 All right, well, welcome, everyone, to Grad Rounds. I'm Eric. So today is the retina update, green rounds. And we're going to do a focus on oncology, although we also have an exciting update within the retina space that I think everybody has kind of heard rumors of. I know we talked about it at a faculty meeting. So we thought it was probably pretty germane to discuss that as well, given that it has been approved and is going to be, as far as I understand, very shortly on our formula area. And that's the new injectable drug we have for geographic atrophy. So we're also going to talk about that. And we wanted that to be an open discussion as I'm sure there's questions about who should we be referring, who are the patients that we're going to be treating, et cetera, as it affects not just our retina colleagues, but people who are also seeing anybody with macular degeneration. So we're going to start with a couple of presentations on oncology by our retina fellows who have all done a really phenomenal job putting together these talks. And the first talk is Dr. James Kohler, who's our first year retina fellow. He's a jolly good fellow, too. Let me tell you about that. I mean, he's going to be talking about uveal melanoma prognostication. There will be a time in between each of the talks we can have questions and a little bit of discussion. So we'll be provided some time for that. All right. Can anyone hear me? I think so. So I'm just going to get started because I'm fitting a lot of information. And I just wanted to start off that I have no financial disclosures. And I'm going to be talking about castle biosciences a lot, but I have no affiliation with them. And I just wanted to make that clear. So I wanted to start off with a presentation of a 50-year-old male who was referred for a cordal mass in the left eye. And you can see that his left visual acuity is a little bit reduced at 20, 30. On exam in the nasal mid periphery, there's an elevated melanocytic lesion with orange pigment. And on fundus autofluorescence, you can see there's kind of this halo of hyper-autofluorescence signal consistent with subretinal fluid, as well as these punctate specks of hyper-autofluorescence, which are likely lipofusion deposits. And then on OCT, you can see there is subretinal fluid and these hyper-reflective deposits as well as that elevated caroidal mass. B-scan ultrasonography was used to measure the size of the lesion, which is about 9.3 by 8.6 millimeters. And then it has a thickness of about 4.4 millimeters. And then on A-scan, you can see that it has low to medium internal reflectivity. So all of these are highly suggestive that this is a uveal melanoma and that it requires treatment. And we need to discuss with the patient prognostication. But how do we do that? So first, I wanted to give a little background information. And these clinical pathologic prognostic factors have been used in the past, such as the older the patient, more likely it is to metastasize the larger the size of the lesion at initial diagnosis, where the lesion is in the uvea, and then also if there's tumor extension beyond the ocular contents and the histology. All these bear a worse prognosis and more likely to metastasize. But as we'll see later, they're not the greatest prognostic factors. Chromosomes can also be used. And depending on the copy number changes, it might confer a greater risk or lower risk of metastasis. Loss of chromosome 3 or a gain of chromosome AQ are both worse prognostic indicators. And we'll get into monosomy 3 a little bit more later. But the downside to this is it requires a larger tumor sample. And these tumors can be quite heterogeneous. So if you get a small sample with fine needle aspiration biopsy, you might not be getting the whole clinical picture. And you might be only getting a clinical picture of part of the tumor. So therefore, it's prone to sampling error. And then this figure just kind of demonstrates what monosomy 3 looks like. In the left side, you can see two copies, the two red signals within each cell, which is normal. But on the right side, you can see these typical cells with only one copy of chromosome 3. And why is this important? Well, ultimately, these tumors do metastasize. And we want to be able to tell patients who is going to metastasize and who is unlikely to metastasize. And then we also need to get labs and imaging to determine if they have had any metastasis. So knowing where these happen is important. So most commonly, it's the liver, followed by lung, bone, and skin. And rarely does it metastasize to the lymph nodes or the brain. So to help us determine and prognosticate and determine treatment follow-up, you can do a vitrectomy and a vitrector biopsy. You could also do a fine needle aspiration biopsy, depending on the tumor location. And then at the same time, we usually place a plaque, brachytherapy, and do cryotherapy to close the wounds and avoid any extraocular extension from the biopsy. So the plaque stays on the eye for about four days, and then it's removed, at which time the patient goes home. And they then return in about two to four weeks to discuss the results of their cytology. And then these other three are the Castle Biosciences labs, the gene expression profile, which looks at the mRNA, the next generation sequencing, which is looking at DNA mutations, and then the brain status. So here's a short video. I hope it'll play. This just illustrates how the biopsy is taken with the vitrector. So you really just kind of stab right through the retina, create a retinotomy, and then using the vitrector cutter, you're taking tissue and aspirating it through, and it goes in a little tube. And then you transfer that to the bios that are used by Castle Biosciences. And then after you exit, you laser around the lesion. And sometimes these do bleed, but usually it can be easily controlled with just raising the intraocular pressure. And also, you really don't have to do much of a vitrectomy with this simple core vitrectomy. And then just right around where you're taking the sample is really all that's required. These rarely form into a regmetogenous retinal detachment because you get this buckle effect from the tumor. So then this is the first step and very, very useful for prognostication is the gene expression profiling. So again, this is looking at the mRNA that is being expressed in these tumor cells. And by using this, we can stratify patients into lower high risk of metastases. And you can see the 15 gene expression profile listed on the right, which I'm not gonna get into the individual ones, but there's three controls and then there's 12 other genes that are used. And based on the sample, it helps classify patients and stratifies them. Yeah. So, and I don't have time to necessarily get into how these genes were decided, but we can talk about that later if anyone's interested. So once you send the lab, send the sample off, you get a report back, usually in a week or two from Castle Biosciences. And it looks like this. It has the patient information at the top. And