5-ALA Fluorescence-Guided Surgery for High-Grade Gliomas

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- Hello, ladies and gentlemen and thank you for joining us for another session of the Virtual Operating Room from the Neurosurgical Atlas. Our guest today is a dear friend, Dr. Costas Hadjipanayis from Mount Sinai Health. He's a professor of neurosurgery there, he's truly a pioneer in research related to fluorescence for high-grade gliomas. And today, he'll be talking to us about the use of 5-ALA. Costas, thanks for being with us, and I'm very much looking forward to hearing about your lecture, please go ahead.

- Thank you, Dr. Cohen-Gadol, really a pleasure to be here today to share with our experience, to discuss 5-ALA fluorescence guided surgery for high-grade gliomas. I do have disclosures. I do have a financial conflict with Gleolan, which is the marketed agent of 5-ALA in this country. I've also received some honoraria from the microscope companies. So today, I'd like to talk about some of the concepts that surround fluorescence guided surgery. And of course, we have to talk about high-grade gliomas. And our current paradigm of extended resection and some of the unmet need for neurosurgeons as we tackle these types of tumors. We will go into some case illustrations, and highlight some of the concepts in terms of timing of fluorescence guided surgery, and introduce some of the newer topics with other visualization devices including exoscopes and handheld devices that have helped us detect fluorescence better. And then move on to a topic that is now progressing quite nicely since the introduction of fluorescence guided surgery, which is photodynamic therapy. So currently, the number of FDA approved agents for high-grade gliomas is quite small as you can see here. Through the years, there's been a limited number of agents that have been approved by the FDA for treatment of high-grade gliomas. We are fortunate in that 2017 and we'll discuss this more. 5-ALA was approved for visualization of malignant tumor tissue during glioma surgery. And there's been some other nice additions to treatment of high-grade gliomas most recently as well with intraoperative brachytherapy, and of course, tumor treatment fields. So the standard of care for high-grade glioma is pretty well established. And I think everyone would agree that maximal safe surgery is really the way to go with these tumors. And when we say maximal safe surgery, the neurosurgeon does the best job at resecting the tumor while preserving patient's neurologic function. And almost always, patients move on to adjuvant therapies with radiation therapy, and chemotherapy, and clinical trials and even at recurrence, which virtually all these tumors go through, surgery is also a main avenue of treatment for these patients in addition to other treatments. We have a number of papers that have been published through the years that have really hammered out how well extended resection can impact regression-free survival, overall survival, and even help with better efficacy with adjuvant therapies. Currently, our paradigm for a high-grade glioma extent of resection is really going after the contrast enhancing portion of tumors. As you can see here in this slide, you can see the peripheral rim enhancing area of a high-grade glioma in the right parietal region. And the goal of surgery is to go after that, and reset that completely if possible. And that's various terms a bit thrown out with that gross total resection, complete resection. But the challenge is that even though we take out that contrast enhancing rim, we know that there's cancer cells that extend past that, and this current paradigm is quite old and I think it's time for us to consider how we can move on from this, because we know that the more cancer cells we take out the better the patient does. But we have to balance that, we have to balance that with preservation of neurologic function and improving patient's neurologic function. And there's been some new studies that have really helped us understand that going past that contrast enhancing border does impact survival, this is a paper that came out of the UCSF Mayo groups, and even the MD Anderson group had shown this before, it was super total resection. There is benefit when we take out more of the tumor past the contrast enhancing border. The question is how do we do that safely in patients and consistently? And I think that's the basis of what we're gonna talk about today with fluorescence guided surgery. If you look at some of these pictures here, these were published decades ago on the left-hand side, just highlighting this biology of high-grade gliomas, really infiltrating into the surrounding brain. We like to say the surrounding normal brain, but that's actually not true because these glioma cells infiltrate the surrounding brain and it's really abnormal brain, but there are normal cells within that area. So the question is, how far can we go safely and make a difference in patients? Here's a view, an exoscope view that really kind of showcases our challenge here. So what we think we see is tumor, which I have labeled here in the darkish brown tissue. The question is where is the surrounding tumor cells in the brain? The subcortical white matter really is difficult to differentiate those tumor cells. So you see this border of the tumor, and then we know that cancer cells are in this area here. So the question is, how do we see those cells in tumor regions and really go after them, but also again, keep in mind the balance of how we can understand also the surrounding tracks that are present in patients when we do our surgery. So you know, there's really an unmet need for inter-operative visualization. After we maximally resect that discolored tissue, we know there's still cancer cells present, and we use our neuro navigation to help us differentiate between tumor and surrounding brain. But the neuronavigation is inaccurate because there's brain shift, distortion, we use other types of technologies, such as intraoperative MRI, and ultrasound, and those also have their own inherent challenges with real time visualization of tumors. The unmet need is really how do we visualize malignant tumors in real time and delineate it from the surrounding tissue and feel confident that what we take is predominantly tumor tissue? And I think all neurosurgeons would appreciate the challenges with brain shift after we resect tumors and making our neural navigation systems inaccurate. And then how do we achieve that safe maximum extent of resection we've been discussing? So the concept of fluorescence guided surgery is one that's been introduced for quite some time, in fact, in the late 1940s, there was a seminal paper that described the use of fluorescence, which was a fluorophore, and still-used fluorophore for ophthalmologic indications, and even in glioma surgery, where that was used to visualize tumors and fast forward, basically 50 years, and in 1998, the first patient with a 5-ALA had been treated and the publication was introduced by Walter Stummer. The concept is the fluorophore is something that accumulates in tumor tissue. And in the case of 5-ALA it's a pro-drug so it actually goes to the tumor and is metabolized and then what you do is you excite that fluorophore with specific wavelength of light, and that excites the fluorophore and as the fluorophore then moves back down to its normal state, it gives off an emits light and that's the light that we see from the fluorophore agent after excitation by light, in the case of 5-ALA the light that's excited is 410 nanometers, and then in the 600 nanometer range, which is violet red, we visualize that area. So it's quite nice for us neurosurgeons who really