Autologous intestinal reconstruction surgery in short bowel syndrome

Uh, I would say good morning everyone. For me it's morning, but, uh, good day everyone, it's easier. Um, to, uh, uh, another of the, uh, UUSA Ernica webinars, um, today we have uh two. Exceptional guests, uh, uh, Miko Parin and, uh, from Helsinki and Lukas Vessel will talk about autologous intestinal reconstruction surgery in show bo bowel syndrome, rationale and practice. Uh, Mikko, uh, needs no introduction. He's, uh, the chief, uh, of pediatric surgery in Helsinki, also professor at the University of Helsinki. He's the editor for Europe for a Journal of Pediatric Surgery, and he has a specific interest in, uh, uh, short gut syndrome and, uh, intestinal failure. So, over to you, Miguel. Yeah Eager to hear more about this very controversial topic. Thank you very much, Avio. It's a, again, great pleasure to participate in this webinar which is a joint, joint action of, of UPSA and, and Ernica. And Gaia, would you share my presentation? And if you go to the 3rd slide to begin with. Next one, please. OK, here we go. So in this presentation, Yeah. In this, uh, in 15 minutes or so, I, I try to sort of, uh, outline, uh, what's the significance of, of small bowel dilatation because as you all know that the, the dilatation is sort of basis of, of any kind of, uh, autologous uh reconstructive surgery in these patients. Uh And uh I'm sure all of you who are working with these patients have confronted the patients where there is, there is small bowel dilatation and then you wonder, is this significant? What's the uh sort of a clinical significance of, of this, Is this pathological and, and why is pathological and all we know that many of these patients with very severe dilatation, they, this, it's associated with, with the problems, unable to advance enteral nutrition. Prolonged PN dependence and liver problems and so on. But um it would be nice to have some sort of a theoretical and pathophysiological basis when we assess these patients and, and know what we are doing and possibly even more. Is, is that what we're doing surgery? Is it, is it beneficial, and if it is, in what ways? So to address this issue, a few years ago, we analyzed all available country studies, all altogether, almost 180 country studies in 50, 50 different small uh individual short bow patients. And what we did, we measured the maximal small bowel diameter and it was uh marked by X in the figure, and we also measured the height of the 5th, um. A lumbar vertebral column in order to to, to address a ratio, what we call small bowel diameter, uh, small bowel dilatation ratio in, in addition to, to absolute diameter. Next one. Next one, please. So, and, and we published these results in 2017 and about the same time as actually these two papers came out electronically about the same time. One from Ann Arbor, Michigan, uh, from a group led by late, uh, Daniel Teitelbaum, and one from, from us in Helsinki. And such to, just to show you the, the sort of proof of principle that in both of these studies, the, uh, absolute small bowel diameter as a continuous variable was a significant predictor of, of, uh, duration of parental nutrition. As you see in these red boxes, and this was, uh, in both studies also, of course, the, the remaining small bowel or expected remaining small bowel length also predicted the outcome, but what's important is that also the diameter uh turned out to be a significant, uh, factor. And the next one, please. So, we went on and tried to look into the dilatation a bit more uh detail, and like I, like I told you uh before is that we also uh measured the small bowel diameter ratio. And that's mainly because, as you all understand is that if you just look at the, the absolute diameter, that obviously will change, uh, depending on the pace and age and size and so on. So in this figure on your right, you see the uh couple of Meyer curves of the duration of nutrition in, in patients with different maximal small bowel diameter. And as you can see that those patients with greater than 3 centimeters of diameter, they did worse than those patients with a uh not so wide small bowel. But if you look at the figure on your left, you can see the situation when we addressed the small bowel diameter ratio, and that actually looks much better in, in In a way that those patients having less than 2, the ratio dated significantly better than those patients which had a small bowel diameter ratio over 3 or between 2 and 3. So we, we sort of all thought these were promising and went on to, to look into this in a bit more detail. Next one, please. And what we did next was we just uh performed a Cox proportional regression analysis of uh weaning off PN for different variables and just to begin with, to show that both maximum mobile diameter as well as the uh You know, the maximum small bile diameter ratio and as well as the absolute diameter were in fact uh significant predictors were assessed as a continuous variables, and both of these were, of course, uh, were also significant when were divided into different classes of, of dilatation. But as you can see that those patients having A, a ratio below 2 were about 14 times more likely to wean off than those patients having a diameter ratio, uh, of above 3. And was probably more important when we did the multivariate analysis, you can see that the effect of uh small bio diameter ratio uh preserved, was preserved in addition to uh the effect of small bowel, uh, remaining small bowel uh length and the The effect of LLC Calval was uh borderline significance. So, in addition to these very traditional, uh, prognostic factors, these findings to us clearly, uh, suggested that, uh, that also a small bowel diameter is a, a significant player, uh, in this game. Next