Colleagues, uh, Lorenzo, Dewey, Wendy, and Brian, um, are gonna be sharing their research experiences here, uh, with us today. They've all been, um, incredibly productive, um, during their time here. And, um, it's been really a pleasure, um, working with y'all, um, clinically and Professor Rounds and, and, uh, and, um, just, uh, uh, you, I really am excited to see what great work you guys are gonna do in the future and hear about what work you've done while you've been here. Um, so, thanks y'all and, and, uh, let's get started. OK, thank you. Like this. It's mine, yeah. All right. Thank you. 706. I hope that's not part of my, my allotted time. I know it's a lot of us, but um, anyways, good morning. Thank you for the opportunity to present some of the work that I've been uh doing as part of Doctor Peter's lab for this past 4 years. This is some of the research fellowship in review. During our time in the lab, we were fortunate to be a witness of the part of the Omegavin journey, uh, as it came to a successful conclusion last summer after its FDA approval. And my focus in the lab was mostly spent on looking at the omega 3 fatty acids and the effect of, of, of this on different systems and clinical situations. Uh, some examples I will present to you today including, uh, bleeding and inflammation. So, one of our tiny contributions to that Omega V journey was working on providing evidence to challenge the long-living belief that fish oil is associated with an increased risk of bleeding. And this is a problem that we see everywhere and can lead to unnecessary delays in surgical care. For example, this patient was being asked to hold fish oil therapy in preparation for her surgery, and it's, it's not the end of the world if we're doing that on a patient that is taking fish oil for other indications. But you can imagine how big of a problem this can be if you're, uh, saying this to a patient that, whose patient's life depends on it, such as those that are PN dependent and are taking intravenous fish oil therapy. So, truth be told, this is not an unfounded misconception. After all, the N metabolites of omega-3 fatty acids do induce a series of changes that affect both platelet aggregation and blood coagulation that ultimately lead to changes in, in, in platelet function tests and also in bleeding times and have also led to the description of mild bleeding tendencies in Greenland Eskimos, which are the, the, the population that usually um we, we describe as having a high consumption of omega-3 fatty acids. And fish oil. So we do know that there's a direct and indirect evidence that omega-3 fatty acids, when given orally, they do not increase the risk of clinically significant bleeding. And uh after seeing all the patients that had been on intravenous physio therapy at our institution, we did have that anecdotal experience. Um, more so, there's the half-life of, of omega-3 fatty acids. It would take about 20 weeks, uh, after you stop omega-3 fatty acid therapy or fish oil therapy for the, the EPA and DHA that is incorporated in red cell membranes in place. Platelet membranes to go back to their baseline levels. So usually when you go to pre-op clinics and you see surgeons stopping fish oil for 1 week or 3 days, 2 weeks at the most, it, it doesn't make a difference as it takes 20 weeks uh for those levels to return to normal. So, uh, knowing all this, we, we hypothesize that intravenous fish oil administration does not lead to an increased risk of clinically significant post-procedural site bleeding. And to do this, what we did is a retrospective chart review of prospectively collected data. We obviously use the, the Omegavent database which spanned spanned over 10 years. Inclusion criteria included all those patients in that database. So, these were all patients that uh were on intravenous fish oil therapy for intestinal failure associated liver disease. And, and we, we looked at all the patients undergoing any kind of invasive surgical procedure. Looking at the primary outcome of clinically significant post-procedural bleeding, which we defined as any bleeding that required either returning to the operating room or re-exploration, transfer to the intensive care unit or any kind of escalation of care, readmission, or that bleeding causing death. So here's a summary of some of our findings. We ended up looking at 182 patients that underwent at least one procedure. As you know, all these patients, they, they undergo more than one procedure usually. So that added up to a total of 732 procedures. As you can see the distribution here mostly are uh pertaining to vascular access and abdominal surgeries. Uh, of note, the vascular access procedures that were included in this analysis were only, uh, those from the, from using the cut-down technique or, and, and not the puncture ones. I want to draw your attention now to the last row. Of, of, of this uh table which shows the amount of, of procedures that were complicated by clinically significant post-procedural bleeding, which we ended up looking, seeing only 55 events which added up to less than, less than 1%. And if you compare this with the average reported bleeding rate in children, it's, it's pretty much the same or even lower. It's a 2.8%. Um. Out of those five, we saw 2 stomocyte bleedings out of 49, which is also at par with, with what we see in the, in the general literature and the general population, which is a reported 0.7 to 10%. And then for anastomotic bleeding, the same, it was 0.88% and uh that report in the literature is 1 to 4%. So after looking at, at these findings, we, we concluded that hemostatic changes we know do exist after fish oil therapy, although these do not translate into an increased risk of clinically significant bleeding. And, and fish oil therapy should definitely not, should be continued to be offered to PM dependent children with intestinal failure associated liver disease and should not be withheld in preparation for any kind of invasive procedure. And this, this findings could be generalized to also the adult population of fish oil supplementation. And, and what we see this is, this is an extreme model of, of, of fish oil exposure. And think of it. These, these are patients that were getting 1 g per kilo of fish oil intravenously with a bioavailability of 100% fish oil. And compare that to your general adult, which takes Uh, fish oil for, for hypertriglyceridemia, for example, and that's, that's the highest dose that you can take, which is 3 to 3 to 4 g per day. Your average 60 70 kg adult, that, that translates into a dose of 60 mg per kilo, which is significantly lower, uh, to that. Um, given to our patients. So hopefully, hopefully this, this helped put that, uh, misconception to rest. So one of the other learning points of my experience in the lab is, is that I, I came to learn that a fat is not, not just a fat, and, and it is true that lipid provides a significant