Hello everyone, I'd like to welcome you to yet another episode of the Front Row series. Again, this is one of the new series of the Neuro-U, the online educational website for AANS, where we're lucky enough to have renowned experts from around the world in multiple fields, including tumor, skull-based cerebrovascular radiosurgery, and many more. The participant to these events can be present to the live events, and actually the new feature is that participants can submit cases for our experts to review, but also can have access to the archived events for CME in the future. Without further ado, I'd like to welcome our experts for tonight. Our experts really need no introduction. We firstly have Dr. Michael Lim. Dr. Michael Lim is obviously an international figure and a very well-respected researcher in the field of glioblastoma. His clinical interests also include trigeminal neuralgia, among others, but he's really spearheaded a lot of the cutting-edge research in immunotherapy for glioblastoma. He's a professor of neurosurgery and radiation oncology, as well as medicine, as well as the chairman of the Department of Neurosurgery at Stanford University. Today, he's going to speak to us about the state of immunotherapy for glioblastoma. We also have Dr. Mike Ivan. I've been lucky to know Mike for several years now, and I first met him during my fellowship. He is not only a spectacular surgeon, but a brilliant researcher. He's currently leading the research efforts for glioblastoma at the University of Miami. He also has extensive clinical experience with laser therapy, lip therapy for deep-seated tumors. Today, he's going to speak to us a little bit about that. We'll be very excited to hear him. Without further ado, I will ask Dr. Lim to share his slides. At the end, we'll discuss some of the submitted cases. I'd welcome everyone to submit questions in the chat, and we'll address them as soon as we're done with the talks. Okay. Thank you, Dr. Zanonis. Perfect. All right. Can you see my slides? Yeah, perfect. All right. Well, thank you very much for this kind invitation. It's really an honor to be here. I'm really excited to be speaking next to also Dr. Ivan. I've known him a long time, too. Today, I'm going to talk a little bit about immunotherapy for glioblastomas and other brain tumors. I don't really have a lot of, quote, cases to present because obviously, this is much more on the research side, but I did try to include some of the things that I think are relevant for us as neurosurgeons in the world of immunotherapy. With that, I'm going to start with my disclosures. These are my relevant disclosures. I do have research support. I'm a consultant and do have some intellectual property around some of these ideas. I guess to begin, if we think about the state of cancer therapy, there was a revolution that's happened over this past decade. That was immunotherapy. We are at this point where we really have a new tool to use against patients with cancer. The immunotherapy that most people are talking about and you've seen on TV is based on a concept called checkpoint molecules. Checkpoint molecules are the second signal. I don't know if you can see my mouse, but the second signal that's required after a T-cell receptor engages is cognate antigen on the MHC molecule. The second signal either turns the T-cells on or turns the T-cells off. It turns out that cancers have developed a really clever mechanism to turn T-cells off. What people have done has really tried to disrupt the second signal. If you disrupt the second signal, you can actually get T-cells to turn on. As a result, there's been a huge industry that's risen up from this. I think people have seen the drugs Opdivo, Keytruda, and Finzi. It's projected to be over $50 billion in the next few years. Also, Nobel Prizes were won for the CTLA-4 and PD-1 two years ago. Now, I think to give you some background on why people were so excited, there was a series of New England Journal papers on immunotherapies. This was the first one on something called Anti-PD-1. That was the Opdivo or the Keytruda. Now, I think Regeneron has a new one too on the market. Basically, what they did was that they started treating patients with Anti-PD-1. They went and they treated multiple tumors. Melanomas, lung cancer, kidney cancers were amongst several of them. What was really interesting was, this is called the spider plot. This is basically the size of a lesion. After they were being treated with these therapies, a lot of patients had shrinkage of their tumor. What was really remarkable was that some of these large tumors were shrinking away. It took on the order of six months. What was interesting was, I don't know if any of you have ever seen a T-cell in comparison to a cancer cell. The T-cell is like 50 to 100 times smaller than a cancer cell. It really is like a David and Goliath in terms of size. The T-cells have different ways to go and kill cancer cells. They can eat it from the outside in. They can puncture into the cancer cells and disrupt the cancer cells from within. If you think about it, the sheer number of immune cells that are required to kill a bigger cancer cell would be, you would almost think of magnitude higher. It takes a while to do the immunotherapy. It takes six months, but the immune system can be persistent and can whittle away the tumor. What's also interesting is that while the cancer is being attacked, it looks like the cancer grows before it shrinks away. They call it pseudoprogression. Initially on some of these trials, they originally thought that the therapy wasn't working, but it in reality was. As a result, the first prospective trial was published in 2010. Then it was done in melanoma. Then all of a sudden, from 2011 to 2019, we have had multiple indications approved for what they call IO or immuno-oncology. What's interesting about it is if you take a step back and you look at the immunotherapy world, there are three main takeaway points. One, the response rates are low. Only 20 to 30% of patients with malignancies actually respond to this. Second, if these patients go on these therapies, the toxicity rates can be quite high. These toxicities cause things such as pneumonitis, colitis. People can actually die from this. What's disheartening is that a fair number of patients actually develop resistance to these immuno-oncology drugs after time. While we are in a revolution, there's still a lot of work to be done. Even in cancers that are responding, we can still do better. Where were we in the glioma field as this revolution was happening? This was some of the first work. Peter Fetchy did some of the initial work with CTLA-4, showing that this could potentially improve survival in these mice with brain tumors. Jing Zhang, when she was in my lab, showed that anti-PD-1 to Keytruda could work. Now, what's really interesting is this is an example of us as clinicians having the advantage of being able to see many things. Up on the top left here is a picture of a patient that I saw that came into my clinic with renal cell carcinoma. He was on a trial of a drug called MDX-110 back then. Had no idea what it was. Patient came into my clinic, looked like a standard brain mat, and I recommended surgery at the time. I took him to the OR. When he came out, he did fine from the surgery, but the pathology and the pathologist called back and said that there were some interesting findings. When I looked at the final path, it turned out that it was all inflammatory cells and there were no cancer cells. Of course, my interest was piqued. This guy had widely metastatic renal cell carcinoma. Over the ensuing months, over about six months, he had a complete response and he was cured. MDX-110 was short for a drug by a company called Medarex. Medarex was taken over by a company called Bristol-Myers Squibb, and that was Optivo. That was what inspired us to go and look at PD-1 in glioblastomas. Dr. Heimberger's group showed very nicely that the PD-L1, which is the ligand for PD-1, remember that there's a receptor and a ligand, that ligand did exist on the tumor cells, especially in glioblastomas and gliosarcomas. People said, glioblastoma is going to be a cancer that's going to respond. They then started publishing case reports. This is a case report of a child getting anti-PD-1, and you can see that the tumor started melting away. As a result, many people were enthusiastic. The target existed. All these other cancers were responding. Case reports were happening. That prompted Bristol-Myers Squibb to launch a large phase three clinical trial for patients with first-time recurring glioblastoma. This phase three trial, unfortunately, came out negative, both for overall survival and progression-free survival. Meanwhile, while they had that trial going, they launched a newly diagnosed trial. Unfortunately, the newly diagnosed trials also came back negative for overall survival and progression-free survival, both in the methylated and the unmethylated population. Not all was lost, though, for brain tumors. Interestingly enough, they had done brain metastases at the same time. When they gave the anti-PD-1 and anti-CTLA-4, which is another checkpoint molecule, in combination to patients with brain tumors, they saw that about a third of the patients actually had really nice long-term