Sam Chang: Hello. My name is Sam Chang. I'm a urologist in Nashville, Tennessee, and we are very fortunate to have a trio of superstars here at AUA 2022. And these leaders in our field of urologic oncology actually run a course at this year's meeting focused on upper tract urothelial carcinoma. It's a tumor board. It's case-based approaches to treatment of upper tract disease. And so I'm going to turn to the panel members here of this course. Give us an idea of what you do and how you do for this course. So Surena, I'll start with you.

Surena Matin: Well, thanks so much, Sam. So what we thought we'd do today is pick one case that would highlight some of the current issues that we have with this disease and to get some opinions about how we go about treating it. This is a disease where we have very little level one evidence. And so relying on the expert opinions sometimes is the best we can do.

Sam Chang: Absolutely.

Surena Matin: This is a patient who's 75 years old, former smoker, and develops painless gross hematuria. And CT is done that shows a 3-centimeter, left upper pole filling defect with a soft tissue mass being present there. Labs are pretty much normal. GFR is 65. Patient has good performance status. And for the purposes of this presentation, we can say that he comes in having had a negative cystoscopy. Jonathan, what would you do at this point?

Jonathan Coleman: It's a very typical case that we would see for a patient with upper tract disease, a typical presentation, a history of smoking being a major risk factor. Other risk factors would be things like family history and so forth. So those are things that we would want to collect beforehand. But for the workup of this patient, sometimes the controversy comes down to endoscopic approach, whether it's necessary or not, or whether just the finding of an upper tract mass is sufficient to proceed with some form of therapy. I think in the modern era, endoscopic evaluation first is the initial approach to at least get a sense for what's going on in the upper tract. Most of the time it will be cancer. So I think you can be assured that that's what you're going to find, but then getting a biopsy and assessing what's going on as well as mapping out the extent of the disease and deciding or at least determining how much is involved.

One other aspect of this may also be to determine a patient's underlying renal function, which is important in determining what we might do for the patient next as well. So I think there are multiple factors that go into the initial evaluation, but endoscopic evaluation initially, I think, is warranted as well as biopsy.

Surena Matin: So I think is it fair to say that in the modern era, the idea of a reflexive nephroureterectomy based on CT appearance alone in most cases is not something we would do anymore? Correct?

Jonathan Coleman: Well, I would say that under very narrow circumstances, that approach would be used.

Surena Matin: Right. Non-functioning kidney, for example, right?

Jonathan Coleman: Correct. Non-functioning kidney or a situation where there is, as you said before, they have a negative cystoscopy but say a positive cytology so a floridly positive cytology on urine studies. That's a situation where I think you can assume, especially now that cytologists will give us an indication of high-grade versus low-grade based on cytopathology. If you have high-grade upper tract disease or high-grade cytology, nothing in the bladder, and a large mass in the renal pelvis, then there are circumstances where some people would take that patient directly forward with therapy. But as I said, it's a very narrow indication.

Surena Matin: Okay.

Sam Chang: So if you guys are put in that situation, would an outside ureteroscopy be enough, that we visualized a tumor, there's a tumor there, it's large on CT scan. Is that enough for you all to say this patient needs nephroureterectomy? Or would you want to verify it yourself? Because that's a position we're put in, not infrequently, oh, we saw a tumor, and not to throw shade on anyone, but sometimes the sense of comfort is not as great. So is it enough to say that there's an endoscopic appearance by someone? Or do you feel like you need to see it? What about you, Surena? What do you think?

Surena Matin: No, I agree. I think we want tissue these days.

Sam Chang: Okay.

Surena Matin: Because that risk stratification is key now. Twenty years ago, maybe when we didn't really have great options, a reflexive nephroureterectomy may have been reasonable. But these days we do consider neoadjuvant chemotherapy, if by chance they qualify for immunotherapy, if they have more advanced disease or something. So we do want to risk stratify. There is data, as Jonathan pointed out, that helps us risk stratify based on endoscopy. Is it papillary or sessile? Is it high-grade or low-grade on biopsy? Is it really multifocal? Can we consider kidney preserving approaches, things of that sort? I think we do get that information.

If I do have tissue from the outside, I don't repeat the endoscopy. I think it's a lot to put these elderly patients through.

Sam Chang: Excellent point.