then it lists in bold font, what class they are in. So 1A, that's a good class. And then it lists a discriminant value underneath, which essentially tells you how well they fit into that class. So this one is 0.52. Anything over 0.1 means that they fit well. But if they're below 0.1, they might not fit great into that class. And using this as a prognostic factor might not fit perfectly. So you just need to counsel the patient on that, that perhaps they may be at higher risk than what would initially be thought. But listed down at the bottom of the page, you can see that they have essentially, if I could bring it over there. Yeah. You can see here listed are the percentage of metastasis free at five years. So class 1A, 98% remain metastasis free versus only 28% in the class two. And then class 1B is the intermediate range where 79%. So it's extremely useful information for not only the physician, but the patient to know about their risk. And then on the second page, it kind of gives you some background information about the tests and the studies that were used to support this testing. As I mentioned before, we have our gene expression profile, which is listed down here. And you can see stratifying based on class one versus class two in these Kaplan-Meier curves and the overall risk of metastasis. A big spread here, which is very, very good to see. Whereas with the clinical pathologic correlates, there is a statistically significant difference. So they can be used, but it's still not that great overall, even at about 50 months out. Now chromosome three status is probably the second best listed there. And we'll talk again, a little bit more about chromosome three and why that might be. So this is a cellular pathway. I never thought I'd look at these again, but for this I am. And so this gets into the next genome sequencing. And so what this shows is four of the seven genes that are tested for mutations on the Castle Biosciences Lab. And this is separate from the gene expression profiling. And the Genac mutation listed at the top there in red is perhaps one of the first mutation that occurs. And through that, the map kinase pathway is overactivated and leads to cell proliferation. And perhaps that's what takes a normal melanocyte into like a Nevi or an early melanoma. And then the ones listed kind of in the nucleus, the EIF1AX, the SF3B1 and the BAP1, these are all, these are the three probably the most important genes that are tested because they confer a prognostic factor as well. EIF1AX being somewhat good in terms of lowering the risk of metastases, SF3B1 being intermediate risk and BAP1 being the worst and higher risk for metastases. And we'll talk how all these are related in just a moment to the gene expression profile. So when you get this report back, it lists the genes that were identified with mutations. And then it also gives you this nice background information what the exact mutation was and then the evidence to support this testing and why it might be clinically relevant. So in this example, you can see there's a gene ag mutation and a BAP1 mutation. And notice how they don't have an SF3B1 or an EIF1AX mutation. And that's because BAP1 and these other two essentially occur mutually exclusive one of one another. You don't typically have two of those at the same time. That'd be highly unusual. It can happen, but it's very rare. And lastly, prane positivity. So this is extremely useful as well, especially for those who are class one because this probably explains why some of those that 2% in class 1A or the like 21% in class 1B metastasize and prane stands for preferentially expressed antigen in melanoma. And so this, like I said, is what really differentiates those that metastasize and those that don't in class one. And then for those who are class two and prane positive, it's thought that being prane positive might confer an earlier risk of metastasis, not necessarily a higher risk, but an earlier risk of metastasis. So perhaps these patients should be followed more closely than just class two alone. And then to bring it all together with the diagram on the right, like I said, you start with the normal melanocyte. You might get a mutation in genac and that results in an early neoplasm. And then I can go into one of three pathways. You can get the EIF1AX mutation which confers a low metastatic risk and it probably and is correlated with class 180 gene expression profile. And so that's a good thing to have. Whereas if you have UVO melanoma and an SF3B1, you're now in this intermediate risk and perhaps this destabilizes the chromosomes more and that's where you also find this prane positive status and you get worsening chromosomal instability and more likely to metastasize in this intermediate metastatic risk category. And then in the third pathway, you have a BAP1 mutation which leads to much higher chromosomal instability and is correlated with being in the class two gene expression profile. And then they are at the high metastatic risk regardless of their prane status. But as I said before, prane positive in class two, maybe just confers an increased risk of metastasizing earlier. So that's why getting all of this information can be very useful. And similar to the other printouts that we get from Castle Biosciences, prane positive or prane negative is listed in bold and then it gives you some background information and some studies that support its use. And then finally, using the NCCN guidelines for metastasis surveillance, essentially when you diagnose a patient with UVO melanoma, you typically get blood work to see if there's any signs of metastasis early on checking liver enzymes and electrolytes and then you also get imaging to assess for any lesions. And then after biopsy, you can use their class, their GEP class status to say whether they are low, medium or high risk. And that kind of determines how often you're going to image them and see them and get labs for workup. But there's still many unknowns. And so with this prane classification, we're still trying to understand it and determine what we should do for these patients. So especially patients who are perhaps class one A and prane positive, should they be evaluated every three months or should it be six months rather than every 12 months? And is there an adjunctive therapy that should be started for patients who are class two or prane positive or have the BAP1 mutation? So all of these are questions that we don't quite know the answers to yet but hopefully in the near future, we'll have some more information because there is targeted therapies that are being evaluated in numerous trials that target these pathways in UVO melanoma and metastasis that could perhaps be started early to treat early metastases and avoid complications and allow patients to live longer and more fruitful lives. And along these lines, if patients are living longer, we're catching metastases earlier, we probably will have an uptick in radiation retinopathy which typically presents at least a year after the plaque is placed. And so how do we