 So I want to talk a little bit today about ROP. It's kind of, to my interest right now, are pediatrics and retina. So it's kind of a nice bridging topic for me to discuss. So kind of a generic case to start off with. Baby boy was born at 27 weeks gestation, weighing 980 grams on oxygen and NICU. When and how often do you screen these babies such as this for ROP? They do have ROP, when do you treat? And then the question also is, how do you treat? So just briefly on some of the screening guidelines. These are, people have different, there's different guidelines out there. Some are more stringent, some are a little bit more loose, but kind of the currently accepted APOS guidelines is any baby born before basically 31 weeks, regardless of their birth weight. If a baby's born 1250 grams or less, or any baby that the neonatologist deems as high risk. And then when do you screen these babies? If they're, it should be performed at 31 weeks post menstrual age and infants that are born basically 427 weeks. Or if they're born 427 weeks, then four weeks chronological age from that point on. And then there's also some criteria that suggests maybe screening at six weeks of life if they're born before 25 weeks. So once you see these babies and you say, okay, this baby looks like they have some evidence of ROP. When do we follow up? There's kind of four categories of follow up time periods. So the first is one week follow up, one week or less. These are babies that are high risk, babies that have stage one or two ROP in zone one, immature vascular or aggressive posterior ROP. Then the next category is the one to two week follow up. These are kids that had zone one ROP but are unequivocally regressing stage two, zone two, and then also just immature vascular in the posterior zone two. And then the two week follow up, these are kids again that are getting better and better unequivocally regressing ROP zone two and some still immature vascularization. And then the third category is kids that are clearly getting better that are into zone three but still have a little bit of evidence of ROP. So how do we screen these kids to know who has ROP, who's at risk for ROP? It's a really hot topic right now in research and literature. There's some different research going on on monitoring IGF-1 levels as an indicator for risk for ROP. Also monitoring VEGF levels and pigment epithelial derived factor and also erythropoietin levels. These have all shown some evidence but not a ton yet. It's still not quite clear how effective these are, how sensitive and how specific these are going to be at catching all the kids that we need to screen. So another reason it's a big topic is not every hospital with a NICU has pediatric ophthalmologists or retina specialists easily accessible to screen all these babies that may need screening. So that brings up the telurentinal imaging idea. This has been shown to be really good for clinically significant ROP but kids that have mild ROP that are in the early stages, it's not that, it hasn't shown, been shown to be great yet. People have looked at different maternal risk factors, preeclampsia, diabetes have been shown to be associated with ROP but there's a confounding effect because a lot of these babies that come from preeclampsia or diabetic mothers are born premature. And then also another way to monitor these is look for kids who have high oxygen saturation goals. There's a decent association between how high that goal is and how high risk they are for ROP. Kind of the underlying principle of those, there's nothing really beats taking a look and getting imaging hand in hand. So once we decide that a kid has ROP, there's basically three criteria for when we say, yep, we need to go ahead and treat. So zone one ROP with any stage of plus disease, zone one ROP stage three with no plus disease or zone two stage two or three with plus disease. So then it leads to the question, how do we treat? And this is probably where there's the most research and most controversy or opinion on a different camp on what the best way to do this is. So laser right now is a standard of care. Some positives about laser, we know that it improves the functional structure outcome versus kids who have no treatment. We know it's effective halting progression of ROP in most kids. There's a lot of negatives associated with it as well. We know it decreases VEGF levels in the blood, although much less significantly than with anti-VEGF treatment. There's destruction of tissue. We've lost peripheral vision, high myopia. We see these kids sometimes growing up to be minus 15, minus 20. It doesn't work for everyone and it's a very high stress procedure for these kids. A lot of stress and trauma to them. So then the other option we have is anti-VEGF treatment. So just some pictures here of some kids demonstrating the difference between laser and ROP or anti-VEGF treatment in some of these kids. So this top picture, this was before laser treatment and this is after laser treatment. You can see where the ridge was and where the laser treatment was done. Vascularization stopped there, halted the progression effectively. And this doesn't happen on every single patient but in a lot of patients, we're seeing kids treated with anti-VEGF. You can see where this ridge was and after anti-VEGF treatment, the vessels continue to progress all the way out to the far periphery. So big questions with anti-VEGF, are they safe? And if they are safe, what's the best anti-VEGF treatment? We have multiple options. And then what dose and what are the long-term side effects? A lot of questions that we're trying to get answers to. Some of the things we do know about anti-VEGF, we know that it increases anti-VEGF, increases the vascularization. There's some evidence that shows that it decreases the myopia, although it's not 100% clear at this time. It is much less invasive for the patient, much less stressful, and they develop better peripheral