Grand Rounds-Fluorescence Guided Resection of High-Grade Glioma: New Developments

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- Welcome. My name is Aaron Coleman. I would like to thank all of you guys, both from the United States and overseas for joining us this evening. Fluorescent technologies have becoming more and more popular in recent years in the neurosurgeons armamentarium, more specifically Fluorescein, ICG and 5ALA have become some of the three more common fluorophores that we use. Fluorescence is going to be a big part of neurosurgery, in my opinion. I'm as strong, enthusiastic and I really believe that literally, literally, the future is going to glow under the operating room microscope. For this importance, I thought we'll start a series of web conferences and having a discussion regarding technologies that drive the fluorescent science or fluorescent science and how we can do better. I would like to start with my disclosures. The first one is that this is a talk that will include an off-label use of sodium fluorescein What this means is that you can use sodium fluorescein for the purpose of brain tumors or vascular cases, as we'll talk about, you will not require an IRB if it's not for research, however, is an off-label use. What's the agenda for this evening? The first part of the talk would be a brief review of current intraoperative fluorescent technologies for brain tumors. We're going to talk about advantages and disadvantages of Fluorescein and 5-ALA an ICG. And we're going to talk about a new filter from a Zeiss Meditec that will allow us to use Sodium Fluorescein. It's the filter is called Yellow560, and it's integrated within the microscope. And just like Blue400, It gives you an ability to detect Fluorescein at low levels and therefore be able to highlight or stain the tumor or the blood flow within in the vessels. After that, we're going to go ahead and review some case presentations. It's nothing more, really important than watching the video and how this works firsthand. At the end, we're going to discuss all the vascular applications of Fluorescein and why it could be better or worse. And how could it, in other words, compliment ICG. And most importantly, you guys are going to have a chance to comment, ask your questions through the phone bridge that we designed on the announcement. Please note that through your computers, you won't be able to comment unfortunately, because of the way this platform is set up. I don't have to spend too much time. Why is it important to maximize resection of gliomas? First of all, we're talking about high grade gliomas, they are 80% of primary malignant brain tumors, they are one of the most common causes of deaths among our patients, among brain tumor patients. Therefore, this is an important topic. And we do know that extent of GM GBMs resection or a high glioma, high grade glioma resection is a primary determinant of a longer survival and therefore whatever technology that would help us safely, resect more tumor, We should be able to help the patient more. So the fluorescence technology is really one way to advance the care of our patients by allowing us to remove more tumor. So why, what is important in surgery? What are we having trouble? And what are the shortcomings of microscope by itself, without the fluorescence technology? Number one, GBMs can be very similar to normal brain and can be difficult to be completely resected. They could feel different. They look different under white lights on a microscope. And most importantly, even for very experienced surgeons, you can actually miss the tails of the tumor within the folds of the resection cavity. If you could think of a resection cavity when you remove the tumor in the middle, the whole cavity collapses and those little folds within the, within the resection cavity where those tumor cells are sort of hiding, that can be very difficult to remove them. Most often, you do a post-op MRI and say, you know what? I wish I could have just removed a little bit more tumor. Intraoperative MRIs technology has been helpful. However, it's very expensive, time consuming, and in my opinion, lengthens the surgery really too much. Therefore there should be a better way to maximize tumor resection. And that's what we're talking about. You see, so let's see how we can help our patients. Now, what do we do today to maximize tumor resection? The microscope magnifies, it illuminates. We have image guidance that facilitates the margins. As you can see here using the, using the MRI that has been on our stuff, our navigation. We use the tumor discoloration, tumor consistency, color fluorescence is a recent technology. And I think is a significant addition. So what has happened in the past five to 10 years is introduction of 5-aminolevulinic acid, which is extremely helpful in my opinion, 5-ALA. It is now exogenously administered within two, three hours of surgery intravenously, within the tumor cells. It is concentrating the form of Protoporphyrin nine. That is a fluorescent under the blue 400 lights. We're not going to talk about emission and excitation, take a physics here. And so it's, it's very helpful. The problem is that it's not FDA approved by, by FDA, and therefore it's use is very