Hello, everyone. I'd like to welcome you to yet another episode of the of the front row series of the of the NeuroU. Again, the NeuroU is the official online educational website of the AANS. And the front row series is a brand new event with renowned experts from around the world in multiple topics. Today's topic is going to be focusing on tumor. And participants have access to both live and archived events with offerings of CME. And for the first time, we have a chance for participants to submit cases for expert discussion. Today we have two experts that really need no introduction. Dr. Fostas Hajibanais is a professor of neurosurgery and site chair at Mount Sinai Beth Israel in New York. And he's really been a pioneer in the field of 5ALAM fluorescent guided surgery. He's going to speak to us today about his experience and the applications for high-grade gliomas. And also, Dr. Khezon Chachana has been a long friend. He's rapidly climbed up the ranks as currently professor of neurosurgery and the department of neurosurgery at the Mayo Clinic. Khezon has done a lot of work in the field of minimally invasive and paraspicular approaches for deep-seated brain tumors. So we're very excited to hear his experience and wisdom on that. So we'll hold all questions for a little bit later. And we may present a case if we have a little bit of time as well. So without further ado, I'll ask Fostas to share his screen. And we're looking forward to your presentation. Okay. Thank you, Dr. Zanonos. And thank you, Dr. Chachana. Great to be with you tonight. And I want to thank the WNS as well for giving us the opportunity to present. So I'm going to share with you our experience on the use of 5-ALA fluorescence-guided surgery, mainly focusing on high-grade gliomas. I do have a financial conflict with 5-ALA, as you see here. And then the other consulting relationships I have do not have any relationship have any relationship to this talk. So I'd like to talk a little bit about high-grade gliomas in terms of extent of resection and really the unmet need for visualization of high-grade gliomas. We'll introduce the topic of 5-ALA fluorescence-guided surgery, discuss a case example, and dive into some of the nuances with fluorescence-guided surgery in terms of timing, visualization devices, and then wrap it up with the concept of photodynamic therapy with 5-ALA. Currently, there are really only six drugs and two devices approved by the FDA for high-grade gliomas. It's quite remarkable over, you know, 40 to 50 years history. As you can see here, Temadar was approved in 1999 for recurrent anaplastic astrocytomas that are newly diagnosed in 2005, and that's really stood the test of time in terms of standard of care treatment with fractionated radiation therapy. There are some other treatments that have been approved more recently, including tumor treatment fields, and then Gametals, which is an intracavitary brachytherapy for recurrent tumors. 5-ALA was approved in 2016, not as a therapeutic, but as a diagnostic, and we'll get to that. So this slide kind of summarizes the current standard of care. We operate on these tumors whenever possible and want to perform a safe maximal resection, and then we follow those patients with treatment with fractionated radiation therapy and concurrent adjuvant temozolomide treatment. There are the other studies we talked about that include tumor treatment fields that are now being used more commonly in patients, and then at recurrence, we take those patients back to surgery if possible, or we initiate Avastin treatment or re-irradiate those patients. We do know that in most cases that a maximal resection and greater extent of resection is really associated with longer progression-free survival and also correlates with overall survival, and then those patients can also go on to chemoradiation with better efficacy, and this has been shown in a number of studies. Our current paradigm really rests on the idea of resecting the contrast-enhancing portion of tumors, as you see here, but we know that that's just not enough with these infiltrative high-grade gliomas. The tumors extend past the contrast-enhancing border. As you can see here, there are tumor cells that go into centimeters past that contrast-enhancing border, and that really becomes quite challenging with these tumors, and how do we visualize those areas better in our patients and perform a super maximal resection for these tumors that do have highly infiltrated portions to them? This is a view that we can see with high magnification, no fluorescence, just the actual tumor, and you can see the discoloration of the tumor and then the surrounding subcortical white matter, but the reality is that the cancer cells extend past this area of the tumor margin into the surrounding brain, and these are the areas that are just hard to see during our surgery for these types of tumors. We use all sorts of technology in each of our institutions, including ultrasound and interoperative MRI. We even routinely use neuronavigation at most, if not all, our centers, and the problem with navigation is that as we resect the tumor, that navigation becomes less and less accurate with brain shift, and as you can see here in this tumor here, the navigation probe is pointing to an area that looks like it's outside the contrast-enhancing border, but that's just not the case here, but certainly visualization of the tumor beyond the bulk of the tumor is one of our challenges and really represents our main unmet need for surgeons in terms of glioma resection, and the question is how do we delineate the tumor from surrounding tissue? How can we confidently resect tumor tissue in these regions and know that we're not hurting our patient and understand how the pathways surrounding these areas can be delineated and understood better, and how can we solve this complication of brain shift so that we can maximally resect the tumor? Fluorescence-guided surgery is something that's been around for quite some time. Actually, Dr. Moore in 1948 first described the use of fluorescein fluorescence-guided surgery, and it was really just visualizing the fluorescence in the tumor at that time. Fast forward now 50 years to 1998, and that was really the first time where fluorescence-guided surgery was actually utilized during surgery for resection of tumors, and the concept really relies on the use of fluorophores that accumulate within tumor tissue, and then exciting that fluorophore with the specific wavelength of light that then allows us to see the emitted light and delineate the tumor from the surrounding brain. We know that with fluorescence-guided surgery, it provides us real-time image guidance, so the concept of neuronavigation then fades away when you have an agent that allows you to visualize the tumor directly, and then you don't worry about brain shift and all the limitations of neuronavigation, which is built on preoperative MRI, or even with intraoperative MRI where you update that neuronavigation still isn't exactly real-time, so this could permit potentially more maximal resection and safer resections ultimately in our patient. For 5-ALE at least, we can't talk about fluorescence-guided surgery without talking about Walter Stumer's landmark randomized phase three study, which was really the sole study looking at randomization between fluorescence-guided surgery and conventional microsurgery with standard light, and in that study that was now published quite some time now ago in Lancet Oncology, you could see the doubling of the complete resection rate in the fluorescence-guided surgery group, and then of course progression-free survival was increased in that 5-ALE group. That study was limited though, however, because it was