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SI, Innovations and Learning, in association with the UCLA Department of Neurosurgery, Linda Liao, the chairwoman and its faculty are pleased to bring you the UCLA Department of Neurosurgery 101
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lecture series on neurosurgery and clinical and basic neuroscience.
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The series of lectures are provided free to bring the advances in clinical and basic neuroscience to physicians and patients everywhere.
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One out of every five people in the world suffer from a neurologically related disease.
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This will be a lecture in discussion
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on a 2024 review on the status of meningioma.
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diagnosis treatment, molecular and genetic data, and clinical courses.
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It will be given by Richard G. Everson, who is in the Department of Neurosurgery at the UCLA Medical Center in Los Angeles, California All the G.
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So, meningiomas have been described as the soul of neurosurgery and the preface to Al Mefti's sort of seminal book on meningiomas. He says the progress in meningioma treatment has mirrored the
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advances in neurosurgery. Advancements in neurosurgery are put to maximal use to improve the treatment of meningiomas and things like the development of the operating microscope, ultrasonic
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aspiration, neuromonitoring, all those things are clear evidence of that. I think it definitely holds true today as we advance even beyond sometimes what we think of as in the operating room to our
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molecular understanding of the pathogenesis of meningiomas as well. This sort of exciting evolution was kind of cool to see when going back to the start when I had the occasion to visit the Cushing
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Museum, which is at Yale. University and houses the collection of brains of Cushing's patients as well as their tumors and you can kind of see where it all got started. And so seeing the continuum
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is really a pretty exciting thing.
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Cushing had some interesting and somewhat disparate thoughts about meningioma surgery, at least they come through in his writing, in one place in a lecture that he gave, described meningiomas,
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typical convexity meningioma that's amenable to surgery as the surgeon's friend and said there is today nothing in the whole realm of surgery more gratifying than its successful removal of meningioma,
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subsequent perfect functional recovery, especially should a correct pathologic diagnosis have been made. At the same time in the preface to his book, he talks about the neurosurgeon who treats
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patients with meningiomas must have more than amateurs knowledge. It's fair to say that few procedures in surgery may be more immediately formidable. then the attack upon a large tumor of the type
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here in disgust and that the ultimate prognosis hinges more on the surgeon's experience with the problem and all its many aspects and it's true of almost any other operation that can be named. So it
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kind of has this warning at the same time. Turns out today we sort of face the same problem in that we would like to know everything that we could about a meningioma, but oftentimes we're faced with
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big gaps in knowledge of what really makes up the tumor, what's driving it, how it will behave, and whether or not we're making the right treatment recommendations all of the time.
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So there are some things we do know. History has given us a lot of information about meningiomas, this term itself is coined in 1922 by Cushing, scribing a slow growing extra axial tumor. This
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meningioma stuck a little bit better than meningothelioma, I guess easier to say Eisenhower postulated the origin from Iraq. going cap cells, which derived from neural crest, these are
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concentrated in major walls of venous sinuses, where there are arachnoid granulations, and this accounts for the most common location of these tumors. 1900s Vercal described the Somoma body, which
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is a common feature of meningiomas.
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Subsequently, investigations into them have sort of converged to an idea that they might actually be a process to slow
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the growth of the tumor And then beyond that, we've learned that most meningiomas by far are benign. And we describe these as WHO grade one. A few are atypical and have a higher propensity for
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recurrence and even slimmer numbers are anoplastic and really have malignant potential.
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1950s, Simpson correlated the surgical resection and the extent of resection of meningiomas with the rates of symptomatic recurrence. And we've also come to know that metastases uncommon, but may
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be seen. you know, across the spectrum of meningiomas. There's lots of statistical data we've accumulated from things like the central brain tumor registry of the United States. We know that
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meningioma is the most common central nervous system tumor. They are mostly considered benign and are often asymptomatic and diagnosed incidentally. Standard studies based on histopathology probably
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underestimate their true incidents by several fold in a study of 2, 000 asymptomatic volunteer subjects who underwent 15 Tesla
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MRI. Meningiomas completely incidental were found in about 1 of them. It ranged from five millimeters to 60 millimeters in diameter and their prevalence was a little bit higher in women and
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in elderly. Beyond that autopsy studies show that That's probably even still a big underestimate in that. people over 60, we can find them in 3 of the time. Most of them are less than a centimeter,
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but that could be up to half or more of all the meningiomas that are out there. The growth and survival of meningiomas, we understand from retrospective case studies, the diagnosis is often made
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solely on radiological means. We don't biopsy these up front to understand them We know that average growth pattern is about 2 millimeters a year, but the range on that is an unfortunate zero to
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basically exponential or infinity. And so it's not particularly helpful in figuring out what's going to happen with one. We know that 10-year overall survival rates for grade 1 meningiomas are
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around 80 plus percent. It's about 50 lower for grade 2 and grade 3s, which are highly malignant, really have a very. poor prognosis with very few long-term survival.
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Progression of the disease is really, it's got varying definitions, but we're talking about either growth or residual tumor transformation to higher grade.
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What does that count from? Because that doesn't match up with any type of clinical experience for grade ones. It's about one millimeter a year In grade two, it goes into the two to four, but where
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did that average growth rate come from? Because I follow a lot of
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it in geolus, rarely do they ever grow at this rate. So how could this be the average growth rate? Yeah, we're,
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yeah, we probably got some of these numbers from, you know, earlier imaging eras where there wasn't the ubiquity of MRI like it is today
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I think we found one more. One meter a year for grade one
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this value just doesn't sound reasonable to me. Sure.
