Dr. Steven J. Fishman - Vascular Anomalies: Lessons Learned from Our Patients

So attempted introduction for fear of what it might have been. I'm Steve Fisman, I think most everybody and I are familiar. And it is really always fun to give a talk at home. I was invited to speak in all sorts of interesting places. But it's something different about speaking home, really home. And speaking in the department where I was trained and where I've been my whole career. And in Dr. Fultman's auditorium, he is a significant mentor for all the work I'm going to present. And we miss him. What I'm going to present today is a little different that I've done in past years when the fellows have asked me to sort of just give an overview of Asker Nomies and what are all those purple things we're cutting off. And I'm not going to do that. I'm not going to give any introduction at all to Vasker, tumors, Vasker, malformations and the different types and the names and all of that. It's going to be a little bit of an advanced assuming you know some of that stuff. And this is actually a reprise of a talk I gave as a keynote lecture at the International Society of Asker Nomies this past spring and Amsterdam. And so far I'm way ahead because I showed up when I walked into the concert hall in Amsterdam 15 minutes before my talk. I walked in the back of the room and Denise was there, I remember this and it was at all Steve there is there is they were ahead of schedule. And I was in the speaker ready room adding in some historical slides just for pictures so people could see what the meetings in past decades had been. They were ahead by more than 15 minutes and they had already introduced me probably the most more embarrassing fashion than for Ocas about to do but I missed it. So I was here on time this morning. So I want to talk about sort of you know maybe old guys perspective on what we've learned over over a couple of decades or more things that didn't make sense. Things that I hope are inspiring to those of you facing challenges with things that don't make sense and that seem like there's no hope. Because the moral of stories if you surround yourself by really smart collaborative and positive people and most importantly listen to your patients listen to your patients as darker folk when we said challenge your exceptions to cherish your exceptions and then challenge the dogma. A few disclosures I'm going to go fast I'm just telling stories it's mostly it's mostly photos I'm dyslexic I don't do a lot of words. Almost everything I'm going to show you is a credit to somebody else or somebody else's work some of them in the room. I am definitely not a basic scientist but I'm going to show some like pathways and stuff so that's a little scary for me. And Denise has heard help me if I get in trouble. And almost everything that we do in in in theatrics and bachelor's in particular is a medication is off label. So this is this is one of the first things that I sort of focused on my career was hepatic and mangeomas and and the senior people in the room have have heard this. And when we came through training in school we learned that hepatic mangeomas were all the same they had this classic triad of hepatic megalyphile pit heart failure and anemia. And it turns out that almost none of the patients actually have that triad. When I got started the therapy options with we're a bunch there's all bunch of choices and the best I could tell about the science of how one shows which therapy to use for an individual patient was if what you used last time worked well do it again. And if what didn't work last time isn't appealing try something else or if the guy down the hall had success with something go with that that was literally what we understood about these things. So I'm just show briefly an overview of how we now in a simplified view look at VASCA tumors of the liver and infants with an a humangeoma on them. And talk about some some of the advances we've made in understanding which is really simplified and improve the outcome of these of these babies. So this term here rapidly including congenital he mangeoma that term didn't exist when I started. And it came up because classic he mangeomas they are the strawberry marks we see in our our daughters in our nieces and granddaughters say daughters because they're mostly in females. And it's the most common tumor of infancy and they're benign to go away we can make them go away faster with drugs for printable now in particular which we didn't have when we were starting this. And it turns out there's a small variation of what we used to call him angeomas that didn't follow this pattern of showing up at about a week after birth proliferating for a year and then invuluding over the next several years. And they were already present at birth fully grown at birth never grow after birth and go away really fast. It turns out to go away really fast regardless of what we do to that right so there's all sorts of case reports about snake oil and fish net and hanging babies upside down the way faster turns out that was because it was before we understood that this variant just goes away you don't have to do anything and this is an example of a baby we saw right as we described this. And you can see on the fetal MRI this quite large tumor hanging on the side of the head almost half as big again as the head and here isn't cross section. Now in early 90s when we started recognizing this phenomena and simultaneously a group in Paris had recognized this phenomena. John Mulliken who's really the founding father and mentor to all of us in this field who's a plastic surgeon here had noticed this at the same time that Odile Angel Ross a dermatologist who we recently lost in Paris had noticed this and so Odile brought her pathologist Michelle was over and they spent a weekend down in our pathology department with John and Harry Kaseke which the pathologist that many of you know who's really good when they asked for a question. And they spent a weekend looking at the clinical photos and looking at the imaging and looking at the histology and they decided that this is this thing from infantile he made a joke and let's call it something different so it can differentiate and John Mulliken is very much a step away for words and making sure things are properly classified so they decided to describe what it does it's there at birth so it's congenital. And it goes way faster it's rapidly invuluting so they decided to call it rapidly invuluting congenital he made you know and John likes to use acronyms for everything we have a lot of alphabet soup as Dr. Falkman say in Vashkanon and so Michelle was said who's a wonderful gentleman who speaks pretty good English but he's got pretty thick French accent. He said RICH, Rish and Harry says no rich RICH is rich in English and John Mulliken says I like Rish better and it's Rish that's what we call that's what we call that's how medical history happens somebody the the four founders just says and this is all the world called Rish and somebody calls it rich we know they're not familiar with the field. So so this is a baby that we saw early on this baby lived in Florida and we got sent these imaging in our comforts and we said it's fine it's just a Rish just delivered the baby probably do a C section you know don't poke it but it'll just go away don't worry about it and both the obstetrician the family were freaked and then we're going to let a Boston so it's okay so came to Boston we delivered this baby to the berigam here's the C section and the baby comes out and and it's already smaller so it's already started invuluting as they as