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SNI Digital, Innovations and Learning,
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the new 3D Live video journal
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in association with SNI Surgical Neurology International, a 2D internet journal.
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It's pleased to present another in the series of SNI Digital Interviews with Clinical Neuroscience Leaders.
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Today's interview is with Mitch Berger,
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who is well known worldwide, and he's going to talk about medicine, neurosurgery, brain tumors, and life
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Mitch is a very long CV, he's been a associate professor and professor at the University of Washington, was the chair, head of neurosurgery at UCSF, one of the big, large and successful programs
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in the country and in the world. As a director of the UCSF Brain Tumor Center, he's been interested in that really for his whole career And the president of numerous specialty societies has won many
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awards of recognition,
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and many endeavors in which he's been asked to participate.
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Okay,
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and I'll add it to this. So anyway, I'd like to welcome Mitch Burger has
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had an illustrious career and known him for a long time. And Mitch, maybe to start off, if you can tell us, I think you started out with Charlie and you see us here, is that right? Yeah, yeah,
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I was a resident there with Charlie Wilson and went there in particular because of my interest in neuro-oncology and developing new surgical techniques for taking out tumors safely. Yeah, that was
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at a time when there was no lot going on and rain tumors and treatment. I think Charlie had probably the most advanced area there where he was really putting a team together. How'd you get
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interested in that? Is that because nobody else was doing it or was it a challenge or what? Yeah, I think there are a couple of reasons. One is I
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was impressed by how dismal the prognosis was with most of these primary tumors I was impressed with Charlie's concept, which was to operate on patients, but to combine it with a team science
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approach, to try and come up with translational opportunities to improve what was the dismal prognosis at that point in time. So I liked the concept of how he was doing this and building a team of
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investigators who were looking at every piece of tissue that ever came out of a patient, trying to study it, investigate it, and look for new potential therapies to try to improve this disease. No,
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that's, I think that's really good. I was on a grant committee to look at Charlie when he was at Kentucky, he had a brain tumor grant You didn't approve it, you went to New Orleans and. And I
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think typical of his personality was determined. He had goals. He kept working on him at the time. It may not have been
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people didn't understand it. It wasn't popular, but I think if you looked 50 years later, it turned out to be right. Multidisciplinary approaches to these problems. Yeah, I think the only thing
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that dramatically changed was the overwhelming concept back then with Charlie and his peers. To be not as aggressive with the surgical approach as it turned out to be later. In other words, we were
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at a very difficult point in neuro-oncology from a surgical point of view in the late '70s, early '80s, where biopsy
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only was the rule of thumb. And in fact, all of the neuro oncologists around the world advocated for that, told us we were wrong by doing anything more than that. And that's where the field was.
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And then I think we decided, or at least I decided
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to do something very, very different, which was to really work on technologies that would make it safer to do a radical resection. So the goal here was to build a career around radical
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resection, maximizing extent of resection, doing it safely with the understanding that there was a risk in doing that, that we might not advance the field. We might make patients worse, but I had
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a hunch that we weren't really moving the needle
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in the late '70s and early '80s, and we needed to do something radically different. So that was the diversion early on. I think just for the perspective of the audience, the microscope was just
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being introduced. People became interested in that. Glimblastoma was still not a really attractive area because the survival wasn't good and we didn't have any good therapy I remember I was at
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Roswell Park and Guy Owens was there injecting methotrexate in the carotid artery
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and you remember that was a very early primitive approach but people were trying at that time. And so for you to think about this
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to do this further, just to put it into perspective, that's a revolutionary, you were alone when you're thinking about that as my guess. Yeah, I think so. I mean, it was really bucking the
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system. I was heavily criticized in the beginning about trying to take that approach because the feeling was after you were called studies by Dandy, where Dandy did hemispherectomies and this didn't
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move the field forward, primarily because we didn't have the adjuvant therapies at that point in time and we certainly didn't have the imaging so we didn't really know what the hemispherectomy was
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doing. But based on that, the feeling was, well, he's already tried it, he's done it, doesn't work, don't do that. Yeah, I remember reading a paper by Bucey, Paul Bucey at the time was
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operated on a guy with glioblastoma, you remember this paper? It was absolutely, I never forgot it. He did a hemispherectomy on the patient, hoping that he could cure the tumor and remember he
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said in the paper, patient came back to curse me because it occurred. I think that was almost the title of the paper. So that was the, that was the milieu at the time. It was really kind of
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hopeless.
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That's what people were thinking. So let me show you another, I'm going to show you a paper that here, can you see it on the screen? This is a paper, I was at that time I did a review on
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neuro-oncology for my paper and his textbook at that time. I came across this paper, I've never forgotten about it by Shearer. You remember this paper? Yeah, the secondary structuring of Shearer.
