Chapters Transcript Caring for Patients with Vascular Anomolies: Basic Principles and New Resources Dr. Sisk hares an overview of vascular anomalies, targeted medical therapies and additional resources for primary care clinicians. For our first speaker, we have Doctor Brian Sisi, who completed his medical degree at Cleveland Clinic Learner College of Medicine at Case Western Reserve University in Cleveland, Ohio. He then came to Saint Louis to complete his residency and chief residency in pediatrics, as well as his fellowship in pediatric hematology and oncology at Washington University School of Medicine. Doctor Sisi is currently an assistant professor of pediatrics, hematology and oncology with WashUMed at Children's Hospital and specializes in pediatric oncology and vascular anomalies. So, thank you so much, Doctor Sisik. If I left anything out, feel free to add to that. No, that's wonderful. Thank you so much. Um, And, you know, you may be wondering why you're hearing from a pediatrician. Well, it's because I also see adults. So, so we're gonna be talking about care that applies to kids as well as adults. So, I'm excited to be here speaking with you all today, um, and I'm representing our, our whole vascular Anomalies Center. Um, and we're gonna be talking about vascular anomalies, and we're gonna be talking about kind of basic principles of how, how to approach these, what they are, what they look like. But then also, I wanna present on a new resource that we've created. That's available for any community clinicians, or really any clinicians. Um, as we get started, um, just in terms of disclosures, I do work with, um, some pharmaceutical companies on identifying new treatments and the best way of, uh, measuring whether patients are improving on those clinical trials. Uh, objectives today, we're gonna give a brief overview of what vascular anomalies are. My goal is that you have takeaways that it's digestible and interesting. We're gonna talk about different approaches to treatment, um, but I'm, uh, you know, uh, medical oncology trained, so I'm especially interested in targeted medical therapies. And so, we'll, we'll talk a little bit in depth about that. And then, I'm gonna end with a suite of new resources that we have available for you or really for any clinicians around the country. Um, and definitely around the region that, that are seeing patients with vascular anomalies and need a little bit of guidance on how to provide care. The key takeaway message is that, you know, at Children's and at Barn and, and at WashU we have a multidisciplinary care team for any vascular anomaly issues, any vascular anomaly problems. We're happy to help you brainstorm, uh, when you're not sure who or where to refer, and we're happy to, you know, manage or co-manage these patients with you. So, please feel free to reach out to me or our team if we can be helpful in any way. So, first, we'll do a brief overview. And I always like to start with pictures, um, to show how complicated this field is. Uh, and these are kids, as you can tell from the photo, but these kids will have the exact same lesions when they're adults. So it applies there as well. If you look at these lips, you can imagine 3 different patients coming into your clinic, and you would say, oh, all of these look like vascular lesions on the lip. What's important is this first one, when you feel it, it's got a really bounding pulse, and it's really warm, and that's gonna actually be an arteriovenous malformation, which means that an artery and a vein made an abnormal connection together, and those can proliferate and expand. They can also bleed like stink if you poke them, or if you try to biopsy them, and they're driven by different genetic mutations. The one here in the middle is kind of soft and boggy. Uh, it's maybe got a couple of little kind of hard bumps in it, uh, but not causing a lot of huge problem. And the one over here on the far right is just completely flat and pink. And these are 3 totally different vascular anomalies, driven by 3 totally different genetic conditions. So, the two on the right are sporadic mosaic conditions, meaning that this abnormal gene is only present in this abnormal tissue. It's not inherited and it's not passed on. This patient here has something called RASA one, which is actually inherited, so they're gonna be at risk for their whole life of developing AVMs in the brain and the spine, and other parts of the body, and they can pass that on. So, very similar phenotype, very similar appearance, but very different implications for their health. Just as another example, you know, here are 3 patients that all have capillary malformations on their torso. Uh, they're flat, it's abnormal development in the capillaries, and they're asymptomatic. When you look at them, again, driven by 3 different genes that represent different pathways, and the one in the middle, this PICC3CA, these patients are known to be at a higher risk of clotting, especially if they have a procedure or a surgery done on affected areas. So, you'd wanna anticoagulate them for safety before procedures, whereas the other two, it doesn't really matter. And so again, knowing both what the phenotype is, what the, the type of tissue is that's abnormal, and knowing the driving gene are both really important aspects of care. But now I wanna take a step back and think about what are vascular anomalies. So, put it simply, a vascular anomaly is any spectrum of lesions of vascular tissue. They're gen they can be inherited, uh, germline, uh, they can be spontaneous, but develop in utero, and they can develop later in life. And really, this splits down into two different categories. One is vascular tumors, And vascular tumors are when you get hyperproliferation of the endothelial cells. So these