I'd like to welcome you to yet another episode of the Front Row series, the new series from the WNS NeuroU, the official educational website of the WNS. Again, with this series, we have renowned experts from around the world focusing on skull base surgery, cerebrovascular surgery, tumor radiotherapy, and many more. Participants have the chance to have access both to the live events as well as the archived events with CME that are bundled. For the first time, participants also have the chance to submit their cases for expert discussion. Today's webinar is not that heavily clinically based as usual. We're changing gears today. But our experts really need no introduction, Dr. Ian Dunn and Dr. Albert Kim. I've known both of them since I was a medical student, just sort of running around helpless. But they were both residents at the time, and it was very evident at that time that they're going to be superstars going forward. And for sure, that was very clear that it happened. Dr. Dunn is the chairman at the University of Oklahoma. He's the Harry Wilkins Chair in Neurosurgery. He has really spearheaded the notion of a skull base surgeon scientist and has produced much of the existing literature in new developments, particularly in meningioma, but other tumors as well. And today, he's going to talk to us a little bit about molecular and transnasal advances in skull base tumors. And Dr. Albert Kim, he's professor of neurosurgery, genetics, neurology, and developmental biology. He's really the prototypical, again, physician scientist that really just constantly looks for the next thing, the next frontier, how he's really going to change the world. And I've always really admired this on him. And today, he's really going to tell us a little bit about how to try and be successful in doing both and really not sacrificing anything. I'm also joined today by Dr. Setri, who has been a very good friend and a gifted surgeon and also a scientist, and we'll have some interesting discussions at the end. To be respectful of everyone's time, without further ado, Ian, why don't you share your screen, and we really look forward to what you have to say. Does that show up okay, George? Yeah, it's perfect. Well, George, thank you very much for the introduction. For the record, George Zanonis has never been helpless, and it was great to see him chart his career, and no surprises, here he is. And Albert and I were co-residents, and the NIH has a budget shortfall because so much funding is going to Albert, so he is a preeminent surgeon scientist, and Dr. Setri, as well, so a terrific company to be in, and I appreciate the chance to talk to you. George, I'm just going to disagree with you on one point, that you said that this is sort of a little less clinically relevant. And I think Albert and I hope to make the point that just as a glioma surgeon would never really manage a glioma without thinking about IDH1 or 1p19q or MGMT, I think we're going to enter an era, even in cranial-based surgery, where what is deriving the tumor really helps define and inform management. And so not your quintessential skull-based talk, but I think it's going to be increasingly relevant as we move forward. And most of you don't know where Oklahoma is, so that's my representation from Oklahoma here. So this is just a, you've seen charts like this for decades, that any cancer center, that anybody on this call is a part of, really defines the tumors that they manage or treat or their colleagues treat, but with an increasing number of molecular alterations. And interestingly, some of our most common tumors in neurosurgery really are not focused on or not dealt with in that way whatsoever. We still define them really by histologic parameters. So there's sort of a gap, a pretty significant gap in our understanding to the point where those tumors at the cranial base haven't joined, by and large, lists such as these. And this is a CV trust data just to justify that and substantiate the point that these tumors are important. It's over half of the tumors that we deal with and that we like to deal with, that are technical in terms of forces, that we train heavily and hard to take care of well. And generally, we're speaking of meningiomas, pituitaries, chordomas, and rare tumors, tumors of the sinuses, metastatic tumors, and things like that, and they constitute sometimes entire practices of ours and our colleagues. This is a gross generalization here, so bear with me, but what have been the major themes in skull base over the past, let's say, 50 years? It's how to do the surgery. Once the microsurgical anatomy was defined, once pioneers like Yazergill and then Rotin, who helped define that microsurgical anatomy and colleagues like that, then you had this entire intrepid area where it was how to do the surgery. And then you entered an era of, well, what about collaborative skull base teams? Who to do it with? How to restore pituitary hemo homeostasis, and we take that for granted now, but there was an era of that surgery where that was incredible morbidity. And so that's been a pivotal development in skull base surgery. And then how to handle residual or recurrence, or in some cases, how to attack de novo and how to treat upfront and the evolving radiation. What's really, really fallen behind significantly is what drives the tumors, right? So that hopefully will be the next row thematically in skull base. So I'm going to give a snapshot of some of the larger efforts going on, and I'm going to not be able to reference everyone's work. I'm just going to give a high level overview of what is going to be a standard part of your pathology report. If it isn't now, it will be in the coming years. You'll either do it at your own center, you'll either send it off, but you'll be getting increasing amounts of information on the tumors that you remove, and you'll use that information to try and predict recurrence, predict behavior, and perhaps try and treat adjuvantly. And so we'll start with probably the most common, what's received the most attention, which is mutational profiling and those implications. And we'll start with my personal favorite tumor, meningioma, but it's also received quite a bit of attention. And what I'm showing on the right is just your general World Health Organization classification. We rely on that heavily. And generally I tell patients, 95% of these tumors are benign. I think increasingly some people are referring to grade two as cancer, but technically it's not. But you can see some of the gaps that emerge if you just study the WHO criteria carefully. You can have fewer than four mitoses in grade one, and you can actually have anywhere between four and 19 in grade two. It doesn't take a lot to imagine that there's tremendous heterogeneity in those bins. But certainly in the last eight years, work from a number of groups has helped us understand that meningioma is not just a tumor that in a sporadic sense is driven by NF2 mutations. Really weakly, there's another mutation identified in the meningioma landscape, but there's a mutually exclusive and overlapping pallet of mutations, and actually in grade one meningioma, that's important, in grade one meningioma, and then an additional number of mutations targeted here that I list here. And these two have received quite a bit of attention. They're rare, but they're the same alleles involved in other tumor types. And Dr. Brastianis and others have spearheaded a trial targeting of recurrent progressive tumors that harbor those mutations. So even that, it wasn't that long ago that we weren't even thinking about molecular profiling of cranial-based tumors, and now it's being used to drive inclusion in particular trials. But that information is not just useful for therapeutic targeting. It's also useful for understanding the biology of these tumors. And so when those two mutations in particular occur, they tend to occur at the skull base, which is helpful because those can be difficult to manage in their current setting. And interestingly, this is work from Michele Kalmarides, inside the grade one category, if you have an olfactory group meningioma, if that tumor harbors a smoothing mutation, that's typically where they occur, they're more likely to recur. So that's really, again, these are grade one tumors, same extent of resection, different biology based on the mutational profile. And then there are increasing numbers of reports like this where that information, this is an AKTM1 mutant, a WHO grade one meningioma, is being targeted, and increasing number of case reports. And it's emerged that the AKT or mTOR pathway is active, and there are increasing number of trials where activation of that pathway is being used as an inclusion criteria for different therapy targeting. And this is a slide just detailing a trial I mentioned earlier, the Alliance trial, and I would highlight Dr. Brastianos' tour de force in pulling this trial together. Jennifer Malterno from Yale, this is a very nice study recently, again, lending support to the notion that mutational information is not just important for therapy targeting, but each of the mutations I show here, that they show on the left panel, is associated with a different natural history within grade, and some more favorable, some less favorable. So within grade, how that information should be used, I think, is still an incredibly large question going forward. Unfortunately, this grade two and grade three meningioma landscape, the tumors that do record more commonly and can be more nefarious to treat, just harbor a totally different mutational landscape. And I think it's really important that the audience just be aware of and know if your foundation or Tempest or Mayo