rely on visualization cues during surgery. The question is, why fluorescence guided surgery for brain tumors? Well, there's no question that we can visualize tumors better with fluorophores, and that's something that, I think has been shown in a number of publications and as experience grows throughout the world, most neurosurgeons feel good about that, and there's really no other way to provide real time image guidance. Even if you have an intraoperative MRI, that's a snap picture in time. You have to get continuous MRI of the tissue to show in real time what's going on, that's just not possible at this point. So you saw the difficulty with brain shift and navigation, and in real time you can actually see exactly what you're doing, and that allows you to kind of push the resection and combining that with other technologies in our toolbox, that allows us to really maximize the resection, but preserve function. The landmark study that really put fluorescence guided surgery on the map was published by Walter Stummer. And this is a landmark multicenter study that was completed in Germany, and published in 2006, and Walter really laid down the foundation for us with fluorescence guided surgery really showing for the first time ever in a randomized study where patients underwent 5-ALA fluorescence guided surgery versus conventional microsurgery, that more complete resections were possible with 5-ALA fluorescence guided surgery, almost a doubling. And of course progression-free survival was significantly better. This was really what set the stage for fluorescence guided surgery throughout the world, including the United States, and there's no question that it's changed how we practice neurosurgery. Now, a couple of caveats to this paper, wasn't powered for overall survival, and then at that time, the stoop regimen wasn't quite standard of care. So there were a lot of different management options of these gliomas that were used, so overall survival probably at that time was difficult to power, but actually when we went back to the data later for the FDA approval, there was a difference in overall survival with 5-ALA fluorescence guided surgery. Just to kind of summarize the concept of fluorescence emission wavelengths, I throw this slide in here from a book chapter a book Walter had put together, and I just want you to understand what we're talking about here. So I've included some of the other fluorophores that have been described in gliomas, and we're not gonna spend much time on those today. We're gonna focus on 5-ALA, fluorescence is one of the fluorophores FDA approved for ophthalmologic indications, however, it is used in glioma surgery, as well, you can see here that its emissions in the 525 nanometer range, 5-ALA 635 and then ICG is a near infrared range and that's in the near for red range of 800 nanometers, and that's invisible to the eye. So going back to 5-ALA fluorescence guided surgery in that prior picture I showed you, you could see as we excite the 5-ALA which is metabolized protoporphyrin in tumor cells, you can see that violet red fluorescence in that area that appeared to be a subcortical white tissue, pretty apparent, pretty obvious, pretty well delineated, as you can see here. This is one of our early videos, we were able to do the first case of glial at Emory, when I was there at Atlanta in 2011, you could see at 12 o'clock, there was some discolored tumor tissue, and again, this is that same picture that I've showed you several times down to the subcortical white matter. And what we do is in the microscope on the handle, we push the button and you can see that now we're shifting over to the blue light, that's used to excite the protoporphyrin which is basically 5-ALA metabolized tumor tissue. And you can see now that there's a readily apparent fluorescence in the cavity surrounding the resection area, where there's visible fluorescence that correlates with tumor. So this is allowing us to directly visualize tumor perform surgery in real time and then we can switch back to the white light and perform the surgery as well. So 5-ALA fluorescence guided surgery is now a well-established adjuvant in our toolbox. And as we just discussed it selectively accumulates in tumor cell, so it's orally administered. It's rapidly absorbed through the GI system into the blood. And when within hours, it's metabolized to its fluorescent metabolite protoporphyrin, and that's what we visualize with excitation with the blue 410 nanometer light. The beauty of this agent is that it's very safe and in fact, really the only toxicities associated with it are skin photosensitivity within the 24 to 48 hour mark and you can have a bump in liver function tests, which will all come back to normal. So that was also something that helped this agent kind of move to the finish line and gain FDA approval in the United States. The other thing that we can discuss briefly is why do tumor cells accumulate protoporphyrin? So the 5-ALA agent is taken up into the tumor cell actually goes to the mitochondria of the cell. And if you look at the heme biosynthesis pathway, protoporphyrin already exists in our body, so it's a metabolite of ALA, which is a natural agent in the body and as part of the heme synthesis pathway and as you look at the pathway here, you could see that there's an enzyme that catalyzes protoporphyrin into heme with the addition of iron. So in glioma cells and cancer cells, this enzyme is lower in the ability to catalyze the conversion of protoporphyrin to heme. So what happens is protoporphyrin accumulates in the cancer cells and hence the selective fluorescence of those cancer cells. The other thing that has been learned is that, less protoporphyrin is exported out of the cancer cell because of this ABCG2 pump and then of course, there's more uptake of 5-ALA to the cancer cell with this tap one or two update mechanism. So another concept that, we can briefly discuss here is, as we look at this fluorescent tissue, we as neurosurgeons want to feel confident that represents tumor because we put our navigation probe on this area and it's outside of the contrast enhancing region. We know that there's brain shift, but are we sure that represents tumor? And the other nice thing about this agent is that it does correlate with really high positive, predictive value that what you see is fluorescent is malignant tumor tissue, and it's highly sensitive and highly specific for delineating tumor. There's been a number of studies that have really hammered this out through the years, really showing high PPV in the high 90s, as well as the sensitivity, the negative predictive value is lower and part of that is, as you move out into the infiltrative margin, the fluorescence signal decreases significantly, even though there's cancer cells present when you look at that tissue under the microscope with histopathology. We were able to complete of US multicenter study, we led it at Mount Sinai, just a study that occurred over a couple of years we're putting all the data together for publication now, but in summary, it was 14 centers. We had 69 patients, and it was a very simple study, we basically biopsy tissue that was fluorescent, sent it for histopathology three to five samples were taken from each patient to really correlate fluorescence with the tumor histology. As confirmed with other studies in this multicenter study with a number of US centers, you could see that the positive predictive value was almost 100%, so that's really a strength of this agent and really helping us feel confident in what we resect is tumor tissue. The other thing that needs to be understood with 5-ALA tumor fluorescence is what we discussed a little bit earlier, so in the tumor ball where the greatest number