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Yeah, and he did, it was a fabulous paper. I mean, when he took a whole series of people with brain tumors, and he did multiple sections, and then looked at the pathology, came up, can you see
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See this? came up and he said, Only about 30 of all gliomas. I'm doing this so the audience can understand the environment. 30 of all gliomas were circumscribed, okay, which is positive, that's
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not a negative. But people didn't take it that
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way.
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And then 60 have a more diffuse character with a widespread zone of growth that exceeding the macroscopically, macroscopically visible tumor 20 of those must be considered diffuse processes with no
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circumscribed tumor, which brings us up through your career. I want to take a detour. I'm going to just stop this for a minute and ask you, why did you go to work with George, Ojiman in Seattle?
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Well, because I had decided early in my career that I was going to be a very aggressive surgeon as it related to gliomas and I was going to test the hypothesis that extent of resection-affected
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outcome.
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I also realized having seen so much morbidity from these surgical procedures that we had to rethink the way in which we were doing it. And I had no clue how to do it, but I started to understand
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some of the early epilepsy type of investigative literature, which looked at language localization, and George was doing a fair amount of this as was Andrea Olivier at the MNI. And
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I started to see that because George was doing these cases awake, I thought there was a potential way in which to do these procedures, testing language, looking for motor systems, et cetera, and
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trying to avoid the morbidity. I can't do the conclusion that it couldn't. it can only help and I needed to see whether or not these techniques were applicable. Well, also, I'm sure you look back
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and said I think I can do better than what we're doing now, which was basically either biopsy or giving up. I know in Europe, I remember reading a paper in Egypt where if it looked like if it
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looked like a glioblastoma in the imaging, they wouldn't do anything or biopsy it, which was really not a very good treatment at that time anyway. So you've got to be able to do better than that.
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I'm sure you were thinking that way. Yes. You know, I was thinking that way. To develop this innovative attitude and this attitude of being aggressive, it must have come from, did it come from
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Charlie or come from your family? Well, no, I think it came from Charlie, but Charlie just didn't have, if I can, you know, just be truthful about it. I don't think he had the patience to deal
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with it. It was clearly something that if you were going to do an aggressive surgery, it wasn't gonna happen within 30 minutes of entering the tumor. It had to be done in such a way that you had to
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look at the function, investigate the function, determine where it was, work inside it, work around it, and do everything you could to get those patients out in good shape And I just don't think
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he had the patients to do it, but he had the foresight to say, look, I think we should be doing more aggressive surgery, but his way of doing it was to go in the middle of it, aspirate, stay
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inside the lesion, and then to take whatever came from it and to accept the morbidity. And I just wasn't willing to do that. Yeah, but again, for the audience, That was a common approach to it
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at that time.
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So, okay, so let's fast forward. And let's go to,
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I think I looked at your 2020 paper, which I thought, Mitch, I thought that was just a superb piece of work. You can see that on the screen here. And you have a cast of 100 here, but I think
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that fits with your thinking And you involve the Mayo Clinic and other, and I think it was another institution, I can't remember. But in putting this together, we're just an outstanding study,
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extremely well done. And then we come to the conclusion here,
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which is, and I'm fast forward reading today, in the conclusion you state that, look, I'm gonna, this is
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enhancing in the end enhancing and the non-insing portion of the tumor. a resection of the non-ansing and enhancing portions in the tumor in conjunction with molecular and clinical information, with
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validation of external tests, so forth and so on. Studies supports maximal extent of resection of the enhancing tumor in younger patients in additional to maximal resection of the non-anancing
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portion, regardless of the molecular status. So, and this is you talk about how you do that So, we're talking about, and this is 50 years later.
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I know you're only 55, but this is, I mean, that's a lot of time here. And here it's a reality. Tell us,
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so you take Georgia's techniques, which he does for mapping speech and so forth. You come back, you apply it to people who've got tumors and sure it's a frontal lobe or the occipital lobe,
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Obviously, you can get into very sensitive areas and you use that to locate where they are.
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And you use brain mapping and your stimulation techniques. And you go and resect the tumor. And this initially is a tumor that is, as you stimulate, the ones that are away from sensitive brain.
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Am I correct about that? Yes, and I think there were a couple of other steps along the way that influenced this thought process. And that was one of very insightful paper that was written years ago
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in the radiation oncology, literature showing that when these tumors, the glioblastoma's fail, they fail 95 of the time within two centimeters of the contrast enhancing margin So that was a clear
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understanding of where the bulk of the disease was.