are actual tumors of abnormal blood vessel cells. And they can range from totally benign to totally malignant. So, you know, hemangiomas of different types, those all fall in that benign vascular tumor um range. They often don't need a whole lot of intervention, especially in adults. There are other borderline vascular tumors like posiform hemangioendothelioma, epithelioid hemangioendothelioma, where they're getting closer to cancer, but they're not quite there. Then there's frank malignancies like angiosarcoma, which is, you know, a very bad vascular anomaly to have. What I'm gonna spend most time talking about today are the more common lesions called vascular malformations. And vascular malformations are defects in the way that blood vessels form. Again, they're almost always driven by a genetic change, which we'll talk about. They're usually present at birth, um, even though they can become more apparent over time. And they can be simple, meaning it's just one type of a blood vessel that's overgrown, like a capillary malformation. Or a venous malformation, or a lymphatic malformation, or they can be combined like lymphatic and venous in a, in a bundle, or an arterial venous malformation, and they can also be associated with other anomalies, uh, like overgrowth. There's some diseases where you get abnormal blood vessels, and you'll get overgrowth of the fat, or the muscle or the bone, things that we would call like Clippotrenin A syndrome, KT syndrome, or Parks-Weber, uh, different disorders like that. So, the important thing is, these patients, as we'll see throughout the talk today, can have very complicated and symptomatic presentations, and they can need lots of different types of management strategies, including imaging, including genetic testing, laboratory monitoring, and interventions. And no one doctor has all the expertise for that. And that's why Our care team is multidisciplinary. And we've got ear, nose, and throat, dermatology, HEMOC, genetics, interventional radiology, surgeons. Uh, we also provide inpatient and outpatient care in the, the Barnes and Children's system. And our goal is to supplement what primary care doctors provide. So, primary care doctors are providing the general medical home. Of helping patients find the care that they need and maintaining their, their general health and well-being. Once you get inside of a medical system where, where you need really complex coordination of care, that's a big ask for primary care doctors to be able to navigate. Uh, and, you know, my team knows the people and has their cell phone numbers. So our goal is that we can become the specialist medical home to supplement, uh, what, what the primary care doctors are providing outpatient. In the, in the general care. And the other thing that I'll mention here again is, it doesn't matter what age we see patients that are 1 day of age and we see patients that are 80 years of age. So, we're happy to see any patient that we can help with. As we talked about, there's lots of different, uh, ignore the MCM, there's lots of different types of vascular anomalies. And when we think about them, we can really split them into low flow and then high flow malformations. Low flow malformations just means how fast is the fluid passing through the, the abnormal vessels. And high flow, uh, is gonna be an artery in a vein connecting, an arteriovenous malformation, or sometimes an arteriovenous fistula. Low flow is gonna be capillaries, veins, lymphatics, or some combination of those. And next, we'll go through some, some pictures, uh, and schematics to, to really, you know, hammer in exactly how these things form, what they look like, and how we think about, uh, treating them. So there's lots of different vascular tissues in the body. I think the most um underappreciated vascular tissue in the body is the lymphatics. And I'm sure most if not all of the people on this call are, are, are very familiar with lymphatics, but I'll say it just to make sure we're on the same page. You know, anytime you go from your arteries to your veins and your arterials, you're losing fluid into the soft tissue, into the extracellular tissue. Your lymphatic tissue, or your lymphatic uh vessels and have little capillaries at the end of them, they intertriginate there, they suck up that fluid, they bring it all the way up here through a big tube called your thoracic duct. And then they jump it, dump it back into your veins up here. This is why we're not all big swollen sacks of fluid, because our lymphatics work. So you can imagine when your lymphatics don't work, part of your body becomes a big swollen sack of fluid. Uh, and so, we'll first talk about Capillary malformations, then we'll get to lymphatics, um, and veins. So, capillary malformations, generally, you can diagnose these just based on physical finding. They're, they're often called port wine stains, even though that's kind of changing, um, cause there's certain patients that don't like being called stained. Uh, but usually you can tell based on the clinical findings, this is gonna be a capillary, uh, capillary malformation. Usually, you don't need an MRI or ultrasound even, because it's all in the superficial skin, cause you don't really have capillaries deeper that are gonna be affected like this. Uh, the symptoms are that it can darken over time, the skin can thicken, and as you get to adulthood, you can get, uh, kind of lumps of these capillary malformations that, that almost pedunculate and get thicker and some can sometimes bleed. Uh, if their patients are totally asymptomatic, they just need to be monitored over time. Um, if they want the skin to be lightened, they can use different laser therapies. If there's big bumps, you can use laser therapy for that as well, or sometimes an excision of the