one, please. And then we also wanted to look how does the small bowel diameter uh affect survival in these, in these children and, and as you can see in these figures that those patients having either a small bowel diameter ratio of 3 or the uh or between 22 or 3, they were doing worse than those patients having a diameter ratio below 2. And this was true when we included all the measurements on the, on the right side or only the maximal measurement for individual patients. So, Short summaries that we believe that these studies show quite clearly that, that uh small bowel diameter or pathological small bowel dilatation is a significant predictor, additional predictor of outcome of this patient in terms of winning of PN and also survival. Next one, please. So then we went on and try to figure out what could be the limit of pathological small bowel diameter ratio and for that we performed our analysis of, uh, for weaning of PM in two ways. One included all the measurements or To just the maximal measurement for individual patients, and this provided a very similar Arak values around 2.75 and we chose as a cut of the Uh, the, the value which provided the biggest sum of sensitivity and specificity, and this proved to be 2.17 when only individual patients were included, but it was very similar also with the, if all the measurements were included. So we Took this as the most accurate, accurate predictor of Pindependency and also use this as a pathological uh cut off for pathological dilatation for, for, uh Additional studies. Next one, please. And, and the next one of course was that the, because the sort of a common thought is that dilatation is, is uh associated with, with the Uh, intestinal, uh, dysbiosis and mucosal damage and, and we'll know it could be associated with liver injury and in the next, next study, uh, we try to sort of, uh, see if we can, if we can really show these, uh, effects in, in human patients with Scherbowel syndrome. And we, what we actually did, we compared the patients with the pathological uh small bowel diameter ratio of 2.17 or more to those with less than 2.17. And as you can see in the table, those patients with pathological dilatation ratio, they had a higher calprotectin levels, significant mucosal inflammation, their citruline levels were lower, uh, probably suggesting, um, Uh, sort of a worse state of mucosa and they also had higher GGT levels which suggested, uh, a more, uh, liver irritation or, or, uh, or sort of a cholestatic or pre-cholistatic stage. Next week, we compare the, uh, sorry, uh we compared the incidence of bloodstream infections caused by intestinal bacteria in these groups and as you can see that those patients with pathological dilatation, the number of intestinal derived uh bloodstream infections were much more prevalent. And next we also looked at the results of, of liver biopsies and observed that those patients with pathological dilatation more often presented with histological cholestasis. So based on these findings, we, we concluded that there is a strong clinical evidence that pathological small bowel dilatation is actually associated with mucosal damage uh. Uh, uh, bowel derived, uh, bloodstream infections and, and liver cholestasis. Next one, please. And this picture just shortly sort of summarizes what can be. Uh, sort of all hypothesized based on these studies that, as, and I'm not saying it's all based on these, but, but these, our findings support these, uh, this sort of a line of thinking that first you get dilatation, this motility, which leads to, to dysbiosis, and mainly increase in proteobacteria which are able to cause mucosal injury. And, uh, which leads to defective barrier, uh, function, and these give rise to malabsorption, bacterial translocation to portal circulation, and finally, liver injury. Next one, please. And I'm not going in very detail of the practical operations because Lucas will tell you uh much more about that, but what I'd like to show just a few, few slides is that what's actually happens in these patients after the um autologous reconstruction procedures and in this respect. Uh, this is just a slide for a couple of years back, uh, summarizing our experience with these patients, but now, in the next few slides, I will talk about the patients who underwent step, lilt, or just a simple tapering. And the reason for this is that all these procedures are sort of uh, the goal is the same, to, to taper the bowel to more or less to the normal size in order to improve motility. And, and sort of uh uh make these. This motility and probably associated, uh, this bias is, uh, less severe. Next one, please. So if you look at the The sort of all the total. Total duration of PN in these patients who underwent, uh, most, most of them had undergone step procedure, and it is clear that even after adjusting for remaining small bowel length or pre, uh, presence of aocecal valve, those patients who underwent tapering, their total, uh, duration is longer, which is quite natural because they have, most of these patients have more, more severe, uh, Disease and they, so outlook is not that, uh, the outset is not that good and those patients who don't need the surgery. But however, in, in figure B, if you, if you look at the duration of PN after the heart surgery, you can see that the Kala-Myerge curves are basically identical to those patients who didn't undergo surgery, which can be interpreted in a way that The our surgery in these patients can sort of uh uh restore their clinical situations to the, to the ones which didn't have this uh uh dilatation problems. Next one, please. And of course, if you look at the sort of uh individual Data of these patients, what happened after tapering surgery is that the small bowel diameter ratio significantly decreased. The all