they typically do. And then the family stayed here for a couple days in southern north they went home in Florida and they we never saw them again but they they sent us photos and we can you can see how this indeed rapidly invulutes and this is a non problematic lesion in almost every case. So when we started trying to figure out the liver lesions and we're calling these big things in the liver, he mangeomas but we'd see them antinately these big focal lesions you can see this in ultrasound or you feel it was a mass at birth so like the skin lesions it's not it's not coming on later it's already it's already there so we surmised and have since proven that these are in fact not infantile he mangeoma these are not response to medications and in fact they just go away so you usually don't have to do anything. Here's an example of a baby we had a local baby you came over and sent a list of this with this big mass and you can see this is a premie so it was in hospital and you can see this this x-ray later it's just gone right you can see the liver has has diminished. So how do we take care of this well most of the time we just follow with ultrasound and everything's going to be fine. We don't use any medications because they don't work and not necessary with the exception of if the baby has high flow sort of arteriovenous shunting in or around the tumor which some of these resillations do in which case we treat them for CHF and if we can't if it doesn't invalute and the shunting doesn't go away on rare occasion we will have an eventuallyologist. Embalize these and the hard for it goes away at the end of the end of the embolisation because it's just a high flow of it's like having a diosyspital that's too big. So this explains in retrospect why some of these babies did okay with surgical scissor with embolisation or in the early days with hepatic arylikation you were just diminishing flow of these things you were actually actually affecting the tumor. So that's the first pattern is focal then there's these multifocal lesions that are sort of sprinkling out the liver and they can be big tumors they can be small tumors they can have big vessels they can have small vessels and you think that the big vessels go with the big tumors and small vessels go with the small ones but that's not true these are big vessels are there because they're shunting there's arteriovenous high flow shunting there and this child will be in heart failure sort of like some of the patients with the large lesions the focal lesions and and this child won't be asymptomatic. So it turns out these are indeed regular old fashioned infotainment jammer like the strawberry marks we stand the skin we prove this with this one stain and you can see here's proof this baby with a little tiny lesions obviously was in heart failure and so it has something that decides the lesions it's all about the shunting. So most of the time we follow these now when I was a fellow or young faculty member you never didn't treat a liver he made your but they were considered scary they're going to die they're going to deliver transplant you don't do nothing now the vast majority of these we do nothing we follow them with ultrasound we same every week uh oh neither we we see lots of them every week and then and then we follow them over the months until they go away if they have heart failure we treat we treat them not only for the heart failure but also for the lesions these lesions melt away with propryndalol we used to use steroid you know if you're not saying it's now propryndalol um treats these things and that's a great story and we don't have time to go into um if they are not responding fast enough or you don't have time for the respond and they're a massive heart failure and they're going to die then we embolyze their shots. And then there's the third pattern which is this this diffuse and these babies present is if they're pregnant with triplets um they're usually several months old and they weren't known to have had any problem before and their problem is that they've got a bowling ball in their belly and they die of abdominal compartments in room. There is no room for the kidneys and testing uh they have loser Venus return to go into renal failure from renal van compression and these lesions to this day are quite quite frightening these are also infantile he mangeoma they do respond to propryndalol um and um these um these are the ones that remind us that well it's not just the birthmark so we have to prevent this from happening we have to detect these early and since we've described this um it's now very very very rare uh it's for a baby with a liver hemangema uh to die. So the most important thing that that came out of this recognition um this this talks about and this really and it is by collaboration many many years ago um we were rounding on a baby up in southern nuts of the north in uh we'll p5 which is not equivalent of seven south uh and uh it was that that baby I just showed you a picture of uh and that baby had um a came here from Akron, Ohio and was past past the point of us being able to do anything we hadn't recognized these patterns yet we were just sort of thinking about it um but we knew enough to know that without the big vessels impulsation wasn't going to be useful um and we treated the baby with the whole and we threw the whole oncology panel of drugs at this patient uh and he uh I even did a fascia otomy to to release you know give more more room the abdomen to to try and release the abdominal compartment syndrome and we decided to attempt uh to intentionally in the crows have to liver to shrink it to buy some time this was an absolute desperation move and Pat Burrow so it was our head of interest reality at time uh want to take the baby down and embalize the rechipatic artery knowing that we weren't you know treating heart failure. In fact when we scheduled the baby the anesthesiologist who can read their textbook and they know that he made him a chemist called his high upper heart failure they said oh we're not putting the baby to sleep until we get an echo and we said oh no no no we don't need that um it turns out that this pattern doesn't have high upper heart failure and they said you want the baby to go to sleep you're getting an echo so we got an echo and the echo did not show high upper heart failure but surprisingly it showed low upper heart failure it showed the ventricle barely contracting the ejection fraction was pathetic and it turns out it was because the baby was profoundly hypothyroid we did not something you think about in babies everybody gets a newborn screen and you either have a thyroid or you don't right you have good thyroid function or you don't otherwise hypothyroid is not a disease of pediatrics so we have seen this a few times over the course of years and every time we get an endocrine consult they would say oh we don't know and here's the medicine to give um but you know we had accounted at the time we had 28 attend again a chronologist and most of them spend you know one or two weeks or a month on service a year so you never get the same one twice we only see one of these babies every few years so it couldn't convince anybody that this was a real phenomenon and I got a little frustrated uh in in rounds and p5 and I said you know you guys got to figure this out these babies are going to keep dying something weird is going on here and this guy Steven Wong was the first year endocrine fellow and uh and he said um I believe you I remember Brianna and I said how do you remember Brianna now Brianna was the last baby three years earlier that we had this experience with