 Okay. Is that a pretty good volume? Oh, I could have done that. Thank you. All right. So like Kim said, number one, I appreciate Kim inviting me to give this. I'm sure she could have easily given this and I could be still sleeping, which would have been a much better alternative, but that's fine. In any case, so I saw that looking through the agenda today, I saw that there's quite a bit about therapy and surgery and what we essentially should be doing with patients. And so I thought I'd give a little bit of a historical overview. Part of my postdoctoral career, meaning the time when I was doing research, was actually a very exciting time for kidney cancer, sort of the time where we began to understand the molecular biology in which loss of this gene, which is probably very familiar to you, the von Hippel Lindau tumor-special gene, gives rise to kidney cancer. So to take care of a couple of housekeeping items, number one, kidney cancer is relatively prevalent. So these are updated numbers from 2014. As you can see in men on the left in blue, it's the sixth most common cancer. And in women, it's the eighth most common. So it certainly makes this top 10 list. And we hope that it continues to, well, we hope that it drops off, but unfortunately, as I'll show you in a second, the incidence does seem to continue to rise. Now, actually I'm showing you that right now. So the incidence continues to rise over time. So this is only up to 1997, but I believe that the trends continue even into the 2000s. A lot of this may be early detection. So there is, as I'll show you in a slide much later, there is a tendency now for us to find more smaller renalges. So as many of you know, patients go to the emergency room for many things, and CTs are essentially required when you come to the emergency room. And these are often found so-called incidentally, meaning they weren't necessarily looked for, but were seen. Fortunately, kidney cancer does not cause as many deaths as it does cases. So cancers like pancreatic cancer, there's almost a one-to-one ratio. Once you're diagnosed, the likelihood of you passing away from disease is quite high. But you can see here, it's actually the tenth most common cause of death, cancer death in males, and doesn't actually make the list in females, fortunately. And so hopefully what we'll see is this drop off, not because everybody else is doing worse, but because kidney cancer patients are hopefully doing better. So what are the risk factors? None of these are actually blaring risk factors, meaning, for example, in lung cancer where we see smoking as being a huge risk factor, this number called the so-called relative risk, meaning your chance if you smoked, for example, of getting lung cancer over a person who did not smoke is around 8 to 10. So the bottom line here is that all of these so-called relative risks, while they are significant when you study them, they're not like they increase your risk to the degree that we see with lung cancer or bladder cancer or other so-called smoking-related diseases. But nonetheless, if you sort of look at what is associated, it's clear that smoking is probably the biggest culprit, and that's why if you, when you first get diagnosed with this, your physician will likely ask you, you know, did you have a history of smoking? There's a number of occupational exposures that have also been associated, again, to some degree, lowly with... I don't know why I put obesity as an occupational exposure, actually. I'll have to change that. But nonetheless, asbestos exposure as well as petroleum exposure has been associated with increased risk of renal cell carcinoma. Patients with kidney failure, who in particular end up on dialysis, they are known, and I don't think the mechanism of action is quite known, but dialysis and end-stage renal disease, these patients form renal cysts. And it's believed that these renal cysts are a precursor lesion to developing frank renal cell carcinoma or kidney cancer. And then there's a bunch of genetic factors now. We know that these sort of inherited familial syndromes, such as von Hippel-Lindau disease or tubal sclerosis disease or Burt Hog-Dubais syndrome, are all associated with an increased risk of kidney cancer that tends to happen multifocal, meaning many places within the same kidney, or bilateral, meaning on both sides or both kidneys if you have them. So there are many histologies of kidney cancer, and what that means is when a pathologist looks under the microscope at a section or a piece of the tumor, believe it or not, you know, to the untrained eye, these eyes may look very similar except the color that they look, but the pathologist can actually differentiate these the majority of the time. And the frequency or the incidence of these is in this row, and you can see that the majority of kidney cancers tend to be this clear cell type, and that's because the cells look relatively clear, and this is actually an artifact of how the tissue is actually