problematic bumps. But this is a lifelong thing. It's gonna likely darken over time, and setting the expectations is really the most important part. We don't have a way of making it go away. And usually, they're not that symptomatic, um, at least not until later in life. So then we'll think about venous malformations. You know, again, your normal veins are straight, your venous malformations are big, swollen, twisted, the valves don't work right. These can affect anywhere, all of these can affect anywhere from head to toe. Most of the time, they're gonna be visible in some way from the skin. Either like the picture on the left here where it's very visible, um, or on the right here also, or you just see a lot of swelling that has a bluish hint because there's poor venous drainage. Uh, they can also involve the muscle and bone, uh, and so often they will have a deeper component as well. When you see patients like this, one initial consideration is, am I seeing a venous malformation or am I just seeing, you know, veins that have gone bad. Uh, and I think that's worth thinking through. Either way, it might be worth, you know, being seen by a vascular team or by an interventional radiologist to see, is this just a single vein or a collection of veins, or is this an actual, you know, genetically-driven malformation. Often, the initial approach we'll do is um an ultrasound and, and interventional radiologist will do that in our clinic as well, where we can all look at it together. And the ultrasound will show you on the next slide what it kinda looks like, uh, or actually, we'll show you, um, uh, how slow these are filling. But the ultrasound gives you a sense of, of, is it cystic? Is there fast blood flow, slow blood flow, or is it more solid? But really, when we're worried about these and they're symptomatic, we get an MRI. And the MRI gives us the deeper imaging where we can see, is this just skin or is it also affecting muscle, the bone. Um, the other important thing with venous malformations is, if a patient has an extremity that has a large venous malformation, they almost invariably are gonna have a very high D-dimer level at baseline. So, let's say you have a patient who has a venous malformation in their leg, And you've never checked the D-dimer, and then one day they say, yeah, my leg is kind of feeling painful. If you check a D-dimer, it's gonna be very high, and it doesn't mean that it's a deep vein thrombosis, cause I've had patients with D-dimers as high as 70,000 to 80,000 as their baseline. So just to keep that in mind, um, that not every patient with a venous malformation has a DVT. Um, and, and often it can be helpful to have a baseline D-dimer when they're not symptomatic, so you can sense if things are changing. Um, The treatments for this, we'll talk about in more detail, but generally, the treatments are you do sclerotherapy, which is injecting it with irritants to, to get them to close down, or thinking about medical therapy. And that medical therapy could be, you know, uh, anticoagulants to decrease the clot burden, which can help with the pain, or it can be targeted medications, targeted inhibitors that we'll talk about later as well. To just add a picture to this, cause I think it's always helpful to, to get a real-life picture. So this is a percutaneous injection of dye by an interventional radiologist. And you can see the needle right here. Um, well, let's see, the needle, if you can see my cursor right here. And the thing to notice is, number 1, how big and distended the veins are, and number 2, how slow it's filling. And I'll show you a comparison later to an arteriovenous malformation to show the difference of how fast the blood's flowing. But in here, you could see there's several different targets that they could potentially take down uh with a sclerosin to, to help with some of these symptoms. So now, we'll think about lymphatic malformations. So, this is when your lymphatic capillaries at the very end of your lymphatic vessels, uh, develop abnormally. And these can take a couple of different forms. One form they can take is what's called macrocystic, and that the patient here is an example where you can see there's deep under the surface, there's very large bubbles, very large cysts. And this right here, If you zoomed in, you'd probably see some little papillary microcystic nodules here. Or you can see patients where it's predominantly microcystic in the skin, just these little, they can be clear, they can be pink, they can be purple. These are actually distended lymphatic blebs, lymphatic capillaries that are growing through the skin, swelling. And they can bleed into themselves. So this is capillary lymphatics, small bubbles that are bleeding into themselves, and they can actually bleed out into the shirts and into the clothes and cause issues. Um, these are Uh, and then sometimes there's a combination of both of these. The way that I often explain this to patients is, you know, microcystic is like the sponge that you're using to do your dishes. It's tons of little tiny bubbles. The macrocystic are the soap bubbles on top, and sometimes, you have a mix of those. When we think about interventions, um, number one rule for really all of these that we've talked about so far is If a patient has these, we've evaluated them, they're totally safe, and they're asymptomatic. There is no urgency to have to do anything. Even this patient here with the macrocystic, uh, lymphatic malformation, If that patient is not having any symptoms, there is, is not an urgent need to go and get them poked. I bring that up because there can be an urge if you're uh an interventionist, and somebody sends you a patient to say, well, I, I have to do something because they referred to me. For patients like this, if they said they were having