amount of calories in our diet, whether it's ally or parenterally. It, it also provides Essential fatty acids that are required for growth, development, especially in our, in the, in the children, uh, that we care. But, but not all fats are, are created equal. And, and the oil source that we use to formulate diets or intravenous lipid emulsions. They, they significantly influence the, the effect these, these compounds have, on a given system. For example, you see here, uh, on your right, the formulation of lipid emulsions have, have evolved over the years, uh, to use less pro-inflammatory oils such as that used in Omegave, which is cold water fish or the newer alternative lipid emulsions that use, um, medium chain triglycerides and olive oil in combination with, with other more pro-inflammatory, um, oil sources. And this, this figure summarizes how these fatty fatty acids can derive into, into more pro-inflammatory products. And then the top half in blue, uh, you see those derived from the uh omega 6 fatty acid, arachidonic acid, which are more pro-inflammatory than, than the ones on the bottom of the figure or the ones in green, which are the, the derivatives of omega-3 fatty acids including EPA and DHA. So with, with this in mind, we wanted to work on, on modifying um some of the dietary strategies that are known to induce metabolic changes and can ultimately alter the inflammatory response. And one of the, the things we did is, is, is work with ketogenic diets. I know most of you have heard about ketogenic diets, and these are very, very low carbohydrate diets that, that lead the body to shift towards a fat-based metabolism and induce a state of ketosis and ketonuria, which ultimately leads to decreased insulin levels or better glucose tolerance. It also leads to improved mitochondrial oxidative status and antioxidative metabolism. So, so with this in mind, we, we, we sought to describe the metabolic and inflammatory changes induced by a new caloric ketogenic diet enriched with omega-3 fatty acids in, in the murine model of endotoxemia. And, and we, we hypothesize that replacing the fat sources with omega-3 fatty acids could improve the response to endotoxemia in this setting. To, to test this hypothesis, we, we used adult male mice and we, we gave them either of three diets, either a controlled diet, the standard ketogenic diet, or the one that we specially formulated in the lab, which was enriched with omega-3 fatty acids. And here, I just wanna, wanna emphasize how, how ketogenic diets work and how they're extremely low in carbohydrates. They have a very low carbohydrate content, and they're very high in fat. On your right, you can see the table of the different compositions. And I want you to pay attention only to, to the, the, what we did with the omega-3 fatty acid ketogenic diet, which is basically replace some of the, some of the fat sources in the standard ketogenic diet with, with omega 3 fatty acid, ethyl esters to make it enriched with omega 3 fatty acids. So we, we fed our mice for a period of, uh, basically a month with these experimental diets. And after that period, what we did is we exposed them to an endotoxin challenge to induce that, that state of endotoxemia. Uh, the endotoxin that we use belonged to a gram-negative bacteria, E. coli, uh, and then, of course, as control, we use isoometric saline. So I'm gonna just briefly show you some of our most significant findings and this uh was looking um At the beginning, we, we looked at the inflammatory response by measuring levels in blood of interleukin 6 on your left and the TNF alpha on your right. And you see both these graphs on the Y axis, you see the, the concentration of the different uh molecules measured and on, on the X axis, you see the different groups. Uh, the, the, the half, the left half of the graph shows the saline treated mice, which of course we expect, uh, no inflammatory response, and you see that, that those in both, in both cases were, uh, undetectable. And then on the right, you see how, how these mice behaved, uh, when, when exposed to the endotoxin challenge. And basically here you see how, how omega 3 fatty acid enrich diets can, uh, dampen and ameliorate the inflammatory response compared to the, to the other two diets. So looking at our metabolic changes, um, one of the most significant ones that we saw was the downregulation of the gene coding, uh, for one of the main enzymes and control points of gleukoneogenesis. And this is an important finding because, because it's been shown in the literature that partially silencing this gene can lead to improved, uh, glycemic control in the setting of, of, of diabetes. So here you see how, how the ketogenic diets in both cases, uh, led to uh an improved um or down regulation of PCK1. So, after, after doing all these experiments, we concluded that and, and confirmed that dietary modification of eukcaloric ketogenic diets can improve their metabolic and inflammatory profile. And we can, we can, what we're doing in the lab right now, it's exploring further modifications of the fat source or sources that are used to, to formulate and change these diets based on their ketogenic potential and also inflammatory potential. And the dietary strategy for use in hospitalized patients with, with catabolic conditions is, is the ultimate endpoint of, of these diets, uh, to improve their potentially improve, improve their outcome. So I feel very fortunate to have been given the opportunity to work with such an amazing group of people, in particular, and especially my, my mentor, Doctor Pewter, all of my co-fellows in the lab, uh, also the Pewter lab team. I know it's a, it's a, it's a long list, but I'm, I'm, I'm truly grateful of all the, all the people that worked uh to make this uh such a great and memorable experience. I would take any questions. Thank you. Is there a time for questions or should we? I'll save it for the end. OK, thank you. Good morning and thank you for the opportunity to present our work. Congestive diaphragmatic hernia or CDH as all, as we all know, is a highly morbid disease of the newborn characterized by a defect in the diaphragm and herniation of abdominal organs in the thoracic cavity. The arrest in pulmonary development is thought to be the major cause of mortality for this condition, which still remains around 30 to 40% in most large population studies. So clearly some additional therapeutic strategies are needed to improve the statistic. And that's where VESF comes in. VESF or vascular endothelial growth factor, is a master regulator of angiogenesis. It binds and activates main receptor, VESF receptor 2 by tyrosine phosphorylation. Now, VESF is a major factor in lung growth. Signaling from VESF receptor 2 is critical for proliferation and differentiation of bronchial alveolar stem cells into endothelial and epithelial cells in the lung. And also, uh, uh, analysis of lung tissue from children