protect these patients vision? Which is usually definitely something we wanna do but the goal is kind of shift when you're diagnosed with cancer but if patients are living longer, we wanna protect their vision as long as possible. So there are several studies that have good evidence to support the use of prophylactic bevacivizumab using it at every like three to four month intervals. And what this does is it decreases the amount of macular edema and it also improves visual outcomes. So that's what we do here currently. We give them an injection at the time the plaque is removed from the eye and then about three to four months later and every three to four months after that. So in our patient, he's now four months out from his plaque brachytherapy and biopsy. He's doing great. He has no metastases found yet and his vision is now 2020. He's gotten two injections so far and the tumor thickness has shrunk from 4.37 to 2.7. So I just wanted to invite any questions or comments. Awesome, thank you. A couple of things quickly. So you can stay up here. You're going to have this amazing presentation what the world see. No, that was an excellent presentation. So a couple of things, you know, the real innovation in the field of uveal melanoma is this gene expression profiling and then the tests that have accompanied it and the ability to run all three of these tests on a fine needle aspiration biopsy basically just what you can get from a 27 gauge needle. So here just based on what we're able to do with cytology or my general approach is for diagnostic biopsies. I will use the 27 gauge retractor to get a higher yield but for prognostic biopsies alone, it's sufficient just to do a needle biopsy and they're able to run those tests that he talked about the gene expression profiling the frame in the next gen sequencing. It can be tough to keep those tests like kind of straight in your mind. So, you know, he did a really good job but a few interesting things I wanted to point out that he mentioned is so gene expression profiling is an RNA based test and it's the expression of those genes, right? And so then it fits an algorithm. And if you notice on that list of 15 genes, BAP1 wasn't there, SF3B1 wasn't there, GNAQ wasn't there. So it doesn't really hit the same genes that we're then testing for with next gen sequencing. Prane is an antigen and you're basically it's a binary response of is it expressed, is it not expressed? The expression of it, which it's a test these based antigen we think de-differentiates tumors is a positive expression means it's a more aggressive tumor. And so we're still learning for the next gen sequencing what that data is gonna mean for us. The Coup3 and the Coup2 is being evaluated right now and so hopefully we're gonna have some more answers as far as what those mutational profiles actually confer because we know BAP1, which is on chromosome three and probably the reason that chromosome three has always been associated with outcomes. We know it confers a higher risk but it's not in that the GEP. So we've had a few actually around the country a number of us have had a number of tumors that come back with class one profiles but then have a high expression of BAP1 and we don't know yet what to do with that. Does that mean that they're really closer to the class two as far as their metastatic risk or do you trust the GEP? We're gonna have that data down the road. So right now, the other way we're using this and a few other oncologists are using it is also for diagnostic meaning you have an indeterminate lesion and how okay, how are you gonna determine if this is melanoma or if it needs treatment, particularly if it's an individually impactful way. Well, you can use not only the cytology, which of course, if you have a link in cells and cytology that points towards a cancer, but also these tests. One, you can use the NGS to say, okay, I got melanoma, it has the correct mutations, GNAQ or a driver mutation, but also looking at if metastatic risk, because ultimately that's what you're trying to say if it's a cancer or not, is if it can metastasize. So how is it gonna behave? So we're also utilizing it in that way, although that's technically not how it was developed. And as he mentioned, class one tumors have those GNA, well, all the tumors generally have a GNAQ family mutation, but class one tumors also will come back on like anivis or melanocytoma, but nine proliferation of melanocytes as well. And so it's kind of important to understand that how these secondary driver mutations work. But anyways, that was a really excellent presentation. I was curious if there's any questions before we go on to the next one. So immunotherapy. Immunotherapy, particularly for metastatic melanoma has been miraculous at times and increasingly. So how do any of these correlate with potential immunotherapy? I'm assuming we're gonna be very similar to skin melanomas, but I don't see much literature about immunotherapy for this and how it correlates with these different antigens and DNA variations. Yeah, so a great question. So in general and historically, uveal melanoma, metastatic uveal melanoma has not responded to the same immunotherapies we're using for cutaneous or conjunctival, which has analogous genetics. The reason for that is multifaceted. One of it is that it spreads differently and so it almost always goes to the liver as he pointed out. The liver has its own kind of immune related phenomenon there that prevents some of the same checkpoint inhibition from working well in that space, but also the eye and its immune privileged status. We think some of the T cell inactivation that occurs naturally in the eye might contribute to the way that it responds systemically. Some of that we're still learning. So there was a recently a FDA approved treatment, the first FDA approved treatment and the first treatment that showed an actual survivor response for metastatic uveal and that's Tabanta first. And so that's a bi-specific immunotherapy that does seem to work for patients, but they have to have a particular HLA haplotype. So only about 40% of the patients we see will actually be eligible for that. So there's some others, as he mentioned some other clinical trials that are looking at different checkpoint blockades or different pathways in the immunotherapy regimen that might be more successful for metastatic. And that's really like probably the next phase of uveal melanoma as we've come to where we are with local treatment, but we really haven't moved the needle on overall survival. So all this prognostication, all this science, it's really exciting, but really at the end of the day, we're still telling patients what is likely going to happen without much ability to alter that. The only way we really can alter survival at this point is to treat early, to catch it earlier, right? I think that's gonna change because now we have a way of restratifying patients. So now that we can restratify them very accurately, we can set up neo-adjuvant and adjuvant trials that can be multi-centered. So hopefully patients