All right. Good morning, everyone. We're going to go ahead and get started. It's my distinct pleasure to introduce our first Grand Round Speaker of the Year. And I want to start off with a little personal story by saying that the first time I ever stepped foot into Boston Children's was December 2018. I was flown out here for my interview in Critical Care Fellowship. And I sat in the back of this auditorium in a black suit at 4 a.m. and I listened to a Grand Round Talk about short bowel syndrome. And the reason that I bring this up, this story is because I'm sure all of you have heard Dr. Jackson's professional story, obtaining his MD at Queens University of Kingston, Ontario during his surgical training at the University of Toronto, PhD at MIT and nutrition and metabolism and his pediatric surgical training at the Toronto Hospital for Sick Children. You all know he started his attending life at Texas Children's Hospital before moving to Boston Children's in 1999 or 10 years later, he'd become a professor of surgery. And all of you, I think know that he's been the surgical director of the care program since his arrival in 1999. But in 2018, I didn't know any of those things. I didn't know what the care program did or what it had to offer for children with short bowel syndrome. Now as one of the pediatric surgery fellows entering their final year of training, this program and what has become is a routine part of what I do every day, as I'm sure it is for everyone. And I think it's easy to take for granted what has been painstakingly built over the last 20 years. On a personal level, I want to say that Dr. Jackson is a steady calm presence for the fellows, a constant professional, but kind and patient. Dr. Jackson's the person that I go to when I want to share a few light hearted jokes and jabs, but also who I ask when I have a difficult problem that needs advice from an experienced surgeon. What I hope for all of you and myself today is to go back and see this talk from the eyes of someone who is inexperienced, who can really appreciate what it is that the care program offers for these children. And so it now comes full circle and I get the honor of introducing Dr. Jackson. Once again, remind us of what we're able to do for children with short bowel syndrome and what challenges they still face. Thanks very much. It's a true privilege to give this talk and thank you for that very kind introduction. To understand where we are in short bowel syndrome, it's perhaps useful to discuss where we have been. And this is a portrait of John Hunter done by Sir William Reynolds. John Hunter is a renowned surgeon and justly viewed as the founder of scientific surgery. And I think as we look at short bowel syndrome, it truly is an excess between science and surgery. Much of what I'll tell you today is through the lens of the Center for Advanced Intestinal Rehabilitation. This is a true interdisciplinary program that is now and it's 2050 year as of September. And it's one that I was fortunate enough to found with Dr. Christopher Duggan. The things we have learned through this program will hopefully help the patients here at Boston Children's but also perhaps around the world. As is usual with any update, it's a bit iterative. We'll talk about mortality trends, definitions, incidents, causes and management current, which is contingent on appropriate nutritional, medical, and surgical interventions. We'll try to highlight the newer concepts and the remaining challenges in our field. Before the late 1960s, short bowel syndrome was nearly almost fatal in children. Peter Rickham, who was a surgeon at Alder Hay and Liverpool, gave the Hunterian lecture at the Royal College of Surgeons in 1967. It's edifying to look at that lecture. At that time, we could administer fluids, also lipid source. Intralipid was available from the early 1960s. And the protein source was an albumin. Unfortunately, the albumin is an unbalanced protein and does not support human protein synthesis. This all changed with a series of investigations done by Stan Duggan. One of the great pleasures of my career was to get to know Stan on a personal level. Stan did a truly amazing set of experiments while a surgical resident in working in Jonathan Rhodes, LaBarrate, at the University of Pennsylvania. What he did was he was able to grow beable puppies, and you can see the pictures on the top of this picture, which were fed intravenously, and they gained weight and developed just the same way as child fed animals below. And he was able to do this because the requirements of the eagle puppies were very well known. Fortunately, human nutritional requirements also by the mid 1960s were very well known. There are some investigators that have been long forgotten, such as William Rose at the University of Illinois, with very terrible nitrogen balance studies to find amino acid requirements. And Dr. Duggan was able to synthesize these and also made the leap that you should administer these centrally. And then he carried out the nutritional experiments he did in puppies in a child. And that child was at the Children's Hospital at Philadelphia. It was a baby with intestinal atreasia. And that truly was a huge change in how a short bowel syndrome was managed. And there was a tremendous increase in survival. For instance, here the survival for gastroschysis went from 20% to 80%. And truly remarkable achievement. Many surgeons went to visit Dr. Duggan. He always said that pediatric surgeons were