Surena Matin: So I do try to minimize that, especially if I think the incremental benefit is minimal. Now, if we don't have tissue, that's another matter. Or if we're really trying to look at kidney preservation, that might be another situation where I would consider it. There is data also that's coming out that suggests that the more manipulation we do with the upper tract with biopsies and such that we increase the risk of bladder seeding. That might be a conversation for another whole presentation and what we're doing to try to mitigate that. So I try to take all those concepts into account when counseling about whether we want to repeat them [inaudible].

Sam Chang: So I'll let you guys go ahead with this case then.

Surena Matin: Yeah. So basically, the ureteroscopy was performed. It showed high-grade urothelial carcinoma. Of course, the CT has no obvious signs of invasion, but as we know from this disease, we may not necessarily see that. That's very obvious, but have it be present. So Jeanie, is this someone you would consider for neoadjuvant chemotherapy or would you recommend they go on straight to surgery? What are your thoughts here?

Jean Hoffman-Censits: Sure. So this is somebody that, in this disease, we have multidisciplinary discussions about patients. Sometimes a urologist will refer a patient to me. Sometimes we'll just have a conversation over the phone. So a couple of things that we think about when a patient comes into the office, whether or not they're a candidate for chemotherapy, I think the age that was mentioned, 75, it's about the average age of patients that we see that come into the office. And 75-year-olds have 75-year-old problems. They can have renal insufficiency, either just comorbid or from the disease itself. We sometimes see that from obstruction. Hearing issues. When we think about neoadjuvant chemotherapy, peripheral neuropathy, cardiac disease, their functional status, just kind of watching them walk into clinic. So it's important, I think, often to have that conversation. To some extent, not anymore, because Jonathan and in our group at [inaudible], there's more and more data coming out to help oncologists make decisions about whether or not to give patients neoadjuvant chemotherapy.

But a lot of it is extrapolating from bladder cancer. And in bladder cancer, the rules are a little bit different. There's much more tissue, right? And we give neoadjuvant chemotherapy for people that have muscle invasive disease. Surena, I've heard you on this stage and say that is just not what you're expecting to get. So we're seeing really scant tissue, maybe just cytology. So the comfort level of giving that neoadjuvant chemotherapy is not always there. So I think having that great communication with your partner urologists as a medical oncologist with this disease is really important because most medical oncologists are not seeing high volumes of high-grade upper tract urothelial cancer and may not have a great comfort level of who's the most appropriate patient to treat.

Sam Chang: Yeah. Excellent point, because the initial gatekeeper is the urologist.

Jean Hoffman-Censits: Right.

Sam Chang: And to be honest, urologists at different centers and different geographical areas and within the same programs have different kind of set points of when to include whom and where those individuals may actually gain benefit. And so the actual numbers can be, I think it's not too far from, when do we refer our non-muscle invasive bladder cancer patients for immunotherapy, for BCG unresponsive disease. Our medical oncology colleagues, it's very few patients they've ever seen with non-muscle invasive disease and we put them in this situation. So I think that collaboration is incredibly essential. So you've got this patient. You've considered neoadjuvant chemotherapy. What'd you guys do next?

Surena Matin: Well, as it turns out, this is somebody that we would normally consider for neoadjuvant chemotherapy. Sometimes we do have preoperative clinical nomograms to help risk stratify and to help guide us as well as the patient. It is a multidisciplinary conversation, and sometimes we do let the patient know, look, there's a risk of overtreatment here. If you want us to be aggressive, this would be the route, the concern being that, especially in a patient with a GFR of 65 and presumably good kidney function in that diseased kidney, they're not likely to be able to get cisplatin chemotherapy afterwards. So we're burning a bridge with the procedure.

So these conversations, I think all of us routinely have with our patients. As it turns out in this case, the patient was being treated elsewhere. And so he went on to have a laparoscopic radical nephroureterectomy. There was limited lymph node sampling. There were two lymph nodes removed. And the pathology showed T3 disease. There was lymphovascular invasion. The two lymph nodes were negative, and the surgical margins were negative. So what do you all think may be his risk of metastatic recurrence based on those findings, either of you?

Jonathan Coleman: A throw up question. No, it's a great question, and it comes up not infrequently. And this is one of the reasons, I think, to consider neoadjuvant chemotherapy is because it's always in hindsight that you look back and say, wow, if I'd only known. And as you pointed out before, there are some nomogram features that we use up front to try and predict stage in patients. And there have been several studies showing that things that will increase your risk of having high-stage disease are things like sessile architecture, larger tumor size, to some degree tumor location, also CT findings in terms of any evidence of invasion. So yeah, certainly in this patient, I think upfront, you would've predicted that this would've been a high-risk case.

