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Around the Practice: January 20, 2021


Hear from key opinion leaders in the urology space as they discuss 2 complex cases across the multidisciplinary approach in upper tract urothelial carcinoma and an incidentally discovered renal mass.

Raoul Concepcion, MD, FACS: Welcome everyone. I'm Raoul Concepcion. I'm a urologist in Nashville, Tennessee. And I want thank all of you for taking the time on this Wednesday afternoon in January. Happy New Years. This is our third around the practice, which is a virtual urologic tumor board. And this officially launches the program as it will now (occur the third Wednesday) of every month, this will be a joint venture between Urology Times and Urologists in Cancer Care, which is under the MJH and Associates umbrella and in partnership with LUGPA.

So as many of you know, the format of this will be 2 cases, all urologic oncology. We have invited providers in the urologic, medical oncologic, and radiation oncology specialties to join us. And every month, we will have 2 different cases. We'll have discussants present virtually, to discuss the merits of the case, management issues, those types of things. Before we start, I'm joined by 3 discussants: Dr. Joelle Hamilton, who is a medical oncologist in Birmingham, Alabama; Dr. Jason Hafron, who is a urologist in the Detroit, Michigan area; and Dr. Jeremy Handel, who's an interventional radiologist, which is going be a new twist for us this month, who's also in the Detroit area.

Okay. So today we have 2 cases. So the first one is going be an incidentally discovered renal mass. So this is a 65 year-old white male who's noted to have an incidental 3 cm right renal mass enhancing on contrasted CT. It's not here in the history, but this patient has a history of metastatic castration-resistant prostate cancer. So this was really obtained as a follow-up for his prostate cancer. He underwent a CT guided biopsy by the local interventional radiologists which showed atypical cellular infiltrate favor primary renal neoplasm, but due to the dense amount of fibrosis and chronic inflammation, a definitive renal cell tumor cannot be determined.

So, uh, the patient met with his urologist and after shared decision-making, patient opted for a repeat CT scan in 3 months rather than going directly to surgery or partial nephrectomy. So in December of 2020, a repeat scan showed an interval enlargement of the mass from 3.1 cm to 4.6 cm of the renal mass and new peri-caval adenopathy, largest being about 2.5 cm. Hounsfield units of the renal mass pre and post were 34 and 70 of the cava- of the caval node, it was 40 to 60. So again, in terms of past medical history, it was significant as the patient had a high grade prostate cancer managed in 2017.

This was a Gleason group 5, 4+5, pathologic T3b, underwent adjuvant radiotherapy due to the PSA postoperatively…had some iliac nodes identified. Then in 2018 basically had a rising PSA. Was started on androgen deprivation therapy, and ultimately went on both ADT as well as enzalutamide for metastatic castration-resistant prostate cancer. Current PSA is 0.03. Had physical exam was unremarkable, no cutaneous lesions noted. Family history was significant for 'bone cancer' according to the patient.

So these are the representative images of the tumor, so that you can see on the far left, it's an upper pole right renal mass. The arrows here point to the peri-caval nodal disease. And again, that's a cross-sectional view of the renal mass. So, let's go ahead and put the first polling question up. So Jason, this is obviously a very challenging case. The question one that you'll see, is there a role for genetic testing in this patient? Yes or no. And then while they audiences go ahead and thinking about this in terms of genetic testing, Jason, what's going through your mind as a urologist enhancing renal mass 3 cm, again, in a very difficult patient in that he's got castration-resistant prostate cancer. What are the things that are kind of going through your mind?

Jason Hafron, MD: Yeah, thanks Raoul. Yeah, it's definitely a challenging case, especially with the metastatic CRPC, you know, looking at life expectancy. But I think what's critical here is the, just the appearance of the mass on, you know, the first image on the, on the far right or the first image is it's not a classic small renal mass, it doesn't have well, circumscribed borders. Uh, the borders are very irregular and it kind of looks infiltrate up a little bit. So I totally agree with the biopsy, you know, because especially with the history of metastatic disease, I'd definitely would biopsy. And I, and I'm a biopsyer. I like to biopsy a lot of my small renal masses. Um, but I really don't like the way that that looks because of the irregular borders. It's just not that classic circular well circumscribed, um, small renal mass.

Raoul Concepcion, MD, FACS: Hey, Jason, in general, and what is the literature sort of recommend and our guidelines? Again, ignoring this case just for a second, does there seem to be kind of a cutoff? You know, when you're more comfortable biopsying a renal mass, do you tend to send them and obviously there's differences in what we can talk... we can have Jeremy discuss this. But are there particular cutoffs, especially when you feel like definitely you would biopsy everything versus no, I don't need the biopsy, I'm going to go straight to surgery?

Jason Hafron, MD: You know, I think the question is, is the biopsy going to make a difference in your management, you know? Is this going to change your management? Is the patient going to treat this lesion, you know? If he's not going to treat it, is a biopsy going to really make a difference? Um, probably not. But if, uh, if you're considering management or if you're considering any intervention, whether it's a blade of, or surgical, I like to biopsy it. And, and just based on the re- you know, I think, um, it's a tricky discussion though with the, the, with the patient because there's a couple of nuances with biopsy.