his greatest fans. And this was reciprocated. And Dr. Robert Miller, from this institution, went and learned parental nutrition from Dr. Duggan. The next big jump in survival occurred with the advent of interdisciplinary teams. And this is an article that actually Bernmode was the lead author of. And it showed that our survival at Boston Children's Hospital went from 70% to nearly 90%. Now, subsequently multiple interdisciplinary teams have shown long-term survival's greater than 90% and we've documented those. Currently, the five-year survival of patients with intestinal failure at Boston Children's Hospital is 98.5%. And this accounts for all cause mortality. So before we delve further into this, we should give you some boring but necessary definitions. Pediatric intestinal failure is intrinsic bowel disease resulting in an inability to sustain growth or fluid electrolyte homeostasis. It involves congenital intestinal pseudo-obstruction, mucosal defects such as tuffing and neuropathy, and short bowel syndrome. Short bowel syndrome actually is a loss of intestine. And it accounts for about 80% of all intestinal failure in the United States. So when we talk about short bowel syndrome in an animal model, the definitions are not stringent, but usually it's a loss of about 80% of the small bowel. We also refer to ultra short bowel syndrome, which is about 90% of the small bowel. We have a working definition that we've used in the past for intestinal failure in children and that's intestinal disease leading to dependence on parental nutrition for greater than 90 days. There's been a recent consensus definition and like all consensus definitions is accurate but is somewhat complex. This from the American Society of Parental and Entral Nutrition, that's anyone receiving supplemental parental nutrition for a minimum of 60 days within a 74 day window is considered to have intestinal failure. So I think scientifically at least multi-center trials will hopefully utilize this definition. So we're all talking the same language. The incidence of intestinal failure is hard to pin down and unfortunately the studies that we have are very old. The first is a population-based study from the province of Ontario from 2004. It's about 2.5 for 10,000 live births. An interesting study which Boston Children's was a part of showed that the incidence of short bowel syndrome in very low birth weight neonates is about seven for 1000 live births. So one would anticipate that actually the incidence as we get better at saving these babies is going up. The causes of short bowel syndrome are things that we know well. Most common are nectatizing and are colitis. Short bowel syndrome patients with neck we have found have the very best prognosis regarding attaining full entral nutrition standardized for small bowel length. It's really important to avoid the term neck to tell us although it is appropriate in certain cases to withdraw care of patients who have nectatizing and are colitis due to concomitant morbidities. One should not do it merely because of their bowel length and we should just give the length of the Bible small intestine and the last of these references shows some outlines some very long term survival in our program even with the patients who are labeled as neck to tell us and then we're transferred to our care. Gastrischisis is the next major cause. It's a combination of sometimes Baha'u Loss but also Mopility Disorder. We've been working with the Vermont Oxford Network to get a 30,000 foot view of the progenitor diseases of short bowel syndrome and the survival in North America really is candy in the United States of gastrischisis is now 98 percent. There is nutritional morbidity. These children usually require a parental nutrition for 30 days as a median time. A small minority have severe motility disorders despite a full complement of Baha'u and require intravenous nutrition throughout their lives. One of the interesting things that we learned to this year's Aspen meeting is that the survival in Africa of gastrischisis is less than 15 percent and an important thing to know in Africa there is no parental nutrition for these babies. So I think this is a huge potential area where we could have an incredible improvement in survival and also since gastrischisis doesn't have attendant comorbidities such as some fallacyl in terms of cardiac defects for instance. It makes sense for in terms of years saved for the amount of money spent. Next thing is a intestinal entree here. This is type 3B. Intestinal entree here we always ask you to serve it to save this termillium. The reason is that these children by and large become fully and fully tolerant and it's just a little bit of the type of surgery we do. A newer thing that we have found is that there are patients with bile elalic TTC7 amutations that have combined immunodeficiency, pyloric atrician, multiple intestinal atrician, mucosal fiability and malabsorption. So if you see a patient particularly with pyloric atrician, it's very important to look at their skin smell and we have one incredible survivor who was now entering high school to HV did a multidisceral transplant on who also got a bone marrow transplant who is essentially a normal pre living eating human with us. Mid-dative ovulus is perhaps the thing that we fear most is pediatric surgeons when we see someone with bilious vomiting in the ER and one thing that I didn't anticipate until I got into this line of work is that patients with