responses, and some of their tumors melted away. However, it was not benign. About 60 percent of the patients developed severe adverse events, i.e. colitis and pneumonitis had to be hospitalized. A lot of people right now have this debate, should we put patients with brain mets only onto these drugs, which have significant toxicities, or do you treat them with radiosurgery, which patients do well from? Of course, there's issues such as radiation necrosis, but again, it's an interesting debate. As I told you, there was a lot of hope for immunotherapy in a lot of cancers. There's a lot of hope and some interesting results, but in glioblastoma, those results were negative. What are we doing for glioblastoma now that we had these disappointing results? There are many different approaches, but I wanted to highlight some of the things that I think were relevant to us as surgeons. Combination approaches, and then I think a very important concept that's central to not just glioblastoma, but it turns out pancreatic cancers and prostate cancers may have similarities in the sense that there are other immune cells besides your T cells and the myeloid cells, which I'm going to go into detail, seem to play an important role. Basically, right now in cancers, there are hot tumors that are tumors that respond and cold tumors, tumors that are not responding. What are some strategies out there to make immunotherapy work? There's these things called combination IO therapies, they call kindling, vaccines, CAR T cells, and targeting the myeloid compartment. For today's talk, in the interest of time, I'm not going to go over the vaccines and the CAR T cells. As I mentioned before, the immune system is exquisitely complex, and it turns out that there are more checkpoint molecules than just PD-1 and CTLA-4. LAG-3, for example, is another checkpoint molecule that's commonly being studied in TIM-3. As clinicians, as surgeons, we have the advantage of being able to look at tissue. Early on, when we had an idea of PD-1 wasn't working, Magda, who was one of my postdocs, started looking for other checkpoint molecules. It should say LAG-3, I apologize, not anti-LAG-3. LAG-3 was expressed amongst other ones. This proof of principle, so we went back and looked at LAG-3. LAG-3 is another checkpoint molecule, but it's actually been more studied in the infectious disease world. It turns out that it binds to MHC class II, and when activated, turns off T cells. As I mentioned before, we had seen it in flow studies, and immunohistochemistry shows that these T cells that are expressing LAG-3 exist. Sarah Harris Bookman and Demetrius Matios had also looked, and they found that this PD-1 and LAG-3 exist in mice models, and when tumors are expressing PD-1 and LAG-3, these T cells are essentially turned off. If you don't express PD-1 and LAG-3, and you block them, just like you do with anti-PD-1 and anti-LAG-3, it implies those T cells have the ability to kill. What they did is we had a knockout mouse for LAG-3, and we had a regular mouse with tumors. When you gave anti-PD-1 or anti-LAG-3 in this situation, we were able to improve survival. As clinicians, you can also take this to the clinic. What we did was we then took the findings, went to a company, was able to get anti-LAG-3 and anti-PD-1, and then went to the NCI, the Adult Brain Tumor Consortium, and started the trial. We had done this with other checkpoint molecules, CD137. I'm not going to talk about that today. As a result, we did it as a phase one study. We were able to meet our primary outcome, which showed that it was well-tolerated and, in fact, had very low toxicities. What we were able to show, though, is that in the patients, this is the dotted line here, that received anti-PD-1 and LAG-3, while the median overall survival wasn't any different, we actually saw four out of 16 patients living. One is at 23 months, and the other three are past 30 months now. This needs to be updated. This is an example of a patient that came in that did well with our therapy. This patient initially had a GBM, had a resection, underwent chemotherapy and radiation. At the time of the recurrence, they were screened for our clinical trial. They went to surgery, had a resection, and this was all that remained. They went on to anti-PD-1 and LAG-3. What was interesting is cycle three, cycle four, and cycle five, that's around four, five, and six months, they started developing what looked like progression. We kept treating because the patient was symptomatically stable. By seven, nine, and 11, you can see that it started progressing. This patient is doing very well. This patient had the pseudoprogression. What's interesting is with PD-1, in the PD-1 trials, you would get this, what we thought was going to be pseudoprogression, and it kept getting worse and worse, and patients had to come off the trial. It turns out that if you do find an immunotherapy and it suggests it works, it will follow this pattern. In our study, we built in some correlative studies. Christina Jackson was doing this work and saw that there was an increased clonality. Basically, the T cells that are presumably targeting the tumor expand, and they become more predominant. In the responder, we saw that there were more clones than in the non-responders. This is something that is a journey. We saw PD-1 not working. We then went to and identified new targets, worked in a preclinical model, then designed a phase one clinical trial, saw some interesting signals, and are now going to a large phase two trial through the alliance to test our question of true efficacy. For the next part of my talk, I want to talk about our possible contributions as surgeons for immunotherapy. This is an area I think a lot of people have been involved in. I call kindling a systemic response. If you think of the tumor as a force that is very damp, all the wood is very damp, and you want to start a fire, it's very hard to start a fire alone. If you can start some kindling, then you can get a fire. One of the ways people are doing this, and this was actually inspired by being in the clinics again. It was a patient that I saw in my clinic, it was actually a brain mat. It was a solitary mat, it was near motor, so we ended up treating with radiosurgery. This patient then developed this brisk T2 response, which is all swelling and edema. We thought, what if you combine stereotactic radiosurgery with immunotherapy? Maybe that could be the kindling. It turns out radiation can actually irritate and cause inflammation through many different mechanisms, cell death, increased antigen expression, and cytokine release. Now, hold on to that thought for one second. As I mentioned before, PD-1 isn't the only checkpoint that's expressed in glioblastoma. Amongst the other things we saw, Tym-3 was highly expressed. This was Magda's work again. we had also looked at TIN3, and TIN3 is another checkpoint molecule that's expressed on T-cells. And it turns out that TIN3 is thought to be another very powerful checkpoint molecule. As I mentioned before, other cancers have developed resistance to PD-1 over time. And so in lung cancer, 25% of patients actually develop resistance to Opdivo or Keytruda over time. And so around the time we were looking at TIN3, there was this really interesting article in Nature Communications that said, when TIN3, when PD-1, or when a tumor develops resistance to PD-1, TIN3 is upregulated. And so it turns out in our mouse model, we saw that when over time, the TIN3 positive T-cells increased over in all the lymphoid compartments. And so we thought, okay, TIN3 seems to be another good target. So what if we combine radiation with anti-PD-1 and or TIN3, can we get the kindling to generate a systemic response? This is the small animal radiator platform that we use for mice. And so initially this was anti-PD-1. This is the red line showing that we got a nice synergistic response. And Jennifer Kim did a lot of nice studies, but showed again, when you give anti-PD-1 plus anti-TIN3 plus stereotypic brain surgery, you could get a very nice synergistic response. And so we're able to take this back into the clinic. This trial is open at Hopkins and we're actively recruiting. This trial will be open also at Stanford in the upcoming weeks. We just got IRB approval. You know, another approach that we as surgeons can contribute is, you know, I think we're all familiar with Dr. Henry Brehm's work with the local chemotherapy. If you can give chemotherapy differently, maybe we could also engender an immune response. If you take a step back and look at glioblastomas and think about what we do, we treat patients with high-dose steroids. We treat them with temozolomide, which basically is lymphodepleting. And we treat them with hyperfractionated radiation, which again weakens the immune system. So we thought if you could just give the chemotherapy locally, then we could avoid all the systemic toxicities of giving chemo systemically. And so what Demetrius Mathios did was gave the chemotherapy locally. We used BCNU and temozolomide. And it's the green line. It turns out that if you give it in combination, we've got a very nice synergistic response. Another place where surgeons can play an important role is in neoadjuvant. Now this is an important concept that's being applied across many