Neuro-oncologist Brian S. Na, MD, PhD, is dedicated to improving quality of life for patients with NF1 and NF2-related schwannomatosis, complex genetic conditions that vary widely in severity and symptoms. In this talk, he explains the great value of early diagnosis, noting red flags in affected infants; provides an update on diagnostic criteria; shines a light on cancer risks, life expectancies and specific tumors; and charts steps for monitoring both pediatric and adult patients for the numerous potential effects of these disorders – which can show up in the skin, eyes, bones, brain and elsewhere. Na reports on the latest drugs bringing benefits and describes the coordinated multispecialty services available at UCSF's growing comprehensive care center for neurofibromatosis.
Great. So thank you again. Um, I'm so glad to be here and thank you so much for joining. Um, you know, during this lunch hour, so my name is Brian Na again. I'm, um, in the division of neuro oncology here at UCSF, I trained as a pediatric oncologist and neuro oncologist, um, and with my interest in neurofibromatosis and smatosis, which, you know, as we all know, is a condition that, you know, really doesn't end in pediatrics, but goes on into adulthood. Um, you know, I ended up pursuing an adult neuro oncology fellowship as well, um, to really be able to provide care for this patient population across the lifespan. And so today I just wanted to talk a bit about the diagnosis and management, um, and sort of the latest updates in our field, um, but both for NF um and schwannomatosis as well. And let's advance the slides here. And so I think this audience needs no um really introduction to NF1 in particular. It is something that we do learn about really in medical school, um, as well, um, where, um, as we know it's an autosomal dominant mutation of the NF gene, which is on chromosome 17. Um, it is a peripheral nerve tumor predisposition syndrome, and it is relatively common occurring in 1 in every 3000 individuals, although with the explosion of, you know, genetic testing, um, and even. You know, at academic medical centers such as ours here and also the 23andMe folks, etc. that it might be even more common than we have initially thought. So some do say that it could even be in one in 2000 to 2500 individuals as well. And this is a nice schematic from a review article a couple of years ago, where neurofibrin, when it's working properly, um, inactivates the active RAS GTPA complex into its inactive form. So when this is mutated, this complex remains, you know, hyperactive as it were, and leads to these downstream signaling effects you see here. Um, leading to the, um, you know, the symptoms and the signs of NF1 that we see because it leads to cell growth and cell survival because the pathways are not functioning correctly. And so again, the NF1 gene encodes um the gene called neurofibrin, which is a tumor suppressor and NF1 um is part of a globe, a more global kind of condition. Um, it falls under the Rasopathy family. So this is a more complicated schematic here, as you can see, you have the NF1 gene here, which suppresses this RAS pathway. And so when this is mutated, this is lost and again leading to this downstream signaling. effects that you can see here. And because the NF1 gene is in all different types of cells, um, that's where we see all the manifestations. So for example, you have the Schwann cell where you have NF1 loss, um, leading to this increased RAS, leading to the neurofibromas, um. Melanocytes where you have NF1 loss, you have pigmented lesions, so the cafela spots that we all um learn about um in med school and in our general pediatrics residencies, um, as very rarely melanoma could also happen, um, the adrenal medulla can lead to, you know, pheochromocytomas and then the glial cells as well with NF1 loss lead to brain tumors, um, potentially as well too. So this is the latest, um, you know, clinical criteria for NF1. It is still primarily a clinical diagnosis. This was just revised. This is a reference here. In case you're interested, um from 2021 with Eric Leis, who's a very um a leader in the field of NF um. Genetics. And so this is the diagnostic criteria. Um, you do need two or more of the following, um, such as 6 or more cafeola macules, um, and you have this differences in size here based on whether a patient is pre-pubertal or post-pubertal. Um, the freckling in the axillary or inguinal regions, um, two or more neurofibromas, um, or a plexiform neurofibroma. The pathway gliomass, um, these eye tumors which are benign, but they're called liche nodules as well. Um, bony lesions and specifically sphenoid dysplasia, um, this aolateral bowing of the tibia or pseudarthrosis, which really, if it does occur, usually in the infants. And of course, I think the big change, I think from the prior criteria to this one in 2021. It's really the emphasis on genetic testing here. Um, so that is, um, has been incorporated as part of the criteria. And in addition, um, if you have a parent who has NF one, and you're the child, and we suspect that you may have NF one, then the child only needs to meet one of these criteria. Um, as we may all be aware, I think the most common referral that we get from Um, our general, um, pediatricians, um, are really the, the cafela macules is really the tip off, um, that is really the initial presenting sign. And some of these other um findings do happen much later, um, as you know, kids grow older. So um really still the mainstay of referral um to our program, really, um, and it's not just our program but other NF programs around the country, it's really our