Good afternoon, everyone. It's my pleasure on behalf of the tumor section to welcome you to New Orleans for the beginning of our tumor section sessions. As is tradition, we always start out this session with one of the most coveted awards that we give in organized neurosurgery for the section on tumors, and that's the Bittner Award. And the Bittner lecturer was named after Ronald Bittner. He passed away in 1997. He was chairman of the Frontier Corporation, a telecommunications company in New York. He died of a brain tumor, and his family provided a generous gift for this lectureship and for this award. Over the years, it has been given to the brightest luminaries and household names in our field. The list, as you can see here, ending up with Dr. Lancer last year in 2017. And it is my great honor and privilege to announce that this year's Bittner Lecture Award winner is my mentor, my colleague, my friend, and someone who actually founded this section on tumors, Dr. Mark Rosenblum. Mark attended medical school at the New York Medical College. He did his residency at UCSF. He then became a staff associate at the National Cancer Institute, and throughout his career had a fully funded laboratory. He rose to the ranks of full professor throughout his tenure as a faculty member at the UCSF Department of Neurosurgery from 1979 to 1992. He then became the founding chair of the NNS and CNS section on tumors, the first such section. And now, of course, that history speaks for itself as our section has grown. He served as the chair of the section until 1991. He was funded by the NIH for his work on clonogenic tumor assays. He developed the first brain tumor bank and the first human tumor culture systems. He was very involved in developing protocols for the modern management of brain abscesses in the era of AIDS and CNS involvement of HIV manifestations, and also, of course, novel therapies for malignant brain tumors. He was awarded the Teacher Investigator Development Award by the NIH and was given the inaugural Wilson Award from the NNS and CNS for his lifelong contributions to neuro-oncology. In 1992, he ventured from San Francisco to Detroit and set the stage for a wonderful legacy, something that I have the privilege of being able to steward and continue to grow. When he became the chair of the Department of Neurosurgery at Henry Ford, he was there until 2014. He's now the chair emeritus. And upon his retirement, we were able to present him with an endowed full professorship in his name on behalf of the Department of Neurosurgery. He's written over 240 articles, seven books. He's trained 63 surgeons and raised nearly $50 million for neuroscience. Currently, he's the adjunct professor at the University of Michigan for health policy. He's a consultant for developing institutes and innovative processes. And his passion to this day, just as it was at the beginning of his career, is the patient and providing hope through the eyes of the patient. So ladies and gentlemen, it's my distinct honor to present this year's Bittner Award winner, Dr. Mark Rosenblum. Well, thank you so much, Steve, for that introduction. It's more than a pleasure to have you continue to run the Department of Neurosurgery at Henry Ford. I also want to thank the Bittner family for their legacy in allowing us to give some perspectives on our experience in the management of this difficult problem that most of you in the audience are dedicating our lives to, either partially or completely. This talk is titled, The Historical and Future Perspectives in Brain Tumor Therapy, and I'd say through the eyes of a surgeon and through the eyes of the patient. And when you become emeritus, you're allowed to say things and give perspectives and guesses, and so I'm going to give you a couple of guesses, hopefully scientifically-based and hopefully that they will actually come true. I have no significant conflict of interest that would impact my talk today. So what am I going to talk about? Well, I'm going to try to review a number of things over the course of the next 30 minutes. And first, the historical perspectives and give you a feeling for what it was like when I started in this era in 1970. I wound up being with Mike Walker at one of the first laboratories at NIH, and so in 1970, many of you were not there at that time, but I can tell you it was very different, and I'm going to try to describe that to you. Then a disruptive innovation occurred, or innovations, I'll describe that. My own personal odyssey of trying to manage these patients and the ups and downs, the role of surgery that we know to date, postoperative treatments to date, and the present disruptive innovation. And it will be no surprise when I do mention what I will. And then give a future perspective or a guess. Conclude with a very important key issue to remember, and make some suggestions. So what about the early history of malignant gliomas? Well, it was 144 years ago that Sir Rickman Godley operated on the first patient in the hospital for epilepsy and paralysis