difficult. There is many regulatory barriers to use 5-ALA. So I think it's really just the right time for us to find another flourphore that has been out there for many years, but find another filter, where we can advance our imaging modality, intraoperatively. And that's why I personally tackle the idea of Fluorescein. So 5-ALA, as you can see in this image causes this beautiful pinkish reddish fluorescent emission signal under a blue 400 camera, and the camera is attached, not a filter, it's a camera. And therefore you can see the background is very dark. So it's very difficult to conduct surgery. It's not impossible under blue400 light, but it's, it's, you have to sort of switch between the blue400 and white to lights to see the tumor, and remove more, and then see how much left again under Blue400. Because you have to switch so much, it's a problem. And you will see that their new filter technology has circumvented some of that problem solving. Although blue 400 does not allow you to comfortably operate under, under the excitation light, the yellow five 60, which has it's emission light within the, visible to magnetic spectrum, would allow you to do surgery because the background field is almost in natural colors. And we've been on, we're going to show some of the pictures to, again, tell you more about that. So what about 5-ALA? There has been some spectacular trials done by some of my great colleagues, Dr. Dave Roberts, and some of the folks in Europe, and we, we know that this system helps. Unfortunately, the overall survival did not differ between the groups in these big studies of more than 300 patients. And part of that is the stereotaxis was not used in these trials. And some of the surgeons who participated, used different methods, but what we determined that although tumor resection, no doubt improved, the overall survival of the patients at six months, did not differ between those patients who underwent the fluorescence guided resection versus those who underwent a regular resections using stereotaxis. So what are the limitation of 5-ALA here? And most important it's not FDA approved. There is some subjective fluorescence at the margins and that's related to the optics of the fluorescence, because if you don't excite the margins because their light can't get there because normal brain is overhanging those margins. You're not going to get a good excitation, so you're not going to get a good emission light, and therefore it can be prone to subjectivity to see what's a tumor and what's not, under the fluorescent mode. And there is, you know, occasional, false positive, false negatives. And that's very important. There is photobleaching. And the patients after 5-ALA administration have to be for about 24 to 48 hours in dark light. So it can be uncomfortable for some patients to stay under dark light. What are the histopathological accuracy of 5-ALA? It's pretty good. In other words, if you take a biopsy of a tumor under microscope and it says it's highly fluorescent, and if you send it to the lab and have them look at it, is it really all tumor or was it just a false fluorescent tissue? And you will see that ultimately the results are pretty good. It's about sensitivity of 0.98 or positive predictive value of 0.98 and decreased to 0.76 at the margins where the signal was vague. And so there have been more new technologies to determine, to determine the quantitative methods that could measure protoporphyrin fluorescent levels, rather than a black and white. This is highly fluorescent or not, to be able to help with determining if this is tumorous or not. So what are the other flourphores we have explored as surgeons? ICG has been effective. However, as you can see in this entropic video, I used it on a hemangioblastoma in the posterior fossa, right there. And as you can see, the tumor lights up pretty well under the ICG and these again this is the nodule on MRI. This is intraoperatively under white light. This is under the Ziess 800 module. This is, this is a good tumor for ICG because it's very vascular. However, gliomas don't really readily uptake ICG. And therefore this is not a great technology for using it in the case of glio tumors. So what are the current needs? And we're going to talk more about that during our conference, for a better fluorescent technology? Number one, we need something more accessible. We can't just be inundated with paperwork from FDA in terms of being able to 5-ALA. And we would like to have more specific flourophores. We want to have something that really nicely binds to the surface receptors of glioma cells and sparing everything else. And it's very black and white. So the surgeon doesn't have to have a subjective decision-making process. And we want to have a module that the surgeon can see the normal brain in a regular colors. So you can continue operating and not necessarily switch between the white light module to the fluorescent module. And we want to be able to see the fluorescent signal through the oculars. We don't want to be operating white light and see the tumors do the tumor surgery, but look over an overhead monitor just like in ICG, because the initial signal is that within the infrared spectrum and therefore is not visible to the human eye. And ultimately more sensitive quantitative fluorescent technologies are necessary. So knowing how many short shortcomings we have, we decided with the help of Zeiss Meditech, to try the yellow 560. 