During the Johns Hopkins Greenberg Bladder Cancer Institute Grand Rounds in October 2021, Dr. Jean Hoffman-Censits and Dr. Nirmish Singla discuss how doctors get together, go over cases, and share their fields of expertise in bladder and upper tract cancers. They provide a behind-the-scenes look at what takes place, who is present, and how care plans for patients are considered. Learn about the power of multidisciplinary care planning.
Welcome to our series. Our team is grateful that you're here. Of course seeing you in person would be perfect. But given the ongoing response to managing the SARS cov two pandemic here at Hopkins in our local communities. These virtual platforms have been proven to be efficient alternatives for sharing information, education and discussion. Couple of updates. Next month, November nine, it will be focused on our unsung heroes, Caregivers and families, internationally renowned cancer navigator lily shocked me. We'll join our co founder, Stephanie Cooper Greenberg for a discussion about the invaluable and indispensable role Caregivers play in bladder cancer. You can find our updated programming and a new newsletter on the web. Just google Greenberg bladder cancer Institute two. And I want to again draw your attention to our evolving group of programs specifically tailored around the experiences of women with bladder cancer developed and led by doctors are mean smith, jeanie Hoffman census and the program team of Pamela gets Samantha Rockler and Stephanie Cooper Greenberg. Their next program is in december and will be a conversation of life with and after bladder cancer with a much respected panel. Their programming is also on our site and of course please reach out and we can send you the details specifically again. All of these are up on our site and if we can help you directly, we are only an email away at bladder cancer at J H M I dot E D U. Thank you for joining us today for a conversation about advances in discovery and clinical care for patients with upper, you're at the upper track your epithelial cancer with doctors, jeanie Hoffman census and nourish Single. They're going to walk us through their this multi disciplinary process for defining treatment plans for patients would come into their clinic. I hope you allow me to the chance to provide a few brief introductions. Jenny Hoff consensus is assistant professor at the Hopkins School of Medicine with appointments in the Kimmel Cancer center in the brady urological Institute. She's a genital urinary medical oncologist and serves as co director of the women's bladder cancer program for the Green Group bladder Cancer Institute. And she obviously co leads the upper track broken here. She attended Jefferson Medical College Medical School and completed residency and fellowship at thomas Jefferson University Hospital and the Fox Case Cancer Center in philadelphia where she worked with our close friend Betsy Betsy Plymouth Rock. Her clinical and research interests crossed several unique dimensions. She has focused on the treatment and development of novel therapies for your epithelial cancers of the bladder and upper track. She has also led to the development of activation of our women's bladder cancer program within the Greenberg Institute which is active at Sibley Memorial Hospital Dr norma Single as an assistant professor of Urology and oncology and the brady urological Institute at johns Hopkins. He serves as the director for translational research in genital urinary oncology and helps lead the multidisciplinary kidney cancer program at john top. We just heard that he got a very nice fellowship young investigator award as urologic oncologist. Dr Singler is a close collaborator with our Greenberg team where he works alongside Dr Hoffman census and our upper tract multidisciplinary clinic, Dr Singla attended the University of Michigan medical school. He completed his residency training in urologic surgery at the University of texas Southwestern Medical Center in Dallas, where he worked with several friends of ours. He then completed a specialized clinical fellowship in urologic oncology at Memorial Sloan Kettering Cancer center in new york through the Society of Urologic oncology. Before joining our faculty, we're very lucky to have recruited him here more than their incredible portfolio discovery. Both gina and norma's represent the very best of our institutes, focusing commitments to patients and their families with upper tract cancers. I'm grateful to their service to our patients, families and larger community. Dr Hoffman census and Dr Singla welcome and thank you for joining us today, Jeannie animas have agreed to speak for about 30 minutes and then we will transition to a larger group discussion and I would ask you to write questions into the chat and save them for the end and I'll moderate the the group discussion afterwards. There'll be plenty of time Jeannie Dermish, Thank you very much. I'll turn it over to you. Talk to McConkey. Thank you so much and thanks to everybody who's tuned in today and allowed us some time to talk about this rare but really important topic. Upper tract your ethereal cancer. Um the title and the charge was a mock tumor board. So what dr single. And I thought that we would do is first provide a little bit of introduction about the anatomy of a protracted epithelial cancer. Go over some grading staging, how we come to that and then to frame the rest of the talk talk about some novel treatments in low grade upper tract epithelial cancer as well as high grade disease. So your theological cancer occurs in about 81,000 patients annually. Um When we think about all those patients that develop your epithelial cancer, the majority of them Will develop bladder cancer, which is the 5th most common cancer diagnosed every year in men. Upper tract epithelial cancer. The statistics on that are a little bit challenging because sometimes the statistics fall within diagnoses of kidney cancer and then sometimes within your epithelial cancer of the bladder. But overall, if you take all the patients that are diagnosed with Your ethereal cancer or bladder cancer every year, it's somewhere between five and 7% then have upper tract epithelial cancer. So what does that mean When we use that term? Um the your the bladder is lined with a tissue type called Dorothy