But I think that what I like to do is biopsy him because, you know, there was a great study from the Toronto group, um, Tony Fanale's group, where they looked at centers that biopsy small renal masses, and this is in Canada. They compared the centers that do a lot of biopsying versus centers that don't do a lot of biopsying. And in the centers that regularly biopsy their small renal masses, their benign, uh, surgical resection rate was significantly lower. So I think it's important to incorporate a biopsy in, in your evaluation of these patients, because the last thing you want to do is, you know, put a patient through a surgical resection that is not necessary.

Um, you know, the plastic numbers at 20% benign rate and surgical resection, but when you look at these centers that were regularly biopsying, their, their, their benign rate was less than 10%. So I think that, that, that's really important. Also, when you look at, you know, it's kind of weird, but most tumors of any, and in the body, we biopsy, you know. So why would renal masses be different, you know? Why wouldn't we, like we bio- we pretty much biopsy thyroid, lung, you know, colon, everything's biopsyed. But for some reason we, you know, urologist never really gravitated towards the biopsy. Um, so I think, I think it's very helpful as long as you plan an intervention.

If this guy was 85 years old, you know, when, or his, his cancer, his c- his prostate cancer was, you know, poor performance status, so I'd probably, you know, and I don't plan to intervene on him, I wouldn't biopsy. But if I'm planning the intervention, whether it's a blade of a surgical resection, I like to get that tissue to avoid unnecessary therapy, if possible.

Raoul Concepcion, MD, FACS: You know, I think to address your question about, and again, I'm, I'm old enough to (laughs) have lived through this, you know, I think traditionally, especially when you know, many, many renal cells, as you know, you know, most of them are clear cell and they tend to be hypervascular, I think our biopsy, uh, technique, and I'm sure Jeremy will discuss this, our, our technique for biopsy, uh, equipment was not as good. We were always concerned about hypervascularity, those things with renal cells. You know, we asked the question, i- is there a role for genetic testing? And, you know, 71%, uh, said, yes, 15% were unsure.

So Joelle, give us a little bit of background and why it's important for urologist medical oncologist to consider genetic testing. I think this is a very, very under-discussed area. And I think we're, we're getting new information about, uh, what is potentially the advantage, you know, what, you know, why should we do genetic testing on patients with, with renal masses?

Joelle Hamilton, MD: Okay. And so just as a caveat, since he has a very unusual history of prostate cancer, the Gleason group 5, um, it oddly that coincidentally Dr. Bivins wanted to present this case and he happened to be that patient. So we had incidentally found the renal mass for the Gleason 5 group. I had done germline testing already. Um, he had his operation in 2017. And so one consideration, uh, with prostate cancer is, should this gentlemen have progression, I would then do, um, genomic sequencing. His germline did not reveal, um, either a prostate cancer or a renal cancer type, um, syndrome. So we did not have VHL specifically. So that's kind of prostate and I know it's an unusual case.

When it comes to renal cancer, um, statistically less than 5% of patients do have, a mutation, a germline mutation such that they have a renal cancer syndrome. He does not fit the, the family history, such that he would have inherited a germline mutation for Von Hippel-Lindau (VHL). Um, generally it's gonna be required to have, um, patients who have family history of renal cancer. That doesn't mean he does not have, um, a spontaneous. Um, but they tend to be in a younger patient set, um, bilateral multicentric. Um, when it comes to genomic sequencing, at this point in time there is not, um, FDA approved data that shows... that finding particular mutations in the act of tumor itself, um, will be, uh, more fitting for a particular treatment over another.

However, um, clinical trials right now are kind of trying to figure out this one treatment better than the other if a patient has a somatic mutation, which is a cancer mutation, um, or if they have an inherited or germline mutation. Um, is that, does that answer that question at all? I know it was kind of two-pronged, um, [crosstalk 00:20:09].

Raoul Concepcion, MD, FACS: Yeah. I think, I think there are, I think there are, um, uh, you know... and I think I, that, that, that question was a little bit vague in that the, that I didn't make it clear, you know, whether we were doing genetic testing for the prostate or whether we were doing genetic testing to specifically try to determine if there was any type of syndromic pattern, which you alluded to, uh, relative to the renal lesion. And again, I kind of [inaudible 00:20:39] it's important for people to understand that sometimes, uh, it's, it's pretty rare, as you mentioned, that there are syndro- that there are hereditary syndromes, uh, that are associated with certain renal cell cancer, you know, Von Hippel-Lindau, tuberous sclerosis, that type of thing.

Joelle Hamilton, MD: Exactly … As a medical oncologist, I have to (laughs) be complete. But the Birt-Hogg-Dubé syndrome, which is in a couple hundred families of renal cancer, but fibrofolliculomas, which will almost look like small little white papules on the face or on the bridge of the nose and they can enlarge. Um, I have never seen one, um, but they also will have mongsis. And then hereditary leiomyomatosis in renal cancer, just for completeness sake. Um, though I, I, I have been waiting to see a patient with Von Hippel-Lindau syndrome and I have not yet, and I've been practicing about 20 years.