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The National Comprehensive Cancer Network has some guidelines on how to treat meningiomas. These are pretty exceedingly vague.
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They basically recommend, if you think you've got a meningioma, you could either observe it, do surgery or do radiotherapy on it. They recommend favoring observation for smaller asymptomatic
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tumors and favoring surgery and post-operative radiotherapy, really depending on what the pathology shows. Beyond that, even in the setting of recurrence, it's basically anything is an option.
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Surgery if accessible, radiation if possible, if not possible, systemic therapy or continued observation if you can do it. The variability in this behavior of meningiomas creates a big problem for
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potential for under-treatment versus over-treatment. You know, the patients who get surprised with a higher grade meningioma, obviously do poorly in the survival curve show that steep drop off in
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the beginning there, which would be folks who were clearly under-treating. But then we know that, probabilistically speaking and based on the differential grades, there's probably a whole lot of
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people who don't really need any treatment. So we've got, you know, sort of a double-edged sword here. So we need better tools to make better predictions. And that's been the focus of a lot of
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research. You know, coming from it thinking about it oncologically, you know, are there risk factors? Are there preventative measures that can be taken? A whole bunch of different things have
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been examined very closely. A few things have found substantial links and some other things have been disproven. Some of the stronger link things are certainly an explosion of ionizing radiation to
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the skull you know, this is going to increase the risk six to 10 fold. It's a scene worn out in atomic bomb survivors with a correlation between the distance to epicenter. It's also seen in people
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who received low-dose scalp radiation for things like ringworm,
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dental x-rays, and then people, especially survivors of childhood cancers which had cranial radiation years out. Other things that have been studied extensively exposure to estrogen and
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progesterones, this was highlighted because of the increased incidence in women. Multiple studies have been conducted but there hasn't been definitive links. There's a lot of theories and even
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mechanistic explanations of why hormones could affect meningioma growth including links to
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progesterone receptor signaling and increasing signaling through NF2 gene, which we'll talk about a little bit later, which is really a central driver of meningianos, but the epidemiologic studies
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really haven't come to a conclusion, at least in favor of
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standard estrogen or progesterones. There are some progesterone-only birth control formulations that are popular in Europe that have been linked to it, but beyond that, most do not have a solid
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link Same thing holds true for traumatic brain injury, large-scale study.
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Then Mark, 200, 000 people basically didn't show any evidence of increased rates of meningium. Same thing for smoking, diabetes, asthma, and eczema, which was of interest because of its link to
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glial tumors, mobile phone use, et cetera, nothing conclusive.
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The only other thing besides radiation that's been linked familial genetic syndromes like neurofibromatosis type 2, leave from any goral encounter, VHLs, or multiple endocrine, neoplasia syndromes.
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We'll talk a little bit more about NF2, as I mentioned.
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Radiologic features on CT scan.
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You can see intertumoral calcifications or hyperostasis remodeling of the bone.
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On CT scan, the meningioma tumor itself is hyperdense or isodense. Necrosis would be evident on a CT, but again, that's uncommon.
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You know, only about 15 to 20 will demonstrate calcification. Same thing with hyperostosis, hyperostosis can be extreme It can be minimal, and it's not proportional to tumor grade or predictive of
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grade.
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It's also, you know, the big controversial whether or not hyperostosis really represents tumor invasion or not. It's actually not that well borne out, but it's likely that there's probably forms
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of both a reactive And hyperostosis and really a tumor infiltration that can account for for the same kind of imaging finding. MRI obviously is a gold standard for meningioma. You're gonna find a
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homogenously enhancing circumscribed, dural-based lesion with a dural tail. You know, it's not the only thing that could have a dural tail. There's other disease types like metastases, lymphoma,
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solitary fibrous tumors, gliosarcomas, non-tumor conditions like sarcoir
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or granuloma disease could also have a dural tail But the constellation of the findings really is what leads you to the diagnosis. You can also see a CSF cleft sign in typically in lower grade tumors.
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Edema often in higher grade tumors but it can also be present in particular subtypes of low grade tumors like secretary meningiomas. Again, we mentioned necrosis before that can pretend to higher
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grade Sort of adjunct MR techniques like spectroscopy and perfusion are also helpful. more so in the post-treatment setting of delineating things like radiation and crosus from tumor progression. On
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that front, pet is certainly something being explored in meningiomas, the standard FDG
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pet has also been used for what I just mentioned in terms of delineating radiation and crosus versus progression. But it also turns out that since meningiomas highly express some out of statin
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receptors, you can actually delineate their extent, especially in difficult to visualize in atomic regions with pet analogs like 68, gallium, dota tape, or dota talk. This is increasingly being
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used in centers where it's available to delineate targets, especially for radiotherapy like in a lesion that I've got here where it's a little bit hard to tell where the tumor ends and say the normal
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pituitary gland begins.
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Treatment wise, as I mentioned, a big majority of these things are asymptomatic, incidentally found. So observation is a pretty reasonable thing to do.
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You're generally gonna favor that for patients with smaller asymptomatic lesions, like I said. Some studies looking at this, trying to catalog their experience, this
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Bebahani five-year perspective study to look at risk factors that could describe
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what type of tumor is likely to grow.
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In their particular study that they published, actually none of the patients that they were following of 65 developed tumor-related symptoms during the five-year follow-up. And this was often,
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despite the majority of them, demonstrating growth increases by 15 or more they did find that a majority of those that did grow, they didn't necessarily continue to grow, but sometimes reach a
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plateau and self-limited before developing symptoms.