who are class two, class two pre-impositive can be on a neo-adjuvant or adjuvant therapy that can actually alter their overall survival. So Tyler, hand off the wand. Has there been any advancement in liquid biopsies in identifying either cell-free DNA or circulating tumor cells within the vitreous? And is there any option of that in the future for cell melanoma? Yeah, there's a few groups and institutions that are looking at that. So what right now has been found is liquid biopsies as far as the aqueous. So you have liquid biopsies in the blood, you can think of the aqueous, you can think of the vitreous. So in the blood, there's not enough tumor burden. It's not like retinoblastoma. It's not a rapidly dividing tumor. So we don't see anything in the blood until it's already metastatic. So it is a way that we can screen for metastatic disease and New York has published on that as another way of rather than just imaging. There's a pretty out of Stanford is looking at proteomics within the vitreous for prognostic, but as far as for liquid biopsying for diagnosis, which is I think the gold standard, there's still not enough that we're finding in the aqueous for it to be effective. So there is, yeah, the KUG-3, which is the collaborative ocular oncology group is gonna be looking at this. They're gonna be doing aqueous and hematologic liquid biopsies in longitudinally and see how they can be actually utilized for clinical purposes. All right. All right, so next up is our senior fellow, Dr. Chris Baer. You all know him well. We're gonna be sad to lose him soon. And he's gonna be talking to you about something else related to melanoma around. All right, morning, everyone. We'll get going here. So talking about a patient who comes in with a chief complaint of floaters and we're not gonna talk 20 minutes about floaters, but he's an 84-year-old gentleman with two weeks of increased floaters in the right eye. Initially eight months ago, he noticed what he described as ants in his vision and he saw his geriatrician who thought these were hallucinations that adjusted his psychiatric medications to compensate for those, but it didn't work and he's continued to have these symptoms. No pain, no flashes, no vision loss. His review of systems was positive for sneezing, congestion, and he has a dog at home with GRD. His negative review of systems, you can see there are no fevers, weight loss, shortness of breath, or chest pain. His medical issue was notable for cutaneous melanoma. This was diagnosed in 2019. We saw him in late 2022. It was on the left arm, biopsy showed regional lymph node involvement. He was treated with nevolumab, switched to pembrolizumab, and stopped treatments in August of 2021. He has a other history of bipolar disorder and then you see the medical history there. No prior history of ocular conditions and just occasional alcohol use, but nothing else in his review of systems. So as an exam, you can see good vision, 2025, 2030, normal pressures, full motility, normal pupil exam. His dilated exam shows moderate cataracts and then in his right eye, he has this, what we described as a string of pearls and fearly, talk about that. Really no cell in the anterior vitreous, no significant haze, and then he has this outer retinal nodule, this kind of non-pigmented outer retinal nodule superiorly along a blood vessel. Here's a fundus photo. We didn't have wide field imaging at the satellite clinic where we saw this patient, but you can see here initially this shadowing from the floaters here on the fundus photo. The differential diagnosis at this point was pretty wide. This could be something like endogenous endopomitis. This could be a malignant condition. This could be inflammatory. So the differential's pretty wide at this point. We've set a pretty broad workup and the workup came back pretty unremarkable. He had a positive lysozyme which was mildly elevated, which can be non-specific. And then he had these new calcified hyalurilmph nodes on this chest X-ray that were new from a prior chest CT. So thinking about next steps, there's a few different ways you can proceed from here, but in a case like this where we need to get a diagnosis, getting tissue diagnosis is the best thing. And so we proceeded with a vitreous biopsy. And I've got a short surgical video here for you. Here you can really see this kind of sheet-like conglomeration of these non-pigmented floaters here. Here we are going in and in a vitreous biopsy, we do this initially without any infusion in the eye. We're trying to get a pure sample here. So here we're using the vitrector to remove as much as we can, undiluted. Here we're taking it out a little bit more. And here we're just gonna continue to work our way down and it's nice to see them finally go away. Here is just a photo. You can see that kind of whitish nodule that we saw in the retina. Surgical video of it, superficial there. And then here at the end of the case is we're depressing around. I just wanted to highlight, as we depress, you'll see right here, these multiple non-pigmented whitish kind of deposits here within the vitreous base. And then we injected antibiotics into fungals at the end of the case because the diagnosis is unclear at this point and remove the last port and that's it, we're done. So we sent the vitreous for all the normal studies, infectious cultures, inflammatory studies. But what came back was the cytology. The cytology demonstrated this cohesive plasmocytoid cells. It's positive for melan A immunostain, which is consistent with metastatic melanoma. So metastatic melanoma to the vitreous is a rare finding and a rare presentation of metastatic melanoma. Overall, metastatic melanoma rarely metastasizes to the eye, cutaneous melanoma does. It accounts for less than 5% of metastases to the eye. The most common side of metastases to the coroid, vitreous involvement occurs for a little under 20% of these ocular metastases. The most common presenting symptom is blurred vision and floaters. And the diagnostic dilemma here is that these floaters can be pigmented or non-pigmented. If it's pigmented, that would lead you towards maybe a little bit more of a diagnosis of malignancy, but non-pigmented cells can occur in a lot of different conditions that we saw in our differential diagnosis a few slides back. These patients often are immunocompromised, which raises a concern for infectious complications. And then the other thing to talk about here is the use of checkpoint inhibitors, which also present with cell. So checkpoint inhibitors, like Dr. Olson said, are this novel class of immunotherapy approved by the FDA in 2011. And they've really kind of been a game changer in how we treat a lot of these different metastatic conditions. You can see the list of a short list here of different checkpoint inhibitors and the different conditions they treat. The common conditions or the common checkpoints that we target with the drugs we use are CTLA-4, PDL-1 and PD-1. This is just a short video, but basically the idea behind checkpoint inhibitors is that cells in the