Raoul Concepcion, MD, FACS: Yeah. There's pretty clear that we're becoming more and more aware of these, again, these, these syndromic patterns that are out there, whether it's, you know, as you said, you, you know, everybody knows about Von Hippel, you know, Lindau, but there's also these hereditary renal cells. And, you know, what used to be maybe thought of maybe 3 or 4 are now bordering 15. And, um, and also what sometimes gives them away is actually the histopathology. So, sometimes papillary tumors, you know, which, uh, clearly are not the most common histopathologic, you know, can kind of point you in direction.

But I think what I'm trying to drive home is, is that regardless, uh, whether it's prostate, kidney, uh, those are the two that we need to start getting better family history. So Jeremy, you trained at an institution where obviously you saw a lot of renal lesions, um, you and Jason worked quite a bit together. Um, kind of, what are your thoughts here on the challenges for this particular patient, uh, whether it be the renal lesion or obviously even going after the caval lesion or biopsy?

Jeremy Handel, MD: Sure. Yeah. So I think they, they're, the kidney lesion itself, the, the nodes or the, the peri-caval lesions, they all look amenable to biopsy. They could, could be done with ultrasound or CT. It's sort of an operator preference thing. I, uh, uh, the way our group practices, this would most, if you're going out to the kidney here, it would most likely be, you know, scheduled as an ultrasound guided approach for that caval nodes, almost certainly CT guided. Um, uh, one of the things you alluded to before is technique, um, we basically 100% of the time, well, maybe not, nothing's 100%, maybe 99% of the time we use coaxial technique, which is, um, has dramatically reduced, uh, track seating which used to be sort of talked about a lot, but it's... with, with coaxial technique, it's, it's exceedingly, uh, rare.

Um, uh, you know, other thoughts that you might have in this are, y- you know, we sort of look at, is there an area of central necrosis that we want to avoid and, so that we don't get a viable specimen. Um, and you know, so sometimes it means going to the edge of the, of the mass. And that on that coronal image, you can see that the image gets fairly central. So as, uh, I would try to biopsy away from the center of the kidney, basically looking to avoid the larger renal artery branches to avoid a post biopsy bleed.

I can tell you that pretty much all kidney biopsies after you take out this, the, uh, the biopsy needle and you got your stylet there, you pretty much always get a pretty good, uh, amount of blood back. So it's, it's pretty common to get some decent bleeding on, on random and bio- and, and mass biopsies. We're, we're pretty used to that. Um, that's a, a pretty common thing. We... to avoid, to avoid, uh, bleeds, we'll either do some prolonged ultrasound on the area to hopefully tamponade. We will sometimes inject, uh, [inaudible 00:25:16], which is kind of like a liquid slurry of gel foam directly through the stylet to sort of plug up anything.

Um, uh, and, uh, uh, I do a lot of angiography work. So if there is ever a bleed, the good news is we have a really good way. We are, uh, almost always able to take care of it right away. So I'm not sure if that answers your question.

Raoul Concepcion, MD, FACS: Yeah. I mean, no, I think, I think this is... Uh, again, I, I think, I mean, in, in your experience, um, you know, especially now, you know, training and now being, being in, uh, being in practice, is this something that you fee- you sort of feel great? Because again, this is something that as urologist and medical oncologist, we started to send it to you guys and depend upon you. But, um, I mean, are you, you know, with, with better imaging, with obviously better equipment, uh, does this become... I me- uh, you know, as you said, nothing is without complication, but do you sort of feel like in general, the technology and the imaging [inaudible 00:26:24], better renal biopsies? And obviously in this case, I guess that's, um, uh, you know, my next question is what about going after this node, especially with his history of, uh, metastatic castration-resistant prostate cancer?

Jeremy Handel, MD: Yeah. So I mean, the- these, I mean, these would be fairly bread and butter cases for, from our perspective. Um, I wouldn't... we wouldn't have a problem going after them. That would be a pretty routine CT guided case.

Raoul Concepcion, MD, FACS: Jason, so your thoughts here. You've got, uh, upper pole, you've got an upper pole mass that previously was suspicious, you've got a pair of caval node, would you recommend biopsying one, kind of biopsying both, go after the, go after the renal mass, go after the caval mass? hat's, what are kind of your thoughts?

Jason Hafron, MD: You know, I, I think I would like to get tissue on, on the caval masses and get some confirmation, but I think the key with this is cross working, you know, a multidisciplinary approach, you know. And when we're dealing with, you know, stage four systemic disease, uh, you know, this is when I call my oncologist and, you know, we work together, um, and get a plan of attack. But I think I know what my oncologist typically is going to say, let's get some tissue here, you know, from the lymph nodes. You know, and it seems a little redundant, but they usually want, you know, tissue confirmation.

And I think then once we get... if we get tissue and if we proceed that way, I think that we, you really have to work with your, your oncologist, you know, because it's clearly systemic disease, and the role for surgery, the role for, for targeted therapy, um, becomes critical. And the sequence, you know, that we start, that’s very important.

Raoul Concepcion, MD, FACS: So Jeremy, is this something where if you get an or if you get a call from Jason or from Joelle and say, hey, we've got this, is this something that, again, as you mentioned, pretty routine for you guys. Is it, is it fairly straightforward that you can go after both the node, as well as the renal mass in the same setting? I mean, there's not a lot of positional issues, there's not a lot of, uh, anatomic issues, that type of thing.