processed. Nonetheless, we shouldn't leave out the fact that there are a number of other types of kidney cancer that affect patients and are very important, so this so-called papillary type kidney cancer can be divided into these type I or type IIs, and not only do they look different on the microscope, but the patients have a relatively different outcome. And then finally, chromophobe kidney cancer, which Dr. Rathmell had a, I would call seminal paper this past year, describing the genetics of that cancer, is another one that, you know, as physicians we don't see as much, so we tend not to think about it as much, but we now know much more about the genetics of this more rare cancer because of that work. So von Hippel-Lindau disease, this is how everything really started, and it's a familial cancer syndrome, and that means that somebody at some point had a mutation in this gene, the VHL gene. And that means that, you know, you start off as an infant, or as an embryo, actually having two copies of every gene, and in VHL disease patients have a mutation or lack, essentially, one copy, so they only start out with one. So you can imagine that it only takes loss of the other one to really give you cancer. And that was what was seen in the pattern, essentially, of patients getting these clear cell type renal cell carcinomas. These blood vessel type tumors, which if they happen in your brain or your spinal cord are called heme angioblastomas. And finally, if these blood vessel tumors happen in the back of your eye or your retina, they're called heme angiomas. And so, Treacher Collins, who was an ophthalmologist, noted this back, essentially, well now 120 years ago, that these patients were coming in, and they had a spectrum of these two tumors in particular. He did not make the association with kidney cancer back then. But he reported this over a decade ago. And now we know that about 100 years, it took 100 years really for us to, not us, I should say, I was, I think, like in high school when this happened. But for very impart people like Marston Linnahan, Burton Zavar to really come up and find location of where VHL was and how it was associated with VHL disease. And we know that it exists on this chromosome. So if you take your cell and you sort of spread it out on a slide, you can see that there's all the chromosomes and they have this kind of banding pattern. So they look black and white. And we now know that the VHL gene resides on chromosome 3P. And I won't really touch on this. I don't know if others will. The interesting thing really is that a number of the other genes that we now know are involved in kidney cancer development are also found very close to here. So for some reason, unlucky to us, nature made it so that you could lose VHL along with other genes like PBRM1 or set D2 sort of all at once. And that likely is a part of why kidney cancer is developed in that fashion. So, you know, who cares about, not who cares, but there's not as many people with VHL disease as have kidney cancer. And so one of the things I did when I was a postdoc was to see, and this is not all my work, I just really compiled all this data from what was published, to see whether or not VHL mutations were associated with so-called sporadic kidney cancer, meaning you didn't have a family history of kidney cancer, you just sort of developed it out of the blue. And what you can or cannot see from where, depending on where you're sitting in the room, is that, you know, in the range of 50, 40, 60 percent of patients who have so-called sporadic kidney cancer, meaning no family history had mutations in VHL, or in the bottom panel here, you can see that they had so-called hypermethylation, meaning not a mutation, but a mechanism which just silenced the expression of the gene. And so what we then really knew was that, you know, 80 percent or so of patients probably had inactivation or loss of VHL, and this was clearly an important step in kidney cancer development. I won't bore you with all this, but I think it's, I'm sure many of you heard of this gene called VEGF, or the VEGF receptor, and these are drug targets for things like Sunitinib, Pozopinib, or Votrient, Seraphinib, Exitinib, and Bevacizumab, so we're getting many of them. And so why does that work, and how do we actually think to target that? And the bottom line is that this VHL gene that I just described sort of negatively regulates this pathway, which is so-called the HIFVEGF pathway. And so you can see under conditions of low oxygen, meaning, for example, if you have a heart attack, your heart becomes deprived of oxygen, this pathway gets upregulated, and you get high levels of VEGF. And VEGF was described at first by this gentleman, Hal Dvorak, at Beth Israel Deaconess Hospital as being a pro-angiogenic protein. So it's sort of a protein that caused growth of blood vessels. So what happens when you have loss of VHL? So either if you have VHL disease and you lose that remaining so-called wild-type allele, or if you're