mid-degvolvulus and the loss of the whole mid-degut can be weaned from perential nutrition. And this is a paper from several years ago where we looked at patients with 9% of predicted bowel lanes who had mid-degvolvulus 7 of 12 weaned fully from perential nutrition took a long time about 1700-18 days as a median. And as time is going on there have been even more patients with this who have weaned from perential nutrition. So this is not a diagnosis where that is hopeless. It's also interesting that if you have gastroschesis plus mid-degvolvulus and a true loss of the mid-degut weaning becomes much more difficult due to the concomitant motility problems. Also with these patients beware of de-lactic acidosis we tend to feed these patients so hot they don't have an iliosycopalp they get a non-anagap metabolic acidosis so when you see that in the ER think of de-lactic acidosis the treatment is a treatment of bacterial overgrowth. This is a cartoon from one of our reviews and it makes the point that the short bowel syndrome is actually a multi-system disease it affects many organs and regardless of the etiology there's a fairly fairly stereotypic phenotype that results. The best treatment for a short bowel syndrome is anteline nutrition. It prevents further hepatic injury to a large extent and also it removes the central line which is in many ways the nitrous for infection and can kill these patients. This paper of that packet javid was the lead author on and it shows the resolution of hyperbilaropenemia in patients with intestinal failure associated liver disease with anteline nutrition. It doesn't happen like that. It takes usually about four months for the billiardrumants to totally normalize. An interesting early study from our group tried to correlate small bowel late to weaning from parental nutrition and the light colored bars are babies who weaned from parental nutrition and you can see on the obsessive residual small bowel length. At that time the 50th percentile or likelihood of weaning from parental nutrition occurred at 35 centimeters of small bowel. As time has gone on and for reasons that I'll explain later this is probably moved now to 20 centimeters but those of you who are carefully looking at the data will notice this tremendous play and the play is largely due to motility issues so you can have enough absorbed at surface area but if your motility is bad then you're not going to weaned for parental nutrition. But if you have to keep one number in mind now it would probably be around 20 centimeters. If you have 20 centimeters of small bowel there is a reasonable chance you will weaned from parental nutrition. Normal baby will have two to three hundred centimeters of small bowel. So sometimes we don't have intestinal lengths of measurements and one thing that we've been doing in our group is using serum citrallines, citrallines and intermediate in the urea cycle. It's made fundamentally in the intestinal neocosa and if you take a look at this serum citralline levels are highly significantly correlated with the antial intake, the higher the serum citralline, the more antial intake. Or if you look at it even more carefully this isn't actually a linear correlation it's a step function. If your fed and your serum citralline levels are under 15 micromole per liter, persistently you are very unlikely to weaned from parental nutrition. You just do not have enough surface area to absorb. So why are we successful at bowel rehabilitation at all? And one of the reasons is that the human adapts after significant bowel loss there is increased billisheit, crypt death and bowel dilation, sort of textbook knowledge, adaptation is thought to be enhanced by antial feeding. But one thing that's underestimated is a correlate that those of us who studied nutrition know as the clever equation. So it turns out that large mammals such as elephants have very low requirements on a per kilo body weight basis while smaller animals such as shrews, every high requirements. And if you think about what's happening to the human that's what's happening. We're going from very little high metabolic units to larger slower metabolic units. So let's take a look at these data. So this is a graph that was created by a ranopolarton. And the yellow line shows protein requirements on a per kilogram body weight basis over time. You can see that there's an almost exponential decline over time. And if you take a look at energy requirements, which is the red line, there's a little bit of a shoulder during toddler craziness phase and then another exponential decline with as time progresses. And as pediatricians, we know the holiday-sager role in terms of fluids and exactly the same thing happens with fluids. So if we can keep these babies going, time favors us. And it makes us look perhaps much better than we should look. That we're just actually playing out the game and that's how we went. So if it is true that that is a key factor, then we should see a almost symmetric weaning pattern. And that is in fact what we do. This graph shows percent of patients with neonatal onset, short bowel syndrome in our group, weaning from parental nutrition over time. And you can see that there's a 70% probability of weaning from parental nutrition over a 10-year period and there's a 76% chance overall of weaning. And that graph is very similar to our drop in requirements. So our intestine grows in proportion to our length. Even if we chop out a piece of intestine, it doesn't have