Jeremy Handel, MD: Yeah. In, in, in this case, don't actually get a lot of requests for that. But in this case, I think it will be very reasonable, probably in this case, uh, looking at that axial image, that i- i- image, um, the third image. You could pretty easily do a CT guide and get them both at the same time. That's not unreasonable request. I would... Interestingly I don't seem to get a lot those requests for simultaneous more than one, more than one site, but certainly, certainly not unreasonable. And then, you know, if a patient starts to do... If you do one and they're not tolerating it and you need to stop and stage it, then you just stop, but it's not, not unreasonable.

Raoul Concepcion, MD, FACS: Okay. So Joelle, u- um, let's just say that you s- you know, this patient, (laughs) I know it is actually your patient, you know, you get, you get tissue back that now is a little bit more definitive for renal cell. But let's just say for the sake of discussion for the, for the viewers, what if the caval, what if the peri-caval node, and to Jason's point, what if the caval node is consistent with renal cell [inaudible 00:30:25]. What if the caval node is consistent with renal cell and you have this upper pole mass, how does that... Can you talk to me a little bit about sequencing, the role of neoadjuvant therapy in the setting of metastatic disease? Uh, kind of clue us in about to, to Jason's comment about the sequence, the sequencing of therapy at that point.

Joelle Hamilton, MD: Sure. Um, so I'm biased in this particular situation. And I've already kind of pre-thought if this is the case. So for this gentleman with a low volume of, of cancer, of specifically renal cancer, as med-onc persons with kind of a, I, I would almost call it oligo metastatic, if you will, um, the options would be resection or the option would be systemic therapy. And you mentioned neoadjuvant, and that has been looked at, there are no phase three published trials that show us data. But we have done if a patient is not resectable to do something like either a VEGF-TKI inhibitor.

So you've got, um, Sutent Votrient, and response rates may be in the 40% to 50%. And I've done that in either patients who do not have resectable disease or they are not at that moment in time, an operative candidate. So not very robust data, but, but it is done because it's a patient in front of you and we're not treating a guideline. Um, my bias would be towards if remotely possible to resect what he does have. Otherwise, if he doesn't have a resection long-term, I am committing him to long-term systemic therapy. Um, if, if say he were to be able, um, to have resection of lymph nodes in the renal mass, that differ of course, to Dr. Bivins who's on the call, about the technical feasibility.

We would have a discussion about adjuvant therapy of renal cancer after resection. Um, there are not survival benefits, um, of, that when adjuvant with adjuvant either sunitinib or Sorafenib are compared to placebo, we don't have a survival benefit, but we have a progression free or disease free survival benefit. So essentially the patient's on an oral agent for a year and on average, they have a one-year delay of recurrence. So instead of about five and a half years, it's six and a half years. That's a little bit hard math to sell a patient on for a fairly toxic drug. Um, well, my routine so would be, I would look to see what clinical trials he's a candidate for with his history of prostate cancer, that of course makes him not a candidate. Um-

Raoul Concepcion, MD, FACS: What about the role these days of immunotherapy in renal cell?

Joelle Hamilton, MD: Um, so there's a really interesting, um, trial looking at neoadjuvant than adjuvant Nivolumab called the PROSPER trial. They're actually enrolling in Birmingham, so where, where we live. Um, and, uh w- that would be great for a person who doesn't have, um, prostate cancer [inaudible 00:33:46]to remold the trial. When we look at, um, immunotherapy i- is going to be something like either combination immunotherapy, like in checkmate, ipilimumab or nivolumab. Okay. There, I can tell you that down. I have a partner in my office. So, (laughs) so... Um, so that's one option in resectable or metastatic.

Um, there's also the pembro-axi. So pembrolizumab in or agent axi, um, um, in the keynote study in metastatic patients and when to have systemic metastasis, those are kind of the options I'll look at. So it's either a dual immune therapy, or it's going to be combination of immunotherapy with a tyrosine kinase inhibitor. Um, there are many oncology arguments we can have about which to choose. And, and sometimes what I'll do is look at the patient's comorbid conditions, um, to see which would kind of better align with them.

Um, I tend to bias towards the pembro-axi just because while the dual immunotherapy has CR around 10%, um, with the pembro-axi we actually have a little bit more, I guess, response rate, if you will, or shrinkage of tumor. And we are seeing survival now, um, uh, markedly improved a couple of years out. Did that answer the question? I know it's a huge-

Raoul Concepcion, MD, FACS: You know, I think it's just a, you know, again, I asked that question because I think the viewing audience and all of us, right, there's the, the explosion of trials and the use of different agents, whether... And, and, and there's obviously confusion about the role, although TKIs, where they're approved, whether it's for high risk patients, whether it's for metastatic patients. But again, I think the role of, of how they should be in, used in a neoadjuvant setting to, to Jason's point.