unlucky enough to have both of these alleles or genes, copies of this gene lost in your kidney, you basically get upregulation of this whole HIFVEGF pathway. And we believe that's why those blood vessel-type tumors that happen in the back of the brain or the eye, or kidney cancer, which is notoriously hypervascular or has a lot of blood vessels, is related to this gene. And HIFV does a lot of bad things. So not only does it turn on that VEGF protein that creates blood vessels, but it does a lot of other things that are important for tumors to continue to grow and proliferate and do things like metastasize or spread. And so back in the 90s, early 2000s, we actually had this model and it's really reiterating what I've been saying. And that is really that if you had VHL disease, you were born with one copy of VHL that was just gone. And that you're fortunately able to prevent cancer by having one copy. But if you lost that second copy, you really upregulated this protein called HIFV, which regulates VEGF, and that could cause these cysts in your kidneys that weren't frank cancer, but could easily lead to cancer. And back then, when we wrote this, you know, the other so-called hits, meaning the other genes that were involved in developing kidney cancer weren't actually known. But now, thanks to efforts from the so-called cancer genome atlas amongst other individual groups, we know that these other hits are clearly things like PBRM1 or CETD2, and they actually reside on that chromosome right next to VHL. So clinically, you know, when I was in residency, I do remember hearing that kidney cancer was the so-called internist tumor. And that's really because, you know, not a lot, but 10% of patients would present with this so-called triad, meaning these three symptoms. And that was basically flank pain, meaning you had pain near where your kidney was. You had hematuria, which is a medical term for blood in your urine. And when you went to the doctor, the doctor could feel like there was a mass there. Okay. So it was really called the internist tumor. And that obviously predates the advent of things like CTs and ultrasounds that we can now just sort of look for these things. But it was also interesting about kidney cancer. It's also called the great masquerader. And I think that that, what that means is that it fools us a lot because it does funny things. It acts strangely and variably. So as I'm sure many physicians can attest to, you have a really broad spectrum of kidney cancer, some that do quite well, meaning they don't grow very fast and can kind of sit there. Others that do more poorly, meaning they grow quicker. But it's interesting that this cancer can actually, this is primarily the clear cell type. I don't mean to generalize, but it can really spread to weird sites. You know, like your thyroid is a pretty good one that we know does happen a low frequency pancreas. I myself have not seen testes, but it's certainly reported in literature. And so the bottom line is that it does weird things. And I think as physicians and as patients as well, it's very important to keep this in mind when you see strange things happen in a patient with pre-existing kidney cancer. So I alluded to this earlier. Fortunately, even though the incidence has been increasing, if you look at some of the tumor characteristics of the kidney cancers that we're finding, they're of a favorable nature. So basically number one, the percentage of tumors that are asymptomatic, meaning that the patient didn't go to the doctor or the ER because they had flank pain, has changed, you know, back in the 1970s where it was only about 10% to now 60%. So 60% of patients now don't really have a symptom. The average size has been shrinking, so it's about a centimeter different. And then finally the organ-confined tumors, meaning it's only confined to the kidney. Well, back in the early, late 1980s was only about half of patients now. It's three-quarters of patients. So that likely explains why, despite the incidence, meaning the percentage, the number of patients in the U.S. who are developing kidney cancer is going up. Fortunately, the majority of these are probably sort of being found earlier and we're doing better with them. There's a bunch of so-called perineoplastic syndromes. So these are syndromes that don't appear to be related to the kidney cancer at face value. But if you treat the kidney cancer, many of these can get better. And so I won't get into all these, but things like high blood pressure, high calcium, weird things going on with your liver, high red blood cell count, et cetera, are all sort of a spectrum what we can see here. Okay, so when I was actually going through the historical thoughts about this, you know, it really struck me that kidney cancer therapy, think about it, it's all about keeping the faith. And what I mean by that is that the two major, I would say therapeutic advances in kidney cancer have come through persistence. And number one, immunotherapy, which I