with CDH also revealed a deficiency in Vsche expression, as well as upstream regulated hypoxa induced factor of HIP2 alpha. Interestingly, this deficiency was seen in the postnatal alveolar phase of lung development, which brought us to the first question of today. Can we provide exhaustion of VF during the postnatal period as a therapy to accelerate lung growth? To answer that question, we use a model of compensatory lung growth after left pneumonectomy to stimulate uh pulmonary hyperplasia. Mice will undergo left pneumonectomy followed by randomization into either the control or the VESA group. VESchef was given a 0.5 mg per kilogram via intraperitoneal injection. They were then euthanize and post-operative fall for a series of studies. Now, you might say 4 days, such a short period of time. Turns out that everything is much faster in mice. 4 days in mice, about 4 months in human. And we saw the VESA administration significantly increased lung volume compared to the control group. On morphometric analysis, there was also an increase in total alveolar count, but interestingly, maintenance of mean sepal thickness. This was important for us to show because VESF is known to increase endothelial permeability. So, it was crucial for us to demonstrate that VESA treatment did not result in pulmonary edema. On Western blood analysis, VESF administration significantly increased activation of VESF receptor 2 in the lung, it means that VESF systemically delivered, was able to fight and engage with its receptor in the lung. So, clearly, systemic administration of VEFF works, but systemic administration of any growth factor naturally raises some concern. And so, in order to expand the clinical profile of this therapy and frankly, to improve its chances of being approved for clinical trials, it was also important for us to demonstrate the feasibility of topical administration of VF and that was our next task. So, we repeated the experiment, but this time with a different route of administration for VHF. mice would again undergo left pneumonectomy followed by randomization to receive either saline or VHF, but this time via nasal installation. Now, we saw that with topical administration of VEGF, we significantly decrease the amount of VESF absorbed into the bloodstream. But the effect of VESAP on lung growth was preserved, if not better. VESAP administration still increased lung volume on post-op day 4 and this effect persisted until post-op day 10. On morphometric analysis, again, there was an increase in total alveolar count and septal surface area, but again, maintenance of mean septal thickness. At a molecular level, just to orient you on these micrographs, lung endothelial cells will stain green, and KI 67 positive cells and marker proliferation will stain red. So, cells that double stained and appear yellow are proliferating endothelial cells. As clearly shown by this, by these pictures, Bacha administration significantly increased endothelial proliferation on both post-op day 2 and 4. So, we have shown that VA treatment works in a small animal model. So, the next task was to test its effect in a large animal model. This was pretty much a required pre-clinical study, and for this, we use a Piglet model. The problem was compensatory and growth in piglet was a complete black box to us. So, We had, there were a series of preparatory experiments that we had to do even before we could look at the effect of VEGF in piglets. And so, the first thing we had to do was to master the technique of left pneumonectomy in piglets, which was followed by determination of the natural history of compensatory lung growth, compensatory lung growth in piglets. We saw that maximal lung growth was achieved around 1 to 2 weeks after surgery, and so we decided to use 1 week as the duration for the pilot Vech experiment. Then the next task was to determine the pharmacokinetics of VEFf and piglets. We tested three different doses, 100, 200, and 400 mcg per kilogram. And it was very clear to us that the lower doses of VEF 100 and 200 resulted in much, much better volume of distribution and clearance. And so to balance pharmacokinetics and maximal effect, we decided to go with the 2 middle dose, 200 mcg per kilogram for the pilot Vech experiment. So with all of those preparatory experiments done, now it was time to perform the pilot VSA experiment. Piglets would undergo left pneumonectomy followed by randomization into either the control or the VESA group. VESA this time was given via daily infusion at 200 mcg per kilogram. They were then euthanized and pulsara 7 for lung volume and morphometric analysis. And again, in the Piglet model, we saw that VESA significantly increased lung volume, septal surface area, and alveolar count compared to the control group. So, all of those results were very encouraging. But as we were working on those pre pre-clinical studies, one thing we also had to do concurrently was to anticipate the potential challenges to the therapy. And one of them was actually brought up by Doctor Hamilton, and that was VESHF is a heparin-binding growth factor. So should we worry about the interaction between VEFF and heparin? This is relevant because we anticipate that a lot of the patients who would require VESFF are the sickest of CDH patients, those who are on ECMO and require systemic anticoagulation with heparin. So to answer that question, we again use the model of left pneumonectomy, a compensatory long growth after left pneumonectomy with 4 different groups. The control group receives saline, the heparin group receives systemic anticoagulation with heparin, the VESA group, and a combination of heparin and VEGFF. And the results were very fascinating. First of all, systemic anticoagulation with heparin significantly decreases lung volume and alveolar density compared to the control group. VESFF treatment increases lung volume and alvel count as we have seen many times. The combination of heparin and VESF clearly isn't as good as VESF by itself, but it is better than heparin by itself. So, these results show that systemic anticoagulation with heparin impairs compensatory lung growth, but in the face of heparin, VESEP could serve as a rescue therapy. But heparin is not the only anticoagulant out there, so we also repeated this experiment, but this time replacing heparin with bibauddin. A direct thrombin inhibitor that doesn't interact with VEGFF, and the and the results confirm my hypothesis. Buruddin doesn't compare, doesn't impair compensatory lung growth, and the combination of bivalluuddin and VEEFF is just as good as VEF by itself. So, is it time to rethink our anticoagulation strategy? Just some food for thought. And finally, the last question of today. After all, why are we so focused on angiogenesis? All of the studies so far have been done on piglets and mice. Is there any clinical evidence to show that the deficiency in pulmonary vasculature is a