So Jason, in, in the last two minutes of this case, I'm going to give you last word from a surgical standpoint. L- so, you know, le- again, let's just say the biopsies come back renal cell and the patient decides that, okay, first I want to get this taken out surgically. Um, two questions, obviously, number one, with the prior history of two biopsies inside of three months, does that affect your approach and, um, sort of, what are you thinking, you know, can you still do this robotically? Is there going to be so much inflammation because of the two biopsies because of, you know, may be from the, uh, the, uh, the therapies based upon the first biopsy, a lot of infiltrative process, how does, how does all this, uh, affect your surgical approach to operating on this patient assuming that you're probably going to go after a partial nephrectomy.

Jason Hafron, MD: Yeah. So I think, you know, for this guy, uh, eliminating the issues with his MCRPC, you know, his best chance and, and kind of what Joel alluded to, you know, to avoid long-term systemic therapy is surgical resection. So, uh, I would do anything and everything, you know, the MCRPC is a confounding factor and is life expectancy, but I would, you know, do everything to, to resect him. I would try to do a, basically a partial cytoreductive surgery with lymphadenectomy. I primarily am a robotic surgeon, most of, you know, 90% of what I do is robotically. But, you know, I don't think this is a great robotic case just because, you know, based on the images to, you know, we're going to have to mobilize the cava, get, you know, even behind the cava.

And it's, you know, I'm going to, you know, in this case have vascular on standby. Have them potentially get involved because, you know, we're going to be, you know, you know, working, moving the cava around to get those nodes out. But I would do anything and everything to, to do, uh, uh, a partial and then do an aggressive lymphadenectomy because, you know, this is his real only hope, um, for, for potential even curative intent in, in an advanced disease.

Raoul Concepcion, MD, FACS: And what's gonna be your boundaries of the, uh, retroperitoneal nodes' section. Is it gonna be very similar to a testicular type of a full clean-out?

Jason Hafron, MD: I would just go do, you know, take it, you know, pretty much a full clean-out, you know, get the caval exposed, come all the way down, um, and, and clean out those nodes. I don't think I would go, you know, do a little, you know, renal caval but I, you know, I wouldn't do like a, a, a double-sided template. Kind of, yeah, I guess I would do pretty much, uh, a modified, you know, um, to stick their cancer template.

But I think the key is to get behind that, you know, cava, get, get those nodes cleaned out, um, have vascular on standby. The biopsy, you know, it, it it's there, it makes the [inaudible 00:38:45] adhesions and makes the dissection a little more tricky. Just adds, you know, basically I look at as adding more time, you know, because there's going to be a little, you know, adhesions from the biopsy. But, um, I think, you know, we got... You know, the only chance for this guy is a surgical resection. Otherwise we deem them for systemic therapy for the rest of his life.

But, you know, it's a, it's an, you know... Dr. Bivins is here, it's a difficult discussion when you're talking with a guy with a, uh, already with a terminal cancer, you know, uh, the morbidity associated, associated with the life expectancy of that. I mean, this is, this is a hard case, um, and, and, and a difficult discussion wi- with the patient. Um, you know, close collaboration with, with hem-onc is going to be critical. Um, at the end, a difficult surgical resection. This is, those nodes are, are ugly looking.

Raoul Concepcion, MD, FACS: Right. Well, listen, let's, let's move on to this next case because we've got about 20 minutes. And I want to thank Mike Bivins who's Joelle's partner. And Mike is, uh, down in Birmingham who contributed this case. And it's obviously pretty challenging, especially given the, the biopsy as well as obviously his, his, his, uh, his past medical history. So we're going to stick with kind of our, our, our renal, um, approach here a- and renal cases. So this is an upper tract transitional cell carcinoma. So you got a 64 year old white male who presents with a three-day history of asymptomatic gross hematuria, no voiding complaints, no history of stones, two pack per day smoker for 25 years, basically is a retired banker, past medical history is otherwise, non-contributory. Has a history of colorectal cancer and both his younger brother and father.

The exams are unremarkable. Cytology is non-diagnostic. Office cystoscopy is negative for any type of bladder [inaudible 00:40:37] Uh, um, the provider who chose to remain anonymous for this case actually went ahead and did an upper track workout per, upper tract workup per per guidelines. And Ed, let's go to the next slide. And basically this is the, uh, upper tract CT. And as you can see here, we've got filling def- we've got a big filling defect in the left renal pelvis as well as in the... uh, excuse me, i- in the left renal pelvis.

So again, let's ask the first question. And, I'm going to let Joelle lead off. Is, is there a role for genetic testing in this patient? Yes or no. Joelle, so obviously this is not something that would necessarily immediately come to medical oncology, but just to, so again, this sort of how do you educate us a little bit why is there a role, is there... would you say there is a role for genetic testing in this particular patient with an upper tract what appears to be a urothelial cancer?

Joelle Hamilton, MD: Yes. Um, so there actually is a role here. And the first thing that comes to mind is Lynch syndrome. And I think because I'm immersed in the GU world, that is literally always the first thing that comes to my mind for upper tract urothelial cancers. Um, and so Lynch syndrome is when there is a mutation such that they have an MMR deficiency. So it is, um, and repair of DNA mutations. Um, there are actually four different veins that are looked at, and it can be looked at with immunohistochemistry.