in the same unit he said well I was an intern and I was rotating through the ICU service and I remember on Christmas day on Christmas day you and doctor folk when the two Jews came in to withdraw support with the family and they maybe died I said that's right he said well I got to finish out this clinically year I need a research project I'm spending my next two years figuring this out so he went to his mentor his his chief venecronology Joe Mejou who said well that's great Steven he said but you know we're pediatric doctors we don't really know we're care about the thyroid that's an adult organ you know the pediatrician's treat can genomic thyroid he said but you know there's a lot of smart people in Boston why don't you go next door to the brigham and there's this guy there he has read Larsen and he's an internologist who only thinks about the thyroid he's a full-time thyroidologist and he has a lab and he does all this metabolic stuff and maybe he'll help build figure this out so so this baby ended up we couldn't we couldn't help this baby and we offered a transplantation this is a situation considering a pediatric transplantation and the family was not interested and they went back to Akron for terminal care they refused autopsy in Akron except for the fact that Steven had bonded so much with his family that they agreed at the bedside for the surgeon to do a quick little incision in the belly get some of this liver and freeze it and send it to Boston and he used that specimen for the next two years and he went over the kinetics with with Reed so this is a log scale so the TSH just follow the blue line here the TSH was 216 normal is 0 to 5 so it took us nine times the amount of thyroid replacement that would take to replace an adult with a total thyroidectomy to get him into the u thyroid range and so that was a hint of them that there was a destructive thing going on and they did all this work and they came to me they said we think we've got something so it was they said well it turns out that we found this this diionase type 3 I had a thyroid in the eye and I said cleaves eye a diion off a thyroid hormone whether it's endogest exactive it doesn't matter and it inactivates the thyroid hormone and so this baby is just destroying it and we have to just keep giving more and more until we give more than the baby can destroy it's just a race between production and destruction and they said you know this is really exciting I said yeah who hands could cool have the mechanism you know you don't they say you don't understand this is the first human disease ever discovered to be caused by abnormally rapid breakdown of a naturally occurring hormone and I said that's ridiculous they said well name one and I went through my medical school remembering all those ectopic productions all that kind of stuff and they said yeah what about destruction and even to this day that this is it right so Stephen who was for his fat he was a fellow still first paper he ever wrote first author new indrural medicine and I said Stephen's all downhill from there I had the opportunity a long time later to read a letter for his promotion to associate professor where his most recent paper now he was senior author in the new in the journal on another sort of situation with the same dehydnase and he went on to become the first pediatric full-time therodologist just left here in a good industry but but uh so his whole thing and he didn't care any about gastronomy it just came from being in the right place at the right time and being willing to collaborate and listen um you know so it's it's it's really valuable to look at first mark people down the hall across the bridge etc he the first time he presented this in this room um he he was showing this chart and I was sitting right down in a second afterwards I walked up to him and read the article with the brain and I said you know I've been kind of ignoring it but you know my tsh is elevated um I've just gone like to rigor you know it's screening visit with my internist you know it was like six months earlier and my sister and mom was in turn said you should probably should treat that blew it off so my tsh was sixteen which is not 216 but it was too high and they said you need to treat that and relarce and wrote me a prescription sitting here in the second row and now the ORA nurses said hype or a thyroid or hype both I write because if you're a hype both I wrote you'd better not treat it uh so uh so how do we treat these lesions when we see one of these lesions we jump all over them with high dose perprano law uh we treat them with very aggressive a thyroid replacement the thyroidologist that endocrineologist around the country do not around the world do not believe how much you have to give it's easy to follow the kinetics in fact it's a great way to follow the evolution of the tumor because as the it's you have a biomarker as the thyroid replacement requirement goes down you know that your tumor is infeluting it's just a volume effect and it turns out that all he mentioned was had his dehydnase because he even went back and sat down with Harry and pulled a bunch of historic specimens even the ones that were removed cosmetically and they all expressed his dehydnase um if you get these babies too too late that this is a situation to consider transplantation so after Stephen published this it didn't take long to three years before somebody published the first case where having recognized this uh that uh you could save a baby and this guy had called Stephen and helped with with with the kinetics uh and now this is standard care routine everybody in the vastram is world knows this all-dentocrineologist in the world noticed uh and he changed the world just by listening as a as a first year fellow to a frustrated surgeon who raises voice a little bit because nobody wanted to pay attention so um that's one of things that can happen in Boston medicine all right so what do I do surgically um because I never operate in liver hemantium I didn't show you surgical excision for all any of those right with it's not surgical disease almost almost not exceptional um with exception of appeasional section of transplantation so this is a condition that I'm not going to go into details of it other than this acronym uh uh you know it's again describes a bunch of the components of this condition um and this is a condition that was um uh also described by um one of our group members Amal Amari our current chief interventionalogy uh and Amal sort of just went through our database we have a one of the most common entries in our vastram is database is a something called Poova and so we like to use acronyms Poova stands for provisionally unique vastram anomaly meaning we have no clue right so we just check off the box Poova in the database so mod spent a long time going through all the Poova is looking at their images and looking at their photos and he said can I take some ten minutes to conference one day and he hit the next next next next one he and he shows 19 of these kids that look like this so I said oh yeah this is different um and we were sort of fading in other categories anyway those of you who have operated with me see this is I off this is what I do this is what my clinical world is I um have these big extra pieces and and and cut them off um and so this is uh you know I take pictures without the blood in them but those who've done them know that sometimes there's a little blood issues we do these uh in one at a time you attack the anatomic areas and we basically treat this like a like a like a birthday present and I open up the wrapping and I take out