Frank Attenello, MD, MS, a neurosurgeon at Keck Medicine of USC, discusses the nature of primary brain tumors known as gliomas, including the latest surgical treatment options and an overview of new genomics research with implications for brain tumors and brain injury.
Yeah. Hi. My name is Frank. Turn yellow. And I'm an assistant professor of neurological surgery as well as biochemistry, Molecular medicine here at the Keck School of Medicine of USC. My focus as a neurosurgeon with my patients and in the operating room is on brain tumors and specifically malignant brain tumors, tumors that both arise from the brain and metastatic from other parts of the body. I also focus this with the work we do in our laboratory, and what I'm gonna do today is talk to you for a short time on understanding at least the basics of one type of major brain tumor that affects a lot of people. And that's the type of tumor known as gliomas. So the first thing to understand is that not all brain tumors are the same. I think the average person thinks of a brain tumor, and they think of this outside strange thing inside the head. And while that's true, um, that picture on the left here, uh, does depict that somewhat, But these types of tumors very tremendously, and there are hundreds of types of tumors when you break it down. But one of the most distinct differences between classes of tumors is where they came from. There the tumors that come from other parts of the body and left their original location and found their way to the brain and those air metastatic tumors. But I'm going to talk about is the type of tumor that came from the cells of the brain itself, meaning that the brain is made of different units called cells. And those specific units at some point had a problem, either in their replication in something that induced something to go wrong. And they started growing differently, and they show themselves in different ways. Some arm or aggressive on some are less aggressive. And what you see in this picture in the middle, is what we classically call t too intense signal. That's a memory of the brain you're looking at. It kind of from the top down is if you slice the head and kind of like a loaf of bread, and that bright area is a is a tumor. Now this type of tumor is a little less aggressive, and the tumor you see on the right is a little more aggressive, and it looks a little different. You're looking at a different sequence here. I won't go into details on that. But what you're seeing is that it forms this kind of ring and thes by experience from a lot of experience we know grow a lot faster, and they've affected a lot of people. In fact, they affect 20,000 people per year. It's the most common and most aggressive primary brain tumor. So now I'm talking about glioblastoma multiform. Um, this is the most aggressive of those gliomas I talked about. So of the tumors that start in your brain, this is the most aggressive and the most common. And unfortunately, over the last 20 years, we always cite this paper on the New England Journal of Medicine Stop, which sites just over about a year of survival with all treatments. That's with doing everything surgery, chemotherapy and radiation. And it's affected a lot of people, not just political figures, but Beau Biden, Ted Kennedy and John McCain is many people may know, but also Gene Siskel, Ethel Merman, um, and other people in show business as well as thousands of people worldwide. So, um, what this ends up doing is really affecting lives because it's not a chronic disease. It's something that even with all treatments, ends up causing ah, decrease in survival for whoever gets it. And thats quote came up after Beau Biden unfortunately passed away in 2015. I'm not a researcher. I'm not an oncologist. I'm not a geneticist. I'm a vice president of United States, But I've been on the other end of the need. Um, and that was Joe Biden 2015, after a son unfortunately passed away, leading to the cancer Moonshot, which was a boon for all cancers but ended up being in response to kind of the understanding that 20,000 is a lot of people. But in the grand scheme of over 300 million people in the U. S. Some people might not know about glioblastoma, but it is really is a big deal and hundreds of lobs, air studying. But this moon shot with 1.8 billion dedicated to cancer came from that. And I think the next question from an audience is you know, how How do you find out this is there because it's in the brain. Um, headache is probably the first thought. A lot of people happen. It is a common cause, but not always the cause. There are a lot of other reasons that can happen. You do have headache and nausea happening. Um, you can have, unfortunately, seizures or confusion when they're in certain areas that affect seizures or your ability to think. But there's the idea that the brain is broken up into specific areas. There's areas of speech, there's areas of sensing feeling things. There's areas of moving in those areas of seeing. And if the tumor forms there because again it arose from the brain itself. It it came from the parts of the brain that we're doing that job speaking or seeing or moving as it grows. It starts to hurt that area, the area that originally functioned and as a result, you see, if you have a tumor in the movement area, you start to become weak and so on. So these tumors were found, and then typically you will present to a neurosurgeon where, um, you know, ultimately we will talk about the the options, but really, it's a matter of finding out what it is, and that will mean getting a sample. And once you get that sample. If it is a glioblastoma and that's what we're talking about, then you have to remove the tumor in orderto improve survival. And that's the first step in and what we see in this picture of this little gap in the head from a manuscript who wrote, uh, about 10 years ago. And you supplement that with chemotherapy, which is most typically Team Uzoma Team is all my team and our which is this a pill that you can take, um, that causes DNA damage and tumors have a lot more replication grow fast, so DNA damage hurts them, and you have radiation therapy on top of that, um, and then you know there's new therapies that have really kind of emerged over the last 10 years. We're still seeing early results, and, um, we're still not at a point where we definitely know that he's gonna help. But we're seeing helmets that changed the electrical polarity in the head that