And, um, so we're... I'm accustomed to saying this up until the last five years, it's going to be in a colon cancer, um, pathology, because they're going to tell us about microsatellite instability and they're looking at four different genes; MLH, MSH, MSH PMS2. Uh, always look those up, uh, do not keep those in memory because I can look them up, which is beautiful.

Um, and the reason it's important is because up to maybe 15%, 20% of persons, you have Lynch syndrome. So that's germline or inherited mutations. They will develop at some point in their life, either a ureter or renal pelvis type malignancy. Um, and so if you're the person and you have done resection, so your options are either you can send them to a genetic counselor or your favorite person to talk to the patient about germline testing, or you can do, um, just on the stains, the IHC, can tell you if you need to do further testing. Um, in addition, you could always do, um, genomic sequencing.

So we happen to use foundation. There are many other excellent companies who do this, . The thing in the family history that also just perked my ears and it would allow it to be covered by insurance. So that, that does have to be a practical part. Is it, this person has two relatives with colon cancer, I am simply going to make an assumption that their brother who's younger is diagnosed at a younger age. And again, these are some requirements that I look up instead of keep them in my brain at all times, that persons with family history of colon cancer diagnosed 50 and below. Um, also uterine cancer is included in that, Or if a person has more than two or three relatives who have a collection of the malignancies and they are multiple, and they're almost every organ in the body, but it's going to be colorectal, uterine, gastric, ovarian pancreas, urothelial, bra- brain, usually a GBM, biliary tract, small intestine, um, [inaudible 00:44:25], et cetera. Again, I'll look those up.

But it's almost like a laundry list of solid organs, if you will. So this patient to me would qualify, the easiest way again, is going to be immunohistochemistry. It's the cheapest. You can get that done if you have sufficient tissue. The second way, if you have enough tissue would be next genomic sequencing. And then the third way would be genetic counselor. So with a genetic, um, counselor or with your favorite med-onc person. That I'm an advocate for it. And I do evaluate these patients.

Raoul Concepcion, MD, FACS: Yeah. I, I mean, I think the reason why I bring this up is as Joelle as you pointed out, and I, I think a lot of people don't realize this. And although we don't see, you know, we've obviously thought of urothelial cancer and TCC as a field change disease. But the, but the reality is as Joelle pointed out is that upper tract TC, upper tract transitional cell carcinoma is probably a whole different animal. Uh, they present different... You know, we, we've always associated them with, okay, especially if they had a lower tract tumor.

But as, as, as Joelle pointed out that, that in Lynch syndrome, which again has she's quote as a, as a mutation in mismatch, mismatched repair genes, MSH2, MSH6, MLS1, PMS2, which actually work as heterodimers. That Lyn...that, um, that upper tract urothelial cancer is actually the third, most common tumors in patients with Lynch syndrome. So that's why I, I think it's important for the viewing audience to understand that. So, Jason, um, this is something that, you know, you see all the time, so you've got this, you've got no, no lower tract disease, from a diagnostic approach and a therapeutic approach, walk us through how you would manage this patient next, relative to making a diagnosis, add diagnosis, is it important to differentiate low grade versus high grade disease and sort of what our options and, and how you would sequence those, those interventions.

Jason Hafron, MD: You know, I think it's, you know, we've seen a lot of transformation or a lot of change in the management of upper tract, um, and what we'll go through it. But my first step would be to do ureteroscopy. Um, to go up there and, uh, take a biopsy of that lesion, I think you, you need to get tissue. No longer is the radiographic images adequate for a- any surgical resection, I'll get to why. But - I would go up there, you know, take a biopsy. I take the biopsy with, um, a basket, I think I get, you know, tissue is king. And without, with a forceps biopsy, you really don't get good tissue.

Um, the, you know, so I would just put a basket around that and, and get a big chunk of tissue off to the pathologist. Also do selective, um, cytology. Uh, I think that's critical as well, um, you know, to get further stage of this disease. And then I think the issue of pathology becomes very important and it's kind of a new thought process, a new way to look at these lesions. Um, because with the advent of, of newer agents, and I'm sure with chemo ablative agents specifically Jelmyto, that there is potential now for nephron sparing approaches to these lesions.

So historically we would only consider nephron, um, sparing procedures for bilateral disease, solitary kidneys, patients with acute renal insufficiency or chronic renal insufficiency. But now, you know, what we're starting to see is that there is an option for nephron sparing surgery, um, or, you know, uh, endoscopic surgery in patients with low grade disease. And low grade disease typically represents about 30% of, of, of patients who present with upper tract masses. So the tissue is, is very important, and the greater the tissue is very important. Um, and it's a little bit different than bladder.

You know, the, the greater the tissue in, in upper tract correlates much better with invasive disease. High-grade in upper tract is considered invasive and I consider it as a systemic disease. But you know, it's different than bladder because we know we can get high-grade lesions frequently in the bladder that are non-invasive. So it's not the same as bladder. We try to extrapolate a lot, but high-grade disease is a different disease. But if you find a patient with low-grade disease and their tumor is less than two centimeters, they have, uh, low-grade selective cytology.