general pediatricians really picking up on these cafe macules and seeing more of them, um, than you might expect. So in terms of, um, you know, the genetic testing piece of it, why it's becoming more emphasized is this idea of the genotype, meaning, you know, as we all know, it's the actual mutation that we find in the NF1 gene, and then the phenotype, which is, you know, what we might expect in terms of clinical signs and symptoms. So a lot of families appropriately ask us, right, hey, doc, you know, like we know what kind of mutation that, you know, I have. Can you tell us what we might be able to what we might expect in the future? And unfortunately, the answer is we really don't know. Um, there's over 4000 mutations that we know of that lead to um NF1 in terms of the condition. Um, and there's only a handful of them where we can really advise, um, and provide that anticipatory guidance. And so the two broad buckets that we really think about really from a genetic standpoint, are, you know, the specific NF1 variant, so like the exact mutations that we find, um, through genetic testing, and as you can um also guess we have, we follow families that have NF1 and even within families with the same mutation that's present. They um may have different manifestations. So clearly there are other modifiers such as, you know, epigenetics and stuff like that, um, that really help. You know, that really does, you know, in all essence, complicate things when um families do ask us um for guidance in terms of an anticipatory guidance as to what to expect later on. But some couple of them that have um been found, for example, are NF one microdeletions, which is the deletion of the whole NF one gene, we think um leads to more severe manifestations of NF1. There are certain other mutations here and certain amino acids where patients may develop, for example, more of the plexiform neurofibromas and some other point mutations as well that have been um suggested um that might have some um you know, pheno genotype, phenotype correlation. So this is just another, you know, slide just to show some of the different mutations that have been. You know, have that have been found in terms of a genotype and phenotype correlation. So for example, there's sometimes there are some overlap with um Noonan's syndrome here, um. You know, where we may have some patients that may fit the criteria of NF1 but may also have um symptoms um and signs of Noonan's syndrome as well. So you can see the cardiovascular abnormalities, for example, with specific um types of NF1 mutation. And so, um, it is recommended if possible to still obtain um genetic testing, um, if that's feasible, you know, obviously there's sometimes insurance issues and obviously, geneticists, you know, are are very um You know, are very popular and sometimes very difficult um to find um depending on the geographic region um that, you know, um, we're practicing in, um, but this is really the big reason why that it can really help guide us, even if it's in the minority of patients. And this is just a um a nice schematic again as to what we do expect in terms of um NF one findings throughout the lifespan. So again, the hallmark is this um cafe au lait macules that we really do find in the early years, I'm usually in infancy, and of course, the bony issues such as the orbital tibial dysplasia and pseudarthrosis, and we have plexiform neurofibroma. Which are neurofibromas that come from your actual nerves themselves. We do think that these are congenital in nature, so about 50% of patients we think are born with plexiform neurofibromas, um, and they can stay very small or they can grow bigger over time. And so that's where, um, that's, um, we think that begins here. As patients get older, I think the more, most common thing that we do hear about um from our families and our parents are these learning deficits, um, ADHD, autism spectrum disorder, motor and or Speech delays, um, probably are really the biggest concern that families do bring up with us. Um, and there has been more research done in this realm, although still really preliminary, I would say in sort of more the basic science world. Um, and then we have optic pathway gliomass, which are benign tumors that are in your eyes, um, and about 10%, usually they don't cause any issues whatsoever, surprisingly, um, even and vision is usually preserved, but there are some patients where it does cause issues, so we do follow those patients very closely and then you have um. More skin manifestations as patients get older like skin fold freckling, these lish nodules which are benign tumors of the eye. And as patients grow up, scoliosis can be um an issue that comes up more of these neurofibromas like on the skin and stuff which are different than the plexiform neurofibroma. So you can see, and you may have seen these um Tumors in NF one patients that look like bug bites actually, and those are completely normal. They're completely benign, can cause some itchiness and some pain. Um, but they they do grow in number as patients get older. And, um, although on the brain stem, obviously, that's a very um scary location, understandably so for our families, um, but these are also benign tumors that we just watch, um, if they're not causing any issues. And then as they reach adulthood, um, you know, some of the more aggressive tumors can happen. Such as malignant peripheral nerve sheath tumors. I know that's a mouthful, so we shorten that to MPNSTs. Um, we have breast cancer that can happen in our um young adult population as well as high grade, um, gliomas or more aggressive brain tumors can also occur