different cancer types. Neoadjuvant means that you give the drug before you take the patient to surgery. And for some reason, that sequence makes a difference. And so this was a trial that was run out of the IV consortium. Tim Clossie was the first author. Turns out that in patients who got the anti-PD-1 after the surgery, which is the blue line, did worse than the patients who got anti-PD-1 before surgery. And so it turns out that somehow giving the anti-PD-1 causes inflammation. There was another study that was done out in Europe by Nacho Molera. And in both cases, they found that the T-cell clonality increased when you gave the PD-1 before the surgery. So there's a lot of interest in doing larger trials. There are a lot of other interesting trials that are coming down the pike. People are using laser ablation and focused ultrasound in combination with immunotherapies. So I think that we as surgeons have the potential to play an important role in the next, or version 2.0 of immunotherapy for patients with brain tumors. I wanna make one quick word. There's also these things called peptide vaccines that are out. David Reardon has been doing a lot of work on this. People are now taking tumors, sequencing them. We think that there's these computer programs that can basically predict which ones will be the epitopes. And then basically we make those peptides and give a vaccine back to patients. There's two studies, one out of Harvard and one out of Heidelberg. I think it's one out of Germany. And those are some interesting, exciting things that are coming down the pike. Last thing I wanna talk about is, are we recruiting the right cells for immunotherapy? As you may have heard, I keep referencing the lymphocytes of T cells. And if you look at a glioblastoma, it turns out that there are very few T cells, but there are a lot of things called microglia and macrophages. And one term that everyone keeps throwing out is we have to target the myeloid population. Now, if you go back to immunology, the myeloid population after you, these immune cells come out of the brain, I mean, out of the bone, can become myeloid or lymphoid. So the lymphoids will do like natural killer cells, T cells, B cells, but the myeloid cells are many things. So it's not just the dendritic cells and macrophages, which is what really most of us are referring to, but there are eosinophils, neutrophils, basophils, and all of these are myeloid cells. But basically what we're trying to do is activate these myeloid cells. So it turns out these myeloid cells can be suppressive. You want to facilitate antigen presentation and you want to facilitate migration. So there's been a lot of work in looking at trying to find different inhibitors, but basically what they're doing is they're trying to target these things called tumor-associated macrophages, which is the myeloid population. In theory, if you hit those cells with those modulators, you can convert them to a immunopermissive phenotype, they call an M1. And then what they'll do is they'll start doing antigen presentation, and then they presumably go down to the lymph nodes to then teach the T cells what to kill, and those T cells will go up to the brain. This is Tomas Garzon-Mouvdi's work. He showed that if you combined it with poly-IC, which is a very potent activator of myeloid cells, you gave it PD-1, we were able to get very nice improvement in survival. He also worked with other agents like CSF1R and FLT3 ligand. This is Derek Wainwright's work where they gave the 1MT, which is another drug that targets a pathway in myeloid cells to make them activated, particularly macrophages. And again, when you get with PD-1 and CTLA-4, they got this amazing survival curve. So a lot of people are working on that. It turns out that this story is not so straightforward. It's not a binary thing. These cells are not just on or off, but there's actually like 14 different states. So in the next decade, I think most of us will be focusing our efforts on this. With the last minute, I just wanna talk about a couple interesting things. So the immune system, it turns out is very susceptible to environmental cues. And so we always talk about your health and your diet and all these things can affect how the immune system work. For example, one other thing that's environmental is that cancers, it turns out in pancreatic cancers is really dense and fibrous. I mean, very dense and fibrous. And so if you give something to soften it like this FAK inhibitor, you can actually soften the tumor and these T-cells can come in. So basically the composition of the tumor can affect how T-cells can come in. It turns out that if you have high levels of extracellular potassium, it makes T-cells dumb and high levels of potassium come in when you have necrosis. It turns out glycolysis. So if you have an aerobic environment or an anaerobic environment, the T-cells work much better in an aerobic environment. And then also what you eat, it turns out that the bacteria in your gut can actually determine how T-cells work. And this was a very interesting experiment where they had two different microbiomes and they basically did fecal transplants and traded them out and showed that you could make the immune system work better. So lastly, we have to recognize that, as I mentioned before, even with current immunotherapies and tumors that respond, they develop resistance and it's a dynamic process. And so the immune system and the cancers are in a constant state of evolution in a battle to try to survive. And so we have to, even if we come up with effective therapies, we have to anticipate resistance. So I told you a lot of information today. So in conclusion, initial immunotherapy results have been disappointing. There's this high intrinsic and adaptive resistance in glioblastoma. I think as surgeons, there are a lot of opportunities for us to participate with these different combination approaches. Have to anticipate that the GBM microenvironment is hostile and we have to anticipate resistance. So with that, I'd like to acknowledge folks in the lab that I've worked with, my collaborators and with students and postdocs, as well as clinical trial teams that I've worked with. Immunotherapy program requires input from many folks and this is my relevant funding. Thank you for your time. Wow. Dr. Lim, really a tooth-to-force overview of the immunology and immunotherapy for GBM. It just really invigorates hope for exciting things down the road. We all know everyone that treats this disease knows that this is not a surgical disease and all this really spark some light at the end of the tunnel. We'll hold some questions for now and we'll have Dr. Ivan share his knowledge on lip therapy and then we'll answer some questions at the end. Okay, great. Can you hear me, George? Yes, perfect. Great. Well, thank you, Dr. Zanonos and Joey Ness for inviting me. It's always a pleasure to do a talk on laser surgery and tough doc to follow. Dr. Lim, you did a phenomenal job there summarizing, I think, what a lot of the future of GBM treatment will entail. But I'm gonna talk about LIT for deep-seated surgery. Again, my name is Michael Ivan. I'm one of the brain tumor and skull base surgeons at the University of Miami and I head up our research program here. Here's my relevant disclosures. And I'd like to start with this quote here by Hippocrates, which is, what cannot be cured by medicaments is cured by the knife. What the knife cannot cure is cured with a searing iron and whatever this cannot cure must be considered incurable. And I'd like to say that Hippocrates, if he had the laser available, would probably replace the searing iron with a laser. And that's what I'm here to talk to you about today. I'll go over a quick case report of LIT. I'll go over kind of just the background. I think many people have been exposed to this before. What our experience has been and what the literature has kind of demonstrated thus far with LIT, the procedure really quickly and then future application. So this is a great case example that I always like to start with and kind of highlighting where is the role for LIT in brain tumor procedures. This is a 55-year-old teacher with recurrent ependymoma, recurrent recurrent ependymoma, two craniotomies in the past, fractionated radiation and stereotactic radiosurgery. And now patient is still teaching great KPS, no disseminated disease, and this is the only lesion, but it continues to grow. And so what are your options here? Deep-seated lesion in the eloquent left-sided area, I'm sorry, in the left dominant side, you could see that the skin is quite thin on the top and it's challenging. There's not a lot of great options. There's not great chemotherapy options for ependymoma, but if this was another type of tumor like metastasis, maybe there would be. And then the question becomes, do you stop chemotherapy to do surgery or not? Typically that would require three weeks of stopping or four weeks of stopping before surgery and another three weeks after surgery, a major interruption if there's systemic disease. If we decided to go back in and do a third craniotomy, we all know that the risks of third-time surgery is significantly increased with morbidity. Wound healing issue has become an issue. Now the wound's been opened twice and radiated