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the studies that Pat Kelly did. And Pat Kelly had an idea of vocally resecting enhancing tissue, but at the same time he was doing these serial deep section biopsies looking at infiltrating tumor
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cells. And what he also showed was that the vast majority of these infiltrating tumor cells were within a few centimeters of the contrast enhancing margin So based on that, the philosophy in my
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career was
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do the resection of the contrast enhancing tissue and do it safely. Get that morbidity well under two or 3. Then if you can do that, go to the next step. The next step was go beyond the
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enhancement into that zone of risk, which is the flare abnormality on MRI scans. That's the brain adjacent to the contrast enhancing tumor, which we call the non-contrast enhancing tumor. And what
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happened with that was the statement in that paper that if we take out the enhancing tumor and we leave less than five cubic centimeters of non-contrast enhancing flare, those patients by achieving
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what we dubbed as a gross total resection plus, otherwise known as a super total resection, that those patients got into a 36-month median survival for the classic IDH wild-type GVM, regardless of
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MGMT status. So that, I think, was the defining moment in several years ago, three years ago, three, four years ago to put that into print. regardless of the molecular status, we're now at an
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age where the standard of care for cleoblastoma surgically is to achieve a complete enhancing resection as well as to go as far out into the flare as is safely possible. That is the best option for
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the patient. Well, let's go into that a little bit because this gets into what you're working on now And I'll go back to the paper by Shearer. And this is yours, Shearer. And so the question is
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the non-enhancing area. They're talking about 60 of ugly, almost have a diffuse character, widespread zone of growth, exceeding the macroscopically visible tumor. And that gets into how do you
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identify, let me get out of this for a minute, how do you identify the It's
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the tumor margin, it is the growth margin with all the blood vessels
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and so forth, and then you get the infiltrative margin, which he says not only goes for a small distance, but it can go for a long distance. So, a lot of the work has been spent on using imaging
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agents, I guess, to see if we can find where the non-enhancing tumor is, right? Well, yes and no, that is correct. We use agents in imaging that extravagously from disrupted blood-brain
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barriers like gadolinium to find out, you know, where the bulk of that angiogenic tumor is located. The issue is how do you find these infiltrating tumor cells? And that's been a tough one because
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the ALA, or the aminolovellinic
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acid,
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which gets into a tumor cell. has nothing to do with the blood-brain barrier.
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You could see those on mass, but it's got to be more than, you know, several millimeters in thickness. So that is not a good way to identify microscopic tumors. So the way that we've been
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advocating and publishing, we just published this work in Nature Medicine, was to use a technique discovered by an Indian physicist by the name of Raman. Many years ago, Raman 80 plus years ago
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identified a strategy in which you could shine light through tissue and based upon the reflectance and the characteristics and the time frame of that reflectance pattern that you could identify tumors
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that were amorphous, cells that were amorphous, meaning they weren't normal glial cells or normal cells in general. And so this is a technique called ramen. stimulated histology where we are able
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to take tissue in the operating room and within one to two minutes, we get a curve based upon the reflectance of light in using an artificial intelligence algorithm we're able to determine based on
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normal tissue from cases like epilepsy, et cetera. We're able to distinguish tumor cells infiltrating from non tumor cells So the next step from that paper I wrote in 2020
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is to not only get into the flare, but now do a Raman histology study that looks at different degrees of removing these infiltrating tumor cells to see if we can even improve survival further. Let
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me take you back a few years to
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the time when you started doing the work. I work at the NIH when they were doing leukemia. And this is, you're talking about a solid tumor in the brain, leukemia is a diffuse blood tumor. And
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using some of those statistics,
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if you calculate it out, about 100 gram tumor is about 10 to the 11th cells. I think this is for my NIH days. And so if we look at surgery, surgery would take two logs of cells out Radiation may
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take another one to two logs of cells out. So we're down to 10 to the 9th, 10 to the 7th. Maybe chemotherapy will take another. We're down to 10 to the 6th. We still got a million or 100, 000
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cells. We can't see which fits with what Shira was saying. Yeah, that's exactly right. And so the reason it comes back is because you can't get it all. That's correct. You can't get it all But
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you have to understand that not all of these cells are programmed. to enter the cell cycle to proliferate, to create angiogenesis. Some of these cells don't do anything. They're part of the
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microenvironment that do not stimulate growth. Obviously, they exist. There's a potential for them to change because they are neoplastic. They're programmed to be that way. But the reality is
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that a lot of times when you take out the mass of the lesion, you reduce the cytokines that are produced by that tumor that stimulate those idling cells to do something. So it makes sense. And I
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think that's what's proven the theory that if you take out the bulk of this tumor, you can reduce the growth kinetics of these infiltrating cells and potentially keep them in an idling state longer.
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Have you written that up because I don't know that? No, that's something that would be almost impossible
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but it is probably a leading theory now in terms of cytokine induced growth from the
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tumor microenvironment to these cells that are proliferating or entering the cell cycle.
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Well, so now we get to, and in this we're in 141 countries so there are people all over the world looking at tests. And there's some people in low to middle income countries are places which are
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also exist in the United States where you've got limited resources. And you, and so, and that's probably most of the world. Yes. You're talking about what you're doing is just a very small
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section of the world. What should these people be doing? And I know, let me just show you this. There is another paper by, I'm sure you know, about this, by Melon Koff And this was a paper.