of cancer cells are, of course, you're gonna have the greatest number of fluorescence. So if you look at this slide here, moving from right to left, the tumor bulk, the tumor core is on the right. You can see it's got a solid red fluorescence, but as we move towards that contrast enhancing border and move past it, that fluorescence becomes more vague, becomes pink or in color. And as you can see here, as we move either further out, you see no fluorescence, but even still there are cancer cells present and that's just the ability to detect florescence at this point, so this is where technology is gonna help us. We're gonna be able to basically kind of get over to this area and really kind of understand how we can visualize fluorescence better and really kind of help with seeing fluorescence better in this area here. And I think that's where some of the handheld technologies are gonna help us as we move along, because we can see the pink fluorescence, and we could see, the tumor bulk florescence quite nicely now. And some of this concept of fluorescence intensity allows us to understand each of the tumor microenvironment. So if you look at the area here where there's necrosis, so really in the center area of the tumor, well fluorescence is really low here, and we don't see it with the microscope well, but then as we get to the tumor bulk and the tumor edge, as you see more fluorescence, and then as we move out, past the contrast and see border that fluorescence becomes a little bit more vague. And then as we move even further out, we can't see that fluorescence anymore. So I think the concept here is, how can we see past that contrast enhancing border? And there's been some work that's confirmed that is 5-ALA tumor florescence does extend past that area of contrast enhancement on MRI scan. So we feel confident that fluorescence is more sensitive at detecting the tumor margin than neuronavigation, of course it's real time, so the concept of brain shift and distortion goes away with 5-ALA tumor fluorescence. So we also have to talk about safety. I think, the agent is safe itself. We talked about some photosensitivity, difficulties and basically some LFTs bumps, but no one has ever died of 5-ALA administration, even patients who have been overdosed by accident when the pharmacy gives too much, the worst thing that can happen is respiratory depression that just gets monitored and patients get better. So that's something that's really promising and helpful with this drug that we use now. Really the most important point is what happens when we use it, so this is where in the landmark randomized study by Walter and our colleagues in Germany really helped us understand that, okay, if you take out more of the tumor with 5-ALA fluorescence guided surgery then, there maybe a transient change in neurologic function so in the phase three study, they looked at NIH stroke scale scores and at six weeks, right after surgery, they found there wasn't a deterioration NIH stroke scale score. But then as you move past six weeks, that all balanced out with the conventional surgery group. So as we push the envelope, we have to balance this as neurosurgeon. I think this is a very important point that when I talk to our residents and others faculty members about 5-ALA fluorescence guided surgery, we can't just go in and take out everything that's fluorescent, we have to balance our approach with our intraoperative tools, such as neuronavigation, in addition to intraoperative monitoring, cortical, subcortical, mapping, phase reversal, all these things that we normally do without fluorescence guided surgery still has to be part of your decision-making on how far to push your resection, and it's not uncommon to leave behind some fluorescent tissue because the cortical spinal tracks are traversing that area, or there's a speech function that's intimately associated with that fluorescent, so the same concepts that we use without fluorescence guided surgery has to apply with our patients, but we can push the envelope safely with this agent if done with the appropriate tools and expertise. There are some false-positive of fluorescence, I think that's been reported and that's been something that's mainly found in the recurrent GBM setting where patients have undergone radiation therapy and chemotherapy there can be some fluorescence of the tumor cavity, but you will not find 5-ALA tissue fluorescence outside of the tumor resection cavity. And that's one of the main difference of this agent in regards to the other fluorescence that are used by others. The others are relying on the blood-brain barrier breakdown. So if you touch the brain with your sucker by accident, that area could fluoresce with fluorescence or ICG, not with 5-ALA, remember 5-ALA has to be metabolized by the tumor cells intracellularly to its fluorescent metabolite protoporphyrin. So it's highly specific for the tumor and its resection cavity area, but there are some cases of positive fluorescence in non-tumor areas within the resection cavity, likely related to reactive astrocytes maybe after radiation therapy or chemotherapy. You can have fluorescence with radiation necrosis, and we know that radiation necrosis usually always has some component of tumor in it examined thoroughly. And then autofluorescence of normal brain tissue is really a rare cause of false positive fluorescence, I don't think I've ever seen that, the ependymal surface of the ventricle is something that we've learned can fluorescence 5-ALA, now there are published reports of subependymal invasion by GBM tumors. And remember these tumors do originate from around the ventricle, so, there is some basis for fluorescence to be dependable surface, but that's one area that I'm very careful with resecting, unless I do have evidence radiographically that the tumor does involve dependable surface. Now false negative fluorescence is something that can be seen and I think the main culprit for that is really taking the patient to the OR too soon, you have to let the 5-ALA agent after being orally administered, get to the tumor, be metabolized well, so you can see it. So don't take a patient to the OR within two hours of administrating the drug, because it's just not gonna be a robust fluorescence, in fact, I wait as long as possible for performing 5-ALA florescence guided surgery, we have adopted a standard practice at Mount Sinai where we wait at least six hours before we actually use the agent. So it's not uncommon to have it as the second case, if we do administer it as a first case, if it's an inpatient, we'll give it at 4:00 AM, that way by the time we get to the tumor, we can really three to 4:00 AM we could really see the agent quite nicely, so there's a sweet spot, I think between the four and eight hour mark where the fluorescence is quite robust. Now the FDA approval label is really 2-4 hours before surgery, so at three hours, you should still see a robust fluorescence of the tumor, but I'd say within two hours, that could change. Some other things to keep in mind is as you do fluorescence guided surgery, blood overline, that the fluorescent tissue can interfere with the fluorescence visualization and certainly the photobleaching phenomenon is a real one if with any fluorophore, if light stays on that area of tissue, the fluorescent signal decays, and that's called photo bleaching. Now, if I may delay that to about 20 minutes or so. So if you're looking at the same area in your resection cavity for 20 minutes, which you're probably not gonna do, then the fluorescent signal could decay. So that means you just have to wipe away that layer of tumor tissue so you could see some new fluorescent tissue. Other concepts to make sure you're aware of is again, as you move out