significant problem and more, and more importantly, a persistent problem in CDH patients? Luckily, we didn't have to look very far to answer that question. The BCH, the CDH clinic at Boston Children's, which was established in 1991, is the largest of its kind in the country. It provides a unique opportunity to study the natural history of lung development in survivors of CDH. There is a note of precaution here, though. There is an inherent component of selection bias in patients who regularly come back to clinic for follow-up. So, any sort of external generalization has to be, has to be taken with a grain of salt. But with that in mind, we use a generalized linear model to fit longitudinal data and we saw that ventilation perfusion mismatch is, in fact, a big problem in this population. The average VQ ratio at baseline is already 1.6. Normal is less than 1.2. And that ratio continues to increase as the patients get older. But this is the interesting part. We broke it down into ventilation and perfusion separately, and we saw that ventilation doesn't change much. It is the relative perfusion of the Isi lateral side that continues to decline with time. We took this one step further and stratified this analysis based on defect size, an important marker of CDA severity, and we saw that we can mismatch in patients with large defect size COD starts out high, and that ratio increases at a much faster rate compared to patients with small defect size A or B. We broke it down to ventilation perfusion separately again, and again, ventilation doesn't differ much between two groups. It is the relative perfusion. It is the pulmonary vasculature that differs between the two groups. Patients with larger defect size have more severe deficiency in pulmonary perfusion. So, these results strongly suggest that the lack of lung parenchyma, the lack of the pulmonary capillary beds will persist and potentially worsen over time, especially in patients with severe CDH. So maybe, and just maybe, Angiogenic stimulation in the early years in this population may, may help, uh, may play a role in alleviating the problem down the road. So in conclusion, VESHP, as we have shown, is a promising therapy for lung growth. VESHP could also serve as a rescue therapy against the prohibitory effect of heparin on lung growth, and patients with severe CDH have persistent deficiency in pulmonary perfusion, and those are the patients who may benefit from early angiogenic stimulation. And finally, I just want to say, um, the last 4 years of research, it has been an amazing experience. I'm deeply grateful for the opportunity to do what I love, and I'm grateful for the opportunity to make mistakes, and more importantly, to the people who helped me, uh, learn from those mistakes. So to that end, to my advice over the last 4 years, Doctor Peter, thank you for taking a chance with me. Thank you for everything you've done for us. Thank you for putting up with me for 4 years. I know it wasn't easy. I hope it was worth it in the end. No, no, give it time. OK. Uh, of course, uh, I have the entire PEUA lab to, uh, to thank Kathy, Paul, uh, Alexis, all of the former and current fellows. But I want to single out our wonderful lab manager, Amy Penn, and my partner in crime, figuratively and literally over the last 4 years, Lorenzo, um, of course, the people who got me this job, Hal, uh, and Chavo. Doing research is difficult, but it was made infinitely easier thanks to the Vascular Biology Program. So thank you, Doctor Moses, Doctor William Birt, and, and the entire BPP. Uh, thank you, Doctor Buck Miller, for your mentorship, especially over the last year. Thank you for allowing me to participate in these really interesting projects. Uh, many thanks to the CDA Study Group of Department of Surgery, Doctor Schamburger, Doctor Lillahi, Doctor Fishman, uh, Doctor Fauza, all of the attendings whom I have learned so much from, the fantastic staff of the department, especially Terry McCarthy, all of the funding agencies, the Department of Surgery, the NIA SHA, the Harvard Longwood T 32 Program, and finally, the people that are most indebted to my family. Um, My, sorry, my parents and my wife who's in the audience, um, none of these would have been possible if it wasn't for them, and uh, Uh, I'm forever a product of the support and sacrifices. Thank you. All right. Thank you all for the opportunity to uh present my research. Um, so as you all know, I've spent 2 years here. Last year, I was a clinical fellow with the, uh, ICU program on 7th South. And then this year, I've had the opportunity to spend a year doing clinical research with Doctors, uh, Brent Wheel and Chris Walden. So my research focused on sort of several categories. One was surgical oncology. Another was uh cancer survivorship, which uh we do uh through a collaboration with Saint Jude. Um, surgical critical care, obviously, and, um, some other projects that, that I did on the side. So with respect to uh clinical projects we did in surgical oncology. Um, largely led by Arn Maddenci, who's one of my co-fellows. Um, we were able to, uh, put together a risk stratification model for, uh, predicting malignancy, um, based on preoperative variables for, um, ovarian malignancy, and that was published this year. Um, I was also able to work with a group of my colleagues over at, uh, the Brigham, uh, to use the Dana-Farber database to, of, uh, neutropenia patients. Uh, to sort of better characterize timing and outcomes, um, related, uh, to patients who undergo abdominal surgery while on chemo or other, for other reasons, they're neutropenic. And then, uh, which I'll elaborate more, a little more on now, um, uh, we just submitted under, uh, revisions of a paper looking at, uh, the therapeutic impact, um, of, uh, lung biopsy in patients, uh, after stem cell transplant who present with respiratory failure, uh, pulmonary infiltrates, which is sort of a, a, a topic of, uh, debate. So, looking at this, what we did was, uh, we retrospectively, uh, reviewed the Dana-Farber, uh, children's experience of, uh, uh, stem cell transplant patients here. Uh, we reviewed their charts to look at early postoperative complications and then to look at, uh, histopathologic findings with the biopsy specimens, and then Reviewed the charts fairly, uh, detailed to see if there's any changes in therapy delivered, mainly to identify whether or not we were actually doing good for these patients, um, when the medical services asked us, uh, uh, uh, for biopsies. It's what we found, or what we, we identified 555, um, uh, stem cell transplant patients over the past 10 years. And, um, among those 48 lung biopsies were performed, which is just under 9%. We found that the 30-day morbidity was about 17%, which is pretty consistent with um Uh, previous studies, and that the 30-day mortality after surgery was 10%. But if you look at the reasons why these patients were dying, it was mostly