or whatever, or in-house pathology report in these tumors in particular, suggest TERT mutation, BAP1 loss, or CDK, N2A, 2B loss, those are significant predictors of recurrence across grades, but especially higher grade meningiomas. So what about pituitary and perineum pharyngiomas? I'm sure you see tumors like this in your practice. In pituitary, I would say, as common as they are, still not a lot known about what drives them from a mutational standpoint. You should know that fewer than 5% are part of familial syndromes. I just annotate those here. And these are genes that, by and large, are not altered in sporadic tumors. And really, the two most common genes that are altered in sporadic tumors are still GNS and growth-homogenic tumors. And more recently, and I'll talk about this in the next few slides, a USP8 mutation in Cushing's disease in ACTS-3 tumors. And I think there's a lot of excitement, and that's been incredible work done recently. Overall, very few mutations across your standard pituitary adenoma when you compare it to other tumor types, and that wouldn't be surprising given their overall natural history and growth rates. This is, I think, the most exciting mutational work done in pituitary in the last few years, and it's been the identification of this particular mutation in Cushing's disease in a gene called USP8. And a couple of take-home points, and a very small percentage of recurrent BRF mutations in Cushing's adenomas, but a couple of take-home points here. If you harbor the mutation, those tumors tend to be less invasive and have a better chance of remission. Their USP8-mutated tumors have a higher expression of SSTR5, which has implications for other adjuvant use. And so overall, if the feasibility is right, it may be useful to genotype for USP8 mutations in ACTH-expressing adenomas that are resected. A lot of attention to craniofringoma. Most of the audience are probably familiar with this, but I think it's absolutely critical. I would suggest probably mandatory to be aware of this work at this point if you're dealing with craniofringoma overall, which is that in general, these two subtypes that we classically learned about are really almost exclusively driven by a single mutation in each one. So most attention being given to the BRF mutation in papillary craniofringoma, which unfortunately is a rare subtype overall. And that's led to a very popular trial, well-discussed trial targeting the BRF mutation in papillary craniofringomas. And I just want to show a couple slides. This is a patient who had two operations. I operated a third time, had a complete resection. And two years after the surgery I did, this was essentially a minimally symptomatic recurrence. so I always feel like those patients would be ideal almost really to enroll in trials because there's really no symptoms and it's a rare graphic recurrence. These are the inclusion criteria for that trial that I alluded to, and this is the cohort B for recurrent craniopharyngioma, so the patient was enrolled in that. I would highlight actually cohort A, which hasn't gotten as much attention, but to be involved in cohort A, you actually just need to have a biopsy. I think that may, even if it isn't already in some centers, is actually changing the surgical paradigm for, I think, less surgically avid groups are really sticking to these inclusion criteria quite avidly, so theoretically, you could just do a biopsy, and there are some radiographic indicators suggesting papillary tumors as well, but I personally, I believe very strongly in the recurrent cohort for sure. Interestingly, three weeks after starting BRF inhibitor treatment, this was an MRI in this particular patient, and that's been durable over a year and a half. I want to highlight an even rarer tumor, chordoma, and this is a landmark paper from a couple of years ago, not a complicated genomic landscape for chordoma, but generally driven by amplification of what has now really become a pathognomonic marker, histologic stain marker, a brachiori amplified in about a third of patients. We'll come back to some interesting strategies to target this at the end of the talk, but I think a couple of things I would hope the audience would remember that there are genomic drivers identified for a large number of meningiomas now, unfortunately less prominent in the more difficult-to-treat, higher-grade meningiomas, and mutational profiling, we really need to understand them as neurosurgeons, not only to understand which patients of ours may be eligible for trial enrollment, but also they have different natural histories overall. Pituitary tumors, very few mutations, and I think USPA is particularly interesting in Cushing's adenomas, and I think BRF mutations, again, it goes without saying, that's changing the landscape of how to manage chronic meningiomas. I think the next couple of categories are still not really used principally, but I think increasing outside and internal tumor profiling are evolving this information, so it's useful to review, and I'll focus mainly on meningiomas, and that's really the notion of copy number. What does a chromosomal complement in a tumor look like compared to a normal cell, and generally just as a cartoon showing that as you ascend and grade a meningioma using meningiomas that have not been tested yet, you have an increasing spectrum incidence of chromosomal destruction compared to the normal complement as you ascend and grade, and generally, what has been accumulated in literature is that there is a specific hallmark pattern of those copy number changes or chromosomal alterations in grade one versus higher-grade meningioma, and really, overall, there's actually, if you say, what is that relationship between a standard histologic grade one to this copy number or molecular grade one, there's actually a pretty incomplete comparison or fidelity between the two, and you wonder if biologic indices like copy number or other biologic metrics are really more of a faithful footprint of the behavior than histology, but this is really nice work from radiation oncology star at the Brigham, Alizer, very simple, the greater the number of chromosomal alterations controlling for grade in the extended perspective of meningioma, the more likely to recurrence, so there's some biologic relevance to that, and Linda B. and Sandra Senegad and others at Brigham are driving a really nice molecular classifier right now where, again, just aggregating number of chromosomal alterations that are reported, and in general, that arithmetic sum is more predictive of recurrence than your standard histology grade, so when you see lots of copy number alterations, particularly lost in meningioma, even in grade one, that tumor is likely more, is certainly more prone to recur. That information in other tumors at the cranial basis is certainly less well-annotated. Pituitary tumors have an interesting pattern of copy number alterations on both of these. These are from different groups. Pituitary tumors have absolutely no chromosomal alterations. Some are highly disturbed. The exact clinical significance of that is unknown at this point. Even chordoma, this is work from Dr. El-Mefti well over a decade ago, and just showing even in chordoma, just one or two chromosomal alterations dramatically alters the recurrence-free survival prognosis controlling for extended perception, so there's a theme that the more disturbed the chromosomal complement in a cranial-based tumor, the more likely these are to recur, and that these may inform recurrence and survival, and it's likely, and we'll talk about methylation in a second, but these more faithful biologic indicators, more faithful than histology, are certainly more likely to explain some of these in-grade differences of behavior that we all have, that we all see in our practice, and I think that genomic profiling, not just mutational profiling, will certainly become part of our standard practice overall. Just briefly, I want to talk about what I think has really been a huge sea change in meningioma in particular, and that's the idea. We talked about genomics for the last first 10 minutes of the talk, but looking at the epigenome, and this is work from Felix Somm, and I think Felix Somm and Gelo Rezade and a few others and Ken Odape have really driven this work, really in an unbiased way classifying meningioma by their methylation pattern, and this is a very powerful Lancet paper from a few years ago, and generally subdividing meningioma and their behavior into five overall classes, some of which, by methylation pattern, I won't linger too long there, but in general, some of it correlates with genomic findings, but I think it's probably good enough for this talk just to suggest that you look into that further because it's incredibly powerful work, and again, I want to highlight Gelo Rezade's work as well, and they have published a really nice work showing that DNA methylation can be incredibly powerful as a predictive tool in understanding recurrence. I'd say the only drawback probably here is that it's not as scalable yet as standard genomic techniques, so it is more difficult to obtain methylation profiling than it is your standard, for instance, foundation or other reports. Just like I mentioned earlier, this is almost like a flight map comparing histology. This is from Felix's paper, histology, a large complement of tumors, and how sort of unfaithful it is compared to methylation class, so again, likely these other indices of behavior will be more predictive than histology, and the last word on epigenomics, really, I want to highlight work from Dave Raleigh at UCSF. This is a super-answer work, but using super-answers and other epigenetic