560 is really an emission signal that the filter detects. And we wanted to see how sodium Fluorescein could be affected. There is going to be critics for this approach. Number one is, sodium Fluorescein has been allowed for a long time. For 60 years, we have injected in tumors and we know it makes the tumors fluorescent, but there is a lot of extravasation within the tumors. So how can we fix that? Well, maybe using an image intensifier like, Yellow 560 through a filter could help. Some of our Japanese colleagues have used that, but it set up within the operating room has been very cumbersome and having a microscope integrated module would be very helpful. So, sodium Fluorescein is readily available. It's very safe. It's been used in ophthalmology for 60 years. However, it has been used in neurosurgery and most of it's used for brain tumors and high-grade gliomas has been using very high doses, almost 12 one to two grams per person. And when you use such high doses, the tumor will definitely fluoresce and get stained under natural light, unaided vision. However, there's a lot of externalization as you're removing the tumor, the brain cortex that is injured by coagulation also starts leaking because you break the blood brain barrier. So what we were set to do is use Sodium Fluorescein which is very common, and we don't have to go through a number of regulatory barriers and find a way to detect a glioma cells better. And it is, fluoresce is within the visible spectrum. And what does Fluorescein do? And I want to be very clear tonight with, with explaining my rationale behind using this, this dye. Fluorescein, as far as we know, we are at this time conducting research in the lab, is not being actively, concentrated within real live cells. However, it is a very nice marker of contrast enhancement. In other words, anywhere in the brain, if you had a blood-brain barrier breakdown, Fluorescein is a small molecule and would cross, and it would stay within the interstitial space. So I want to tell you, based on this discussion, I personally use Sodium Fluorescein under this filter as a marker of contrast enhancement, and not necessarily as a marker for glioma cells. But we know in surgery, our goal is to remove the contrast enhancing area. More importantly, what the advantages that this provides is that, not only you can remove gliomas, but metastasis, anything that enhances, you can remove using this technology, but if you don't do the timing, right, don't do the dose right, which is really the point of concentration tonight, you will have leakage and you will not be very happy. So if you want to use this technology, you have to be very careful about timing and the dose, and be a little bit conscientious about how to perform your surgery, but it really provides you a nice way to resect tumor under almost normal background appearance of the brain and the normal parts. So we're gonna, we have been using Yellow 560. It comes only under Pantero 900 and not on the classic Pantero. What is the efficacy of Fluorescein? See there has been studies performed that shows that if you use high dose of Fluorescein, in about 20 patients, in about 33 questions this was performed on, as you can see here, and the sodium Fluorescein at the dose of 20 milligram per kilogram. So really high dose. The doses we're going to talk to you about tonight is three to milligram. All the studies have been performed has been five to six times higher, and that's why you're going to have some externalization. And the ocular field is not very clean. So knowing that the studies recently have been using such a high dose, there's still been no statistically significant increased survival. So knowing that result, which was very similar to 5-ALA, and as you can see, their positive and negative predictive value are very similar to what 5-ALA can provide us today. This is how I started originally. This is one of our first cases. You can see we used about seven to 10 milligram of Fluorescein per kilogram. And you can see, if there are any small area of the brain that was even slightly injured during craniotomy. The Fluorescein really comes out at you, under the yellow 560. But look how beautiful. You can see the brain almost in natural colors, which means you can carry out most of the operation under a white light. But one point that I want to emphasize here, number one, this is a right side, right temporal lobe, right frontal lobe. The black suture is demonstrating the borders of the tumor. Here, also please note, we injected the dye about 15 minutes before. We found out what all the studies have done so far were not really accurate in terms of the timing. If you injected five to 10 minutes before, which is at dural opening, you still gonna have a lot of high concentration of Fluorescein in the blood. And when you coagulate the margins of cortex to remove your tumor, those parts of the cortex that you have injured become highlighted with Fluorescein because you broke the blind blood brain barrier. And that's what you can see here. You can see at the margins, some of the brain, normal brain was fluorescing, and it wasn't ideal because you really want to have a very specific dye. So what have we done so far? This is our initial study results, or please note that this is probably the most important slide of the night. We did about 10 to 15 patients and did different dosings. Started at 21 to 15 milligram per kilogram and injected at different times. Obviously all of these other IRB approval, and found out to this date, where the last 10 patients haven't performed. Again, this is the most important part. We use 250 to 300 milligram of Sodium Fluorescein about one hour to one and a half hours before tumor resection. 