Uh, we got, uh, two, presentations here that are totally unrelated to each other, but very important. So we put them together. Uh, first we have, uh, so Mack Harmon, uh, from OSH Children's in Buffalo is moderating this, uh, has been doing this with us since the beginning of the update course. So thanks, Mac. We have, uh, Doctor Greg Tia who is one of my five bosses, uh, who is, uh, the director of pediatric surgery at Cincinnati Children's, and we have Doctor Gloria Coca Gonzalez, uh, who is moving now, uh, soon to the Cleveland Clinic, uh. Uh, uh, coming from, from Santiago, Chile at, uh, Calville McKenna, uh, Children's Hospital. So take it away, guys. Thank you. All right, all right. Well, thanks for having me here and it's a privilege to serve as Todd's pseudo boss. He, he really doesn't have a boss. He just, you know, does a lot of different things at children's, uh, but it is a privilege. What's that? Well, we're, we're trying to minimize this, but we are gonna ask Todd that question right off the bat. What's a matrix metaloproteinase? But I've, he already said at the beginning that he has no interest in, um, um, um, proteins and things along that line. But in the next few minutes, I'm just gonna touch on a couple of things that are relevant for biliotresia, a disease that, you know, I have a fair amount of interest in. And what we're gonna try to touch on is a concept that I think we're all quite familiar with, which is a timely diagnosis of biliotresia is critical to prolong the native liver survival. And what's the challenge, of course, is we all face is that oftentimes these kids come in late, they take a little bit of time to work up, and so the end result is we're offering surgery at later and later dates. And so the key for biliotresia is to establish an early diagnosis. And this is where this biomarker that really came out of Georgia Bezarra's lab, my, my research mentor, um, he identified about 10 or 10 or so years ago in terms of it as being a diagnostic biomarker for biliaryresia. And this all ties to this critical concept that I think we all know, but we don't necessarily integrate, which is you gotta get your casa done as soon as possible. And, you know, the tradition, I think when I was going through training was you get it done by 60 odd days, you're probably OK. But the curve has really moved as data has come out showing that the sooner and sooner you get it done, the more likely you'll save the native liver. And so this all goes to a, a scenario where you want to establish the diagnosis as quickly as possible. So this actually was a little guy who showed up just a couple of weeks ago on our service here. He's a, a 38 day old child. So, again, pretty standard, right? has a little bit of jaundice, um, he passed meconium on the first day. He's gaining weight, so doing all kinds of good stuff, but he's noted to be jaundiced. Pediatrician says, oh, it's physiologic jaundice of a newborn, but then it persists. So this is when things start to get triggered. His stool, in this case, is pretty clay colored. Um, I have some of the labs there in which it's pretty classic for biliotresia. And so, again, this is the diagnosis or the conditions that our pediatricians are facing. We then refer them into a hepatologist who then starts a workup. And of course, as we all would want, they'll get an ultrasound here. And in this particular case, it had pretty classic findings for biliotresia. But the challenge that our pediatricians face is the differential diagnosis for needle jaundice is pretty long. And there are a couple of conditions in that grouping that we don't want to do a Cassai for. You do a cassai for an ages, you do a cassai for a Pic, you just converted that patient to needing liver transplant before they're a couple of years of age. And so this is what the pediatricians are facing in terms of a workup. These are the standard conditions that uh they're dealing with. But what they're really looking for is a diagnostic tool that is sensitive, specific, and improves our efficiency. Then there's a whole series of things that people will end up doing during that workup, and we're gonna touch on them in a second here. But the key is to distinguish BA from other uh non uh physiologic cholestatic jaundice conditions so that we can get our CSIs done at an earlier, earlier early stage. Next slide. So this was the first audience poll. So we have a patient like this. You have an ultrasound that's suspicious for it. What are you gonna do? And so this is where I listed a couple of different options and we'll see how people respond. But I don't know how many people in the audience are doing the casa. I think more and more institutions are having focused people do them, but it's kind of an evolving topic. That again is a volume outcomes question, but are there any of the participants here doing casa? Bargaville left, so I know he, he was doing them in Kansas City. But, so, you know, for those of us who are doing Cassese, what is your decision making here? So we can go to the response. All of those options are actually correct because it depends on your institution, right? At our institution, we stopped doing HIDA scans. We stopped doing HIDA scans about 25 years ago. And the actual NASAGA guidelines for a workup for cholestatic jaundice is not to do a HIDA scan. But there continue to be papers coming out showing that they have a value in some institutions. The challenge that we face with a uh a HIDA scan is it adds about 5 days to this study. And there's some data