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On the contrary, another series doing a similar kind of thing demonstrated about a quarter of them with significant or rapid growth factors that correlated with that were things like tumor size,
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especially those above 40 millimeters Absence of calcification, peritumeral edema, hyper intensity or iso intensity on T2. So these are basically, you know, it's a little bit of the flip side of
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calcification, but it has some intrinsic properties too. And they took these variables and basically created a calculator, you know, risk calculator app that you can apply to your patients at,
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you know, from this impactmentingiomacom.
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and large scale validations of this model are underway. And so it'll be pretty interesting to see if that bears out. And certainly if it correlates with some of the other things that we'll get to a
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little bit later in the talk with molecular pathology andor grading.
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But so this calculator that they have also give some recommendations on interval follow-up, how frequently it should be, it was basically patients following into the lowest risk care, lowest risk
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groups not really needing continued follow-up. But beyond that, guidelines recommend annual follow-up for about five years after diagnosis.
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Surgery for meningioma certainly is the option or the preferred treatment for patients presenting with mass effect or related symptoms, things like seizures, weakness, focal neurologic deficits,
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cranial neuropathy. This is going to warrant a prompt evaluation and some kind of intervention at least. Certainly, location matters exquisitely with the size of a lesion when it becomes
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symptomatic, things like near the optic canal or CP angle are gonna require surgery and much smaller sizes.
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There's other features that I mentioned before, they need to be, can be taken into account peritumeral edema, bony invasion, but they, again, they don't perfectly correlate with grade But
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they're often part of the equation.
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Translating what we do in meningiomas to principles of surgical oncology,
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or the goal in tumor surgery is to take as much tumor with as wide of a margin as possible, as long as one could safely do that. The traditional concepts derive from really, orthopedic oncology or
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in the extremity of things like performing a radical resection, which is the removal of the entire affected tissue compartment are not really feasible when it comes to the central nervous system.
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This would be removing the entire dura. So really, probably what we're looking at or looking for is a wide margin, which is taking a margin of normal tissue surrounding a resection. This is the
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concept that was illustrated very well by Simpson in the 1950s with basically increasing
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extent of resection and wider and wider margins around the tumor itself correlated with decreased recurrence at 10 years. A grade one resection was macroscopic, complete resection of the tumor,
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excision of the dural attachment, abnormal bone, and when involved, venous sinuses.
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We'll talk a little bit more about that later. Grade two is the tumor with coagulation of the attachment. Grade three is just the tumor without any manipulation of the dural attachment. Grade four
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is debulking and grade five is biopsy only. And the recurrence rate increases so proportionately with those. However, recent studies, probably due to the effect of modern radiation therapy,
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show progression for free survival is not really statistically different between grades one, two, and three compared to
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each other compared to four and five. And this leads to the concept of what we would term a gross total resection of the tumor versus a subtotal resection. Even so, it's still recommended or felt
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that it's worth recording an operative note because your only time that you're to be able to actually count. and measure a Simpson grade resection is intraoperatively. You can't do this
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postoperatively. And that's sort of what I'm illustrating there with the figure of removal of this olfactory groove meningioma of, you know, you can't tell what was done to the Dura.
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Unfortunately for surgery, we don't have randomized controlled trials to compare surgery to other therapies directly. This extended resection data like from Simpson and from other series is all
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established by institutional case series. And as I mentioned, this concept has formulated that in modern clinical trials, most of the time we are defining center of resection as either gross or
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subtotal. Again, because Simpson is really impossible to derive on, you know, large scale data sets unless it's specifically recorded. So when you're correlating to a gross total resection
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you know, it's still parallels what was seen in Simpson with,
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you know, around 10 to 20, five-year recurrences in grade one, 50 in grade two, and more like 75 in grade three. Other surgical guidelines support the use of intraoperative adjuncts like image
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guidance, intraoperative imaging, like ultrasound, to use for a concept of adaptive hybrid surgery, which would be, you know, leaving a small volume residual for SRS will kind of go a little bit
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deeper into that. Interoperative neurophysiologic monitoring to minimize deficits and, you know, the use of endoscopic techniques are certainly supported and found to be viable, but no study has
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demonstrated a clear superiority of endoscopic versus open cranial techniques, especially,
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was evident in a meta-analysis comparing olfactory groove and tuberculumcellum in an NGM was operated via endoscopy or cranial It's basically dealer's choice. and
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up to, you know, the expertise of the surgeon. There are some fundamentals of meningioma surgery that I think apply to all cases. You know, you have to maintain the concept that these are extra
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axial lesions. You need to remove bone performer craniomy of sufficient size in order to define the tumor or at least the approach corridor in order to minimize injury to surrounding neurovascular
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structures
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The process of surgery then moves to de-vascularization of the tumor to minimize bleeding, debulking the core, and then dissecting the now malleable capsule from neurovascular structures. There's
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not a rule that always has to proceed in that order. Only, there certainly can be an iterative type of thing in order to mobilize and remove large tumors. We've in our conferences have certainly
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discussed the concept that meningioma is a surgery of veins that's that's certainly true for many tumors, but with the variety of locations that these appear, I really think all interfaces with all
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types of anatomy and neurovascular concepts come into play. The one here on the right certainly would be one that you would give consideration to the superior sagittal sinus, but it's also indenting
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into leg motor cortex of the brain
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The one to the left of that, CP angle meningioma, entering the IAC, you're gonna be mostly concerned about nerves. The one here that's engulfing the carotid bifurcation, you're worried more about
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arteries. This one here that developed central necrosis, well, you're really thinking more along the lines of oncologic considerations
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because that necrosis certainly would be worrisome for development of grade three type tumors. Just a note, consider the adjacent brain if it's adherent. you know, there's our extra axial tumors,
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but certainly, you know, it's not a foreign concept to need to map the underlying brain to understand where things like primary motor or supplementary motor area are, and that's an easy enough
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thing to do. And things like parasaginal meningiomas by phasorversal.