any compensatory increase in length. This continues to grow as we grow taller. And by, it has to work a lot less harder proportionally as time passes. So what are we doing in terms of nutritional therapy? As you know, on the word, we follow growth curves very carefully. It's very important not to overfeed patients because that can cause liver damage in the old days. We used to consider parental nutrition hyperalimentation. That was an unfortunate tendency to give very high quantities of calories, which can destroy the liver. And of course has other deleterious consequences. And we've learned with time to be very careful around puberty in a recent article where Kate Calbrea's was the lead author. Patients with short bowel syndrome turn out to have tuberal onset in a normal time frame with an appropriate increase in height velocity. So it's really important during that time to provide them with the nutrients that they require. And we tend to be a little bit conservative in weaning patients during that time in order to optimize particularly their height. The other thing that we should all know is that there's a tremendous risk of metabolic bone disease. We simply can't stop enough calcium and phosphate in intravenous solutions, as we don't like bones forming in our IV nutrition. And that results in a low bone mineral density. In fact, about 34% of our patients have significantly low bone mineral density. One unpublished bit of data that was just looked at by Emily Ness. It says, someone unfortunate that despite optimizing as much as we can weight bearing exercise and giving enough calcium, we don't seem to be having a profound impact on this metabolic bone disease. So there's much work that needs to be done there. So, intermediate stuturational therapy and hepatotoxicity has been a problem, particularly in premature babies. And it's been shown to be associated with soy based lipids. The first of these studies were done in Paris. One of our gastroenterologists got a pre-trip to Paris to see if they were actually telling the truth. And what you found is that a parental nutrition administered greater than one gram per kilo per day of intralipid was associated with intestinal failure associated liver disease. And giving less than one gram per kilo per day in children reversed hyperbilarubinemia and short bowel syndrome. And that led to the Parisian model where they had a lot of success, where they stopped lipids totally in patients. They tested for essential fatty acid deficiency. When it occurred, they just give a dollop of lipid. And those of us who are old know that that's exactly how we used to give lipids, even adults, that we gave them not with measuring any levels, but just giving them once weekly. These are data that have been presented by Mark here. And these are a wonderful series of studies and humans that Kathleen Geron-Mark were responsible for. And what you can see is that if we switch the intralipid to an omega-3 formula, the brand name is a mega-ven, a proprietary formula, there is a drop in bilirubin that is very similar to what we see with the intral nutrition. Here you get about total normalization in about 20 weeks. So all of this kind of points to a toxin in intralipid. And in fact, that is what probably is at play. So right now, if you can give soy lipid formula one gram per kilo per day, which is all that many countries in the world have because it's the cheapest formulation. This is an FDA approved formula and given in modest quantities can alleviate intestinal failure associated liver disease. However, you need to follow lipid levels. Fish oil at one gram per kilo per day, a mega-ven, which was used as monotherapy, by our group here, does not have that similar loss of essential fatty acid. And it's interesting that there may be some, if you will, reverse synthesis of the essential fatty acids. Or maybe that the essential fatty acids aren't quite as essential as we think. And it's icosopentinolic acid, and ducosol hexadolic acid that are more important. And your formulation is small. That's what we use in the majority of our short bowel patients. We use that as the lead formula. It has one advantage. We give it in a little higher quantity, usually with 1.5 to 2.5 grams per kilo per day. We can give a mega-ven to 2 grams per kilo per day safely. However, small, the colligative properties are much better defined. And we can give it as a 3-in-1 bag, so we don't have to give multiple bags, as we do with a mega-ven. So what is the toxin? The toxin is probably, if I to steer all, the one that's most often investigated is stigmasterol. So it would be wonderful if we could just take that stigmasterol out of the formulas that are plant-based, soy-based. However, it turns out that's a bit of a biochemical trick. And the other thing that's, and I don't know how to say this kindly, so I'll just say it's straight out. One of the problems with this is that all of these formulas were developed. By a single company and are owned by a single company. And that means that various trials are bit scuppard by that and are attain to perhaps by commerce rather than science. But anyway, we certainly have made progress in this realm. And it has been really a pleasure to see this. How about continued liver dent injury? Well, one thing that we were startled by was that even patients that we converted to full-antro-nutrition, and you see that in the top panel, still have a persistent elevation and ALT. It's irregular, but it's still