 So, thank you Chris, thanks organizing committee for allowing me to share some of my musings on neo-algument therapy prior to surgery. Some of the definitions up front, what is neo-algument therapy? It means treatment given prior to planned surgery, the surgery has to be given with a curative intent. So we think we're going to cure patients with these interventions and it can be form of systemic therapy, pills, infusions, or it can be local therapy such as radiotherapy. Now why is neo-algument therapy relevant and I think even more relevant than in the past is because our landscape of systemic therapies has expanded tremendously. We now have drugs that actually work and then they may be targeted therapies or more excitingly they can be immunotherapies, drugs that turn on our immune system. Let's not forget that modern radiotherapy is effective, traditionally radiation has been sort of food food in the world of kidney cancer but we now have modern techniques such as stereotactic ablative radiation or saber that's highly accurate and enables delivery of high radiation doses with excellent local and systemic control rates for our patients. So let's not forget that. Why would one consider neo-algument therapy? Well first and foremost to improve survival, improve our long-term cure rates. There are some technical aspects that can be useful. It may make surgery easier, decrease complications, allow us to resect things surgically that we could not resect without systemic therapy. And the only other reason I would ever consider this type of approach for technical reasons would be to for preservation of kidney function in an imperative setting to avoid a need for nephron replacement surgery, nephron replacement therapy. So can we make tumors smaller with targeted therapies? Yes we can. There's a plethora of anecdotes like this where a large tumor with bulky adenopathy probably borderline receptable by some standards could be shrunk down to something that's very very manageable and maybe safer to do with less complications, less blood loss, shorter hospital stay. You get the idea. The best study on this subject actually comes from Dr. Karam and Dr. Wood. They did a phase two trial looking on excitant prior to surgery and have shown us very nicely that you can shrink the tumors but the shrinkage percentages are I would say modest 30% or so. So certainly not a home run. So yes, there are some borderline cases that maybe not receptable up front, we can shrink them maybe by 30% or so and make the surgery more palatable and easier on our patients. Now we know that a lot of, you know, up to 20-30% of our kidney cancer patients present with a tumor thrombus and this can be quite significant. Some of these thrombi can extend all the way to the heart. Surgery for something like this is complex with high complication rates, requires sometimes going into the chest, astronomy and sometimes requires a cardiopulmonary bypass. Can we give targeted therapies to maybe shrink the thrombus and reduce the morbidity of the surgery? We've looked at that. We had 48 such patients that got targeted therapies prior to surgery. And again, what we've noticed is not a home run. Yes, in some patients maybe in 10% of the cases we can shrink the thrombus, maybe make the surgery more palatable and easier. But in majority of cases there's no change and you have to weigh the risk of this approach against the fact that in some patients the disease can actually progress. Again, certainly not a home run. Now this is, I think, something more interesting and something more feasible. In some instances, removing the removal of the whole kidney can render our patients ineffric or in need of dialysis. Can we give targeted therapies up front to shrink the tumors and allow us to remove the tumors and save the kidney? There's several trials. I'll just highlight one from Cleveland Clinic where they looked at 25 patients where patients would have been rendered ineffric essentially and they gave them posopinib, which is a targeted agent prior to surgery. And you can see there's two examples of such situations where probably the whole kidney would have had to be taken after posopinib, the tumor shrunk and this patient was managed with a partial nephrectomy, preserving the kidney and allowing him not to go on dialysis. And so in this particular study, 80% of the patients that were thought not to be candidates for partial nephrectomy, then were able to receive partial nephrectomy after they were treated with drugs. There's certainly a feasible approach and something to consider, potentially consider in some of these cases. Now, can neo-adjuvant therapy improve survival? As of 2018, none of our systemic therapies in perioperative setting can improve survival in an adjuvant or neo-adjuvant setting. So we don't have any data to suggest that. There are multiple drugs, sutens, posopinibs, excitinibs that have been tested in an adjuvant setting after surgery with curative intent. And none of these trials so far have demonstrated any survival advantage. I think it will be remiss to think that usage of such drugs or targeted therapies prior to surgery would also result in improvement of survival. Now, the hottest things in cancer therapies now are drugs that target immune evasion or checkpoint inhibitors. And remember, you may have already heard this today, tumor cells are very smart to know how to turn off our immune system. So now we have drugs to turn our own immune system on. How about giving such drugs in pre-surgical setting? Well, I think it actually makes a lot of sense because unlike targeted therapies, our immune therapies, and this is in metastatic settings, actually produce complete responses. So we can now actually cure patients long term with checkpoint inhibitors or immunotherapies. And so what that means is that now we have capacity to eradicate micrometastatic disease, which we did not really have with drugs such as Sutent or targeted therapies. Now, I think there's also a great rationale in giving these drugs prior to surgery. Now, think about your kidney tumor as an immune factory that has been shut down. And what these drugs can allow us to do is actually turn the immune factory back on and increase the immune cell production. There