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You know, and again, it comes down to a lot of what you see at surgery, even some of the biggest mastiest tumors on MRI can sort of fall right off the brain, like, you know, like a rib fallen
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off the bone of a nice, slow, slow-cooked barbecue.
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But you often aren't going to know this until you get in there. So your plan has to take into account what you're going to do if it is adherent to potentially eloquent brain. Sagittal sinus
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involvement, you know, historically, there were a lot of advocates for complete resection and reconstruction of the sagittal sinus, certainly much more controversial now, data that we have
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supporting really good
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long-term control of small residual with stereotectic radio surgery. It was held pretty firmly that resecting the anterior third of the superior sagittal sinus is not likely to cause complications.
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But that doesn't really hold up in the face of retrospective case series that show non-zero mortality, even when it's described as completely occluded The reasons that are posed for that is there got
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to be collaterals draining the brain somewhere, or diploid veins going through the skull that get destroyed with the craniotomy. A detailed understanding of the venous drainage pattern is certainly
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warranted for any such explorations. People have advocated testing the pressures in the brain with menometry, putting a needle in the sinus, clamping it somewhere and seeing if the pressure really
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This is, you know, suggested in describing techniques, but there's not really any high level evidence to support it.
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Manipulation of the sinus, obviously thromogenic will require intercoagulants, also controversial. Opening the sinus with direct closure again, you know, high risk with the successive SRS,
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especially for small volume residuals, it's hard to justify in the modern era. And then there's another concept, certainly of stage resection, allowing the sinus to go down and then completely
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occluded sinus to occlude and allow the development of collateralization and come back at a different time and resect it than when it's safer. Bridging veins are another concept entirely.
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Even some of the strongest advocates for resectioning sinus would say that, you know, the repair or attempted repair or reconstruction of a bridging vein is dangerous and safety would not support
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doing that remove or change
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your Simpson grade resection from a four likely two at three.
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Similarly, embolization is a thing that's discussed a lot. There are some guidelines that actually recommend against embolization due to really a lack of high level evidence supporting it.
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Post-op cardiovascular complications above a rate of about 5 will negate pretty much any demonstrated benefit, which is, you know, this time, basically only a reduction in surgery time and
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potentially a blood loss or need for transfusion, but even that's a little bit questionable. Most people would not argue with the concept there that for a deep seated tumor, that's very difficult
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to access like a petroclival or a tintoral meningioma, embolizing the deep branches that you will reach last in the operation could be helpful There's still no, no guideline or data to back that up.
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Same thing for timing of intervention, you know, everyone has a different theory on it and, you know, some, some people say you shouldn't analyze anywhere other than, you know, a hybrid OR
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suite and other people might do it months before. But again, you know, we just don't have a level of data to support a recommendation Other things that were advocating the past that I think a
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little bit more questionable now. CP angle cavernous sinus surgery are very risky to cranial nerves.
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Most series even in expert hands, you know, demonstrate rates of, you know, 35 of cranial nerve deficits post operatively and CP angle, especially with larger tumors cavernous sinus even higher
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50 to 80 And
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that's, you know, potentially permanent So many authors now advocate debulking extra cavernous portion and using radiation on the rest. I would say that the time that you might consider a really
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aggressive surgery is if the situation has become what I would describe as sort of oncologic where there's life-threatening situation and a planned morbid operation for life-saving measures might be
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necessary.
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Radiotherapy, yeah.
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Definitely a destination of
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an isolation of isolation and such work at those strategies. There has, long term, I don't think it really panned out. There are, I think, as many reports of successful inducing the tumor to
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become necrotic and die off as there were of inducing hemorrhage, edema, prediation, seizure. So, I'm not aware of a randomized control trial showing that or anything that. that has more solid
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things. There's just, you know, a lot of it is expert opinion.
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issue, I agree with you. It's rarely necessary. You can take the middle mening, geo often surgically. And, but for patients who are cash paying, you'll see that, you know, the hospital offer
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them a, okay, if you come for your meningioma resection, you need to pay60, 000 cash. If you analyze it, it's160, 000 cash. It's100, 000 for that
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immobilization. And we're going to be increasingly viewed by third party payers and all that, on how our value basis in terms of how we treat patients with value, how much it's a cost to treat them.
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So as we keep on telling you, So I open this pester bipolar and all that. There's a reason that - This is gonna impact your career. You got to do the right thing for the patient, but embolization
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is a waste of money, and it's not safe in 5 of the cases, so.
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Yeah, 5 is a good expert center. Having had experience at centers with higher complication rates, I can tell you the balance is
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a little bit different.
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Radiotherapy, the concept, obviously, is did you increase recurrence and improve local control? It's not advocated
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or useful in radically resected grade one meningiomas, 'cause that is associated with a pretty high rate of cure. SRS or 50 gray of external beam radiation is
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an option and incomplete resection of grade one tumors. It's a good idea, like I mentioned in cavernous sinus, or if a subsequent operation is not feasible to remove the rest of the tumor. Grade
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two meningiomas, the role of radiotherapy is very controversial still. It's a little more advocated in cases of incomplete resection. We'll go a little more in depth in that in a second. Grade
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three, on the other hand, are so malignant that it is standard of care to give high dose 60-gray radiation post-op, and that's correlated with increased progression free survival
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NCCN has guidelines outlining exactly what I just said, as well as
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contouring guidelines and sort of target delineation.