There are some genomic markers that are out there as well. Things like p53 positivity in tumors also predict for higher stage disease, whereas FGFR3 mutations predict for lower stage disease or less aggressive cancer. So in centers where those types of studies can be done up front, you can help to stratify to some degree. Again, that's not sort of guidelines data, but that's information which is now coming out that, thanks to groups that Surena and the MD Anderson group and Baylor and others have put together, as well as at MSK, have looked deeply at those genomic patterns to see what information we can gain from that.

But now, yeah, we're in a situation where we're kind of guessing. But there is data, there's a trial, a large randomized prospective trial that Dr. Birtle ran, the POUT trial. And I would certainly put this patient back to my medical oncology colleagues, and I would strongly urge them to consider Adjuvant therapy because these cancers, and Jeannie will comment more on that pathway, but the problem here is now the patient's behind the eight ball, they're down a kidney, they are limited in terms of their therapeutic options of what they can receive. And the types of therapies that they can receive are probably not going to be as effective as they would've been in the upfront option. But instead of worrying about it now and trying to retrospectively go back, you say, look, we're dealt the hand we have.

Sam Chang: This is where we're at.

Jonathan Coleman: This is where we're at.

Sam Chang: Yep.

Jonathan Coleman: We've got to go forward. And just getting back to the multidisciplinary conversation, just to add on one more time is I think all these patients, from the moment they come in the door, if they ever have high-grade disease, should always be seen by a medical oncologist. Regardless of what the surgeon decides they're going to do, I think having that discussion with a patient as a full informed consent in terms of what their options are, is worthwhile because there is strong data suggesting that treating in the neoadjuvant setting may be more beneficial because of things like the courses of chemotherapy, how well patients are able to tolerate a full course of chemotherapy in the neoadjuvant setting, as opposed to the Adjuvant setting.

Sam Chang: That's an excellent point. And I think probably one that, to be honest, many practicing urologists would be somewhat ignorant of why would we want to do that? Why would we want to do that? So at this point, Surena, I don't know where the patient's renal function is. But those are the things that, obviously, Jeannie, you take into account. What's the next step for this patient then?

Surena Matin: Well, we can say, basically, he's recovered well at this point. There're no lingering issues with surgery. GFR is 43, but performance status is still good. And so our options are fairly limited. And we turn to someone like Jeannie to say, hey, what can we give this gentleman to reduce his risk of recurrence? Because we do think his risk of metastatic recurrence is going to be fairly high. And when these patients recur, they do recur fairly quickly within the first couple of years. And then, of course, it's not a curable situation. So what are our options at this point?

Jean Hoffman-Censits: Yeah. So there're a couple of options in the Adjuvant setting. I think to take a step back as a medical oncologist talking about treatment in the Adjuvant setting is one of the most difficult conversations that I have because patients just went through a major kind of life-changing procedure. They're recovering from that. A nephru is an easier surgery than a cystectomy so a little bit less in terms of recovery time and things like that. But I usually give them about four to six weeks to recover, get a set of scans, so we have a sense of what disease state am I actually talking about. Does this person have no evidence of cancer, and we're talking about the Adjuvant setting? Or unfortunately, are we going to get that set of scans and they already have metastatic disease. And that certainly happens when patients come to me for Adjuvant therapy, and it's, of course, upsetting really for everybody.

So Jonathan mentioned the POUT data. Alison Birtle, we talked about this before, really one of the people putting upper tract disease on the map, just like these guys have. So bravo to her and for you guys for even having the conversation to talk about this today.

So we have the option of Adjuvant cis/gem. This person can't get that with a GFR of 43. That's just not going to happen. So we could use carboplatin/gemcitabine. So in that study, they did use carboplatin. There're some discussion points about how people think about the carboplatin group of patients in terms of whether or not they got the same degree of benefit.

Sam Chang: Sure.

Jean Hoffman-Censits: I know the study wasn't powered for that, but I would say if someone is really not a cisplatin candidate after surgery, getting carboplatin into them is not always the easiest either.

Sam Chang: Okay.

Jean Hoffman-Censits: Because the GFR issues can still come up, and sometimes we'll see renal insufficiency and other kinds of issues. So it's not always the easiest course to give chemotherapy after surgery. There's also the data on Adjuvant nivolumab so that's an option as well.