body contain these checkpoints that tell the immune system that you don't need to attack us, we're good. Unfortunately, cancer cells can mimic these checkpoints and prevent the immune system from responding in a helpful way. The idea behind checkpoint inhibitors, and that's what this is showing here, cancer cells will mimic that, the event checkpoint inhibitors that these inhibitors come, they block these checkpoints, allowing the immune system to be ramped up and target and attack cancer cells, leading to more effective treatment. Now, the downside here is that there are, when you're turning off, or when you're turning off these checkpoints, you can also turn off checkpoints and attack things that we're not meaning to attack. And so there are complications in the body, but specifically in the eye, the things that we see are typically inflammatory. So UVitis, keratitis, and myositis and orbital diseases as well. But these have been really important in changing survival curves in metastatic melanoma, taking survival rates from less than 10 to 20% up to over 50% in a lot of these metastatic cases. Specifically talking about metastatic melanoma to the vitreous, this is something that we're seeing more and more, the incidence of this is increasing. And I think the big publication to highlight here was published a couple of years ago by Jasmine Francis and her multi-center collaborative group looking at this metastatic melanoma in the vitreous. This is the largest series of patients with intravitreous metastatic cutaneous melanoma. It's a multi-center retrospective series that we ran for about nine years. It included 14 eyes of 11 patients, six women and five men. This is a table just showing the kind of characteristics of these patients. A couple of things to pull out here. All of these patients except one presented with either floaters or blurred vision. The other things to talk about is that with regards to treatment of this disease, nine patients out of the 11 had controlled or responding disease. One patient out of this group required a nucleation and five of these 11 patients had vision that was 2,300 or worse. The other thing to talk about here is looking at systemic disease. Eight of the 11 patients, which you can see here, were on a checkpoint inhibitor. We're using a checkpoint inhibitor either currently or in the past. Which shows that in this era of checkpoint inhibitors, we're seeing as checkpoint inhibitors use more frequently, the incidence of this metastatic melanoma presenting in the vitreous is increasing as well. How does melanoma reach the vitreous? Well, there've been a few different hypotheses. People have postulated reaching it through the coroid. Typically when metastatic melanoma goes to the coroid, it is hematologic spread. But in these cases, the coroid was normal. So we think it's probably less likely. There's thought that it could be direct invasion from the CNS. These patients often have CNS metastases and could it transport through the optic nerve into the eye? The optic nerves in these cases were normal in a nucleated specimen that they did in this series. That was also a normal optic nerve as well. So the leading thought is that this is probably likely through retinal circulation. Here is a picture. This is from a nucleated specimen from a post-mortem analysis in this study. And you can see here at these arrows, the fine level of layers of pigment right along the vasculature through the retina. In the systopathic logic sections here, you can see melanoma cells in the retinal circulation and extending through the retina into the vitreous. And so the thought is is that it's likely through the retinal circulation, invading into the vitreous and then retinal involvement after that might come from the vitreous sitting that we see there. So the theories behind why this is happening, why we're seeing this more often are a few. There's this thought that you can have this unmasking effect by checkpoint inhibitors. Checkpoint inhibitors tend to modulate the blood brain and potentially the blood retinal barrier, which can unmask a previous disease. We also see this phenomenon in a pseudo progression in systemic disease when we use immunotherapy. You can often have an initial flare where it looks like the disease is getting worse before it gets better. And that's from the ramping up of the immune system. Probably the more likely is that checkpoint inhibitors are allowing for long survival and we're increasing our surveillance and recognition of this, which is leading to more diagnoses being made of this. The key point to remember is that when you see non-pigmented cell in these kinds of patients, malignancy should be on the differential. We talked about that with checkpoint inhibitors, uveitis is a common thing. Vitritis can certainly present in these uveitic checkpoint inhibitor conditions as well. Infectious things are also important and can present with vitritis. But when you see these, it's important to remember that malignancy should be on the differential. Treatments for this, historically, in these kinds of conditions, a nucleation or external beam radiation was the historical treatment of choice. But now that these patients are having increased survival with checkpoint inhibitors, we're needing new ways to treat them. So the way that we're often treating these patients, we have injections options. So melphalan is being used to treat metastatic melanoma. Melphalan has historically been used to treat retinoblastoma, but it's shown a lot of efficacy here in treating metastatic melanoma as well. Methatrexate has been used in treating metastatic melanoma. However, metatrexate is typically thought to be more of a control, less likely to be curative. And so combining it with other treatments might give you better responses. In these conditions, you can get knee vascularization either from the disease itself or from secondary radiation therapy. And so using innovative FN combination can be helpful as well to treat that. Surgical debulking has been used for metastatic melanoma elsewhere in the body for many years. The idea is to reduce the tumor burden by surgically debulking, removing that tumor. And in the eye itself, we see that there is benefit there. So using doing of a trectomy, taking out any cataracts so you can remove the posterior capsule will reduce the tumor burden within the eye and potentially make the rest of these treatments more effective. External beam radiation therapy can be used. Melanoma tends to be radio resistant. And so it requires higher dosing. And so these patients often get really difficult to control the vascular glaucoma, which can lead to secondary enucleation if you use external beam radiotherapy. Our patient just as an update here, he underwent systemic imaging for metastatic disease. His initial MRI brain showed no evidence of metastatic lesions, but his PET CT showed these lymph nodes that were increased, which was consistent with disease progression. So he received a melphalan. He underwent surgical debulking with a trectomy and cataract