means to derive transcriptional networks and how that's incredibly powerful, again, not only for natural history prediction, but also for deriving novel therapeutic targets. It's also relevant for pituitary adenomas. You remember before 2017, we had a very blunt way of understanding pituitary adenomas. That's in the top right here, that it was either atypical or, I mean, I think I've seen one carcinoma or two, very rare, but generally typical or atypical, defined by sort of really blunt histologic metrics, and I think it's gotten more complicated since 2017 with the new World Health Organization, but it certainly tracks along…now pituitary adenomas are defined by transcription factors, but those also track along methylation and epigenetic patterns, so that's also relevant in pituitary as well, and just to remind those that are a little bit behind on those World Health Organization metrics, these are five high-risk pituitary adenomas we should all bear in mind in our practices. And so, certainly, methylation is to redefine natural history of meningioma, and I would urge you to dig into, in particular, Ghelleray, Azadeh, and Felix Sam's work, and Ken Odape's and others, and Dave Rowley's, and like other classification methodologies, it will be very useful for natural history, recurrence prediction, and target identification, and overall, I think another question…actually, Albert has written extensively on this, you know, what's going to help us understand which tumors may respond well to radiation and which won't, and just other incredibly important clinical questions like that, and that's going to be…that's going to rest on how well we understand the biology of these tumors. We really can't talk about any tumor right now without talking about biomarkers and checkpoints, and so, just like in cancer, it's also reached the skull-based and cranial-based world, and I don't think anybody really needs a reminder of what that means at this point, but those are…checkpoint blockade essentially turns off the off signal to activate immune cells against cancer, and that's being widely…or attempted to be applied in cranial-based disease as well. Sandra Senegade and Ziming Du have shown a few years ago that as you increase in meningioma grade, you increase in the expression of PD-L1, probably the most commonly discussed checkpoint at this point, and that's led to David Reardon and others employing that anti-PD-L1 strategy in recurrent high-grade meningioma, and the paper publishing that trial is just coming out now. Chordoma also expresses a wide range of checkpoint proteins, and this is a really nice report showing a few successful deployments of nivolumab in relapsing cases of chordoma a few years ago. I don't know about the rest of the panel. We have tried that, and I've seen that tried in a few patients with varying degrees of success, but PD-L1 is also expressed in pituitary tumors, and there's been a few nice published efforts where…describing market responses of particularly hypermutated ACTH-secreting tumors in the pituitary to checkpoint inhibition. So in salvaged cases, you may consider staining for PD-L1 and PD-L1 staining and employing immunotherapy if you're really in a desperate situation. We have tried that clinically on one patient and multiple recurrence, and we did not see a significant response, but it's obviously not that simple. Just because we're in the age of vaccination, I want to highlight, I think, a very interesting strategy to attack chordoma, and those of you who deal with chordoma, there are those difficult chordoma cases that we face, and I want to recall a slide that I showed earlier where the hallmark alteration is amplification of a transcription factor, which by itself can be difficult to target, and brachioradialism involved in epithelial-mesenchymal transition, but there's been an interesting and it's ongoing phase one trial of a yeast brachioradial vaccine, so I felt compelled in the age of COVID to show this slide, but just showing you attempts to harness the immune system using traditionally non-targetable alterations like amplification of a transcription factor. Even benign cranial-based tumors can express immune checkpoints and have varying profiles, and those include meningioma, pituitary adenomas, I mean, every tumor that is going to be surveyed is going to have some degree of expression likely at this point. It's been deployed in treatment refractory tumors, and for less energetic tumors, obviously efforts are ongoing to understand how the immune system can be manipulated there. So I mean, this is your standard, I want to end with this, many institutions now will give you a standard pathology report, but by and large, for a skull-based tumor, we'll give you grade, and maybe you'll get approval for the next, but I think it's going to get much more complicated, and I think probably most people on this call are seeing versions of that. You'll see, maybe you'll get non-invasive biological, maybe you'll get a liquid biopsy before surgery, which you'll use to perhaps treat new adjuvant, if you're able to assess some sort of therapy target in that way, and the patient is treated, maybe has surgery, and then that tissue is going to be subjected to an ever-increasing panel of assessment, and so forth, and that information will be used to understand or suggest response to adjuvant treatment, additional therapy targets, and so forth, and then upon recurrence, that cycle will begin anew, but at the core of all of this still remains doing a really good job in the operating room, and I would just suggest to all of us, even though it seems non-surgical, I think we are probably in the best position to understand and deploy this information in our own practice going forward. Thank you. Wow, Ian, that was a spectacular tour de force of both the existing data, as well as really a glimpse into the future, and where things are and should be going. We're going to hold any questions for now for our live participants. Please put your questions in the chat, and we're going to switch gears to Dr. Albert Kim, and he's going to tell us how to be successful as a skull base surgeon or a surgeon scientist. Thank you. So nice to see all of you. Great. So thanks again, Dr. Zanonos. It's always great seeing you. It's been, I mean, I guess with Dr. Zanonos and Drs. Dunn, we're almost pushing two decades in terms of how long we've known each other. It's, it's remarkable. And I knew both of them would be leaders. And so that's great. And, and Vroon, nice to see you. I know your trajectory is on the upswing as always, and nice to see you. So, you know, I'm going to be talking about a very different topic. This is not only going to be skull base based, although I would argue that there are many lessons here from other tumors that you can bring to skull base. And maybe these, it amounts to just a bunch of thoughts by me, maybe some of them misguided, but perhaps they will help some people in terms of paving your way to an academic career. These are my disclosures. So there are a lot of challenges for a neurosurgeon scientist, as many people have said, this is really like doing two jobs or maybe even three jobs. And why is that? Well, there are a lot of things to consider, right? And they're, they're all of these things, time management being a really big issue. And so there are all these issues to juggle, not to mention things like refinancing your house and mortgage and things like that. And so, so how do you do it? Well, I would say, first of all, it is totally worth it. And you know, I, it is challenging certainly in the first three to five years of your career, but looking back on it all the hard work I feel was certainly worth it. And, and I'm sure Ian Dunn would also agree. I mean, he is now literally on the bleeding edge of benign tumor, meningioma pituitary genomics, and it's just so, so great to see that. And so it is incredibly rewarding. So my practice is about a third lateral skull base, a third anterior skull base and a third intrinsic. And so I've really dug into each of these areas to, to, to learn about each of these tumors. So I would say, generally speaking, my research looks at sort of malignant tumors as well as, as well as aggressive features in benign tumors. And so what do I study in the lab? And this is the building we're in. We're on the sixth floor. It's beautiful. We can actually see the arch from there. And so, you know, the first thing to think about is what are the sources of inspiration for the kind of studies you do? And so there are a number of places you can look at and you can think about just pure curiosity about fundamental biology of a disease that's possible. I mean, maybe it's transcription factors or epigenomics, like, like Dr. Dunn was saying. It could also be a clinical technique that requires better understanding, things like that include things like maybe focus ultrasound or, or laser interstitial thermal therapy. You know, we have some idea of how they work, but perhaps we don't entirely understand the biology that they, that they influence. And then finally, of course, clinical observation that, you know, a really well done case series, case series can still shed a lot of light on on important aspects of a patient's biology and disease. I, to this day, I firmly believe that. And so let's talk about a few of these. And, and again, these are not all directly relating to skull base, but I think you can get some lessons from them. So I'll tell you a few vignettes. We're going to begin with pure curiosity about fundamental biology. So this is a study I did with Dr. Dunn's brother, Gavin Dunn, as well as some, some very talented people in my lab and a genomics expert, Chris