BOB in Ped Surg 2023 - EUPSA Winner - Dr. Rebeca Figueira

Okay, so time to move on. Now we have Uxa. This is an old friend of ours. Um, he they were with us last year. And now we have two presentations from them. Actually, they uh chose three, but unfortunately, one of them couldn't make it today. So, um we only have two, but they are the best from Uxa this year. So, first we have Dr. Li Josephine Manhern, that it's um a pediatric surgeon from the Department of Pediatric surgery in Emma Children's Hospital in Amsterdam, and she brought to the ring risk of malignant transformation and tumor recurrence of sacral teratoma, a multi-center worldwide retrospective study, and their aim to assess the risk of malignant transformation of this sacral teratoma at primary resection and risk of recurrence with risk factors after the resection. And then we have Dr. Rebecca Figuera from the Hospital of Sick Children's uh with fetal lung vascular development is reduced by amniotic amniotic fluid stem cells, extracellular vesicles um in experimental congenital diaphragmatic hernia. So this study aimed to investigate whether the antenatal administration of AFSEVs rescue fetal lung vascular development. So two very interesting um works and let's see what the poll says. Have you checked out the new stay current app update? There's a new space. The European Pediatric Surgeons Association has joined the Stay current app with questions, videos and lectures. So we can continue to spread knowledge about pediatric surgery to surgeons across the world. Plus, get ready for our new Usa question release series coming to you soon. Until then, remember, knowledge should be free. Okay, so this was also very tight and the poll is going crazy, but we have one to show that it's the one from Dr. Rebecca Figuera from Hospital Sick Children uh with fetal lung vascular development um in it's reduced by amniotic fluid stem cells extracellular vesicles in experimental congenital diaphragmatic hernia. So we have the video there, we can play it now. Wait a second. Hold on. Didn't did hospital for sick children win last year? No, I know it was Caps that won, but not Yusa, but it was a I thought it was sick children. All right, let's go ahead and play that video. I mean she Chairpersons, ladies and gentlemen, Fetal lung vascular remodeling predisposes fetuses with CDH to post natal pulmonary hypertension, which plays a central role in the poor outcomes of these babies. There's consensus that the prenatal period offers a window of opportunity to promote normal lung development. However, no antenatal treatments tested to date have been successful. In search for a therapy that could fully rescue normal lung development, our lab started studying extracellular vesicles derived from amniotic fluid stem cells. We reported that AFVs promote growth and maturation in fetal hypoplastic lungs. And that these beneficial effects were exerted via the release of RNA cargo. With these studies, we have demonstrated that AFVs improve fetal lung growth and maturation. But what about vascularization? The aim of this study was to investigate whether antenatal administration of AFVs would also rescue fetal lung vascular development. We isolated the Vs using ultracentrifugation. And characterized them in accordance with the International Society of extracellular vesicles guidelines. We used the well-established model of CD in rats and performed the antenatal approach at E18, where either saline or AFVs were injected into the amniotic sac. At E21, fetal red lungs were harvested and allocated to control and CDH plus saline or CDH plus AFV treated groups. Fetal lungs were assessed for vascular density, mean wall thickness of pulmonary arteries and the gene expression of angiogenic factors. Moreover, we calculated the full tone index, which expresses the degree of right ventricular hypertrophy, and indirect marker of pulmonary hypertension. We observed that vascular density was rescued back to normal levels after AFV administration. and that vascular remodeling was also attenuated in CDH treated lungs. Gene expression analysis revealed that angiogenic factors were rescued back to normal levels after AFV treatment. Moreover, AFVs attenuated the severity of right ventricular hypertrophy in CDH hearts. But are these findings relevant to human fetal lungs? To address this question, we first isolated and characterized EVs from GMP grade human AFSCs and used our human fetal explant model of pulmonary hypoplasia. Lung explants were divided into three groups, normal, hypoplasia and hypoplasia treated groups. At 96 hours lungs were harvested and assessed for markers of vascular development. We again observed that vascular density was restored by AFV treatment, as well as vascular remodeling was attenuated in hypoplastic treated lungs. Similarly, gene expression analysis showed that angiogenic factors were rescued back to normal levels after AFV treatment. After these very exciting findings, we then asked, what are the lung endothelial cell specific responses to AFV administration. To answer this question, we performed single nucleus RNA sequencing on the left lung of fetal rats. When we analyzed the endothelial cells by condition, we observed a striking difference between control and CDH in the pattern and distribution of endothelial cells, which was rescued to normal