in London, and he partially removed what turned out to be an oligodendroglioma from that case. And how did the world perceive that? Well, the localization proved to be accurate, and the glioma was extirpated without difficulty, as was reported, but the patient died of secondary surgical complication. It was a severe episode of cerebritis at the time. So an outcry arose that the operation was unjustifiable, but the Times published two sensible articles suggesting that there had been an advance made on surgical interference with the human brain. What happened subsequently, obviously, this organization represents the work of Harvey Cushing, obviously, making surgery safer in the early 1900s. And then eventually, pathology was defined by Bayley and Cushing and Kernighan, so that we knew a little bit more about how to identify these. But the surgical science was unknown, and of course, there was no effective treatment. So as I mentioned, what I'd like to do right now is put you back in what I experienced in 1970. What was the care like? Well, first of all, and particularly before 1950, there was major morbidity and mortality, especially at that time. We really frequently didn't know what really we were doing. Preoperative localization was poor. And can you imagine, you localize and operate based only on the neurologic examination? And we trained our residents to actually look in the eye and say whether or not it was an increase in pressure because of an evaluation of the fundus. But that's how we were doing it, as they had done before. There was inadequate imaging. What type of imaging? When I first started, we were looking at the pineal gland shift. We then, when we were able to do an angiogram, which we frequently did before operating, we would try to identify abnormal blood vessels, and this is an area of abnormal increased blood supply and aberrant blood vessels consistent with the location of glioblastoma. And then an incredible advance in imaging occurred, radionuclide brain scans. For the first time, we could actually identify sort of in three dimensions where something was. Can you imagine? We were really touting then. Depending on that. So what about intraoperative localization? We would operate on these patients. We'd do a big craniotomy. The brain would be coming out at us. We'd try to control that. And this was our stereotactic tool. It's a needle. It's called an Ellsberg tannel. I don't know if many of you have seen this. I left mine at home. I was going to just show it. It's a little tool. But you would do a cortisectomy and make an incision where you thought the lesion might be, and then you'd pass this needle under tactical control until you could feel an abnormality. And once you felt an abnormality, you'd then open up the brain to see what you got. And what happened then? Well, it's pretty obvious. There was a subtotal resection. Not only was there a subtotal resection, but that subsequently brain started to swell. Despite the use of urea that we were using often, actually, in 1970, and then eventually mannitol and certainly decadron became more used, we even questioned whether or not surgery made tumors grow. As silly as that sounds today, but there was really very little ability to control these patients' care immediately after surgery. And what else did we do? Well, we gave whole brain radiation therapy for all these patients because we felt that radiation did work. And medical therapy started with the Brain Tumor Cooperative Group that was particularly run by Mike Walker through NIH, Charlie Wilson, Steve Mahaley, and a number of luminaries that helped actually start this section. First trial was with mithromycin, failed miserably. The second one was BCNU, and it actually did succeed. And in 1978, Mike Walker published in the Journal of Neurosurgery an article that showed survival increase. The major increase was with radiation therapy, not chemotherapy, but it did show some effectiveness and that we could continue to do trials that we're very dependent on today. Then a disruptive innovation occurred, and that disruptive innovation was promoted and fostered by Godfrey Hounsfield in London. And you see here some of the original Polaroid pictures that one would take on some of the original scans. Well, that should have been celebrated right from the very beginning, but as you'll see repeated here multiple times in this lecture, true advances are frequently met at first with skepticism. So what happened with him and how he presented this? Well, he thought he had a good idea, so he went to a neuroradiologist at the National Neurological Hospital at Queen's Square in London, who explained to him that with pneumoencephalography, and anyone who's done that, come and see me afterwards because that is a bear of a test, plain tomography and angiography, there was no existing brain lesion that could not be diagnosed with imaging already. There was no obvious clinical use for a computed tomographic machine because tomograms in general weren't really very useful. So he was