bloodstream, bloodstream infections in decreased, intestinal bloodstream infection actually also uh decreased and after the procedure in this series, we didn't have any, and the liver uh values improved, albumin improved. We didn't find any, any increase in citrullin, which I personally don't find uh very surprising because you're, you are not actually making more bowel by, by tapering it or, or dividing it. But we also found a borderline decrease in, in, in calprotectin, suggesting that probably the inflammation was, uh, was lessened after the procedure. And next one, please. And just a few words about the rehabilitation because it's, it's obviously a, a very central problem in these patients occurring about 40%. In, in most series and, and just a few words about the study, we did the incorporations which, with ped pediatric surgeons from Sweden in, in several centers and in that study we included 27 STEP patients and about 40% of them um had underwent a repeated STEP. And actually, the only predictive factor for that, what we found was that those patients who didn't have all cecal valve were much more likely to undergo repeat, repeated procedure. And what might be causing that is that this is from another uh work is that it seems that those patients not having isocecal valve, they, they presented with less crip cell proliferation, but on the other hand, more severe mucosal inflammation. Than those patients with retained ICD and of course this might be mediated by, by GLP-2 or, or, or similar an endocrine hormones which are secreted from, from that area of the bowel. So, this was sort of a short summary of the, of the rationale of, of the surgery, why, why you probably should expect that if you, if you choose the patients correctly, you might, might find that, that the oncologist reconstruction procedures. Leads to, to beneficial effect, but I'm, I'm sure Lucas will tell you more about the selecting the right patients and, and doing the actual procedures. Thank you very much. Thanks, you too. OK. How do we change? Screenss. OK, perfect. I see Luca's talk already. So, um, welcome everybody from my side also. I have the pleasure to introduce um Professor Lukas Vessel. He is head of department of pediatric surgery at the University University of Mannheim in Germany, and he is an ERICA member um from the start, um, has a lot of clinical interests, um, not only in uh treatment of uh CDH but also in um treating of children with shortcut syndrome and especially chronic liver disease. Uh, and Lucas has not only experience with The SEEP procedure, Lucas, uh, um, Nico mentioned, but also with the Bianchi procedure, and I'm sure he, he will talk about that, um, too. So, Lucas, it's a pleasure for us to have you here this afternoon, uh, with us, and, uh, we are looking forward to your talk. Thank you, Martin. Thank you, Augusto. Thank you, Miko, for your introduction, which is really, um well, well done, I think. And I hope that I can continue a bit about it. Well, um I started in pediatric surgery in Mannheim '91. And 10 years before, my former chief, Karl Ludwig Mark was the first one to introduce the Bianchi procedure in, in Germany, and he started it in Mannheim. So we do have a lot of experience in uh bowel lengthening in, in short bowel syndrome. Um, Together I think we had more than 100 patients treated. So my disclosure of conflicts of interest, I am in the advisory board of Takeda, the Takeda Group for Shire, that is the The, the company who is, um, uh, producing uh Troglutida. So when we speak about short bowel syndrome, it means that we talk about children suffering from intestinal failure. The intestinal mucosa is not able to sufficiently absorb proteins, energy, fluids, and electrolytes. And this can only be realized by parenteral nutrition. In many cases, patients are suffering from dilatation, leading to malabsorption, madigestion, and failure to thrive. Dependency on parenteral nutrition will exist for more than 4 months, and the residual small bowel length, in fact, is irrelevant. Only optimal treatment will be uh affords an interdisciplinary team, as stated by Mico already. Um, so also in Mannheim, we have a lot of pediatric surgeons, but also gastroenterologists, dieticians, nurses, ambulatory service, and EPN, uh, service psychologists who are working together. The major issues are loss of resorptive mucosal surface and capacity and the motility disturbances which Mikko mentioned already, so the impaired transport, but also malabsorption and madigestion. This leads to the increasing dilatation with impaired transport, bacterial overgrowth, translocation, sepsis, and liver disease, as you can see in this baby. Liver disease is associated to intestinal failure or to parental nutrition. Mice, Most of the times it is both of the two. But as you can see, this is the same child. Some years later, it can be resolved when you have a good option, a good therapeutic option. Consequences of these intestinal failure is the dilatation, as you can see in this chart, that is the chart on which you could see, um, on the former slide. First of all, It is important to avoid short bowel by preventing ample resections. Second loop procedures and laparostoma may help. It is crucial to avoid long-term enterostoma. When it is inevitable, do restore the continuity as soon as possible after resolving septic complications. Fasting has a negative trophic effect. Breast milk is best, besides complex nutrients. The impact of a stoma, so leaving an enterostoma, means not utilizing all of the resortive surface, especially in deactivated bowel. Most in jetinum, people will have a high output stoma, hampering resorption of fluids and electrolytes. Risk of liver disease. is increased by endotoxins, reaching the liver by the portal route, and it is