that's coming out from a Midwest study where every 10 days that you um delay a Kasai translates to 20% worse outcomes. And so all of this translates to biliary trees is a strange disease process. As a person who's been focused on this for 20 years and has had funding for it all those years, I still have no idea why the diagnosis even arises or the condition occurs. But it is one of those things where the earlier we can intervene, the better off we'll be. And so this translates to some work that led to um this MMP 7 study. But all those other options, a liver biopsy, some institutions will do. Some institutions will take them to the OR, do a diagnostic laparoscopy, a liver biopsy, a changiogram, and then decide on the CASai. Some institutions will just do an X lab, um, cholangiogram, CASA. So all of those are different things. But the trickiest patient population, when you go that. Route without having a clear diagnosis of bilioregia beforehand is alligs, and every year, every pediatric transplant program is dealing with uh Ali's kid who got a casai done. We've done it ourselves because that cholangiogram is really, really difficult to differentiate from biliaryresia because those ducts are hypoplastic and it becomes really difficult to distinguish if there really is anything going into the liver. And so this is still where our pediatricians and hematologists face this challenge, which is, if they can help us figure out biliotatresia beforehand, it'll make our decision making so much easier. So about 10 years ago, Georgia took on some data from the Children's Network. And for those of you guys who are not familiar with it, Children's Network is a national consortium of about 14 centers in which all the cholestatic liver disease children were enrolled in the study. It was um enrolled in the, in the, in the registry. And he took about 70 or so patients from that, some who had biliotresia, some who had um um cholestasis. idiopathic cholestasis and did proteomics on it. And he screened about 1000 proteins and they actually found 70 or so that were elevated in the VA population, of which MMP 7 was the most clear. And so this is the data on the next slide. Actually jumped by it back. Can we go back another yeah, um, one more slide. So this is the One more slide. So this is the discovery cohort where he looked at 35 patients with biliotresia, 35 patients with uh cholecytotic disease, not biliaryresia, and he looked at outcomes and he looked at GGT and MMP7 as being the two that most predicted a biliaryresia in terms of a diagnosis. Now, the challenge that he faced is that when you look at the disease frequency, even in the children's network, you're only seeing 20-300 kids a year. So to do another study to validate this was very difficult. Well, this is where he took advantage of the incidence being higher in the Far East. Next slide. And this is where he actually validated it in just 2 years in a study that was done in, in, in the mainland China, where the frequency of biliary trees is much higher. And of course, they really strive to get those kids a cassa very early because if they don't, living donor liver transplant is their only option. It's not readily available and so those kids face a mortality risk. And so what they did is they valid validated this study through a series of efforts to really show that MMP 7 is a diagnostic biomarker for bitrition. And this is really where it's now being integrated into the algorithm for workup. There have been a couple of other series that demonstrated the same um uh predictive nature of it done in a variety of different countries. So MMP 7 is here. It is now a, a, a, a validated biomarker for biliotresia. It's not perfect. And actually, if you just look on the table here, the sensitivity is pretty good, but the cutoffs that the different teams used varied because it's an assay that's still evolving in front of our eyes and depending on how you do it, if it's in blood spots, and if it's, you know, actually in Eliza on the blood, it's all stuff that people are working out. But this all translates to this then next question here, which is, when are you gonna do your Kasai? We got 2 minutes left, so I would maybe go quick on the poll and then just give and again all of these answers. are understandable and acceptable. But what you actually have to integrate into your whole process is you get this diagnosis. This is not, oh, I'll get them scheduled in 1 week or 2 weeks. We put these kids, our commitment to our the patients who come to our institution is within 7 days of them showing up. If they have it, they're in the OR. And this is where we've moved our dial. Now this is the next slide is just a study from the Children's Network in which Rick Cupperino looked at the. Registry through like 2010, in which they showed that the average data of ability to treat a patient going through a CASai in North America was around 75 days. But then there's been a whole series of other national registries. Next slide, this one came from Europe, where they actually showed that if you did your CASAI before 45 days, you'd actually reduce the incidence of transplant need in that patient population. And so all of this is moving the dial to Integration of MMP 7 into your workup, so you make the diagnosis at an earlier age, so that you get these patients on to a CASai if possible. And this is really the last point, which is a Kasai por neurostomy done before 45 days is the goal. We actually will do it before 30 days if we can establish the diagnosis because