there. And in this particular study, it continued for greater than 20 weeks after the cessation of parental nutrition. And in the recent study that was published, we looked at in the area of the paddle protective PN, what happens to ALT levels over time. And unfortunately, 73% of PN fed patients, regardless of what kind of formula they're given, have persistent ALT elevations. And in antirely fed patients, that's about 16%. So the question arises, what is going to be the consequence of this? And we are obsession about following these patients' liver studies over time. How do we do this? Well, we developed a new technique to look at this stabilized atomic technique using one C13 mithyanine. It's an elegant technique. Mithyanine is metabolized in the liver metacondria. The one portion of one carbon of methyenine is cleaved in the first step of degradation. It collaborates with the CO2 pool. So just by measuring the C13 from CO2, that's expired. We can calculate how well the liver is working. This is, as you can imagine, a somewhat complex thing requires specialized instruments. And not the greatest thing to do in times of COVID, where once doing breath tests and breath electrons. What has sort of supplanted it is a fiber scan. You'll see that we ordered fiber scans in our patients. And its vibration control transient, allostography, it also correlates with the amount of fibrosis within the liver. And it also gives an index of statoces. We like to usually get a liver biopsy at one of the initial operations for short bowel syndrome and then correlate this over time with our fiber scan results. But all of these are things that are in evolution. And we have to find out what the long term effects are of intravenous nutrition. So how about infections and CVL loss? Well, this is another area of progress. We don't tie off vessels. We reuse access sites. We repair CVL breaks. We have our IR colleagues, new vascular interventions. We have careful patient and family teaching, including simulation sessions. We have a small molecule back here, cytolox. The most valuable of these is ethanol. And this was an old study of ours that showed 20% reduction in central line infection rates in patients who had central line infections. Then we're given ethanol locks very promising. But, and we use this, but it's important to note that now the standard infection rate for pediatric intestinal failure centers is 0.5 for 1,000 catheter days. And that's reflective of much better nursing care bundling of how we put in these lines and how we care for them. How about medical therapy? Well, if you're interested in medical therapy, we have a nice review in the New Moon Journal of Medicine. And since we're surgeons, we're not that interested in it. So we'll skip that except for one thing. And what I'd like to talk about is to do glatine. This is a long acting GLB2 ad log. It was really the work of Daniel Drucker. Daniel Drucker was a postdoc here in Boston and then went to the University of Toronto. He's an endocrinologist. And they were studying proglucogan. And of course, GLB1 is on TV all of the time now. It's an analog for weight loss glucose control. But GLB2 is also very important. And Dr. Drucker being a physician also knew that there were case reports of patients with proglucoganomas who had a majorian small bowel growth. So he did a series of incredibly elegant, basic biochemical studies. And he showed the GLB2 caused intestinal neocosal proliferation, caused bowel proliferation. And further, he substituted it to an a long acting anviline. The subsequent randomized control trials of to do glatine in humans, in adults, and in children are powered to show 20% reduction in PN volume. So although we are positive, it doesn't mean that these people have come up for anteline nutrition. In fact, to the contrary, in the pediatric trial, only 10% of patients who are given to do glatine come fully out in. Why is that important? Well, we have to learn what the benefits are of to do glatine, also what are the risks, but also have to factor in the cost. Costs about 20,000 dollars per month to be on to do glatine right now. So to do glatine is utilized clinically in short bowel syndrome children's, in short bowel syndrome children who are over one year of age, FDA approved. We have a registry that was run through Boston Children's Hospital. I'll show you some data very shortly. To do glatine requires daily subcutaneous injections. It is a hormone. So you have to give it every day. There is something called apraglutide that it's injected only once weekly and even longer acting analog. It's currently being evaluated in an adult-based three trial. This trial has just closed and we'll see what the data showed for them. So here, and I just have to acknowledge Lesette Emanes, who is one of our colleagues in the care program, Lesette ran the pediatric to-do glatine registry. There are 142 children enrolled across 14 sites. 