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Again, there's not much question about grade one and grade three is really grade two, that's a bit controversial. SRS, just a quick note, I mean, this is an established alternative therapy to
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surgery. The data is very clear. that per small size tumors, you get a pretty comparable result to a Simpson grade one resection with 95, 96 10 year control rates with doses above 13 gray.
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Interestingly, retrospective studies have shown that you're actually more likely to improve cranial nerve problems than worsen them with radiation by a factor about two to one But the incidence of
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cranial nerve problems is not immediate like surgery. It's actually born out over long term. One thing that's been recently advocated for to try to mitigate against that is fractionated serotectic
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radiocergery. It's evolved within the last couple of years or decade or so to break up the fractionation to be a little gentler on the normal surrounding tissues. Studies of this have not shown any
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differences and
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you know, I need decreased local control.
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haven't demonstrated yet, you know, a statistically improved toxicity, but again, this is a relatively newer technology. Again, I mentioned grade two tumors. The problem here may be that, you
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know, the studies that have been conducted are not necessarily haven't studied the same types of tumors You know, the recommendations, again, for atypical meningioma following growth disorder or
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section are sort of up in the air due to conflicting evidence. The best thing that we've sort of got on hand so far are some meta analyses. And we've got basically one big one of a bunch of studies
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that did show a statistically significant improvement in five-year survival, but that's sort of offset by another one which didn't.
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There's some other studies that are a little bit relevant here, but unfortunately none have been specifically. targeted or designed to answer the question of what do you do in the setting of a
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completely resected grade two. Others have sort of lumped those in with recurrent grade ones.
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And, you know, they have showed pretty good control rates, at least comparative to historical controls. But thankfully, we've got an ongoing multi-center phase three randomized control trial
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happening now that we'll answer this question is basically randomizing post gross total resection grade twos to 60 gray of radiation or not. And those results are eagerly awaited to answer this
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question.
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Systemic treatments remain experimental because the results have just not been great. They're reserved in the guidelines for recurrent progressive disease that people who've exhausted radiation and
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surgery possibilities. The NCCN does recommend, you know, about clinical trials for all cases that meet that definition. The problem in assessing systemic treatments to date has been some
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difficulty with standards and definitions. More recently, there's been somewhat of a consensus agreement on definition of progression as 15 increase within six months, and that the relevant
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endpoints ought to be six-month progression-free survival, although some would advocate for an imaging response to 70 six-month PFS
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is sort of the benchmark for what the field thinks would be an acceptable useful therapy. A whole bunch of things have been tried and failed in grade one. I've got them listed here.
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The sort of big one that knows there was a phase three randomized control trial with Smith and Pristone, which of course has been in the news a lot lately. But that was unsuccessful in meningianism.
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Grade two's and threes. same kinds of agents as well as high-dose kind of sarcoma protocol chemotherapies like cyclophosphamide, ageromycin, the
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likes of those, which also were ineffective.
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While there aren't RCTs to support it, there are, you know, in the field these days, some enthusiasm for agents which target androgenic pathways like Bevacizumab, syninib, and mTOR or
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somatosatin-related pathways like Everolimous Triotide.
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NCCN comes out with some very weak recommendations for those agents, and so those are an option now, according to the NCCN guideline, and then really, you know, these agents have sort of changed
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over the years, and that's kind of what's available currently. You know, the whole problem that we run into in all this is inconsistent definitions of meningioma grades, especially over the
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decades and that are required to study and understand meningioma behavior. You know, right here I have listed the WHO
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2016 criteria. These have actually recently changed again and some of these categories have moved around like papillaria, rhabdoid histology now doesn't automatically make it a grade three. There's
39:36
other molecular features that take that place and there are some other markers which move in But basically, the strongest delineator of separating the grades is the mitotic rate
39:50
per 10 high-powered fields, less than four is grade one, four to 19 grade two, and greater than 20 is grade three. That helps stratify survival actually pretty well. It does a fairly good job of
40:04
this. The issue that we run into is there's a considerable number of patients, especially grade ones, whose tumors unexpectedly relapse early. And conversely, we have patients with grade two
40:17
meningiomas, especially undergoing complete resection that have a long indolent course even without radiation. So how can we improve on that? You know, like I said, this histopathology was a
40:28
basis of a lot of classification schemes, but as we've moved on in time and changed those, the proportion of grades has changed as well. You know, the update between 2000 and 2007 bumped grade
40:43
twos from 5 to 20. 2016, now we get about a third tumors
40:51
as grade twos. And some of the other updates recently might even push that harder with some molecular definitions, especially for clear cell meningioma. Molecular pathology, you know, this is,
41:05
if you understand one concept about the molecular pathology of meningioma has this gotta be NF2 is, you know, is the gene that's mutated in the germ line. syndrome which causes neuroferomatosis
41:16
type two, but it's the most frequently semantically altered event in
41:22
meningiomas. Commonly, we see a loss of one copy of the gene, as well as a mutation in the other. And that's kind of the two-hit hypothesis and really the central driver of meningiomas in a large
41:36
proportion of lesions. Interestingly, tumors that are driven by NF2 are much more likely to encompass grade two and grade three and have a higher malignant potential to progress. And then even, I
41:54
think as a surgeon, one of the most interesting facts is that these are actually associated pretty strongly with convexity meningiomas rather than those of the skull base. And particularly, those
42:04
actually located behind the
42:07
coronal suture.