You know, you really want to consider nephron sparing, um, approaches. And I think a lot of that has to do with, you know, the approval of, um, upper tract chemo ablative Jelmyto. Um, and hopefully we can talk about the trial, the Olympus trial. But I think that there's a major educational deficit in urology. I see it with my partners, is that not all tumors in the upper tract have to... have a, a radical nephrectomy, you know. It's, you know, you need, there's 30% of these patients potentially qualify for nephron sparing disease, but the critical aspect is the evaluation, the workup, and you really have to make sure that they're truly, truly low-grade disease.

Raoul Concepcion, MD, FACS: Okay. So, so you get your biopsy. And, and, and again, I, I appreciate the difficulty for, for those, uh, for those urologists out there. I can appreciate the difficulty in sometimes accessing. You know, this is going to be pretty straight because it's sitting there, it looks like it's a big filling defect in the renal pelvis. That's, that should be a relatively straightforward as, as, as Jeremy said. Uh, but you know, oftentimes because again, we're, we're generally using flexible ureteroscopy, sometimes there can be access problems. Whether it be because you've, uh, a body habitus, torturous ureter, ureteral structure.

But what is, what if this is a filling defect, say in a minor KLX where you cannot get deflection of the scope with your biopsy forceps. Uh, Jeremy, what, what's the role there of percutaneous access in order to, uh, get tissue, uh, as Jason pointed out is going to be so critical because it... that will change management. Um, give us your thoughts about percutaneous acc- access, especially in a minor and major KLX, you know, what easy to get to, what story with track seating, all that kind of thing?

Jeremy Handel, MD: Well, this is a, this is not something that we see a lot. I can think of one case where I actually had... actually did get access and then, uh, for ureteral mass, and then I ended up doing a biopsy for. But I, uh, when we, when we look at nephrostomy or for example, is nephrostomy access one, one of the things where we, we divide cases up. And two is dilated or non-dilated. So when we're doing a, a nephrostomy access for something like a surgical injury or some type of leak, or fistulas communication, the non-dilated system, as opposed to, uh, uh, uh, obstruction where they have a dilated, uh, uh, calyceal system.

So, uh, when you're, when we're trying to get nephrostomy access into a decompressed system, uh, it's like trying to slide a needle between two pieces of paper, you know, deep in, deep into the belly. And so that can be pretty challenging stuff. Um, sometimes, uh, we... So we have several a- approaches to that. Um, one is, one is what we call tandem technique, where we, uh, intentionally stick a 21 gauge needle centrally knowing full well, it won't be our definitive access. But we use it to scan the collecting system. And that allows us to visualize and then, and then stick a safe place that we can upsize to a more definitive access.

Um, another option is to give Lasix in contrast, uh, intravenously. There's sort of a, a cocktail that, that, that people say, uh, works. Um, and those.. is one of the things people talk about. Uh, and there's recently been a, a paper published about it, but if you to, to just give yourself visualization of the, of the collecting system for, for access to give you transient, uh, pacification, or, or just ID contrast to pacify it.

Um, and so, and then essentially once you get in, I guess it would depend. I mean, you're either going to have to access probably, uh, away from where the lesion is and then, and then try to manipulate towards it. This might even be something where, uh, uh, this is definitely like a, a discussion with the, uh, with the urologist, uh, maybe even both of us in the room at the same time, kind of a case, maybe even have retrograde access at the same time to make sure we're all agreeing that we're biopsying the right spot. Track seating, um, I guess, I don't know off the top of my head, if there's any significant difference between a, a track seating here. Um, i- if we get the access, I don't see why it would be any different from, uh, from retrograde risk.

Uh, um, so those are kind of my thoughts in this case. That's, y- you know, [inaudible 00:54:14] biopsy, that, uh, that's a nice, nice size, uh, cal- calyceal system there. That wouldn't be a problem, but if, id it's not dilated, that could be tricky, just simply getting access can be a very tricky, uh, procedure.

Raoul Concepcion, MD, FACS: Okay, perfect. So in the last few minutes, um, so, uh, because again, we're, we're, we're running a little short on time. so Jason, if it come, if your biopsy, I'm, I'm going to give you two minutes to comment to, two, two and a half minutes to comment on low-grade disease. Um, you mentioned nephron sparing surgery, pathology calms back low-grade disease. Give us a brief overview in two and a half minutes, what are the current therapies that are current, that are approved for the management of low-grade upper tract urothelial cancer?

Jason Hafron, MD: Well, to be honest with you today, there's only one approved therapy and that's Jelmyto. Um, you know, 2020 was a rough year, but I think one of the biggest publications of the year was the, um, the, the trial or the Olympus trial that read out this year that led to fast-tracked FDA approval of Jelmyto, which is a thermo reversible gel that has mytomycin.

And, and, you know, the trial led to, you know, the approval of the drug and it's a chemo ablative drug where you basically instill this liquid that is a liquid when it's cold in a body temperature, it, it, uh, turns solidifies, and you can get six to eight hours of mytomycin up into that area. The Olympus trial w- was, was great in the sense, or interesting in the sense that, uh, it was truly a chemo ablative that, you know, to get into this trial, you had to leave, you know, a half a centimeter, a centimeter and a half of tissue.