associated with chronic inflammation, fibrosis, and cirrhosis, as already stated by Mikko. Well, beware that the bowel is still remarkably growing in the first year of life, so do not plan lengthening too early. In our experience, do not do it in the first year of life. In our cohort, there were at about 10 children growing remarkable length growth depending on which part of the small bowel was preserved. In the case of small bowel atresia type 5, only small parts of the bowel could be preserved. You here see the small part of jedenum and, well, some centimeters of ileum. But after early restoration of continuity, weaning could be achieved at the age of 4 years. And when all of the colon and the ileocecal valve can be preserved, it is marked and it is better. In the past, several procedures were tried to ameliorate resorption and transport like anti peristaltic segment, valves, colonic interposition, or blind loops, all without positive long-term effects. Until 1981, Bianchi introduced lilt, and 2003, SE was introduced by Kim. Well, indications are dependency on parenteral nutrition and massive dilatation with bacterial overgrowth, so you must have a double diameter of the small bowel, but not less than 5 centimeters, otherwise it is. Technically not really possible to make A Banke procedure. You need to eliminate reservoirs for bacterial overgrowth and translocation like stenosis, fistula, and blind loop. But beware of supposed stenosis like in this case here you can see part of the colon which has a normal diameter, and this is not a stenosis, but it is the effect of the dilatation of the small bowel. Contraindications are motility disorders, especially CO, or if you don't have dilatation of the small bowel, this will be a technical problem. And in these cases, as Mikko already pointed out, you have a good chance of weaning. In case of severe liver disease like portal hypertension, impaired coagulation, uh, you first have to address the liver disease before operating, otherwise, the child will not survive the bleeding. When there is no possibility to insert a central, a central line anymore, I think it is wise to contact a transplantation center to talk about the best option. And in distinct caraxia or sepsis, you first have to treat it. Here you can see a child with CIO and in this case, uh, uh. Restor, um, well, bowel lengthening will not be useful. There are two methods, as we already heard Bianchi, according to Bianchi, called lilt, longitudinal intestinal lengthening and tailoring, and the step procedure, serial transversal androotomy procedure. What about the literature? Well, in the last publication from Manchester, Bianchi and his group showed better outcome following Lilt with better survival and less need of TPN. And multidisciplinary approach and teams are advocated. Treatment of intestinal failure should be centralized. But on the other hand, there is much doubt about the usefulness of lengthening procedures as stated in this, um, publication of British gastroenterologists. Especially bowel expansion, the heterogeneity of surgical procedures, and lack of knowledge about a spontaneous improvement in adaptation is unknown. These colleagues question the advantage of surgical procedures. So that's the fact, uh, which, uh, which, uh, with, with which we are confronted for the moment. So for the future, there has to be done for studies also because these procedures are very challenging and not easy to perform. Most of these children do, um, show a lot of tough adhesions, uh, which may be extremely difficult to release. You may choose a, um, an oblique or, um, a median incision. The principle is that you have in the mesentery leaf vessels going to the right and to the left of the bowel and running back, and these must be separated without compromising the viability of the small bowel, so that at the end, at first you have one intestinal plate and you will have to make two plates of it. Well, uh, with trans illumination, it may be more effective, but, uh, you should control, um, the preparation also, uh, always by several persons not to run into complications. After creating two intestinal plates, these must be tuberalized again. In former times, this was made by hand with separate or running sutures. This procedure, they take a lot of hours to complete all stitches, as you can imagine. Here I can see for the better understanding what we are doing after having created to uh Loops of, of, um, intestine. So we make the, uh, semicircular. Um, continuity, continuity of the small bowel. Nowadays we use the stapler of endogia, which make the procedure much easier and quicker, but you have to take care that there is no leakage despite the stapler. Staples may be the reason for inflammation and cause ulcers resembling. Crohn's disease. This is how it looks afterwards, and you can see that the diameter is much better after the procedure. It is important to have good anastomosis without stenosis. This is what Nico already, uh, showed, the step procedure, and it is important to have a smooth and more or less the same, um, diameter everywhere. Well, in, intestinal lengthening, um, you will, In fact, never reach more than half of the of the lengthening because you divide the The intestine in two. In this step, it should be possible to have more lengthening afterwards. Um, weaning off is possible in both. Um, I think it is always very difficult to compare both of them because Lilt was started a lot of, uh, a lot earlier. So sometimes you are, um, comparing oranges and apples together in the 90s and in the 80s, there were, um, much other, um, Therapies afterwards, and it was not so, we didn't have these, um, interdisciplinary order or multidisciplinary teams. Mortality, um, was at about 23%, but not related to surgery. Um, That is the