progression of their underlying respiratory disease and not directly related to the uh surgery. And then if you look at the pathology specimens, uh, 70% of the patients had a diagnostic, uh, lung biopsy. And then if you look at whether therapy was changed, 80% of these patients, um, had therapy changes. And you can see kind of here. Um, when you split these up, diagnostic lung biopsy is just over 70%, and most of these, uh, patients had a therapy change. There were a couple of patients who had a biopsy that gave a diagnosis, but there wasn't a change in therapy. And these were people who had bronchiolitis obliterans, were already on maximum medical therapy, and the sort of reason for, um, or the indication for surgery was to look to see if there was any additional, um, Eologies that could uh describe the respiratory failure, i.e., was there infection or something else that could be treated, um, to try to salvage the patients. Interestingly, in the non-diagnostic, um, biopsy specimens, just under half of the patients weren't diagnostic, but the medical team was able to change their therapy based on the findings. And what this, uh, predominantly was, was that, um, uh, imaging wasn't really obviously consistent with infection. BAL specimens weren't growing anything in particular. And so, Um, uh, they wanted a biopsy specimen so that they could formally rule out, uh, infections since BALs are sort of plus minus as far as their utility for that. Um, and so, a negative, uh, a biopsy that didn't show any evidence of infection allowed them to really, uh, ramp up steroids and other anti, um, inflammatory therapies. And then obviously, there's about 17% of patients in whom there was really no benefit to doing uh the lung biopsies. So ultimately, um, I think this is helpful in that it sort of, uh, gives a little bit of support to the rationale for the oncologists wanting to pursue lung biopsies in these patients. Um, another part of our work and a fairly significant part, um, is, uh, our collaboration with, uh, Saint Jude Research Hospital. And, um, Through the childhood cancer survivor study, which I'll get into, uh, briefly, we've been able to, uh, do multiple projects looking at the long-term outcomes, um, in children who are treated for childhood cancer that are then followed out 1020, 30 years, um, to see sort of what, uh, chronic conditions and surgical conditions they develop long term. Um, we have two papers, uh, or two projects that are currently either submitted or about to be submitted. Um, one looks at the late onset of anorectal disease, um, and sort of the psychosocial impact of that in, uh, now adults or survivors of childhood cancer. And what we found was that patients who are treated with high-dose radiotherapy to the pelvis are more likely to develop anorectal stricture and, and, uh, a fistula than those who aren't. Um, and though that to us probably seems fairly, um, obvious, had never been shown before, and, uh, um, is gonna be very useful for sort of education purposes for, uh, primary care doctors who manage these patients long term. And then another thing which we've just started uh looking at more is what are the long-term surgical implications of uh treatment for childhood cancer. Um, Arn Maddeny was able to show, um, a couple of years ago or observed a few years ago that, um, Patients who undergo surgery or have abdominal tumors as kids, uh, probably obvious to us, are more likely to undergo exploratory laparotomies for, uh, bowel obstructions in the future, and that those patients have a much higher mortality than, um, those who don't. And so, uh, we've started to look at other, uh, common surgical procedures and what the, uh, likelihood that these people undergo these operations are. And so I've, um, uh, just did a study looking at late cholecystectomies in these patients. And then there's a couple of other, uh, projects that we're doing looking at sort of the global burden of, uh, surgery and these survivors, and then, um, also looking at the impact of surgery upfront, uh, uh, on the long-term risk of end-stage renal disease, specifically in patients who get, um, nephrotoxic chemo plus, uh, uh, nephrectomy. So, um, in brief or in brief, a little bit about the cholecystectomy project that we're doing. So we looked to identify the incidence of and risk factors for late cholecystectomy in these uh cancer survivors, um, you know, 30, 40 years out from their, uh, initial uh treatment. And so what the childhood cancer survivor study is, is a retrospectively ascertained cohort of 5-year survivors, um, who then are have been prospectively followed, um, for, uh, uh, many years. These pieces, these people received their treatment, uh, between 1970 and 1999. And then, um, Uh, at intervals since then have been getting, um, validated surveys sent to them, and then they, they reply with, um, uh, medical conditions and things that they've developed. And they've accrued over 25,000, uh, survivors in a comparison cohort of about 6000 siblings, um, from which they're able to, um, Uh, perform these studies or we are. So we queried the database for people who reported cholecystectomy over 5 years after their cancer diagnosis and then use multiple, um, uh, multivariate regression models to uh evaluate associations between uh variables of interest in late cholecystectomy. What we first did was I just wanted to sort of characterize what the um uh rates of uh cholecystectomy are in survivors versus siblings. And so siblings had about 5%, 5 to 6% um cumulative incidence of cholecystectomy by age 50 years old, which is pretty consistent with um The reported literature. And if you look at uh survivors, they're about 30% more likely to undergo cholecystectomy. And the predominant cancer diagnosis below that or, or that drives that is ALL but also um soft tissue, sarcoma and bone cancer patients. And you can see within this, uh, these leukemia patients are much higher cumulative incidence at 50 years. And then when we looked at risk factors, what we found was that obviously, female sex, increasing BMI and actually attained age all were significant predictors. But also, um, platinum agent, vin alkaloid, chemotherapy, which are common in the, the sarcoma patients, as well as total body irradiation. Um, We also risk factors for, uh, preceding the late cholecystectomy. And sort of the rationale, um, that we have is that both of these chemo agents, um, can cause acute or subacute hepatotoxicity during initial treatment, and that, uh, causes alterations in, uh, bile metabolism and may actually predispose to calcium gruminate stones. And so ultimately, these patients may just have a higher stone burden upfront. Um, and this has been sort of shown in the, uh, uh, stem cell transplant literature also. Interestingly, total body radiation. Um, despite not necessarily increasing BMI changes the lean body and fat mass of these patients. So oftentimes, these patients