of the resection cavity, the fluorescence becomes less and less because there's less cancer cells fluorescing, so that's where the weak fluorescence becomes a little bit more challenging to see and we're now using other devices such as confocal microscopy spectroscopy to help us push that resection further. So that's something that we can talk about later in the presentation. So let's jump into some case examples. These are all cases of mine, of fluorescence guided surgery with 5-ALA, so this is a 50-year-old right-handed male who presented with progressive headaches and left sided weakness. This is the MRI scan we obtained, you can see this large, right parietal occipital lesion causing significant mass effect and cerebral compression, it's peripheral enhancing, so this is something that's consistent with a high-grade glioma. This is a gentleman who we took to surgery and he was administered 5-ALA 4-5 hours prior. And the dose is 20 milligrams for kilograms and orally administered dose. And he was positioned supine and change the left for right primal, craniotomy or navigation use. We perform cortical, sub-cortical motor mapping during surgery, we did identify the motor pathways anterior to the tumor and we use tractography visualization for all our cases, with the synaptive system, it's quite nice to help with surgical planning and then of course we did the 5-ALA fluorescence guided surgery. So a couple of pearls here that I want to throw in with this case, so the timing of 5-ALA is important. We talked about that's you have to wait at least three hours and the longer you wait, the better, the focal point of the microscope should be about 30 centimeters. You don't want to get too far away because you can imagine as you move further out, the fluorescent signal could change, so you wanna keep it at around the 30 centimeter mark, so you can properly excite the tissue. And then this concept of photobleaching really is not an issue, but it's something that you should just keep in mind as you're doing the surgery. Necrotic regions of tumors do not fluoresce, one thing that I do in our residency we switched between the white light and blue light, we turn our heads away from the microscope because we want our eyes to adjust to each of these new lighting parameters. And that really helps you continue to look at it as it switches over your brain, kind of takes a little bit of time to readjust so just turn your head away, switch to each mode, and then look back and let your brain readjust. As you move past the tumor bulk, the margin is pink. Really do a nice job with hemostasis as you get better and better with fluorescence guided surgery, the ability to perform hemostasis with blue light is much easier to do. With some of the scopes, you can actually see they're not as dark as others when you're doing fluorescence guided surgery so the hemostasis becomes something you could easily do under the fluorescence you don't have to switch back to white light. The other thing that's important to learn as you're building your experience is, how do you wanna perform fluorescence guided surgery? Do you want to do it at the beginning of your resection and see the tumor, or do you want to perform your standard conventional microsurgical resection, and then at the end turn on the blue light and then touch it up and resect what's residual and fluorescent? I'll tell you early in my career, because I was just so excited to use this back in 2011, we had the first idea open for this in a clinical trial. I was really excited to use it at the beginning because I was just mesmerized by the tumor fluorescence and using it throughout the surgery, but now as I do my surgery, because of just timing and efficiency, I'll do my standard microsurgical resection with white light and then at the end, I'll switch on the fluorescence and then really kind of go ahead and touch up my resection cavity with removing residual fluorescence that I feel is safe to remove. So again, I'm gonna keep harping on this. Remember to use your other tools in your basket, to really determine what pathways and preserve your patient's neurologic function. So here's just a video of that case, the tumor extended up to the surface, and you could see here, as we switched to the blue light from the white light, you could see the tumor fluorescing through the peel surface, so this is quite nice. You can see kind of where the tumor is right now directly, and you can feel pretty confident to enter through that peel surface, to do your tumor debulking and begin your surgery. So then as you do your debulking, and we're gonna have more videos where I can help you with this, and you can see here that, as you get to that border, you see a more pink type of fluorescence instead of that violet red and it's a little bit off the center of the screen here, but that tells us that we're pretty good at where we are the resection. And you can see right there that transition between the pink to just the standard blue light of the subcortical white matter and that's in a good spot for stopping with your surgery if you feel that you've done your resection. And of course, this is the post-operative scan. So we talked about this at the beginning of procedure, we wanna take out the current paradigm is the contrast enhancing portion of the tumor, but we know that tumor extends past that area, so we believe that with 5-ALA florescence guided surgery approach, that you'll push past that contrast against the border. Let's go on to a second case, so well we can just talk about this case a little bit briefly, so he actually did go on to get his adjuvant therapies. He developed another recurrence I had to resect and he survived about 2 1/2 years from his first surgery. And unfortunately he passed away recently, so, but just goes to show you, we used 5-ALA twice in this gentleman with his recurrence as well. This is another case of gentlemen with a recurrent GBM. And I wanna show this case because I think, in the recurrent setting, it's quite helpful as well. And part of that is, as we do recurrent GBM cases because of the treatment effect of the surrounding brain, with standard microsurgery, that area is even harder to differentiate from the tumor, and I think this is where 5-ALA really helps out in these recurrent cases where we can get in and resect the tumor. So this is a little bit of a longer video kind of showing the robust florescence you see with 5-ALA and you can see, it's really obvious, there's no misunderstanding here. And again, we know that represents tumor tissue based on the studies that we have shown to you. So of course, we developed a lot of this tumor, but that edge there is still robustly fluorescent. So we know we're not at the edge here, we're still kind of in the tumor bulk. And we can continue with our debulking here and really take it all the way to that pink and no fluorescent zone. So this is a gentleman, who had a large tumor, and I think we resected it appropriately, and he went on to his adjuvant therapies. Now this is just some slides showcasing what we're talking about so that violet red is really tumor bulk and then as we move out towards the edge, we see that pink, and that's really the infiltrative margin of the tumor. This is another case where it was a recurrent GBM, and I don't have the tractography here for you, but the motor pathways were just posterior to this tumor, right on that poster contrast enhancing edge were cortical spinal tracks and we did a fluorescence guided approach for this case. You can see here, she had a large cystic portion of her recurrence as well. And she presented with left sided weakness, and we took her to surgery to resect this recurrence, as you see here, and pretty robustly fluorescent. And