vision, assuming they can go ahead and progress to the periphery. Some of the negatives, we know that it decreases the VEGF levels in the blood. This is one of the biggest questions, is this safe? Then you can also see kids that get this chronic arrest of the vascularization. Kids sometimes reactivate after treatment. There's been mixed results of successful treatment for these kids. And then also there's been shown to be some abnormal vasculature. The significance of this is unknown at this time, because these kids are still so young and it's hard to tease out how much of their abnormal vascular is from being premature versus the treatments. So here's a picture from a recent study showing this chronic arrest of the vasculature after vavacizumab injections. You can see pre-injection and post-injection didn't really progress much. So one of the big questions I mentioned earlier was the VEGF response systemically in these kids. You can see in this study by Kong et al. With laser, the VEGF level systemically did drop a little bit for a time period, not as much as the intravagal vavacizumab. But there was a drop there. And then the levels of anti-VEGF seen in this. So in the serum for eight weeks, you see a decrease in the injected eye. You see it for eight weeks. And even in the other eye, the fellow eye, you see a decrease for a couple weeks of VEGF levels. A recent study that we're actually a part of here was looking to see what dose is going to be the most effective. So basically what they did in this study was took six to one premature infants with type one ROP and I started treating them with different doses of vavacizumab. Every time a group was successful in their treatment, then the dose was cut in half. So you can see 10 out of 14 infants received 0.25 milligrams and then it dropped down to 0.125 and 0.063. And finally it is 0.031 milligrams. Basically one 20th of the current of the beat ROP dose, which is one of the bigger studies measuring how much and what medication to treat with. So this was showed to be quite successful. Some of the downsides of this study was a small study size, a short fallout period at this point, although it's still being monitored. And we didn't monitor the VEGF levels. Yeah. So what was the way to do it? That was the very last of it. We did actually measure the VEGF levels. We did, okay, I misread that. The VEGF and the serophilic, I'm sorry. No, no, please. I missed that. No, it's okay. That was my mistake. Another study recently came out called the CARE ROP study. And they looked at using Rannabisimab, or Lusentis instead of Avastin, and using even lower doses than we currently use. So they took two groups. One group had 0.12 milligrams and one group had 0.2 milligrams. And found that in both groups, the vascularization went all the way to the auricerata. The systemic VEGF was not significantly suppressed. There were a few eyes that needed retreatment in the 0.12 milligram group and in the 0.2 milligram group, one kid needed a second retreatment, so three injections total. It was interesting to note that the vascularization of auricerata was better in the 0.12 milligram group versus the 0.2 milligram group. The reason this is significant is Rannabisimab is a smaller molecule has a shorter half-life. So theoretically, if it is getting into the system, then potentially it's not having as much of a systemic effect. So some of the important points about this study. The seromente VEGF levels were monitored for up to eight weeks, longer if there's more retreatments required. And as I said, I mentioned previously, there was not a huge decrease in the systemic VEGF levels. Some of the kids did need to have rescue treatment, which basically means they didn't respond at all and needed laser within the first 28 days. And there was one kid, one child in the 0.2 milligram group that had respiratory failure that was thought to be likely to the anti-VEGF treatments. And I've not shown this slide was the kids who had the 0.2 milligram dose needed to be on oxygen for a significantly longer amount of time than the kids who received the 0.12 milligram group. So even though the anti-VEGF levels were not measurably decreased, there seemed to be some effects, which that's gonna need some more research to figure out exactly what's going on there. So overall, in all these different studies of different anti-VEGFs and different doses, there's a lot of mixed results. Aaron Bulu and colleagues found that four out of five kids improved to 14 out of 16 eyes. Ian colleagues found that in a larger study that there was good to success. Castilenos and colleagues found that six out of six kids treated with randomism map had complete resolution. But then there's other studies. One colleagues found that six eyes treated with randomism map five had reactivation of ROP and within an average time of six weeks. So in conclusion, some of the big things that we are kind of taken away from all this research is that right now it's still unknown if anti-VEGF treatment for ROP is effective, safe and effective, more research is needed. Novel screening methods are continually evolving. Nothing beats an indirect exam with imaging. Lower doses and short acting agents may be better in terms of vascularization and lower morbidity. Again, more research is needed there. Right now, laser is the standard of care but anti-VEGF is increasingly shown to have a role in treating these babies with ROP. And for now there's no FDA approval for anti-VEGF treatment for ROP. And finally, when it is decided to treat these babies with either laser or anti-VEGF it's very important to have a very detailed informed consent process to explain the risks and benefits of both these treatment because there's no perfect answer for this very, very possibly devastating disease. Any questions, concerns, yes, please. So my sense is, and I want to be corrected by retinal colleagues that even though there's still a lot of questions