will have high fat mass, um, despite a normal BMI, and that could, uh, lead to changes in, uh, cholesterol metabolism. So, moving on, a couple of other things that um we've been working on uh with the Seven South Group. Um, we've been working on a quality improvement project to develop a protocol for the manage identification and management of uh abdominal compartment syndrome and intraabdominal hypertension in the ICU. There's a significant, a, a significant number of patients whom they have concern about that, uh, there isn't really a very good protocol for them to go by. And so, um, uh, we've completed that and that should hopefully be, uh, rolled out in the next couple of weeks. And then some other projects um here and uh in the adult surgery uh with Doctor Kim and Doctor uh Modi, which uh I've uh had the opportunity to work on. But, um, sort of most importantly, I've grown up and, uh, this year, uh, or excuse me, last year, I had my daughter, or my wife had my daughter. But, uh, um, uh, Lily, she was born uh in January of 2018, and she has grown up quickly, and it's been very, uh, uh, it's been very great to be able to spend a lot of time with her. So, um, With that, I'll say thank you, a special uh acknowledgement to Brent Wheel and Chris Walden for their, um, um. Uh, mentorship over the past year. Certainly, a, uh, thank you to all the attendings, um, and your, uh, guidance, uh, over the past couple of years also. And then, uh, I will say that, um, I am making a little bit of a career change and have decided that I won't be going into pediatric surgery, but instead, uh, vascular surgery, um, after this. So, thank you all very much for everything and, um, I'll see you around. All right. Good morning, everyone. Um, and thank you for the opportunity to talk about my time doing research with the EA team over the past two years. Um, so having very little pediatric surgery experience prior, I became exposed to the multiple complexities of pediatric surgery while doing the Critical Care Fellowship here. Um, after already completing general surgery residency in a place that actually does a lot of adult esophageal surgery, I noticed many differences. And this brought about many questions, such as, why are we paralyzing our EA kids for so long and what is this tracheopexy that they keep doing? So, in order to answer these questions and future questions, I needed a database of patients and procedures that I could work with. Um, however, there was really no uniform database when I started doing my research. And so that actually became my initial work was to put one into place. Um, however, the only place I knew how to do that was through Excel. So I literally took over 460 patients and put them in a big Excel sheet, um, with multiple, as you can see, variables, and I actually was able to, from this database, um, put together an abstract for APSO last year that was a poster presentation. However, in order for this to be sustainable in the future, I then ended up transferring this to Red Cap, and if you can imagine, if anybody's done this, it's quite a big undertaking. And so I really have to thank um Michelle Dawson, who is crucial in helping to organize and refine this, and really taking all of my messy data and being able to put it into Red Cap. Um, cause as you know, um, All of the EA kids, there's multiple nuances and uh technical complexities and operations, so nobody's really the same and being able to capture all of that in Redcap for the Future was, I think, a big undertaking. As a result, most of my research has been retrospective in nature. We've looked at, um, updating outcomes in patients with long gap esophageal atresia, duojunal interposition, and also looking at the use of CT in the preoperative workup of, uh, patients with tracheobronchimalacia. I'll briefly touch on some of these results later, but I would actually like to spend some time talking about a different project that I've been working on. And that's our tracheopexy to the floor QI project, um, that was initiated a few months after I started my dedicated research time, and the pilot phase is actually officially ended this past January. So the background for this project is that we as a multi multidisciplinary surgical anesthesia, and nursing team have really become more facile in taking care of patients with tracheobronchimalacia. Um, patients who would originally go to the ICU intubated and stay in the ICU for multiple days are now being extubated in the OR, staying in the ICU less than 24 hours, um, and requiring minimal, if really any ICU interventions during that time. Thus we sought a way to bypass uh ICU, the ICU for these specific patients with the goals of decreasing unnecessary resource utilization and really streamlining the recovery process for these patients. So our target population were patients who were greater than 6 months of age and who had, um, were going to undergo just isolated uh surgery for tracheobronchomalacia. We excluded patients who had, uh, respiratory, uh, required respiratory support at baseline as many of these patients would not even be floor candidates, um, if they were undergoing any other surgeries. And we also excluded patients who had simultaneous esophageal surgery as many of these patients require, uh, intubation and paralysis after their procedure. From this, a retrospective review of 12 patients that met this criteria was performed, um, to really highlight to the task force and the stakeholders what kind of postoperative care these patients actually required. And one of the things I want to highlight is that even in this group, the median, um, ICU stay was 1 day, and that is just kind of an overnight was what we counted as 1 day. So although this slide might be hard to read from the back, um, the key point from this driver diagram is that there were many, um, pieces that need to be put into play in order to make this pilot project a success. More specifically, we worked with the um anesthesia to review case eligibility of patients. We worked with the pain service to come up with a more regimented, uh, postoperative pain management program that included the use of paravertebral catheters and PCAs. We also engaged PACU providing education to nurses on the immediate postoperative management of these patients and developed a standardized handoff, uh, that could be filled out, um, upon provider sign out to the PACU and then could be, uh, used for PACU sign out to the floor. We also held education sessions with both the day and the night nurses um on 10 East, and I actually have to thank Dori and Sig who really spearheaded all of the education efforts for this. And we also provided a roadmap of what the general expectations would be, um, each day from the time of surgery until discharge. So once this was complete, we got a green light to begin our pilot project. It actually started in July of last year and lasted for about 5 months, and