again, we're resecting it, we're trying to get to that, pink area and try to push our resection, now this is a case where the patient did worse after surgery. I resected too much tissue, I think that posterior edge where the cortical spinal tracks was very associated with that fluorescent border. So going after that pink tissue in this case was not a good idea because this patient ended up being weaker on the left-hand side and she never regained that function, and again, once someone who comes in with a recurrent tumor who's compromised, and then we take away what function they have on one side, that's really a devastating situation because now you've made their quality of life worse. Now you can argue that they had recurrent GBM and prognosis was poor to begin with, but that's not right because that patient, while she was weak, she was not as weak as she was after surgery. So I think that's an important point that, we have to balance these approaches that our patients and help with making sure that we do the right thing. So as you can see you on the MRI scan looks nice, this patient did have left sided hemiparesis that was pretty profound, so she was never able to walk again after surgery. So 5-ALA is just like any other agent that goes through the FDA process, is something that takes a number of years, and you can see here that, the first study published by Walter was in 1998, and then the randomized study occurred with approval of this agent 2007 in Europe. And then we started the first clinical trial in 2011 and then fast forward all the way to 2017, we were able to get this thing approved with the help of a number of people that really allowed us to take this to our patients in the United States. So it's not a therapeutic, this is really a tool, and I think everyone should understand that it's really another tool in our toolbox for a high-grade glioma surgery. And these are just some slides that I threw in here with the FDA process, how we kind of attack things with visualization of tumor tissue, maximum extent of resection and really patient outcomes that helps us get it through the finish line with the FDA. And there's just a number of people that helped us with this, with industry, with family support, with our neurosurgeons in the US that really allowed us to get this work. And so, what's the update with 5-ALA, so it's still the only approved agent for real-time visualization of high-grade gliomas in the US. At this point, since the fall, 621 neurosurgeons have been trained to use it. 177 centers in the US have added gleolan to their formulary and worldwide usage exceeds 80,000 cases, so that's pretty amazing. And it looks like based on what the company NX Development has provided me in these slides then that in the US about 50% of high-grade glioma cases are undergoing 5-ALA fluorescence guided surgery. There's an ICD-10 code that was approved in October of this past fall that you can now use for billing purposes that incorporates 5-ALA fluorescence guided surgery, and I think, the other thing just to note, there's just other tumor types coming in line with 5-ALA including meningiomas, I think there's a phase three study that's being performed at pediatrics, we're gonna get into that too. But of course there's still challenges, I think adoption of fluorescence guided surgery by neurosurgeons is still something that hasn't occurred in a lot of places, I think you still need hardware modification, either a new operative microscope, which is a capital purchase in this day and age, especially the COVID crisis is very difficult or modifying your scope. You have to get it on your formulary, so of course that requires some time, and the cost of gleolan is not insignificant, $2,500 per vial in some patients who are over 75 kilograms require two vials, so this is something that is not an adopted by everyone yet, but I think the technology and again, the tool that this has become is quite helpful for us, and of course, there's always other technologies that are present and the timing of the surgery could disrupt your schedule, and since we have to give it hours before surgery. Here's an older slide, I have this data from 2019, but you can see that fluorescence guided surgery in terms of publication, peer review publications has really exploded since 1998 I think now we're probably over 400 publications now in early 2021, and it's just something that's really kind of taken off. So if you look at what it's approved for, it's approved for all high-grade gliomas, as you can see here, and currently being investigated for meningiomas, ependymomas, subependymomas, hemangioblastomas of course, low grade gliomas. And we also can use this for stereotactic biopsies for detection of high-grade gliomas. CNS lymphomas light-up quite nicely with 5-ALA. I'm putting some other slides in here, we'll kind of go through here quickly, but combining 5-ALA imaging has been quite nice and Walter has provided this study with FET-PET, which I think is agent that's used more prominently in Europe. And I think here, the concept of using 5-ALA in low-grade gliomas and George Benham in the Austrian group has really helped us understand how in low-grade gliomas, there's foci of anaplasia or malignant gliomas and both the Austrian group and the Munster group, the Walter group have shown us that they have regions of malignancy in that can be detected with 5-ALA. So about 30% of presumed low-grade gliomas actually are high-grade gliomas because they have both sides fluorescence present, this has been studied with histopathologic studies. This is a video just showcasing a CP angle meningioma from my Austrian colleague highlighting how meningiomas light up as well, and it's interesting because most meningiomas are not malignant, but they robustly fluoresce, which, again needs to be studied better. So up to 94% of meningiomas can fluoresce after 5-ALA administration and there's now studies looking at whether the dural tail, surrounding bone with fluorescence correlates with tumor tissue. So stay tuned, I think this is going to be a probably another indication that may also be provided with 5-ALA fluorescence guided surgery. PEET is another area that we've been trying to jump started pushing this country, I think pediatric brain tumors really are in need of this extent of resection does impact survival, even more profoundly in the pediatric population. So high-grade gliomas in children can fluoresce, of course other types of tumors can fluoresce. So this is something that we're hoping can be initiated in this country, there are other studies that are looking at fluorescence guided surgery in pediatric population with fluorophores as well. And then of course there are other cancers, this is ovarian cancer with peritoneal mets. You can see fluorescence of the metastases present. So the timing of 5-ALA fluorescence guided surgery is something that we've been looking at more closely, and Walter and his team have showed us that, actually the peak fluorescence may actually occur after six hours, more than the 7-8 hour range originally when it was described in rodents, the peak fluorescence was found up to six hours. But I think now we're all learning with our experience, anecdotally that the fluorescence can occur for quite some time, so I think more and more centers may move to wait a little bit longer, we certainly are at Mount Sinai, and this is a case that as part of our multicenter study, you could see at Henry Ford, the patient was dosed, and then they had to wait 24 hours to do fluorescence guided surgery because the patient had developed a transient fever, but you can still see that the tumor was fluorescent a day later and the patient underwent successful removal of her high-grade glioma. Exoscope, we