the present um and um and then you have all this extra space and extra skin uh in uh take out the extra pieces and close it up and and tighten up the wrapping paper and try and make it look nice and that's about all the science there is to what I do in the operating room um so then we move on to the next anatomic part um and here you can see this uh evolve our problem uh same idea um and make them as functional uh as you can and then we move on to the next part is it all the same girl and now we're doing the the thigh hip area same thing take out the present put it back together uh make a look as nice as you can these are non-trivial I don't want to minimize this these kids are drains in forever they sometimes get a lot transfusion they get infected their wounds fall apart it's kind of misery and then I kind of ignore them in the best of them is their practitioners just take care of them thank you to them um and um so here's the next it's same patient so we've done the torso we've done the body we've done the vault though we've done the thigh so so now we've got this so there's this medius dynallnesian which is very common in this close syndrome uh and um uh it's supposed to hear me a stythomas and you know we know it's not malignant because it's all contiguous with you know with this out here that we remember I debunked this uh this is afterbocking and it's contiguous here um I know it's going to be the same kind of lesion so I had her scheduled forethought thoracotomy to take this out um and the day before uh mom was in my office to do consent and to talk about this and and I and I kind of lost it a little bit and I remembered two years earlier when I had done the big debunking on her chest wall that she had an unbelievable amount of bleeding and the secret to not bleeding the death on the OR table and vascular malformations is closed um the bleeding can't come through the skin the form of hematoma we put a drain in uh and um uh it drained usually have a limped draining seriously this drained blood and this drained blood for a long time I mean a couple of months she went back up to dartmith and was bleeding and got transfused periodically and then finally came back down that they couldn't handle it more and and um I was out of town and rusty Jennings was was covering a servicity I don't know if you remember this rusty uh and uh we decided to uh uh squirt some some thrombin into this drain and then pull the drain and wrap it and it worked um so thank you for that you probably remember that's a long time ago uh so I now I'm a couple years later the day before the thoracotomy I remember start remembering how much this thing bled and I said that mom you know the reason she didn't die was because we could close I said well we're in the chest like that closing is not gonna stop the bleeding and I said to her I said I think there's a 50% chance that she's gonna die on the table and and uh you know I started crying she started crying and I said I really wish her something we could do you know um um you know I wish we had a pill so some of you are wondering well why would you be contemplating an operation with a 50% mortality for that thing right it's benign don't you're not gonna take a chance at dying well we didn't okay that's actually what you looked like at the time we're having this conversation okay we had watched it for a couple years to this point and it had now filled the chest and now you got a kid who's just a few years old who has no room for lung development left side and that's why we're contemplating it so even at this point I said I'm not gonna do this and the mom said no you're not gonna do this and I said I I don't know what to say I wish I had a pill and the light went off in my head and I said wait a minute maybe we do operations canceled so we had always had this dichotomy the way we describe these patients you have vascular tumors which are proliferative they're usually benign but they proliferate they're neoplasms and you have malformations which are you're born with like having a dr. mechernia and perforatainus sindakli you're just born with that it's not gonna change over time well but clinically we sort of noticed that they do change over time many years ago this is we posted this back in in 2005 we had done uh with marcia moses some analysis of vascular tumors and vascular malformations looking at some of the angiogenic factors as well as metallic proteases and turns out that even the malformations their metallic proteases increased based on the sort of clinical scoring of a limited condition moderate or extensive and we are and we know that we watch these patients over time and these lesions get worse even though they're not histologic tumors uh and so this is showing that in fact they're breaking down matrix uh and something active is happening right so this is you know a long time ago and we were theorizing gee wouldn't it be nice that there were a drug that will be able to prevent these things from progressing so denies atoms who's here in the room and and now runs our vascular malice center um i wouldn't say with me but she runs the vascular malice center um and she had this experience when she was in sindakli was she was thinking about this um and she had this patient which has a composed form he manjo in the theliala this is a bad actor this is the lesion that causes uh kossabok maric phenol and platycount to two thousand uh you can't get back up sometimes these kids die of head bleeds etc she had given this patient all the standard therapy and some non standard therapy and this kid just wasn't responding and most of them do respond uh to these to some of these medications so a prepared mind right so this is like steven hawk right this is another genius moment so denies was familiar with some of the uh people in her institution who uh were working with tuberous sclerosis and some of those patients have angel myeliacomas which are vascular tumors in their kidneys and they were treating patients with throlumins right which are transplant people of course use every day and she realized that the gene for tuberous sclerosis was in the mTOR pathway and we knew that some of the vascular lesions had gene mutations upstream like p10 and ty2 that are upstream in in the mTOR pathway but we didn't have any gene for this we still don't have a gene for this uh and so she sort of theorized in desperation for this child but maybe if you gave serolumins we have a justification and maybe it will work okay which is different than the story that most people in the western world think is thinks she's a gas and got lucky so here's how this child did uh something of a miracle right so she started a trial and was pretty inclusive including all sorts of horrendous vascular malformations uh with some selection criteria followed them like an oncologist was would do in a non-college trial with outcomes because she's a non-collegeist and she's familiar with clinical trials and this is an example of a response um that is dramatic these tongue lesions are just just absolutely miserable and this was like a miracle when we saw this the first time and then there's some other conditions again we're not gonna spend a time about about the name but you can see all these lymphatic lesions in bone and they're melting away uh and here's a patient with uh a plural effusion three months later um and then she published this uh and this was really um this is a momentous paper in in the history of astragramas this is really demonstrating yes um you know when John Mullick and a Judith Fulp and I used to sit around our conference table on Wednesday night or we used to be