same for a step procedure. Mortality mostly, um, is depending on the underlying complications like liver failure, sepsis, and pneumonia. Complic complications can be in both, um. As you can see, um, a lot of, well, one of the problems is intestinal necrosis in, in lilt, which we did not see until now in Mannheim. Perforation and inter-enteric fistula is, um, well, a, a problem. Here you can see one case report in um a child uh suffering from gastroschisis with incarceration, and he had um a, a marked dilatation with a lot of sep septicical complications, so we decided to perform the Bianchi procedure, uh, early. And afterwards you can see that his weight was catched up and that also his length was, and he was growing better. Issues is the relapsing dilatation after lengthening. It is, uh, well, as Mikko already stated, primary dilatation is pre predisposing to relapse and does have a, um, a worse outcome also in our experience. Um, in step, we did see the dilatation earlier and more marked than after lilt, and well, we also see that it is due to bacterial small bowel overgrowth that can lead to stenosis, ulceration, and also fistula in the operated bowel. Local cyclic antibiotics are very controversial. We did, um, apply it in the past, but, um, today we try to, well, to, um, To do it not all the time and to also to have, uh, times that without, um, without antibiotic therapy. Probably sequencing of stools may be helpful in order to know which bacteria are very, um, problematic. The role of pre and probiotics is controversial. Here you can see the, well, um, Like, um, an inflammation, like in Crohn's disease, it is called Crohn-like disease. Um, yeah, and in some of the babies, the, the, of the children, we had marked diarrhea, vomiting, and failure to thrive. In this case, you can see stenosis or Like here after the Bianchi procedure, um, an enter enteric, um, fistula, which also is very difficult to, um, to resolve, but it is, well, it is possible, but you, we had to intensivate the parenteral nutrition afterwards. Here you can see that when The Um Uh remaining. Um, bowel is very small, less than 20 centimeters. It is, in general, not possible to wean off TPN, um, but it is better than in step, in the step procedure. Um, outcomes, uh, when there is a lot of colon left, um, then the outcome is much better than when colon is, um, is failing or only 20 centimeters, something like that. Most important questions are, is intestinal lengthening worthwhile, as, uh, Niko already stated, you are not able to produce more resorptive surface, but it is the diameter which is, um, which is, um, um, ameliorated. Um, is that recommendable in all cases, and the time point of lengthening procedures are not, uh, really. Um, clear. How to face with redilatation, with bacterial overgrowth, and with anastomotic ulcerations due to To the, um, And Eclipse, no, not the eclipse, the, um, the staples. And are pre or probiotics or the GLP two therapeutic options in children. Um, as for GLP-2 therapy, there are some premises, do not do it in the first year of life. It is, um, Well, appropriate for patients with congenital or postoperative short bowel syndrome, and if they have an intestinal failure, independent of the remaining length, and they should be dependent on TPN. Um, But do not do it, um. Before you. Tried to improve the situation under home parental nutrition, and the children have to be in a very stable condition and wait long enough after restor rest the surgical procedures, at least 6, better 12 months. GLP-2 therapy may be. Worthwhile Um, we tried it in 3 patients, but only when they are on oral and or enteral and a bit of parenteral nutrition. In one case, we had, um, a child with very severe small bowel syndrome, remaining only 40 centimeters of jedenum and 20 centimeters of, um, rectum and, um, sig sigmoid. And we tried it because of, um, marked, um, Um, malabsorption and also, um, Bacterial overgrowth and in this child we had a good improvement and for the moment she is off parental nutrition, but it is only one case. Um, it should be optimized, but we have to rule out stenosis, motility disorders, and it is unclear whether bacterial overgrowth may be a contraindication. One case is only one case. Um, well, it is very important to have a good, um, follow-up of these, uh, patients. Uh, I will not go further to it. Um, intestinal failure, especially, especially short bowel syndrome, is severe and a very serious condition. Optimization of parental nutrition is always important. For the diagnostics, we need weight, bloods. Urine radiation methods, also for monitoring and for planning further therapy. Best results are achieved with our interdisciplinary and multidisciplinary approach. Uh, also for choosing which kind of lengthening procedures are appropriate. GLP 2 therapy may be, um, yeah, possible to further optimize oral and enteral and parenteral fluid and food, food supply, but, uh, well, we are not, um, we do not have enough studies about it to be sure about this, um, kind of therapy. And well, Thank you for your attention. This is one child after one week, um, performing the Bianchi procedure. Thank you, thank you very much, Lucas, for the very nice talk and also, Nico. There are a couple of questions in the, in the chat already. And the first one is, um, regarding another lengthening procedure called the spiral intestinal lengthening and tailoring the silt. Any experience with that? No. Um, I don't think, well, yeah, of course, you, I am not convinced of this method. I must con con um, yeah, I must, um, say, um, because I don't see the, the real, um, advantage, um, when you compare it to the Bianchi procedure. When it is possible to do the Bianchi procedure, I think you should do the Bianchi procedure and not something else. Yeah, if