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that you see here, it was a review and it turns out that what he says is that basically it's a surgery you're talking about, but after that it's radiation therapy and temazolamide for different
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grades of
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the tumor, and we're going on the low-grade thomas, we'll get to that in a minute. So what we're talking about is what you can do in the rest of the world, what's your suggestion for people in
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other areas, let me get out of here, in other areas who are low-resource environments, they can't afford all this stuff. What should they do? Well, let's just back up for a minute because I
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think there are a couple of different
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ways to look at this in those environments. Excuse me. The first is to understand that throughout the Even in low resource areas, standard of care is the way forward after surgery. So virtually
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every center, and I've been in many of these centers, every center is capable of using radiation therapy and virtually every center on the planet, excuse me, is also capable of using Temidar
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because Temidar or Temazolamide is
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not terribly expensive. The issue that creates this huge disparity in outcomes from these low resource environments is they're not starting with a maximal safe resection because they don't have the
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tools to do it. And by that, I mean not so much the bipolar or the suction, it's really the mapping techniques to be able to push the resection safely,
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No matter where I go throughout the world, I hear the same thing. We just don't want to create that kind of morbidity. We don't have those techniques. So I think what I've done is I go on a
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mission every year to the Philippines where we operate at the Philippine General Hospital, one of the most indigent hospitals in the world. And through that experience, I've come up with a new
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technology to map brain using a very inexpensive new brain mapping system that allows us to do language mapping, motor mapping, a wake or a sleep, et cetera. And I'm about to achieve FDA approval.
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And then we'll test the first prototype in the Philippines this summer. But the bottom line is that device is going to cost, literally just thousands of dollars. It's not gonna be expensive.
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Whereas the current technology in our country, like the Integra, the Ojiman Stimulator, which now doesn't exist anymore, was 50 times to 100 times more expensive. So I've decided to make a system
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that the third world and beyond can use so that they can do these safe resections and do maximal resections in preparation for everything else they can do, which is the standard of care. Now, when
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we get into low-grade gliomas, we'll talk about the new drugs, the inhibitors, and the enormous expense of those inhibitors that would prevent low-resource countries from using it. But then it
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gets us back into the extent of resection and outcome, and we'll talk about that as well, how important that is. But the bottom line is we have to provide low-resource setting.
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places, the technology that's affordable so that they can do everything I can do in the first world, if you will. I think that's terrific. We've got grand rounds we have with Sub-Saharan Africa.
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There's a billion people. That was 50 countries. And
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they're, to afford something that's5, 000
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is a big expense. And so if it's something that's reasonable, fine. And then you've got also have the backup, which is the therapy, the radiation. A lot of these people disappear into the
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wilderness and never see them again. And people have to. So it's a long haul. But what your history shows is you're willing to be patient to get there. I mean, if you didn't have the patience,
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then you were talking about that with Charlie. And I can understand that. And you just wouldn't persist. So so we got a couple of things here. One is the tumor edge and the other is a chemotherapy,
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which I think is really good. First of all, in the tumor edge,
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how do you, you said you have this technique from this Raman in India. How does that, how does that, how far does that go to the tumor edge? Have you got some studies that show you're, you're
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already into normal brain, or is it infiltrated between normal brain tissue and regular tissue, which is what Shira was telling us? Well, you, you can actually use the technology to chase down
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tumor cells. So basically the way it goes is you do your maximal safe resection, and you use navigation to the best of your ability, considering the shift that occurs during surgery, to get to
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that beyond contrast enhancing region And then you begin to serially, serially sample the tissue. insert it into the ramen system, get a readout. It tells you whether it's tumor or no tumor. You
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keep going and you keep doing that. And you can get that, the key in surgeries to get immediate real-time feedback on what you're doing. In other words, you look at a piece of tissue you, know
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this as well as anyone, that you look at that tissue and you're not convinced it's tumor, but maybe it's tumor. Does it feel right? Does it look right? Does it have tumor in it? Well, this is a
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way to do that. Versus 30 minutes for a frozen section, this takes two minutes. So I think that's the way you do it. You just keep going until you're out into very, very sparse, if at all,
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infiltrated tissue. And that's the way we do it for both the high and the low grades. So obviously that gets you up in the morbidity area because well, mapping reduces that. Yeah, but okay So,
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uh. Okay, now we get to another issue we're just bringing up. And this is in the low grade gliomas, and this is a paper, we're acid in low grade glioma. And I think Tim Clossey has a paper on
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that. And it showed really some benefit from a very targeted chemotherapy in tumors Is this the
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future?
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Well, I would say in no uncertain terms, this is a game changer for us for a number of reasons. And we can dissect all of those reasons.