Miller, where we looked at a bunch of ID21 wild type tumors. And we found that if you took two different sectors from a given tumor, you would find that half of the mutations or more were different. So if you take a single site biopsy, you're not really getting a good sense of the GPM. And the interesting thing about this is this is true, or even more true in diseases like high-grade meningioma, which Dr. Dunn has shown. The, the number of subclonal, in other words, mutations that are not shared between different areas of the same tumor is just incredible, more so than even GBM. And so this is something you'll see in a number of different tumors. And so, so we saw this and we thought, well, what are sort of the implications of that? Well, that means that if you have a bunch of tumor cells in one tumor and they have different mutations, for instance, that if you impose a stress on them, that maybe you'll only get a subpopulation of them responding. And so what is some hard data for that from, from the GBMs? This is what we found on the left. If you think about this from a precision medicine standpoint, you'll see that in one sector, you'll see mutations and potentially drugs for certain mutations, but in the other sector, maybe you see one drug in common, but the other, the other possible targets for precision medicine just aren't there. And similarly, if you're looking at different neo antigens, and this is as predicted from, from the exome data, and you think about possible vaccine approaches on the left here, you see a number of neo antigens that are shared between two sectors in the same tumor, but then look at this. There's a whole bunch of neo antigens here that are only in the second sector. So you really have to think about this in a multi-sector way. And so, you know, I think about that and, you know, at some level you think it's like tumors and especially GBM are, are, are basically like genomes that have a grenade thrown into them, right? How do you, how do you understand the mechanism of a grenade exploding? I mean, that's at some, some people would say that's, it's impossible. So another way to think about that, and this is something also that Dr. Dunn mentioned is, well, how, how might the genetics be funneled through a common mechanism, perhaps of epigenetics? And that's what we've been thinking about. And so epigenetics as everyone knows is how genes are expressed. It's not the DNA mutations themselves, and it can involve things like DNA methylation, as he mentioned, as Dr. Dunn mentioned, histone modifications and transcription factors. So all of these remodel how you express genes. And so, you know, why that is important is in tumors, and I would argue probably most tumors, there's a sort of a genetic clonal component here, where you have different mutations and different subclones, but you also have at the same time an epigenetically defined sort of network or hierarchy occurring. And this is certainly true in glioblastoma, where you have a stem-like cell, like a glioblastoma stem cell, and that gives rise to more differentiated cell types. And this is likely to be true in a number of different tumors as well. And so that is clear that this is epigenetically regulated here on the right. And so what we do is we study, among other things, glioblastoma stem-like cells. We took them out of a patient's brain, we get them onto addition 30 minutes, and then we do assays like this. And what we found is that when we look at them, they look like these little hairy creatures here. This is on, we're using smooth electron microscopy. It's kind of fascinating just staring at these. And when we look at them at a molecular level, at an epigenetic level, the interesting thing we find is that they all express SOX2. So it doesn't matter, we have 170 lines now for GBM stem cells, but regardless of the mutation you express, all of the lines express SOX2 in a majority of their cells. So something epigenetic is going on here. And moreover, Suva and Bernstein, in one of their seminal papers, showed that SOX2 is really important to reprogram your cells into tumor initiating cells. So there's something special about SOX2 that's sort of a common funnel for all these different mutations and different genetic contexts. And so that's what we were interested in. And in this earlier paper, we showed that this interesting ubiquitin ligase, which controls mitosis, not only controls mitosis, but also protects SOX2 in glioblastoma stem cells. And more recently, we've been interested in how SOX2 stability is controlled. So what we did there is we immunoprecipitated SOX2 from these glioblastoma stem-like cells. We put them through mass spec and we found a whole bunch of proteins. And in a more recent story that we're working on right now, that's led by this very talented MD-PhD student, Tatenda Malikuzera, we found that there's this choreography, this dance between different proteins that are different E3 ligases, some of them protecting, and some of them degrading SOX2. And what we think that's what's happening is that basically acute microenvironmental changes probably allow you to flexibly change how SOX2 is acting as a transcription factor. So that's one sort of area from which you can draw inspiration. Another is a clinical technique that requires better understanding. And, you know, one thing that is a fundamental challenge in our field is that the BBB or VTB are restrictive. And so you get systemic therapy that can't get into the brain because of the BBB, VTP, and the tumor grows, right? And so we and other centers are using laser interstitial thermal therapy to kill tumors in an inside-out fashion. But, you know, beyond just heating them and denaturing proteins and killing cells, there are other things going on. And so among those might be disrupting the blood-brain barrier. And early evidence for that was from Eric Luther and others from my institution who showed through different MRI, fancy MRI techniques, which I don't entirely understand, as well as from serum biomarkers, that there's this window of time after laser, about four to six weeks, where regionally, locally, the blood-brain barrier is open or the blood-tumor barrier is open. And so we were interested in studying that. And so we set up a mouse model here using a laser system that is very similar to the one that's used clinically with approximately a 1064 nanometer laser. And this was led by Dr. Salehi, Dr. Patel, and we had a collaborator, Robin Klein, who was really a world-class neuroimmunologist. And so she was helping us with this as well. And we could achieve temperatures that are very similar to what you achieve with laser, something to the order of, you know, 43 degrees to 60 degrees, and we could do this in mice. And so we found that when we do this in mice, and this is in brains as well as in tumors, that we can open the blood-brain barrier for about the same time that you would find in a human, about four weeks. And this is just, these are sort of BBB assays showing that fluorescein comes out and is going into the parenchyma, and these are time courses in the BBB on the left and in tumors implanted on the right. And the amazing thing is you can get things as big as human IgG antibodies, which are huge, 160 kilodalton proteins through after laser. So you can see that here, that antibody that you inject systemically, this almost looks like the sun actually, this is just antibody staining after laser, can get into tumors after laser. And so that suggests the possibility that you can get other therapeutics that are antibody-based into tumors after laser interstitial thermal therapy. And we think the mechanism involves at least two things. One is tight junction disruption, as you can see here in vitro after heat or laser, and also involves something called endothelial cell transcytosis. And so they're apparently everywhere else in your body except your brain endothelium, there's just cavial and vesicles just streaming across from the lumen to the abluminal side of the vessels. And this can carry drugs, for instance. And so what we find is that after laser, this transcytosis across endothelial cells is also increased. And so what we see is when you do laser, you of course have this hemorrhagic coagulative necrosis in the middle. But then in what I'm calling this laser penumbra, you see this increased BB permeability for about four weeks in humans and in mice, and that involves both tight junction disruption and increased endothelial cell transcytosis. So, I mean, the cool thing about this is this has also allowed us to think of new clinical trials as a result of these phenomena, for instance. So here in a mouse version of a preclinical trial, what we do is we use doxorubicin here, which never gets into the brain, by the way, it's actively effluxed. You can see here that with laser that you can actually get the doxorubicin into the brain. And if you do a little preclinical trial in mice here where you have mice with syngenic tumors implanted into mouse brains, that if you do laser, you get a certain amount of increased survival, but that if you add doxorubicin on top of that, that you can get increased survival. So this suggests that we're getting the doxorubicin into these mice with the laser BBB effect. And that's led to a clinical trial, in fact, that we're wrapping up and we're sending out very soon laser plus doxorubicin. This is in humans. And so that's very exciting. And, you know, in addition to BBB effects, they may be intersecting somewhat with this other effect. There clearly are immune stimulatory effects we think that laser is also producing. And so there's another trial that we're also performing of laser plus anti-PD-1 antibody. And