I, if I may say something relating to this, and what also what Lucas said that is that It's very difficult to because. If, if you're Perfectly honest to yourself and very critical. And as Lucas said, there is no evidence that these procedures make these patients better. There are, of course, these few patients which are doing very badly and it's quite obvious that when you work with these patients that, that they might uh benefit from, from any type of, you know, step or lilt, but at the same time, the situation being like this. I think the less is best. I mean, I think we should do the least. Uh, The smallest procedures and only for a real need because like I said, there's a lot of things we don't know yet and it's very difficult to choose these patients. And even more, it's almost impossible to, to sort of uh very critically choose the right patients for the operation because some of them are not doing very good in the long term. And to know that which patients are those, it's currently, we don't know that. Mhm. OK, thank you. OK, the next question again for both, uh, is, uh, is there a perfect, uh, or ideal age to operate? We heard that it's better not to do it when they're infants below one year of age, but When, when do you think it's the ideal age to, to do these procedures? Well, um, we always, uh, decided together with the pediatric gastroenterologist, and in fact, it is when we have, um, a marked dilatation and we have a lot of, uh, septic complications. And as also Miko stated in his, um, yeah, in his, um, uh, could, could show in his, um, publications, when there is liver disease. I think this should be, well, a possible option, and then we will decide, yes, we do it when we do see that there is no more optimization anymore after, well, Doing, uh, Changes in enteral and parenteral nutrition. Mhm. Yeah, I mean, like Lucas said that also it's the same with us that very rarely below the age of 1 year when you do that. But it, it's also, I would like to point out that some of these patients have quite uh marked dilatation, and they are doing perfectly fine. Weaning off, you're able to reduce the pm so. And that, that's the issue is that It's always with us, the patient has to be severely symptomatic before doing any surgery because some of them are, if you look at the just the X-ray, the other patient is doing perfectly fine and the other one is miserable with a similar dilatation. There's a question from uh Rashida Lamiri asking, um, any role for probiotics, um, to treat the bacterial overgrowth? Well, if I go first, in my opinion, no. There's, it's very controversial, some of these patients being, uh, shown or several patients to have an septic, uh, bloodstream infection caused by the probiotics, and there is no, no evidence whatsoever to, to support the use of probiotics to treat that at this point, in my opinion. We don't use them. The only thing is that, uh, in Paris, and I think they have, well, a very large cohort, um, They use, they really use probiotics, uh, but not in all cases. And I talked about it with, uh, Olivier Goulet, but, well, He He cannot always tell why he tries it in several patients, and in, in other patients, he don't do it. So I think we don't have enough evidence for it. That's right. It is a very difficult topic. A lot of times I think there's also uh parents are coming forward with uh Uh, proposing, uh, the probiotics, they, hear about them. There's a lot of, uh, uh, uh, uh, there are a lot of ads and commercials about probiotics in general. That's sometimes where doctors are, uh, almost forced, uh, to use in a way, uh, what also parents, uh, suggest, and then sometimes you have some results and it's difficult to interpret. Yeah, yeah, well, it's, it's very difficult and very complex situation about the whole intestinal microbiota and. I, I think it's a little of a, it would be too easy just to pick up from. And Any probiotics, I mean, even the word probiotics, what does it mean? I mean, Sometimes I really have to. It is like, like, uh, putting a glass of tea into the sea and and hoping that it will be less salty afterwards. That's good. I like that. Um, all your patients, do they, do all your patients have a, a peg for enteral nutrition? But we, we always prefer them eating orally by themselves and currently use, uh, gastrostomy, uh, very selectively and only when. When it's really, really needed. We, we, we used to use them much more, but we have more and more moved to the direction that the babies eat by themselves, what they take and And try to go from there because as Lucas said, especially nowadays when, when the GLP analogs are coming along and it's very important to be able to use them is that the babies, the internal, they can, they're able to take internal nutrition and, and And even it would be even more beneficial if they're eating by themselves. So in, in this respect, uh, we, we don't use them, especially some, of course, some patients do need them, but, uh very, very seldom nowadays. Well, there's a lot of discussion in with the pediatric gastroenterologists in, in Germany. They are very fond of gastrostomy, and they are using it, it also during night to, to feed the children. But, um, well, I I think it, it is not, it is not always the best, the best way. I, yeah, I think it's better when they eat themselves or drink, um, they can drink uh breast, breast milk. Brings us to the next question uh from Mitul, um, asking what are the, what are the nutritional issues after surgical intestinal lengthening procedures in terms of feeding? Compared to a non-operated conservatively managed child with a shortcut. Well, in the beginning, after, after doing such a procedure, you will have, uh, a lot of, of, uh, gall reflux and, uh, Um, Intestinal reflux and you have to wait until um