nowadays, more and more nurseries are screening their their kids at discharge. And if you have a total bilirubin, a direct bilirubin over 1 in the newborn period. That's also very sensitive for biliotreasia. So those kids get plugged into GI teams sooner and sooner. So we're actually seeing our Kasai in timing going from 50, 60 days to now we're shooting for 40 days as from a programmatic standpoint. The 20 day old Kasai is anxiety provoking because you're doing a JJ and a, and a tiny little kid. And you actually have to start thinking about putting him in the ICU for monitoring afterwards, but we are pushing to do these casais as soon as we can because we think it really makes a difference. And all of this goes to my end goal, which is put ourselves out of the transplant business. That's awesome, Greg. Um, thank you. Uh. I'm just curious who is sending out MMP sevens here. That's what I was gonna ask you. So, so there is a dilemma. So Georgie, when he established it, had it in Cincinnati, then he went to UT Southwestern as a chair. They took it. But now more and more center, um, hospitals are um putting MMP 7 into their standard, um, uh, ELISA assays because it actually has value not just for Byresia, but it actually has rheumatoid arthritis. There's other conditions in which MMP 7 actually has a, a, a diagnostic indication. And so it's an evolving process. We're trying to operationalize this in the Midwest Pediatric Surgery Consortium in the sense of trying to. Do it prospectively to get all the, all the patients, um, blood sent to a center that has it. Um, Cincinnati is, um, our team's putting it back online in the next few months. So Greg, people are like in the chat. People are gonna wanna know. I mean this, we started sending it out in Akron. I don't know where we send it now. I guess down to Georgia. They all go down to, um, Georgia right now, but, uh, in, in UT Southwestern, but it's a bio, it's a a bioassay that can easily be Eliza that can easily be done across the board. And this is where actually you actually have to know the how the assay. And the actual assay values are, there are some assays which if you look in the Far East, they had a 2 2.5 nanograms per mLs being elevated in, in North America in Georgie's assay right now, it's 18 when I was in Cincinnati, it was 50. So this is where the assay is still being integrated into the workup in a way that's gonna be useful. Yeah, it's game changing. That's why I was really glad we're talking about this because, um, I was behind the times, but I know that we're catching up. All right, thank you, Greg. That was awesome, fantastic. Hello, I'm Gloria from Chile. Coming to Memphis, so I'm going to talk about an old update because this is a, is a technique that is used in adults and I bring it to the children and I, I'm talking about LiPool in uh meds. So why we're talking about this osteosarcoma specifically, they have like a till 50% of the patients have uh lung meds. So during their disease in many cases they have only two or one nodule. So what we are going to do with that, go ahead. Surgery can improve survival. We know that. We know that we have to take out all those nodules and if we have one or two, we can do it minimally invasive because we know what about minimally invasive versus thoracotomy. Go ahead. So first, if you want to take a nodule for like minimally invasive, it's a 1 centimeter nodule. What's the rate of conversion due to failure to localize subdural nodules during thoracoscopy, and that's the first pool. So what do you guess? So yes, what's the answer? Is 47% so. The conversion rate is really high and you say well one centimeter I'm going to see it I'm going to look at it and if you don't or or you can get a double tube in there is much higher so what we are doing now. So pre-op localization techniques we talk about that in the biology intervention, uh, section uh we can do many things with, uh, radiology localization with imaging during thoracoscopy, meaning ultrasound or fluoroscopy like city guidance, preoperative location techniques like dyes like methyle blue contacts medias, radionucleate, adhesive chlora, many things, or hook wire placement. Go ahead. That's the second question, which one are you using now? So today we talk about and and I heard somebody from the audience that they use wires, metal and blue. Intoan in green, those were some of the, the questions. No, can you see the answers? I'll go, thank you. So, none. Is 47% and injection dyes blah blah blah. OK, go ahead. Why I don't want to use thoracoscopy images CT you're exposing the patient for radiation all the time. Ultrasound is difficult performing the ultrasound when you have really small, uh, nodules. If you have one nodule like 22 or 3 centimeters, you are not going to see it. And in case of the uh the osteosarcoma, the calcified lesions, they're really difficult to see. So there's no use for that. Why not hook wire? Why I don't like it dislodgement. The rate reported for dislodgement is 2.4% to 22%. Uh, and in my case, because I don't have the CT in my OR, the patients have to go to the CT scan under anesthesia and go to the OR and in that case, the dislodgement is much higher. And when you put the pneumothorax, the wire again is dislodged. So you will, you say, well, we can do blue uh metal in blue, you know, with the wire so I can see both things. Go ahead. And we have seen. Metal and blue all over the chest but not in the nodules too many times. And what about ICG? It's a really good option, but if you have a deeper