34 of those were at BCH. We have 35 now total at BCH. We don't have the data from the registry. However, from our own data, three have weaned fully off-can and intravenous fluid. So that's roughly in the realm of what we have seen. The improvement is not linear as to some kids don't respond to the do glatine at all. So we have to figure out exactly who responds best. As with any news therapy, there are new complications. And one thing that our gastroenterologists have noticed, our phobia ulergastric hypereplasia, and this is basically our large hyperplastic polyps. Two of them have occurred right in the pre-piloric region and one in the cardi. So we'll have to see whether these are progenitors of malignancy in the future. And dosphopies are incredibly useful in short bowel syndrome. That's why we are continually looking at our patients. And you know, it's helped us understand bacterial overgrowth, the allergic aneritis, which we treat with amino acid formulas, intralate. But I just like to point out the last two articles in this list. The first one shows that if you treat patients with bacterial overgrowth with antrolanderbiotics, they have improved growth and decreased symptoms. So that's the first study to show that. The second study is I think even more interesting. And that describes a new disease, which is this inflammatory disease that occurs in patients with severe short bowel syndrome. It's an IBD-like disease. And it's taught perhaps to be due to the increased permeability, which allows antigens to cross and crosses an issue with the immunologic problems with the intestine. And we are trying to treat these patients as they were IBD patients. So how about surgical therapy? Well, surgical therapy, the principles are the ones that we always hammer into all of you. Preserve as much intestine as possible with the initial operation, particularly small bowel. One centimeter of a small bowel, if you flattened out the villa and microvillage is 80 to 120 times the surface area. So even though it's a centimeter, it's a lot more than a bed. Use second look operations and silos to obviate a compartment syndrome, obtain entral access early at G-Dub. Org can be converted to a GJ tube. Reestablished bowel continuity as soon as safely possible. That allows us to rehabilitate these patients promptly. The use of manometry preoperatively is something that's underutilized in North America. We're very lucky to have it here. It helps us plan our operations. And intra-op and doscapita truly understand the pathology that we're dealing with as surgeons is really important. So this is an x-ray of a typical patient with a short bowel syndrome. They have dilated bowel. And that's because the blood supplies at right angles to the intestine. The bowel doesn't compensate by saying, gee, I've lost bowel. I'm going to increase in length. There's no blood supply for it to do that. Instead, it gets wider. This is a useful adaptation until it is. And it can result in suboptimal absorption, disordered motility, bacterial overgrowth. The first operation to address this is the Long Etonal and Testinal Lengthening and Tailoring Operation, a LILT operation, or the Bianchi operation. I've got to know Dr. Bianchi as well. It was quite the character and a very courageous surgeon. It's a complex operation. You have to divide the mesenterian too and to leaves. Then you divide it and slide it isoparasitalkically and then ask the most of them and ask the most of the segment. So a lot of complex things. And of course, you can only do it once because they're only two leaves of a mesenterian. The next operation was the CO Transverse Center Planski. We had done a Bianchi operation on a patient of mine. They improved a little bit, but not much. And H.B. Kim, when he was a medical student, saw the Bianchi operation and said, gee, I think I have a better idea. And it was the CO Transverse Center Plasty. The CO Transverse Center Plasty just involves the flying staplers at right angles to the bowel across the mesenterian, making his zigzag a bowel at tapersit and lengthensit. The first paper was the animal paper which fell into the Dr. Folkman Rubric, interesting, it's true. And then we gave the first human example of this H.B. I think one of Rosencrantz award and nothing much happened. But then on a really slow news day on August 3rd, 2003, the New York Times put this on the front page, not because they were that interested in the step operation. They were more interested in how operations new operations evolved. And one thing that we did do was we had IRB oversight for this operation and IRB oversight of the consent process. And that's really what they were writing about. But they also drew how to do the step operation in one of the pages and suddenly people started doing the step operation from the New York Times. So we set up a little video to show them how to do that. And I think that helped survival over time. This shows the data before and after a step operation. This shows an in vivo step patient. If you're really interested in the science behind this, we have a paper in the analysis surgery and growing pigs where we used to reverse segment. This was the brainchild of Daria Pausa and he told us to try 50% reverse segment, who's absolutely right. In the 90% follow-the-section, we had step versus control. We found that there was decreased over growth after a step increased absorption, preserved motility in a subsequent study where beer and moody put motility catheters down pigs less than trivial endeavor. And we also found that they had increased surface area. The question is, well, why did they have increased surface area if you followed their citrallying level? They increased over time in the step versus control animals. And the reason is that you've linked in the bowel and then it re-adapts, so it grows bigger. And that's how it works. So I've never really understood why you want to lock off a huge chunk of bowel through a, if you have a short bowel. It's always better to try to preserve as much length as possible. So