as well as patients, um, you know, get older. So overall, in addition to being a peripheral nerve um tumor predisposition syndrome, in essence, it's really the most common cancer predisposition syndrome that we see. Um, and so for example, we have the malignant brain tumors and patients are at a higher risk of developing high grade gliomas. Um, endocrine issues, particularly feel chromocytomas. Thankfully, it's usually solitary in nature. So just removing that tumor with our, um, very skilled endocrine and general surgeons here, um, really does the job, um, and they do have a higher risk of that. The big one is this MPNSTs which are very aggressive solid tumors. Um, we have early onset breast cancer and then very rarely, leukemias or acute lymphoblastic leukemia. I must say I've only had like one young adult patient that had an NF1 associated um leukemia, but it has been Described in the literature, as well as non-Hodgkin um lymphomas as well. But the leukemia lymphomas are certainly much rarer than some of these other um conditions um that um NF one patients are um predisposed to. So I think it comes as no surprise because they have increased cancer risk, they do have a shortened life expectancy, really, if they do develop one of these aggressive tumors. So you can see the risk is greater compared to a general population that you can see here. And when and just overall when you look at different um cohorts, you see that the life expectancy is lower overall on average um for NF one patients. And along those lines, cancer does remain the greatest source of mortality in people that do have NF one. So this was a really nice article back in 2021 that followed a really robust group of NF1 patients and compared to those who did not, um who had um cancer versus those who did not. Obviously you can see, you know, this, you know, no surprise here that if you had a cancer diagnosis, your overall survival, you know, obviously, you know, is much lower than those who did not and um because patients are predisposed, right, as I mentioned earlier to different um. Tumors, so they stratified based on the different tumor types that um that they, that patients developed essentially and showed that, you know, the high grade gliomas are aggressive brain tumors and UPS which are um you know, undifferentiated pleomorphic sarcomas, and you definitely don't need to be an oncologist to know that, you know, that that. You know, is, is a very aggressive um solid tumor. Those patients did not do as well as those with some other types of um cancers here. And you have the malignant peripheral nerve sheath tumor patients here also that um did not do as well as some of the other cancer types. Um, so one big focus, so we are, um, we have a growing, um, and robust, um, comprehensive NF center here at UCSF, and our director of translational research, Doctor Harish Vasudevan, um, who's a radiation oncologist here and also runs a basic science lab and sees a lot of our NF patients who really do need radiation, so meaning they have. You know, a pretty aggressive cancer um that needs um radiation as part of their treatment. So in his lab, he does study this, um, the MPNSTs in particular, where here we have um neurofibromas, um, that are from the Schwann cell lineage. So as we all know, those are your normal nerve cells. You have NF1 loss, and then that um predisposes our NF1 patients to develop neurofibroma. So this is a representative um MRI here where a patient has and, you know, um, this neurofibroma that's present, sort of in in the In the head right here as you can see her on the left. Um, and these are benign again, obviously, this looks scary, but they're benign, they don't metastasize, um, they obviously can cause a lot of functional pain and a lot of issues with function, as you can imagine from seeing this MRI. And depending on the location, but you need other um genetic mutations as well, such as CDKN2AB loss, which is a cell cycle regulator, so it tells our cells to stop, right, growing, so if you lose that sort of um break, you know, that obviously can lead to, um, you know, some more deregulated um cell cycle signaling leading to Um, this MPNST, um, some other, um. You know, mutations or heads that. We have been suggested that's needed is PRC2, which is an epigenetic regulator as well. And so when it becomes an MPNST that's where we know, again, it's a malignant peripheral nerve sheath tumor, they're malignant, and they do tend to metastasize usually to the lungs, for example, and very occasionally, um, although very rare, and these MPNSTs can occur in Patients that do not have NF one at all. And um when you compare and these are very small numbers as you can imagine, um, because these are very rare tumors, um, you see that patients who have NF one associated MPNSTs still seem to do. Um, not as well as those um patients who developed MPNST who do not have NF one. So this is a big area of study in his lab, um, in our group overall. And Um, we also work with very closely with our sarcoma group here, which is extremely robust. It's one of the largest centers in the country, so we actually looked back at all of our MPNSTs here and just really saw, you know, um, how, you know, how our patients have fared over the years and it really um. Is consistent with other um big cohort studies that have been done, so. You know, our overall survival really, you know, is around 50%, which has been reported out by other groups. Um, when we looked at, hey, can we see if there's any prognostic factors where we can try to figure out maybe which MPNSTs could be potentially more aggressive, um, versus others. There's