pain every month, or every week or every day, absolutely, we'd intervene. But if they say, I've had this, you know, I'm 50 and I've had this since I was 5, and it doesn't bother me at all, we can just keep watching. And that's important to know. The big complications these can have are pain, bleeding, leakage, swelling, sometimes infection, they can get red and inflamed, and we call that a flare, cause it's usually a mix of inflammation with or without an infection. Um, so those are the most important things to think about. And then again, later, we'll talk about interventions, we'll talk about medical therapies, and then also, some of those medical therapies like serolimus, come in a topical form that you can actually put on these lesions. Then we talk about arteriovenous malformation. And this is where we transition from low flow to high flow. And you can see on the patient here, uh, his thumb is involved right here with an arteriovenous malformation, and you can even see there's a distended vein going all the way down, and that's because there's so much fast flow blood that that vein is arterializing, meaning it's expanding and thickening its wall in response. Um, you can often again get a sense of these on clinical exam. Um, however, it's really important to get imaging on these because they can progress, they can, uh, be causing underlying tissue necrosis. The, and the imaging of, uh, is usually again gonna be starting with an ultrasound. Then going to uh an MRI and then if we're concerned enough, uh, we'll actually do, um, you know, real angiography where you're injecting dye into the veins and arteries to, to map out the, the vascular system. The, the symptoms these patients can have, they can have just direct pain and swelling and decreased mobility. These can affect anywhere in the body. They can also, especially on the head and neck, they can start causing skin breakdown and deterioration. The other important thing about these is that they can progress and can get very bad. So it's important for these high-flow lesions to get evaluated early on and think about whether there's a surgery or an intervention or a medical therapy that could help. The other thing is they can cause pain directly because of their size and the pressure they're exerting. They can also do what's called vascular steel. So if you look up here at the pictures, you, you know, your artery is supposed to give all these nutrients off in your capillary bed. If you have an AVM right next to it, where it's lower, it's higher flow and lower resistance, more blood is gonna go down this pathway, which means less is going here. So you start actually getting Uh, cramping and potentially ischemia to the areas surrounding the AVM, not even the AVM itself, because you have vascular steel from the healthy tissue. And we'll talk a little bit more about that. The other important thing to talk about with AVMs is, of all vascular malformations, the two that most people have heard of are hemangiomas and AVMs. And the reason that causes problems is that, um, Many different vascular lesions will be labeled as AVMs. And so, if you have a patient who's coming to establish care with you and their chart says they have an AVM or a history of AVMs, it's very important to think through whether it really was a high-flow arterial venous malformation, or whether it was some other lesion like a venous malformation, which is a lower-risk lesion. And that matters both for risk in the future, that matters for um, Uh, for the treatments we might offer and what we need to monitor. There was actually a study in France that found that patients who came to their multidisciplinary center, uh, half of them had the wrong diagnosis when they, when they got there. So, uh, always, always, um, maintain a little skepticism about what your patients have been diagnosed with, um, unless they've been evaluated by, by experts in the field. So now, thinking about high flow malformations, this again is injecting dye, and look how quickly this blushes out and it spreads through all the vasculature. You can tell this is a high-flow lesion when you compare it. To this low flow lesion. Um, and so this is one of the real key characteristics when you look at imaging. Number 1, this is complicated. Number 2, all of these areas could potentially bleed. And so it takes an interventional radiologist to really think through where are these arteries feeding, which ones can I block, and you wanna make sure you don't accidentally block blood flow to healthy tissue, cause that can cause necrosis and lots of other problems. So that's the, you know, the 30,000 ft view of the most common vascular malformations you're likely to see coming into your clinics. Um, the big question is, how do you decide what to do and when to treat them? When we're deciding whether to treat these patients, the, a couple of things are important. One is we wanna make sure that the patients understand for the majority of vascular malformation syndromes and vascular anomalies, these are lifelong disorders that don't have a cure. And so, the goal is, how can we make sure this is not causing Symptoms or impacting your quality of life. How can we make sure that you're living the life that you want to live as best as we can give that to you? And when we think about that, it really relates to functional impairment. So, if you have somebody where it's affecting their airway or their tongue swells, they can't eat, it's affecting their eye, you know, these are things where you say, uh, that's a big deal, we really need to intervene because your body's not functioning. Aside from that, the other reasons we think about treating is when we're discussing with patients and families, you know, tell me about your pain, tell me about your swelling, your flares, tell me