250 for thinner patients, 300 milligram for more heavyset patients. And we do it when the patient enters the operating room, right at induction. So we don't wait until we're opening the dura to inject the Fluorescein. What that does, we found out, that it allows the Fluorescein to be cleared within the blood, but still concentrated enough within the tumor and not cleared enough from the tumor. So you, you lose good fluorescence or fluorescent signal within the tumor. So please remember when the patient enters the operating room, gets the 300 milligrams of Fluorescein intravenously. We go ahead and open the craniotomy, usually takes us about an hour, an hour and a half. By the time patient is intubated, positioned, craniotomy performed. If you do it less than an hour, you're going to see some extravasation because still a lot of Fluorescein in the blood and the kidneys haven't had a chance to clear that Fluorescein within your blood. Within the blood of the patient, I apologize. So we found that nine out of 10 tumors that we have done based on this protocol remain intensively, stained, as consistent by neuro navigation data. Their fluorescence was not detectable by an unaided eye. This is a very low dose we're using. Most importantly, in one patient and non dis- A non neo-plastic inflammatory lesion that did not enhance alerted us, even though the pathologist suspected a tumor, we stopped, sent more specimen. Now, fluorescence was more accurate than the actually pathology frozen section, to determine if this is a high grade glioma or not. So this can be a very effective technology. We sent 50 histopathological sections, randomly at tumor margins where florescence was vague. So this is where I really pushed this specificity and accessibility of fluorescence using Sodium Fluorescein. And we found that in 42 sections, the degree of florescence corresponded correctly to the amount of tumor within that specimen that was sent to the pathologist. In other words, I named every specimen at the margin that was vague, minor fluorescence, major florescence, or moderate fluorescence. We'd had all those reviewed by our pathologist and they measured it, how much tumor was within that section. And we determined that ultimately the specificity, or in other words, their positive predictive value was 90%. And the negative predictive value was in 5%. So if something is major fluorescence, 90% of the time you have some tumor in there. So it is pretty much what ALA is providing for you, but it's easier to do. So what are the limitations? Is that due to a small molecule, there is a very slight amount of extravasation, but it's very minimal. And we would like to minimize that. And we'll see the new technology using amino Fluorescein making the Fluorescein a bigger molecule, so it doesn't extravasate as much. Ultimately I think the future would be ligans of Fluorescein which fluoresces within the visible spectrum. So you can use the high def technology or what the filter does in terms of making the background almost natural colors, with another molecule, like folate, that has very high degree of receptors for folate on a glioma cells. I think that's the best combination and we would love to see those happening. So what are the conclusions before we go to our videos? That low dose of Fluorescein for us was very helpful and I've had some of my colleagues use it and they have really found it very effective. Our post operative MRIs have undoubtedly being more clean then compared to the ones before the fluorescent era. And I really believe it does improve extent of resection and obviously more studies are necessary. So let's go ahead and talk about our case presentations. I'm going to start with the first video, as you will see here. And one of my colleagues will make the video larger for you as it comes about. And within the first video this is a very basic case. Before we go into my more complex cases. A 30 year old female, with this recurrent enhancing tumor, as you can see right here. And the patient had an oligodendroglioma removed about five years ago, returned with this in a recurrent de deficiency of the tumor. We use mapping under sleep conditions, and here's the tumor. It's pretty obvious. And in this case you probably don't need fluorescence, but I want to just show you as the first video, how accurately this corresponds to the tumor you saw in the white light. It's pretty impressive. You can see the dura, doesn't have a blood brain barrier, and therefore it does fluoresce. And this patient had the administrational Fluorescein about an hour and a half