Sam Chang: I was going to bring that up.

Jean Heather Hoffman-Censits: Yeah.

Sam Chang: Yeah.

Jean Hoffman-Censits: Yeah. So now we have multiple different options to talk about.

Sam Chang: So you got this patient whose GFR is in the low 40s, healthy otherwise, ready to go, wants to be aggressive. You have your gut telling you certain things. You've got some data that a small percentage, I think 20%, 25% were capped off in the NIVO trial. What would you give this patient? And I always like to phrase it in, okay, if you were the patient, because it's a situation that many of us are asked. It's like, okay, if you had your choice, what would you choose? And you have no other contraindication to gem/carbo and no issues with getting an I-O therapy. What do you give this patient?

Jean Hoffman-Censits: Yeah. That's another really tough space, I think. One thing you can do, one thing I think about is I go back to the protocol. So the eligibility criteria for that Adjuvant nivo study, patients either should have had or if they had neoadjuvant chemotherapy or if they didn't, were offered and either refused or couldn't get Adjuvant chemotherapy.

Sam Chang: Got it.

Jean Hoffman-Censits: So I think that's kind of one way to think about that. If you're a practicing physician ...

Sam Chang: Already a second line type of ...

Jean Hoffman-Censits: To have that information. But sometimes patients have already heard about this data, and there continues to be, for good reason, a bias about chemotherapy in general. And so sometimes patients will make a decision that they'd rather not get chemotherapy and they get something instead. Chemotherapy, it's a pretty short course so we give four cycles of Adjuvant chemotherapy with nivolumab. It's a year of therapy.

Sam Chang: Right.

Jean Hoffman-Censits: So it's kind of a different animal in terms of how often they have to be coming back in. And in general, the side effect profile of immunotherapy is relatively good, but not always. I say it's like riding in an airplane. Most of the time it's okay, but when it's not, it's really sometimes not okay.

Sam Chang: Got it.

Jean Hoffman-Censits: And so I think there's a lot that goes into that discussion. The other kind of issue with that Adjuvant nivolumab data, and again, lots of discussion around that, is that the subgroup of upper tract patients that were in that study didn't look like they did as well as the patients with bladder cancer.

Sam Chang: That was the headline. Yeah. Yeah.

Jean Hoffman-Censits: Well, I mean, I think there's probably a lot that might go into that. That was a global study so I'm wondering whether or not those patients had a lymph node dissection. I'm wondering whether or not they were exposed to neoadjuvant chemotherapy. We don't know yet, but certainly yeah, it's always a very long conversation in the Adjuvant setting.

Sam Chang: Yes.

Jean Hoffman-Censits: And now that we have observation, nivolumab, and carbo and gem for a patient with a borderline or a low GFR, it's sometimes even two or three visits.

Sam Chang: A longer conversation.

Jean Hoffman-Censits: Right, before you make a decision.

Sam Chang: So did this patient then choose a certain pattern because now I want to see what happens next.

Surena Matin: Yeah. So pretty much patient received Adjuvant chemotherapy. At our institution, they, until recently, favored what they called a nephron-sparing regimen of gemcitabine, Taxol, Adriamycin. There's a little bit of data.

Sam Chang: A little MD Anderson slant, which is not uncommon.

Surena Matin: But admittedly not universally accepted.

Sam Chang: Yeah. Yeah.

Surena Matin: There's limited data that does support it. I guess until very recently also, depending who you talk to, carboplatin doesn't work or does work.

Sam Chang: Right.

Surena Matin: And then they worry about the bone marrow toxicity of it too, I guess, which is one of the hard things with carbo.

Jean Hoffman-Censits: Yeah. It's very immunosuppressive.

Surena Matin: So in that case, patient did receive Adjuvant and did well afterward. And this patient is from a few years ago before even immunotherapy was available as it is now with the data that we have. But it is nice to see that at least some other options are available for these patients.

Sam Chang: So I'll end with this patient in terms of this patient gets Adjuvant. Tell me, Jonathan and Surena, what is your now follow-up protocol for these individuals in terms of their bladder, in terms of their upper tract, their renal function now is at 40, 43. Let's throw out the current lack of ability to get contrast for any of our CTs. Say we got everything at hand, that GFR, at our institution, we'd have trouble getting a CT with contrast. They would balk. So tell me about the follow-up protocol for this patient. What would they do in New York?