And they looked at three months, whether the, the mass was still there, biopsy and cytology. And what's impressive about the Olympus trial is that almost 60%, 59% of the patients with half a centimeter to a centimeter and a half of tissue, uh, you know, uh, responded. There was no tumor there. So I think, um, you know, i- it's very appealing. You know, I've had, I've been, had a handful of patients that we've used it on, and I think it's, you know, going to really improve, um, you know, our care a- and, and save a lot of kidneys so that we don't always have to go to the radical nephroureterectomy.

We potentially can decrease our recurrence rates, um, with this and potentially, uh, hopefully, you know, that, time will tell and, and, and minimize our progression to, to, you know, to invasive disease. So I think that-

Raoul Concepcion, MD, FACS: It's important for the audience to understand that, that the, that the agent that we're speaking of is approved for low-grade disease, right? It's for low-grade disease and should not be used in, in the, in the high-grade setting. And to your point, Jason, 60% of people with upper tract urothelial cancers present with high-grade disease. And so that's why I think your diagnostic approach getting, histopathology, as you say, tissue is king, you know, really becomes very, very important, especially when you're thinking about nephron sparing surgery. And again, one last comment was, was there another drug I thought I saw yesterday that the FDA is going to look at to get fast tracked in this space as well?

Jason Hafron, MD: Yeah. It's kind of interesting. It's, it's, uh, made by Steeba, S-T-E-E-B-A. It's a, uh, Israeli company that, uh, TOOKAD. It's kind of fascinating. They, they tried to get the drug approved in prostate, um, but the, you know, the science is fascinating. It's, it's basically based on LG and it's a systemic infusion, and then once you exposed, the tissue, whatever your target tissue is to light, um, that will cause necrosis of the lesion. Um, they're, they, you know, they're opening a trial, uh, I think this year, um, to look at, you know, using, you know, Steeba TOOKAD. this systemic infusion, then applying light to the area to, to, uh, to kill tumor n- necrosis. You know, time will tell. You know, well, you know, I think it's an important area. I think it's great that now we have an option for low grade disease using this gel.

I think what's critical when using this gel is that these patients still have to be monitored. Um, they still have to have regular ureteroscopy and imaging. And another thing that, you know, we have to talk about is that, you know, there was over a 40% urethral stenosis rate. So I think that, you know, it, the, the complication or side effect profile is real. Um, that is another thing that you have to consider. And I thought, and recently at the SCO, I don't know if you saw this, um, Dr. Surena Matin was presenting the, you know, the long-term data from the Olympus trial. Showed great durability, 75, you know, uh, response rate, 75% response rate.

But what Surena was talking about was he's using a, you know, because of the stenosis rate, he's transitioning to, you know, placing nephrostomy tubes and applying them, uh, myto gel through, through the, um, nephrostomy tubes when hoping that that will decrease this ureteral stenosis rate. So I think, you know, we're going to probably transition to, uh, and using nephrostomy tubes, um, to apply on Jelmyto. But, you know, I think it's an active area, this is new therapy, you know, very exciting, solid data that, um, probably the brightest spot, one of the brightest spots in 2020 for urology.

Raoul Concepcion, MD, FACS: Great. And Joelle, you're going to have the last two minutes because we're re- we're butting up on time. What if the pathology comes back high-grade? You know, all this high-grade, what is the role... You know, basically those people are going to probably end up getting, going directly to, or getting nephroureterectomy at some point. What is the role, what is the role of either adjuvant or neoadjuvant therapy? Because I know there's a lot of discussion, uh, with regards to that.

Joelle Hamilton, MD: Okay. I'll, I'll try. (laughs) Bless my heart. Um, so I, I do always like to have a sufficient tissue such that if I make the decision with the patient and shared decision-making, that cisplatin is of benefit to them. Um, what we do know from a meta analysis is that adjuvants cisplatin increases cancer specific survival. [inaudible 01:00:49] also overall survival. And neoadjuvant trial, um, was open like 2015 to '18 NCI, and it was going to be system, uh, GemCis or accelerated impact versus GemCarbo if the patient was a candidate. And it recruited very poorly. Um, data's not out yet. It's like 38 patients.

Um, but there is when you pull all the, the kind of phase twos together, um, there's benefit in overall survival and cancer specific survival. It, it is difficult to get patients through, um, but I have treated patients in the neoadjuvant setting and do talk to them realistically about expectations. Um, but at least if they don't get neoadjuvant or an, a discussion with a med-onc person to have a discussion in the post-operative setting about their cisplatin options.

Raoul Concepcion, MD, FACS: Perfect. That's perfect. All, thank you so much. And to the viewing audience, thank you, I hope this was a beneficial discussion. Um, [inaudible 01:01:47] taking some follow up emails, uh, regarding from, you know, cases. Um, probably many of you ca- uh, the, the folks can, can get ahold of me if you want to, uh, submit cases. And again, I really want to appreciate, uh, the panelists for taking their time on a late Wednesday afternoon. Again, I hope I hope this was beneficial. And, uh, once again, um, have a great new year, great evening. And this will be a monthly, monthly program, the 3rd, 3rd or Wednesday of every month. And we will be presenting across the board all geo malignancies. And again, any difficult cases that any, any of the viewers want to submit, we would love to have them and happy to present them. So again, on behalf of the panelists, uh, thank you so much and have a great evening.

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