how this is distressing to you cosmetically or psychologically. Those are all important factors that we take into account and we make a shared decision with that family. About what they want to pursue, how they want to pursue it, and, and, and when, um, and we will often dissuade families from interventions if we think either A they're asymptomatic or B, that it's gonna be more harm than good. Um, and so that's, that's one of the really important things because we've all seen patients who've come in. They've had multiple, multiple interventions or multiple, multiple surgeries. They were largely asymptomatic early on, and now they've got long-term sequelae and consequences of all of those interventions. So, I'm a big believer that we treat to make the patient's life better, and otherwise, we don't intervene. So now let's talk about intervening. So there's a, I, I just wanna give a little bit more detail about some of the different types of interventions, and then I'll spend most of the time talking about the um uh molecular inhibitors. So to give a sense of what sclerotherapy is, here's a schematic of a venous malformation. And the same thing would apply for a lymphatic malformation. The only thing that changes is what they decide to inject the, what liquid they're injecting. But the idea is if you've got a big lake of abnormal fluid, you can puncture it in some way with a needle, then you can inject an irritant called a sclerosis. Sclero just means scar, so it's, you're just inducing a scar within the blood vessels. It gets really inflamed, so if you ever have a patient getting sclerotherapy, you wanna make sure that they understand they're gonna be inflamed for about a week or so. That inflammation is what helps it to then shrink down and scar down. The other important thing about sclerotherapy is that Um, it is not a cure, it is a symptomatic relief. And so, if a patient has an area that's very symptomatic, it can make sense. But it might be that when you shut down one abnormal area, that flow, fluid still has to go somewhere, so it could be another area swells up and becomes symptomatic. So it's important to, for patients to know, this isn't a one and done deal. It's not even a 10 and done deal. It's, we need to do this when you're symptomatic to improve your, your, your burden of disease. Here's just some actual pictures of sclerotherapy. So you can see right here, there, this is actually a lymphatic malformation, a, a large lymphatic cyst. They suck out the lymphatic fluid, then you can see they inject in that sclerosin, and then subsequently, you can see how it's shrunken down into these tiny cysts cause that big cyst has been closed off. The other invasive thing to think about is surgery. Um, and there, if this was 25 years ago, surgery was really, 30 years ago, it was really all we had to offer. The big challenge with surgery is, as we'll talk about, these diseases are driven by genes that are stuck in the grow position. You know, it's growth pathways that are stuck on. And if you do a resection, you can't tell where the normal and the abnormal tissue. Uh, meat, and often they're, they're mixed in together. So you would have to get very, very wide, dangerous margins or take off entire limbs to cure these lesions that might be minimally symptomatic. So, surgery is, is really been restricted to specific needs, specific use cases, like, they've got a big malformation in the sole of their foot that happens to be in one spot, well circumscribed, and they can't walk because they're always pressing on it. Sure, that makes sense to take it out. Or they've got so much swelling in their foot, they can't fit a shoe on. Sure, maybe it makes sense to debulk. But general debulking, we don't do almost at all anymore, because they grow back, they develop scar, and they become more complicated. And the adults that I see who are often in the most pain are the adults who have had the most surgeries and procedures. So, so we're really trying to make sure we're targeting the procedures towards their symptoms. There's other things that can be done, like you can do laser resurfacing, you can do thermal ablation, which is either hot probes or cold probes to, to kill off tissue. Um, lots of advancing techniques. There's, there's newer techniques that are looking at nanoparticles, um, And, and, in very rare cases using radiation therapy. But generally, these are the main approaches. And then where, where my job comes in is thinking about the targeted inhibitors. So to talk about targeted inhibitors, um, we all like medicines we can take by mouth as opposed to needing to get it cut open or poked with needles. Um, but to talk about these, we need to spend a little time talking about the genetics of these diseases. And which I find really fascinating. When we think about genetic diseases, uh, you know, especially when our patients hear about genetic diseases, we think about diseases where the mom or dad has the disease, the sperm or egg has it. If the patient gets it, every single cell in that body is gonna have it, and you're either all yellow or all white. You're either all affected by that gene or not affected by that gene. This is not what happens in the vast, vast majority of vascular anomalies. In vascular anomalies, what is more likely to happen is what's called somatic, uh, mosaicism. Like a mosaic, if you go, you know, in Saint Louis to the new cathedral, and they've got the mosaics, which are all the different tiles put together, that's really what our body is like. Our bodies is like stripes. Everywhere in our body, you'll find small differences in DNA. What happens in vascular anomalies is that these precursor cells in the, in the embryo or in the fetus, will develop a gain of function mutation that turns on a growth pathway for vascular