is certainly pre-clinical data, especially in mice, that shows that neo-adjuvant checkpoint inhibitors actually produce better results than giving these drugs in an adjuvant setting or after the surgery. And what's more important is that the duration of neo-adjuvant exposure doesn't have to be long. So the patients or the mice in this setting can progress the surgery very quickly and not waste time after initial exposure to the immune agents. So this serves as an impetus or served as an impetus for the Prosper trial, which I think is probably the most interesting trial right now in kidney cancer. And this is a trial where patients actually get randomized to a checkpoint inhibitor in the volume lab for two infusions. And then they go on to surgery and they continue their nevalum up afterwards. I think it's a very important trial. It accrues now in over 180 sites in the United States up to this point. I think about 90 or more patients now have been enrolled out of 700 plus. And any Canadians over here? Yes, so this will be open in Canada very soon. Again, I think very important trial is very important for us to support this. Now, moving back to the radiotherapy as I suggested, and we've talked about stereotactic radiation, we know that this modality causes rapid endothelial death. It can cause necrosis of the cancer cells and it actually induces immune response. With excellent local control rates in metastatic or local setting. And there's multiple studies that I've shown that. So what we at my institution hypothesize is that in patients who are at very high risk for recurrence after surgery, such as patients with kidney cancer and tumor thrombus, where the metastatic risk may actually be increased by manipulating the thrombus during surgery, that giving the stereotactic radiation prior to surgery may actually reduce the metastatic risk. Again, by killing those tumor cells prior to surgery and eliciting immunologic response. So this is the trial that we actually have ongoing in our center. Patients, again, with very high risk for relapse, patients with cable tumor thrombus get five doses of stereotactic radiation into the thrombus. And then proceed to nephrectomy and thrombectomy. The study, we already finished our safety lead in of six patients. And the primary endpoint is one-year recurrence-free survival. This is just sort of an example of what we're targeting. Here you can see a large primary kidney tumor with a tumor thrombus going up the Cava. And this is what we're radiating. We're radiating the tumor thrombus. Again, the idea here is not to treat this cancer completely and forget about it. All these patients progress to surgery. The idea is to sterilize these cancer cells that are sitting here and then released into the circulation as we manipulate this thrombus during surgery. So again, the initial sort of lead in safety phase of this trial has been finished. There's really no untoward radiotherapy related or surgical effects. So the patients tolerated the surgery and radiotherapy very well. What we have noticed is that two out of six metastatic patients that were enrolled in this trial exhibited a very nice and very unusual upscropal effect. And just by radiating the thrombus alone, you can see here that pulmonary nodules have disappeared or gotten smaller in a lot of these patients. There's certainly a test to the fact that there's an ongoing immunologic response to radiotherapy that's giving to the thrombus. Obviously, with testing all these patients, we checked the various serum parameters and immune responses. So we're gonna, I hope to learn a lot from this trial. Now, can we combine radiation therapy and immunotherapy to maximally prime the immune system prior to surgery, right? Radiotherapy elicits the immune response. We can prime with checkpoint inhibitors prior to surgery to elicit immune response with the primary and place key. But can we combine the two modalities to produce maximum results? I don't know, but this is a trial that we're about to open at our institution where patients, again, we know that majority of these patients with really bulky tumors, positive nodes, receptable metastases, even though we can put them through all kinds of surgery and do it very well. Technically, we know a lot of these patients will relapse. But can we combine our radiation experience with our checkpoint experience and really prime the immune system? And so in this trial, again, these patients are exposed to a checkpoint for two infusions followed by radiotherapy to either primary or one of the metastatic sites. And then they go on to nephrectomy and a resection of all visible disease, followed by, again, checkpoint inhibition afterwards. I'll keep you updated, but again, I think this is a very exciting trial, and hopefully we'll produce good results. So to summarize, what is the current role of neodermal therapy in kidney cancer? I think in some select cases, this can be used to improve receptability, to render something that we don't think we can resect prior surgery to something that can become resectable, maybe decrease excessive morbidity, prevent unnecessary complications. Maybe in some select patients who would be rendered a nephreg by surgery, maybe we can allow them to have a nephron sparing surgery and keep them off the analysis. I think this is actually a minority of excitement here. I think the major, the most exciting thing here are therapies such as checkpoint inhibitors and modern radiation together or separately. And I think these therapies prior to surgery can actually revolutionize the neo-adjuvant paradigm and actually move this field forward. If you don't remember anything about my talk, remember, as of now, neo-adjuvant therapy in kidney cancer is investigational, which means if there is a clinical trial looking at this concept, and it's reasonable, I think we'll have to support it. It's a very interesting paradigm. We'd like to thank all of you here, obviously, our patients and our families that have contributed to these studies and have helped move this field forward. Again, please support the clinical trials. Very important, and I list here my email. If there are any questions or you guys want to reach out to me directly. Thank you very, very much. Thank you.