liam. And I think about like what that looks like. Um it's almost like a very thin saran wrap type lining of the inside of the bladder wall and that's continuous with the Ureter is those are the yellow straws that connect the inside of the kidney down into the bladder. That's a continuous connection as well as the renal pelvis, which is the inside reservoir of the kidney, the spongy part of the kidney, that's where blood is filtered and urine is made and that urine is then transitioned into this reservoir called the renal pelvis down into the ureter and then dwells within the bladder. Sometimes when dr single and I meet patients in clinic, um, they're they've never seen a picture of this anatomy before. So this is oftentimes a picture or a picture like this that we show. Um, just to give a better sense of what we're talking about with the other tracks. So, the upper tracks when we discussed that and we're talking about that today, we're really talking about all these different structures. So that includes the ureter, which is this long tube here as well as um, the renal pelvis. So tumors within this structure outside of the structure into the kidney are called kidney cancer. We're renal cell carcinoma and that would be a topic of a completely different talk altogether. Next slide. So when we think about your epithelial cancer, can we go back to one slide, please Watson. Thank you so much. So, when we think about your ethereal upper tract epithelial cancer. Um, these are some of the thoughts and the challenges that we have when we're um, than introducing the rest of the talk when we talk about staging clinical trials and treatment. So, first, it's a rare population. So, what does that mean? Unlike more common cancers like lung cancer, breast cancer, the number of clinical trials that are designed and developed just for patients with your epithelial cancer, upper tract epithelial cancer pretty small. So what that means is that the extent that we can look into the literature and get and do large randomized clinical trials with hundreds of thousands of patients every year. They don't really have the ability to do that both because it's a rare cancer as well as other fats, it's around the disease, which we'll talk about. Dr singla can give you great information about trying to get biopsies in this area. As you can tell, it's pretty hard to get all the way up into the renal pelvis. So, even getting a diagnosis can sometimes be challenging. We know that get when we do staging and we'll talk about how we, as physicians provide our patients with staging information then oftentimes the anticipated stage based on the information provided um, in a pathology report or on a cT scan may not be really reflective of the final stage and that's called up staging, as we discussed there, there are very few what we call large prospective clinical trials. Um, so the data for which we're using to define standard of care is very small. This is also a special population in that for many patients, a standard option is an effort to redirect me means taking out the kidney altogether and as expected that would come with a decline in kidney function after surgery. Um we know that from our colleagues in europe and we'll talk about this later in the talk that there is robust data for for some patients to get chemotherapy after surgery. But again, that poses some special challenges because as of now, our best chemotherapies are metabolized by the kidneys. Next one. So I'm going to pass it to Dr Singla, who's going to talk about cancer staging as well as low grade disease. Thanks, Dr Hoffman sends its and also thanks dr McConkey for that really kind introduction. Um so, you know, when it comes to how we think about treating this this disease entity, there are certainly several nuances that Dr Hoffman had sort of outlined in the last slide and in large part of our decisions are kind of predicated on ultimately, what do we think is the stage of the of these tumors And also what is the grade of these tumors. Because the decision as to whether or not there needs to be involvement of the urologist alone, a medical oncologist alone or some combination thereof, largely amounts to kind of what our overall risk profile would be for for certain patients. And so, sorry. Next slide. And so just to kind of show some examples, you know, our our current paradigm for staging is largely reliant on a combination of cross sectional imaging. So classically something called the C. T. You're a gram, which you see here would be the gold standard approach to trying to diagnose and and stage these tumors. But also um you read arthroscopy and getting biopsies. The problem is that there is limited information sometimes that we can garner from both cts and biopsies and so um and so sometimes we have to kind of make these decisions based on only limited information that's available with the biopsy. That the limitations amount to simply having a very small working channel through your telescopes to be able to pass instruments through and get a sampling of these tumors. And there's only so much depth that one can go, especially in the ureter given the risk of potentially causing harm by going too deep. Um, with ct scans, we don't always get a sense of how deep tumors are going or in some cases not even being able to pick up on tumors all the time. And so undoubtedly there are still areas of need to improve our accuracy with this. But nevertheless, with the tools that we have today, we've still been able to identify a number of patients and appropriately stratify them to personalize therapeutic plan based on the information we're able to get this is an example of a patient here who had a left distantly regional tur So the tumor circled here is in the last part of the ureter and you can see upstream of that circled area, there's actually quite a bit of dilation into that kidney. Um On the other hand, there's another there are more aggressive forms of cancer as well. And if you advance to the next slide, just another example of a patient who falls on a more aggressive end of the spectrum, someone with metastatic disease. These dark areas that you can sort of make out here in the liver and there's one in the spleen are examples of metastatic sites and this would be a case that would be better served through Dr. Hoffman