this marker called KI 67, um, that our pathologists do very routinely, which is a marker of cell proliferation. So it's a staining that they do when they look at these tumors under a microscope. And we saw that um when it's above or equal to 60%, those um tumors tended to be more aggressive um than those um that did not have that were less than 60%. Um, we also found that this was published in 2020 by our group, um, that there are two, seems to be two groups of MPNSTs um based on the sort of the DNA and the RNA types of markers that we look at. And we're still doing a bit more work on that based on, you know, what separates these two groups, so that's ongoing work that's being done. Um, but what one thing that we found is overall, you know, some, um, folks, um, some groups will have suggested that, you know, when we do surgery for these tumors and remove the um tumor completely, you may not necessarily need to do radiation. Whereas for our group, we found that for a cluster 2 specifically, although we're still figuring out what. This cluster to really entails, we found that after surgery and then doing radiation afterwards did, um, you know, lead to better outcomes. So, Overall, our group here, unless there there's some mitigating factors um that we will, you know, tend to after a surgical resection, we usually do advocate for radiation afterwards, just from our experience here um um at UCSF. And just um switching gears to another um type of tumor, um, again, these NF1 mutant gliomas are very similar in a way. So just like the MPNSTs where we say that it's just one big Although it's one group, and that's how our pathologists reported out, there's obviously some nuance there, um, that we're still, you know, researching actively and same thing here, another um aim of our center. looking at these um NF1 mutant gliomas and specifically glioblastomas, which are very aggressive brain tumors that occur in adults and leveraging our work with our adult brain tumor colleagues, which is a major um brain tumor program here. Um, looking at our NF1 mutant glioblastomas, saw that they did fall into these three different groups based on DNA methylation, which is increasingly this DNA methylation, which is looking at the markers. So we looked at the tumors, and basically it's sort of like a stop and go sort of traffic light signaling type of patterns. So like, you know, Red light, yellow light, green light or red light yellow, yellow or green, red, yellow. So you have all these different permutations. And um that can help us um in our oncology space to really see what tumors that we might be dealing with, um, especially in those where pathologists may not be able to make a, you know, clear diagnosis. So we saw that we found 3 different groups here. And in particular, um, and this is a paper that's being, um, you know, it's under revision currently in our um in our research program, but CDKN2AB loss, which, as you may recall that I mentioned a bit earlier, um, is a cell cycle regulator, we do know, um, it seems that for NF1 mutant glioblastoma patients, having this loss, um, does mean that although it is an aggressive tumor. Overall, those tumors with that loss tend to be more aggressive. Um, and we actually are working towards and have some clinical trials open at this time, um, for those patients who have this loss, um, in their tumor. So those are some of the more exciting things, um, I think from a research perspective and translational research perspective that we're doing within our NF center here, um, but from a broader, just from a clinical care perspective. The biggest thing that we do see are really the non-tumor manifestations, um, especially for our pediatric population. Um, really, this learning disability is present in 50 to 75%. Um if you look at some of the case, um, you know, reports and series, um, ADHD, um, seizures can occur, and of course pain as well. So, you know, we work very closely, for example, in our program with our neuropsychologists, specifically Dr. Shannon Lundy, who's one of our big um um is part of our program, sees our patients. We have a multidisciplinary clinic once a month on our West Bay campus at Mission Bay on Thursday afternoons where we, um, she is part of that team and helps, you know, um, With neuropsychology testing, neurocognitive testing, and of course, resources with IEPs and stuff, um, and all that they need, um, because as we all know, plugging our um families in if possible with the resources at when they're kids, and I'll say as someone who also sees our adult patients now, um, with NF one, it makes my life a lot easier, I must say, because there's just more resources, although we can always Use more, right? But there are just more of those wrap-around services available in our pediatric population and usually once they're plugged in as kids, as we all know, they, um they usually stay on um through adulthood. So that provides us with more options um for those services as they sort of age out of the pediatric age range. Um, skeletal issues can also be an issue. There's no real big guidance, um, surrounding this. Obviously for scoliosis, we, as part of our multidisciplinary team, we have our orthopedic surgeons, as well as our physical medicine and rehab doctor comes to our pediatric multidisciplinary clinic again on those Thursday afternoons, um, to just evaluate and make sure everything's going OK. Um. This is really more expert opinion, but some centers will recommend annual vitamin D levels and just making sure that, you know, kids are getting their calcium and vitamin D. Um, cardiovascular wise, you know, hypertension can be