twice. Typically patients that get to this point have other systemic problems. And then there's delays for interruption of whatever therapy they are. A radiotherapy, you know, third-time radiosurgery, it may be possible, but you have to worry about the risk of radiation necrosis and what is the maximum dose now to the structures who may have already gotten the maximum dose in the past. And so prime example to do a minimally invasive procedure, which is a thermal ablation, what LIT could provide. So what LIT does is provide a small opening, three millimeters or less, allows you to, because the opening's so small, to kind of continue your chemo-radiation with minimal interruption. We actually only ask a week of our oncologists to stop in chemo either before or after this procedure. Typically you're able to wean steroids very quickly within 48 hours, which is a surgery normally takes two weeks. There's no risk of radiation necrosis. There's no limit to the number of iterations of LIT you could do, and it doesn't prevent you from doing any one of those treatments in the future. And it preserves the quality of life of these patients. Most people end up going home very quickly to post-update one. And many patients who have advanced cancer or advanced glioblastoma, they don't have a lot of time left. You don't want to take away that from them by spending a week or two in the hospital. This is a follow-up to this patient. Here's two weeks. This is what the ablation will look like. You have this necrotic center with kind of an enhancing boundary. 12 months, so basically the same size. 24 months. And then finally, we're starting to see shrinkage of the lesion by 30 months. Patient's still doing well, still teaching, and still with a great KPS. So yeah, a great story in this specific situation. So how does this work? Well, as far as laser light, and why we use that is because laser light's monochromatic. It uses one wavelength, which is very well controlled. It's coherent, so the light is very tightly focused. Again, allowing it to be very well controlled to the distance and to the area it's being given to. And it's collimated, so it's narrow over a long distance. And all this allows you to have a very controllable source to provide excitation of the surrounding tissue that then results in thermal energy that then causes an increase in temperature and then thermal ablation. And we know from many data that thermal ablation leads to DNA breakdown and eventually leads to cell death, the apoptosis within 48 hours. But it only happens when you achieve a certain amount of temperature for a certain amount of time. And so controlling the temperature and the time is very critical, especially with this procedure. If you're too low, then you don't achieve really cell death. And if you're too high, then you can get coagulative necrosis, which causes caking on the end of your laser fiber, or you could even cause a vaporization or boiling. And so the goal of LIT is to be able to control, to create this well-circumscribed focal lesion that's very predictable in its dimension, but avoid extreme heating, which can lead to tissue vaporization, cavity formation, injuring the healthy tissue, and charring. And so what does it look like? Well, you have a laser source which emits a laser wavelength at either 980 or 1064, depending on which one of the two systems you use. We use VisualAce at my center, so much of the slides are gonna be focused on that, but I've got an opportunity to use both, and they both do a very, very good job of providing very similar results. And the applicator then goes into the brain. You have a transparent kind of sheath around it that has a cooling, either fluid or gas, that controls the temperature to a very good degree at the tip of the laser. And then as the laser kind of gets emitted, if it's a homogeneous tissue, it's very, very regulated in a very spherical shape. And then we'll heat the tissue in this area. Then from conduction of heating of this tissue, you typically have extension of the heat thermal damage to a few millimeters beyond that, allowing between 1.5 and 1.7 centimeters of total ablation, and then irreversible damage, and then you have an additional warming of the surrounding tissue, but that's reversible. And with tumors, it ends up working really well because there's a very high water content in tumors, and that recreates a high absorption coefficient, which means that the tumors will basically create a lot of energy in that area where there's a high water content, but that falls off quickly as you get outside the tumor and the low water content of the normal brain is in that area. And so you end up having, being able to shape the dimensions of the tumor actually more characteristic than you would think just by knowing that it creates a spherical shape. And we've looked at this very carefully. We published the data just on the post-operative radiographic findings. So post-op day one, you typically have this kind of concentric zones where you see the catheter going here in the middle, you have the necrotic area around it, and then you have this transition zone of kind of the border of where the reversible and irreversible damage occurs. And then you have this kind of marginal area, and then finally the normal brain. And this rim typically correlates to where we think is the Blumenberger breakdown because that's where the new gadolinian enhancement expands to. And so, as I said, the most important part about this is to control the temperature. And we're really, we're only able to do this in the last 10 years with the development of MRF thermometry, which allows us to detect kind of the vibrations of the protons in the tissue and through a mathematical equation, estimate what the temperature is exactly in the tissue that we're seeing in real time as we're doing the heating. And then through a separate equation, we could then estimate what tissue damage when it sees a certain temperature for a certain amount of time, the Arrhenius equation then shows you what tissue damage is. And you're trying to get the tissue damage to exactly match the tumor or even beyond the tumor. Obviously, protecting the surrounding brain is of the utmost importance, and both systems allow you to place these safety markers in the surrounding tissue to prevent the thermal damage to go beyond where you would want. And then also you have a marker in the middle to make sure that the overall high temperature right next to the fiber doesn't go too high and cause vaporization. Either a limit will automatically shut off the system. Where do we use this now that we understand how it works? Well, primarily we use it for small lesions, less than three centimeters. And that's for two reasons. One is because when it gets larger than this, you're worried about the overall mass effect and size of the tumor and laser doesn't make that go away quickly. And so surgery is likely the better option. Additionally, laser fiber typically only expands about 15 to 17 millimeters in radius, and therefore you're limited by that three centimeter dimension. Obviously in deep surgical inaccessible lesions or not inaccessible, but maybe difficult to access without significant trauma to the brain. Treatment refractory lesions, patients who have already undergone surgery and radiation and have failed and now don't have great options. Patients who can't tolerate a prolonged anesthesia or blood loss, or perhaps their skin is extremely in frail shape and you don't want to have a large incision. People who have good KPS. We try to aim to ablate 100% of the lesion, but we found that if it's at least 85 or greater, you still have a significant benefit to the patient. And obviously a reason to be there in the first place. Is the tumor growing? Is the patient worsening? Why are you treating this patient? We recently looked at our first 100 patients treated with LIT just for brain tumors published last summer with our group. And these are just some of the kind of learning points that we have from that series. First and foremost is what kind of tumors can you use this for? And I would say the most cases that we've used this for is for metastases. These are patients who have already had radiation and failed radiation or surgery and radiation. And now you have a difficult choice in deciding if you want to re-irradiate or not. So 45 cases of metastases, 20 cases of radiation necrosis, recurrent glioblastoma 14, newly diagnosed 11, and then meningiomas. A couple of other low-grade tumors that were very deep, we treated, and then one high-grade sarcoma. What we call deep lesions are anything more than two centimeters below the surface. However, as you can see here by the charts, a majority of these lesions were four centimeters or deeper from the cortical surface. And we looked at the differences and what the depth target is on these patients and whether or not we could achieve the ablation, the progression-free survival, or overall survival, and the depth does not make a difference. Then we looked at basically the different tumor types to see, is there a scenario for laser ablation and what would it be for what tumor type? And we could see here that the best local control outcomes were in radiation necrosis, meningiomas, and metastases, are all the top three bars. Obviously, there's