failure and the ICU. But from our standpoint, the worst thing is the more fat that you're generating and that fat goes into various storage pools in the child, not something we want to do. And unfortunately it can also go on the liver and cause hepatic statoosis. So what happens in patients who have liver disease due to perandural nutrition? The best way to get rid of it is actually anteline nutrition. And this is a study from 2005 where we show that there's a nice drop with a billarubin and things to get better. In 2000, the groups from Paris reported that stopping or decreasing infallipid also resolved the liver disease secondary to parental nutrition. The next study was repeated by the late Dan Tite-Lombs group in the University of Michigan in 2012. A&R Center through the work of Mark and Kathy, there's a development of a megavan. A megavan was a formula that was already manufactured by Frisinius Cabe. It was thought to be useful as a supplement for patients with critical illness. Chris and Kathy used it in a patient who was allergic to soy, Mark's basic science work, and with Kathy, Mark, and Kathy started using this as a therapy for patients with intestinal failure and severe hyperbularidemia. You can see here a very nice drop in billarubin with the use of this formula. We now have three lipid therapies available in the United States. We have soy, usually an intestinal failure. If it's used, it's used to reduce dose of one gram per kilo per day. If you get in real trouble, you can stop it. But unfortunately, you need about 2% of your calories, perhaps 4% in premature need to be fats if you're going to avoid fatty acid deficiency. You can use fish oil, and 1-2 grams per kilo per day. It's FDA approved. We use this as a salvage therapy here for patients who have bilirubins greater than 2 milligrams per desoleter. Then you can use another formula, which is the soy, MCT, oleic acid, and fish oil formula. Oleic acid is olive oil. This is called smoth. This is the most common formula that we use in our patients initially. It's intriguing that if you stop the soy formula, your liver gets better. If you use a fish oil formula that has, of course, no plant-based materials, you can resolve colostasis. It's interesting that smoth seems to be relatively gentle, though not completely so, to the liver. It raises the question whether there's some sort of a toxin in soy. One has been identified. It's phytosterols. If you take a look at the content of phytosterols and soy, they're very high. Fish oil is zero, and it's smoth much less depending on how much fat you give. This is a story that continues to revolve over time. No question that intro-lippid was a life-saving formula, but it may have caused unintended harm just in the way it was made. Is everything wonderful in the liver? Once we put patients on our hepatoprotective measurements or even feed them, the answer is no. This is a study which looks at patients who are in the very best cohort. These are fully transitioned to enthral feeds. What you can see is that their bilirubins drop, but their ALTs continue to stay up. Jamie is working on this now, taking a look at all of our patients. But the majority of our antially fed patients eventually will normalize their ALTs. However, the ones who are on PN almost invariably have elevated AST and ALTs which tend to bounce around quite a bit in terms of their levels. But it does cause us to have some concern about the long-term outcomes of our patients who are on PN. What do we do about it? Well, we have a study now that's ongoing using once-e-13 methanine. The protein is broken down in the liver metacondria and we're tracing liver metacondrial function in our patients who are on chronic parental nutrition to see if their liver is R in fact getting better or getting worse. If they're getting worse, their oxidation of methionine will decrease. We're also using Fibroscan, this is a study that Beren-Modi was the senior author on. Fibroscan is vibration-controlled transient leftography. It can differentiate between high and low metavir scores, so can the ones-e-13 methanine breath test. So we're looking at two things. We're looking at structure with the Fibroscan and we're looking at actual metacondrial function with the ones-e-13 methanine. So time will tell as to how these livers are really doing. What's another thing to do? Well, the other thing to do is to prevent catheter loss and avoid sepsis. One thing that we do here almost reflexively is we do not tie our vessels. We reuse access sites. We tend to use silicone lines, which we think have a better safety profile in polyurethane lines. Those of us who are old know that in the past we used polyurethane lines, then we switched to silicone lines. And now we've kind of switching back to polyurethane, but we're not doing that in intestinal failure because our lines are so precious in terms of being true lifelines for our patients. We have used 70% ethanol locks to reduce catheter central line associated bloodstream infections. They're very effective. Ethanol is a small molecule. It encircles into this biofilm, which is found inside all of the central lines that we place. And this is a study that Brian Jones did when he was with us. And it shows with ethanol locks and home PM patients, you can reduce their CD central line infection rates