sent packing. So what did he do? He was persistent. He went to their main hospital competitor, Atkinson Morley. He spoke to a neuroradiologist there. They connected him with an individual who had just made a lot of money in the music instrument, in the music industry through the publication of the Beatles records and electronic musical instrument company, and hence the CT scan, the ME scan was developed and in 1974 became commonly available. So surgery in the 1970s was improved by the development of neuroanesthesia. There was no really neuroanesthesia until that time. Safety obviously following CT imaging and improved visualization with improved lighting, the advent and use of the microscope very much, and our intraoperative ability to follow these cases was predominantly dependent on intraoperative ultrasound images, which was a significant improvement. Medical treatments in the 70s included work that was coming out of the cooperative groups that I was describing with tumor boards just starting to develop and tumor banks just starting to develop in the mid-1970s, with a focus on the delivery, usually intravenously but in other ways, of purely cytotoxic agents with a lot of side effects. Radiation therapy was refined in that you could give radiation to the CT-defined area plus two centimeters, and that was a significant advance. The field of radiation therapy had tried back then and continued to try to improve the effectiveness of radiation with radiation sensitizers. I can say that without doubt that's not been a very successful venture for them, but certainly the development of stereotactic radiosurgery in Gamma Knife at that time led to a significant advance in the management of many of our lesions. And then brachytherapy with temporary seeds, in particular as promoted by Phil Guttner at UCSF, had its day in the sun. Then another disruptive innovation occurred as a consequence of work by this fellow, Paul Lauterboer, and he conceded NMR imaging. Well, imagine what's coming next. He filed a preliminary patent disclosure, but at the 12-month point arose when he actually had to spend some money to file the patent he received advice from all over that magnetic resonance imaging, MRI, had no imaginable commercial value. He allowed the deadline to pass without filing. He published it in Nature after proving and begging the editor to publish this because it was going to be only of limited specialist interest, MRI. So instead, this fellow here, Raymond Demedian, developed the first commercial scanner, the Phonar, and he had the advantage, the commercial advantage. Lauterboer did get the Nobel Prize for it, however. But again, similar type of story. Disruptive innovation, people don't usually accept that at first, but perhaps maybe should. The advances to the present time, we all know in regard to surgery, there's been a stepwise improvement over the many decades to lower morbidity tied to imaging, especially stereotaxis beforehand and during, and functional mapping, similarly, to decrease morbidity. Radiation therapy remains focally administered, and of course, radiosurgery, particularly for meds and acoustics and maybe in other types of recurrent benign tumors, has certainly proven to be very useful. And medical therapy has not lived up to the promise, with chemotherapy having marginal effects and overall disappointing to date. So that's the history, in general, of what's happened in many ways. Now I want to propose you what I personally went through, and I feel like a ping pong ball. And anyone who's done this over the course of time has to feel that you've lived through a period of hope, and then failure, and more hope. We're in the more hope phase right now. Success, failure, and more success, and then advances, disappointment, and more advances. So I want to tell you right now, you can get up from your seat, and you can go home, because I've cured brain tumors. I've cured malignant brain tumors three times in my career. Now, why do you say that? In 1970, I helped Mike Walker operate on this fellow. He's a 50-year-old physician from Lincoln, Nebraska, who was actually the first case, and I was the one that gave it, the first patient to get CCNU. He lived well. He lived for five years. He was going to cure brain tumors. This is going to be easy, ladies and gentlemen. Of course, it wasn't. That was silly. But we thought at that time, first person, well, perhaps it was an oligo. Oh, by the way, he also got a post-operative infection. Perhaps the immune system had something to do with it, but that was pretty silly. On the other hand, when CT scans became available, multiple patients had a complete gross total section of the CT-enhanced lesions with Charlie Wilson at UCSF and many other places. Now surgery is going to cure this, and there was nothing left afterwards. So it was going away. What about the invading cells? What about Peter Berger and showing in Pat Kelly? Well, obviously, that didn't happen either. But the final period of time when we thought that this was really going