extraction. Here you can see the pigmented cells on the posterior capsule of his lens prior to his surgery. And after receiving a melphalan, the repeat vitreous biopsy that was done at the time of the surgical debulking showed no residual tumor cells, showing that, you know, we had had good treatment response locally with our local treatments. He also reestablished care with oncology and was started on a pembrolizumab and levatin. Unfortunately, while his eye had been doing well, his systemic treatment was not as effective. He was admitted to the hospital for encephalopathy, found to have a new frontal lobe metastatic lesion and elected to return home on hospice. And that's where he currently is at this moment. So these are our references. And then, you know, big thanks to our ultimate reference here, Dr. Hansen. It's really, really nice to have him here and he's really, really helpful in putting this together. So any questions, comments? And Dr. Hansen, I'm sure you might have something to say too. Not excellent presentation. I think it's a really interesting topic that has an overlap with what our OEVitis colleagues are seeing with the checkpoint inhibition. Still a lot of unknowns on the why's and the what for's. What's interesting is the checkpoint inhibition in metastatic melanoma does appear to work with CNS disease in many patients. Of course, as clinical trials in their design are important for how we understand disease, many of the original trials excluded those patients, but there were asymptomatic lesions that they could go back and look at at hawk. And then clinically we're seeing that there is response. But the more we learn, the more we realize the eyes immune privilege is not the exact same as the brains, right? So even though that the blood vaginal barrier and the blood brain barrier are thought to be pretty synonymous, what actually happens from an immune standpoint within the brain, within the brain, parenchyne versus the eye does seem to be different. So maybe that's why we're seeing a protected sanctuary site with vitreous, whereas the CNS often will still respond. We don't know what the perfect treatment is. We published a paper about using debulking in combination with a trivitral melpholin. It has pretty good results. Melpholin's a pretty toxic medication though. The patient when he just presented luckily was still 2030 and was really happy with his vision, but we definitely see vision loss sometimes with that treatment. And so it's an emerging topic with a lot of, I think, interesting things to explore. Are there any questions? Good. No, I'm kidding. All right. So we're gonna switch gears a little bit and we have another presentation by one of our retina fellows, Dr. Fuller is one of our first year fellows here. And he is gonna give us an update on what's going on in the macular degeneration space because we have some really exciting news. And we also have Dr. Fleck inside with us as well to share in the excitement. Thank you. I should, doesn't matter which microphone is, I'll probably just use this one. Hi, nice to see you all. Thanks for coming and great presentations, James and Chris. I'm grateful to be able to speak to you today about a landmark moment in the treatment of vitro renal diseases. There's a new medication called Cyphovery, that's Pegsida Copeland, which is a new FDA approved treatment for geographic atrophy secondary to age-related macular degeneration. I don't have any financial disclosures. First, let's talk about pronunciation. It's pronounced Cyphovery. Probably say however you like, it's fine. You're wanting to just understand how the company is encouraging you to pronounce it. That's how it is. Here's just, we'll start with a short case. This is a patient that has autofluorescent findings of central hypo-water fluorescence with a rim of hyper-autofluorescence, multifocal, already involving the fovea. Vision is eccentrically 2200, 2400 depending on the day. And you can see here on the OCT outer, so the photoreceptor loss, as well as RPE atrophy and loss of the cryocapolaris. Now in her fellow eye, this vision here is 2025. You can see that there is also multifocal atrophy sparing the central fovea. And she's quite anxious about her atrophy, how it's spreading. Patients with geographic atrophy of this sort often report kind of vague, or at least it's hard to describe vision complaints as their atrophy grows in spreads and coalesces. And we know that multifocal atrophy has a higher rate of spread compared to just one focal area of atrophy and extra foveal spreads faster as well. And I'll get into some more numbers about the spread of geographic atrophy, but up until a few weeks ago, unfortunately there was nothing to even offer this patient. And I think it is pretty remarkable that now we have at least something to discuss. Does it mean the treatment is right for every patient? By any means, and patients need to determine for them what is the best treatment for their ocular disease, but to have something that could potentially give them a central vision for longer is pretty remarkable. So the scope of geographic atrophy affects about 5 million people worldwide and around 1 million people in the United States. It accounts for 20% of legal blindness related to age-related macular degeneration. And the median time to development of foveal geographic atrophy is 2.5 years for patients you have central GA that's sparing the fovea. The risk factors for geographic atrophy are genetics, about half of the risk, as well as age, obesity, history of smoking and diet. Smoking and diet are modifiable as well as potentially like obesity, but now there's also other trials about addressing the genetics of age-related macular degeneration with trials ongoing. So kind of pay attention to the space in the future for changes there, but currently at the moment we don't have any ways to affect the genes inside the eye. Research over the last decade and plus have shown that there is a connection to the complement system that affects the progression of geographic atrophy. It's been shown to be increased in GA lesions and there's increased systemic levels of complement in the blood of patients with GA. Here is a depiction of the different pathways you might remember from your medical school days that you have a classical elect in an alternative pathway for complement activation that converge on C3. There's a branching point C3A and C3B. It has an amplification loop back to C3 and C3B specifically drives an inflammatory arm and then a cell death or a dysregulation arm. Hence, you can see how the complement system could be affecting the cell death that we see in the photoreceptors, the RPE and the cryotepillars. Syphogry is a molecule that has two proteins. One is an inhibitor of C3 and one is an inhibitor of C3B. The idea is that by attacking these two kind of molecules you could prevent the pathway favoring cell death and dysregulation. The phase three Oaks and Derby trials were done and completed last year and it was involved 1,258 patients. It was multi-center 232 sites and