not powered for overall survival, and there's some other things that just weren't consistent between treatment groups in terms of neuronavigation, and then most patients at that time did not undergo temozolomic chemotherapy. You may have heard of other fluorescent-guided surgery agents that have been used. We talked about fluorescein that was introduced in the late 40s, and then of course 5-ALE is the one we're talking about today, but fluorescein is really visualized within the standard white light spectrum, and 5-ALE is in the 635 nanometer light range, and then ICG is another one that's been recently reported on, and that's in the near infrared spectrum that's invisible to the human eye. We're going to focus on 5-ALE today, but there are other fluorophores that are used now in high-grade gliomas. Going back to that same patient I showed you before, you can see that when we turn on the blue light, this patient had 5-ALE administered two to four hours before surgery, and you can see that the tissue fluoresces within that subcortical area that was felt to represent just normal surrounding brain. So this is a real finding, and it accumulates within the cells. It's rapidly absorbed within the GI system within one hour and gets to the tumor cells, and the beauty of 5-ALE is it itself does not fluoresce. It's actually the metabolite of 5-ALE within cells, protoporphyrin 9. That's actually what we see with fluorescence. This is that same patient. This was in 2011. I can't believe it. 10 years ago. This is one of our first patients we had with my IND with glialand, and that was, you know, the first year. That was the year we did the first glialand patient in the United States with my IND at Emory, and this is just the cavity you can see here, and we're just pushing the button on the microscope and switching over to the blue light, and you can see in real time the fluorescence. I apologize the video is older. We have, you know, high def video now, but, you know, you can see that that violet red tissue is guiding my surgery in real time, and I can see residual tumor that I'm confidently able to go and resect and remove. That provides my real-time image guidance, and with the button switch, we go back to the white light and continue on with hemostasis and resection of the tumor. It's an amazing agent, actually, that we are fortuitous to have developed in neurosurgery. It selectively accumulates within tumor cells. It's excited in the 400, early 400 nanometer wavelength, and the other strength of this agent is that it's essentially non-toxic. In about 10 to 15 percent of patients, they can develop photosensitivity of bright white lights, especially UV light from the sun. It exposes their skin, and most patients, we take them out of bright white lights, and it's never an issue, and it's really just a sunburn, and that's it. You know, no one's ever died of a 5-ALA overdose, and the liver metabolism, while it can bump the LFTs, they essentially all go back to normal within weeks of the administration, and this is just some of the pathways that we've learned are involved with accumulation of the protoporphyrin 9 in tumor cells, as you can see here, but the enzyme that's really involved with the accumulation of 5-ALA is really furrochelatase, and what happens is the furrochelatase in glioma cells is less, so protoporphyrin 9 backs up, and that's why we see visualization of protoporphyrin 9 in those tissues. Now, skin can accumulate protoporphyrin 9. The bone marrow can accumulate protoporphyrin 9, and these are some of the organs that we see, and then, of course, there's some difficulties with pumping out of protoporphyrin 9 in gliomas with some of these different pump transporters. So, I just want to briefly touch on some of the diagnostic accuracy of fluorescence visualization in tissues, and really, the 5-ALA demonstrates unprecedented high positive predictive value and sensitivity for delineating tumor, and a number of biopsy-driven studies have just shown positive predictive value in the high 90s, and this is something that's just really been able to be reproduced in a number of studies. Sensitivity is quite high as well. The negative predictive value has not been as high or the specificity in studies, and part of that is the biology of the disease, and we'll get to that. We were able to complete the first U.S. prospective multicenter study through Mount Sinai, New York City. We had a total of 14 centers, and again, just showing that the high diagnostic accuracy of biopsying these tumors that were fluorescent and correlating the histopathology. Now, this is now in press in JNS. You'll soon see it, but our sensitivity and positive predictive value were in the high 90s, so this is just another study to contribute to the literature, just again confirming the diagnostic accuracy of 5-ALA in high-grade gliomas. Some of the other concepts that I want the group to understand is the different fluorescence visualization in each of the tumor microenvironments, so the tumor bulk itself is the more robustly fluorescent area, and then as you move past to the contrast-enhancing border, you can see that that fluorescence becomes pink and less robust in contrast, and then as you move past that, it becomes less and less fluorescence, and you lose that fluorescence. Well, we know that through studies, Dave Roberts and others have shown us that the contrast-enhancing border of high-grade gliomas, the fluorescence extends past that area in biopsy-driven studies, so that's really interesting to understand is that fluorescence is more sensitive at detecting the tumor margin than the contrast-enhancing border of neuronavigation. And, you know, safety is something that's well established. We talked about that. The more important concept to discuss briefly is the neurologic deficits after 5-ALA fluorescence guided surgery, and in Walter's landmark phase 3 study, you can see as you moved out past six weeks that the deficits really balanced out between the ALA group and the white light group. There's no question that in this randomized study and then other studies that deficits seem to be higher at first in the fluorescence guided surgery, which makes sense because resections can be more radical in the fluorescence group in comparison to the white light group, but it seems like those balance out in most of the studies out there. There are some 5-ALA false positive fluorescence that is found, and that usually is found within the vicinity of viable tumor cells and in areas that underwent radiation treatment. That's really where that has been described. Otherwise, you don't ever see distant false positive fluorescence in 5-ALA in patients, and false negative fluorescence is also reported, and that can be a timing issue if you take a patient to the OR too quickly after surgery and not wait at least the three hours or so. We do know that the longer we wait now, the better the fluorescence is, and I'll show you some of that data in the next few slides. Blood covering the area of fluorescence is another area that you may want to pay attention to, or overhanging tissue, but in high-grade gliomas, over 98 or 99 percent of those tumors fluoresce, especially the glioblastoma patient population. Now, the WHO grade 3 non-enhancing tumors, there is some controversy there in terms of fluorescence and how high that fluorescence rate is, but for the contrast-enhancing tumors, especially the glioblastoma tumors, the fluorescence rate is in the high 90s. This is a case of a 50-year-old gentleman I just want to present to the group. I want to be respectful of time for a case or presentation, but this is a patient who had this right-sided parietal occipital high-grade glioma. You can see there's vasogenic