to work was with several patients treated by us with Avastin at Henry Ford in 2009 and a lot of other people. So I have to ask you, how this image doesn't suggest that we can cure brain tumors? There's a recurrent glioblastoma in the dominant parietal lobe that six weeks later looks like this. I mean, we finally found that silver bullet. Of course, that's that pseudo-cure we saw because it changed the image as well, but changed just the vasculature. And we really did succeed in changing this local disease to gliomatosis cerebri. Good job. So the bottom line is, all of you eventually, most of you will probably, through your careers, feel like a ping-pong ball. But I'd suggest to you that we are not going to be able to find a single silver bullet, even if other ones might be. There's a lot that needs to be done and understood biologically. But the cure of these tumors are not actually going to be a cure, I don't believe. More realistic goal is to make glioblastomas a chronic disease like diabetes or like AIDS that we saw a lot, and some of the people in the audience actually were my residents at the time. But when we first identified what was happening with AIDS in San Francisco and New York, that eventually yielded a multidisciplinary, multi-pronged approach based upon a better understanding of the disease and eliminating or minimizing the chance of resistance developing. And AIDS is an example of this. Then and now in the United States, now there's cocktail of three or more anti-HIV drugs that lowers the chance for resistance for treatment. And what's been the outcome? The total life expectancy of an HIV-infected individual at 20 years old in 1981 was one year. It's now 70 years. HIV deaths due to AIDS, again, was nearly 100 percent. It went to 78 percent. Now it's 15 percent. So the medical field has been enabled and have improved the outcome of this devastating disease by understanding science and then administering multiple things that then can try to control it. So let me switch gears to where we are today in the role of surgery. This is a neurosurgical audience. We're interested in surgery, and most of us do have that feeling and conviction that extensive surgery will improve survival. And LeCroy in 2001 nicely showed that if you can get at least a 98 percent resection, likely you will improve survival, albeit 4.2 months. And Sinai actually suggested that you could even get away with improved survival when you just removed about 80 percent. But that's not the whole thing, right? McGurk in 2009 addressed the issue of what about if you develop a deficit? What happens? And they looked at 306 consecutive glioblastoma patients with good performance status and compared, took a look at the actual just survival, not just quality of life, but survival of these patients afterwards. And this slide summarizes the results. It'd be really great if you could gain 4.2 months or 4 months, but you develop a deficit, and on the average, you lose all of it or most of it, not even in counting for the fact that the quality of life during that time is not what you would want. So take that another step further. Ray Sawaya proposed a very simple way to look at the tumors and where they're located. Grade one non-eloquent or near eloquent or eloquent parts of the brain. And then Young and Lancer in World Neurosurgery in 2011 took that one step further in a model. And this is really a model, but it was illustrative to me. Let me just describe these three curves over here of the tumors resection in eloquent, near eloquent, and non-eloquent area. The black curve represents the average months of survival expected with an 80 percent cytoreduction. The red curve represents expected average months of survival lost due to perioperative complications. And the shaded area is what we should expect by trying to get these out. Tell me how effective it will be in the eloquent area. On the other hand, it suggests here generally, and it's probably reasonably well proven, that if you're trying to remove these tumors in the non-eloquent areas where you want to go, or maybe in the near eloquent area, as long as you don't develop deficits. So you need a deficit-sparing approach if you're going to try this. Finally, we do need to really realize that these tumor cells are not just in the enhancing area. We all know that. These are cartoons that I made with Charlie Wilson years ago describing the preoperative model of the tumor here in solid. And after you remove it, the fact that there are still cells at different distance sites. The majority of these tumors recur within two centimeters. So in circumstances which would be permissible to not cause deficit, perhaps you should go after that. Well, that's the flare image. That's not a round lesion. But realize that those, the flare is an area that probably contains not only edema, but the invading cells. So, if you try to go, get more out, go after the flare safely, however. So, what's the value of attempted growth cell resection? It does, it should likely increase