something to, you know, watch out for. We do usually recommend annual blood pressure checks, um, and so that could be different, that is a little bit different, um, than the, you know, the AP recommendation and simply because we Um, there is a higher risk, right, of, you know, vascular disease, although rare, it does happen, renal artery stenosis, etc. So if a child does have higher blood pressures um consistently, then, you know, referral to, you know, our nephrologists um can be very helpful just to really rule those um things out. And of course, um we all do this already, but, um, you know, measuring height and weight and making sure patients are growing on the right track because precocious puberty um can occur um really more idiopathic and precocious puberty, um. Uh, and so if that does occur, refer referral to our endocrinologists can be feasible, and this is something we would be happy to partner with all of our um pediatricians on. And really help with, you know, triaging and all of that um as part of the program. And again, we have a multidisciplinary clinic, um, once a month on Thursdays right now on our West Bay campus where we do have all of our subspecialists really for um patients who may. We need more than 3 subspecialists and for those who are, you know, um, as you know, our catchment area for the specialized program is fairly large, um, for those who are coming from far away, um, to really try to coordinate their care, so they don't have to make multiple trips down here to the Bay Area. Um, one big thing, um, you may have seen patients on this already, um, that I did want to mention because it's becoming more and more common are meth inhibitors. So this is a treatment option for NF1 related plexiform neurofibroma. So this is a paper from 2020, um, published by Doctor Andrea Gross, who's a pediatric oncologist at the NIH. Um, or where we looked at celllumeib, um, which is a mech inhibitor that, you know, is downstream from the NF gene, um, where let's say a plexiform neurofibroma, which if it's very symptomatic and our surgeons are not able to operate on it, um, because when we do operate on it, we try to get a complete resection. Um, if they're not able to do that, we can think about me inhibition and as you can see here, it really has shrunk a lot, um, and you know, and patients have a lot of functional issues you can imagine if you have this tumor here, it's really hard to move your neck, etc. And um really the progression free survival, when you compare it to the natural history um of these tumors, um there is a natural history study that's going on right now, um, for plexi for neurofibromas, you do see that there is a clear benefit. So this is FDA approved right now. In terms of side effects, what we really do see is dermatologic. So that, that's the biggest thing. So this can range from really bad eczema to acne. So really, almost everyone will have some kind of rash. We don't usually do anything about it unless there's really a lot of symptoms, um, and You know, honestly, um, our general pediatricians, our audience here, you guys can definitely. You know, are the experts at this, right, um, in terms of really moisturizing, making sure when it gets, when the eczema, for example, gets really bad, we also recommend like the bleach baths, for example, and slathering them with um Aquaphor, etc. to keep the moisture and um we will, if there's acne sometimes start acne medications, for example, so that's really the biggest one that we see. Diarrhea can be another thing. Usually, we try to symptomatically manage it, um, and we have them follow and get echocardiograms, um, routine eye exams, very rare, but this can happen, and there is a theoretical bleeding risk. The celllumeib capsules do have vitamin E in them, so that's part of the reason why. But what we traditionally do, let's say if there's some major surgery or something that patients are undergoing, then we will just hold it for about a week or two before and then as long as it's safe, just start a week or two after, um, you know, the surgery, um, is complete. So these are the recommended monitoring quote unquote guidelines. So usually yearly, um, in clinics like in programs like ours, if it is available, um, an eye exam because of the optic gliomass, um, usually for patients less than 10 years of age, doing the height and weight checks, blood pressure, spine, um, for signs of scoliosis, infants for signs of pseudarthrosis, the learning disabilities, um. The big part, you know, that's still up for debate are these routine MRI scans and pediatrics we we usually do not do any routine MRIs unless there are reasons to do so. Some centers will do or try to do whole body MRIs, um, but I will say that's not the norm. Most centers will not do MRIs unless we have concerns from a symptom standpoint. Really the same thing in the adult population as patients age out, this adolescent young adult population because I do know, um, you know, for pediatrics, you know, we usually go up to the age of 21 and if you're adolescent medicine trained, you know, you do see patients even beyond that, for example. And so for our adult patients, same thing, just having a touch base with us once a year on visual assessments, continuing the blood pressure monitoring, maintaining good bone health. You can imagine if they had learning disabilities and ADHD and as they enter this complex world that we live in, um, and managing multiple things as you go into adulthood, making sure their psychological well-being is you know OK and they're doing well from that standpoint um MRIs, um. So women who are under, you know, starting at the