Friday night and we'd look at these horrible cases and say we need a drug and we hope there be a drug honestly i'm not sure i mean doctor Fulp can probably knew but John Mullick and i really didn't believe that every drug in our lifetime in our career and he's still going so it's in his career uh and uh and so Denise single-handedly really proved this as possible and made this happen and now there's an onslaught of interest and activity and she's leaving more trials with others and getting this done okay so now we've got this baby and um we've been taking off pounds of this stuff for decades so we have a whole pathology lab full of this stuff and now molecular genetics is coming about to become something that's reasonably practical so matt warman who's a geneticist we actually the clinical geneticist by training he and i were fellows together but he went on to be a basic scientist does three patients anymore is actually left and came back and now he's the director of orthopedic research because his interest is in uh genetic anomalies of uh mzinkimole sort of tissues always been interested in vascular anomalies actually was on the first paper to find a heritable mutation uh Mendelian uh heritable mutation for vascular lesions definitely when we were fellows and so he started looking at these tissues right because we've got pounds of them healing in a few cells and unaffected tissues which we can get from blood or cheek swab and start to look at all these different conditions and he surmised and of course was correct that that most of these non heritable not inherited lesions and most of these are sporadic are somatic mosaic mutations so he looked at clove syndrome which is what this girl had that were worried about this lesion in the chest and did this needle and a haystack analysis with with um next generation uh sequencing uh and deep sequencing uh in a bunch of patients and found um in a bunch of patients that the only common somatic mutation was this a pick three c-am mutation which was a known gene uh that uh in other conditions we started putting things together and now this is later than this this is like the best figure that now we're all showing uh erin green just just actually just wrote this paper this is a uh a review paper um that that erin has won our parts of surgeons has written in this is putting all these are the names that we have sort of inherited over the centuries and made up over the last couple decades um for vascular malformations uh and vascular tumors and it turns out that these a couple pathways is what we talked about tie two pick three c-a m-tore um this is all now making deniesis theory makes sense so now we've got this baby who's got clove syndrome map proves to us that's picked vascular which is also in the same twerpathaway and we and i'm talking to this mom crying i said i wish i had a pill like oh maybe we do now nobody had treated clove yet but it made complete sense cancel the operation and um we gave this baby trolumas um and you can see here's where we started 12 weeks 24 weeks 48 weeks this thing is melting away okay this is way better than surgery guys so here we are surgeon trying to find a way to put themselves out of business um because they hang out with smart people and here is the chest x-ray which is sort of well what were we thinking about with the thoracotomy all right with the 50% mortality and here we can see the volumetric response for this baby okay some of you have heard me talk about blue rubber blebnevis syndrome we did not make that one up okay that one is um kind of a crazy silly name they're not blue they're not rubber they're not blebs they're not nevi but um we're called bean syndrome uh who who said the first describe it but we don't like that because actually it was described in 1860 by gascoy and nobody's gonna remember that and call it gascoy and syndrome so we we still call it BRBNS and um many of you have operated with me on these cases and and I was sort of naive surgeon coming into this field 25 years ago and um and people said well this is not a surgical disease because um although they're having significant GI bleeding uh from these lesions in the bowel there's no point in operating because we're just gonna come back and I like guys I know I'm new but I mean like you just told me that we were gonna have tumors or we have malformations and tumors can come back and malformations can't right an anus isn't gonna become imperfect once you perpetrate it so why would this thing uh that's bleeding in the gut um come back and if you're telling me it's a malformation and I'm a general surgeon and I see a patient GI bleeding and I see that I'm gonna say I'm gonna cut that out right this is not rocket science so we started doing that and it works um now the interesting thing is that these patients particularly the older adults tell us you know I keep getting more of these not all of them but some of them and now a patient just say you know I'm 30 and this thing here on my arm wasn't here when I was 20 and this one here in my cheek wasn't here last year I'm getting new ones right so now we're stuck with this paradigm we've got tumors we have malformations and so John Maul can I have to explain it to fit our paradigm right we have to explain what the patients are telling us in our pyramids oh they're not new they've been there since birth they were just too small first to see and they're expanding because these things have abnormal smooth muscle and we know venous malformations expand these are these are just venous malformations and I kind of slept okay with that but it's kind of listening to the patients saying these are new and I also was looking at the fact that many of these patients have what I call a momolation right they'll have one really big one and a whole bunch of little ones which looks a whole lot like a primary malignancy with a whole bunch of metastasis and so but they're not dying and they're not malignant histologically and if they're dying the dying for blood loss not from tumor so we had a couple decades figuring this out and I've had a whole bunch of these patients and I spend a lot of days and I mean days doing this operation and many of you in the room have done this operation and then we just pluck these out this it's not a typical operation it's just a tedious operation if there's two or three or four of them a four is the least that I've ever seen this it's not a very difficult operation you just got to find them all but if there's 544 it takes a long time and this woman had 544 and the way we know when we stay sane as we you know keep it whiteboard and record how many we take out but it's not difficult any general surgeon could do this operation here's an example of the momolation and the little baby lesions like really seriously that that didn't come from that all right so we're struggling so I was pushing and pushing some of our other molecular genetics colleagues in Brussels to figure this out before Matt came back this was a long project and I and I said we got to figure this out and the literature said that these are heritable okay they're not heritable okay there's we've never seen two in the same family the things that are heritable are a different lesion that is nothing with details but it doesn't have this same phenotype and they're usually in mucosin and small lesions and and so they're all confused you look back in literature we are there's still to this date no heritable case of this BRBNS condition so finally last year okay they figured this out in Brussels and and and Laurence Gwinn came over here and she took all our specimens went through all our charts and