before. And as you can see I use the bipolar and none of the normal brain is fluorescing and the blood does not fluoresce either. So it's a pretty nice way of resecting this tumor. But that tumor wasn't really very difficult to remove anyways. So let's talk about cases where florescence can be effective, like deeper tumor where folds of the resection cavity fall down. And really the tails of the tumors are difficult to, to detect. Let's review one of my patient's cases, 52 year old male with a visual dysfunction. This is a classic left occipital GBM, obviously a trance occipital approach for this section of this mass. This is a post-operative MRI. Before we go to the video. And just to answer Dido's question, this presentation will be available afterwards, tomorrow for all of you guys. I'll send a link for everyone would like to watch this video and this recording afterwards. So continuing with our presentation, you can see the postoperative MRI shoes me a nice, clear resection. What I have realized previously, that I often miss a little tail of the tumor here. You can see that little cavity, and I'm going to go back and show up that pre-op MRI. You can see that little tail going to the ventricle or little, this enhancement in that sort of corner. I often miss that in this very difficult to, to resect those. And that's where really the essence of fluorescence technology is and where it shines in terms of helping us. So let's go ahead and review the video here of this patient. This is, again, you can see this one. We did the crayon a little bit too fast, and dura is enhancing a little more, more than I want. But when we go to the brain, you will see that the tumor is very distinctly stained. So here is doing a small chordectomy. This is in the right occipital lobe. As you can see the tumor really brightly shines. It's very hard to miss it and the surrounding vessels are not fluorescent at all. And we'll go ahead and continue sort of resecting this tumor. I'm going to also show some of the pictures of the stealth on the right upper quadrant. You can see that under white light, the tumor didn't look very different at its capsule. And here it is their margins between the tumor and the normal brain. So much to appreciate that differentiation that we all look for. Please note that the necrosis does not pick up fluorescence. So as much as, as surgeons we removed tumor that looks abnormal under white light. We may be using, only removing tissue necrotic because that looks very different under white light. The contrast enhancing area could look very similar to the normal brain. And that's the part which is the active part of the tumor. And that's the point that it has to be clearly removed. Again, you can see the clear margin of fluorescence versus normal brain and the necrotic tissue at the heart of the tumor is not being stained. So here is you can see how everything is nicely, and this is the upper pole of the tumor. And you can see here, it corresponds to the upper pole of the tumor on, on that neuronavigation. Momentarily, we're going to go at the depth of the tumor and you'll see how that tail that I talked to you about corresponds very nicely to neuronavigation data. So if you guys have any questions, please go ahead and chat your questions as the video is running. And some of you guys want to see the findings of the fluorescence signal on the microscope, with your, sort of own eyes. I can answer some of the questions now for you guys. Again, here is we are going deeper within the tumor, and we're going to see that tail on the right upper quadrant, under stealth coming up shortly, corresponding directly to the deep tail of the tumor. You can see the blood is not stained with fluorescent. The amount of externalization is very minimal, the dura does enhance with fluorescence as we talked about. Guido is asking how many of the yellow 560s? Here we go, and what I was talking about, about the tail of the tumor at the end, and how you can follow it very carefully. I've done about 50 cases using yellow 560s, either for vascular cases or brain tumors combined. Here's the tumor coming out. And you can see a little bit of residual tumor at the end of the resection cavity that is being removed and you can see the bed looks very clean. Here is again the postoperative MRI. Let's talk about a 51 year old male with subtle speech difficulty. Here is the tumor before surgery. Here is the tumor after surgery, really very clean margins. That has been essentially every GBM case since we have started using the fluorescent technology, I have not had any problem unless the functional cortex limited me in terms of achieving the goal to resection. So let's talk about other ways we can use fluorescence by using Sodium Fluorescein. 