age of 30, um, should get mammograms actually, um because there are higher, um, there is a higher risk of breast cancer. If they've never had an MRI done, most adult um centers will try to get an MRI brain or spine. Um, dermatology has been recommended as well, and of course, with the increasing rates, you know, of colon cancer these days, you know, um, routine colonoscopy as well for our adult patients, although there has been no association that we know of just yet between NF1 and um colon cancer at this time. Um, so switching gears a little bit, this is much rarer, but this is NF2 related schwannomatosis. Um, it is less common than NF1. I mean it's 1 in 25 to 33,000. The average age is in our late teenage age between 17 and 21, and the formal diagnosis does happen usually um. In patients in their twenties, it is an autosomal dominant condition, um, although just like NF1, actually, most patients are the first members of their family to have it, so 56%, and um the life expectancy is again shorter um than those um for patients who do not have NF2. So this is the updated um terminology for Schwannomatosis. So NF2 is the most common. Um, so this is under the umbrella of Schmatosis, so you have NF2, you have SMAR B1, these are all genes, LZTR1. These all live on chromosome 22, so you have 22Q related schonomatosis. So today is actually my clinic day today and I'm actually seeing a patient with that 22Q related ommatosis later on today, for example, um, and then you have your classic not otherwise specified, um, for those who did not have any genetic testing and not otherwise classified. So those who had genetic testing and we still are not able to find the genetic cause. Um, this is a very busy slide, but, um, I just wanted to just mention that this is the criteria that we do use. Um, we can diagnose NF2, um, either with bilateral vestibular schwannomas, um, which are the hallmark of the tumors. I have a picture later on in this presentation of that, or, um, genetic testing on two different tumors that have the same NF2 mutation. Other than that, you have these two major criteria here or one major and then two minor criteria. So if you are interested, um, Doctor Scott Plotkin, who has been a, um, who's an adult neurologist, neuro oncologist. Um, has been a huge, um, leader in the NF2 field and Schwannomatosis field in particular, um, you know, published this in 2022, and this is the um criteria that we're now using to diagnose our NF2 patients. So, um, just nerding out a little bit about the genetics of honomatosis, um, you have here, um, chromosome 22, where you have the LZTR1 gene, the SMARC B1 gene, and the NF2 gene. So for rarely speaking, we have LZTR1 Smar B1. When you have those mutations, that's not enough to cause hoomatosis. So here you have the SMA B1 or the LCTR1 hit. You have the normal chromosome, the other chromosome 22, you have the other normal allele here. So you have to have the loss of that other allele, and then you have to have another NF2 hit for that to then cause tumors. So, uh, On those lines take home here is that's, you know, you need to have multiple hits along the way. Um, we do follow I would say a couple of families that have the LCTR one mutation. Um, and that's where we're just following, um, over the years, um, to see, um, because you still need that, you know, other, um, losses, um, for that swannoma to occur, and, you know, we, we don't know, um, unfortunately, just yet, um, how we can predict that in our families at this time. So here's just an example of one of my patients who had genetic testing for SMARC B1 related schwannomatosis. So the blood I'm testing here um shows this particular SMARC B1 mutation, and then you have the same mutation present here in this tumor. And then you have the chromosome 22 loss that I showed you in the prior slide, and then you have the NF2 um gene mutated again here. But because she had blood testing that showed. This mutation, and then the same mutation in the same gene in the tumor that was able to um with that, we were able to make that diagnosis of SMAR B1 related hoomatosis in this patient. Um, and so for NF2 in particular, um, the hallmark again are these bilateral vestibular schwannomas. They're sometimes, you know, um, referred to as the ice cream cone shaped, um, tumors, as you can sort of see here. Um, they are also predisposed to meningiomas, which are other benign tumors of the um brain and spine as well as appendemoas as well. And um as you can guess, the symptoms are localized to tumor location. So because it's on your hearing and seeing nerves, so it comes as no surprise that deafness, tinnitus, imbalance can occur because of the tumor location. In pediatrics, though, it is more challenging to diagnose. The biggest one that we do find is really eye issues, is really the predominant symptoms. So, Um, our astute ophthalmologists will sometimes refer patients to us because they find cataracts. So obviously there's other reasons to have cataracts, as we all know, um, you know, metabolic, you know, issues, for example, come to mind. But really, the first thing that we do find, um, for NF2 patients are really cataracts um before the other manifestations do come up. So for example, for our pediatric NF2 patients, although these are a very small number of them. For example, we won't, they won't have vestibular schwannomas, right, when we get an MRI scan, but they usually, for whatever reason, and that's something that people are studying in the lab, why do they happen much later, right, than, than, than when they're much younger. Um, and so the eye symptoms are really the first things to really