edema. There's a necrotic portion of the tumor. We administered the 5-ALA four to five hours prior to surgery. We actually wait at least five hours at Mount Sinai to give 5-ALA, and the dose that's administered is 20 milligrams per kilogram. We did perform cortical and subcortical motor mapping for this tumor, and I recommend that you continue to do that for all your cases. There's no reason why you shouldn't, even with 5-ALA, really map out eloquent pathways. So, you know, a couple pearls with this case. You know, the focal point for the microscope is about 30 centimeters. The concept of photobleaching is one that, you know, if you look at the same area for 10 to 15 minutes to 20 minutes, then you could have some photobleaching, but that's really a rare circumstance. You're always kind of working. You're wiping away tumor tissue, and new tumor tissues explode, so that's not really an issue. Necrosis does not fluoresce well. It can be weakly fluorescent. The margin is pink, as we talked about. Hemostasis is important because that can cover some of the fluorescent areas of tumor. When you switch from the blue light to the white light or white light to blue light, turn your head away a little bit so your eyes can adjust. That's just something I've learned from doing these surgeries that it's helpful. And then the question is, do you want to perform fluorescence-guided surgery at the beginning of your resection, or do you want to do your maximal white light resection first and then switch on the blue light afterwards? And I've adopted this approach now where I kind of turn on the blue light after I've performed a maximal white light resection and kind of touch up the resection, but when I first did my fluorescence-guided surgeries back in 2011, I did perform that at the beginning. So that's something that you'll kind of evolve in your practice as you move forward. And then just remember, there's other tools that you still need during your surgery so you can preserve neurologic function. This is just a visualization of the tumor before we actually do the resection. You can see the fluorescence beneath the peel surface. It's quite nice, and that's that robust violet-red color. And then the other concept that we talked about is as you move it through the resection, you get to the margin, you get to this more pink color tissue, and then you're wiping that tissue away, and then you're seeing less and less fluorescence. And it doesn't mean that there's no tumor still there, and that's why the negative predictive value and specificity are lower than the positive predictive value and then the sensitivity. It's just that we can't see it with the microscope. Our current tools just don't allow us to visualize that fluorescence in that patient. So this is the resection you get, and of course, you want to make sure you don't violate the patient's cortical spinal tract and subcortical pathways because maximal resection with 5LA can still lead to hemiparesis and hemiplegia if you go too far. This slide I like showing just really reveals how long things took to get approval of 5LA in the United States. We were fortunate to be able to lead that with our European partners, but you can see that Walter did his first study in 1998, and then in 2006, he published his randomized phase 3 study, and then EMA approved it in 2007. It took us 10 years to get FDA approval, and there was a lot of heartache and strife that occurred in that 10 years with multiple FDA beatings, but we took that on, and we bore those challenges, but thankfully, we were able to get it to the finish line and really get the FDA approval for glialin as an optical imaging agent for suspected grade 3 or 4 gliomas during surgery. Much of that was built off the visualization and diagnostic accuracy of 5LA correlating fluorescent tumor with histopathology at a very high PPV and sensitivity rate. Then, of course, the extent of resection and the progression-free survival with the landmark phase 3 study was really the icing on the cake, but adopting a diagnostic approach was really the way to get it to the finish line, and it took a lot of players here to get the FDA approval of glialin in the United States, including industry partners, as you see here, and our academic partners, and even private practice partners, as well as patients. So just a quick update. There is an ICD-10 code for Gliolan, where this can be rolled up into a DRG and third-party payers. This is something that will be expanded, and there will be a CPT code at some point for fluorescence-guided surgery. I know the companies are working on this. Other things to know, there's programmatic expansion into other types of tumors. You heard about meningiomas. There's currently a phase three study going on, and then breast cancer, ovarian cancer, and then we are in the process of getting a pediatric study up and running. With any new technology, there's always some challenges, and you can see here that the adoption of fluorescence-guided surgery is occurring quite nicely in the United States, and other countries, but you do have to get a microscope modified, or purchase a new one, so that's a new capital purchase. Formulary addition, the cost of Gliolan is $2,500 per vial, which is not cheap, but the ICD-10 code is helping with that. Timing can disrupt flow of surgery, since you have to wait two to four hours before surgery, and then, of course, there's competition with other technologies. So those are some of the challenges that surgeons in this country are facing. This just summarizes some of the indications of 5-LA for what it's approved for, and what's it being investigated for. Low-grade gliomas, where there's non-enhancement, which we think are low-grade, are actually high-grade gliomas in about 30% of these cases. So this is another case where I have explored the use of 5-LA in these non-enhancing tumors, and see if I can find some patchy enhancement that could designate anaplastic foci, where I could sample that and diagnose the patient with a high-grade. Meningiomas are being looked at in this country, as well as globally, with a clinical trial. You can see 90% of meningiomas fluoresce with 5-LA, which is amazing, since it's a non-malignant tumor in most cases. The pediatric story, stay tuned for that one. We're trying to get a study off the ground for that, so we can better understand what tumors fluoresce. Other cancers, ovarian cancer, we can see here metastases in the peritoneum. After 5-LA administration, there's an ovarian cancer that's coming to fruition. So the timing of 5-LA fluorescence-guided surgery is something that we're studying and others, and we believe that the longer you wait, the better it is. And Walter confirmed that as well early on in a publication two years ago. And he's actually changed his ways with this as well. This is a case where 24 hours prior, surgery was performed 24 hours after 5-LA administration. We published a paper on this in a series of 16 patients where 5-LA was administered four hours or more prior to surgery. Other types of technology enhancement with fluorescence-guided surgery with overlay of white light is really nice. Stay tuned for these adjustments on the microscopes. Handheld devices, there's just a nice introduction of multiple different handheld devices that you'll soon see. And for better detection of protoporphyrin-9 within and around tumors. And that's something that others have done, including us. And you'd be surprised at how sensitive these handheld devices are at picking up protoporphyrin-9 even in the low-grade population. So this is out of the UCSF group by George Vidhelm and as well as the Dartmouth group. MRI is another area that's being looked at with 5-LA. You can see that 5-LA stands