survival. Avoid deficits, however. It depends on tumor location. And the question now is, is there a role, a value for supermaximal resection in non-eloquent to near-eloquent areas of the brain? And there might be for the slow-growing, relatively less invasive tumors, some of the oligos and so on. So, post-operative treatments to date have been modest. Radiation therapy clearly has a role. Chemotherapy, modest. Maybe the FDA did approve chemotherapy in Gliadel for my friend Henry Brehm in the audience. But, and for others that have used that tumor treatment field, I don't know why that works. But it has been approved and seems to work. And then, obviously, a lot of appropriate hype in immunotherapy and a lot of attempts at a variety of types of immunotherapy, viral deliveries, oculitic for gene delivery. So, there's a lot of activity going on. Those latter two haven't necessarily been proven yet to date. But remember, everyone, as you do, that all treatments have potentially negative consequences. And we're not just talking about the surgical consequences. Now, we're talking about the therapy consequences. And radiation therapy, when you get beyond 18 months, has a significant percentage of patients that will get necrosis. And then, the long-term survivors, depending upon where you radiate, certainly can get cognitive defects. I learned that personally with a number of patients with radiation, a lot of radiation and metastatic disease. It doesn't feel very good to have a patient live five years later and not be able to function. Chemotherapy, as I said, has some marginal improvement, but again, universally systemic normal tissue toxicity. And that's how, in fact, the dose has been developed to treat our patients, based upon near-tolerable systemic toxicity. So, let's switch gears to the future and where the future might be leading us. Innovations suggest, and I think most people would agree, have been critical in advancing the field and improving patient outcomes. And so, I'd like to separate the concept of innovations. And everyone says, oh, this is innovative. But to technical innovations that clearly have improved the segment of our population, like spinal fusion, radiosurgery, endovascular therapies, and so on. Clearly innovative, clearly making a difference, clearly which things that we should be doing. And I define disruptive innovations as those changes that change an entire field, like neuroimaging with CT and MR. And I'd submit to you that this is a phenomenally exciting time that we're living in right now, with caveats, of course. Why? Because the next disruptive innovation is occurring right now, the concept of molecular medicine. That it will permit us to understand the development of multiple types of diseases and the prediction or predisposition to it, as well as how they develop. Understanding disease progression, profound in our era in gliomas, how and why does a low-grade glioma progress to a high-grade glioma? There's some hints to that now. And to change the entire concept of cancer care, to minimize the indiscriminate, in quotes, use of cytotoxic agents, which is indiscriminate for the most part, and to develop cross-cancer therapies. Imagine breast cancer and melanoma and others being treated the same way that the glioblastomas are that have the same potential vulnerabilities. And this leads you to the concept and the future concept and the future hope that the molecular biology advances will lead to molecular therapeutics. People started to talk about this as personalized medicine. Now most everyone uses the term precision medicine. And this really does hope. But it's not there yet, ladies and gentlemen. And we all know that. And we hope that it is real and it will follow. And every time someone actually does well, you're having cured this disease but hopefully making a stepwise approach. Well, there are still the questions that remain. What molecular abnormality that's observed is important? What about tumor heterogeneity? Listen, we knew about tumor heterogeneity. We, Caren Han knew about tumor heterogeneity. That term has always been there. But it's becoming profound now because whether or not it's heterogeneity in the clones of cells that happen to be there, either by themselves or because of epigenetic influences, it is profound because those are the targets that we're going to be directing ourselves against in space and in time. What about the tumor stem cells? These are the cells that have the ability from a single cell theoretically to develop an entire tumor. But they're a fraction of the cells. How important are they? They certainly should be important. Should we only focus on that? Probably not. But how important are they? Are they still the key target? What about the invading tumor cell? These are cells that now have started to move. Is it because they're at the edge of the tumor? They are now going to be moving rather than replicating. The effect of the environment is going to be influencing certainly their phenotypic behavior. Can you actually identify