Jonathan Coleman: Yeah, it's a great question, and one that I was thinking about addressing is, I was going to ask Surena his follow-up protocol. I think all of us probably do the same. But what's interesting in a case like this is that you have a team now around this patient. So it's you and the medical oncologist who are now managing this person.

So in the setting where we don't have a medical oncologist involved, for example, maybe a low-grade upper tract patient where you've done a procedure, then it's on the urologist to follow up with imaging. But here this patient's going to be imaged by your medical oncology colleague. So in this setting, you're really monitoring their bladder for recurrences. And the data's not really clear on whether bladder recurrence is less in patients who've either received neoadjuvant or Adjuvant chemotherapy, but the regimens are typically for most of us. And at our institution at Sloan Kettering, we'd follow that patient every three months for the first year with a cystoscopy and a cytology. And so we're monitoring the bladder for recurrence. And then in the high-risk setting, somebody who has high-stage disease, we would be getting a CT scan at least every six months. Our medical oncology colleagues will take over in that regard for us.

I think the other thing to pay attention to here is renal function. And that is patients who are undergoing therapy with your medical oncology colleagues will also suffer from renal dysfunction for some of these therapies that they're on, including nivolumab, even though it's well-tolerated.

 So there is a new field of nephro-oncology or onco-nephrology, depending on which side of the equation you're looking at. But it's a growing field now, where we work with our nephrology colleagues. And we often will early on refer patients to them, especially when they're showing signs of things like proteinuria. And so those are things that we monitor as well. And that's getting a urinalysis in addition to a cytology, as well as checking on renal function, including creatinine and monitoring GFR. And if they start to show signs of some underlying renal dysfunction or even some ongoing hypertension as a result of some of the therapies, then I think seeing a nephrologist is also very important.

Sam Chang: I am so glad you brought that up. I had a conversation earlier regarding a difficult decision tree when it comes to upper tract disease. And one of the things I mentioned was the fact that we bring in our nephrologist even prior to the nephroureterectomy, just to discuss about the possibilities of here's the impact of platinum, but this is actually the impact of platinum and a nephroureterectomy. So it's like our cardio-oncologist for our angio deprivation therapy for our advanced prostate cancer patients, all of a sudden this field has kind of evolved. And there's no question that, to be honest, in our institution, there are certain nephrologists that really know or have a better idea of the impact of certain agents and can be very, very helpful in terms of helping our patients and us try to decide this kind of decision tree. Yeah.

Jonathan Coleman: But there's one important point also to make here, and that is the urologist is the gatekeeper here.

Sam Chang: Yes.

Jonathan Coleman: And that's something that we have to pay attention to. And while we get a lot of help from our medical oncologists and oftentimes we'll have back and forth discussions with medical oncology about how patients are doing, and they are also monitoring kidney function as well. But it's important for the urologist to realize that they're the primary care provider for this patient, because they're still handling the bladder, they're worried about their kidney function. And so ...

Sam Chang: Contralateral upper tract, everything.

Jonathan Coleman: Contralateral upper tract. You've got to be the primary caregiver in that case for that patient. It's very important.

Sam Chang: Surena, anything different, anything to add?

Surena Matin: Yeah. My follow up is a little different. For a patient like this, who's got high risk of recurrence, I do follow them every three months with imaging. Interestingly, within the past couple of years, I'm not sure what our radiologists are doing different, but they're giving contrast down to a GFR of about 35.

Sam Chang: That's good to know.

Surena Matin: And patients seem to be doing fine with it. And I do think they're taking the precautions with it. So that's been great because we can get contrast in a patient like this. My cystoscopy, however, I have curtailed quite a bit. So I'll get it at three if they have no prior history of bladder cancer. I'll get cysto at three and six months. And then it's basically six months after that. And if it's been negative for a year, I pretty much stop. If they're worried, I have their local urologist start doing it.

And that's a little bit the European guidelines I think. And I may not be perfectly correct on this, but I think it's like one cysto at three or within the first six months.

Sam Chang: Right.

Surena Matin: And if that's negative, then I think it's either it or they get one more, which I think there are some patients who will get a recurrence at six months or so. But usually if they haven't had a recurrence within that first year, they're very unlikely. It's not like they won't, but just very unlikely to get it. So I've curtailed my cysto schedule quite a bit for these patients.