up, stands with MRI, really shoulder to shoulder in terms of the ability to resect tumors. So I'm just gonna close it out here just by talking about the next evolution of fluorescence-guided surgery and how I think it's gonna blend in with the next area called photodynamic therapy. And you can see here that visualization of 5-LA with the approval is going on quite well. But now there's an area called photodynamic therapy which has been around quite a long time where we're now combining the use of an intraoperative laser after a patient's gone through FGS to actually treat the tumor cavity. And the French were the first to really showcase this in a phase one study with placement of a balloon after resection of a tumor, as you see here. And I just wanna show you this video in the OR where Nicholas Rains is a neurosurgeon at the University of Lille placing a cavity balloon in a resected tumor after 5-LA fluorescence-guided surgery and doing the photodynamic therapy of the cavity. So this was just published this year. I was able to help with that paper. And please read that because I think that's the next frontier. So in summary, there's no question that new intraoperative visualization technologies are essential for glioma surgery. I think 5-LA is just a wonderful agent that we have available to us. It's the only FDA approved agent for glioma surgery and provides real-time guidance and delineates the tumor with high accuracy and is not affected by brain shift. There's a number of applications and tumors that we're using it for. And I told you some that are in development currently and there's new visualization devices coming down the pipeline. So stay tuned for that. And then finally, I think that we are gonna be branching into the therapeutic arm of 5-LA and you'll see that and you will now see it with the phase one study that has just been published. So I just wanna thank everybody, there are centers that were involved with the multi-center study, my laboratory members and then of course my partners and colleagues and of course industry partners that we couldn't have done this without their support. So thank you very much. Dr. Argebeni, this was to the force of all the data related to that and really exciting to hear that this specificity is moving into the therapeutic arena. I've been using 5-LA since I started essentially and we didn't really use it much during training. It's really changed the way I practice in operating these tumors. It's really fascinating that you can trust it. The specificity is even more important than the sensitivity in many ways. And do you think this currently should be a standard of care? I mean, there's so much data in a way if it's available, that's something that if it's available, it should be used. Yeah, great. Yeah, did you want me to respond to that or do you? Yeah, go ahead and we can go over some other questions later. Yeah, I think so that's a great point. I do think that it's an established tool that is safe and I think it does help in surgery. And when we see that fluorescence, as we do more and more cases, we are confident that what we resect is tumor and that's very important, right? And I don't know if we could say that definitively with some of the other fluorophores that we see out there because we know that 5-LA is metabolized in the cancer cell. So we know that it's in the tumor cell. So that's quite helpful when we do our surgeries. Kayseran, do you want to share your screen? Yep, I can share it right here. Let me stop sharing and Kayseran, you jump on. Okay, sorry. Okay. Perfect, you want me to just go ahead and get started? Yeah, please. Okay, perfect. So I'll be talking about minimally invasive paraphysicular surgery, also called MIPS for deep-seated brain tumors. I want to thank everyone for the invite, especially you, George. Disclosures-wise, I'm a course lecturer for NICO. Otherwise, I have no other conflicting disclosures. So the subcortical space is really the issue we're talking about for minimally invasive for paraphysicular surgery. So it's the area of the brain below the cortical surface. So it doesn't really involve the cortex. It's tumors that go below the cortex, doesn't involve the cortex directly. The structures in this area include the central semiovalley, intraventricular space, the basal ganglia, thalamus, and deep nuclei lesions, as well as several white matter tracts. Access to deep lesions often requires transgressing uninvolved cortical white matter structures. Traditional techniques can cause significant morbidity, and there's advances that allow access and visualization to these deep-seated brain tumors. So the traditional approach to these subcortical brain tumors were some images that you see here. This is a paper by Spetzler and colleagues that shows really for an aneurysm, but a similar concept. For what you do is you do a large craniotomy. You place deflated retractors to retract the skin or the brachium edges, as well as the white matter tracts to access the deep area. You have to spread a little bit wider for deeper areas just so you can get the light down there and visualization. So sometimes that requires one brain ribbon, sometimes two brain ribbons, sometimes four brain ribbons. There's potential sources of injury with this approach. So the exposed brain can be injured. The retractor blades themselves can cause a lot of injury, either through sheer forces on the white matter tracts or pressure changes on the surrounding parenchyma. There's also white matter dissection that takes place during this that causes injury. When you go in and out of the resection cavity, it can also cause injury where your suction catches some white matter tracts or some cortex with repetitive entry into the resection cavity. Tissue creep, what that means is the tissues on the side, as you can see in the bottom left image, they go into the cavity and you can tag those structures causing injury. And then this is required to create a corridor just so you can visualize what you're doing. So there's several critical cortical areas and white matter tracts that are important. As we're specializing in brain mapping, we're finding out that more and more of the brain is more important. It's just a matter of what you're looking for and how you can test it to determine what areas do what. Common things that are known to be critical are your language areas, which are your brofas and your Wernicke's area, your primary somatosensory and motor areas, your primary visual cortex, your basal ganglia and your thalamus. White matter tracts, you have your projection fibers, which are the areas that connect your higher brain areas, your lower brain areas, to your cortical spinal tracts and your optic radiations. Your commissural fibers, which connects the hemispheres, mainly your corpus callosum, as well as your anterior serocommissures. And then your association fibers, which are the ones that we have been regressing and not knowing some of the injuries that we're causing until we do a lot of neuropsych testing before and after these are your SLF and AF, which are your superior longitudinal fasciculus and your arterial fasciculus, your inferior longitudinal fasciculus, your IFOP for your inferior frontal occipital fasciculus, your uncement fasciculus and your frontal assign tract, to name a few. And these are not only important on the dominant hemisphere or the left hemisphere, but also important on the right side as well. And they each have different functions and damaging these structures can cause significant morbidity. And so minimally invasive paraphasicular surgery, or MIPS, is really minimally disruptive. So it just doesn't mean it's a small opening. It just means you make your skin incision, your bone and