we were one of the sites that administered the medication. The patients were randomized into a monthly and every other month and then sham monthly and sham every other month arms. At the 12 month period, the primary endpoint was the change in the total geographic atrophy lesion area on fundus autofluorescence. And at 24 months, the secondary endpoints were things like vestrected visual acuity, reading speed, microprimetry for the Oaks trial lesion growth. And then patients after the two years were able to enroll in a three-year open-label extension study which that data collection is ongoing. The key inclusion criteria are that the patients older than 60 years, they had to have vision better than 2320 and there were some geographic atrophy lesion requirements. Of note, geographic atrophy lesions that were foveal or extra foveal were allowed. And additionally for the exclusion criteria won't go into all of it but CNV and the fellow I was not exclusionary. Although CNV and the study I was exclusionary. The results, overall there's about a 17 to 20% reduction in GA lesion growth and that I'll show you data about monthly versus every other month. And there was a greater reduction in geographic atrophy growth rate for patients who did not have sub foveal involvement. As the trial went on, you can see, I don't know if I might not see, but at the six month mark, there wasn't that big of a difference between the every month and the every other month, but that gap widened as the months progressed. And also the treatment effects seem to progress from 12% at zero to six months to 24% two years for the every other month injection. And we don't have data past two years but the thinking is that this effect will continue to be larger as time goes on when compared to the shame groups. So what was Cyphovery FDA approved for? It's actually a really broad indication. This indicated for the treatment of geographic atrophy secondary to macular degeneration age-related macular degeneration. Any geographic atrophy foveal, sub foveal of note having neovascular AMD in the eye that has geographic atrophy is not a contraindication to starting Cyphovery, which is interesting and I'll get into that later because there is an increased rate of development of neovascular AMD in patients that receive Cyphovery. Contraindications are periocular or ocular infections as you might imagine and then active ocular inflammation. Here's the adverse event table from the phase two trial, the Philly trial. And as you can see here in the monthly arm, 12% of patients receiving Cyphovery developed neovascular AMD, 7% in the every other month arm developed neovascular AMD compared to 3% in the shame arm. And also interestingly, optic ischemic neuropathy was reported about 1.7% of patients that were treated monthly, 0.2% of patients treated every other month and no patients treated with the shame arm. And I've talked with the reps and others about this and we could discuss more about all of the patients that had an ischemic optic neuropathy had discs at risk, cardiovascular risk factors and all the patients but one had return of vision with time. And I think there are only five patients in the trial that developed it but there are some concerning features about the medication that might kind of predispose a patient to like already at risk of an ischemic optic neuropathy to developing it when receiving the medication so frequently. Also one thing I wanted to point out and they kind of split out intraocular inflammation here they didn't split out in this table actually but you can see here is about 4% in the Cyphovery monthly group, 2% in the every other month and less than 1% in the sham group. In 2018, they actually stopped the trial because they figured out that there was a defect in the manufacturing of the medication that was causing significant ocular inflammation. They restarted the trial in 2019 and since then the rates of serious ocular inflammation went down significantly to where only around 20% had even mild intraocular inflammation usually anterior cell and anterior vitria cell. And most patients were able to continue the medication despite developing mild inflammation. Just interestingly for the risk of neovascular AMD in these patients, the rate of development of neovascular AMD in the untreated fellow eye for these patients was four to four and a half percent that's consistent with the epidemiologic studies about the incident development of neovascular AMD. So if you're treating a patient every other month and they have a 7% risk of neovascular AMD you could compare that to a four to four and a half percent risk of an untreated eye the absolute risk increase isn't terribly high for every other month. It is definitely significantly high for the monthly group though. Features of the medication that it's a very viscous medication you actually have to use a different needle as the half inch then we'll 29 gauge needle that comes in the package or you can also use a 27 gauge needle. You need a lure lock syringe because again it just you have to inject it slowly and it's as you're injecting 0.1 MLs that the eye pressure does rise and if you didn't have a lure lock on the syringe you would potentially pop the needle off and that would not be good. So for imaging studies for AMD I have on here imaging studies that maybe a referring provider might be obtaining prior to referring to a retina specialist. So obviously macular OCT, funnesotofluorescence maybe even an FA if you're concerned for neovascular AMD these are things that non retina specialists could have in their office. Also something that we get as retina specialists would be a OCT and geography if we wanted to look for a neovascular network that we also where we didn't want to or can get pre off the fluorescein in geography. So what is the ideal cypherypatient? That's kind of the big question we're all discussing. I think that's really interesting to think about and we're gonna be figuring this out as a community. So it's to be determined but kind of this patient that we that I brought up at the beginning it's a monocular patient that's lost central vision because of geographic atrophy that where in the fellow eye they have center or foveal threatening atrophy and they want to take on the risks of this new medication while giving themselves chance at prolonging the function of their central vision. It's important that all these patients know that this medication is not a silver bullet it will not absolutely stop or reverse their atrophy their vision loss from geographic atrophy. There is a high treatment burden they'll need to be getting injections every month although most are in a specialist I've talked to definitely favor the every other month arm has kind of that sweet spot between balancing benefit and risk and patients need to know that they have to be ready. The trials all the patients received the medication consistently they weren't disappearing it wasn't a real world trial where they were disappearing for a few months and then coming back and so we don't know what