a significant difference in the type of pathology here in glioblastomas and recurrence obviously do much worse in all situations, and so it's no surprise that they are lower on the chart. When we looked at the multivariate analysis, we could see here, independent of tumor type, that the extent of ablation was the most critical aspect in controlling tumor long-term. You could say that, well, it's different for every tumor type depending on what it is, and that's true, we looked at each tumor type, and I won't go through them all, but the most important one, I would say, would be glioblastoma, where we found very consistently an extent of ablation greater than 85% correlated with a significant benefit in local control as well as survival benefit. And this shadow is very well, the literature that we already know that's been published for the last 20 years in surgical resection of these lesions, first by Lacroix and then by Dr. Sinai and Dr. Berger, showing that the more extent of resection that you're able to achieve in these enhancing lesions, the better the patient will do with survival. And so when we looked at our newly diagnosed tumors, we first looked back in 19 with our early series, and then we republished it with 100 patients. So we had 11 patients where we had deep-seated, newly diagnosed glioblastomas, these are thalamic lesions or lesions in the peduncle. We had a survival, overall survival of 32.3 months, where we performed a biopsy and performed LIT in the same patients. And if we looked at either our patients or patients in the literature in a kind of a control, those survivals were typically seven to 10 months. And so there is significant benefit here. Obviously this isn't a case controlled or clinical trial, but there are people looking at this, but this is early data that's very supportive of how to use this, that there is benefit for these patients who have very challenging tumors. In addition, we don't go past the point that we do get a biopsy in all these patients. And so you're able to still get the genomic analysis and the mutational analysis of these tumors to then guide what the adjuvant therapy would be. This is not a glioblastoma controlled only by LIT. This is just the first step, just like surgery and many rounds of chemotherapy and radiation follow. What do we know about then recurrent glioblastoma? Again, we have this vertical data that shows extended resection is important. Dr. Sanaya published this as well. And then the John Hopkins group with Dr. Quinonez and Dr. Chakana showed that by each resection, additional resection in recurrent glioblastoma, you can increase the survival, although it's decreasing with each one. And so again, showing that even recurrent glioblastoma, the more tumor you die, the better these patients will do, the more tumor you kill. And so we looked at our series of 14 recurrent glioblastomas. Again, these are tumors that have been refractory and had multiple rounds of surgery, already had radiation chemotherapy, and now have a recurrence that is either deep-seated or we're worried about reopening the incision again for additional surgery. Again, when we were able to achieve 85% of the lesion ablated, overall survival was seven months, which is very similar to the historical controls for patients that are undergoing repeat surgery for glioblastoma. Again, we only had one complication in this series, which was a superficial wound infection that required just antibiotic treatment. Again, there's no craniotomy to remove here. So it's a small opening and it can be treated almost with antibiotics only. Now, what about more complex lesions like butterfly gliomas? Again, a very challenging surgical disease. And there's been mixed reports about what is the morbidity, true morbidity of a resection of these tumors. And it's difficult to say because they're in all different locations and they encapsulate both hemispheres at different amounts for each patient. So each patient is definitely different. There's been several case series talking about the safety of bilateral laser ablations for these tumors. Really not a lot of data so far on the overall progression-free survival, but we've done it in three patients. And again, no significant complications. The patients, again, followed the typical timeline of in the hospital for one day, home, off steroids within 48 hours, and back to their neurological baseline preoperatively. Again, the series of three is too small to really talk about control rates, but the safety profile in and of itself is good news. When we look at some of the other data, there's been a great series already published on LID. It's hard to go through them all, but this is one that I wanted to note, a multi-site retrospective trial of series with high-grade gliomas from Mohamedi and Luther et al, looking again about how extent of ablation for these high-grade gliomas makes a significant difference. And in both this series and our series, you could almost say that this is a control in and of itself. And when you don't meet the standard TTT line or the 85% resection line of 85% ablation line that you're trying to go to, it's almost like you're not ablating at all. And these patients don't have any significant benefits in doing that ablation. But when you do meet it, then there is a showing that laser is actually having some benefits in causing cytoreduction and causing a benefit in survival and progression-free survival. Overall for gliomas, we think that LID will prove to be a very good treatment. Again, more data as to how to combine this, to amplify and synergize its ability with other things like chemotherapy and immunotherapy, like Dr. Lim said, will be key in taking this to the next step. Metastases, which is our number one diagnosis that we've used this for, we had the longest progression-free survival of any lesion that we looked at, 55.9 months. And again, these are not primarily metastases that are new. These are metastases that are already refractory to either surgery and radiosurgery or radiosurgery alone, and that now are growing again. And so it's always a question of, is this ratio necrosis? Is this active tumor? All of our cases, we biopsied in order to prove that they were active or not. And with active disease, we still had a great control rate. These were a little bit more details about the cases that we did, 45 cases of metastases alone with a mean follow-up time here. And when we look at the overall survival, we see that the overall survivor of these patients is 25.5 months, which is significantly less than the progression-free survival. And so what does that tell you? It tells you that with the treatment paradigm that we have and lit, that you could actually control the CNS disease for these refractory cases. And the patients are not then succumbing to their CNS disease, but they're actually succumbing to their systemic disease. And that's good news for the neurosurgeon or oncologist, because we want to be able to control this as much as we possibly can. When we looked at the overall control and the overall survival for the different disease, metastatic type, the most common breast, lung, and melanoma, there's really no significant difference in how laser works or affects these different subtypes in and of themselves. What is interesting though, is that whenever you ablate a lesion, it tends to increase radiographically in size. And there's a couple of reasons for this. One is because the tumor itself just has some edema in some cases, but more commonly it's because you're trying to ablate the total lesion and a little bit more of the lesion. And so postoperatively, that ring enhancing image that you're seeing is actually the new ablation zone where the blubbering barrier is broken down. And so it's not common to see significant increases in the volume initially. But what we looked at is in all 45 cases of metastases, that again, we see that there's a significant increase in the volume preoperatively showing the lesion was growing. Then there's a significant change. And then the first 100 days kind of is very unpredictable in what that volume would be. But after that 100 days, all lesions kind of regressed in size unless they recurred, which is the red lines. And what we found was that in all cases, the lesions actually ended up becoming smaller than the initial size of the volume of the lesion at just over different time points. And so there is this collapse and involution of these tumors that will occur. It's just a little bit less predictable what time that will happen. What about the posterior fossa because of this edema? Does that cause hydrocephalus or new neurological problems? Well, we looked at this back in 2018, and then we actually just published a new series of multicenter series with Rutgers and Penn State. And in either series, we didn't show any kind of significant neurological complications, development of hydrocephalus or the need for shunting in any of the cases where we had to do a posterior fossa ablation. And so in the right patients with the right selection criteria, this can be done safely. What about radiation necrosis? Again, radiation necrosis, there's many treatment options that are available upfront, such as steroids, sometimes just watching if they're asymptomatic and not doing anything, Avastin