dural opening can be small, but the key is to minimally disrupt overlying cortex and surrounding white matter tracts. You want to do trans-sulco as opposed to trans-gyro if you can help it. So the trans-sulco approach goes through the sulcus. And what that does is avoids, minimizes the amount of gray matter that you transgress and also puts different types of white matter tracts at risk. When you're going through the sulcus, you usually engage the U fibers, which connects adjacent gyri as opposed to projection association tracts, which connect adjacent lobes. Trans-gyro approach can sometimes be used, but you engage more of the projection fibers and the association fibers. So paraphasicular means by going parallel to the white matter tracts or the fascicles, what it does is it minimizes tension and shear forces on the cortex and white matter tracts. So there are a variety of different tubular retractors that allow this to happen. So the advantage of a tubular retractor is it creates 360 degrees of equivalent retractive forces on the white matter tracts and minimize shear injury. So you have your peel-away catheters, which is ideal for endoscopic intraventricular surgery that you see here with an opening around eight millimeters, use smaller openings, but depends on your working channel endoscope or what type of device you use. You have oval-shaped retractors, which you see here, and they can come in variety of sizes, the typical one being 17 millimeters in diameter. And then you have the circular-shaped retractor, which you can see here. For a size comparison, the diameter of a dime is around 18 millimeters. They've done several cadaveric studies that show that the white matter tracts really can take some shear forces, but only really up to about 15 to 16 millimeters before they start shearing. So the problems working through these tubes is that you have to visualize what you're working with. So there's a variety of different visualization tools. You have your endoscopes, such as the one that you use to repeal a weight catheter. In the top left image is a working channel endoscope. So it's a camera that you put through the tube and you have different channels that you can put in one by one to help perform the surgery as to what you want to do, whether that's cauterization, grasping, or aspirating or biting the certain lesion that you're going after. Microscopes can also visualize down these tubes. For the smaller tubes, it's very hard to get the light down there. And then nowadays there's exoscopes, which hover over the field and they provide an ergonomic advantage where you can look straight ahead at a screen. They also have more magnification than a microscope because it depends on your screen size. So the larger the screen you have, the better your visualization. And it also gets out of the way. So if you're trying to work at non-orthogonal distances or non-perpendicular distances, you can also look straight ahead and still have visualization of your cavity. There are a variety of surgical adjuncts that helps in this MIPS approach. You have high quality MRI, especially with DTIs to look at the white matter tracks. Intraoperative navigation is obviously key when you're working down at these deeper depths. Intraoperative monitoring, that includes cortical and subcortical mapping. You have ultrasound, so you can assess how much you've resected and the post-operative complications, such as a hematoma. You can also use fluorescence, as just was mentioned as well, and as well as brain mapping. So MIPS approach for deep-seated high-grade gliomas. Here's a case example. So this is a 54-year-old male presented with right-sided weakness, or is actually on the, I'm sorry, left side with right-sided weakness. And you can see here is a thalamic legion, a posterior thalamic legion. Here we use the interparietal sulcus to access the area, and you can see the visualization here. So this is basically a one-by-one cotton-weight opening through the dura. We are using an exoscope for visualization. So here's the exoscope that we used to use, but no longer. It's a 2D exoscope, and now we use a 3D exoscope. We're dissecting the sulcus to free up the vessels. And once again, by using the sulcus, we minimize potential injury to the cortex. So when you're accessing the posterior thalamus, and you're trying a superior parietal lobule approach, you don't really wanna engage the parietal lobule. You can help it, because it can cause a lot of deficits, not only language, but apraxia and weakness. Here we're placing the tube down the cavity with navigation device for accessing the tumor, having a protected corridor, which we're working in. Here's a 13.5-millimeter diameter opening. And once we remove the retractor, you can see the surrounding gyrite come together. We disengage the U-fibers to get down there through the interparietal sulcus. And so this is a near total recession. There was some leftover in the medial aspect, but the pathology came back as an IDH wild-type anaplastic astrocytoma. The neuro exam improved, and they were recurrence-free at 11 months, but had recurrence at that time. So we've also applied the same approach to excisional biopsies. So a standard approach is to use a needle biopsy for deep-seated lesions. The disadvantage of the needle biopsy, however, is that you can't get very much specimen, and you're subject to sampling error. And sometimes when there are certain situations where you want to relieve some pressure, such as that bottom right image where they have hydrocephalus, you can do an excisional biopsy with this approach. So these were 11 patients that were prospectively followed, deep-seated locations below the cortex, mainly the basal ganglia, thalamus, and middle cerebellar peduncle. And these revealed great yield. Diagnostic yield without any complications. And similar to a needle biopsy, they went home post-operative day one. We've also applied these to deep-seated metastatic tumors. We've also used laser interstitial thermal therapy, but in some cases where you want to resect the tumor, and you want to try to get rid of that edema, this is very advantageous. So these are, once again, all deep-seated brain tumors. And we achieved maximum resection, majority of the cases with one patient who had worsened weakness from the internal capsule edema. The median hospital stay is two days for these cases. Likewise, for high-grade gliomas, like I mentioned in that case before, we use this for high-grade gliomas that are deep-seated. So the case of lesions for this approach is not for any such tumor. So it's really, you want to use it for tumors that you can readily differentiate tumor from non-tumor. So what that means is when you're working these tubes, sometimes the visualization can be challenging, and therefore you have to have tumors that are readily discernible. So lesions where you can discern it, you don't really want to use it for. So the ideal lesion types are your metastatic brain tumors, your intracranial hemorrhages, your colloid cysts, your GBMs, and your abscesses. Non-ideal tumors are where it's not readily distinguishable, such as your low-grade gliomas, and typically your meningiomas, as you don't want to traverse cortex, or you don't want to work in a superficial space. You want to work in deep-seated locations through or around white matter tracts. So here are some examples of these cases that we've done. So here's a metastatic non-small-cell lung cancer located in the basal ganglia, this intracranial hemorrhage through a clinical trial. That's why you see it's cortically based, and they were enrolled into the surgical arm. A colloid cyst, a glioblastoma, and intracranial abscess. So location's also important. So this approach really