Sam Chang: Interesting. All right. This has been awesome, obviously, with three superstars. I'm going to let you guys give, don't you hate when people ask this, one really kind of key takeaway point that you'd want to tell a urologist, an oncologist, a urologist. We'll start off with Jonathan.

Jonathan Coleman: Well, first of all, thank you for the invitation to be here today. It's great to be able to get some information out there about this disease. I've always sort of thought of as being the orphan child in the field of urology that hasn't really been looked at this closely.

Sam Chang: It's starting to get some pops, starting to get some traction.

Jonathan Coleman: It's really important to have this conversation. Yeah, I agree. But I would say the one thing we didn't talk about was Lynch syndrome. It's something that we've all talked about quite a lot. Surena's written quite a lot about it. But one thing that I think is worth paying attention to in your patients, both old and young, and I don't think we have a good age cut off right now. I've seen patients in their 80s with no other family history, no other prior history, where we've diagnosed Lynch for the first time.

Sam Chang: Interesting.

Jonathan Coleman: And so I think just from the standpoint of a high-risk disease, the number is somewhere about 15%, maybe in some series a little bit less and some a little bit more, but it's a high probability for this patient population that they either have Lynch or that they have some Lynch-like disease in their family. And it's worth looking for it. So your pathologist should be doing reflex testing with MSH or immunohistochemistry studies to look for Lynch in your patients with upper tract, regardless of the age, and that's in all samples.

Sam Chang: Great point.

Jonathan Coleman: If you find it, you can have a major impact on not only that patient, because some of the medical oncology therapies that we have can be tailored based on those results, but also looking at other risks of cancers they may have in their own life or their family members.

Sam Chang: In their families, sure, absolutely.

Jonathan Coleman: And if you can find Lynch patients and we're talking about for Lynch, ovarian cancers, we're talking about endometrial cancer, gastric cancer.

Sam Chang: Yeah.

Jonathan Coleman: Colorectal cancers. And these are cancers that don't respond as typically as you'd expect for standard therapy. So I think it's very important.

Sam Chang: Great point, Jonathan. Surena.

Surena Matin: Yeah. I think those are really excellent points that Jonathan made. I think the one thing I would add maybe for the routine patient who presents with upper tract cancer, I would ask urologists to consider two things side by side, looking at the disease and what their assessment of that risk of disease is. And at the same time, look at the kidney function and think ahead one step. How is this patient going to do with their kidney function if I were to remove this kidney? And we can be somewhat subjective or have some educated cognition by looking at the CT or you could get a nuclear renogram that could give you some split differential function, not perfect, but still it gives us some sense for what to expect and use that information up front to decide what kind of recommendations to make, again, in a multidisciplinary fashion if it's high-grade disease. But I think for me, that's one of the things that I've come to grips with is that I really need to think one step ahead and then take that into account upfront when I'm counseling the patient.

Sam Chang: Yeah. Excellent point. Obviously, we're going to save the best for last. Jeannie, thoughts for our medical oncologist key takeaway.

Jean Hoffman-Censits: Absolutely. I would say that these patients should absolutely be considered for neoadjuvant chemotherapy. The POUT data is really important. It's randomized phase 3 data, but at the same time only kind of thinking about that data and saying Adjuvant chemotherapy is the standard of care is certainly a standard of care. But I think these patients should be considered for neoadjuvant chemotherapy. From a comfort level standpoint, you may not get the same information that you're expecting to treat a patient with bladder cancer, but that's okay. You can have those conversations with your consulting urologist.

The other thing about neoadjuvant chemotherapy, for the right patient, it really gives you important pathologic information. Did that tumor melt away with chemotherapy? Did it not? And if it didn't in the Adjuvant setting, if that patient still has disease that's invasive, no positives, that's lived through chemotherapy, well, then you have another opportunity to potentially give them effective therapy with nivolumab or clinical trials. And by the way, there're several clinical trials that are running throughout the country for patients with high-grade upper tract disease, for low-grade disease as well. We didn't talk about low-grade disease. So absolutely look at clinicaltrials.gov, reach out to any of us or local expertise.

Sam Chang: It gives me a great idea for our next conversation together in terms of exciting clinical trials for upper tract disease. I want to thank our folks here. These are really three of the true leaders in the US and actually internationally when it comes to upper tract disease. And so I want to thank all you guys for being with us today.

Jean Hoffman-Censits: Thank you.

Surena Matin: Thanks, Sam.

Jonathan Coleman: Thanks so much, Sam.