for 1000 catheter days from about 9.9 to 2.1. So very marked decrease. There's of course more to it than this. You need to have sophisticated teams that monitor central lines, which we are lucky enough to have. How about medical therapy? Chris is going to kill me because I'm going to spend two slides on medical therapy. But medical therapy there basically consists of slowing the intestine down. There's a very effective anti-diroreal low paramide. We start this at 0.4 milligrams per day in advance to 0.8 milligrams per day. How about secondary dysmeltility that we see in short bowel syndrome? What can we do there? Well, the answer unfortunately is not much. We can do, we can give a rethermysin, but a rethermysin really just works on the stomach. There's some question whether is this the rethermysin might be better. I haven't seen convincing data to show that. Cisopryde does work. Cisopryde is a prokonect agent that works on the small bowel. It's unique in that realm. However, it also causes torsade de point. So it's been taken off the market and we have to get it only on a compassionate use basis. But it is a useful adjunct in some patients. So what's really new in medical therapy and what's really new in medical therapy is GLP2. It's a very interesting story and it involves this investigator, Drucker, who was at the University of Toronto. And Drucker, when he was here doing research at the eye in 1984, was in a lab that was isolating proglucogun. And it's a very interesting thing that patients with proglucogunomas, they're extremely rare, have incredibly large intestines. And that made people wonder which portion of proglucogun could possibly be a intestinal trophic factor. And through some very basic studies done in a very careful way, Drucker isolated GLP2 as being that hormone. And unfortunately GLP2 can be broken down fairly easily. So he created with the help of industry a substitute at GLP2 called to dupletide. To dupletide is a wonderful growth factor for the intestine and animals and humans. And this is a phase three study by O'Keefe, which shows that in adults, if you give to dupletide, you actually decrease their requirement for PN. The end point here was a 20% reduction. Since there have been safety trials done in children, we were part of those trials. And to dupletide now is available for children. So we are now using it in our cohort. And I think may really be a game changer for some of our patients, particularly those who are relatively close to weaning. And one of the nice things, as you recall, it requirements drop in our patients. It may be that we only give this for a shorter period of time. In adults, you have to give it forever. But in our patients, we may only need to give it transiently, get the Moth PN, improve their quality of life, and get rid of their central lines. And DOSCO is very useful in our patients. It's to diagnose GI bleeding, which can be due to many things. Little ulcers, which are due to perhaps allergy, but also perhaps ischemia, or perhaps bacterial overgrowth. We also culture intestinal effluent to see if they're white is actually growing. And then we can figure out how to treat bacterial overgrowth, which is a big problem in our patients with dilated bowel. And on table andoscopy to those of you who are surgeons is an incredibly useful thing to do as you're trying to figure out complex anatomy and deciding what to do to reconstruct these patients. Let's talk about surgical therapy. This is surgical grand rooms. And ultimately, the time that the child spends in the operating room is probably the most important time for any short bowel patient. It's important to preserve as much small intestine as possible, any way you can do it. Second look operations are a good idea if there is any bowel, which you think may survive with time, obtain antelaxis early through G tubes and GJ tubes. We also realize that our goal is to use these defeat at night and let the patient then feed during the day by mouth and obviate oral aversion. And that's our general algorithm. Close film is as soon as it's safely possible. Often in our patients that depends on their pulmonary status. Since so many of our patients are premature, a lot of them have severe lung disease. And if you do the operation too early, you can actually cause a considerable grief. How about a thologist and intestinal reconstruction surgery or heirs? This has always been a controversial area of surgery. There is actually some very good science, which I'd like to show you about that. We know that the blood supply to the bowel is at right angles to the longitudinal axis of the bowel. So if you lock out the blood supply, the bowel can only really adapt by growing wider. And that's in fact, what does occur in our patients? There are some theoretic and in fact documented on toward consequences of these dilated loops of bowel, they do increase absorption, but they dilate too much. There's suboptimal absorption because the food is not in contact with the surface area of the intestine. And the surface area of the intestine is hard to imagine how much of it there is. And in an adult, it's two tennis courts worth of if we could flatten out our mucosa, that's how much it would cover. So there's a huge amount of observed area. There's disordered motility and bacterial overgrowth. The first