tissue. Whatever cell that occurs in, what that cell turns into, will also carry that. So, we see this exact same thing. The, these patients here can have the exact same mutation. This patient on the left here, this patient, it developed very late in development and only in the cells that affected this tiny area of the neck, that's a very small lymphatic malformation. This patient had happened a little bit earlier in, in an, uh, uh, a more dangerous cell, and they've got their full face and neck affected. This patient on the right happened even earlier, and they've got overgrowth affecting the majority of their body. So I've got patients with a 1 centimeter lesion, and I've got patients with head to toe lesions, and they have the exact same somatic mutation. It just happened in different cells and at different times. And this is the chart that I, I go over with patients to explain this, cause it's not, it, it, it is, but it's not really that complicated. So, our body has proliferation pathways because we have to be able to grow our tissues. Uh, you have to grow from a, you know, a baby ICN clinic to an adult. But you don't wanna overgrow because if you have too much growth, uncontrolled growth, you know, that's cancer, that's overgrowth syndromes. The way our body manages this is with, uh, you know, kinase cascade where you can only turn on this pathway with growth signal. What happens in a lot of slow flow vascular malformations. is you get a mutation, it's most commonly in this gene right here called P PICC3CA and sometimes in the receptor, where they're stuck in the on position. And that pathway is then constantly churning, and that's why you're making these abnormal veins, or abnormal lymphatics. The cool thing here is that there's two different drugs we have that can block this pathway. You can have erlius, which has been around for 35 years, is used for transplant all the time, and this can block at the very end of the pathway. And then as we'll talk about in a couple of slides also, you can have alpeliib that blocks directly this mutation. We're very, we're very fortunate that Adult cancers also like to use this pathway. So breast cancer often will turn on as one of its tricks to, to grow, will turn on this pathway. The reason that matters is then, the drug companies invested in developing an inhibitor for this, and now we're benefiting with that same inhibitor. But thinking through the timeline, this is where I always try to give my patients a lot of hope. Cause I see many patients coming in and they say, you know, I've, I've spent my entire life trying to find expert care, trying to get the care that I need, and I just run into, you know, people who don't know what I have or, or try to give me the wrong treatment. And I try to give them hope because this entire pathway wasn't even known until 1980s. The, the PICC3CA causing disease in humans wasn't known till 2004. And an entire arm of diseases called PICC3CA related overgrowth spectrum that affect many vascular anomalies wasn't defined until 2015. So with really this disease being defined in 2015, now we're in 2026, and two years ago, we actually had an FDA approved treatment for these, these patients. So, it's actually leaps and bounds of how quickly we've been advancing in our, in our knowledge of this field. I always like to throw this slide in, um, to say, you know, it's obviously not as simple as I've mapped out. There's a lot of genes, a lot of crosstalk, and a geneticist once told me, every genetic diagram is wrong, but some of them are useful. So, even this is simplifying it. But the important thing is that there's targets in here where we can have different genes. And now, I wanna tell a story about how this all started. Because, you know, as we said, it wasn't really till 2015 that we knew P PICC3CA was driving a lot of these diseases. But this is the, a picture of the very first patient who got serlius therapy for a vascular malformation or for a vascular anomaly syndrome. This was at the time, I believe at the time, this might have been actually at Cincinnati Children's. This is a vascular tumor called KHE. And this was a patient, you will often see patients like this, um, where the tumor swells and it starts trapping all of your blood and your platelets and causing clotting problems. And this patient had already been treated with different chemotherapies, with steroids, uh, and nothing was improving. But then based off of some of the ongoing studies, they had looked at signaling and said, well, I think MTOR might be up-regulated. I think this pathway might be turned on. So they empirically said, why don't we try Serolimus and see what happens? And you can see what happened. There's a dramatic response, and now the patient has been off of Serolimus for a long time and is doing very well. Um, and such a response that this is now the mainstay therapy for this disease. So because of this success, they said, well, we've got, you know, 6 other patients who are uh having life-threatening disease with vascular anomalies that we haven't been able to address. Let's give them serulimus. And they found that they all responded to therapy. So that was enough to get a grant to then do a clinical trial. And that clinical trial of again, giving serulimus to complicated vascular anomalies, 47 of the patients had a response to medicine, 3 had a stable disease, and 7 had progressive disease. And the important thing is this all happened before we were able to even do genetic testing. So, this is just blindly treating patients that we think have these diseases. This is what, this study here is what has created the foundation of how we treat vascular anomaly patients, and that's why we've treated now for the last 10 years with serlius. So as we think about this drug that slows down that