all our photos and images brought them all back to Brussels and one of her junior colleagues spent you know literally years working on this there is more information to understand genetic conditions in this slide they they working this out this this is really genius now it took me about two weeks to understand so it turns out there's four conditions this is the one that had been found in the early 90s this is Mendelian right so 50% odd Osama dominant 50% of the family's habit and this is back in the early 90s finding a gene for anything was a big big deal right there's a family up in northern here and and north in northern New England that has this and John Mulligan spent his weekend driving around New England and drawing blood from these patients and it was like a four-year project to find the tytoe mutation for this condition which is heritable you could do that in a weekend now right we have people sitting in this room who could do this project in a weekend and find an odd Osama dominant mutation so here these are it's a germline mutation okay and then it takes a somatic second hit okay now these are all mutations all these conditions in the tytoe gene same gene okay there's this multifocal lesion that is not heritable right not germline so so happens after conception after fertilization and also takes a second hit right here's one allele right and then a second hit in a in a in a in a mosaic fashion and you get now you have a double mutation two hit so these both are two hit conditions in the tytoe one where the first hit is is germline and one where where they're both somatic okay then there's this regular old-fashioned garden variety venous malformation which turns out that that's a single somatic mutation and it's only in one place okay it happens in asel and it grows in that area then there's this bizarre condition with the mama and the babies this blue rubber blood niva syndrome lesion that the patients are telling us they get new ones right but they're not heritable and so this is almost unique in biology okay but they figured it out so the gametes are normal okay it's also a double hit it takes two hits to the tytoe mutation both post-psychotic and they both have to happen in the same allele right so it's either the maternal or the paternal allele so two hits so it's a double cis mutation in order to get the phenotype so this is one unique thing about this there's a few of any other conditions that require that but that doesn't explain the mama and the baby thing so but now that we have the genetic explanation they were able to look at the multiple lesions and it turns out that they're clonal so this and this are from the same clone so we proved indeed this has been nine metastasis they are not histologically or biologically malignant but they are either metastasizing from the big one or they at least come from the same angioblast precursor early on maybe this happened before birth but when they say it's happened 30 years later it's probably happened 30 years later so again hanging out with really smart people right it took me to each understand this lie little I'm trying to do the work so now we've got the blue river of medicine drum and we've got that it fits in the same pathway and Aaron's beautiful chart here and again same pathway so a bunch of people including Denise said well you know these things like 20 hours operating these kids who you know the surgeons operating these things we may be a medicine so they started giving serolinous to these patients that are bleeding and these patients don't exangling they just bleed chronically and I patients have a 2, 3, 400 units of blood over you know a decade and so this is one example of one patient thank you Denise that shows that transfusion transfusion transfusion transfusion serolinous stop transfusion okay we see a lot of these patients now I don't operate this condition very often now if they have three or four 10 lesions it's probably better to just go take them out and wait till the 20 or 30 years till they form more if they do but if they've got 544 lesions I'm out right if we can hold them out a decade with medication we do now some of them eventually come to surgery but it really it works okay so this is a condition that I operate all the time this is the most common thing that I do and the operating is operate patients with this condition called clopotronone syndrome again a vascular malformation with overgrowth seems a little bit like that close condition then we spend a lot of time differentiating a phenotypically who was KT who was close so they went mat found mutation for this it's the same picture see a mutation these are just different manifestations depends which cell in the embryo had mutation at what time to determine your phenotype so here's what we do I call this the phalaya fish operation open up the leg lift out the phalay close the package this is a often a variability operation there's a turnipon on here and here as a happy patient afterwards oops now so that's just surgery but these patients usually have that this is the lateral aspect of the leg this this massive vein going up the side right so the saffonus veins on this side does not supposed to be a vein going up the lateral aspect of your leg and this is a primitive embryonic vein and I call it the vein of surveillance is described by a French surgeon surveillance over 50 years ago and the thought when I started doing this working in this field was that this vein is incredibly important because some of these patients have an abnormal or absent deep venous system and this is the only way that they get blood out of their leg and if you do anything to that vein they're going to have impaired alpha and they're going to get flake meshes through the delus so I spent several years telling people sorry unless we prove you have a deep system that's normal I'm not going to operate I'm not in the bucket I left people with those big legs but I was wondering because when they stand up it gets really big it seems like a vericose vein looks like a vericose seal it's gravity dependent there's no good vows in there I don't think this is doing much for this patient but this is what we did we would map these out and if this one I was going to bulk her torso and I was really careful in the operating room I marked out where the vein is make sure that when I do my my present on rapid I don't go too far and don't damage that vein or she's going to lose a leg and so we would save these now I was starting to wonder if this made sense but it's kind of a difficult experiment to do how do you say well I don't think it matters I'm going to take that vein because if you're wrong you've just maimed somebody or caused them to lose their leg so listen to the patients so this girl was in an orphanage in China with her sister and she was adopted by a family in Texas whose parents wanted more kids their kids had gone off and gone to college and they wanted some more kids the father was an ENT surgeon nearing retirement I didn't know much about fasconomics but he's a surgeon and he's got this kid in this orphanage in China he's trying to adopt these sending bandages and all this kind of stuff and he's doing his research and he gets her and goes to Atlanta to look at the foot and the foot surgeons at Scott is right tell them that they're going to three operations to reduce this toe and to get this foot debauched so that she can fit into a shoe and he comes to me and says well what about all this and I said he said I understand you like operating the stuff all the time I said yes but we had imaging and your daughter doesn't doesn't have a normal deep