the effect will be if patients do that in the real world but if they can commit to these regular treatments then there is a chance that we can slow down the rate of their vision loss from geographic atrophy. So yeah, we'll open it up to questions. And I'll admit I'm gonna invite Dr. Fleckenstein to comment but I'm gonna admit that, you know what's being billed as, oh did you have a question? The biggest thing since anti-vay, fast comment. I'm still trying to figure out how I'm gonna use it and how I'm gonna incorporate it myself. So Monica knows way more about this than I do but I just don't think for the residents arrest to realize that the first person proposed the compliment system was involved in macron generation was our own Greg Higman. And it was considered such a wild idea that the head of the National Institute when he submitted a grant called him personally to say but the NEI would never waste its time or money on such a stupid theory that everybody knew it was senescence related. So this is an interesting involvement going forward. And Monica, I think you should just briefly also about not only this but what our own clinical trial and where we are which is obviously working in a different area but also having to make impact here on competence and impact on macron generation. I'll turn it over to you because I gotta run to a meeting. Thank you so much, Spence. This was a great presentation. Thank you so much. Do you wanna come up here? You wanna come up here? I can do, of course. So compliment obviously plays an important role or a crucial role in development of AMD in general but obviously also plays an important role in the progression of geographic atrophy. It's quite interesting because natural history data did not really show a huge impact of compliment in the progression but their theoretical thoughts and also the data of this study. And actually there's also another study by Iveric in the pipeline also compliment inhibition and these drugs obviously are able to prevent to a certain degree the progression of geographic atrophy. And Dr. Olson has pointed out we are right now doing a phase one trial and this is actually based on Dr. Hageman's research work for the past 30 years. And this is actually gene therapy and the idea is to induce protection to patients with age-related macular deterioration. And this is in this phase one trial, we right now recruit patients with geographic atrophy. It's one injection and is every six months. No, it's really it's one injection gene therapy and we just screened our first patient last week. We are waiting for the go. There are already two other patients in other clinical sites who are enrolled in the study. And so of course this is extremely exciting and of course the advantage would be one injection but coming back to Cyphory, we are all very much excited. It's the first time that we can offer something to our patients. It's maybe just 20% reduction in progression but again it's really for the first time and the patient you presented would probably be the perfect candidate to offer this medication. I think it's all about patient education here. Like you pointed out, patients need to understand it's not making any better. It's really slowing down the progression and so this is what patients need to understand. It's not like treating wet A and B where they experience an improvement in vision or where we can show nicely on the OCT image how it works. And yeah, so we really need to trust in the data. The patients need to trust us and this is, we have a lot of, yeah we are the ones who need to explain to the patients what the background is of this medication and I think it only works if patients really understand and what they may gain. So it's about five years treatment gaining one year. And we will find patients who are extremely excited about this and we will also find patients who say, oh I'm 85 years old now, will I really benefit? Do I really come in every six to eight weeks for treatment? This is where we need to make a really good risk benefit assessment with our patients and include them into the discussion. So it will take some time to talk with these patients but we already did and it looks like that we can offer this treatment within the next weeks. So the team surrounding Steve, Christensen worked very hard on this and we are right now this week on a pilot phase where we pre-authorize for patients with Medicare A and B and we will wait for the response from the payers and then we go. Awesome, thank you. Anyone else have any questions or Sean? Yeah, I'm just kind of wondering clinically, I think it's probably too early to tell what people are actually gonna do, but do you think it's reasonable to have some flexibility with patients? Obviously they were in the study, they were tested in a Q2 month or Q monthly regimens. I mean, if a patient's willing to do every 10 weeks or every six weeks, do you feel like there's some flexibility to work with patients on that? Like that would be a reasonable way to approach this or? Yeah, that's a good question. We have thrown around the idea among the retina faculty six weeks, sorry, not six months, as maybe kind of an in-between but we don't have data on that. So it's already new. I think we're already a little excited but nervous and cautious about it. So I think to go out just to lead with like an alternate treatment regimen would be atypical, but I don't know what do you all think? So the label gives us a lot of flexibility between 25 and 60 days. I think you showed it on your slides. So 10 weeks will probably be problematic from the payer's view because we do, I do not know what they will say if we propose 10 weeks, maybe they are happy, they do not need to take more off. But, you know, Spence just said it, we do not really have that, we do not have the data on this. We also do not have the data on smaller lesions, lesions smaller than a disk area. So from looking at these images and first analysis, we know that these lesions progress quite slow. So that's really the question. Should we treat these patients? Should we watch them for one year and see how fast the progression is? So these are all unknowns and this makes it very exciting. Yeah, I think the real world data is gonna be fascinating. There's a lot of talk about this. Do you treat smaller lesions, right? If the effect increases over time, then maybe those actually are the ideal patients, right? Those are the people you actually can save their vision for their lifetime if you think about it, but we don't know. And then the other thing is, do we need biomarkers or imaging markers to identify the best patients, right? The people that you can say, oh, you're the right candidate based on imaging or biomarkers, so that's another thing that people have talked about. So yeah, it'll be interesting. I think a lot of people are going towards the Q6 to Q8 week in the real world from my conversations at the conferences the last couple months. Any other questions? Yeah, I think that was awesome. Very excellent and thanks for everyone for joining.