may be an option. And so, and candidates that fail those and progress either with lesions that are growing in size or they're having steroid side effects and you're having difficulty weaning the steroids or they're just becoming clinically symptomatic, what do you do in those situations? And this is again, where we've turned to the laser when surgery and resection is not an option. And in these cases, we've had also very good success. Symptomatic radiation necrosis, which we've said is either relying on steroids or clinically symptomatic, have remained 75% recurrent free. In each one of our series, we confirmed with multiple intraoperative biopsies that there was no evidence of active tumor demonstrating that they were a biopsy proven radiation necrosis by our neuropathologist. And when we looked at our series, what we've noticed is that because radiation necrosis tend to be a little bit smaller, a lot of these lesions end up causing symptoms because of the surrounding edema, we're able to get a radical lit ablation, which means more than 120% ablation. And we're able to achieve that, we actually were able to get 100% control of the lesion in that cohort of series, showing that this is a very controllable disease with lit, especially if you catch it early when the lesion is small in a non-elephant area that you could get a super maximal ablation. Again, how do you know if it's radiation or active tumor? I think it's a very challenging question that troubles us all. We've looked at our MR perfusion data and we look at that a lot from all of our tumors. When we look back at our biopsies, we see that the MR perfusion is much more specific in predicting active gliomas than it is for metastases. 80% in gliomas, but only 55% for metastases, which is why it's very important in all these cases to do a biopsy, not just ablate upfront. And biopsy is always the gold candle, but what's good about lit is that lit could always be integrated into the stereotactic biopsy workflow. We take multiple correlations from all directions in our cases and we haven't had any difficulties with that. You still have the risk of a biopsy, which is hemorrhage, but that risk is slow and it's been very minimal for us, luckily. It helps not only with a frozen if you're unsure what the lesion is, but also obviously in any adjuvant therapy that will happen after laser surgery, of which any of those are options. We've done everything from chemotherapy to radiation after lit, depending on the situation. When we look back at the safety profile in the 100 patients, very minimal complications, only 4% and they're all minimal. Two wing infections, one seizure, one transient facial palsy. In the literature, if you look across all the data that's been published on lit, there's really been only one or two major complications, one or two hemorrhages that have occurred. And I think those are all learning points and you can read about those separately. When we look back about patients who had a second lit procedure at the same site, so these are tumors that recurred in the same location. We went back in a very similar trajectory for a second laser procedure. We had nine patients. They all tolerated the procedure well. There was no significant side effects, no increase in edema, no increase in any kind of hemorrhage rates. And so indicating that, again, lit is something that you could do over and over again, if needed, and if it's the right patient. So quickly, I'll go through the operation. I think many of you have had experience with this, but it consists of trajectory, image registration, bone anchor placement, laser, a catheter delivery, and then MRI confirmation and ablation. I think when you're planning your trajectory, obviously you use the same rules as any biopsy or DBS placement, avoiding corticovascular, sulci, peel surfaces, avoiding the ventricles, if at all possible, and targeting the long axis of the lesion, because again, you're limited by the radius, not by the length, because you could move the catheter in and out. You have to think about heat sinks, which are areas that are going to be difficult to thermally increase the temperature at, and these would be any kind of CSF space. Additionally, anytime you're close to the bone, like at the skull base or at the cortical bone, accuracy of placement is always key because you're limited by the radius that you could ablate. And so we use an interoperative CT scan, but many places you could use interoperative ORM, interoperative, I'm sorry, we use ORM, but we use interoperative CT or interoperative MRI in order to ensure accuracy. You could always use a frame as well to place these catheters. Again, this was just some pictures of what placing the bone anchor looks like. This is the drill. It's about two and a half millimeters. Here's the bone anchor being placed for the visual asymptote system. And then after that, you confirm your location with the fiber. Here's a case where two fibers were placed right next to each other. Again, you can't place it too close because the bone anchors have flanges and you need to kind of distance them apart. But for larger lesions or lesions that are irregular shapes, this is possible, and we have done that a few times. This is from one of the Rutgers series. After this, you go to the MRI scanner, place your safety margins as I talked about before, and then you start your laser ablation. You confirm you're in the right location. This is a great example of a deep thalamic lesion where you're first ablating the deep area here, you pull the laser back, and then you could ablate the lateral cortex of the lateral part of the tumor. And you can see how well it shapes the actual shape of the tumor without really being perfectly spherical. And that's really because of this, the different densities and different water content of the tumor base of the normal brain, which will really help you with your ablation as you do it. We've also used the ROSA robot for increased accuracy for placement of those. And so for those who have that, I would encourage that it definitely has increased our time of placement. So where are the future directions? Well, I spent a lot of time today talking about extent of ablation. And I think that we still don't have a great understanding of predicting exactly how the ablation will go to the millimeter. And that's because each tumor type has a slightly different density and they're also quite heterogeneous in some cases with necrotic and necrosis in the center or cystic components. And so it is challenging. We attempted to look at this. We published our predictive model of kind of using radio genomics and preoperative MRIs to kind of characterize how the ablation would go. This is one instance here of a radiation necrosis up top and a meningiome on the bottom. And you can see just the rate of ablation and the size of ablation is completely different for the same size lesion. And being able to get that 85% or 100% ablation, if that's so critical, then being able to predict this, it becomes all more important. And I think we're gonna see significant leaps in this ability as the next few years come by. Dr. Katsui has done a great job with looking at this for spinal lesions. He's published his paper on 19 patients where he's used LIT for separation surgery for ablating part of these tumors between right next to the spinal cord in order to attempt some separation for subsequent radiation. It's obviously a delicate procedure that you need a lot of experience with, but he has had success in both controlling the tumor in that area, but also improving pain, quality of life, as well as changing the thickness of space between the tumor and the cord. What about LIT for the Bobo Berra breakdown and chemotherapy delivery? There's been a lot of research dating all the way back to 2003 in this paper by Dr. Sable, looking at the Bobo Berra disruption in rats leading to increased distribution of Paxilitaxel and this is a sham surgery where they just did the fiber itself and then the fiber with LIT itself showing significant diffusion increasing with LIT. And then Dr. Luthart took that to the next step in 2016 when he looked at patients that he did laser surgery on using a DCE MRI, looked at the K-trans and showed that this is a kind of a correlation of the Bobo Berra breakdown in the first four weeks, and then also looked at the serum brain specific enolase in the same time point, and two methods where you could kind of estimate that the Bobo Berra may be more open than you expected, which would focus your time point of giving chemotherapy within the first four to six weeks after treatment. And we've seen a lot of transitions now of, okay, well, how can we take advantage of that going forward? Now we've seen where it could take us, but what is the next step? How do we synergize this technology with everything else that we use to treat some of these very difficult tumors like malignant gliomas? We looked at initially just how does this affect the immune system in the patient by looking at the neutrophil lymphocyte ratio in our glioblastoma patients. And what we found was that in patients that postoperatively have an increase in the ratio showing that their immune system may be upregulated by LIT, they tend to have a much better response to this and shrinkage of their