 So, to complete this morning, at least the first session's comments, we've invited a radiation oncologist, and let me just make a few comments. Most people think that radiation oncology in relationship to kidney cancer, the kidney cancer, as you heard from David earlier, is what's called a radiation-resistant disease. That may be true, but the technology associated with radiation therapy has been changing dramatically over the last number of years, and its role is becoming increasingly important again in the management of kidney cancer. So, we invited one of our faculty members, Steve Schell. Steve, join us. Steve trained at the University of California, San Francisco. He's a practicing radiation oncologist with an active laboratory, and I'll talk to you a little bit about the novel radiation therapy approaches that we might be using in kidney cancer. Great. Thank you so much, Bob, for such a nice introduction, and thank you everyone for coming this morning. So, this is, so I'm going to talk a little bit about the role of radiation, and as Bob had already mentioned, there has been kind of sea change in the way radiation has become involved in treating kidney cancer, mostly because of advances in the technology itself. So, let me, one second. So, what is radiation therapy? So, I have to apologize. I'm covering for one of our other faculty who said there, so I'm changing the things. So, some of these aren't my slides. So, radiation therapy, you know, has traditionally been thought of as kind of toxic, you know, almost the way you would think of, you know, a laser, you know, burning a hole in something. So, we, we had long thought that radiation is a cell intrinsic mechanism. So, people think about radiation in terms of how, in terms of how many tumor cells can, can you kill with radiation, you know, and that's kind of one of the ways to think about it. But, but I think that as our understanding of the biology has evolved, we understand that radiation is more than, than the number of cells that you kill with radiation. It's also about how the body senses the, the cells that have been damaged by radiation. And it's that, your body's ability to sense this cells damaged by radiation, I think that has allowed the technology, which has also advanced to change the way kidney cancer responds to radiation. So, X-rays, the kind of fundamental idea behind radiation is the delivery of ionizing high energy to, to tissue. So, what that really means is that, you know, similar to lights or, you know, microwaves or things like that, that, that X-rays themselves come from the ability to they, you generate kind of wave energy particles that, that kind of free up, free radicals and then they're by damage the DNA in cells. And so, what we see here is that, that there's free radicals that get produced in response to radiation and that this damages the DNA and this is kind of the conventional way to think about how radiation actually works. But it's changed, it's advances in the ability for imaging over the last 10 years as well as kind of advanced computer modeling that have allowed us to really deliver high doses of radiation in a way that protects normal tissues. So, one of the reasons why historically it's been a problem to deliver radiation and why it's not been a greater part in treating kidney cancer is that there's been a lot of toxicity associated with radiation. So, it's very common to see in, especially in movies where radiation, you know, affects people and their skin falls off and, you know, they change into zombies. But, but that does not happen with radiation. And what we've done, what we have now is very sophisticated technology that allows us to shape the beams of radiation such that we can deliver hundreds, sometimes thousands of different beams, beamlets of radiation to focus on one spot. Almost like if you're on a stage, you see, you know, you don't see the beams of light that come in, but you notice that there's a spotlight on the stage. And so, that's the same way that we have learned to deliver radiation itself. So, what we use nowadays is something called a linear accelerator. So, a linear accelerator is not, doesn't use a radioactive source. So, unlike a nuclear bomb that was shown earlier, that a linear accelerator is based on, you know, almost similar properties like a microwave where you can plug in this and obviously it's a little bit more sophisticated than that. But, but it generates high energy x-rays that are allowed to treat the patient. And so, patients are positioned kind of floating in space. And so, I don't know, many of you have had radiation or even seen it, but, but there's a couch that's made out of carbon fiber and it essentially suspends you in space. And so, that way it allows our machine to rotate around you in 360 degrees. And we can deliver beamlets that come out of the, the top of the, the top of the, the linear accelerator right there. And so, one of the ways that, historically, that radiation has been used was that we give a little bit of radiation every day. And that was to allow the normal tissue to recover. And so, part of that, so historically when it's been delivered that way, kidney cancer doesn't respond that way. So, kidney cancer, every tissue type has a, a particular biology. And kidney cancer itself is very resistant to very small doses of radiation. And it's probably related to the different proteins that Dr. Kim had mentioned that are getting expressed in kidney cancer. And also, the way that kidney cancer is sensed by the body's immune system. But, so rather than doing that this way, now that we have advanced technology, what we can do is deliver extremely high doses of radiation in very short amount of time. So, you used to spread it out over five weeks. But now, we can do it, what we would used to give in five weeks, we can deliver in a day. And we can do it safely by protecting all the other normal tissue. And so, hence the term, radio surgery. So, we kind of coined this term because radio surgery is, it's highly precise almost, you know, like a surgeon's scalp, although nothing touches you per se, but it allows you to deliver a single dose of radiation to a specific area. And if you were to deliver it to a very wide area, it would be very damaging to normal tissues. So, the precision and the imaging is what allows delivery of high doses to be safe. And so, this kind of picture illustrates how the target is very important. And so, you know, we're down to submillimeter accuracy in terms of how we deliver the radiation. And so, unlike previously where in order to treat the tumor, you kind of have to hit lots of different things outside of the target probably in order to be sure you treated the tumor properly. Now, we don't need to do that because we can image patients before every single treatment. And so, you can hit it right on target. And hopefully, you have a better response though than the baby. And so, this is just an example of, for instance, tumor that would be found in the spinal cord. And that way, you can see the tumor here is, sorry about that, is leaving the bone and it kind of compresses the spinal cord. This is a very common situation we encounter in radiation oncology. And what we do is we use our sophisticated technology and we map MRIs, CT scans and kind of available imaging. And we delineate where the tumor is. And then, we focus a beam right on it. And so, we're allowed to do sophisticated planning. So, we