we collected demographic data, um, some acute outcome measures, and then, um, we also did, um, family surveys, which were done, um, by phone call 2 weeks, um, after the patients were discharged. So looking at the initial comparisons um between the protocol group and the pre-protocol group, um, there's no difference in demographic variables, the degree of tracheomalacia, the surgical approach, um, or OR characteristics between the two groups. Um, what we did notice was that length of stay was approximately one day shorter in the protocol group, and there was a significantly shorter time to initiation of a diet postoperatively. Um, another, um, big thing that we found was that no ICU stats were called during this, uh, for any of our protocol patients. There were no readmissions and there was only one ICU transfer, um, for a non-airway issue. We also looked at um potential financial savings and found um that there is a significantly lower cost for ICU level of services, um, and the median difference and savings of about 2700 per patient in the protocol group. As I mentioned, we also did family surveys, and um these were, there's two surveys that we were given. One was an HCAP survey, um, in which we found 100% of these, of the families felt that um explanations were understandable while they were in the hospital and that they were treated with courtesy and respect during their stay. A more surgery-specific, uh, patient survey, um, found that 100% of patients of, of, uh, families felt that their child's pain was improved, uh, their preoperative symptoms had improved, and they didn't have any concerns about the procedure that their child had undertaken. These are just, um, this slideshow just shows some comments from the parents and kind of the take-home message is that with the positive feedback from about the nursing, child life, and really the whole experience just highlights the importance of really um developing a multidisciplinary approach to patient care and improvement. So not only did this QI project allow for a shorter length of stay and quicker return to oral intake, but it also showed cost savings, um, a higher rate, high rates of patient satisfaction, improvement in resource utilization, and after, um, our stakeholder meeting in January, now all patients that meet this criteria will be part of the tracheopexy to floor, um, postoperative management plan. So for the remaining time, I, um, as I mentioned before, I just wanted to provide some snapshots of the other projects that I've been working on. Uh, the first project was looking at the evolution and subsequent outcomes of treatment, um, on our treatment of patients with long gap esophageal atresia. Uh, so dichotomizing patients based on, um, their year of surgery is either before or after 2015. What we found was that, um, our time on traction is less. Uh, we have, um, significantly shorter lengths of paralysis, length of intubation, as well as, uh, length of stay. Patients in this contemporary cohort also um have found have less anastomotic leaks. Fewer um percentage of patients require stricture resections now, and with our decrease in length of paralysis, our fracture rates have also decreased. This is just looking strictly at the contemporary cohort of 47 patients um since 2015 who underwent the Folker procedure. Um, at one year of follow-up, uh, 28% of patients, um, were on a full oral diet, while another 30%, um, had consistent oral intake, but still did require some tube feed supplementation. Um, I note, we did a subgroup analysis, um, and patients who had been transferred to us after, um, an attempted esophageal anastomosis at an outside hospital, um, and underwent a FOCer procedure with us which we called rescue folkers. Um, this sub-cohort, um, does take longer to eat, and at the one-year follow-up, none of them had, were on full oral intake, but patients who had their initial surgery with the Fokker procedure, which we call primary Fokers, um, are similar to these numbers where 33% were on a full oral diet. So talking about focus and complicated long gap esophageal atresia patients leads to my next research project, which was looking at the um outcomes in patients uh undergoing a junal interposition. So this design was very similar to our long gap esophageal atresia study where patients were dichotomized um into a historical and contemporary cohort based on the date of surgery and then compared. Um, and similarly as well, um, paralysis times and length of stay were all significantly decreased in the contemporary cohort. Uh, looking at feeding outcomes, patients in the contemporary cohort had a shorter time to, um, first oral intake while in the hospital, and 45% of these patients, um, have consistent oral intake at less than a year follow-up. Um, the time to full oral intake was numerically shorter in this, in the contemporary group, but although it wasn't statistically significant with these, um, with this analysis. However, this is looking at patients um in the past 10 years, so both the historical and contemporary group, um, and there's a higher percentage of patients um who were eating preoperatively, and this even includes sham feeding with an esophagostomy. If they're eating preoperatively, um, a higher percentage of these patients, um, had consistent oral intake, um, and, um, Uh, had a much shorter time to full oral feeding. So with that, I would like to segue um slightly to my work looking at the role and utility of CT scans in the preoperative workup of patients with uh tracheobronchoalacia. Specifically, one project was to identify the prevalence of great vessel anomalies in, in this population and compare the, um, The prevalence between um patients who just had tracheobronchimalacia and patients who also had uh esophageal atresias. We felt like these two groups were um very different. And so, kind of looking at this, when we look at the CT scan, some of the um examples of great vessel anomalies that we identified were double aortic arches, right arches with retroesophageal left subclavian artery, um, as well as the nominate artery compression. And in summary, what we found was that um patients with just isolated TBM, a higher percentage of them had um aortic arch anomalies, um, under a higher percentage also underwent both posterior and anterior work in the same operation and to kind of go along with the, um, higher incidence of great vessel anomalies, a higher percentage of these patients also underwent, um, great vessel and airway surgery, uh, simultaneously for symptom relief. Um, in the EA patients, these patients were usually younger at the time of surgery, and there's actually a higher percentage of laryngeal clefts which we look for as part of our preoperative workup. However, there was no incidence in the actual percentage of patients that had at least one great vessel anomaly between the two groups. Um, and finally, after this past month, I presented