venous system and you know we're really aren't supposed to do anything for that and I'm sorry and he said to me what's the evidence that you can't do this he's ex I've seen from support groups etc what you've done for other kids and I don't want my daughter having to grow up like this if you can do it what is the evidence he said I don't want to have my daughter go through three foot operations grow up in a teenager decide on her own to take the risk to debulk this lose her leg and having been to three operations when you're going to throw the foot out I want to find out now before I put it through the foot operations and she'll grow up as an amputee if she has to lose her leg and she can you know if she's only you know three and a half years old kids grow up better amputated three and a half then they do it 18 like wow there's like you don't get a more informed patient than that he said I'm flying home this weekend you and I both do the research if you are I can find anything convincing that they're scientific evidence you can't do this then we won't do the operation otherwise I want you to do it so without that family I would have never had the guts to do this so we decided we're gonna go for Brock right he's got he's giving me carp wash and I don't want to put it through multiple debulking so we did so we did a big one here you can see she got this massive vein and just all messed up veins not normal veins in her thigh you can't find a real deep femoral vein etc so we start doing the usual sort of thing we and at this stage I used to do the thigh and put it separately but I decided to do let's go for Brock and let's find out so I did her thigh and her butt it all together and took it apart and put it back together here's all the extra pieces and here she is after surgery and she's not perfect but she can get in blue jeans and she got the result that he was looking for not only that her leg not fall off she didn't get infection her flat said no problem her drains came out a reasonable amount of time she had like the perfect outcome despite the absence of a normal deep vein system and she went on to have her foot read it's right all because the courage of this set appearance right listen to the families okay so this is an example this is not this patient so this is what our interventionalogy team has figured out and a mod has been very persistent about this so this is a patient that's got this big vanister valve and the deep system here's sort of poppital vein is sort of washed out not there and that it's kind of kind of not normal here right but when you embellize which we now do routinely the vanister valve amazingly all the blood gets diverted and you get better flow especially with turnipids on approved they all have a deep system it may not be normal but it's there how did it look anymore right I don't even look and in fact in the don't need to be bulking we take these veins out now even when like a year old electively we they go to the IR they put a laser wire up there to an IV zapsapzap and they go home it's a very simple thing to do when they're small if you wait till they're a teenager and the vein is that big from all the reflux it's a big messy operation to deal with the vein because the laser won't deal with the vein that that big but the real reason to do it when they're young is and it took me a long time to convince my colleagues in Europe that this is a real phenomena it's a volume thing you have to see enough patients you know for rare things to be to be to seem real and here's the patient that we debalked before we sort of understood all this about the veins and you can see this as an old an old CT but you can see this big pulmonary embolus okay we've had 19 pulmonary embolus in patients with clippable trinaniaclose syndrome you don't think if pulmonary embolus being very common children these kids get PEs and yes we've had kids die after an operation and I say that to my colleagues not not so loudly because I want them to understand the importance of this when they're doing this so now I won't debalk anybody until we've done a survey for the abnormal veins and we've taken them out okay and here's an example of you know this is actually a close patient this is a torso and this is a primitive vein on the torso and in the arm and this is the kitchen sink of wires that our IR guys put in and this is preventing pulmonary embolus so this is again a common thing I do this is a woman who was in her mid-30s from New Mexico nobody would ever touch this thing she grew up with it you can imagine sort of the social and personal difficulties that this would cause and everybody's go away right I didn't learn that by medical school I didn't learn that in residency I don't know what it is I don't know what to do go away right it's not your problem it's 20 minutes off the visit you know it's here again she still has to live with it okay and she was our life and somehow she found us and you know set us up picture and I said yeah we'd probably do with that come on in this okay and some of you have done this is a routine simple 45 minute operation no transfusions no risk of then get a little blood in your shoes and her outcome was was great and and she went on to her after I have a child and she's a social worker and she after the surgery was very gracious to speak to our social work in the vestigomies center of the time to talk about you know what her experiences were growing up with this and the challenges with intimacy et cetera and and really has helped us to deal with other patients to understand them so listen to your patients so this one looks not this one's trivial right this is a little girl this is nothing like that she's not going to be problems it's just a discoloration well the reason she presented to us wasn't because this coloration is because she was bleeding she vaginal bleeding spotting and little girls bleed out of a jonna not normal people get really nervous so we looked at her imaging and it just looks like a little Venus malformation in the labia not a very big deal we can close that when she's older if we need to but if you look up higher she's got her rectum full of and surrounded by this stuff and if you look carefully you see this big vein that is not supposed to be here right so this is a order this is the vena kava and this is the infirm as in taryk vein okay way way way bigger than than it's supposed to be you know pretty small vein right so we noticed it took again you have to notice bad things before you see the pattern so this is an sma arteriogram we'll let it run through a few times so injecting this pure mesenteric artery and you're seeing the the bowel fill right and then the blood is supposed to drain from the veins and go up the portal vein which you're seeing here that's normal but what's not normal is it's also filling downwards here it's going down towards this rectum in this malformation the infirm as in taryk vein is flowing backwards just like that vena cervelle in the leg okay the blood is going backwards big deal all right well if I can stop it okay so here we've demonstrated this retrograde flow it is a big deal because that blood going backwards is causing a scyphen effect it's basically scyphen blood out of the portal mesenteric system causing a low flow situation and it's and the portal vein thrombosis and you get to have in this transformation and you have the lifelong ravages of portal hypertension some of these patients have gone on to liver or liver bowel transplantation so I kind of looked at this like okay well this is another vein that is like really big and is doing the wrong things causing the