in terms of laser for benign tumors, I mean, I certainly don't use it for pituitary tumors, but in the occasional multiple meningioma setting or recurrent meningioma setting, I'll use it. I haven't had as much success with the newly diagnosed meningiomas with laser. Now, a third source of inspiration is clinical observation. And I think Dr. Dunn mentioned this before. We've been interested in the response to therapy of grade two meningiomas generally. And what we found earlier was that after subtotal resection, there was some relationship between necrosis and adjuvant radiation. And so whereas just here, if you look at the multivariable analysis, adjuvant radiation comes out as being significant in terms of local control. Necrosis falls out, although it is significant in the univariate analysis. So we thought maybe that's because there's some dependency between necrosis and adjuvant radiation. And so what we found is that if we stratify grade two meningiomas into necrotic and non-necrotic tumors, and you basically find that necrotic tumors do not respond to radiation. And so here on the left, if you have subtotal resection only, you have this control rate, which is not that good. If you have radiation in these non-necrotic tumors, then you have quite good results. But then if you look at only necrotic grade two tumors, basically the subtotal resection and the subtotal resection plus the radiotherapy lines are overlapping. It looks like the radiation is doing nothing. And so we became interested in this effect, which has also been shown in the University of Toronto data. This is led by Sunit Das. So what we did was to study this phenomenon, we basically took necrotic and non-necrotic tumors and we looked at tissue DNA. And that's what we started with. And we found was, and this is in unpublished data led by a resident, Dr. Bhavik Patel. We found that necrotic tumors tended to have more NF2 mutations. Okay. That was interesting. And in fact, if you look a little more deeply at this, looking at our data, as well as Baylor data, and this amounts to something on the order of over a hundred meningiomas that are grade two, there's a relationship between NF2 mutation and 22q loss in these tumors and necrosis. So we thought, great, maybe it's NF2 loss and mutation generally that's causing us to have necrosis and therefore radio resistance. And so this was our first hypothesis. NF2 confers radio resistance. And so what Bhavik did was he took IOMMLE cells and he knocked down NF2 here, as you can see on the right using lentivirus. And he basically irradiated them and he did clonogenic survival. And what that looked like was like this. So each one of these purple dots is a colony. Okay. And so this is a control receiving radiation. And then this is NF2 receiving radiation. The problem is when you do clonogenic survival, there really isn't that much difference here. This is not very good. So I thought, oh, you know, back to the drawing board, NF2 loss alone is not really conferring radio resistance. But then we thought about the fact that we're in the sort of in the context of necrosis, right? So genetic susceptibility plus microenvironmental stimulus necrosis may be sort of the two things you need to convert radio resistance. And so our new hypothesis was that NF2 loss plus hypoxia might lead to radio resistance. And so we did that experiment again. This was an amoxia data, which looks kind of not so good really. But in the presence of hypoxia, whether that's chemical or true hypoxia in the chamber, what you find is that the two together, NF2 loss plus hypoxia, and this is using two different RNAi, by the way, really increases the radio resistance. And so we thought that was interesting. So right now, Dr. Patel is interested in what the mechanism of that might be. Why is it that NF2 loss plus the hypoxia causes radiation resistance? And so we think this has implications for not only predicting what might be resistant to radiation, but maybe perhaps we could think about sensitizers in this setting. And so I think that's interesting. And so to end off, I'm going to have a few slides just more generally talking about what I think about academic neurosurgery. I mean, the path I've gone through is obviously one of a lab scientist and a surgeon. And I think that's just one of the many paths that are possible that's represented here. But you can also be a surgical innovator. And a great example of that is Eric Luthar, who just recently had FDA approval of the first BCI device. I mean, that is incredible. That, by the way, took him 12 years to do. You can go through leadership as well. That's another excellent way to have a great career in academic neurosurgery. And increasingly, I think we need more clinical trialists also, not only for the neuro-oncology space, but we need surgically oriented trials. I think that's a very important part of our future. Now, how did I exactly get here? And this is really, you know, it's kind of a choose your own adventure thing, right? So maybe people don't remember these books, but I had a bunch of these books and wonder what I would be, you know, later on in my life. And so I met Dr. Dunn in residency at the Brigham and Women's Hospital and Children's Hospital. It was a great time. And it was at this time that I did my postdoc with Azad Bani, who's a world renowned neuroscientist who currently works for Roche, actually. He's no longer in academics right now. But he is a basic scientist who studies the development of neuronal connectivity. And that's what I did during my postdoctoral fellowship. And the reason I did that was, you know, I had already done a PhD, and it was in developmental neuroscience. And so I wanted to double down on what I already knew. Now, at the same time, I think it's equally great if you just seek out a new field. I think it really depends on your passion for what you want to do. And what I thought the goals of my postdoc were, and I still think this is true for, at least for a scientific career, is to publish something reasonable, which you can make the cornerstone of your early faculty position, and then also potentially to generate preliminary data for a K. I think those are really the goals that I had, and I think those are very reasonable still. And after that, I did a clinical fellowship in skull base and vascular neurosurgeon in Miami, where I met these two incredible surgeons and characters, Dr. Morkos and Dr. Harris. And, you know, the funny thing about that, it certainly helped me to be a better surgeon and skull base surgeon. That was really the primary focus, but the other unanticipated benefit was just sort of the, the extra emotional reserve I had in setting up my lab at the beginning, I had already seen a lot of big cases so you know with during fellowship and so in my first few years, I think that allowed me to be have more sort of resilience and reserve emotionally to set the lab up and so I thought that was a great benefit a bonus from having done the fellowship. Coming to wash you their number of mentors and teachers I mean I, I would say I came to watch you because of the leadership and it was it was Ralph DC. At the time he's still here he was a wise, wise individual and leader, and he really got me focused on on sort of what I wanted to do my ambitions and my vision. And at that time, Greg simple. I had known him for since the 1990s actually he had, he had gotten his r1. He was on his way and academic medicine I thought, I, you know, I can make it happen here. And here I also met Dr. Luther, again, who is a great innovator, also NIH funded, and then Dr. He was really the go to person, I would say among the go to people regionally and perhaps nationally for skull based tumors and so he was, you know, I could always bounce cases off of him and so that certainly helped out at the beginning as well. And so what my life looks like now is, is like this I'm in the lab 40% of the time I do about four surgeries a week. I round one, I have a day of clinic, and I around, you know, six days a week probably like you guys do as well. So, you know, something to consider synergy with your clinical practice. So I for instance use samples I acquire my surgeries to fuel the lab. Okay. And and so, but that's different from from how it was in the first few years so in the first few years, it looked more like this. And so, you know, lab clinic more more sort of dedicated lab time and fewer cases I would say and so what that amounted to was sort of 170 cases, 290 cases, the first couple years, general and tumor call and then when I did a few cases too many Ralph would always say to me Albert, what are you doing, focus on your lab. And so he was certainly helpful in that. So, just the last few slides cases success as a surgeon scientist passion is the most important thing I think it's number one, and you really need an environment where leadership values the research and and Ralph these who certainly did mentorship is it plays a big role, as I mentioned my mentors, and I think it's important to give back and so I think you know whoever wants to send me their specific games I'm happy to look at it for instance, for, for a grant, you need a research niche that gives you a unique advantage as a neurosurgeon, you want to recruit the best people into your research environment, and you have to learn how to say no. And then I would say this is probably my last few slides. You really need to find your identity and be comfortable with it. You cannot do everything and so you have to focus but you just have to be comfortable with that identity. Remember you're a neurosurgeon you have to be an authentic neurosurgeon, and then take time to consider deeply who and what you want