currently use a microscope for visualization of our fluorescence with binoculars using conventional lens microscopy but I think the exoscope is now taking it off, and I routinely use that during my surgery, not for the fluorescence guided surgery portion, but for the tumor debulking, and part of it is because of the longer working distance and the panoramic view, I think positioning of the device is actually nice and not your head so I have less neck and back pain after surgery which is important. And the other thing I like is that my team is engaged with the heads up display during surgery. And you can see here with that panoramic view with the exoscope it sees these cars on the side much nicely and it gives you a better overall view of my opinion that also can be a higher definition and more magnified. This is a case where we use the exoscope version of the microscope to really do the fluorescence guided surgery, so this is having the scope above the patient. And we're looking at a heads up display and doing the fluorescence guided resection, so it works just as well and I think, this is something you'll see more and more coming out I think in the near future, there's some other companies with microscopes, exoscopes that can allow a fluorescence visualization. So this is something that I believe will take off more and more moving forward. And there's this also this ability to overlay the fluorescence image on a conventional microscope view. So that's called multispectral imaging and the group in Germany by Dr. Charalampaki, she has published this recently where she can overlay the fluorescence, which is actually green in this case on the actual white light view with the microscope. So you can imagine that's quite helpful in operating in real time and not having to switch to the blue light mode where hemostasis may be a little bit more difficult and operating really on standard microsurgical white light conditions with fluorescence overlay may allow for further resection, these are all tricks of digital imaging that that's gonna push the envelope of microscopy, that's a whole another talk. We can have here where we could talk about the visualization devices and digital microscopy. But I think this is really where we're heading to now is the ability to overlay images that we can help view things better, delineate things better and push our surgeries even further. And that takes us to this concept where we now have handheld devices being developed, where we can kind of use and visualize the resection cavity in tandem with the microscope to really detect any other types of fluorescent residual areas of tumor tissue to help us resect the tumor tissue. And this is a device that has been used in patients, and it's even superior to the microscope and that's what we want, we want to use the microscope to debulk and then bring in our handheld device to do our touch-up and resect what we can safely. This is something we described years ago, five years now with a spectroscopic device, really detecting things, orders of magnitude better than the microscope. So this is real, this is real and I think the microscope companies are all trying to figure out a way to bring this to you, so stay tuned. And we can also use this for low grade gliomas, the UCSF and the Austrian Vienna group have showed this to us as well, we can see protoporphyrin visualization in low-grade gliomas, again combining it with imaging important, and we're not gonna spend too much time here, but this is something we describe with whole-brain MR spectroscopy. And then of course, FET-PET can allow you to push things visualize things by imaging and then combine that with florescence really provides even better abilities to resect tumors. IMRI and 5-ALA now there's been some studies come out, which has really helped us understand how each of these can play and I think, this meta analysis that was recently published, I think it was kind of need to show that they're both superior to neuronavigation, but between each of them, there's really no clear decision, which one's better, so I think you could take the standpoint that if you have iMRI and certainly using 5-ALA, I don't think you would be able to do anything better, but if you don't have iMRI, at least for high-grade gliomas, I think, there could be an argument that you're good to go with just 5-ALA fluorescence guided surgery. So this is a story that continues to evolve, and it will be interesting to see where that goes. Combining fluoro force is another area where this may happen as well, where we give fluorescein and give 5-ALA is a little bit more specific and sensitive for the tumor but fluorescein may allow us to highlight the region of the tumor and that may help us see that you're better, so that may occur with other fluorophores as well. So lastly, I think, I just want to kind of close it out here. So we've talked about intraoperative fluorescence guided surgery and how that's now one of the approved FDA tools for our use and now is standard of care, well the next concept within this, can we then perform photodynamic therapy in our patients? So what does that mean? So we're dosing our patient for fluorescence guided surgery and we're resecting the tumor and we have a cavity afterwards, but we know that there's cancer cells that extend past that resection cavity. Well, the concept here is, well, if you apply a laser light at 635 nanometers, you can actually excite that protoporphyrin metabolite of 5-ALA and you can actually kill the cancer cell. So this may be the next evolution here is not only are we using 5-ALA imaging agent in the operating room, but we're also using it potentially as a therapeutic agent. So you can see here and this type of schema, that it would be kind of a double edged sword, one for visualization during fluorescence guided surgery, and two at the end with laser activation of the protoporphyrin in residual cancer cells and killing of the cancer cells. So this is something that's actually being done, there was a phase one study by the French group at the University of Lille that completed this, and they had published the initiation of the surgery at in 2018, and now their phase one results are under review. And this is such an interesting study where they've put a balloon cavity in the resection cavity and then apply to laser light to the resection cavity. And I have a small video that they had provided me to showcase this, I want you to see that really kind of highlights this concept. So that laser light in the resection cavity and a balloon is then kept on for about 30 minutes. So the concept here is we're now using PDT to kill the cancer cells after maximal resection with FGS. So I'm going to summarize everything here and, thank you for allowing me to share our experience with FGS. I think we can all agree that new intraoperative visualization technologies are essential for glioma surgery. 5-ALA is the only FDA approved optical imaging agent for glioma surgery and really provides real-time imaging guidance that delineates the tumor with high accuracy and is not affected by brain shift. There are a number of applications we discussed that are being used with 5-ALA fluorescence guided surgery. There are a number of new technologies and visualization devices that were studying, and then lastly is PDT, the next chapter for 5-ALA? We'll see, does it allow for better patient outcomes in the treatment of glioblastoma or other high-grades? We'll find out. So I just wanna acknowledge my team and just other centers that were involved, I think, this is always important to acknowledge your partners, you can't do these things without help from your surrounding family team members. Thank you very much, thank you to Neurosurgical Atlas.