them? And do they have a different type of Achilles heel? Important. And the resistant development. It is inevitable whether or not there are clones of cells that are resistant a priori or the development of ways to get around our therapy that these tumors, that they're smarter than us. And frankly, they're going to continue to be smarter than us. So we have to out-snot them in some ways. And then finally, normal tissue toxicity, systemic and brain, particularly if we're going to be administering things locally. Well, molecularly directed therapeutics is having an initial advent into the selection sometimes of some of the treatments that we have. There's certainly a lot of excitement in immune checkpoint inhibitors, other types of immunotherapies. This is a field that started a long time ago. Steve Mahaley, Darrell Bigner, and others have been promoting this, and now everyone's jumping on this appropriate bandwagon. And agents targeting mutations, abnormal proteins are all over the place now. But we depend on clinical trials to prove its value. The lucky part about this is that we don't have to prove its value only in brain tumors. We're getting hints of the value that might be presented to us by treatments of other diseases as long as they can identify the response as they do in, as we do in gliomas. One very nice article that just came out in Neuro-Oncology this year by Virhak says something very important that we need to understand. And that, they looked at low-grade gliomas that then became recurrent as higher-grade tumors, and over the course of time, sometimes even stayed theoretically the same. And they showed clearly what we had initially thought when we were starting to work in stem cells, that the tumor at the initial phase before treatment isn't necessarily the same tumor later. And it's likely it has changed its genetic composition. What's the implication of that? Well, it's pretty clear that it may not be. If you identify the therapies which you use at the initial treatment, hopefully with a combination of therapies to, like AIDS, outlive and outthink the tumor cell. But at recurrence, it may be different. But I bring you back to the question of is it really a recurrence? Sometimes it might not be. So you have to be a little careful. I'll give you one example. Here's a patient in 1994, it seems like an eternity ago, it was, that I operated on this 36-year-old man with seizures, got a gross total resection of an anaplastic astrocytoma. Post-operative gave him just 54 grade and PCV chemotherapy for a year and a half. And he was normal. One-year post-op, normal. Two years later, he develops left arm weakness. For over the course of two weeks, got an FDG PET scan that was positive. I'm going to debulk this thing so I can start him on other therapies. You get it. It was radiation necrosis. Okay? And this guy is alive and well, reasonably well. Twenty-four years later, he's still around. In fact, Jack Rock, I think, just recently operated on a bone flap of his not too long ago. Radiation necrosis, 54 grade. So just be cautious in what you're saying is a recurrence, obviously, because you're going to now give other types of therapy. So sometimes rebiopsy is necessary. But particularly, I believe, rebiopsy will be necessary for molecular analysis. Unless we can develop surrogates like CSF and blood. But I'd suggest that we might not be able to do that in a fashion necessary to apply new therapeutics. How do you develop it? Obviously, there's the selection I described. But you need relevant preclinical models. You need confirmed in vivo activity. And then it gets there. Brain delivery will remain an issue. Likely, we'll need, as I said, and I'll say again, we'll need therapeutic cocktails. And I don't think we can do this alone, nor can NIH do this alone. Industry, government, and foundation support is going to be absolutely critical to see this to the next level. Okay, what about future treatments? This is the fun part. Can anyone predict 40 years from now? Is brain surgery going to be really simple that almost anyone can do? Will we be out of work? Will we have to operate for food? And will someone in Alaska be operating on our patients in Boston or the other way around remotely? A lot of technology is being developed. I'd suggest that we're not going to be out of work. So here's actually a number of cartoons that I made up a couple of years ago, actually. And I'll take off using that. I think that in the future, tumor biopsy is always going to be necessary. We're not going to go out of work. We're made to be doing things differently. But we're going to have to have surgery, at least biopsy, for tumor confirmation and molecular diagnostics. And then if we're able to minimally invasively resect these lesions without disrupting function in a minimally disruptive fashion surgically, fine. Because we're going to have to actually take some of the tissues from various areas of the tumor, maybe even the invading edge, in order to understand really what our targets should be