to be in five to 10 years and reverse engineer your plan to become that person I think I think that's great advice, something that I tried to do. And so you can chart your own path forward. That's just one way to do it. Thanks. Excellent. I wanted to ask one question, actually kind of for both of you, you know you touched on a very important topic about cell population heterogeneity, you know, and I look at this more from an NGO must you know which I'm more familiar with. I always knew there was a lot of histological heterogeneity in those tumors and that was tumor sampling was always a big issue with sometimes why we see what we detect in histology doesn't match up. You know with the clinical course, and the hope was that genetics or epigenetics would be a unifying driver that would not that would obviate the issue at sampling. As you point out that may not be the case. And I'm wondering if you have any insight on, as you know, like with the WNS as in a group of neurosurgeons, where we can move towards kind of prescriptive guidelines on tumor sampling, and where that may come out of. That's a great question. I'll maybe I'll take a stab at it first but, you know, we know that there's certainly literature that has featured multi sector sampling just as Dr. Kim described in GBM. So, you know, even within one minute Yoma shows different histologic grade in tumor, and then really an evolutionary genetic sequential series of events you can track in that tumor. So, I say that that's that's not a despondent answer but but I think, honestly, it makes the case for just as I think is happening glial by stomach right now right I think Albert was a really important part of a position statement that's emerging about the need to iteratively biopsy, and the need to actually sample tissue I think really, I'd say it's probably a call for more extensive resection and having more material to to really harness a faithful representation of what's in tumor. And that will be supplemented or perhaps even obviated with really advanced radio me techniques that might be able to discern and ascertain that information through complicated and sophisticated AI algorithms. You know it, it's it's a problematic issue I totally agree with everything done said, it's. I mean, particularly for as many jomas as I remember the more, the more you sample, the more you found right in terms of mutations. And so that's scary that's scary prospect. I mean maybe in the future. You will literally just take a resection sample different areas mix the DNA up and sequence it that's possible. No, I agree we're not even doing enough biopsies right for the recurrence we're so nihilistic about it especially for GBM, and for certain multiply recurrent meningiomas. I think we have to, we have to reevaluate that that sort of nihilistic attitude and. And first of all, just do more even single site biopsies because I'm that's certainly better than nothing I would argue, but maybe in the future, things like liquid biopsy will give you a more comprehensive view of it I that's another possible thought. Perhaps it's, you know, you're sampling more of the entirety of the tumor to, you know, when you're doing that with liquid biopsy there's also thoughts to supplement that with, for instance, you know, things like I think a number of people are thinking perhaps you want to open up a number of different areas of the tumor and then sample that liquid biopsy and that gives you a better sense of the entirety of it but that that's, it's certainly a problem. I mean, not to mention I mean even more simple things right like, I think, gala Rosada mentioned that. Well, about great too many jomas and, you know, brain invasion now being a criterion for that. Does everyone remember to give the brain invasive part of the pathologist and mark that I mean that's, I don't think I we I can do that all the time sometimes I forget something I need to get better at. What was the best way of detecting a small areas of microscopic brain on your other samples. Yeah, I didn't remember where that paper came out of but there was one where they post prospectively change the way they were sampling for brain invasion and doing increased sections in that area and it drove the brain invasion rate way up, you know, and what they were finding. Regarding that, when, when a tumor is a is classified as a grade two. Because of that, do you tend to think about it and I will know we spoke about, you know, a whole area of other things but you know that does that classifier for you put them in the same category as, as, as one that has like a ki of of 18, let's say, I personally would wait, the, I mean we see, we see, sort of, I think, microscopic subjective brain invasion, even with great women as you know so personally I probably higher but again I think we're going to. We talked a little bit about chromosomal disruption, and I think we're going to have more reliable sort of pass to the truth, like what is the true monster of this minijoma and I think the cast 67 the brain invasion copy number the method which these are all factors we're going to integrate to try and understand, you know, what's the nature of the beast so I think it's a, you know, which which of those two way I think is a hard question but but you know it also another another big just leads to another question is sort of what, what do you radiate, you know, can you use any of this information to, to, to help understand if you would radiate it completely. Let's say you're confident in Simpson grade one or section of a grade two minijoma. You know, are there, and it's a large field in a 35 year old, you know, are there are the predictors of more benign clinical behavior that you could leverage to maybe not do that. So I think that's just a huge one of a number of questions that this information will help guide decision making going forward. Yeah, I mean I totally agree with that I, I mean brain invasion just seems too much like gambling to to base a criterion, but personally I. I mean in fact there is a paper out there I forget which group it is if you have brain invasion alone. That group seem to be better actors than the rest of the grade two minijomas if I remember. And so I think certainly brain invasion with other grade two a typical criteria, probably is a bad thing because probably maybe one thing he would suggest is that you always have a subtotal resection right in that case, because there's brain invasion, but I don't know I think the jury's still out as to what it might mean alone. But I think these ideas of molecular diagnostics for prognosis and response to therapy that's really going to be important. But George, interestingly, just to interrupt but, you know, it's also interesting that we talk a lot about KSC seven and one, but it's really not part of our grading scheme either. Right, you know, it's never my I mean I feel like I waited quite heavily and there's a huge amount of I mean I feel like I review a paper a week on it, but it's not really part of our grades. Yeah, yeah, no, you're right, you're right. So just to spice things up a little bit, I brought a couple of cases and I'll have the three of you. See what you would do is actually a one of the cases I treated, you know, shortly after I started. I had a 55 year old man had a ll when he was a child he had kind of spinal radiation have multiple multiple mini GMS and multiple surgeries before and most of them had radio surgery had radiation therapy had standard statin, and then have this left large recurrence with a six no positive partial six no policy. Coming with it and happily you know I so laterally. I took him to the OR and essentially resected everything but the part that was extending in the superior to Fisher, and the cavernous sinus and just left left that it was very ugly planes from prior surgeries and he woke up with a little bit of a fissure that that promptly resolved, but his fissure was was essentially, it was all all scar. And he was the we had actually sent for foundation one, he came by as a grade to ki 15%. They had sent for foundation one. And there was really nothing that we would do much about at this point. I don't know. What do you think about this. I guess we'll start with Ian. Do you do anything else at this point. Well, already been radiated right. Yeah, I have had radiation. Yeah, they were. I'll get to what we did but you know I would say I would probably, you know, I want to know, we talked a little bit about, I'm a big fan of copy numbers I'd want to always answer question with a question so. So I want to see that information. I think, you know, if you had access to methylation it's such a powerful I think way of predicting sort of the malevolence of this type of great to so is this a wolf or sheep really is a great to is one of the questions I guess this information really doesn't lead to too much. I think actionable work right now. And how was, how would any information that you get from, let's say copy number, etc. How would that change what you would do at this point, I don't think it changed management really at all I guess the one there is part of the Alliance trial is if you have to alteration and I think, again, we want to see if there's 22 key loss to but it's a synthetic lethal with with FAK inhibition so that that's another arm of this Alliance trial that that's come up so that that's probably within the realm of a consideration. Potentially. Yeah, I completely agree with that I think consideration for the FAC inhibitor. If they're eligible for that trial. For instance, might be something to think about for this kind of person, actually we would have also thought about we have two clinical trials here, where we put together sort