pathway. If you've heard of Sirlimus or rabamycin, you've probably heard of it in the context of getting an organ transplant, because uh it is the main thing that helps to prevent rejection of liver and kidney transplants. So with that, you need to think about infections. And so, this is a couple of studies that have come out to look at how much infection risk there is. So Cir Limus Well, in this study at their center, they only had about 10% of patients that were having serious adverse effects. Most of the ones that they had, 9 of those 14 were actually um infections, and most of them were viral infections that just got harder to control and created a viral pneumonia. So we did a similar study where we looked at all reported uh infectious complications of serullius, and there were a lot of viral URIs. Oh, a fair amount of pneumonias, but importantly, when we looked at the really, really critical outcomes, like, are people dying of infections? Are they getting bacteremia? Are they getting pneumocystis pneumonia? Extremely low rates. So, to me, this, you know, patients can have side effects, but this gave me a lot of, of um reassurance that this is a safe drug for our patients. So that was the first drug. Now, we're at the next step where we said, well, we've got another target up here. Maybe we can use that breast cancer drug, alpeliib. And to get, you know, long story short, um, it seems to be working. And so, here's some examples. This is a French group that, that designed this. This is one of the first patients to get it. And as we said, these are incurable diseases, but you can see all of this significant overgrowth right here. And then you can see over time, over the course of 180 days, how much of an improvement there was. And in addition to this was improvement in mobility, and in pain, and in leakage through the skin. So, this is kind of the worst of the worst in terms of symptomatic patients, and you can see that there's a very notable response. Here's another patient from another study. Again, it doesn't make everything perfect, but you can look at how severe this was, and then how, over time, there was a, a greater improvement of, of the overgrowth and the ability to speak, ability to eat, things like that. So, it's not a miracle drug, but it was, it's keeping several patients alive. And as a result of that, it got approved. So this is the only drug that we have for vascular anomalies that is FDA approved. Um, and that has spurred a lot of interest, a lot of clinical trials, uh, and a lot of new drug compounds and new investments. So, this is important, not only for us to know clinically, but it's important for us to tell our patients about because many of them come in without hope. They've been in pain, they've been, um, you know, unable to, to kind of figure out what they have and what they need. And it's, it's really important for them to know the excitement that people are looking into trying to help them. And The important thing though is we've talked about all of these different high-tech treatments of interventional radiology, and different medicines, and targeted inhibitors and all of this. None of that matters unless. A patient gets to the care that they need. So, another area of my research is really digging in on what are the factors that make it easier or harder for patients to access the care. And that's what I'll spend the rest of our time talking about. And I'll summa summarize a couple of different studies. Um, one is we talked with parents of kids with vascular anomaly syndromes, and then adult patients as well. And this was a, a large qualitative study where we mapped out what are the factors that are influencing their ability. Um, so, there are individual characteristics, like, are you willing to be a squeaky wheel? Are you a strong self-advocate? There are things like scientific progress of, you know, how am I supposed to find care when nobody knows what I have, or how to diagnosis or what medicines there are. The other important thing is social networks. Social media is, is in any of these rare disease spaces, spaces is hugely important for families to try to get, um, to get knowledge about their disease. Healthcare system issues, you know, you know, we have a backlog. It takes us a couple of months. Some of the other larger centers around the country, it might be 6 months till you get in. Or, you know, we've had patients where they get referred to us and their insurance tells them, sorry, you have to go to someplace out of state because that's the closest experts that are in-network. So, there's all of those issues. The most concerning to me though was luck and privilege played a huge role. Um, did you have means? Did you have, uh, did you happen to be born in the right town that wasn't a rural area that had limited resources? Did you happen to go to the right hospital that had the right doctor? Even within the health system, did you happen to get referred to the right specialty? There's a lot of problems of, of uh, you know, random chances that, that determine whether or not patients were able to get the care they need and whether their clinicians were able to help them navigate that. The other challenge is there aren't a lot of adult specialists to take care, to provide medical care for these patients. In vascular anomalies, it's mainly a field driven by pediatric hematology and oncology. Um, and there's been very little, um, buy-in by adult medical specialties yet. So, this was a survey study that we did, uh, and for this reason, that's why almost every vascular anomaly center, even for adults, is gonna be housed at a children's hospital. Uh, we did a survey of adult hematologists and oncologists, and to summarize, what we learned is that the vast majority of them said that they had no knowledge about