the, the motility is, is restoring and then we'd start with um Well, for the beginning with something like this, um, um, Fluids that you give after diarrhea with, uh, with electrolytes and a bit of glucosis, and when they, and then afterwards we, we start with, with, um, milk, something like that, or with, um, not milk, um. Um, yeah, with formula, formula, yeah, and when they are bigger, the children, and they are, they want to eat something, we will be. You know, when motility is restored again, we let them eat also, but piano, piano. No I got another question myself, Miko, you, you, you emphasize this small bowel diameter ratio and, and the cutoff value of 2 something. So at, how do you measure this and at what age do you measure that, this? Well, the, the sort of, uh, uh, the reason for using the ratio is that That you might sort of think that it's not that much depending on the size of, or age of the patient and the absolute diameter, and that's why we use the ratio. Of course, it doesn't totally abolish the, the effect of, of size, but in that sense, you measure it when, when you have clinical indications. Uh, of course, many times you can choose the, the age of the patients, why you need to do that. But I would like to also emphasize that in those studies, I showed the ratio and the cut-off value that was more or less for scientific purposes to enable to divide the patients and to get some sort of idea of what might be pathological. I don't mean that it's as such directly transferable to, to clinical use and coming into that, we're actually currently working in, in In this subject even in more detail I'm trying to analyze these X-rays also regarding the colon and duodenum and, and, and really sort of uh trying to look into it that is there any way we can predict how these patients will do after the procedures or, or not being operated. So, I think in clinical use, as Lucas says, is that the 5 centimeters is sort of a Because then it's safe and possible to, what, what, what do you decide to do is a little first step or that, but in order just to To show the effect of the annotation, we, we chose that limit. In our experience, um, I think, yeah, that's right, what, what you are saying, when there is a marked dilatation from the beginning, these are the children who are not, well, uh, who are not. Be able to be weaned off in our experience. And I know that there are other experiences from, um, well, from North America that when you had a gastroschisis and afterwards a marked dilatation, that these children will not profit from lengthening procedures. In our experience, it was at about half of them that had an amelioration afterwards, an improvement. And in most of them, and, in, well, in other diseases, it was at about 70%. So I think this, um, this dilatation at the beginning of the disease is really something very serious, which, uh, should be studied more, yeah, more thoroughly. And, and, uh, um, going back to the measurement, you do it on, uh, regular X-rays, or is it when you do, you do, do contrast studies, or yeah, that's a contrastudy to, to be able to identify it. The And of course it's a It's sort of a surrogate of the dilatation because of course the contrast is a dynamic procedure and, and you know, but, but I think at the moment is, is something that we can do and of course it will be interesting to see. I, I know some centers are already doing MRI enterography for these patients and it probably will provide more information, but I, in our experience, it's very difficult for, for small babies in, in practice. We have a last question from Lavinia Stretku who was asking about the percentage of children with short bowel syndrome that uh uh need to undergo a lengthening procedure in your centers. So if you look at the ones that you manage uh non-operatively, uh, versus the ones that instead undergo a procedure, what is the percentage of the two groups? Well, children who are born in our center, I should think that, uh, less than 20% are, um, operated upon. But, uh, the difference is that, um, we become a lot of patients from, um, from other centers in order, well, for these lengthening procedures. So, Um, yeah, that's a different point. But, well, we did about 100 procedures in 40 years. So then you can see that it is not very much in 1 year. We have 2, between 2 and 4 patients one year, something like that. So it is not so very often that we do perform these, um, these procedures. I think for you, Mikko, it's the same. Yeah, I think, I think it's, uh, I think we have treated like 120 patients and, and the individual patients who had undergone tapering it's uh, about 2025 patients. So, and I think during the recent years, we've been, becoming even more you know, restricted and have to be very sort of careful thinking. So I think it's, it's clearly about the same figure. It's less than 20% of, of our own patients. And, and regarding the, the indication to operate, uh, and, and Lucas showed the data on teoglutide. Is there ever a patient that you would consider giving teoglutide before surgery? Well, you wanna go first? No, you go, go ahead, go ahead. Well, we have, uh, also been involved with the, the clinical studies of, with the teal tide and, and we have all together treated. I would say a bit more than 10 patients now. And some of them have undergone lengthening procedure prior to the tide. And uh I don't think it doesn't, does make much of a difference, like Lucas said, it's, it's important to, to be sure that they don't have. Uh, severe dys motility, which I've treated, but I think This is a very important issue that this sort of truly effective uh medicines are coming, coming to the market, which, which uh even sort of um, we have to think even more carefully which patients are suitable for surgery, should