truly successful operation to combat this was the Bianchi operation or the longitudinal intestinal lengthening and tailoring operation. Most people now refer to it as the mild operation. It's a tricky operation where you rely on the fact that the intestine has two leads, a medsentary, which you split longitudinally, then you have to slide them. And then isoparastaltypanner and nastomostom. We had a patient where we did a Bianchi and you redilated Dr. Kim drew a little diagram for Steve Fishman. I think it was on a napkin where he said, have you thought of this operation where we could just put staples across the intestine transversely and lengthen the operation that way. Obviously we hadn't, but we thought I was pretty clever. And then with the help of a dairy of housing and a huge number of research fellows, we took this to the lab. We showed that we could do this lengthening operation in pigs. This is what happens in a child and you can see that the dilated intestine is successfully narrowed. This way it looks like in vivo when you do the operation. The animal model for this was a miniature swine, which grew up, I learned to 80 kilos, so they're not so miniature. But we put in reverse segment to dilate the bowel, took out the reverse segment, resected 90% of their intestine. And then we had patients, patients where we did a step operation in the others. We just left them in continuity. And what we found is that the step of pigs maintained weight, the others lost weight. And we also found the following that there was a decreased overgrowth when we cultured the bowel. There was increased absorption, there was improved mortality, and increased surface area. The last risk for improved mortality is a little kudo to Dr. Berenmody, who is my fellow, I actually put the menometry catheters down the pigs and managed to get Sam Nercot to read them, both of which are miracles. If you take a look at serum citrallyn levels in the animal model, you can see that serum citrallyn goes up. And the question arises, how wide is surface area increase after you do a step operation? And the answer is that you've lengthened the bowel, then it's re-dilates, and you've increased surface area. Hopefully it doesn't re-dilate too much. We think that if we can wean those patients off before they continue to re-dilate, those are the ones that are successfully weaned. Those who are not weaned can make continue to re-dilate. We have the same problem again. An interesting set of experiments that was done by Dave Sigileckman, he was in Calgary, shows that in a rat model of staff, the GLP2 receptor expression goes up and post-prandial GLP2 concentration goes up. So it may be that the step operation is in fact partially that salut, that salutory effects are partially mediated through GLP2. Our concept now is that if we have a patient who's not weaning from the end, we'll treat them with our GLP2 analog to dovetite and then reserve bowel lengthening to those who have failed that medical management. Again, repeat the step. This work of Hannah Piper. The issue with this is that sometimes you are dealing with the dysmortality disorder. And if you take a look at the data for repeat steps versus primary steps, the weaning likelihood is less. This is the results of the international step registry and the indications for a step were outlined very nicely by HB and the first paper describing step. And it's nice to see that that's actually what it's being used for. The majority of the step operations done around the world are for intestinal failure, where antial teething advancement cannot be attained, refractory bacterial overgrowth, and neonatal atreasial with limited distal bowel length. And I showed you a picture of that earlier. This shows a patient with short bowel syndrome who has a dilated segment. This case, it's the duodenum, which made it a little trickier, but you can taper that bowel using a step technique. This patient had refractory de-lactic acidoses. These are the data from the international step registry looking at 111 patients, 14 with repeat steps, fallout of one year, and then the third wean from parental nutrition, and sorry, two thirds showed improved dental tolerance, about half a wean completely from the end. Those who wean tend to wean relatively promptly, with usually less than a year. There have been multiple other studies around the world, both in the United States, Finland, elsewhere, Germany. They have looked at this and have had similar results and trends. So what other ways can we increase bowel length? As Errastee has shown, and of course, Alizarov was the first to show it, attention and used growth can cause growth of the bowel. We have been using extra lumenshape memory polymers, and that does grow bowel. These are polymers. And when placed in a liquid and warm environment auto expand, we continue to work with these. And now we are trying some extrinsically applied polymers, which fit almost like a sheath over the bowel and stretch them to grow bowel. Tissue engineered bowel is being worked on primarily by Tracy Grigscheid in California. However, this is something that is not close at hand for use in humans. How about transplantation? It's easy to become depressed with transplantation. This is a cover from Life Magazine. I actually have this Life Magazine. And it says the tragic