42:11
NF2 is not the only driver of minigiomas. There's been some large scale efforts to sequence,
42:19
sequence minigiomas.
42:21
Other drivers have been identified. This is a study here sequencing 300 minigiomas published in 2013
42:30
that identified a whole host of other drivers that very uniquely correlate anatomically with the location of the tumor I mentioned that NF2 are along the convexities, posterior skull base,
42:46
smoothened, or sonic hedgehog pathway genes occur in the midline anterior skull bases or your sort of olfactory groove minigiomas.
42:58
A combination of mutations for KLA-4, TRF-7 define these secretory minigiomas that are often, you know, sphenoid wing locations and another gene. that I was even more recently identified in Poll
43:13
R2A, are basically only seen in Tuberculum cello lesions. So, you know, knowing this and knowing that these mutations are mostly mutually exclusive does help us correlate, you know, what the
43:27
drivers are for meningiemos, you know, probabilistically speaking, just by knowing their anatomic location. These molecular drivers also correlate with their grade and expected behavior. They
43:42
also, of course, would give us a target if we have a therapy that hits that particular target. And shown here is basically a list of different inhibitors, which hit the different sort of pathways
43:53
that we just mentioned. When I was a fellow at MD Anderson, I did a study looking at the molecular profiles of a few hundred meningiemos, which were submitted for -
44:09
Next generation sequencing with a company called Keris, which does a sort of multi-platform analysis. It's kind of like foundation medicine. I think we're probably familiar with that here. And it
44:19
validated that these targets are present in the vast majority of tumors, which are submitted for this kind of analysis, which of course are gonna be ones where people might be looking for a
44:32
molecular therapy As I mentioned, the WHO 2021 classification is changing a lot of things. It's now incorporating sequencing as a recommended study. It takes into account these driver mutations for
44:49
the different categories. And actually in the case of a SMARK E1 for clear cell grade two meningiomas, that's sort of a pathomomonic mutation. There's another one, that one, which is present
45:05
primarily in rhabdoid subtypes, which most likely, are going to fall in grade three categories. Additionally, two other recent molecular alterations have been given a designation that if they're
45:18
present in a meningioma, that tumor is grade three, regardless of its histology. And that's a pretty new concept for meningiomas. And those are the turt promoter mutation, which we're familiar
45:30
with. Actually, both of these are familiar with from gliomas. The other is CDK and
45:39
QA And the interesting fact is, what we derive from this is that some of these mutations are actually seen as tumors progress. For example, the turt promoter mutation seems to be one that lower
45:53
grade tumors can acquire as they become grade three. We use all this information and put it together to kind of develop this sort of framework to keep in mind of the sort of frequency of mutations
46:06
along with the anatomic location of the tumor. And it sets up this little bit of dichotomy where the tumors that have a higher malignant potential might be more amenable to a resection. The ones
46:18
that are more difficult located in the skull base, thankfully have lower malignant potential, but obviously we've got a different problem with potential for residual tumor. This concept also helps
46:29
us understand the molecular pathogenesis of these tumors. And it really helps them fall into two or three large categories, depending on the driver mutations. The ones associated with skull base
46:44
tumors are, again, they're separate and mutually exclusive to those driven by
46:53
NF2 or SMARC, E1B1. Those tend to fall in the ones that are - I would classify as susceptible to malignant transformation or secondary upgrading to a grade three, especially with the acquisition of
47:08
the turt. mutation or additional chromosomal instabilities. Taking it a step further beyond just mutational analysis, multi-OMIC profiling has helped us understand what's happening throughout the
47:25
genome and transcriptome and epigenome of these meningiomas and can be used to even better stratify the expected behavior and outcome of a given tumor.
47:41
Shown here in this diagram are the different categories and methylation classifiers, these MCs at the top that were derived from a study in 2017. The first study that was published was based on
47:53
about 500. Meningiomas, they subsequently updated it to about 3000. They looked at methylation profiling across the tumor Basically, some total of all the genetic events in a tumor impact
48:11
the methylation of the tumor's DNA. This can be measured by sort of hybrid array and generate sort of a fingerprint of what the methylation status is within a tumor.