think all of you are probably very excited about and have heard about in the past year. If you look at this gentleman, and this is not to say that all the work has been done by this gentleman, but if you look at sort of him as a pioneer, this is Steve Rosenberg who's at the NCI surgical branch. I don't know when this was taken. But nonetheless, he was clearly younger here. Decades went by and he's much older now, okay? But the bottom line is, you know, back in the 80s this guy believed in immunotherapy. He persisted despite what I would, I don't have facts on this, but I would assume a perceived lull in the field of immunotherapy, meaning if he applied to the, well he didn't actually have to apply because he's intramural, but if he applied to a study section at the NIH, it would probably have sort of been thought to be out of vogue or frowned upon. But he persisted for decades and now this past year or two we now know that these immune checkpoint inhibitors are quite beneficial to patients. And so if you look at a tumor, he was very focused on this lymphocyte. He didn't give up. He persisted. And so I think this is one story where sort of keeping the faith or believing in your own ideas had paid off. And then if you think about the other thing where we've made great strides in kidney cancer, it's really anti-angiogenesis. So it's basically blocking that VEGF protein. It's inhibiting that pathway. You know, recognizing that these kidney cancers are vascular and can we modulate their tumor size by doing this. And this is Judah Folkman, who unfortunately is now deceased. In fact, I was going to the, he passed away on his way to a tumor-angiogenesis meeting. And I think, I don't know if you were going, I was there at the meeting waiting for him. He was a keynote speaker. And when I got there to check in, they unfortunately had a picture of him with the year which he passed away. And he died on the way to that meeting in the airport in Denver, unfortunately. So, but nonetheless, you know, he spent decades, so in 1971 he sort of wrote this seminal sort of thought piece in the New England Journal describing, and I actually have a slide of that, describing the fact that tumors require angiogenesis or growth of these blood vessels to continue to grow. And, you know, he, he went through some troubled times, I think scientifically as well, in which it was questioned whether this was actually a real, did anti-angiogenesis hold a real promise? He put a lot of faith in this molecule called endostatin, which, when I was a fellow there, clinical trials, and it didn't look very good. But I think he, again, persisted through this and others joined the bandwagon, and now we have drugs that do a really good job of targeting this pathway. So, Judah Folkman, he focused on these endothelial cells in the vasculature. And again, I think it's really a story of keeping the faith and persisting through decades of work. And that got me to this, you know, for kidney cancer, when you think, when you, at least as physicians, when we read these articles and journals, you know, they give, like, this history of development of something, it's always linear, you know, it's like 1971, such and such to this, 2000 this, this, this. But, you know, it's, for kidney cancer, I would make it almost like a circle. You know, Dr. Folkman and Dr. Rosenberg had these ideas back in the 70s and 80s, and they sort of came back around in a better manner, okay? So, this is one of Dr. Rosenberg's, one of the first reports in the early 90s of IL-2, high-dose IL-2, and its efficacy in kidney and melanoma amongst other tumors. And what is the bottom line? The bottom line is, you know, there was efficacy, so some patients had a so-called partial response, meaning their tumors shrank. Some patients had a complete response. But the biggest problem was that there was a lot of toxicity. So, despite being able to achieve shrinkage of some of these tumors, the toxicity was really big. And so, it really became a balancing act of whether or not, you know, toxicity being on one side, much like any drug, frankly, and benefit on this side. And you can see that, you know, back then, two to five percent of patients were dying during this treatment. So, you can imagine if five percent are dying and you're only really helping five percent, what does that ultimately, you know, get you? And so, you know, you're skipping, really, from the 1990s to 2012, when these two great articles about blocking this immune checkpoint pathway came out in the New England Journal. And what is this all about? I mean, who's here heard of PD1 or PDL1? Not everybody. Okay, so that's good. So, what these are, are these are actually proteins that exist on tumor cells? I'm sorry I should have made a slide of this. But essentially, you know, there's always been this belief that tumors should be seen as foreign, meaning they're just like a bacteria or a virus and they should be eaten and sort of disposed of by your own immune system. And obviously, I