only applies to deep-seated locations. If you're traversing a cortex, then it's not really necessary to use this approach. So your ideal lesion types are those that involve white matter tracts, such as your association and your projection tracts, as well as your basal ganglia, your thalamus, and your cerebellar hemisphere and vermis. Non-ideal tumors, once again, are your cortical-based tumors. And here are some examples of those cases. So here's a cortical spinal metastatic renal cell cancer. So you kind of, in this case, we were obligated to use the rolandic fissure or the central sulcus. So we opened the central sulcus, used the two-piece approach, and debulked the tumor. Here's a basal ganglia leo-sarcoma, a thalamic anaplastoblastoma, a cerebellar hemisphere, non-small cell lung cancer, and a cerebellar vermian intracranial hemorrhage. Depth of cannulation. So these cannulas come in different lengths, but typically the smallest one's around 50 millimeters. So you want to be below the sulcal boundary. So when you take a coronal image and you draw out the sulcus, you want to be below that sulcal boundary. If you're working above that area, it doesn't make sense to use this approach because you would have to traverse parenchyma above the sulcus, and therefore it's not really advantageous to use the MIPS approach. So ideal lesion types is just below the sulcus, which is typically around three centimeters. Your basal ganglia lesions, your thalamic and your middle cerebellar peduncle lesions. Non-ideal tumors, once again, are your superficial lesions. And here are examples of all different cannulation depths. So here's that metastatic renal cell cancer that's approximately three centimeters below. The intracranial abcesses is five centimeters below. A middle cerebellar peduncle cavernoma that was seven centimeters below. And an eight and a half centimeter basal ganglia intracranial hemorrhage that was rolled into a clinical trial. So besides that, the size of the abnormality is important. So the tube diameter itself is 13 and a half millimeters. When you put this tube down, you can toggle it basically one diameter in each dimension. However, that varies really on this lesion type. So the softer the lesion, the bigger the lesion you can do. The deeper the lesion, the larger the lesion you can do because you can toggle it a greater degree to access more of the lesion. Fibrous tumors, it's harder to do that. So it's usually size constrained by that. So here are some examples of different sizes. Here's what was a challenging small glioblastoma that we really meant for an excisional biopsy that when we got down, we just resected the lesion. That was readily apparent where the lesion was. Here's an astrocytoma. That was 3.7 centimeters. A glioblastoma that was intraventricular. That was four centimeters diameter. A very large colloid cyst that was 4.6 centimeters and a six centimeter glioblastoma that was accessed through two ports, one on the right hemisphere and one on the left frontal hemisphere. So also experience comes into play. The most challenging lesions with this approach are those lesions that are interventrical. The reason why is that when you access the ventricle, the bleeding can happen outside of your tube. So when that happens, it can become quite challenging to achieve hemostasis. So here's an example of a renal cell metastatic tumor that was interventrical. That's quite challenging. Your hemorrhagic lesions, such as your comangioblastomas. Here's a right cerebellar hemisphere comangioblastoma. That's a good size, but because of the vascularity and trying to get it in block, it becomes challenging. And obviously your thalamic lesions are difficult, whether they're in the anterior thalamus or posterior thalamus, different access points can be associated with significant morbidity. So it just depends on where the white matter tracts are and where it is in the thalamus. So here are some challenging cases that I've had. Here's an interventricular renal cell cancer that I said that had some injury to the thalamus post-surgical, just because of trying to achieve hemostasis. This cerebellar hemangioblastoma did well, but in hindsight, probably it was too challenging to do through a tube rather just should have done a conventional approach. And this biophthalamic lesion really meant just to do an excisional biopsy, but it was very suckable. So we try to take as much out as we can, but unfortunately she woke up with increased weakness on the contralateral hemisphere. And I think that's just from encroaching on the white matter tracts within the lesion itself, within the posterior limb of the internal capsule. So you just have to be cognizant of where the white matter tracts are and DTI is not the full answer, especially for tumors. So, in conclusion, oncofunctional balance is critical, so what that means is trying to remove as much tumor as you can while preserving function. It's important to preserve as much cortical and subcortical structures as possible, even outside of the known eloquent structures, and that tubular retractors can allow safe access from resection corridors to deep-seated brain tumors by providing a minimally invasive paraphysacular surgery approach. Visualization is critical. Nexusopes may provide some advantage over traditional surgical microscopes. So that's all I have. Okay, so really impressive what you, you know, how you've pushed the envelope and how much you've been able to accomplish through tubular approaches. It seems that, you know, seemingly impossible things that were thought to be, things that were thought to be impossible to do before are more and more feasible. We'll just present one case, and then we'll go on. I know it's been a long day for both of you, likely. I want to be respectful of your time, so let me share my screen, and then we'll maybe go over a case, and then go over a couple of questions. And for the participants, please, if anyone has any questions, please place them in the chat. Okay, can you see my screen okay? We don't, I just see the introduction screen. Okay. Yeah, this screen. Yeah, yeah, we see that. All right, there we go. Yep, perfect. So just as a little bit of a curveball, I wanted to see your impression. This is a 65-year-old man who presents some headaches, a little bit of confusion, some weakness. He had a history of F1. He lived with his brother. He did have a history of drug use before, as well as alcohol abuse, and he's been on a baby aspirin. A little bit of weakness on exam, but otherwise intact, and and has this sort of imaging. I guess, Dr. Hadjouanahis, what are your thoughts when you first see this with his history? Is it something, it wasn't really, there was some DWI within there, but it's kind of plus or minus if you see the SWI as well, so. Yeah, yeah. I mean, it's an IV drug user, you know, you worry about immunocompromised state. Distant IV drug use. He's not doing it anymore, but he did have this history. Yeah, I mean, the question is, does he have a history of HIV? You know, does he have, because if that's the case, then, you know, you worry about some other lesions in the differential, such as toxo, crypto, and some other types of, right, you know, lymphoma, or, you know, when we see a peripherally enhancing lesion, you know, with a necrotic coral, we think of a high-grade glioma at the top of our differential. So what, how would you, you would proceed with a biopsy then, since you're giving, or would you, would you do something else? Would you use a tubular approach? Would you do a needle biopsy? How would you go around this? Well, the patient's platelet count's 81, right? No, no, he was just on aspirin 81. Oh, aspirin 81. Okay. Yeah, I think, obviously, you know, with