pop up. For our patients who do not have um NF2 related schwannomatosis, there's some of, some overlapping manifestations, um, you know, so that's where the recommendation of still getting a brain and spine MRI can come into play. Um, we do the genetic testing. Um, if they have tumors, um, removed because of pain, um, we will try to send genetic testing on all of them. And really the biggest thing is the pain is really the most common presenting um symptom. So, in terms of imaging and monitoring wise, um we do want, um, you know, obviously testing to try to confirm the diagnosis and identify any potential problems. Um, MRIs of the brain to really look at the hearing and seeing, you know, the hearing and balance nerves on an internal auditory canal, getting plugged in with your eye and eye doctors and the audiologists. And really, it's just evaluating initially, usually every 6 months, I would say, um, in terms of MRI scans until we can really determine tumor growth rate, um, and then we can space it out from there. Sometimes these tumors, especially the schwannomas can occur, for example, let's say on the vagus nerves, etc. um, or have, you know, the hearing and balance nerves can press in, you know, if it's big enough to like the facial nerve, so our ear, nose and throat and our head or our, you know, our head and neck colleagues, surgeon colleagues really are very important, um, and so we do sometimes refer um based on symptoms to our Um, different subspecialists within the head and neck surgery department, um, depending on the symptoms they have, such as we have a specialized swallow and Um, voice center here that's led by Doctor Clark Rosen, for example. We have a vestibular balance clinic here, um, and work very closely with them, um, for that. And so we can help direct um patients to um specialized head and neck surgery um programs here depending on the symptoms that patients have or exhibit. One thing that you may have come across and seen, this is really specific for our NF2 patients who have hearing loss. So these are patients who have hearing loss and where surgery may not be the best option for them. And so bevacizumab is an IV medication that is commonly used for this indication. And so this is again um from Doctor Scott Plotkins, um, who's been studying this for many, many decades. Um, this is his initial paper from 2009 looking at um teenagers and adolescents and young adults, although 153 year old snuck in there, um. And in the 2009 paper and then the 2023 1 as well, um, most recently to to determine the ideal dose. Um, really the long term side effects of bevacizumab, um, you know, the how this acts is really a vascular endothelial growth factor receptor antagonist. So it can, it modulates sort of the blood vessels, essentially, so. What um we do look for, you know, obviously we get blood work, your standard CBC, your, you know, your electrolytes, um, you know, making sure, for example, no clots or bleeding episodes, right? Um, those are very rare, but that they can happen. Um, the more common ones because we do anticipate these patients are on this treatment for a long period of time potentially. are renal issues, so high blood pressure can happen um with proteinuria, etc. So, um, there are times where we have started um ACE inhibitors, um, as long as there's no contraindication to try to help with the blood pressure and try to help the kidney, um. And so that we have used in the past and or spacing out the bevacizumab, you know, over a longer period of time, so not doing as high a dose, but doing it, you know, intermittently, you know, getting, you know, holidays off of it. So there are different types of um protocols that are out there. Um, another big thing, especially for our female patients are, you know, ovarian failure, so we do counsel our patients on that. So I've had occasionally patients who have undergone, you know, egg retrieval, for example, before starting on bevacizumab um for their hearing issues. And so that is something that we do advise our patients as well. One other medication that's coming down the pike um is called rigatinib. Um, so there's a huge trial that's going on right now, um, looking at the NF2 related tumors. So you can see here appendeomas, meningiomas, the nonvestibular schwannomas, and the vestibular schwannomas. So these are medications that we're testing that are repurposed from other tumors to see if they work for NF2 patients with tumors that are not able to be resected completely or may cause too many issues if they went in surgically. So, um, this was a paper again published just this past couple of months in the New England Journal of Medicine. Um, so rigaib is actually used for non-small cell lung cancer. It is FDA approved. Um, we found, um, through this initial trial result that it seems to work, as you can see here, the negative is actually a good thing. This is showing tumors that have shrunk potentially from baseline. That overall it seems to work um to stabilize tumors or even see some tumor response and all tumor types for NF2 with the exception of vestibular schwannomas. We are following these patients long term, you know, over the next 10 years, so we will have more information um in that over the next couple of years, but for right now, um, we. Um, do know that it seems to be helpful for those patients. So in very select, um, cases, we are thinking about using rigatinib, um for um certain select NF2 patients. So you may see that medication potentially um in clinic, although much rarer than obviously the mec inhibitor I talked about earlier. Some of the side effects of rigatinib, really the biggest