moving forward. Now, if that's not possible, perhaps we'll be able to use, or we or someone will develop a way to robotically vaporize these tumors under MRI guidance, let's say. Why not? Could be. We're not just talking about freezing it right now, but getting rid of the mass of the tumor. And then subsequently you're left with a hole and you've got invading cells. So I'd suggest that perhaps nanoparticles, virus, or something else would be administered into this cavity. It will then mark invading cells because it will be able to penetrate. And then you'll give blood-brain barrier-penetrating molecular cocktail for tumor growth, invasion, angiogenesis, mutagenesis, and what you should add here is immune therapy, enhancers of some type, one or multiple ones. And then a novel therapy is going to be administered to kill every invading cell. And it's not going to be radiation therapy. It's going to be something that would be specific and focused on why you targeted it. In fact, I'd suggest that maybe radiation for glioblastomas might even become obsolete. We've got to be careful about using and believing only in those things that we're doing today. And then if there's systemic toxicity, perhaps an antidote could be given that doesn't cross the blood-brain barrier. So my statement is you have to take all of these ideas with a grain of salt, but what you shouldn't do is take away anything other than the fact that we are, we have, and we are, and we will continue to be an area that have changed, and we need to embrace it as long as it further advances the field and improves patient outcome, even if it affects present activities, expertise, and bias. And I'd like to give two illustrations from industry to support this, and there are many others. And first, I'd call the Tylenol story. Sterling Products, which was a branch of Bayer Aspen, originally a German company after World War II became an English company, was developed to set a manifin in 1956, and they were first to bring it to market in Britain, but did not bring it anywhere else for fear of competition with Bayer Aspen. Well, McNeil Laboratories grabbed it, marketed it in the U.S. and elsewhere, and it became Tylenol in 1958. And of course, it's the dominant analgesic worldwide. The more profound example is the Kodak story. I think all of you probably know this. Kodak invented monofotography, we know, in the early 1900s. Then it invented digital cameras in 1975, but did not develop it for fear of competition with Kodak Film, an enormous company that was worth $10 billion in 1980s went bankrupt in 2012. Embrace disruptive innovation. Keep your mind open. It's possible, but you've got to prove it. So, I'd like to switch gears now to something near and dear to my heart, a key issue that with all these technological innovations and everything that's wonderful that we're going to be doing and providing hope and so on, but the key issue to remember is see the disease through our patient's eyes. They're the reason that we're here. They're the real reason we have a job. So, what do they see? When you tell them, or someone tells them, usually not you at first, but you have brain cancer, what do they see? Shock, loss of hope, and crisis. And not only one crisis, but the crisis continues along the patient treatment continuum with anxiety and a change in their feeling of hope and devastation and a change in their quality of life. And I like to segment these crises into four different ones. When you first tell them, it's a shock and unknown. The anticipation and anxiety with each and every new scan. Speak to any of your patients. Ask them how do they feel Monday morning when they're going to have an MRI scan Monday afternoon. Understand that. Make it easier for them. Defeat and limitations once the disease progresses, and it does, we know that. Rather depressing time. And then eventually with terminal expectation and limited legacy at the end, which is important, both of these latter ones, not only the patient and their family. So what are the patient's desires along the treatment continuum? And this is not new, but I just put this together because it really is very important for us to realize and act on it. Be honest and compassionate. Tailor information and take more time communicating. Why? Because poor communication and information transfer negatively affects patient outcomes and leads to up to depression and up to 90% of patients, and anxiety in 50% of patients, and negatively impacts quality of life along the way, and many other untold effects that we frankly don't measure well. And if we really did measure it, we'd be quite surprised. And try to take care of it and treat it. We need to include the family, and we need to support the patients through their expected emotional crises all the way along, as Rabbi Harold Kushner said in a talk that he gave to the general cancer community. I remember I was in the audience and wrote this down. He said that patients with cancer are most afraid of pain and abandonment. Now, our patients don't