nodule like 2 centimeters deeper nodule, you cannot use ICG. So yes, it is a really good option for really superior lesions, bigger than 5 millimeters, but I cannot use it in all the cases. So what I'm doing LPO do go ahead. So the marketing procedure is in is is under CTE. Uh, those are the biologists interventional, uh, doing this, so they, they mark the nodule with Lipiodol that is an odious oil, um. Die, die, so it, it stays in there like 3 months. So I, I don't do the surgery the same day if I if I can't, for example, I can do it like 1 week ago, 1 week later. I'm sorry, go ahead. And this is the setting in the art. I put the CR under the patient. Put the laparoscope, so I, there's always, uh, some imatome or something in the surface, and I'm looking at the. The images in the radioscopy, put the stapler on. Check it under the R C arc if I got the the spot, you know, the lippiol spot fire my stapler. And take it out. With this technique You can go ahead. Well, uh, after I, I, I do the palpation with uh for the tissue, I mean, and I know verifying the radioscopy palpation and after that, uh, doing an, uh, radioscopy of the lung that I don't have any libiodol left in the, in the lung, so I know we have the nodule that we have, uh, we, we went for. So what we have done. Now it's 33 nodules, but patients, I mean. We have 3 or 4 nodules until 3 or 4 nodules per patient if I, if I want to, and there's not, uh, osteosarcomas, uh, not all of them are osteosarcoma. I mean we have a Ewing sarcoma, Wilms, uh, infectious disease like many, many, many, many sties, and, uh, we have done like, um, well, like I said, 50 nodules something like that with 100%, uh, sensi sensitivity. So now the last question. Would you consider changing your practice? I love that you put this question in while it's coming. This is a classic Mac Harmon question that you always need to put this question at the end of your presentation to see, uh, go back to that. Uh, I mean, go back to the poll, sorry. That, I mean, look at that. That's pretty incredible. That's not even subtle, uh, so that's awesome. John, Amanda, do you guys have comments on this? No, uh, no, that's an awesome presentation. Thank you. Um, I, I know, um, in our research lab one time, uh, Dan von Almen and I, we, we tried some lapayaol again, I don't think we had the proper technique, um, uh, for us it, it, um, the la lapayadol, you know, wasn't kind of staying in the focal area for, for, you know, during that procedure, but it sounds like it stays there for many days and even a couple weeks. Yeah. You mixed it with glue. Um, I think, uh, well, um, one thing, the key with, um, the wire, the wire technique, um, is the key is when the, the lung is being deflated, right? So, um, what we do is we'll actually, um, actually sometimes active actively kind of push the wire in as the lung is going down or cut it at the skin surface and the surgeons when they get their scope in there. Um, without having the lung come down very much, they actually helped pull it in through, through the chest wall. I know Tim, uh, mentioned actually leaving a little micropuncture set so that wire isn't, it's not the friction of the chest. Jesse slides through the, the micropuncture set. I thought that was a great technique. Yeah, and yeah, and uh it does help, yeah, move it, you have it in the hybrid where we don't actually don't have that transfer. There was one patient that actually came up. We, we used to put, we used to do them in CT. We would build up gauze, we put Dixie Cup things over it to kind of protect it, but there's one case that the patient got up to the OR and during the prepping of the patient, um, one of the nurses like, you know, what is this? And actually, you know, yanked it out. So, um, that happens too. I, I think this is a great example of just find the techniques that works for you in your institution, um, you know, a lot of people have had success with the wire. I don't love the wire, but, you know, I think what you're doing with, with lapaadol is very similar to what we do with coils and what other people do with fiduciials, which is to have something that just goes next to the nodule and can't be dislodged, and then you use flora to find it. Yeah, I, I wanna ask you that, uh, about the coil. Because, uh, there is a problem with the, the sample kind of the, the results, you know, histology, I mean it might be difficult with the gold put it in there. So how do they manage the specimen? I do warn the pathologists when they're getting ready to slice it that you're gonna find a piece of metal in there somewhere, but they're so small that they haven't had trouble with it, yeah. So, uh, this was a phenomenal session and I just decided that I'll need help Em and Cecilia. But after this event, there's so many new things that were just presented today. We still have more, a few more. Um, I want to make sure we do better on executing from this event today to practice. And I think there's a missing component of. Access to all of you guys to say, all right, we are ready to start this. Please point me in the direction on actually how to start because it's a great idea. We go back to our practice. So maybe what we'll do is go through all the things with a contact of someone you could reach out to to say, hey, we want to start MMP 7. Please tell us what to even begin to do. We wanna do, um, every, so, uh, we'll do that. This was phenomenal. These are very provocative. Thank you guys for updating us.
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