our work on trying to predict which patients would benefit from a descending aortopexy. And for this study, what we did was we measured the distance between the anterior border of the spine and the, um, anterior border of the descending aorta, as you can see here in the picture on the left. Um, uh, and this was measured at the left main stem bronchus. So in patients with left main stem, uh, bronchoalacia, the positioning of the descending aorta, as you can see in these pictures, um, is critical to the success of the, of the bronchopexy as further compression of the left main stem can result if the position of the descending aorta is not addressed. On multivariable analysis, we found that um greater than 50% collapse of the left main stem on preoperative bronchoscopy uh was the most significant predictor associated with the performance of a descending aortopexy. So I know that was kind of a lot to get through, but kind of just, here's a summary of what I've done over the past 2+ years, um, including I got my MPH degree last week. Um, so I want to thank everybody on the EA team, Critical Care, Department of Surgery for your support over the past few years. Thank you. Well, Lorenzo, Dewey, Brian, and, and Winnie Joe, congratulations. Your, your, uh, presentations this morning, very well documented all that you've accomplished in your last, I guess, 1 to 4 years that you were working in the lab, and Brian, for your clinical work as well. I must say I've been very proud of the presentations that I've been able to witness that each of you have done at the, at the national meetings. You've always represented us, uh, remarkably well, and I appreciate you for that. Uh, are there any questions or comments that people in the audience would like to make, particularly the mentors? Or go to resting then. Uh, two things. First, I want to thank Wendy for all her hard work in the Eat program. Not only did she compete all around the country in gymnastics and get her MPH, she built the database and pulled out all this data, and that was only in 2 short years, so incredible accomplishments. But I did have a question on them. On the presentation about omega 3. When you did the studies on inflammatory markers, you, you had the vast majority of the fats were 6s and partially hydrogenated. Stuff which is all evil stuff we all know that it's been taken out of diet, and a little bit was omega threes, omega 3s that powerful that you can actually change inflammation by adding a small percentage. It's a, it's a great question. And that what we calculated that dose that we did is, is a little bit, but it is, it's equivalent to a dose that what we would give it to an adult. Um, so, I mean, you can replace all the fat with omega 3 fatty acids because it doesn't, wouldn't provide all the essential fatty acids. So you replace a little bit. And what we're doing in the lab right now is, is using other, I know, and you, you brought the point of uh having a lot of uh hydrogenated vegetable oil or omega 6 fatty acids which are evil as you mentioned. I mean, not at all, not, not entirely evil, but, but we're trying to play with those concentrations as well to even bring down that, um, even further. Well, 4 really fabulous talks, um, Dewey, I had a question for you. Um, you've had major successes the past 4 years, as has Lorenzo. And I was wondering, could you say a few words about the kind of influence that your CDH research has had clinically in the clinical world. I Uh, that's a loaded question. Um, Um, well, um, so, Doctor Peter and I, um, of course, trying to, um, move this, uh, VESF therapy into, uh, clinical trials, and, uh, we, uh, recently co-founded a company to, um, uh, hopefully bring Vetchef, and we are doing more pre pre-clinical studies with piglet models in a lab which will be headed by, uh, Uh, Tori and Jenny, uh, so exciting result, uh, to stay tuned for, um, but hopefully, the, the goal is to bring it to patients. Um, and we're also, uh, uh, exploring other, um, pro-angiogenic therapies in the lab as well. So, um, we are sort of attacking this from different, multiple different directions so. Oh, Doctor Weldon. So I just want to say congratulations to all of you and uh especially Wendy and Brian, uh, you were selected for your potential and you obviously proved that today. Furthermore, I would ask and recommend that you don't look back so much as you look forward, and you've created a great foundation to spring into a career. Uh, Wendy, you're going to Kansas City. I know you're gonna have a great two years, Brian. You've had a remarkable success with us, and your, your change of path is certainly kudos to you and a recognition of knowing yourself, and we support you all the way. I also wanna comment that the one project you really didn't talk about was the um late burden of surgery period in the cancer survivorship cohort or you didn't stress it enough. That'll be a New England Journal of Medicine quality paper, uh, and that will something you will take with you as you will all take projects with you. Most importantly, don't forget those as well, cause that's really the low hanging fruit that you can bring home, but congratulations, great work, and we're very proud that you were with us. Final comments from Doctor Peter. I, I just wanna say I really appreciate the work that both of you, uh, put into this. I know it's been a lot of nights and weekends, and, uh, it made a big difference and potentially a big difference clinically. Uh, they left out a lot of projects that they've done, but everything, uh, is translational in nature, whether it's Uh, a couple of patents and, uh, forming a company around some of this work. And also, uh, Lorenzo didn't mention some of the best work was actually on the brain research he's done, which actually he's able to demonstrate in the method, uh, the approach to, uh, reducing aging, uh, dramatically and, uh, with particular knockout and also his work in sickle cell disease. So I just wanna say I really appreciate the work that you both have done. Uh, I'm gonna kind of miss you. They haven't gone and he's already missing you. So, Lorenzo Dewey, Wendy, Joe, and Brian, thanks again for all the great work you've done in the last years. Right Yeah, she's the wake me up. you that He's still. That Yeah. That. Uh, I'm sure I'm. I. I And I'm. Yeah. I know we're sharing. I don't know. I Yeah. Yeah Um So. So. Yeah That's I. Another another week. I. Congratulations. Yeah. I'll see you again. I say. it I. And that's OK. I agree. Oh yeah So I think that I, I can do. I Yeah Oh yeah. So I That's how OK Yeah, it's almost. Yeah. I. Yeah It's like a kidney stone, yeah, like a kidney stone. I had a kidney stone. But So like you're not that that's the that's the biggest compliment that the kidneys so is pretty nice. I thought I was. It. This is You can go to that. He
Click "Show Transcript" to view the full transcription (55693 characters)
Comments