tumor rather than patients where they don't have this immune response. And so the question then comes to, okay, can we combine this with immunotherapy? Can we combine this with vaccines? And how do we do that? What time course and what time period? There's many of the clinical trials are ongoing today. I don't have that data like Dr. Lim because many of those have recently been started and the data isn't published yet, but in the next year or two, it's gonna be very exciting to see that. In summary, what's the benefits of LIT? Is, you know, it's a small, it's a procedure that's minimally invasive, low complication rate. You could do a biopsy at the same time, wingless steroids, no radiation necrosis limit and no limits to your iterations. And most patients go home on post-op day one. And again, when to use it, small lesions, which are deep treatment refractory in frail patients with good KPS where you can get a good extent of ablation. Thank you so much for your time. Here's some more of the work cited. And again, this is the work of many, many people that have been here at the University of Miami. And I just like to thank them all, both the clinical side, the fellows and in my brain tumor lab. Mike, thank you very much for a fantastic presentation. That was a really very nice overview of a powerful tool that's now, you know, a routine part of the armamentarium. We're gonna jump to a couple of quick cases. One that was submitted and I had a quick case as well. We'll answer a couple of questions. I know it's been a long day for for both of you. So, can you see my screen okay. Yeah, that's good. Okay. So the, the first case is a refers to a 31 year old man. He had a great to this is a case that was submitted, and actually has not been done, at least the whole presentation has been provided. He had a great to all go and enter the Alma one p 19 q code deleted verbally low k I 67 and GMT promoted methylated IDH Newton etc. This was instantly instantly discovered after he had Lyme's disease. He was resected 18 months prior. He was initially weak, as you will see this was likely an SMA syndrome but recovered completely, but had slow progression of flare T to signal change, sort of posture to the lesion in his motor stroke. I guess I will, I will ask Mike first, what, what, what do you think about this, how to. What would you recommend. I guess, you know, would you recommend you know the classic regimen. Yeah, I mean I think that again this is a, you know, it was a low grade tumor grade to IDH one mutated illegal. And again, there's concerns here because it is growing into was likely the motor cortex, but it's a very small change, very small flare change and I think that it doesn't sound like he's symptomatic from this, and so I think you have a lot of medical concern for her tissue is whether or not this has transitioned into a high grade, and whether or not you need tissue, but I think that it will unlikely be changing the management at this time point, given the small progression and that you would you would probably just proceed with with chemotherapy and additional radio surgery or if you didn't have radio surgery already. So PCB plus radio surgery or just. What was the treatment that you have first I missed the not anything which is just resection. Yeah, yeah. So then, so then chemotherapy and radiation. Dr. Lynn, I know you've had a lot of experience with radio surgery for what, what are your thoughts here. It's different than the standard. You're muted. I'm sorry you're, you're muted. Sorry I'm muted. Did you say IDH mutant or not I apologize. Yes, yeah. I mean look, I mean, at this point, you know surgery can help unless you get like a super total resection I mean this patient got a great resection and there's some that recurred so you know the, there was very nice studies that showed that doing the PCB chemo is I think a big difference and these patients can do really well with that. So, you know, I think, you know what my recommendation would be going down the PCB with, with any with radiation or without or something on radio surgery or not or. I believe it's just PCB right and then if you have additional growth you have the option of radiation. The thing is now that this patient also has an ID mutation there's some exciting trials coming down the pike. And that could potentially, you know, put them on an IDH inhibitor to so there's, you know, a couple different options for these patients, and, you know, I think that there's really nice, you know, phase three data that shows that PCB works, probably good on that path. Right. Excellent. Just one more quick case. 65 year old man present with some headaches and a little bit of confusion, but overall oriented in some left side weakness up past my history was, he does have NF one. He does have a previous history of IV drug use but claims to have stopped. He's an aspirin. He has these elision here. Relatively sizable leisure and can enter stride and budding internal capsule. There's some diffusion restriction internally but it looks more like hemorrhage. So, next steps. Can you go back to the, to the clinical description. So, relatively well functioning. Some, some four plus weakness ambulatory. Okay. Actually, I'd be curious to see what you think like, you know, in this situation it's a deep sea lesion. I think the guy is already getting weak it's not any 65 years old and sounds like he has some comorbidity so I think it's not unreasonable to consider doing a biopsy get diagnosis. And, you know, the patient's going to probably need to go into chemotherapy radiation. There are people have done stuff like tubular retractors and gone in there and developed. And I've seen some people doing that. But, you know, I've seen some people. And I was hoping you could comment where you've put a couple of those lasers down there and, you know, been able to quote get your 85%. Is that a situation you would do that. Yeah, no, I think that's a great, great way you know I, there's definitely reports of the tubular retractor, I went when it's this intimate in the, in the internal capsule. I think I find it difficult to kind of understand, you know, the anatomy when you're looking through that to kind of preserve that post care border especially if you get in there and it's very vascular tumor which on that sequence, then the next slide indicated it could be. So that would make me a little bit concerned about trying to do a big surgery in a small port so I would I would favor laser surgery on this one. Again, Dr. Lynn bring up a good point is that it does look slightly larger than the three centimeters and have to measure it carefully to see if, if you could get it in one fiber on a different trajectory, because sometimes you don't have to come down from here you can kind of come more through the forehead. If that's long access because again these are such small incisions, you're not limited by the hairline again. And then the question becomes, you know, if you can only get a 90% of less in which way do you focus do you focus more close to the post your aspect that's closer to the internal capsule because you're trying to save that, or do you spare that area because you don't want to risk making the weakness worse, and that's kind of still up for debate. I tend to go a little bit closer to the area that I definitely want to kill with very close margins and try to ablate that we have done. I've done three cases with two fibers. It's, it's challenging but it just takes a little bit longer than expected but the patients have done very well with that and we haven't seen any problems with that. So obviously biopsy would be important to right so I mean it was, it was also isn't, you know, this looks very much like a GBM, and that my, my initial reaction was to proceed with a biopsy potentially even just proceeding with human radiation, I'm back as clear plus number after discussion or a tumor board was felt that it was really bulky and some cytoreductive surgery would help getting through treatment. I was, as Mike said was, I was a little bit concerned about the tubular approach just because you don't really have good landmarks, it was sort of working at the depth and especially with that abutting the internal capsule in the back. So, a little bit unconventional by. May seem a little bit too much for for someone like him but actually worked out well sort of going intoospheric. And just a brief video of the labor, the point of similar, similar cases but going from one hemisphere in terms of, you know, and then eventually making the contra lateral ventricle. So, is again on tier is posterior. They get a call us out of me. And jumping to into the tumor. We use up cortical motors. And when it got down to 5 milliamps of stimulation in the internal capsule was, you know, as usual, stopped. But, and then obviously as concerned for the anterior strides so when when there was some bleeding I sort of, I thought to be more conservative, so we stopped, but left a decent amount, you know a carpet over the internal capsule. But this I include this case to see actually if Mike would would have tried like to to laser for us to try this is a little bit more on the, on the border where we would do something like this. Yeah. A little therapy. So I wanted to get your opinion. He was not the greatest. As