the aspirin, we wait a few days and let that wash out. I probably would try to go for a biopsy first in this patient, and just get, get confident to know what the diagnosis is before I jump at it with the resection, although you could go after it with a resection. He's got midline shift, and, you know, based on Kaysorn's talk, you know, I think it'd be nice with a port or, or, you know, tubular access to this. Kaysorn, is it something that you would do a tubular approach for diagnosis and, and treatment? Yeah, I think I would. I mean, just like Dr. Hajimani said, I would try for a biopsy, like an excisional. I would put the port down, look at what we're looking at, send frozen to see what it is. Obviously, with this guy's history, even though it's remote IBD, I would get a systemic imaging just to make sure there's nothing systemically that they can go after first, but I would go through a right frontal translocal approach, either the superior frontal sulcus down to that lesion, dock on the lesion and get some specimen first, and just see what it is. If it's lymphoma, then I would back out. If it's an abscess, readily apparent, or glioblastoma, I would continue to resect. Do you use 5-LA during the tubular approaches? I do. I really like 5-LA a lot. In this case, if I'm concerned that it's something not, then I probably wouldn't, but if I thought it was a glioblastoma, I definitely would. I think it's a great tool. Would you give them 5-LA a priori? Because if it is a glioblastoma and you're in there with a tube, you will go ahead and resect, correct? I would, yeah. I would ideally give it. I would just add that it would help with the diagnosis too, because if you see fluorescence, high likelihood it's going to be a high grade, although CNS lymphoma lights up with 5-LA administration, but it would be quite helpful. So very good points from both. First of all, I was a little bit unclear about the diagnosis. We thought it was likely a high grade glioma. Obviously, you don't have the benefit of looking at all the imaging, but your gut feeling was both correct. It was that this was likely that, although given his history, we wanted to be sure. So we did a biopsy, a needle biopsy, and it was indeed glioblastoma. Based on that now, would you proceed immediately with a resection, or would you have concerns about resection? Yeah. I mean, based on what Casehorn said, I would resect this. The one thing I'd like to get to is tractography. I think that would be really important here, but a superior frontal approach would be nice here, and then look at the tractography in terms of its relationship to the tumor. You know the medial border is going to be involving important pathways, as well as the posterior border there. So I think that's the danger zone, but if you come from a superior frontal approach, you should be able to get to that relatively easily. Do you have any concerns about, let's say lenticular striates coming from, you know, sort of this approach as opposed to something else? I don't think so. I think you'll be medial to those. I think the main thing that I would worry about, just like you were saying before, is like the genuine posterior limb of the internal capsule. I think the DTI may help you a little bit. There's obviously a lot of smoke in there, so I wouldn't trust the DTI completely, but it looks like internal capsules push back posterior and medial, and by going to medial, like through a superior frontal sulcus, all the lenticular striates should be lateral to you. Yeah. One other thing I'd like to add, too, to the group. This is a very good example of a case I would probably not take out all the fluorescence. So in other words, I'd probably leave behind some peak tissue because if you go after that fluorescence medially and posteriorly, there's no question he's going to be left permanently plegic on the left hand side. So, you know, this is that one case where, you know, you don't want to go for broke with the fluorescence resection. You may want to leave some fluorescence behind, especially if you do some mapping and you also combine, you know, some subcortical information showing that, you know, there's functional tissue there. What's your threshold to stop with your subcortical stim, Costas? Yeah, I mean, I'd like to give myself, you know, a 10 millimeter or so, you know, stimulation barrier, buffer, so to speak. So milliamps then? Yeah, well, I'd probably go up to maybe 50 to 20. But, you know, if I elicit within that range, I'm probably going to back off around there. I'm sorry, you said? 15 to 20. Oh, yeah. And that correlates to about, you know, 10 millimeters or so. Right, right. Well, I do use a decent amount of tubular approaches. What I was worried about this is, again, the internal capsule in the back and the ability to use the subcortical mapping appropriately there. And I'd be interested to hear Keiser on about his, you know, his experience about using subcortical mapping, you know, through the tube. I found sometimes it's a little bit hard to actually get things down there and adequately sort of, or even get your bearings when once you're in the tumor. So this one that he essentially did a contralateral sort of interspheric approach with a linear incision. And you've all seen the, but he had a very, very generous subarachnoid spaces. So there's a video just, you've all seen this. But importantly, with the positioning about 60 degrees and then using the retractor enough on the fox to go contralaterally, we've got a good opening in the contralateral lateral ventricle. And this is a good, the four of them in a row is a good landmark for the genu, obviously. So sometimes that gives you a little bit of some bearings or where things are. We did not use 5ALA for this one, although we typically do. But use the subcortical stem. Typically I take it down to 5 milliamps. And if when, whatever is stimulated at 5 milliamps, I just stop there. But obviously that will be still fluorescent tissue if you did that. And we left, we left some of the tumor again, but I got the the internal capsule all along it, but, but otherwise he did okay. It wasn't an IDH wall type, so I think it was reasonable to perform. He, he didn't get better immediately, but eventually had some improvement. How about this case? Well, this case, because I love neuroendoscopy, you know, I think this is a great one for a biopsy with a port endoscope, you know, and then find out what you're dealing with before you go after this. This is one of those cases you really need to know the diagnosis before you really go after it, in my opinion. So do you, do you use a port, and, do you use a port and, and do the biopsy and the resection at the same time? Or do you, do you a working channel endoscope, do a therabrine trick and a biopsy and then decide? Yeah, I, I would do a working channel endoscope here. I mean, the vents look a little bit plump. The third, I can't tell the lat, the lateral ventricle may be enlarged. Yeah. I mean, I think, you know, an ETV is very reasonable here and then do a biopsy, you know, after you do your ETV, do the biopsy and then decide, you know, what this is and then decide on your approach afterwards. I wouldn't do a resection with the port, with the working channel endoscope for this. How would you do the same? I would do the working channel endoscope, do an ETV and a biopsy and see what you're dealing with. And then, and then for the resection, how would you approach this? Yeah, I mean, we get, we have to determine what we're dealing with. I'm sorry. So there's, there was a, the, the biopsy is performed as well as with an ETV. It's a, it's a pineal parenchymal tumor of intermediate differentiation. Intermediate, great. Yeah. More, more towards a