78 year old male with confusion, presented with this GBM extending into the ventricle. Older patient. The [inaudible] score is not very high. Probably don't want to resect it, you want to biopsy it. So if we're doing a biopsy, how can Sodium Fluorescein help us? Well, here's what we have used here. We inject the same amount of 300 milligram and we do the biopsy, but we take a picture of the tissue, the biopsy core under the yellow 560 camera. If the tissue is highly florescence, that's diagnostic tissue. If it's not fluorescence, you don't have diagnostic tissue. And here is this piece of, actually biopsy was performed right here, not in the tumor. And as you can see, it is not fluorescent. This tissue right here, however, was obtained within that contrast in ancile area. And as you can see, it's highly fluorescent. So one way you can use this technology is if you don't want to wait for your pathologist and you know what, I have a fluorescent tissue, it's diagnostic. We haven't come to the point of abandoning our pathologist for the frozen section for our biopsies. However, we have an ongoing study to minimize the waiting time for our pathologist. And as we get a fluorescent core of tissue, we proceed and close, and therefore minimize the amount of time that, that we have to wait for the pathologist. Ian from Mayo Clinic is asking "What are the microscope requirements and what is your source of sodium flouricine?" Excellent question. I will be, I will send that to you, where we get that. But there's really only one form that I know in the hospital, which is the sort of fluorescent dye the ophthalmologist use. The microscope requirements, I will leave that to Guido for you to comment. It's a Panterro 900. It's the new generation of the classic Panterro, which is HD. That gives you the opportunity to have both ICG and yellow 560. You cannot add, as far as I know, yellow 560 to the classic Panterro. So here's another case, a 67 year old female with a nodular enhancement on a previously known tumor. It was non-enhancing. She did not want to have surgery. This is pre-op. You have, you can see this is very small nodule of the tumor and you really want to get that piece, but in surgery using technology of neuronavigation, it can be really difficult to find the small nodule. So we went in surgery, we removed this using sleep mapping, and let's go to the video and see how you can use the fluorescent technology to remove that very tiny piece of enhancing area that maybe otherwise not possible. So here it is, this video from that patient. This is a right frontal lobe, right temporal lobe. You can see they are tumor margins and you see under fluorescence, we looked for that little nodule to see where it is. And here it is, you can find that sort of fluorescent signal, which was a really very obvious on, under white light. And that's important because you want to give the patient the most accurate diagnosis rather than just, sort of biopsy the whole tumor, especially in tumors that undergo the differentiation and only a very small nodule is enhancing. And finding that under neuro navigation can be a very difficult. So I'm going to close this presentation with one vascular application. I'm primarily a vascular neurosurgeon. I do tumors for fun. Obviously it's not fun for the patient, but I, I find vascular neurosurgery one of my most important passions, my most important passions. And so we have used Fluorescein for many of our vascular cases. It has certain advantages over ICG because it's HD, it's a better quality image. However, you cannot repeat Fluorescein and geography unless you wait about 45 minutes. ICG, you have only weighed about 15 to 20 minutes. Also the dose we use for aneurysm cases or ABMS is 75 milligrams versus 300 milligram. And we inject it right just like ICG, at the time that we want to see that flow within the vessels and make sure the aneurysms arbitrated or flow within the ABM is excluded. So I use the Fluorescein and yellow 560 for deep aneurisms where I can not just get enough light. And the ICG looks very grainy. We have had a number of surgeons who have been complaining that ICG at very deep holes, where there's not enough lights can be grainy and you will not be able to see everything. Also, the important thing about this, is that you can manipulate the vessels under yellow 560 because the background is almost normal colors. Under ICG you have to ask someone else to look at the overheads and monitors to tell you what things look like as you're manipulating the vessels and looking around the aneurysm to make sure the perforators are intact. So let's, let's look at one of vascular application of this case. This is a 51 year old female with an unruptured, 15 millimeter, right M1 aneurysm, which was very fusiform and very challenging case. Here is exposed at surgery. Right temporal lobe, right frontal lobe. This down on M1. We had to do trap the aneurysm, suck the blood within the aneurysm, using it suctioned to being attached to that 25 gauge needle. Ultimately, a very compressed reconstruction at M 1. Here, as you can see beautifully on a very high magnification, you can see Fluorescein but the ICG just looks grainy at such a high magnification. And that's because of the physics. And we called what we call chromatic aberration, related to bandwidth of ICG which is within infrared spectrum of the visible light. So saying all of this, I think the future is bright. The future is glowing. I'm excited, and I would love to see more applications or more of you guys comment on how we can improve our ability. And I want to, again, thank all of you guys for joining us this evening, and I appreciate your comments. Thank you.

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