distribution following AFV treatment. We identified 245 differentially expressed genes. And we observed that these genes regulate vasculogenesis and angiogenesis and were down regulated in CDH lungs and upregulated in CDH treated lungs. The rescue of endothelial cellular interactions in the treated lungs can be explained by AFV cargo that contained some known micro RNA that control processes like angiogenesis and proliferation and migration of vascular endothelial cells. In conclusion, AFVs rescue vascular development and attenuate vascular remodeling in rat and human fetal hypoplastic lungs. They also modulate angiogenic processes and rescue the expression of genes involved in lung vascular development. AFV cargo contains some micro RNAs that regulate lung vascular development, pointing to a mechanism of action. Therefore, antenatal AFV treatment is a promising avenue to restore normal vascular development in hypoplastic lungs and potentially prevent post natal pulmonary hypertension attention in babies with CDH. I would like to thank the lab and all the sponsors listed and you for your attention. All right. So we're back. Um right, we're going to have to like disqualify you guys from this event in the future because you're too good. You guys keep keep. So Um and by the way, before we I we're going to add an extra I want to add 30 seconds to the timer because I just want to say something. So um a little thing that tell everyone be aware of is so we had 1,700 people sign up for this event. And last night we sent out an email to 1,700 people with the login instructions and Google thought we were spamming. So, uh they put our email on hold. So if you have a question or a comment, email me Tsky@gmail until we can explain to Google that we were not spamming by sending out 1700 emails. Um All right. Let's hit the discussion, very impressive paper, Tony. Yeah, fantastic work, congratulations. It really is impressive. Um you know, obviously, the next phase is how do you translate this to patient care? Uh would you imagine using the micro RNAs that you've identified that have these effects or would you use the whole uh AFVs in a way of trying to transduce and then in followup to that, how would you give it to the to the uh baby? How would you get it into the fetal lung or could you give it to the mother that would then get to the fetal lung? Yeah. Thank you for your question. These are really uh very pertinent questions. Um so first question, um we we are we already have ongoing studies in large animals. So the first step to uh translate it to into clinical is to study this um treatment in a large animal of uh and a large animal model of CDH. So we're doing the lamp. We wanted to make sure that we know the right dose, the right route route and the to see if we will need or not multiple um uh administrations of the same uh um treatment. And following for the second question, yes, we do want to give the as it's uh the cargo uh itself is the most important part of it and we know that the miners are uh one of the the let's say the main uh uh components of it, but we also we also do know that there are other things. So the Es as um itself are like less immunogenic and then we can also make sure that the babies are receiving uh the whole cargo and not only thes. So we do know that thes have a great um it makes a difference in the treatment because it has a specific uh they the ones that were highly showed in our baby cargo, but we also know that the other uh components are important as well. And um for the following how we would give. So I would like to actually uh mention a paper that was published in the New England journal of medicine uh that actually even was published in the New York Times. I don't know if uh you guys had any uh uh any idea of it, but it's it was really interesting and it was uh treatment for an enzyme replacement therapy and they did it in they used the umbilical vein as uh like a way to administer their treatment and they did it at multiple times, at least six times uh every second week. So that would be also a way to do it. Um, so far we do want to do a less invasive type of treatment. So we have tested that not only intic, we're also doing uh trying to doing the large animals, but let's say in the future, we have experience as well in uh giving it to the mom. So we can administer to uh the mom, give it to the vein uh and thenus and and we do know that disease they reach the lungs. So that's also something that could be applicable in the future because I think the less invasive the the the better for the for the mom and the baby. Okay. Tony, do you have a final comment before we go or are you good? Uh for the sake of time, I'm good, but fantastic work, Rebecca. Keep it up. Thank you. Thank you so much. Thank you joining us. Uh and by the way, by the way, I've been criticized in the past rightfully so because the way we chose papers was me saying, oh, that's a good paper. uh which we all know is about the worst way to decide a good paper. But what happened was Augusto Zani rightfully so said, Todd, you keep choosing papers that are procedural based. What about basic science? I said, I'm not smart enough to understand basic science, so I never choose those papers. And and and they keep uh they keep winning. So clearly he was right. People do want to hear about the basic science.