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First of all, starting with a new WHO classification in 2021, we now are mandated to determine the IDH status of the tumor Of course, these lower grade tumors mutated. And when they're mutated,
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their metabolic activity is very different than if they're wild type. The wild type GBMs don't rely on this metabolic pathway. So
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if you could change the metabolism of the tumor, you could potentially reduce the growth rate of the tumor significantly And so the goal was to develop a strategy to inhibit the product of the IDH
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mutation, which normally IDH converts to alpha keto-glutarate to
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to hydroxy-glutarate, or prevents that from happening. If there's a mutation in IDH in the IDH gene, you get the byproduct of to hydroxy-glutarate
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That drives the metabolic function of the tumor. So in that setting, If you can block the mutation, the ability to make 2Hg, you could potentially put the tumor into an idling status. So this
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study, to make a very long story short, this study is the third generation of IDH the inhibitor, which affects both the IDH1 mutation, which is the predominant one in low grade tumors in the
33:49
IDH2 mutation as well, gets into the blood brain barrier exceedingly well, which is critical in low grade gliomas because they don't have a disrupted blood brain barrier. And this study showed a
34:03
remarkable finding that it not only prevents the time it takes to have to act on the tumor, meaning that the growth. occurs and you have to do something else after you start the treatment, but it
34:20
also dramatically affects progression-free survival in a hugely statistically significant way to the point where this was a randomized study and they had to stop the arm that wasn't getting the drug
34:37
So essentially what this has done is it's provided a way to make the tumor idle. Now we don't know this study did not ever get into the issue of survival because it's too soon. All we know is that
34:57
it can significantly change progression-free survival to the point where you don't have to do anything. So if you back up to the patients, now the patients have an option so that if we cannot remove
35:13
these tumors completely and they're IDH mutated. then they can be treated with this drug. They don't have to undergo radiation. They don't have to undergo chemotherapy, which can cause a change in
35:26
the mutational status of the tumor and actually make these low grade tumors transform the higher grade tumors. So the standard of care based upon a radiation therapy on a college group study called
35:40
9802 published over 20 years ago was to put the patient on a radiation and chemotherapy. Now we have another option. We don't have to do that. We can do surgery and the IDH inhibitor. So it is a
35:55
game changer. Well, that was a paper I just had up. There was a paper looking at the molecular action. The IDH inhibitor, here's the
36:09
alpha-ketoglurate, isocitrate cycle and here is the mutated IDH get you the 2D2HG. It's all complicated for the audience, but what it does is you write it, it kind of
36:26
sidetracks the tumor from growing and metabolically, and
36:32
it puts it almost in a chronic state. So it's a major accomplishment, I agree with you. So that's where things are going to go. I think there's a paper on crony for angioma, where again, you
36:47
find the same thing, we just had a group from multidisciplinary group, from France working on patients with a very rare type of avium in the face, published in the New England Journal, that has a
37:02
genetic defect, a little different than this, but they were able to target that and essentially stop the growth So it's,
37:11
again, a multidisciplinary approach. something you thought about 50 years ago. And I think that's, to me, that's the way to go. Yeah, I agree with you completely. So, look, I guess we get
37:25
down to another question and that gets back to Shear and the preparer about Paul Glussey, about the guy who came back
37:36
to curse me. Obviously you've made inroads progressively with the tumor you can take care of and now you're getting to the one that's much harder to do, is this a surgical disease or is it gonna
37:48
become a biochemical disease? Well, unfortunately it's always gonna be a surgical disease because a lot of times due to the growth of this tumor, which is rapid, we see patients, we've seen many
37:52
patients who for whatever reason had a scan six months before they presented with a GBM,
38:13
and the vast majority of them never have anything seen on the scan. So this is a rapidly growing tumor, which gets people into trouble. And the only way to deal with that rapidly is surgery. So I
38:25
think surgery is clearly not gonna go away for that reason. And in the very near future, it's not gonna go away because we must get the tissue to do the very extensive sequencing, looking for DNA
38:40
alterations, looking for DNA methylation profiles, all the things, all of what we call the omics, omics, which are these various tests looking at proteomics, looking at all sorts of DNA
38:56
determination, looking at mutations, alterations, methylation status. We have to have that tissue to do that. So I hope things surgery is gonna evaporate overnight,
39:12
Primarily because these patients get into trouble. Now the low grade tumors, it's very different. They present with seizures and they can often be controlled. So you do have time for different
39:21
types of strategies. For example, you could envision a scenario where you could do a biopsy, determine IDH status or we're working on technologies now with
39:38
magnetic resonance spectroscopy where we can actually identify to hydroxyglutarate as a peak. If we knew that,
39:47
we could potentially think about treating some of those patients with IDH inhibitors and see if we can turn that into a non-surgical disease. I don't know if that's possible, but it's something that
39:58
we have to think about. But certainly for GBM, surgery's not gonna go away anytime soon. I think that's right Let's shift into part two here, which is a little bit about you and your thinking. If
40:15
you had everything to do over, what would you do differently? Well, I don't think I would do anything differently. I think my philosophy early on was to not follow others. It was to make my own
40:32
path forward and to have others follow me if I was right. And if I was wrong, I knew as long as I didn't hurt patients with these tumors along the way that it was okay. It was just a career issue
40:47
that maybe I made a mistake in, but I wouldn't have done anything differently because in the very beginning, I knew I had to take a risk. I had to go into a different direction. As long as I did
41:01
it in a calculated fashion and I wasn't gonna hurt anybody, meaning the mapping, then I was fine with that.