that the general ways of interest is moving where recently people are using VEGF inhibitors rather than lasers. Are we at the point where more than half of these kids are getting treated with VEGF? I'm not sure about that. But yes, there's greater interest. Lubee brought study, mainly in zone one, poster zone two, and the guidelines from the American Academy of Pediatrics and Ophthalmology are to treat zone one or eyes that are near death. But there's been a wave of interest in treating all type one severe ROPs of that zone two as well. And the concerns, as Chris nicely pointed to, are there. So even in the ROP-1 study, which is one of the trials that we're enrolled in, at one-twentieth of the B-prog dose, serum veg up was reduced for over a month in these babies. So the babies are developing. See, the other problem with all the studies that come up is that we tend to look at them and think that premature babies- We don't even know what we don't know for 20 years. Right, well, some of them are from India, some of them are from, and the babies are older developmental age and they're larger. So when they get the same dose of anti-vegF in a larger eye that goes into a larger blood volume, the concentration is much reduced compared to the premature babies that we have in the United States or in countries that really regulate oxygen or have the resources to do that. And in which 22 and 23-week gestational age babies are surviving. So we really can't compare the two, they're apples and oranges. And those babies that are so developmentally immature, there are lots of things going on besides their brain and their lungs that are developing where veg up is important. The coreroid, the photoreceptors, the circuits that develop within the cells within the retina are all developing and they may need veg up signaling. And our lab has shown that when you inhibit, so we figured out what's the optimal dose of anti-vegF. So we used a very representative model in a lab because we can't experiment on babies. And we knocked down, we figured out what cells were expressed in EGF. So Mueller cells do a lot of that. We knocked down the EGF by using a cell specific promoter and a short here pin RNA to the EGF. And so it knocked down the EGF two levels that were in the retina that were the same as a room ear rat of the same developmental age. So we felt that was physiologic. And even when we did that, we had long-term thinning of the outer nuclear layer. So what does that mean long-term? I don't know. We had some neuroprotective factors that were also released. So maybe the retina is able to respond, but the red is full term. So we really have a lot of questions we don't know. I think that what we're getting at now is that we need more than just anti-vegF. We need protective mechanisms. We need to be able to introduce methods that will allow the babies to vascularize or a vascular retina. Have protection against that compromised vascularity within the already developed vessels that occur with high oxygen. And then also allow the baby to develop and mature. And so anyway, that's where our lab is working toward looking at that and some of the recessors that might be useful in that way. Projectly those, as I go around in different places, there's more and more I sense. This is what they're doing. If you want those questions, then answer. They're moving to vegF injections rather than using them. It's so much easier to do an injection. Laser is very, it's hard as a body, you know, of the assertion. Kind of experiment on the progress which is happening in developing countries when anti-vegF treatments became available. A lot of people moved with some disastrous results to doing injections entirely, not knowing that kids would come back with fulmin and RLP. So in a lot of cases, it isn't a decision between anti-vegF and laser is becoming a combination of both where Dr. Hartman's colleagues are treating the posterior fulmin and RLP with anti-vegF. And then instead of worrying about that taking time bomb of having RLP coming back, going ahead and doing laser. So in essence the same eye is getting both treated. Thanks Chris, I think that was a really interesting talk. And kind of to Emmy's point, I just had a quick question. It's not well resolved in the literature at present what physiologic systemic vegF levels are in these preterm infants. So even though most of the studies that are done compare treated babies to babies with RLP with an alternative treatment like laser, maybe those babies have higher systemic vegF levels and that's one hypothesis that's out there and one group out of Japan has shown, in fact that's true, they have a very small sample size of course because it's so difficult to look at these babies but. And Emmy's point as well made that different populations have different age ranges in which we're seeing RLP due to the technologies and ability to administer oxygen, et cetera. But they did show that the treatment with anti-vegF while it did access the systemic circulation, it did not lower systemic vegF below what we were seeing physiologically in babies of similar gestational age. But that's one very small study and I just don't think it's well resolved in the literature. Did you get a sense of that at all in your meeting? I think that was a big point that I thought about was there's no clear resolution anywhere. A lot of big question marks, a lot of, you know, can't pull me in for directions, you know, using their database to back up, you know, the feelings they have, of course, usually, et cetera. Yeah, yeah, thanks. And I will say that RLP, I agree with you Leah, definitely. And in the RLP one study, we also measured veticism in the sample, which that Japanese study made it come as well and it was still elevated, so. The dragon stuff. Yeah, yeah. I don't think that's published very so. Interestingly though, this is becoming standard care across the country. It absolutely is. Writing at Westanger.