thing is elevated um creatinine kinase. It's usually asymptomatic, so we usually don't act on it unless obviously patients have symptoms. And so that's something that you may come across. Um, and some, these are some of the other side effects. I know just for the interest of time, won't really mention it, but you can always reach out to us if you have any questions. So summary wise, um, this, we have revised diagnostic criteria for NF1 and shonomatosis. We do know that both tumor and non-tumor manifestations such as pain, learning disabilities, etc. Contribute to morbidity and mortality, right? Um, and our screening recommendations really do center around establishing a baseline and that then that can help potentially guide our therapeutic approaches. And as I mentioned earlier, especially with our NFY. One segment that genotype, phenotype correlation is a work in progress and hopefully over the next few years or so, we'll be able to help guide our families in terms of anti-story guidance, etc. as to what they may expect. So the big part I just wanted to end, is that the pediatric to adult transition of care is extremely complicated, as we all know, this is a a wonderful figure that was um published in the NCCN by my, one of my pediatric oncology colleagues, Julie Wolfson, who's at University of Alabama Birmingham, and you can see that there's different factors, right? So you have the patients on themselves and families. Um, where they're located and their access to care, the insurance, um, where they're being treated, right? This is really done from an oncology standpoint, but this can really apply for many other types of lifelong conditions, right, where they're being treated, right? You know, we understand, right, the battling into. Up to San Francisco is not easy for everyone. It's not easy to cross that bridge, right, even if you're coming from the East Bay. And then you have a lot of different approaches, right, such as clinical trials, collaboration among multiple subspecialists and all of that really sort of all in, you know, intertwined and to trying to provide the best outcome for our patients and their families. And so our neurofibromatosis Center was formally really established in 2018 under Dr. Alyssa Reddy, who's one of our pediatric neurologists and neuro oncologists who came from the University of Alabama, which has a major center for NF. Um, she established the pediatric clinics both at our Mission Bay and Oakland campuses, and the program really grew rapidly, um, to the point where, um, you know, I was, you know, You know, interested, right? And I was brought up to help establish this AYA and our adult enough piece of things to really form a comprehensive enough center. Um, so we have an adolescent young adult transition program currently at Mission Bay right now where I, I personally am seeing the 1617 year olds, um, because I am pediatric neuro oncology trained as well. And then we have our adult program at Parnassus, um, for those who are above 18. And we have committed pediatric and adult subspecialists, um, for all the care that patients with NF and autoomatosis may need. Um, we have monthly, you know, tumor boards and really even have monthly depending on what it is like a meningioma tumor board to even. Schwannoma and lateral skull-based tumor board that meets monthly right now. So, um we can really, you know, have patients with, um, depending on the type of tumor that we need to address, um, these multidisciplinary conferences at this point. We are now also um the only right now neurofibromatosis type one and Shamatosis Comprehensive Center in California, and this is designated by the Children's Tumor Foundation, which is a major patient advocacy organization for NFHomatosis. And as part of their NF clinic network, um, they designate, um, each site, um, that applies based on our patient numbers and the clinical trials that we have open and we are the only comprehensive center at right now and based on those designations in California right now. We are one of the only formalized adolescent young adult adult and enough programs right now in the country. Most of them are based in the Northeast actually. Um, one of my, you know, colleagues, um, does have one in, um, at UCLA in Southern California, um, and so you have, you know, one in Southern California now up here now in Northern California. And now we were recently accepted into the um Department of Defense um sponsored neurofibromatosis Clinical Trials Consortium or the NFCTC, which was such a great honor um recently in the last year, which will provide more clinical trial options for our patients with NF andronomatosis, um, in the Bay Area as well. So, you know, um, in terms of pediatric patients, you can always put in an Apex referral to pediatric neuro oncology. This is our number here. Um, for our adult brain tumor Center, you have our number here and you can put in a referral to neuro oncology. You can always reach out to us via Apex. We'll be more than happy to talk, um. And also here are our email addresses, um, you know, you can either reach out to Doctor Reddy or myself. We'll be more than happy to, you know, help, um, in any way possible, um, for, you know, any patients that you may have questions on or for referrals, and we can help direct you because I know sometimes it can be hard at a big Center like ours where maybe one of your patients may need, you know, a subspecialist before they may be able to see us. So we understand that that's a very real possibility, so we can really help guide um in any way possible and be a resource for everyone um in the community and out there.