they be treated with these drugs? Should they have both treatments in, in some cases, and there's a huge amount of, amount of information we don't know. But I think in the future, because right now we're in, in, in a, in a way, in, in a, in a nice position because we have the drug in our use. So currently, basically we are able to start the drug for any patient we want and The situation being like that, I think. You know, if the patient doesn't have clearly very severe dilatation associated problems, which would preclude treatment with the teleide, then I would go first with the tapering procedure and then hopefully get the patient on, on medication. But on the other hand, if the patient is just Not, uh, progression with enteral feeding and being able to wean off PN and there's no, no, er, severe dysmotility dilatation and, and, uh. A bacterial overgrowth, then naturally, I would treat the patient first with the medication to see whether or not that patient needed surgery at all. And one other question, there are, you know, patients with this kind of ultra-short gut where you really worry whether the liver receives any nutrition at all. And, and there is, there is some studies suggesting that rectal feeding could help. What is your experience? So in, what would you ever consider feeding through the anus in ultrash? Got children? Well, I think the rest of the, the, the, the rectum and the colon is really very, very important. Um, I don't see that you have to feed it from, from the anus, but, um, well, give some, some, um, formula are also a very, um, Yeah, um, complex, complex, um, fibers that can be, um, Uh, that can be, um, um, Yeah, um, I don't know, uh, hydrolyzed in, in the colon by the bacteria. I think that is very important. And it is known that when you have enough colon, that at about 30% of, of the nutrient, um, needs can be, um, resolved by the, by the colon. So it is very, very important. Yeah. I have a pro provocative question, uh, in a way. I want to know what you think of. I think there's already some literature about this, uh, centralization of, uh, conditions such as, uh, small bowel syndrome. I can imagine that in Finland, uh, uh, most patients would come to you, uh, Mikko, um, uh, we have an experience, uh, for instance, here in Toronto where we have a dedicated center and, uh, we do have, of course, um, it's not just a matter of the surgery which actually paradoxically is the easiest part, uh, I'm not, um, um. I don't want to, to disregard the what uh um the, the step and especially Bianchi actually it's not that, that, that, that's uh simple but it's more the multidisciplinary team around and the research, uh, clinical basic uh research around this. So I was wondering what's happening in uh Germany. Is there a sort of a, uh, uh, a centralized, uh, um, um. tended the trend whereby patients tend to go by themselves to a specific center or everyone does everything as it happens in Italy. Well, in Germany, nothing is really centralized until now, yeah, and patients are centralizing some, um, yeah, some diseases like, for example, CDH, um, that's Well, because they, they are looking into the internet and they are coming then to, to Mannheim. Um, it would be, I am absolutely a friend of, of centralization, uh, and that it should be very important to centralize all these children and to have, well, more teams who are cooperating together. And I think that we can reach a much better, um, Um, therapy for most of the, the serious diseases in, in children when, when it's, uh, you know, when it is, uh, when we have more centralization. That's, well, that's a problem in Germany, I think. Don't you think so, Martin? Well, I, I, uh, I cannot agree more. We need intestinal rehabilitation centers, uh, for these children with a lot of pediatric gastroenterologists, nutritionists, and also don't. Forget all the social workers, you know, these children, usually they, they're not infrequently, the parents are divorced, because such a child is really a big burden to any family. And sometimes we see, we say, patient alive, family dead, right? So it is, it is really a problem which would make an entire own web seminar. Um, but this is not a good last word. Uh, I, I, I think, but this is with the same, we, we see it also here, Martin. You touch on a, on a, on a, an issue that is, uh, it's really very true. There are some families that unfortunately fall apart because of the complexity of these, of taking care of these children, uh, long admissions, and, uh, yeah, no, it's, I think you're right, it will be a webinar on its own, and with the pandemic, it's only been worse for these families. OK, as we are over the hour now, I think uh we should close. Maybe Augusta, what do you think? Absolutely, yeah. Although I, I would have had much more questions, Ethan No Lo and the Elioal valve again, but I think we need to move on, yeah, to move on. Uh, thank you very much. Again, uh, Miko, thank you, Lucas, for sharing, uh, your expertise in this complex topic. And as always, uh, we will, um, edit the video and put it on our YouTube channel. Gaia will put the link of our YouTube channel in the chat, um, that you can be a member and, uh, follow both Ernica and um Yupsa. And, uh, well, I, I really love this Ernica Yupa collaboration and, um, That's why maybe, um, yeah, Lucas and Miguel, on behalf of Ernica, you have the last word. Well, I, I think you said it all. Yeah, thank you, everyone. Uh, I'm very pleased to, um, to have the opportunity to, to share my expertise, and I think this is very, very important to do these webinars. Please continue to do it. Thank you very much for organizing it. Thanks everyone, and thanks, Gaya. Yeah, yeah, thank you, Gaya. Well done. Thank you. Hope to meet you soon in Athens. Yeah, bye-bye. Bye. Bye-bye. Bye.