 Thanks all the doctors. Thanks for your lectures. My father is 94 years old, two and a half years before he found, occasionally found a small renal mass in the left kidney at 1.2 cm. Now it grows to the 2.5 cm. Still in the so-called active surveillance. During this time, he had a stroke, recovered pretty good for the stroke, but after that, he used some drugs to prevent the stroke and also majorly concerned stroke again, so he used the plavix. According to the insert, one of the side factors, the plavix, it will cause the Y cell count to reduce. If that may potentially cause immunopropane for the kidney cancer, this is the first one. Secondly, one of the options it says it can do the partial nephronectomy, but some doctors said because of his age and also even without aspirin or pravix, it may cause difficulty recovery. So the partial cut may be more difficult to recover than the total cut. Is that true or not? Thank you. I think Dr. Rampers, I will let you answer the question. I guess maybe I'll rephrase, and you can tell me if this is correct. One question is how does plavix affect decisions about going to surgery and then also how do you decide when you're going to go to surgery or not when there's these other factors? Yeah. The plavix causes the Y cell count low. Will it affect the immune response to the existing cancer or not? Okay. We'll let Dr. Moscos take that one afterwards. I would predict, I'm not very confident about the plavix side effects and what types of white blood cells have been affected. If that affects the neutrophils, which probably would be the case, then these again are innate immunity cells that are not significantly playing a role in the overall cancer and recognition and everything. So if plavix does affect non lymphocytes, I would say that they will not affect response to new therapies. Yeah, and I would think that we would, in that case, that in the patients with cardiovascular disease, we would see disproportionate percentage of patients with immune-modulated secondary malignancies. So what was, can we go back to what those questions were? One was the, how old is the patient? I'm sorry? It's 94 years old. Two years before was no much complaint. There's still no complaint about the mass in the clinic. No urine, no blood and nothing, but it had a stroke between the two years. Yeah. So what you're describing is you're talking about a tumor that's incidentally diagnosed. Right. That isn't doing anything to them. Not yet. Not yet, good verbiage. Not yet, but in a patient that has significant comorbidities, including age, not the least of it. You really have to put things altogether again, like I said before, and you determine what's more likely to hurt the patient. Is the treatment of the tumor more likely to hurt the patient or is the tumor more likely to hurt the patient? In a situation like this, again, without having met your relative and knowing them and their functional status and their other medical history and not knowing whether or not their parents lived to be 120 years older, without knowing that there are very few people that are gonna encourage an intervention at this time, considering that the likelihood of hurting that patient with an intervention is higher than the tumor hurting them. Thanks, Ron. And by the way, even with, by size criteria, and though that's growing, let's say you're talking about a four centimeter sporadic tumor that is kidney cancer. Let's just make those assumptions. The likelihood of, I mean, what you're worried about is you're worried about that spreading, right? So first of all, it's gonna, it's growing reasonably slowly, and the likelihood of that spreading is somewhere between one and 3% per year. So even that is still low, right? So. Do we have another question? I just wanted to ask Dr. Harrison a question, and maybe the answer is nobody's looked, but now that all the immunotherapies are coming around, has anybody looked at PET scans or novel imaging in, and maybe Dr. Moscos can comment too? Yeah, so he may be more of an expert on that than me, but I know that people are interested in that, in imaging PD-1, I don't know if it's possible. So, you know, that falls into the, how to decrease the cost and find patients who most likely respond to the therapy. So there are some promising tracers, so it's a little bit complicated. So I told you that there is a number of mechanisms of immunosuppression, one of which has to do with the enzyme it's called indolamin deoxygenase. It is an enzyme that basically metabolizes an amino acid that's called tryptophan. So there are some tracers that we are actually interested at UNC to use that actually called C11AMT, which is an analog of tryptophan, that we hope that patients who have immunosuppression, they would have high levels of the tryptophan analog. And we would plan to design a trial where we would image them before treatment and then give the PD-1 and see whether we can correlate activity of the tracer with response to therapy. But nevertheless, the community, yet I think, and again, that's my bias, the communities, there are so many of these that we have to do. There's so many options and right now there has not been a commitment towards one but seems that AMT is more likely to move forward, I think. Question back here. So many cancer therapies are partly immune suppressive and the tyrosine kinase inhibitors, of course they have off-target effects that could be partially immune suppressive as well. So if you put that in the context of the immunotherapy approaches where you treat with blocking the PD-1 pathway and you get responses in about half the patients on a good day, like you said. Is there a correlation between the response rate to the initial therapy, the specific tyrosine kinase panels and target affiliations with the response to the PD-1? Could you use that as a predictor? You got to ask me. I'm asking anyone. Yeah, maybe I can take that. So again, with the caveat that I'm not an immunologist, I know that different companies are developing PD-1 inhibitors and PD-L1 inhibitors and they seem to have their own assay for looking at PD-1 positivity. So in the trials, PD-1 positivity doesn't perfectly predict response and then also patients that are PD-1 or PD-L1 negative also seem to respond. So I think, and you can correct me if I'm wrong, but there's a lot of nuances as whether they're looking at tumor cells or other cells and what they're using is the cutoff. And I was told there was, I believe it was AACR, there's a whole session about this at some recent meeting about just how