41:11
had a happy ending, but
41:14
I think in the beginning in one's career, you have to identify something that excites you. I mean, everything excited me in the beginning in neurosurgery, how could it not? It's such a dynamic,
41:27
magnificent field of medicine to be in, but you can't do everything great, you can't. I mean, we're not all people like Jim Osmond who did a lot of great things in a lot of different areas. It
41:41
just doesn't happen that way. So you got to focus in and I think you got to take a risk. And so that's basically how I built my career and I wouldn't have changed it for anything. I had lunch with
41:55
a businessman one day and I
41:58
asked him, what's the secret of innovation? He told me, find out what everybody else is doing and don't do it I think that's that's right, but I do have You have to do, if you're going to do that,
42:14
you have to do things that make sense or you think they could make sense and there have to be signals. As I said, I got signals from the literature in the past and went from there.
42:28
I mean, just take a side trip for a couple of minutes. You presented a paper which was kind of a thought paper after 20 or 30 years of doing stimulation of the brain and the speech area Can you
42:40
remember that back in the Western Neurosurgical Society? Yeah, yeah. I thought it was very interesting because you were thinking about, well, geez, I hadn't really thought about all these things.
42:52
And I discovered a whole bunch of things here that are not related to the tumor and the brain tumors. It's how the brain functions. Can you say that a little bit for the audience? Yeah, well, I
43:04
think again, there were two ideas here one was built around.
43:12
being a tumor surgeon. I'm a tumor surgeon. I'm not a functional surgeon. That's the first thing to emphasize. And therefore, my goal as a tumor surgeon was to test the hypotheses that radical
43:26
resection was beneficial for patients with gliomas. Now, having said that, I needed to figure out ways to do it safely. And that's where the functional side of things came in As that evolved, I
43:39
began to learn some incredible things that had never been published in the literature, let alone in the neurosurgical edition, that had to do with not just cortical language localization. We had
43:55
published that landmark paper in 1980s,
44:02
I think it was, no, 1991 with George Ojiman in the Journal of Neurosurgery showing the largest collection ever. of human language localization in the brain based upon work that I did with George.
44:17
He was the first author. I was actually the senior author on that paper, which was phenomenal. And we then built upon that to the point where I published the New England Journal of Medicine article
44:29
on mapping, especially negative mapping and outcome from a morbidity point of view And this has translated the basic fundamental principles of language localization, both cortically and
44:46
subcordically, then allowed my resident, Eddie Chang, who now has become the chair and replaced me as chair,
44:57
to say, look, with all this information that we've seen that have come out of these surgeries, let's move this forward to brain-computer interface,
45:09
I think it's great. It's not something I'm gonna get into this late in my career, but he's already begun to do these implants to use the language information to identify the code that exists through
45:22
high frequency gamma activation that connects different cortical regions, decode that information that's recorded and people who can't speak can't move and get them to artificially speak and move So
45:37
you see, it's come from a continuum. Now, if I hadn't paid attention and said to myself earlier in my career, wow, this is interesting. I didn't realize that the vast majority of language was in
45:48
the perisylvian system. I didn't realize that one area is connected to another through high gamma frequency activation, which we recorded during the operating room. In other words, if I hadn't
45:59
have thought beyond just extent of resection and outcome, we wouldn't have had that substrate to build some of these brain computer interface. So I think you have to always pay attention to what
46:14
you're doing and then ask other questions in other areas that may not be your primary interest but can lead to discovery and advancement of our field. And that's what we're here to do. Well I,
46:27
think that's right. What you're looking, what I always see it as you're looking, I'm looking for, if you see some anomaly, I'm looking for experiments of nature I mean, I could sit there for 50
46:38
years and never do that. All of a sudden, nature presents me with something. And if you aren't asking the questions, you won't find the answer. And I think that's what you're saying happened.