48:25
Clustering those together and looking at similarities and differences, all of the meningiomas will cluster together away from all of their skull-based tumors and then of the different subtypes of
48:41
meningiomas. We developed this concept of these benign, intermediate and sort of malignant phenotypes. These do fall in line with the different mutational drivers that were mentioned before,
48:56
with NF2 being pretty separate from those kind of skull-based related genes and then the presence of the TURP promoter and CDK and mutations among the higher-grade types They do fall. in line
49:10
somewhat with histology, somewhat with gender. And of course, again, are correlated with survival. In the updated version, I think this has really given me hope that this will be something that
49:25
we can translate into meaningful clinical application in the future. What's shown here are basically some total combining things like the methylation profile with histology, with other chromosomal
49:44
alterations to develop with a score. And looking across the
49:49
different grades and how they end up falling when you take all these into your account, you can see that there are some tumors that would be initially classified as grade one, which going through
50:01
the sort of molecular analysis pipeline ultimately will cluster and behave more like the intermediate
50:09
Same thing with ones that were expected to be grade two. Some of those actually end up clustering more with mowing net ones. This leads us to, you know, expected outcomes, survival curves, which
50:23
stratify better. And I think, you know, most helpful to us is shown in this figure here where we basically have taken the ones that, you know, originally were grade two show up as, you know,
50:42
grade one on the molecular. And we see that they end up stratifying with the other grade ones better. The ones that were called grade one, but molecularly are grade two, parallel the grade two,
50:54
much more closely. And so this will hopefully be the sort of answer that we're looking for of what really is a grade one, what really is a grade two. How can we use these treatments? what do they
51:06
actually do? How do we, you know, to a place where we don't get studies that say the opposite thing, you know, where we're lumping a bunch of things together, you know, actually separate them
51:18
out, understand what's happening and get answers to what we're doing. Here at UCLA, we're adopting some of these changes to 2021. Most notably, we haven't developed methylation profiling yet here
51:34
on the clinical level. It's actually
51:37
a difficult thing to do on a CLIA sort of manner. And right now, we do have an option of sending tumors to NIH, mainly for classification of or diagnostic classification. Is it a meningioma? Is
51:49
it a some other kind of tumor? But we have adopted an IHC-based classification, which includes a lot of the markers that I just discussed, BAP1 and CDKN. H3K27 was one I didn't really go into,
52:03
but it does pretend a more aggressive type of tumor, turt promoter is available. And then we'll One of the things that should be rolling out in the near future is a next generation sequencing panel
52:13
with about 1, 000 cancer genes. That would be an in-house test with hopefully short turnaround and would include all the genes that I just mentioned. So, with those things in mind and these
52:26
advances in treatment, we do have in our group here, some ideas of how to advance treatments for these tumors. We have a couple of hypotheses, which are, I'll go in too quickly before I wrap up.
52:41
Some of these are that treatments, if we're gonna develop a
52:47
systemic therapy that gets administered to a patient, we shouldn't bother with targets that are only relevant for grade one tumors, which are basically curable with surgery and radiation. We've
52:57
looked at targeting an antigen that is expression is correlated with high-grade meningiomas called NY ESO1.
53:08
We have a way to target it with engineered immunotherapy and this shows activity in vitro against cells which express the marker. That was some work done by our former resident, Matt Sun. Josh is
53:24
working on targeting methylation itself. This is an important determination, a determiner of meningioma behavior If this is what helps classifier stratify these, well, if we could change that, if
53:38
we could change the
53:42
methylation program in a cell, we could potentially change its behavior. So Josh is looking at a target called
53:50
EZH2, which again correlates with increased expression as seen in higher grade tumors. And we see increased activity against those tumors that express this in, you know, in, in, in vitro studies
54:06
with, you know, pharmacologic inhibitor of EZH2 is actually FDA-approved.
54:13
Maya is helping sort out how we can correlate these genomic alterations with sensitivity to radiation, using some novel technique called BH3 profiling, which, you know, assess the cells for their
54:29
sensitivity to apoptosis And, you know, we see a suggested relationship between grade, the presence of NF2 alterations and sensitivity to apoptosis. This
54:44
would not only theoretically correlate to radiation, but also for the use of agents which could sensitize things to radiation as a different type of measurement than is traditionally done So even the
54:58
aforementioned easy H2 inhibitor other epigenetic agents, as well as several others, you know, in combination with radiation. will hopefully be measurable with this type of assay to help us
55:12
understand what the relevant targets are and their interface with standard of care treatments like radiation.
55:20
Just a quick plug before we finish up, all this research is driven by tissue, which we bank. And unfortunately, we as an institution have not done as great of a job with meningiomas that have a
55:36
clear blastoma And as evidence here with an increasing number of meningioma surgeries, we have not seen it corresponding increase in tumor banking and blip little this saw We. meningiomas of
55:47
then a little drop off. I would note that the initial blip of increased banking corresponded with when I started working here. And Maya wants everyone to know that we should feel shame when we don't
56:02
bank meningioma, 'cause we got a lot of research to do to figure these out.
56:08
And with that, I will say thank you and I'll take any questions.
56:17
Oh, I just I have a question actually about your last point about the banking. What's precluding that are people just not calling? Yeah, it's certain dependent.
56:30
Oh, okay. Well, whoever the surgeon is, yeah, shame, shame, shame. Patience beforehand and activating our tumor bank.
56:42
You know, the other differences, you know, surgical techniques certainly lends itself, I think, better to, you know, meningioma and metastatic brain tumor collection, you know, or metastatic
56:54
gliomas. You know, meningioma has come out piecemeal. There's not like an often a big chunk to send. So that might be a reason, but it's not a good one.
57:04
You can send less than a choosol that way. That stuff is very essayable. And even better is the Myriad, the Niko Myriad.
57:20
Yeah, yeah, you probably can't call for being a new fight happens.
57:25
Yeah, so, so just, yeah, when you're in the case, just, you know, ask the circulating nurse to call the tumor collection person, and they'll collect it that they're on call 24 seven so just
57:35
please don't forget
57:42
the current policy for the follow-up of the patients who had surgery, radiation, because one of the pathologies, farmer pathologist said, it has to be followed indefinitely, because it may absorb.