expected from his age group, etc. Okay, he was on your place on a stop regimen. Just a couple of questions and one for Dr. Ivan. What, what would you think is an ideal case for primary treatment with lit. I think that if you're early on in your lit career, I mean, choosing the safest tumor in a safe trajectory in a safe area is the best one to start with. I mean obviously as you get more experience you can understand that but tumors that are, I think metastatic tumors that are refractory to radiative surgery and surgery, or radiation necrosis that is refractory are really the best. I think that's where it has the best advantage and that's what we found in our data as well it's we were using the most, and we've had the best local control, and these patients leave and they just we follow them and the tumors just kind of involute on themselves and so that's definitely the best scenario. We have a stone was I think the future holds combination therapies and with something else and I think that's where we're going to see a big benefit. Excellent. And one last question for Dr. Lim. Dr. Lim if you had to choose one modality that you thought would be the most promising in immunotherapy going forward, what would that be. I think that's a great question. So, um, you know, I think that there are a lot of interesting approaches. You know, I do kind of agree with the majority of the folks in the sense that, you know, going after just T cells, like the, you know, the checkpoints may not be enough. And I think that there are a lot of these new myeloid inhibitors, you know, macro patient, and such macro page and microglia and dendritic cells and I think that that's where we'll probably make a dent and see some results. I have a question for Dr. Lim as well. What progress have we made in understanding the immune system and the immune status of the tumor preoperatively before we have to make some of these decisions on what immunotherapy to use and what you know if we go to some of these immunotherapies are using before surgery whatnot like how well are we going to, are we learning about that and where do you think the future is with understanding it before we, we even get to the tumor. Yeah, I mean I think, well first I think you highlight the problem that glial blastomas are really a heterogeneous group of tumors, I personally think when we do these randomized phase threes we're doing what I call basket trial, because we've come to appreciate that glial blastomas there are many subtypes within them. And so there's probably signals with some of these immunotherapy trials that just, we're not picking them up. And so, as we get better in being able to. First of all classify these tumors and I think I'll have to be done invasively. Then we can do the correlative stuff with like all the neat things with like the circulating tumor DNAs and to be able to help classify and then we can figure out what the Achilles tumors are and if indeed it is an immunotherapy that can work against them. Then that's, you know, where we'll be heading. But, you know, right now. It's, I think that we have to be a little bit more biomarker driven for these trials and and to do the neo adjuvant trials it's more of a mechanism and an understanding what their drugs doing but it's not necessarily ready for. I think we're trying to do it in lung cancer but we're not really ready and glial blastoma yet. If we find something that impacts like 20% of glial blastomas then certainly we'll go down that path. But, you know, there it's it's interesting like the stereotactic rate of surgery, there was a big abstract they gave stereotactic rate of surgery with checkpoints in melanoma, and there's actually a something like a 19% improvement in survival There are things that we as surgeons will be asked to do and we'll be seeing coming down the pike for at least immunotherapies, maybe not with glial blastoma initially but with other things. I have a follow up question. Right. And if it's a deep seated lesion that's lower. Would you mind commenting and sharing like your tricks to try to because being off by one or two degrees can be a pretty big problem for deep seated tumor. Yeah, yeah. So I mean, we use. I mean the first thing is accuracy we use the five bone fiducials, and then we use the Rosa robot for accuracy. But before that when we were just using kind of the mobile arm we did have some issues with skiving especially when you're going through thinner bone, or in the back. When you're going through muscle either the temporalis muscle or the occipital muscles, it becomes really challenging you definitely have to open up the incision a little bit more. The other thing is is just getting used to kind of these trajectories that are not typical you know like going through the forehead, going through things that are different areas where you may not have really thought you could do an incision before we've we've done that to try to prevent that skiving but yeah anything more than, you know, 25 to 30 degrees is where you run that risk of the drill kind of going off on the outer cortex and kind of going into a wrong trajectory. And that, that makes it very challenging and it's rare to need that kind of trajectory for the skiving but it does happen. And in those cases, you know, we just try to make sure we anchor is as close to the bone as we can, and just go, you know, really careful with the drill and then make sure you confirm that trajectory intraoperatively because you don't want to leave the operating room we have an MRI outside the operating room so we have to leave the operating room, you want to get to the operating room and find out that you're five millimeters off target and you're not going to get a full ablation because then it's, it's basically just making one case into two cases for the day. I know Dr. Lim has to leave but I can't let George leave with that case so I have a quick case for you George a very similar one if you don't mind. Okay, of course. Yeah, so 49 year old gentleman who's a lawyer comes in with just some mild right sided weakness. I don't have all the imaging but has this large lesion. If you look at it carefully there's a lot of mass on the lateral aspect and the medial aspect in the ventricles is quite cystic and CSF filled. So, you know, what would be your, your options here I mean you have some concerns of hydrocephalus he doesn't have it yet but he probably will soon some mass effect, very mild weakness. No, I don't have them right now but it doesn't go into like the deep soundness, it just kind of, this is kind of the depth of it doesn't go into the brainstem evolving kind of the corpus callosum and a lot, this, this wall of the filament wall here on the left, down to the, to the capsule which is pushed a little bit lateral here. Did the T to suggest like a neuroscience. No, no. Everything's invest GBM. So this, this is emanating from the thalamus. Yes. Okay. I think like a similar approach, like a contralateral in terms of Eric, I think that will work well. Potentially, you can dive into both ventricles I think the one going on the right side is not as extensive so coming from the right and going to the left. Yeah, I will work well for that. We talked about that as a possible option I thought that would almost be best because it would kind of help his hydrocephalus. But when we were, I was kind of also the fence of Dr. Lim of saying well I don't really trust that radio, radio, radiation and radio, radio, radiology is saying GBM and I really want to buy a scene if I'm going to do a biopsy, I should just laser it as well. So I lasered it, and I chose the technique of kind of going on the lateral aspect here, you can see laser ablation here on the lateral aspect. I didn't try to get all the deep stuff in the ventricle because it was very flimsy. I came back as a GBM IDH one wild type MGMT wild type. And he went on to get radiation chemotherapy, he had a little bit of transient weakness for the first two weeks post operatively. And this is him 15 months later, with only stoop protocol and laser. So, why that happened in this case and not in some of the other cases I wish I could tell you as much as Dr. Lim could tell you why immunotherapy works in some cases but we don't. You know, sometimes, you know, that this works incredibly well and this is just one of my own cases that I've had. He's still practicing his law practice and he's doing really well we did have to place a shot as you can see here. But other than that he's doing very well and so far as well controlled. So, that is remarkable. This is a story to end on for laser. Yeah, great case. Well, I'd like to thank again for Dr. Lim and Dr. Ivan, for all the wisdom tonight and all their time I know it was at the end of a long day, an ongoing day for Dr. But, um, I, I learned a great deal listening to both of you and I know everyone that's going to be watching this webinars will as well. So thank you very much again, and I hope to see you soon. Life. When all this craziness goes away. Thanks so much. Pleasure. Take care guys. Bye bye.

immunotherapy

brain tumors

glioblastoma

checkpoint inhibitors

combination approaches

laser interstitial thermotherapy

minimally invasive technique

tumor shrinkage

recurrent glioblastomas

indications for LIT

benefits of LIT

low complication rates