three, they're hedging a little bit. Yeah. Well, you know, we, we published a paper, you're, you're, go ahead. Sorry. No, I said a CSF was negative. Craniospinal imaging was negative. And all the markers, et cetera, we're doing. Yeah. I mean, for, for me, I like the infratentorial super cerebellar approach and, and actually we've been doing these with the exoscope now and, you know, you don't need to use the sitting position. You just use the concord position and the exoscope does the work for you. I mean, you drop the exoscope down and it looks up to the tent and you can get all the way up to the vein of Galen quite nicely and, and do your surgery. So that's the way I've been doing it. And I've been very happy with that approach. The other approach that I've done too, that's nice in case one can comment on that as well as use endoscopic assistance. So come lateral, don't take a midline approach, come lateral and use your endoscope, your storts endoscope, or use, you know, use the EAM scope and come down along the super surface of the cerebellum. And then you go around the veins and then you come right to this lesion and then you could, you know, resect it that way. But I I've been doing the exoscope midline approach and it works quite nicely. And it really allows you to, to resect these types of lesions. Well, would you do the same or would you, I would do, I I've always done sitting on these. So sitting super cerebellar infratentorial, I like the idea of that lateral approach. I have never done it that way, but I do use the exoscope for this because it does create, allows you to create that trajectory without having to extend your back or look straight up. It makes it a lot more ergonomic, especially for this case. Cause there's all those videos, especially I've seen one with Dr. Harris Nimi that's like, he's completely extended. His back is like, he's upside down basically. Sometimes you have to do that for this case, but with the exoscope, you can look straight ahead. Yeah, I agree. I think the visualization is just outstanding because you are putting your neck in position with the microscope to really see that area. Well, otherwise. So I, I don't have the video for this, but we was, Oh, we're the, interestingly when I, I usually always use the super cerebellar and I've done a few of them. I do do the sitting, trying to do a little bit of the slouch position. So with the Venus air embolism, kind of the, the Sammy school of, of doing things that does put you a little bit of an, a, in a less of a, an ideal position because you're less flexed than you usually would be. But for this one, just because when we went in initially to do their working channel, he had a very large frown row. And indeed the Venus angle, it's something I, I usually will look at for transcoital approaches. The Venus angle was far posterior on the right side when we did the biopsy. So using, I thought that would be quite easy actually to go back and do that. And with a very short splitting of the, of the Venus angle, there was a pretty wide view of the tumor. So we resected it through, through a tube actually. Although I'm generally very dogmatic about cisternal approaches for, for things like this. And just to be respectful of everyone's time, just a couple of questions. Kai, what do you think is the next frontier of, of, you know, or cubital approaches? I mean, these have been around for, for quite a while, obviously experience is growing, but what, what do you think is going to be the next step? Well, I think the next step is try to combine some type of visualization that's better than the exoscope. So like an endoscopic visualization through the tube. Obviously the tube is so small that an endoscope would take up a lot of the working channel for it. But I think if there's a way to look around these tubes to provide some type of a smaller camera or smaller device for visualization, I think that's probably the next wave because that way we can go smaller and smaller and have less and less damage. All right. And Costas, you, you touched upon it a little bit, but you, you, you, you gave a teaser about potential therapeutic approaches with, with 5ALA and potential other agents as well. Can you tell us a little bit more about that and, you know, for centers potentially, or practitioners that would potentially want to entertain something like that, or, or being involved in a study that, that looks at that? Yeah. Well, you know, I think we're in an area now we're lucky where we've kind of studied how to see the tumors well and use it during visualization for surgery. And it so happens that we have those same agents to use as therapeutics if you use light in a different manner. So we're going to be probably starting a study in the near future. And this is probably going to be a multi, we're going to probably have a single center feasibility study, but then we'll jump into a multi-center study. And I think you'll start seeing this also with other fluorophores that are going to be used for fluorescence guided surgery that have the ability to become a photodynamic therapy agent. And it's just, it's really cool to see that diagnostic aspect and therapeutic aspect all wrapped up in one. And, you know, if we can do it and make a difference, you know, it's going to add 30 minutes to our surgeries, right? You're going to do your surgery, you're going to do your FGS, and then you're going to put in either a laser fiber or a balloon, and then illuminate that area for 30 minutes. And if it, if it doesn't hurt our patient and can provide better outcomes, then why wouldn't we do that? You know, why wouldn't we take that extra time in the OR and provide that therapeutic punch that, you know, these terrible tumors need? And you also spoke a little bit about it, but how about 5-ALA for other tumors? Where do you think we are? And, you know, I know people have spoken about both meningiomas, and I know there's an ongoing trial, but also pituitary adenomas, et cetera. Well, I think the pituitary tumor story is becoming a little bit more clear and it's hard to, to see 5-ALA making a difference in those types of tumors. But for meningiomas, I do think it's going to get approved probably in the next year or so. And that'll be a secondary indication for meningiomas. Now, you know, meningiomas, we, we kind of all do it at some point and, you know, the, the straightforward tumors probably don't need FGS for, but for the recurrent tumors that have had multiple surgeries, that have had radiation that involved the superior sagittal sinus, I think there's going to be a role for 5-ALA. And, you know, the question is, you know, can we see some of the hyperostatic bone involvement? You know, is that going to help us guide our surgery better? A lot of question marks with that still. And I think some of the studies going on right now will help us with that. No question that other cancers like head and neck cancer, ovarian cancer, you know, these are going to be some big time cancers where 5-ALA is going to probably make a dent in difference going forward. All right. Well, it's been a fantastic session. I certainly learned a lot from hearing both of you speak. There's always a little something that you pick up here and there. I'm sure all the audience that's going to be watching this lectures on the website is going to benefit as much or more. I want to thank you both again for being here and sharing your wisdom tonight and stay tuned for more episodes soon. Thank you, everybody. Thanks for having us.

5-ALA fluorescence-guided surgery

tumor resection

NeuroU

high-grade gliomas

deep-seated brain tumors

real-time image guidance

fluorescence visualization

safety

intraoperative visualization technologies

glioma surgery