what are the mechanisms for this? This is from David Sigilette, when he was working at the University of Calgary and a rat model of stuff. Increases GLP2 receptor expression. Increases post-pandial GLP2 concentration. So in a sense, there's an interaction between what we do surgically and what happens with administering GLP2 exogenously. And I think it'll be very interesting in the next decade or so how the operation interacts with the administration of GLP2. Now obviously we're in an era where the administration of GLP2 is the first line of therapy. It's hot to be at this point, but I think that there's still a way for a bowel length. So this is a data from Hannah Piper, who was one of our fellows, who can repeat the step operation. Why do we do steps? Well, in test and failure, where antial feeding investment cannot be attained, we're attracted back to your lower growth and the innate latrisia. Those are the results of the international step registry. You can do it if you have back to your lower growth and you don't want to toss aside, absorb the area. This is a case report of a patient with a very guy led to do a dean of what we did a step obviously watching out for the fella. It can be done in with intestinal atreasy if you have very limited distal bowel length rather than throwing away, absorb the area you can step the proximal portion. One of the results, well, they're interesting. In the first 111 patients in the registry, 14 with repeat steps, 66% of the independent children showed improved antial tolerance, 47% of the independent children were weaned from the end completely. And subsequent studies by other groups have showed that the Bianchi and the step had never been compared head to head. However, sort of rough meta-analyses seem to show that the step operation is equally efficacious and sacred. What else can we do for ethyl agicentestinal reconstruction surgery? Well, tension and use growth is a fantastic thing. We did that with a company from Atlanta where you had auto-expanding polymers and you can grow bowel through tension. David Dunn's group and Stanford is doing that with rings. Tissue-entredeered bowel was first done by J. Vittonfee at Mass General and is still as an area of active investigation, but we're a long way away from utilizing it. How about transplantation? Well, the first published report of transplant was actually by Dr. Lilahai Zonkel, Richard Lilahai, the great Lilahai surgical family that were privileged to have here. And in 1988, where the first long-term survival, one in Kiel, Germany, went into University of Western Ontario in Canada. Over the past 30 years, technical issues have been largely resolved. This is a five-kilow patient who received a multi-visual transplant from HV. It's quite amazing what technically things can be done. What are the indications for transplant and short bowel syndrome and stage liver disease, portal hypertension, severe coagulopathy? Serosis per se is not an indication in our own data from the care program. If you have serosis, you still have a 95% chance of five-year survival if you're an antially family. Absence of IV access now a relatively rare problem, but thromboambalism remains a problem for all of us. There's a new article in Journal of Pediatrics, where Bearing is the senior author, which shows about 28% of our patients have a cumulative incidence of thromboambalism. And this is an important area where we need to get better. The other indication for transplantation is potential improvement quality of life. I think particularly patients who have motility disorders tend to have a bad quality of life. And it may be as they get older, saying around 18 that they may choose this. But there is a problem with that in that they accept a higher mortality. These are the current data on intestinal transplant. These are from 2022. All of these are look retrospectively. So the 2022 data actually are 2020 patients. They're over a thousand patients in the United States alive with intestinal grafts, about 50% are children. They are some encouraging one year graft survival data, but the three and five year grafts' survival are unchanged from 2009. The current five year survival for intestinal intestinal liver transplant is 60% and unlike what we thought before, there are no survival differences between isolated and test nerve combined grafts. Last year in this 2022 review in 2020, there were only 34 patients worldwide who received pediatric intestinal transplants. It's a 64% reduction from 2009. It probably reflects an improvement in intestinal rehabilitation, but that doesn't mean we should stop doing these because they are definitely patients who will benefit from these transplants. And hopefully transplant will improve over time as it has in almost all other transplants. So what have we said? Well, first interdisciplinary bowel rehabilitation is the main state of short bowel syndrome therapy. Great progress has been made nutritionally, medically, surgically. Surgical therapy is focused on preserving bowel lengths and maintaining reliable intravenous and antial access, establishing bowel continuity, and promptly treating complications. That's why I think surgeons really need to be part of these programs because the first question we always ask is what is the plumbing like? What is the anatomy and surgeons are the best to address those issues? Bound lengthening and test on transplantation or viable options in select patients? So what are our ongoing challenges? Well, now