record of heart transplants. It's 1971. All of the people that you see here had heart transplants within a year of having them they all died. And people thought, wow, that's a terrible idea of this transplantation. But in fact now heart transplants are routine around the world. And the same thing has happened with intestinal transplants. Intestinal transplants started in 1986 with David Grant at the University of Western Ontario and Canada. And now are actually becoming routine. Who should get transplants and stage liver disease, portal hypertension, severe quadrilopathy. And you have intestinal failure. Definitely should get a transplant. Serosis per se is not an indication. But I have seen proven serosis in this article. We showed that we have a 95% one year and 90% five year survival if they are transition to full anteline nutrition. So our patients just because they have intestinal failure is serosis. They do not get a transplant. But we do follow them carefully. Absence of IV access is another indication for transplant. Intestinal transplant is rare now. A potential improvement in quality of life. That I think is going to be the main indication for isolated intestinal transplant. Because there is going to be a group of patients that despite the very best battery rehabilitation is not going to lean from potential nutrition. And then in the end when there are adults or as they're nearing adulthood, they're going to have to decide if they want to live with parental nutrition or they want to try intestinal transplant. This is a case that HV did relatively early here, five kilogram baby. And it just shows that how technically these are in expert hands can be done successfully. Some multi-bisterile transplant. So what are the intestinal transplant data? Unfortunately they lag a little from the current. So the latest ones that are available are from 2017. An interesting thing with the intestinal transplant, with the intestinal transplant, surgeons themselves, note is there's been a 25% reduction in intestinal transplant numbers. And most of all of these are done in the United States. And the reason I hope is because we have better intestinal rehabilitation. However, there are over a thousand patients alive in the United States with functioning intestinal grafts. So it's no longer a one of and approximately 50% of those are children. The five year pediatric patient survival, this is patient survival, a isolated intestine is 75%. The first transplant was done in five years after I was an intern. So this is unbelievable progress. And the five year pediatric patient survival for liver intestinal transplant is 62%. Hopefully that is a demographic that with successful bowel rehabilitation will be able to reduce that there'll be less and less of those patients who will require liver and intestinal transplant. So in summary interdisciplinary bowel rehabilitation is the mainstay of therapy and great progress has been made. So surgical therapy is focused on preserving bowel length, maintaining reliable intravenous and natural access and establishing bowel continuity, bowel lengthening and intestinal transplant are viable options and successful patients. So what are the challenges one of my favorite quotes or at least a favorite quote and perhaps something that's a saving grace of the human race in general is the following that John Fitzgerald can be said. We choose to do things not because they're easy but because they are hard because that goal will serve to organize and measure the best of our energies and skills. And I think tackling very difficult problems such as intestinal failure is something like this. Of course he meant this in terms of reaching the moon, which was a somewhat more overarching goal. So what are our challenges in care? Well the challenges for the next 20 years are to eclipse the accomplishments of the first 20 which given the talent that we have in our group is going to be relatively easy to attain but realize that the challenges are going to change. We now are going to have adult patients with intestinal failure. Where are they going to go? Who's going to care for them? As we have greater and greater survival, we have to ask what is the quality of life of our patients and how do we optimize that? And lastly we have to ask how many of these patients are actually going to be truly functional contributing members of society. All of these are really important questions. It's important for care to help and create a network of interdisciplinary and test on rehabilitation centers that will prospectively track outcomes, organize investigations, improve quality of care and educate families. In the United States, hoping that the government will do that is not going to occur and we have to do that ourselves. And we need to ensure that every child in the United States with short bowel syndrome has access to the highest quality of care. That perhaps is the most difficult thing because it involves not only medicine but politics and education of the populace in general. Thank you. Oh before I finish, I do have one last slide. I do want to thank basically everyone for the last 20 years. It would just be thank you if I gave thank you to every deserving individual who's helped our program. But I especially like to thank Danielle Stan, Megan McGivney, Elizabeth Castle who are