know that many patients come in and ask me, you know, how can I boost my immune system? And I used to sort of disregard that, but I actually don't anymore. Not that I know the answer, but I do think about it more carefully now. So, these proteins are actually things that are on the cell surface of these cancer cells amongst other cells in the tumor. And I would equate them to being so-called don't-eat-me signals, okay? So, if this tumor is expressing PD1 or in fact PDL1 in particular, the immune cells, when they come in, they'll see that and they won't eat the tumor, okay? Whereas if you're not expressing these proteins, it's not to say that the immune system will get rid of your cancer, but I think it has a bit of a better chance to do that. And so, if you could block this don't-eat-me signal or sort of hide it or sort of erase it, then what they found was that you could actually get relatively robust responses in some patients, not every patient. And these are so-called spider plots and the middle line in all these is, well, there's no middle line here, but the middle line in both of these essentially is zero, meaning the tumor size doesn't change over time. So, this is time versus tumor size. And it goes from zero to 100%, meaning the thing essentially grew tremendously, or it went to minus 100%, which is completely shrank and it was not visible by our imaging. And the bottom line is you can see that there are a number of patients whose tumors went below the line and did quite well, even some for quite a while. And so, there's a lot of interest and excitement about this and you'll hear more about blocking these so-called immune checkpoint pathways later. So, anti-antigenesis, this is the 1971 article in New England Journal by Dr. Folkman. And, you know, he really just, you know, you can't say it better than he did. The growth of solid neoplasms, meaning cancers, is always accompanied by neovascularization, meaning the growth of new vessels. This new capillary growth is even more vigorous and continuous than a similar outgrowth of capillary sprouts observed in fresh wounds or in inflammation. And so, what's quite interesting there is that he equates cancer to sort of a wound and that's something that has also been continued to be followed up in the scientific literature. So, the first drug that was used was this antibody called Bevacizumab, or Avastin. And we now know that it was able to keep patients from progressing to some degree. And now, we now have Sunitanibs, Raffanibs, and Pizopin. I can't go through all of the studies, but they all seem to clearly prolong progression-free survival and overall survival, meaning we're helping patients with these drugs live longer. And I guess one would equate, you know, chemotherapy, which is, it's not like we haven't tried this in kidney care, well, it's before my day, certainly. But, you know, that's really a carpet bombing. You know, we weren't doing a very good job of targeting tumor cells. And I would equate what we're doing with Sunitanibs, Raffanib, a little bit of the so-called targeted therapy, which is more like a drone strike, which had its own problems. I think if you get too precise, we're not doing very well either. And lastly, we've learned a lot about genetics. You know, this is the past two years have been really good. So the TCGA, which is an NCI-sponsored effort to sequence tumors, a single tumor with a ton of different platforms, meaning different omics, per se. Clear cell renal cell carcinoma, which Dr. Rathmel led the RNA expression portion of this huge group, published this article in Nature. And then, as I was referring to earlier, she took this very, I would say, orphan disease called chromophobe kidney cancer and published it, I think, just recently in cancer cell. Again, really allowing us to begin to think about what's going on in these tumors and can we start to develop therapies that are specific to chromophobe kidney cancer. So in conclusion, you know, kidney cancer instance, it is increasing over time, unfortunately, but at the same time, the tumors we're finding seem to be more benign and quite, I don't want to say benign, but less aggressive and hopefully can still be treated quite well. Much of science and medicine is rediscovery. So as I alluded to, we're sort of going back to the 70s and 80s. Immunotherapy, Dr. Rosenberg sort of put that on the map back then. Antigenesis, Dr. Folkman put that on the map back in the 70s. Immunotherapy holds great promise. I think you'll see Dr. Moshkos talk about that later on today. And while it has its own side effects, it's not without its own problems and toxicities. So I've had a couple of my own patients have issues with these drugs. But overall, I think the future looks brighter. I think that as we learn to use immunotherapy properly and potentially combine it with other therapies, I hope is that things will continue to look brighter as we go on and make our own history. All right, I think that's it for me. Thank you.