improve. Ah, survival called, uh, tumor. Treating fields. There's immunotherapy. There's genetic therapies. Eso I won't get into them in depth, but there is a lot of work being done. But the first three steps, in any case, are surgery removers. Bunches possible chemotherapy with team is all mine and then radiation therapy with radiation to that area, usually over the course of six weeks for the radiation with the team was all mind. So what do we do for patients in surgery? Because I'm the surgeon. And, um, removing a tumor is not simple, unfortunately, because the brain is the brain and because this tumor came from a portion of the brain that has function and that portion of the brain, uh, needs to have as little injury and there's little risk done to its function as possible. And this is especially important when it's in an area of the brain that really can't be replaced like motor or vision. There are areas of the brain. Nothing could be replaced, obviously, but their areas of the brain that were so highly developed our frontal lobes. You can make up for injury in one part of the frontal lobe, where you think and have higher order cognitive functions by kind of overdrive on the other side. Um, and what we do to minimize this risk is our imaging has become very advanced, and one of those to those methods are shown here. Here on the left, you see the tracks of the brain, so you have individual neurons, which are the thinking cells of the head. They originate on the surface, and they run the length of the body down to the arms, the face and so on. And when you don't want them injured, that tumor will. Sometimes, yes, it grows from those cells originally not the neurons but the Astra sites, but it will push the neurons to the side. Sometimes he's run like bundles wires, and when it pushes thes bundles of wires out of the way, then you know okay, I can avoid these bundles of wires and really focus on the tumor. The other way we study patients over the last decade is what does what? Yes, generally, certain parts of the brain do speech. But what part of the brain specifically, what definite area can't you hurt? And what we do is called the functional emery. During the process of an image, we will look at speech. We will look at motor function and by the changes in the brain. During the process of the Emory, we can see areas light up and those areas lighting up when you speak are shown here in those areas lighting up when you move are shown it would be a different picture, but we know those air now areas we want to avoid. Um, now what happens if the tumor is in an area where you want to avoid? But, um, you really want to get as much as possible? This the slide is titled optimizing surgery while limiting risk. Well, you want to get as close to that area that has function is possible without hurting it. And what you see in this picture is sub cortical stimulation. What you're doing is it's almost like a mine sweeper. You take this little electrode, you touch the brain while measuring function. And really, this is mainly for motor. These little kind of tendrils out here are motor tracks there the wires, the neurons, the bundles of fibers that are controlling your function, whether it be our movement like movement, face movement. And when we stimulate with our little mine sweeper that that's stimulator. If we see movement, then we know we're getting too close. In fact, the amount of stimulation tells us how close we are so we know when we're one centimeter away, half a centimeter away. So we're able to improve survival, getting as much as possible trying to avoid hitting these areas because we contest them in the middle of surgery. And this is on top of the fact that I'm not even going into this because it's commonplace. But there's a wand that you can point in the head and know exactly where you are on the scan. So what else can we dio? Over the last five years, there's even even Mawr advances, and we want to remove as much as possible. And yes, sometimes the tumor looks different, but it doesn't always look different from the rest of the brain. And in those cases, there's a little bit of concern in the operating room. Yes, it looks like normal brain. Yes, it looks like we might have removed it all, but there's now new ways to make the tumor light up with Flora scene, which is basically a dye that goes through the tumor. Five L. A. It's a different type of molecule that the tumor actually metabolizes, eats up and then in the process, lights up and you can see it with a special microscope and then when the tumor's air deeper in the brain when they're not on the surface, we don't wanna hurt anything on the way in. And there have been multiple methods now to get at deeper tumors without hurting anything on the surface or as little as possible. One of these is minimally invasive surgery through a tube, it's termed brain path. But here you can see a normal hand and how small that tube is now in the tube, the tumors deep in the brain, you can stick this tube all the way through the surface of the brain, deep through those fiber tracts. I pointed out earlier that you've mapped out that you want to avoid and be able to get that tumor without hurting anything on the way in or on the way out. And then another therapy. Gaining traction over the last 5 to 10 years is laser therapy. You know this isn't exactly a laser, but what you do is this is a patient's head and it's an image ing frame. And while you image or at least while you're treating it, you place a cathode. So this little little wire down the surface of the brain into the center of a tumor. Now, it could be very deep in the brain. And you, you put this very, very thin wire even thinner than this. Probably the thickness of this little wire here. Or as you see these cartoon images of a wire down to the tumor, you heat it up to a point where you can actually watch it melt away as you heat it up. And that again doesn't injure the surface of the brain. These aren't always the best method. It depends on the tumor. It depends on where it is. And it really depends on the capability of the surgeons. Um, and what they think is best more than capability, their their judgment. But these are a lot of options now to improve survival and how patients do. So that's surgery. Um, but what more can we do? Because, you know, in the very beginning I talked about how 20 years of research and 20 years of experience in this we're still citing a paper that used the chemotherapy we used 15 