vascular anomalies diagnosis. They had no education about it, and they had low confidence in providing care. You know, we even asked, um, you know, do you have a vascular anomaly center in your area or in your city or in your hospital? And about 80% of them said no. And when we looked, the vast majority of them actually did, but they weren't aware of it. So, lots of problems with interest, with uh knowledge, with collaboration. So, when you take this and a couple of other studies that we had, you can see a lot of factors that are making it harder for these patients to access care. There's lack of availability of these expert clinicians. There's the limited availability, uh, ability to travel. If your patient lives 4 hours away from the center and they don't have gas to get 4 hours or they can't take off work or school, that becomes a challenge. We talked about luck. And then the other, uh, bad decisions some patients have made to be an adult. And being an adult just ends up, in current state, leading to fewer and fewer resources. But the exciting thing from our research is we found that The, the more we can leverage primary care doctors, uh, and engage them in coordinating and care, um, and the more we can improve information, availability, and communication, uh, those seem to be positively associated with improving the ability to access the needed care. So, our solution to this is a program that we started that's funded in part by the Department of Defense and philanthropists and patient advocacy groups. It's called Vccess.org, Vascular Anomalies Care Access.org. Um, it's a totally free website uh with lots of resources that we'll click through. There's a QR code or you can just type in V A C C E S S.org if you ever need this. Um, the things that this website has. One is it's got resources that we'll talk about that are dedicated for community clinicians. We built this with primary care doctors in collaboration, uh, and they're designed for you. Um, we also have a specialty network, um, so that if there are any researchers or clinicians across the country that have an interest in vascular anomalies, we now have a network of about 165 specialists, uh, who, who all collaborate together. Uh, and then we also have materials specific for patients and caregivers, and this can be helpful for patients and caregivers that are seeking information or for primary care clinicians who need to give information to their patients. So, for the patients and families, it's got educational information, it's also got support resources that we've pulled together from different patient advocacy groups. And as we'll talk about uh in a couple of slides, we've got the Find a vascular anomalies Center tool and then advocacy group information as well of how to find advocacy groups. When you're a healthcare professional, and you create your, your, your login, which again is free, um, you've got a couple of different, uh, resources that I'll talk about. One is this ask a specialist. And so, this is, um, if you've got any question that is, I've got a patient, I'm not sure exactly what to do with them, we can give you kind of general guidance about that type of disorder, about how you can find care, help you think through where you might refer, what type of workup you might wanna do. It's your final decision on any of it, but we're happy to provide kind of an educational, uh, resource, and it can be in the form of text, um, you know, secure text-based communication through the website or you can request a phone call. Uh, the other thing that we've created is find a vascular Anomaly Center. Cause even though this is built at WSU and housed at WSU, it's a national program. And so, we wanna be useful for anybody. And so, we, there are about 88 or 89 centers across the country that you can scroll through and within them, we tell you where they're at, how you contact them to make a referral, and then what age ranges they see, since we know not all centers see adults. And so, uh, we have also a map view where you can click in or you can type in your zip code. Um, and then, We've got, in addition to that, patient caregiver resources that, uh, when you go up here similar to up to-date, you can click on the tab of resources written for healthcare professionals or written for patients and caregivers. And when we design these educational materials for clinicians, uh, we even structured the order of material, the type of material, and the depth of, of, of detail. Uh, based on feedback from design sessions and interviews with about 30 or 40 primary care doctors. So this really is When you're going into a room and you have 2 minutes to read something and you have a patient that's got, uh, you know, a lumbar syndrome or, or, um, a venous malformation, that you can quickly get acquainted with it before you go into the room. And with that, I'm gonna pause for any questions, but just to say that, again, this is a resource that's available. If there's anything we can help with, please feel free to reach out. Aside from this, in the region, anybody that ever has a question, um, or aren't sure what to do with patients, I'm, I'm absolutely happy to, to have a phone call with you or help you to get referred in. So then, just the three main takeaways. One, It's an exciting field. There's a lot of these patients, eventually, they're gonna trickle through your offices. And we should give them hope and we should help to get them the care that they need. Um, they have unique management considerations, so we really need to have a multidisciplinary team. Um, and we showed you some resources for that. So, with that, I'll stop and happy to open it up for any questions. Created by Presenters Bryan A. Sisk, MD, MSCI Blood Disorders (Hematology), Cancer (Oncology), Pediatric Cancer View full profile