- Thank you so much Costas a beautiful lecture, really illuminating obviously fluorescence guided resection of high-grade gliomas is an effective method to maximize resection. I wanna play a devil's advocate here and bring up some thoughts and get your feedback. You discussed that the survival, extension of survival in these studies is somewhat difficult to prove. High-grade glioma is such an infiltrative disease that we are throwing as much technology as we can at it, but it's really a disease that will be cured via laboratory, not the operating room. And so we through navigation, fluorescence guided resection, intraoperative MRI, and we'll still have not made a significant impingement in extension of survival. Can you tell me what your thoughts about that? How can we somehow make a effort to be able to extend survival?

- Yeah, that's a reasonable question, I think, we've made a difference in extent of resection with survival. Now, the point that you made which is valid is that it's not a long extension, I think we've changed things by months, but I think, as with any difficult cancer, there's going to be a multifaceted approach. So there's not gonna be one silver bullet that takes it down, I think we're gonna have to continue on with our clinical trials and look at experimental therapies. And I think there's gonna be a combination approach, but I do think that 5-ALA fluorescence guided surgery is here to stay to help us really clean up the bulk and what we can in a maximal way, because we do know that other therapies work better when there's less cancer cells present, so surgeries is the first step. Aaron, I think that's the point you made, and I agree with you completely, but we wanna make sure the surgery is done quite well. So that's where we can hopefully try to standardize that approach and make sure everybody gets the best resection up front, and then they can go on the other treatments that they need to treat their tumor.

- I think that's an excellent answer that we have to remove as much tumor and then let the other therapies that are hopefully are coming, be able to improve significant progression-free survival. The other question I have for you is that you saw that the meningiomas enhanced very intensively for the 5-ALA, how sure are we that in fact, the 5-ALA is really in fluorescing the enhancing parts because there is no blood-brain barrier versus the fact that it's really enhancing the tumor. I know the tumor and enhancing part are somewhat equal but remember there is a blood-brain barrier and any fluorescent agent you give eventually will be able to enhance the enhancing part of the tumor where the blood-brain barrier is broken. I know there are studies that show the agent gets into the cell, but in reality, how much of this enhancement is related to broken blood-brain barrier, just you see like in meningiomas otherwise it wouldn't make sense why even meningiomas are enhancing so intensively with 5-ALA.

- Yeah, great question. I think it's a combination of both, but one of the things that is being teased out is if you look at the dural tail and you look at high prosodic bone, those are two areas that in our literature have confirmed there's tumor present, when you take those parts of the tumor out and you look at the fluorescence, it doesn't exactly correlate sometimes with tumor presence. So I think that's what needs to be studied better to really nail the fact that I think meningiomas, the bulk of meningiomas almost all fluorescence, I don't think anyone's ever going to argue that, but I think the interest that I'm concerned about and want to see a little bit better is whether recurrent meningiomas who've had radiation on other treatments, can we see those edges of those tumors, a budding the superior sagittal sinus, or other venous structures to help us resect those recurrent tumors, and I think that's what needs to be studied. I don't think anyone's gonna debate that the actual tumor bulk itself is gonna fluoresce. So I think that's what some of these clinical trials are trying to tease out those regions of the tumor that probably are gonna be the ones that are most helpful for us as neurosurgeons.

- Fair enough. I think 5-ALA is definitely a very specific agent. I think it's an excellent method, I personally have been using fluorescein as you know, the reason I've been doing that because it's my cheaper, a vial is almost $5. Obviously you still have to have the yellow 560, which is about $50,000 on your microscope, and there is no time limitations, in other words, you just do it at the time of intubation and you'll get a pretty good enhancement. Obviously there is some questions if fluorescein is as specific as 5-ALA because fluorescein really works based on fluorescein contrast enhancement, rather than really getting into the cells, that's number one, number two, I think there is a phenomenon of what we call peritumoral contamination that personally, I believe both 5-ALA and flourescine suffer from. In other words, there is going based on timing of your resection. There is going to be some of the 5-ALA, or just fluorescin that leak out and stain the edge of the tumor, and that's why we were doing tumor reset contrast enhancement resection plus, which is not a bad thing, in fact, that could improve the outcome, but I think that's something that people who use it should know that's gray zone, that barely pink area is that truly contrast enhancement or is that just a peritumoral area that's still to be discussed or discovered? What are your thoughts about those statements Costas?