years ago, and the survival is still just over a year now. many people live longer than that, but unfortunately, a few people live less, so that's an average. But what can we do to make that 10 years, 20 years, and not even a factor where it's a chronic disease? Well, that comes into understanding the tumor more. And here's a picture of different slices of the brain. Here you have a slice of the brain looking from the top. This is looking from the front, looking from the side. And again, the tumor is this bright white area in each picture. This is from, Ah, chapter we did about 10 years ago is well, and there's a lot of theories to why these tumors aren't going away. One of them is that these tumors right next to the ventricle, which is this area fluid in the brain. Your brain has its own fluid, not blood, but its own special clear fluid that bathes it, nurtures it. When tumors arise from the walls of these fluid filled cavities, they tend to recur more multifocal e, and sometimes patients do worse. So there's a thought that, well, stem cells. There's neural stem cells that arise from these regions. They might be contributing to the tumor. And no matter what you do to the tumor, there's more tumor cells coming. There's more. There is a very commonly held idea that the tumor is the central ball of bad cells in the brain. You see in this picture, and you have these tendrils, these microscopic invasions going way beyond the edge of the tumor to the other side of the brain, to different areas of the brain that you can't remove because of all the important things that I talked about, the last few slides that you want to avoid. And no matter what you do to the central core, you're still gonna have tumor cells far away from your core. So, um, the focus has become on not just getting out that part. We can see but dealing with the other tumor in the brain, whatever else it might be, whether it has come from a different area, whether it's migrated from the original area far away or whether it's a little both, um, And then there's an even more difficult solution. We talk about personalized therapy and all of cancer and all of medicine. Um, this is especially a problem with glioblastoma There's a massive amount of genetic variation in these tumors. They are different from patient to patient. They're different from cell to cell within a patient. And when you treat a patient, sometimes it even gets worse. So what do we do? Well, genomics is the program in each cell that tells it not just what what it should do as faras, how much it should grow and what factors it should secrete. Um, but it can be expressed differently. It doesn't have to change with the mutation, which everyone thinks of I. I say it's the difference between the books in the library. You know what's available to check out and then how many of each book you check out When genomics understanding has evolved, People start understanding that it's not just the books and libraries, not just those mutations. It's even gene expression. So the amount of the genes that are expressed even in a normal cell can eventually cause it to act differently. Um, and understanding that is at the core of what we do in the laboratory, in my laboratory and many laboratories. And, um, many people have heard of this new technique CRISPR, uh, and it's revolutionized genome modulation, and, in essence, it's It's a repurpose ing of the bacterial immune system, where it fights off genome changes from viruses on. We've repurposed that to change gene function by causing mutations or in some cases, even adding chemical modulations to that system to change gene expression. So hence my points on gene expression and mutation in the last slide or relevant. Um, and this won the Nobel Prize in October 2020 with, uh, Jennifer Delgado and Manuel, uh Carpentier, who first found this ability and this has come out. You know, these air. These are a few magazines where, um, this ability to change the genome really, uh, was touted. And, um, in our laboratory, we're looking at thousands and thousands of genetic candidates, uh, across the genome, not just in what's mutated, but just simply regular jeans and how much they're expressed. And how much do they affect that, um, invasion across the brain, how much they infect the growth? How much do they affect the response to chemotherapy? So there's a lot to be done, but I think the future is promising, knowing all the adjuncts to surgery we've gotten and all the adjuncts to research. And I think there is a push in medicine to create scientists who are also physicians because they're doing both of these. And I think understanding one helps one to understand the other, whether you're a scientist and that helps you understand the clinical aspect in surgery or whether you're a clinician that understands the science and the future is promising. But it takes a team. Um, it takes ah, lot of understanding. I only skim the surface of glioblastoma, but it takes the neurosurgeon to remove it. It takes the neuro oncologist to, um provide the chemotherapy is not just that initial team Ezola mind. But tell you what Clinical trials, immuno therapies, etcetera that you're, uh maybe a candidate for radiation oncologists to radiate it. Uh, neural radiologist. Um, radiologists are great. Neuro radiologists have a little bit mawr experience, and all they do is radiologist looks at pictures, uh, images of the brain. Um, neuropathologist, the doctor that looks at the sample that came out of the brain and tells you what it is, and sometimes knowing what something is. We'll tell you what kind of treatment you can provide and then the research scientists because where we are is not good enough. And as I said, it takes a collaboration between clinicians and scientists to do this and the scientists have toe, take the next step and see what directions we can go there novel that we haven't tried because what we've tried isn't quite there yet. And here is only a small sampling of, at least at our institution, the various members of these groups that are involved in care just for glioblastoma. Um, once you expand other brain tumors, that group expands greatly. And, you know, if you were to show this picture of just Los Angeles, California, the United States, that group becomes massive, and that's all for this tumor affecting 20,000 years. So there's a lot of hope. There's a lot of people working on this, and I think the future is bright. We're doing everything we can. Thank you