suffer a lot of pain, but they certainly suffer abandonment, and we're partially responsible for them. We operate on them. We follow them as best we can. And even in my personal experience, it's very hard to follow them along, but don't abandon them. And at the same time, as best you can, highlight the positives and provide hope. And hope, of course, it's a balance between optimism and realism, and it's really hard to do it. You can't go too far on one side. But as Jerome Grobman said in a great book on the anatomy of hope in 2004, I see hope as the very heart of healing. Those who have hope may help some live longer, but it will certainly help all to live better. So how do you do this? And this is just an example, a cartoon of the Hermelin Brain Tumor Center that we were fortunate enough to develop at Henry Ford. And you can see this cartoon. There are multiple individuals involved with the diagnosis management and following these patients along the care continuum with the tumor board being basic. And there's the neurosurgeon and the oncologist and nurse. And so, of course, we're the most important people in this whole scheme. No, we're not. Actually, it's the neuro-oncologist and the tumor board. But we can have a more profound effect if we actually help develop that and hire and nurture them. It's the nurse navigator. It's actually a nurse who's a go-to person, I think is the single most important person in the management of these patients. And you ask any patient's family, they'll tell you that every single time. The development of the whole comprehensive center provides continuity of care and support, which is what they need. And also allows you to identify the patient care improvements that make their life a lot easier. So, in conclusion, I'd like to mention just two things. The role of the neurosurgeon now and in the future. And what are our responsibilities? Well, as I mentioned earlier, from 1974 after CT, that wonderful innovation, to the present time, we've been, our role has been to obtain a tissue diagnosis. Our role is to remove as much tumor as safely possible. It's even more important and as well as more possible to remove these tumors safely. And to play a role in tumor boards. But I'd submit to you, ladies and gentlemen, that our role is changing now. We not only should do those things, but we're responsible for obtaining the molecularly directed, the tissue for the development of molecularly directed precision therapeutics. Whether it be in molecular proteins or antibodies or immune therapies. But we're the ones responsible for getting that. You cannot advance the field without it. We should not only play a role in tumor boards, but the development of tumor programs with an understanding that this entire consortium of people make the most difference in our patients that should be our, and continue to be our fine focus. And we should consider safely obtaining tissue at recurrence for new therapeutic selection. There's always the issue of, oh, why do surgery again? I mean, that's really devastating. But it's not that hard anymore. And we could do that safely and with the tools that we have available. So what are our responsibilities in conclusion? As we all know, our responsibility is to obtain, apply optimum judgment, skills, and technology. Our responsibility is to, as I said multiple times, to attain maximum tumor resection without causing deficits. Going after that last tumor cell in a relatively eloquent area or something that might become, without knowing where you are, might not be the best strategy if it hurts the patient and decreases survival and quality of life. Our responsibility is to obtain representative tissue now for modern diagnostics, new WHO criteria is an example of that, and to enable molecularly directed therapeutics. To understand and help lead efforts to make glioblastomas a chronic disease. This is just not a one-off. It will, it should, we should make significant advances if that's our goal rather than finding one silver bullet, which is not going to happen. To relentlessly focus on patient's experience with empathy, compassion, and hope, and to contribute to science and develop new approaches and encourage clinical trials. It is miserable how few patients undergo clinical trials. You can't figure out what to do with the next patient unless we, certainly we in the audience and others, promote clinical trials. And finally, embrace innovation. Whether it be technological innovation, everyone feels that in the area of specialty they're in, but also disruptive innovation, even if it affects what you're doing right now. We have to have our eyes open, our ears tuned, and accept it if it's going to make a difference. Why? Because the future is in our hands. It's no one else's hands. Why? Because it's important. And why? Because the future can be bright and certainly brighter than the past. Thank you.

brain tumor therapy

neuro-oncology

surgical techniques

radiation therapy

chemotherapy

immunotherapy

patient perspective

clinical trials