46:48
You came across something you had totally unexpected and it led you to other things or led you to have other people do things. So let me ask you another question. What do you think your neurosurgery
47:01
is going to look like in the 2100? You know me other than the future a lot. And things are gonna evolve, it's not just today, it's tomorrow, it's coming. Are we gonna be doing this, or is
47:13
everything gonna be biochemical? What's gonna happen? Well, I think for sure, one of the massive advances that is happening now and will continue to happen is our ability to understand the
47:26
diseases we deal with more. And by understanding them, such as in movement disorders, we've been able to think about ways in which we can divert pathways that accentuate others and relieve
47:42
intention tremors, tremors in general, improve walking. So there's a perfectly good example that as time went on, we learned more and more about the origin of movement disorders and where these
47:54
tremors come from. I think we're learning the same thing with oncology and certainly with vascular biology, looking at how. we can change patterns of ischemia and make surgical procedures safer to
48:10
do. And
48:13
along with our understanding of the pathophysiology of the diseases we treat, we'll come commensurate advances in technology which allow us to tap into that. In other words, better stimulators,
48:30
more minimally invasive implantation strategies for stimulators, the ability to potentially obliterate vascular problems with intravascular driven technologies and things that we put in these blood
48:49
vessels that are abnormal to obviate the need for certain types of surgeries. Not gonna get rid of all vascular surgery, but the pathophysiology understanding which is advancing rapidly. And the
49:03
ability to sort that out through very intense bioinformatic paradigms
49:10
with or without AI, because I don't think any of us really understand how AI is gonna affect this field, except to maybe help us process data better. We'll lead to new technologies,
49:26
devices we implant, devices that augment And along with the basic surgical strategies, I mean, you could ask me this question 25 years ago about vascular surgery, many pundits, not you, but many
49:41
pundits in
49:46
the field said, we're never gonna have to open a patient up again to do a vascular procedure. Well, that didn't turn out to be the case, did it? And we do have ways to get around some of the
49:58
surgeries, but we have other ways down. there was the thought that we could basically cure every tremor with geminife or ablation strategies. And yet that didn't pan out. We still have to put in
50:14
devices that can augment function. So I don't think that's going to go away, but I think what it's going to do, it's like an exoskeleton, we're gonna use things to help us do things better based
50:29
on our understanding of the disease So the technology's going to continue to advance, but it's never gonna replace surgery. Surgery won't look like anything like it is today in 50 years, but it'll
50:42
still be a surgical procedure. Well, it's interesting. I think there's several things that in your career that I think have proved true. And
50:55
the French paper I mentioned to you is the same. This fellow is a real.
51:01
a nephrologist who got into AVMs and vascular lesions and he put together a multidisciplinary team which attacked his problem. And I think we're gonna have to go through a period where that's
51:13
basically where it is. It's probably gonna be an academic centers which means academic centers are gonna have to go from silos to multidisciplinary work. And that's a major cultural shift. But then
51:26
progress is gonna be made And if you look back and now we go back to the history where we started, glioblastoma is 120 years ago. I mean, come on, where are we a day? Is this just an immense
51:40
change? And from a guy who is injecting methetrexate into the carotid, where are we now? We just, well, we gotta be a little humble as people, as neurosurgeons and doctors, changes I think are
51:54
gonna be dramatic So if you're advertising a young person today, two things. One, should they go into medicine? And there are a lot of arguments you can give against it, central control and so
52:10
forth and so on. You need innovative people like you are, you need to stimulate those people, you need to encourage them. And if you're in an environment where, like you're doing a randomized
52:23
controlled study, you never find some of these things you're talking about with speech, unless you were really paying attention to it And so we got to encourage innovation, creativity. So, and
52:36
the young people are doing that. Maybe they're going into computer science or something else, like you're a new head. What would you tell people, young people a day, what should they do in terms
52:47
of looking into medicine or looking into the future of medicine?
52:53
In 10 words actually,
52:56
yeah I think it's actually. It's pretty simple. I don't think it's complicated at all. I think it all stems from the basic tenant that physicians are physicians because they serve individuals who
53:14
are sick, and who have problems medically to improve in problems
53:21
that need to be attended to and hopefully fix. So the basic tenant of anybody should be, who goes into medicine, should be, I want to help the sick and the infirm, and the inferred. Basically,
53:37
that's the
53:38
principle. Now, if that is what you want to do
53:43
And saying, you know, I want to become a computer scientist, and I want to work in Silicon Valley and start my own company. That's a different mindset. So if the basic principle is, you know,
53:57
for whatever reason, whether it's personal or. not. I want to help people. I want to help people get better. Now, having said that, I think they need to understand that this is a profession
54:09
that is at high risk for government regulation. It's at high risk for salary compensation alterations that are going to make this not in the framework of socialized medicine. I don't think we're
54:26
going to get there. There's always going to be options for private health insurance. But I do think that if any individual thinks they're going to go into this to make money, they're just clearly
54:41
confused and mistaken. That is not the case. So if the goal is to help people, make people better, if that's a gratifying feeling when you ask yourself that question, then this is the right
54:55
profession to go into. It's not driven
55:00
And I think young people really don't understand what it takes to be a physician. It
55:08
is not the mindset of going to work for eight hours. It's not a shift mentality. You have to, it's a continuum and you have to be prepared to continue into night times and weekends, et cetera, to
55:22
help people out. So I think those are the basic principles Now, having said that, it's extraordinarily rewarding from a personal point of view when you make somebody better. It's very rewarding
55:35
when somebody's grateful to you for helping them. And if those are the things that are important to you,
55:43
then that's really, it's a great profession. But the other thing you have to do in the profession is you have to really focus. Certainly in neurosurgery, neurosurgery, you can't be a generalist
55:54
anymore. You have to focus and you have to pick something that you're interested in, whether it's pain. move into disorders, trauma, and you have to focus in it. And then by focusing in it,
56:05
you'll start asking yourself those fundamental questions, why did this happen? How can I make it better? What can I do in the future to change it? And that will drive your whole
56:19
personality and your whole approach to medicine. So that's kind of how I would see it. Well, I agree with you. I'm really thrilled to hear you say that because
56:32
I remember when I was in my internship at the University of Chicago, a chief resident was doing nighttime work, which is, you know, at that time, that's how people made a little extra money. And
56:44
I asked him, what does it take to be successful and practice my dad have been a doctor and so forth. So he said, you know, if you care about the patient, you'll never have to worry about money.