problem along with you get rid of it so now whenever we see a stain on the perineum boy or girl we look for rectilvenous malformation and if they have a rectilvenous malformation of any kind we just even the birth just put an ultrasound in the belly you're not supposed to be able to find the IMV right if you can find it it's too big all right and then we just go in and now you can just lapiscopically this is the pancreas this is this massive IMV and we just ligate it where it joins the splenic vein so that you have anti-grade flow in the portal vein and you don't have any risk of propagating thrombosis all right I'm right on time Kyle so Kyle is just blood with fat it should only be Kyle above the gut where the where the mesenteric drains fat into the thoracic sister in a carly and goes up the thoracic duct and turns out it can go backwards too just like veins can you can come out your scrotum you can come out your toes it can come in your chest it can come into your pericardium and come into your whatever I've seen it come out under toenails all right I'm gonna go ahead so what we usually do in the operating when many of you've done this is we feed heavy cream in the gut acts like a die we just cause a leak and you just you know take yourself to the doctor and go down here's one that was leaking from the renal highly see all the cream in the gut it comes from renal highlam all the studies went away and we just stripped off renal highlam like it sort of the reflexing channel got lucky uh this is a chocolate Buenos Aires just no decades later fine and I had this crazy theory as we were starting to do lymphangirams to look at these that these are channels that are open but aren't going forward and when I looked at the lymphangirams we did they reminded me of some other things that we see in general surgery of hollow tubes with smooth muscle walls which is what the thoracic duct is right our ET networks of every day it's terrestrial and you can see it move it contracts like a ureter does so I thought these lymphangirams looked like herchfronts disease it's patent but won't go through this part doesn't work a collage it's patent but won't go through this part doesn't work mega-your it's patent but say same thing the lymphangirams on these patients which are really hard to do sometimes looks like this right tell me this doesn't look like herchfronts disease right it's big it goes to the vein but it's not going through and then when you operate this there's massive massive thoracic duct right it's not the big part that's the problems like herchfronts it's a small part that I think is the problem so here's a child that had you know fills thoracic duct comes up and that and just won't empty and if you push really hard on the belly it empties right under floral but it doesn't it's like herchfronts disease this is a patient when we were doing this the mom had mentioned oh and you know when you're there can you do endoscopy because my kids got this you know bizarre GI symptoms so I had after those glues virus come down unfortunately this is really old days photographs and this is the reason it's so dark is because this is all the blue dye in these days we did lymphangirams we had to do a cut down we did inject a little blue dye in the skin of the dermis wait for it to pick by lymphatic take out a microscope and cut down to put a needle in a lymphatic so that's like now we're 12 hours later we get all that done and we put an endoscope down and the whole duodenum is full of this dye injected under the skin of the thigh right so it got taken up into the lymphatics went up and refluxed down into the mesenteric lymphatic into the duodenum into the lumen this was the first proof that protein losing an arompties and mechanical disease it's reflux of chial will just like it coming out your your paracardamine here we actually proved it in this case in the right time we we put some dye down to show that that the refluxing dye that we saw in the phangirium was in fact in the gut lumen and here's a picture from some friends at chop and metriologists who did a dye injection and in the arm and ends up showing dye coming out into the bronchus this is plastic bronchitis so I said why don't we just treat this like herch bronchusies now we can't do motility studies in the thoracic duct we have no idea what markers we should look at microscopically to see if it is or isn't to prove it like ganglion cells or cedocolonesterase so we just got to try it and the first time it's kind of scary because like we're kind of why getting a duct with neck and what if it doesn't work and clots and you're gonna have really the whole lymphaticism messed up but we did it in a desperate patient first and we've now done a few dozen of these and it turns out that if you give all the milk the cream and you find the thoracic duct and disconnect it and hook it up to a valve vein and I can't do this right so years ago Joe often did this and now Amir Tugini does this it's like magic to watch them work on a microscope for those who haven't seen it and half of the patients have no benefit that seems kind of crappy but the other half are dramatically improved or cured okay so we were doing these difficult and phangeograms it was took forever so we started working on how can we do mrland phangeogram and here's some page these pentaneers doing and you can see this is the first successful mrland phangeogram and the page now it's done routinely in humans and here's a human study and you can see this huge problem with this herch-brunx-like duct and you can fix this this is a girl I'm gonna finish here who was in high school and this is vaginoscopy this is her cervix and these are lymphatic vesicles in her vaginal wall and you can see these big long channels she leaked leaders of Kyle out of her vagina every day every single class in high school she would have to go after class in between classes go to the bathroom change three maxi-peds go to math change three maxi-peds go to history change three maxi-peds she was miserable we did this operation didn't help right we didn't close all the holes I tried closing all the holes per operations about a year later she calls as she said it stopped so oh it turns out almost none of them worked immediately you have to wait because the patholice resistance that they've been reflexing out is still reflexing and as you give them a new path forward eventually the whole seal so she's now as she eats a really fatty meal she can make herself leak a little bit one thin pad for the whole day so it's all about collaboration listen to your colleagues there's always somebody who knows something down the hall you don't know there's always somebody smarter than you are down the hall get them on a room together challenge them to figure out how to figure out your exceptions and always listen to the patients thanks let's see if I know the hours well when I'm talking about it thank you for your presentations morning it's always spelled binding to hear you tell us stories over how several decades you've cured kids with these these relations and I think what's most important about your presentation is not the facts of each discovery but really the process that you went through and I think for the for the medical students and the young colleagues here that's the biggest lesson that they got to take home from your presentation how to build a team and how to focus and lots of the faculty hear me saying the office you got to focus on one area and you've clearly done that and with the mentorship of Dr. Folkman who isn't here and Dr. Mullock and you don't have to throw the job so congratulations thank you