- Yeah, Aaron I think with fluorescein, there's no question, you see it in the papers and you yourself I'm sure you could vouch for this. If you touch the brain and you perturb the brain, that area is gonna light up the fluorescein, it's just the way the agent works, it works because of the blood-brain barrier, but I am pretty confident, based on our experience and others, that is a limited effect with 5-ALA, We don't see that because remember you have to have a metabolize in the tumor cell now, could it leak out into the surrounding tissue? Well, it could, but that effect, again, is very limited and that's why I think it has, in my opinion, I feel more confident going after that pink border, because I know that it's correlating with tumor tissue and we've done studies with that where, for example, that area was biopsied and then it was looked at with histopathology, but also the spectroscopic signal was calculated. So if you look at the signals as you move out towards the periphery, and then you look at the histopathology, it correlates really well. You see less and less tumor cells, but you see less and less fluorescence. So I feel pretty good when I go after that pink border in an area that's non eloquent. I'm pretty confident that that's tumor. And as I mentioned before, I may leave that behind an area where there's function right next to that pink tissue.

- Yeah, I have to see that if you're doing a lot of high-grade glioma surgery, you should use some sort of fluorescence. The problem is really that it doesn't matter which fluorescence you believe in, you gotta use something as you know, when you remove the tumor, the necrotic part on the yellow light is relatively easy. The proliferative and the enhancing part can quite often look like peritumoral area especially under white light, especially after you have removed the tumor and the cavity collapses in those folds, those sort of areas within the folds of the tumor are very difficult to see. And that's where the tumor is very often left in. And people say, okay, technically, I'm so good, I can do this, it doesn't matter how good you are with a microscope, the white light and a sizable glioma, you're gonna leave some enhancement on the post-operative MRI. I have to say that before I started using fluorescin, no matter how much I tried you do the MRI, the day after surgery, and you see these streaks of enhancement you see nodule hiding in that little corner, and you sort of convince yourself, well, maybe that's not tumor, that's just sort of blood, even though it's not on T1 and say, okay, that was a good resection, well, this patient is gonna have a poor outcome anyway, so the goal is just debulking. I think we need to step out of that philosophy that a nihilistic approach to high-grade glioma surgery that well, we're just doing debulking and radiation will take care of this. I think if we're doing surgery, we're really need to do a good job, I think that's just something that's been proven in many studies and just the idea of, well, I did the best I could, and this is before surgery, you believe you have to do this surgery and it's very important, but after the postoperative comes back, you see well, this is something radiation is gonna take care of. Well, this change of hearts before and after surgery may not be the best approach in my opinion. So I do believe fluorescence is important, I do believe that you have to use it specially for those folds, those sort of folds that of the resection walls that don't let you see those small nodules, I remove the tumor under white light, and then I turn on fluorescence and find out, look how much I missed within those foals of the resection cavity. So I do believe no matter what you believe in, use of the fluorescence for high-grade glioma surgery is really effective, it's also important when you removing the tumors, especially these low-grade gliomas that may have focal of the differentiation. If you're just biopsying the low-grade glioma, you really can underestimate the grade of the tumor. And fluorescence provides you with really a life saving methodology to biopsy the highest grade of the tumor and provides your patient with best outcome by biopsying the fluorescent area, rather than the non fluorescent area, which would not be a differentiated under white flight. And then last, I think application is use of it during biopsy. We have done ster-tachy biopsy and we take this specimen and put it under microscope before we send it pathology and if it's fluorescing really actively, you're good, you can close and they can make a diagnosis. So it really gives you an ability not to wait 40, 50 minutes for them to tell you have specimen, you can just get out as quickly as possible, what are your thoughts about those last two applications, Costas?

- I think that the really important applications, the biopsy one has been shown in a number of great papers, led by the Europeans where the time for the use of a frozen during surgery is obviated, so, that could take 45 minutes in some centers. Our centers is about that, 40 minutes, so I don't wait for a frozen diagnosis anymore, we'll be doing more of these biopsies and all you need to do is you administer the 5-ALA to your patient and then just have the microscope in the operating room. And as you take the needle out, just put it under the blue light, you'll see the red fluorescence, the violet red fluorescence, so as Dr. Cohen-Gadol, mentioned that's diagnostic, so you could just take your samples, close up and leave. You don't need to wait for pathology to give you that diagnosis, so I think that's something and I think others are exploring. Definitely the diagnosis of anaplastic areas is within what we think are low-grades is important, and I've seen that, I've seen that, actually seen those in the non-enhancing tumors, where we come to a patch of the fluorescence and we sample it and it's a grade three or even a grade four, so I think that helps us again, in understanding the biology and proper sampling of the tumor tissue, so we can get a diagnosis. And lastly, your point that you start out with is the point that I continue to debate this day, it's always a little bit as a neurosurgeon annoying when someone says, oh you know what, these patients are gonna die, don't worry about it, just do debulk and let the radiation and chemotherapy do the rest, but I firmly believe that we need to resect as much of this tissue that we safely can, because I do believe that there are treatments further on are more effective, and I see that every time the patients, who've had really good resections, I believe they do better down the line, so.

- I agree with you completely, Costas, I wanna really thank you for what you have done as truly a pioneer and a big advocate of fluorescence guided high-grade glioma resection and truly respect your career, I've been following it very closely as you know, and I'm truly honored to have you as a colleague of mine. So I wish you a great happy New Year for you and your family, and we look forward to having you with as a guest in the future.

- That's right, thank you so much, Aaron, that was great. Thank you so much.

- You're welcome, thank you.

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