of palliative level radiation therapy with checkpoint inhibitor, one, one involves, actually having requiring surgery so we cut it out actually about three or four months later, which is a nice phase zero approach as well. But essentially the bottom line is that we have these two trials of not even so you have to have gotten radiation before actually, but you have this palliative level of radiation, which in some literature suggests has some immunostimulatory properties and then we do checkpoint and then that we will consider this kind of person for that those two trials room. Not much to add but specifically, you know the presence of term promoter CDK and to a, I've had a couple of recurrent grade twos that you know maybe resected four years ago, five years ago, that then I took their old specimen sent it for testing and came back with some of these mutations that now, in retrospect, would be grade three meningiomas. We had discussed it, the skull baseboard and tumor board etc and essentially had EP with radio surgery redo in that area and the cavernous sinus. But within less than six months he had almost complete ophthalmoparesis from progression of the tumor we had gotten off the trial. He was starting steroids in the beginning whether you know in thoughts that this may have been kind of a reaction to the therapy. And but he kept getting worse he almost completely lost his vision there. Much of the disease though was sort of localized. So in the left cavernous sinus this mostly fat that sort of scarring down. So, what would you do now. So, you said, really no vision and complete ophthalmoplegia nearly complete, he had, you know, marginal movement but he, he lost a great deal of his vision there. Another big question mark would be, you know, for considering anything surgical with a cavernous sinus exoneration is what's the status of his carotid. Is it narrowed by the tumor, or even to the point of considering a balloon test occlusion. But certainly, I'd want to see, is there any other options for trials or medical. It didn't seem that he had stenosis they don't include all the imaging he did have a balloon test occlusion. And he had. He failed in the hypertension. But with only marginal symptoms. I think, for example, a great point just not germane to this case but I would say just because I think it's obviously it's exactly there but if someone is maxed out external beam radiation and a higher grade meningioma I think brachytherapy is also a consideration we've had good luck with that for local control, not not maybe this location but just just a sort of a general consideration for recurrent higher grade meningioma that where you've exhausted ERT but I think Varun is right I think. You're looking at sort of like big surgery and bypass potentially an exoneration and likely, I mean the patient will lose vision at some point so probably something big. Yeah, I agree that that's definitely consideration, I just have to think what else you're going to do though right I on top of that what else you're going to do, because I would imagine they're going to be a few cells left so I actually this is very similar at least in concept to the trials I was talking about. I was going to also consider CT chest just, you know, with a significant increase in the behavior, because if they had mats you know that might change the equation, consider I mean certainly I would re also resample. That's something I would certainly do as well and, and to know what the new, you know, genomic profile is is would be important but you, you can consider a big surgery like you said it, you just need something else though right. Right. So, um, and you know that that wasn't easy. I discussed it with multiple people. And again, you don't have all the information but it did look very localized to that cavernous sinus. And we went back and forth and essentially we did a counter size exoneration. I did prep for a bypass to. But given how how bad his future was from before, and that he woke up a phase I get set up I think what we had discussed is that we would would see essentially, I was going before we delve into this Fisher if we were able to get any plane on it. And, I mean, you've all seen this before. I'm going to speed it up a little bit. So it's just essentially anatomically exposing everything. I did preserve... I saw a question mark pop up there. I want to thank Dr. Champagne. He was our fellow that did this case with me, and he actually edited the video. He was showing the VDN nerve there that we transected. But I did not take his globe. I know that's... It's always nauseating when you cut the nerve, when you have to cut the nerve. Right. But there was actually a good plane over there, ICA. And as Albert said, there's definitely probably cells left there. George, I have a question. Actually, I have a case like this coming up. And one question that came up was, with taking the whole orbital apex, what's the likelihood that the remaining globe becomes ischemic? That's a good question. And I think, you know, it very much depends on, you know, whether you've disrupted the ethmoidals, but it's a very good question. And I think also you're, you know, you get varying ophthalmology. So some feel very strongly that you got to nucleate if you do that. And, you know, obviously you can't see anyway. So I think if you're faced with this, I hate to take it to be gloomy, but, you know, obviously the patient has to know that this is going to come back and this is going to be a chronic problem. Yeah. So did you do any additional clinical sequencing? It's probably in the works, sir. So, I mean, this was, it was actually almost a year ago and- Oh, wow. Yes. So that was, again, one of the first cases when I began. The path was very similar to the prior one, you know, and now I've been following him for, you know, almost a year and a half, and he may have some recurrence in his infratemporal fossa. Very small. And then what would you do at this point? It was part of the kind of a thickening in the pteroid muscles. What would you consider doing now? I know I could have, I don't have all the information that you would have, but guide me a little bit through, you know- Is it focal or it's focal? Yes. It's, well, there's a little, it's more like a thickening in the pterygoid muscles that's becoming a little bit more substantial. I was going to mention, it sounds real, but sometimes if there's question with a lot of recon and whatnot, you know, a DOTATATE or a triotide scan can help clarify. And what would you do with a DOTATATE? That would be if I'm questioning if it's actually recurrent meningioma versus not, just, you know, scar tissue, recon, whatever that is. But I guess to answer your question, the options would be, you know, really nothing much helpful here on the pathology for molecular targets, you know, radiosurgery or observation or, you know, going maybe endonasal, transmaxillary, but I would probably reserve that for now. Albert, anything? Yeah, I agree. You could either do some radiation oncology approach or you could cut it out depending on its size and if it lights up on the DOTATATE, or you could take a, you know, biopsy of it and see if it is truly tumor cells. But I think I would do something for it. Yeah, I would operate. Presuming our clinical suspicion that this is tumor was there, I would, you know, you have eyes on the natural history of this tumor now, so might as well interrupt it or do the best you can when it's small. Yeah, all great points. At this point, we did a DOTATATE scan and it was lighting up and when we had discussed them, the Ludothera came up as a potential trial and with a close follow-up and if this didn't work, we would do additional surgery. So that story is not over yet, obviously. But another case, this is a 52-year-old, had cranial nerve 6 palsy, had a biopsy at another institution. I'm not going to bore you with many of the technical aspects, but had a lower clival meningioma, had a pretty thorough resection, you know, controlling bilateral gerotubercles and condyles. I don't know if you can see the pulse up here, but there's no gross residual on the pulse up scan. So what would you do now, Varun? I mean, I would do adjuvant radiation, whether that be a proton beam or high-dose IMRT to the whole cavity. Albert? Yeah, we'll probably follow with proton at our center. Ian? Yeah, agree with Varun and Albert. So regardless of the resection, regardless of, you would essentially prescribe that for everyone or recommend that for everyone? I mean, personally, in my practice, I think, you know, the goal remains, although I think this is changing, unfortunately, but in some centers, but I think it still remains complete resection followed by ideally adjuvant proton beam. Now, whether there's a subset that perhaps don't need that, they don't need that, I don't know. I don't know the data on that, but that's generally what we do. So that's some of the data we've been working on. This was accepted now, but we had looked at just based on 1p36 and 9p21 deletions based on fish, and they actually read out a percentage because of the heterogeneity of actually within the tumor and the, you know, the biopsy. You know, this applies very much to chordomas as well. If you take biopsy from multiple sites, but there's been a practice to send as much of it as possible to PATH where they do that, and they do give a percentage. So based on that, you know, we had subcategorized in three groups, and I guess the takeaway is that when you get analysis based on, you know, whether they got radiation or not, and based on whether they had GTR or not, the ones, the more benign ones that had almost none of these two pretty much had no change even