56:58
I think that's true. If you put the patient first, money will come. Don't worry about it. If you put money first, you're going to lose everything. Yeah, I'll be including your wife. Yeah.
57:11
Well, I think the other thing that you have to be willing to say, and I've said it over and over and over again, that's been my mantra, is if you treat patients as if you're treating your family,
57:24
you will never have a double standard. No matter who the patient is, no matter where they come from, who they are, the key is if you treat them like you treat, you would treat your family, you
57:38
will not have a double standard. You will give them your focus, you'll give them 110 percent, and you'll do the best you can for them. But it's when you try to think of this process as in a
57:52
two-stage, meaning you would do something for your family versus what you would do for them. That's a mistake, horrible mistake. You can't go down that pathway. It's absolutely right. Treat
58:03
everybody as a through your family. Well, Mitch, it's been terrific. I really appreciate it. I think people learned a lot. I certainly appreciated talking to you and anything we didn't talk
58:14
about you wanted to say. No, I just wanted to acknowledge the fact that I appreciate you doing this. I think it is, you know, you've always been and you always will be known as a legendary figure
58:27
in the field, very innovative, technically magnificent. That's always been your reputation. And I think for you to take this on now and try to bridge the gap between what's happened in the past,
58:43
what's evolving in the current and to speculate about the future, I think it's great because I don't see other people doing it. So I applaud you for doing it and I hope it gets people thinking in
58:56
ways if they hadn't been thinking.
58:59
Well, thanks a lot. It gets back to what you're doing. You get a lot of different people together. You've traveled all over the world and you talk to people. You know that there's bright people
59:07
everywhere. They just are in the United States of Europe. And then when you talk to them, you learn a lot of stuff. And it makes you humble. And I think you've achieved a terrific done a lot.
59:21
And your goals have been very gratifying. And I think the end result is what you just said. What's their treasure in medicine? There's not enough money in the world to buy it. Is the satisfaction
59:35
of helping somebody. If you go into it for money, you made more money than anybody else could ever dream of.
59:45
So basically in your soul, you're a rich person. Yeah, exactly right. Good way to state it. Thank you very much. Bye-bye.
1:00:01
These are the references that were discussed during the interview we had with Mitch. I'll be ready to take some screenshots so you can save it for your records and look up the references if you have
1:00:15
some interest
1:00:22
The first reference is a recent review on glaoblastoma and other primary brain malignancies. Actually it reviews them all and gets to the basic principle that it's surgery for sure, for first
1:00:37
radiation and temazolamide, which as you will see Mitch
1:00:43
talk about can be used everywhere in the world
1:00:48
The second is his outstanding paper that they published in 2020 proving really with a large series of patients, surgery is of direct benefit in extending life, quality life in patients using
1:01:07
techniques that he's developed throughout his career,
1:01:11
brain mapping, stimulation of the brain and taking out the. remnants of the computer-enhanced of the contrast-enhanced tumor and getting now to the non-capped trans portion.
1:01:27
There was a paper published in 1940 by Dr. Shearer from Belgium, which is actually one of the finest papers I've read in medicine. It didn't have a lot of technology, but it was an outstanding
1:01:43
paper in which he sectioned the brain of people with tumors from front to back, multiple sections, and analyzed pathologically the extent of the tumor. It's discussed in
1:01:59
the talk, and particularly with regard to gliomas, that they're very infiltrative tumors. And the question is, that's the pathologic basis for what we're doing today
1:02:15
Next is a paper by Dr. Mellinghoff and a list of authors with
1:02:22
Tim Clausie, who is a neuro-oncologist at
1:02:29
UCLA, who has an independent presentation on SI digital, actually, if you look it up, which he talks about, low grade gliomers, and this very significant step in the management of tumors, brain
1:02:44
tumors, where they can be treated with a targeted molecular acting agent that essentially stops the growth. As Mitch has mentioned, there's a very, very significant change, it's a game changer,
1:02:58
in his words, this is
1:03:03
the key paper that is the key paper showing this targeted therapy is being successful.
1:03:15
And the paper that follows is a very detailed presentation in the British Journal of Cancer seeing what's the molecular sites of action of this targeted therapy - excuse me - in the paper with IDH1
1:03:32
and IDH2 mutants. It's an interesting paper. It's complicated to read, but it shows the fundamental biochemical basis.
1:03:46
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