kind of messed up that the whole assays are for lack of a better way of putting it. Can you repeat the question? Was that the question or not? My question is you've got two competing influences. You've got the anti-tumor immune response and that's what you'd like to get. You also have direct anti-tumor effect by a compound or a drug. So if you treat with a compound that is going to target the cancer cell, for many of those treatments, you're also going to be targeting the immune response. So if the immune response is playing an important role in eliminating the tumor cell, you're actually working against yourself often. But that's gonna depend very much on the target profile of an individual candidate drug. So I guess my question is, when you list these 10 or so various targeted therapies that are being used in renal cell carcinoma, they're all gonna have different kindnesses that they had. They're all gonna have different effects. So do those effects have a predictive value towards the response to anti-PD1? So the effects of the kindnesses? If you have a patient that doesn't respond to a particular tarris and kindness inhibitor, are there kindness inhibitors that don't work? But then that would then predict a response to PD1 because they don't work and part of the reason they don't work is because they didn't block the immune response and the immune response was playing an important role to control the tumor. So now you get rid of the break. Now the immune responses instead of suppressed is enhanced. So I'm not a kidney cancer specialist. I can tell you that these paradigms of combining kindness inhibitors with immunotherapists have been done in melanoma and are ongoing in melanoma because we know that you may actually want to have benefits from both worlds. So like a direct and that humor effect that actually may lessen the immunosuppression of whatever is going on and then coming up sequentially with an immunotherapy, there has not been any clear signal yet because these trials are ongoing. Nevertheless, the combination of these drugs is very kind of toxic. If you give them concurrently, like there's a lot of hepatotoxicity, I'm aware of a trial where Sutent was given in combination with nevolumovid was very toxic. But I have not heard of whether a response to a tyrosine kindness inhibitor would actually correlate with a response to a PD-1. Thank you. Okay, any last questions? One more? As my father's candidate for the potential active watching, we're always concerned, do we need to do biopsy to make sure that cancer or not? As I understand it, for all the medical therapy always required pathology level diagnosis, but the surgery may be not because anyway you can get the tumor and then you can do that. Is that true or not? Yeah, so one of the common statements by surgeons is that if you're going to take it out, that was your biopsy, right? The fact of the matter is in your father, even if you were to know what that was, you're very likely not gonna want to do anything about it considering the whole belt and shock, the whole view of things. And biopsying it, it might give you some more information, but it's not going to affect really what you're gonna ultimately do right now. So there is, it's not as though biopsy is completely without risk. So why put somebody at risk if you're not going to act on the information that you're gonna attain? So yeah, so in a typical patient like you described, typical, right? Never met your dad. Typically, we wouldn't encourage, or I wouldn't encourage biopsy, simply because it's not really going to change, at least my opinion, but then again, patients have to share a decision that's fair, right? We live in America. And it's not, he even told me that way when he was doing it. Mm-hmm. Good, most older patients do, you know, those that have one, right? And we're talking about that 80 plus year old, they've won the game of life largely, and that's easy for a 40 year old to say, but maybe when I'm 78, I'm gonna be thinking, you know, you haven't finished, but 94 year olds will commonly say, why are we doing anything? But I think you, one of the test scans that says, yeah, so I think. Yeah, so you kind of read my mind, I was gonna ask Ed to play devil's advocate, what if Geraint Tuxamab scans were approved? Would you do that? So maybe reassure this gentleman, or would it, you know, maybe add more anxiety if it was positive? Yeah, G250 from the land of these L.A. We, you know, in this particular incident case, even if I knew, so you said it's two and a half centimeters? No, yeah, so on the basis of size, historical pathologic studies, on the basis of size, there's an 80%, slightly above that, 80% chance that it's hidden chance. We know that, knowing it isn't going to really change what you might wanna do. Does that make sense? Whereas if you were in a better total health system, and you were trying to determine whether or not the risk of treatment were worth the intervention, then maybe that would be appropriate, or I would go the other way. I think this question kind of sums up the day. Like we have a lot of new therapies, we have a lot of new advances, a lot of new things to do, but ultimately comes down to every decision, seems like it's very personal, right? From the decision to do surgery, to how to manage the drugs, to how to choose which drugs, and how to do all this is ultimately very personal. So I hope that we've been able to give you a little bit more sense of what's out there, and what goes into some of these decisions, what it is we think about and talk about when we're trying to help guide you through this whole process. So with that, it is three o'clock. I wanna thank our speakers who've come and shared their day with us voluntarily to try to help clarify this. But also to thank you all for coming for being a very interactive group and for taking a really active role and interest in this disease, kidney cancer. I would encourage you to follow up with the Kidney Cancer Association. If you wanna watch any of these again, they'll all be online, I would guess, probably by Monday. The Kidney Cancer Association puts these meetings together around the year, about quarterly, and let us know if there are topics that you wanna hear about. There's way too many topics to cover today. We tried to pick what seemed kind of relevant, new and fresh and burning, but if there are good topics you wanna hear, let Mike know, let me know, let the people at the KCA know, and next time we do this, we'll cover those topics as well, and we're here all the time. And safe travels.