57:56
What is the current? Yeah,
58:02
the NCCN has recommendations stratified by grade for a grade one tumor that underwent surgery. There's, you know, sort of a prescribed course of, you know, three, six, 12 months, two years,
58:14
and then out to about five years. And at that point, it is really up to the, you know, discretion of the clinician, whether or not they want to continue following. But it's true that just
58:25
because you stop following doesn't mean it's not going to come back. There's certainly late recurrences. It's to
58:33
go differentically One friend who had surgery radiation every year she goes for MRI. I doctor check out. And she said, I don't feel like that. I mean, certainly the probability diminishes over
58:46
time. And it's probably not a cost-effective thing to indefinitely scan people on a yearly basis. I like sort of a telescoping, increasing length of follow-up. And after a decade of stability, I
59:03
think it's up to the discretion of decision between the clinician and the patient
59:09
To one of the things as residents, you see a very biased group of patients who are going to surgery and not the other nine patients who we follow in clinic. So most of school-based practice is
59:25
following patients. And
59:28
just as a little nuance, you should order high resolution MRI studies like brain lab studies to follow these because a standard brain MRI, You don't know, they're five millimeter thick slices and
59:39
often skip one to one half. between slices, you cannot follow small tumors or hard to measure growth. Yeah, you can't handle it in volumetric either. So, that's, that's just something that I
59:51
see on the outside, people order whole brain, and it's, it's, it's not very good, it's, it's too insensitive, but,
59:60
but I think some of that older, you know, in retrospect, you go back, well, this, this scan was negative, well, it actually wasn't negative, but they just weren't doing high resolution
1:00:10
studies So if you have no recurrence in 10 years, the chances of a, that tumor coming back, you may get a new tumor, but it is so bad
1:00:28
So that's a more general question. Or the molecular pathways that you described for localization of these tumors to different areas of the skull base brain. For all of the chemotherapy agents that
1:00:41
people have tried for great ones, great twos, do none of those impact any of those pathways? And if they do, people look at like, you know, pay this impacts like, you know, Merlin pathway,
1:00:52
these Merlin ones. So that's a great question The one that probably is most relevant to that is mTOR inhibitors, everelimus, you know, mTOR is something that gets upregulated with NF2. You
1:01:08
know, beyond that, the other ones, the skull based ones have not been subject to trials in the past, but there are ongoing sort of basket type trials that take into account, you know, the
1:01:18
sequencing alteration and they have, you know, a different agent that hits different targets. You know, for sonic hedgehog pathways, There's a drug that was monitored, which was accurate. in
1:01:27
other types of tumors that have the same mutations. Same thing for AKT, there's another one there. So yeah, that trial is ongoing, and they just added another arm for the CDK N2A alteration of
1:01:43
the student on more recently discovered. So, you know, the more targets we find, the more agents that they can match with, you know, this concept could, you know, hopefully come to fruition.
1:01:53
There's only a
1:01:56
few cases that have been reported of actually successfully targeting those pathways. I think one of the reasons is, you know, these alterations occur in tumors that by and large are managed
1:02:10
effectively with surgery and radiation. I don't think there's a ton of people out there who, you know, need that pathway. So, that's, you know, our strategy anyways has been to focus on NF2
1:02:21
mutated tumors because those are, you know, the predominant of malignant ones that are going to need that therapy.
1:02:28
Here are some of these meningioma surgeries are very long and if you take out part of the tumor have specimen should be called tumor collection person early or wait 10 hours later anytime when the
1:02:39
tumor has been sitting in that bucket out in North. Does that make a difference? Yes it does. Actually if it's going to wait it should wait on ice that will preserve things a little better but
1:02:52
they're available you can call them as many times as you want
1:02:57
they will come, you know, pick up specimen A, specimen B.
1:03:09
Do you send molecular profiling on them again a second time and do you find that after an SRS, some molecular profiles actually do change, or do they all seem to consistently stay in the same
1:03:21
profile So, for the most part they stay within the same profile the exception is that term promoter, that's the one that has been identified as something that causes the sort of upgrade or, you
1:03:32
know, the progression, you know, after treatment after radiation.
1:03:45
So the women who have been in Geoma, because some of them have progesterone or steregia receptors. In the breast cancer, they put them after removal of them, they put them on their medication for
1:03:50
five years. How come patients include it in the lead? They have tried anti-prodigestrones, and estrogens, they have not been successful in meningioma. Um, yeah, and you know, the another
1:04:01
interesting fact is the, uh, dichotomy between genders is actually really only seen in grade one, grade two and grade three is much more equal.
1:04:14
There's anecdotal cases where I think you mentioned the women in Europe, but this other ailments where high progesterone treatment is used, and they've shown rapid enlargement of meningiomas, and
1:04:27
they stopped it, and then meningioma actually stopped growing or regressed. We don't want isolated cases. There is something that comes from observations and pregnancy. right, meningiomas can
1:04:39
expand, and then they spontaneously regress after delivery with correlating with hormone. I actually don't think there's COVID-19 to menopause that your tumor actually may stop growing. That's
1:04:52
maybe a reason not to do something now. Let's wait till we see if it stops growing after menopause. If it just stops them traumatic or whatever, you're on the fence. Yeah, I'm gonna have you seen
1:05:05
that
1:05:09
Yeah, I'm not studying it, but it gives them hope when to think about menopause. I don't know if many men who had oaelectomy or any kind, have any change with the amount of your progress. Is
1:05:27
something to you? You know, I'm not aware if any results of a study like that, the one thing that I would, I would correlate to that is. there is an increased incidence in people who are like
1:05:40
brachy mutations, which you know they have an increase incidence of breast cancer. There's an increase incidence of meningium as in patients who have breast cancer too. So all these things are sort
1:05:48
of tied together. So that might be a difficult thing to really assess because people who are getting O forectomy might have a predisposition to forming tumors anyways.
1:06:04
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