that we have these patient surviving, how do we optimize our quality of life? And, uh, uh, Beeren and Patrick Javid are doing some excellent work in this realm. There's a new cadre of patients that's surviving to adulthood. How do we appropriately transition care? The answer is I don't know right now. We're trying. And how do we make short bowel syndrome treatment available and affordable? Because what we have in the United States is not what is occurring in poorer countries and that remains a huge problem. And lastly, I'd like to acknowledge all of the people who related the work for a large percentage of what I presented. These are our surgical research fellows that worked in the care program. The majority of whom are pediatric surgeons and will undoubtedly be the leaders of these field in the future. Thank you. Well, thank you, Tom, for that extraordinary talk. I'm going to say surprised at your concise review of really an entire evolution of a field. It's stunning what can you accomplish in the course of a career. And, modestly, as always, Tom gives credit to all the rest of the people on this slide and not on this slide who participated in this evolution and a several which are in this room and on the Zoom screen right now. You give credit to those before you. Obviously, Stan Dundrick, Jonathan Rhodes. I'm not sure we can go back to John Hunter. I get him credit for anything. In Salve, he's short, but he didn't make us all a surgical scientist. I wonder if you kind of ended with what the challenges are now. And it's extraordinary that the challenges now are things that were at best side issues 35 years ago. Right? From both says, oh, yeah, we had infections, central lines. Yeah. Is the child going to live or die? Is what we were worried about then? And at least in this country in well-resourced institutions and portions of the society survival is not guaranteed, but it is it's extraordinarily high. If you were to take another 30 years, right? Take out your crystal ball. You mentioned we're not really there with tissue engineering of small ball. Transplantation, we're not much better than we were a decade or two ago, really, for intestinal transplantation. What do you think your successors 30 years from now are going to be saying are the things that have gone by and the things that are challenges that remain? You know, I think all of these exciting surgical things like transplant and ball attention and these growth are fantastic. But really the challenge now is how do we turn these patients into normal contributing adults in society? And that is my big question now. And I think one that's being addressed by the current group of pediatric surgeons is we have these folks who are now alive. They're getting here at night. Some of them are maroon 25% are marooned on parental nutrition. How do we get these people to be functional members of society? And even those who are receiving an antial nutrition, how do we do it? And I think people will need to really study that and figure that out. We've got them to survive. But how do they become totally functional human beings? Their challenge. Other questions or comments for Dr. Jackson? I'm sorry for the naive question, but you talked about the definition of short-bounce syndrome, PN dependent 60 days out of 74. How do you as a specialty define that? Is it 100%, 50%, how do you deal with the partial dependence? And then how does that factor into all of the subsequent studies looking at how you come off? If you start at 50-50, do you have a greater chance? I'm just wondering how you deal with that variable. Yeah, so you know this definition is more of a scientific. So we all have a common definition when we write papers. But as a clinician, it's far more murky, right? Because you can have a patient, as we showed you, with the endorsky data, people we meaning from parental leadership, 10 centimeters is a small valve, and they win fully from PN. In their 50-50, we predict that they mean an exponential pattern, but some don't mean. And they obviously have short-bounce syndrome. And there are some patients who have intestinal failure in our program, who have gastric pieces, who have a full complement of small valve. So it really gets them. I think I had another career, which fortunately for most of you, I don't. They, I really like to study mortality because us better understanding that will be factor in how these patients have been overdone. So the way we do it really faries, we, you know, since all of these patients become hypercagin, right? And in order to overcome their short valve, we have one guy who's a root for on the case. He starts every morning by eating sick donuts, you know? And then obviously I think of front valve movement. But, you know, that's what you have to do. So we don't really look at the entry link date component. We look at how much PN you're leaning from. Last minute or so, any other questions or comments? We're a little bit over-voicant. Great. Well, Tom, thanks so much as always for not only your contributions, but for attribution, synthesize it and have a stomach sense for us. And just another one of the sort of really complex problems in in pediatric surgery and and and the realm where member of our faculty has been central to the really transformation in the survival and outcome for for these children and their families. Something really to celebrate and to continue. Thanks for all your contributions.
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