a nurse practitioner, who are the face of our program work tirelessly. Also to the surgical research fellows in our lab who also work tirelessly and care partially because they were press ganged into it. 13 of these are pediatric surgeons now for whom lead their own intestinal failure programs. Thank you. Well Tom, it's always nice to hear long term perspective. Some of us of your group, other groups here are spent every day slogging away and seeing patient after patient and admission after admission and infection after infection. And you sort of wonder like what are we doing? Right. And when you look at this in a 20 year perspective, you see the incredible value of all those little interventions and care points to make a difference. When I was a fellow, we had a patient with, I guess we can't say nectotallis anymore, but where it looked like everything was dead. When we opened open the belly in a very small premature baby, there was a very strong temptation. And in fact often them with chose to do nothing because the hope that we could give them was so minimal. You've demonstrated is that is not case anymore. You can have a patient with, I guess we now call it ultra short intestinal failure and have life. And you're now looking at quality of that life and productivity of that life. It's remarkable how this happens. It's not mostly surgical. It is mostly outstanding team based patient care. And when I look at these patients who come in out of the hospital and we put in central lines, we fix broken central lines and we put in new central lines and we deal with their clots and you only see these patients in the clinic on occasion or in some of us just went into the hospital. And I don't think too much about it. Having had the experience myself this year of taking care of my own central line and doing my own infusion to pick line. I was stunned how these families do this because I only had it for a few weeks and I was doing it myself and it wasn't 24 hours a day. It was just just three infusions a day. And like a couple times I broke sterile technique myself and I'm a male compulsive sterile, neat freak surgeon. So you wonder how these families with three other kids winning around do this. And I think what they do is because it's extraordinary extraordinary teaching and modeling by your team and what you've achieved in which you've transmitted across the nation across the world is really spectacular. I learned yesterday medical staff exact that there's going to be a hackathon sponsor of the hospital. You probably know this yet to figure out how to further decrease central line associated the bloodstream infections. Of course, because we're all being measured and scored around the country based on these. So the hospital itself is motivated. So I'm pretty sure something this room is going to win the hackathon as to how it's basically about how to decrease. Patients accretion stool from getting on central lines you've already demonstrated with ethanol locks the dramatic improvements, but because it's challenge out there for somebody to win a hackathon this. I think it's going to be this late this winter early spring. So so how are you going to get to to the next moonshot right turns out it was easier to get to the moon. Then the end of the end of the game this and and the interdisciplinary team has done this. What do you what do you think that that 20 years from now when you give the next 20 year report you're going to be saying to us. Well, if I'm not drooling in 20 years and I'm here, I'll be very happy. And I won't drool on my central line. That's true. I think honestly the key is to form a team that keeps asking questions, have very talented young people involved and continue that excitement. And in our field, the nice thing is that the patients that we have end up usually being intellectually normal children with great potential and just seeing that I think we'll keep the team going. And honestly, it's just continuing to ask questions. It's hard to predict all of the challenges that will occur in the next 20 years. And we in nutrition know that when we had nutritional support teams, things were much better and they fell apart due to change in economic model. The key is to just keep going and keep your eye on the prize. And I think it'll happen with the folks we have here. We have negative two minutes. Is there an inter a question comments I would like to make Chris maybe. Thanks Tom, really for an encyclopedic review of our history together. And truly if we're I hope we're not the ones giving the talks in 20 years exactly one of the things that we've done and have been proudly doing we can talk to each other at the And one thing you highlight the end was our good track record in in trainees and people have started their own programs and just to follow up Steve on your point, one of our trainees published a nice paper last year, which was a survey of neonatologists and surgeons attitudes towards what would you do if you had a 25 week or with the mid-god ball of the listen 10 centimeter residual bowel and half of the surgeons and unatologists would walk away from that patient. So I do think that the word needs to get out more about how we can best what the potential is for these children's rehabilitation. That training was Patrick Javit. Thank you. Thank you. Thank you.