up to 120 months. There was no difference whether you got radiation or not, and also applied in the intermediate group that, where you had a growth story section. Now, if you were in the intermediate group, did not have a growth story section, there was a meaningful change in progression-free survival. This patient actually was in the lower end of the intermediate group and did not get radiation, and it's been, you know, a long survivor from this. This is actually one of Paul's patients that was operated when I was a fellow actually. So what is it now, like five years almost? That's been with progression-free without any radiation. And then group C are the most aggressive ones, and in which both the radiation, I mean, essentially everyone should get radiation, but also there's a progression-free survival that's pretty poor, and potentially these are the patients that, you know, should be considered early for something like a neoadjuvant or something along those lines. So that's sort of been the paradigm that we've been following the last few years, at least at Pitt, but... Can you go back to the path report on that, on your patient? So you get, is this done in-house or do you, there's a company or... In-house, this is in-house. So essentially you get a, when you say percentile, this is, what does that refer to in your report? Essentially the percentage of counted cells that have the deletion on fish. This was based on a prior paper that came out, it was in 2018. At that time we didn't have enough power to look at the extent of resection within all that, or whether they got adjuvant radiation and how all that played out. But, you know, with the latest rendition now, all that is in, and it's powerful enough that it, at least for the time that these patients were followed, it did not seem that the change was dramatic. Obviously, I mean, this is a very simplistic panel. The KI-67, interestingly, was initially in the panel, but when I counted the multivariate for these two, the KI-67 was not independently predictive. And we had looked at a few other things as well. These are the two that sort of stood out the most. So we essentially made the panel with these two, but there's a lot of kind of more cutting edge things that are in the works. This is more, it's already antiquated, even though it's sort of just- You know, I think the power of this, George, is that, I mean, it's one thing to take the next omics and subject every tumor to it, but, and that's great for discovery and so forth, but it's a lot of it's not practical at this point. I mean, this is a really nice practical, scalable, implementable approach that really any, most institutions can follow. So I think that's a big consideration of what's published is what can be transmitted to, you know, either nationally or internationally. And we're getting some funding, hopefully soon to doing at least validated multi-institutionally. That's going to lend a little bit more credits to, you know, different surgical practices and so on and so forth. So we appreciate any help we can get. This can be done on a par for embedded samples, like retrospectively even. So- I think it's very interesting. I'd be curious, you know, if you did it twice or on the same sample, if you come up with the same percentages, you know, different sections or something like that. There is some, you know, variability to the pathologists and, you know, how it's counted, but the iterative variability is not too high for that. So- That's very cool. That's sort of all we have for now, but- I was going to mention, George, I heard you present this at NASPS, and this is beautiful data from your group. It does bring up one important point, you know, with a lot of sending specimens for next generation sequencing is, I don't know if we have a good handle on the, you know, variant allele fraction, you know, percentages that these reports spit out. And, you know, if you get a TERT promoter, you know, with a variant allele fraction and a meningioma of 25%, is that significant or not? Yeah, that's a- that's a great question. But it- there's no question as in- I think that was a theme in- today, that many of the tumors that would just give them, you know, this deleter or not, you know, may not apply to the entire of the tumor. And then, you know, it may be that, you know, 90% of the tumor may be carrying that or the 90% of the populations of the cells that may have a tumor may have that or not. And that may be even more applicable if you're using, you know, considering someone for neoadjuvant therapy or not, let's say. But obviously, things are going to get a lot more granulated going forward. But in any case, I know everyone had a long day. Firstly, I'd like to ask Dr. Setri if he has any other questions or discussion points for Dr. Kim. No, yeah. I just really appreciate Dr. Dunn and Dr. Kim's wonderful presentations and great discussion. It was wonderful to be a part of this panel. And George, thanks for setting everything up. Just two quick questions, and then we'll wrap it up for the night. So, Ian, what do you think would be the most promising thing to turn down the pipe from in terms of molecular diagnostics? Oh, I think my personal opinion would be the correlation between the information and response to additional treatment. I think Albert touched on that. I think that gets critical. You know, we really don't, I mean, Albert has presented some great data, but I think the masses have an incomplete understanding of, I think the great two questions big. So, I think deploying this information for clinical utility after surgery is a critical issue. And the second is, what can you do the information before treatment? Can you obtain information before treatment? And so, I think non-invasive biopsy, cell-free DNA, liquid biopsy, I think, are there actionable items that you can ascertain before surgery? Can you make a large, massive tumor a little bit more manageable in a new adjunct approach? I mean, we never think about that sort of thing in neurosurgery, but, you know, I think that's on the horizon. So, I think how to translate that information into action postoperatively and how to use information and gain that information and acquire it before intervention. Fantastic. Dr. Kim, for people that are, let's say, considering or have the passion to follow an academic career that, you know, encompasses either basic science or translational science, but may not have had, you know, very much of an exposure before, what would be your advice in terms of, you know, how to set up sort of their step? I'm speaking more about, let's say, residents that are transitioning, you know, into early career academics or, you know, residents that are early in their career sort of thing. Yeah, no, that's a really good question. I think, you know, the neurosurgical models have been, you know, that you just do it yourself or that sometimes you tie yourself to a collaborator or a PhD, right? These have been sort of the older models, at least for laboratory bench-dependent science, but I don't know. I think we should maybe change our attitudes about this a little. Perhaps we should take, you know, a cue from, for instance, neurology or other specialties who have a peer, you know, we get a K award and we're like independent investigators with a K award, but in almost every other discipline, you're embedded within a larger laboratory, you know what I mean, with the K. So, I think it would be worthwhile to think about variations on the model that look a little more like that if you don't have the experience, you know, of a PhD or a really long postdoc. I think that's one thought I would have. Another is to align yourself with really strong collaborators. I mean, it's not that you have to hire a PhD that you work with, but you know, but trying to find collaborators that you can really work with, I think that's really important at the beginning. And in any case, you know, innovation's at the edges, right? The fringe is really the transition points between fields. So, I think having collaborators makes it more fun as well. Can I add something sort of a little bit lower brow to what Albert just said, which is you have to be very mentally flexible about salary. So, if you come into a group and say, I want to make top dollar, but I also want 50% productive time, those are antagonistic. So, something's got to give. And I think this is very hard to discuss in public, but we have these discussions with faculty. I know my former chair, incredible chair, you know, Keoka, very upfront about this concept, which is, you know, if you want to do this, something has got to give, and it's hard to make 90th percentile, like if that's your goal, this isn't going to happen. So, I think, you know, be comfortable with a good salary if you really want to do this, because there's a lot more to fulfillment and your academic life than that. I think if that's your goal, it will be antagonistic to this goal. Well, words of gold from everyone tonight. I know definitely both Dr. Dunn and Dr. Kim have been role models for me, and they're people that everyone should try and emulate. And I couldn't thank you enough for your time tonight and sharing your wisdom. And Varun, thank you again for being such a fantastic cause tonight. I'd like to thank everyone for watching this episode, and we'll look forward to seeing everyone again soon. Have a great night, and thank you again. Thank you. Yeah, thanks. It was a lot of fun.

skull base surgery

surgeon-scientists

molecular advances

genetic profiling

meningioma

pituitary tumors

challenges faced

time management

glioblastoma stem-like cells

laser interstitial thermal therapy

molecular diagnostics

tumor behavior