have a computer mainframe essentially that calculates different beamlets in a way that allows us to deliver the tumor. And so, the positioning and the imaging is very important. So, what you can see is if you're off by a little bit when you do such tight margins, the next thing you'll know, you're into the spinal cord, which is too dangerous. And so, which is why previously, we weren't able to do this safely. So, you can see how we would have expanded that. And so, with this, we have advanced imaging that's associated with the linear accelerator. So, a component that you didn't see in the last scan are kind of different side pieces. So, as we've gotten more sophisticated, different pieces have gotten added on. And so, each thing changes the delivery of dose. And so, we can now focus the different things through kind of a series of different beamlets. And what you can see here, this is kind of imaging that we typically do. We look at it in multiple different planes simultaneously. And we delineate the target that we would like. And what you can see here is an illustration of how each of the different beamlets get shaped. So, this is kind of blown up for ease of seeing. But you can see each of the beams, instead of being a square, like it probably would have been, you know, even 10 years ago, we now have the ability to shape each one to conform to the shape of the tumor. So, you see the tumor shape is kind of round, a little bit oval in here. We make an exact beam shape that's the same. And then we can divide it up actually over the entire body. And so, what that does, it allows us to avoid certain structures so that we can let, for instance, the spinal cord get the dose that we know is safe for the spinal cord, but we can come from multiple different directions to treat it. So, other technologies that we've used to kind of enhance our ability to target properly, you know, we do things like respiratory gating. So, this is a way, so one of the things that we've now done is that we can deliver radiation anywhere. So, the main limiting factor is actually how patients move. And so, you know, the body is constantly in motion through breathing, through digesting. And so, what we do is we have infrared cameras that watch and monitor patients throughout the entire treatment so we can deliver it precisely and so we can target it properly. So, now I'm going to talk, since these are not my slides and I actually put another set together, but I'll talk a little bit about where we go with this kind of technology. So, unfortunately, I don't have pictures to show you, but in general, what we've done with this kind of stereotactic radio surgery has really been to look at these different lesions and we see that when we treat them vocally that we have local control rates in the 80 to 90 percent range. So, previously, before this technology was available, when we did kind of very slow, low growth rate, it tended to be that there was very little control, you know, nothing, no improvement over not treating it with radiation at all. But now, with kind of stereotactic approaches, we can have local control rates in the 80 to 90 percent. So, the first place that we actually saw this is with the gamma knife. So, I don't know if many of you have heard of the gamma knife, but it's a very similar type of technology. But it was really focused on the brain. So, we looked at metastases from renal cell cancer in the brain itself. And we found that, unlike what we would have thought for a radio-resistant tumor, that we could get control rates well into the 80 or 90 percent at five years. And so, obviously, it was very complicated. And so, what we had done now with technology is that we can image it outside of the brain. So, we do it in the body itself. So, we can treat the same thing that we used to treat in the brain anywhere in the body. And so, what we've done, we've also looked at kind of treatment of single sites in the body. And we found that, just like the brain, that we can get control rates that are quite high. So, you know, 80 to 90 percent at one year. And so, current trials are underway to really look at settings in which people have limited number of metastases. So, it's changed the role of radiation completely. So, for a lot of trials now that are being introduced and that we are trying to open here as well, is that for patients with five or less metastases, kind of anywhere in the body, lung, bone, things, we will treat all five of them with high-dose, stereotactic radio surgery. And we will follow them. And we assume that those lesions will, you know, be, have long term control like that. And so, I think in conjunction with a lot of the newer targeted agents, it's a strategy for, you know, in some ways we hope to, you know, accrue more people into kind of the cured or long-term kind of treatment or long-term surviving range. The other thing that's kind of been novel and I think we will hear a lot more about this afternoon is that there's a recent recognition from the biology of radiation that this kind of radiation actually stimulates an immune response. So, there have been a number of papers that are very, that report, kind of case reports. So, kind of very rare things in which treatment of one of these kind of tumors in kidney cancer actually affects the other tumors. So, you can imagine somebody that has two tumors and one gets treated with stereotactic radiation and the other one is untreated. But actually there's an immune response to this one that's been treated and it actually affects the other one. And so, it almost like you get a systemic response by treating kind of one small lesion. And so, that's obviously very exciting for all of us because we're so excited. I mean, when, obviously, when you have metastatic disease, what we're very interested in is developing systemic responses. So, you hear about targeted agents, you hear about chemotherapy, and you're going to hear about immunotherapy. And so, the idea that radiation can stimulate this immune response has really spawned a whole kind of genre of research actually in the radiation field in which we're trying to combine this type of highly ablative radiation therapy with immunotherapy. With the goal to understand, you know, how that, how this radiation can actually generate an immune response and how we can improve that by using immunotherapy. And the idea is similar to just using immunotherapy alone is that maybe you need a way to awake the body's immune system up and then generate and then thereby produce an immune response and can we improve that so that more patients can develop that kind of response, which is what we're looking for. And so, kind of going forward, what we do, you know, a lot of, so contrary to popular belief, radiation is a radio-resistant tumor in the way that, you know, historically it's been delivered and done. But I think nowadays that with stereotactic radio surgery, we have the ability to treat lesions kind of anywhere in the body. And so, for a limited number of metastases or even primary tumors, we have pretty excellent control rates. And I think that will play an increasing role there. And then I also think that as we understand the biology better, things that my lab studies as well, we try and influence the immune system. So we really want to understand, is there a way for kind of the body's natural defenses to be reawakened and radiation, we believe will play an important part in that.