sense its expertise. Whereas perhaps the last patient could be one that may benefit from our combined expertise in a more multimodal manner. Next slide please. And so in general, when we think about the stage of these tumors, there are there are a few different components we look at first, we look at the primary tumor itself. So the tumor that's located uh, well, we first want to understand is the tumor in the ureter. Is it in the renal pelvis slash kidney? Is it in both places, Is it just one tumor? Are there multiple tumors? Um, and so we look at this information, we try to get a sense of the depth of the tumor invasion. And again, unlike bladder cancer, where you can sometimes get a more accurate idea of whether or not there's invasion into the muscle layer. We don't always necessarily get that information alone and sometimes rely on the final pathology if a patient were to undergo removal of the specimen to understand how deep it's actually going. But the T. Stays what we use to understand the depth of the invasion with T. One through four. Designating essentially increasing depth of invasion from a more noninvasive form to these deeper, more locally advanced forms of cancer. We also look at the lymph nodes to see if there's any involvement and this is pertinent as particularly with respect to the use of systemic therapy and improving patient's overall prognosis. And so we look at both the number of nodes as well as the size of the nodes involved to help assign an appropriate lymph node stage or an end stage. And then finally whether or not a patient has a disease and other sites of the body can amount to what we call the M. Stage with metastases stage. And that helps us again further classify patients according to what therapeutic approach would be appropriate for them. In many cases, patients with metastatic disease may not be best treated with surgery. Next slide. And then the other thing that's important to make note of is the tumor grade. And if I go ahead and if you can show them, just go ahead to the next arrow and then one more time. Um So when when it comes to grade this is actually particularly important to garner if we're able to do so as accurately as we can. The idea is that at the time of getting a biopsy, if you can get a sense of whether a patient is low grade versus high grade can sometimes allow us to make an appropriate decision as to how aggressive we need to be with removing the kidney itself versus potentially doing what are called kidney sparing, Orn Effron sparing approaches because it becomes a fine balance of overtreatment, um, and kidney function concerns versus making sure we're controlling the cancer adequately. And so, um, one caveat when it comes to getting these biopsies again is that sometimes you only get limited information and you're at risk of potentially under sampling tumors. And so the truth of the matter is that if you are to take out every single kidney for someone who, for all patients who are designated as low grade on an initial biopsy, You may actually be under grading up to about 50% of those patients, according to some series. And so that's just an important caveat to bear in mind. And that's why it's, it's particularly important to get to be a little bit more confident in our ability to kind of adequately great patients before we subject them to some form of therapy and through a combination of tissue sampling and also looking at the urinary cytology, we can sometimes get a clue as to what our degree of suspicion truly is, uh, for low versus high grade tumors. Um, and the reason why this is important is because you'll see how we have divided this talk. I'll talk a little bit more about the management of low grade tumors and kind of the urologist role as sort of primarily managing these types of tumors, which can sometimes be difficult to manage believe it or not. Uh and then Dr Hoffman census, we'll talk about our multimodal approach to managing patients who have higher grade tumors. In the second half of this talk. Next slide please. And just a little bit more background information. Epidemiologically like Dr Hoffman says, it's had indicated, you know, you two you see is is not a very common cancer type and it is leading to be along the spectrum of bladder cancer, but extending essentially towards the upper tracks, although again, there are nuances as to the biology behind the disease. This often tends to be a, certainly in the United States, a disease that affects the more elderly population. Even older than patients on the average, you have bladder cancer statistically tend to be male predominant. And with the United States more often, the common risk factor tends to be tobacco exposure, although there are other parts of the world where we sometimes see a unique exposure to particular intake of chinese herbal medications due to a particular plant called aristolochia. Uh, there was a low kick acid and which is an ingredient in many chinese herbal medications that you actually tend to see an increased prevalence of the disease in both asia and believe it or not, another area within the mediterranean called the Balkans. Um and then there's also genetic predispositions to forming this disease as well. And in particular there's a disease called lynch syndrome or hereditary non platypuses, colorectal cancer that can also increase one's chances of having this um, this entity. And these are very unique to U. T. U. C. As well. Like Dr Hoffman census had indicated um, you know, the challenging aspect about these patients is by virtue of their disease and in often cases their exposure to tobacco, there are a lot of other co morbid medical conditions unrelated to the cancer itself that have to be taken into consideration things like, you know, what is the overall kidney function? What is the overall cardiovascular status? What is their overall functional status? And these are important because this ultimately translates to how we perceive patient's eligibility for treatments such as receipt of first line cis, platinum or platinum based chemotherapy agents or whether or not there would be an appropriate surgical candidate to undergo a surgery such as removing the kidney. And so, um, so these are definitely very important facets when when we treat the patient as a whole with with upper track your fellow carcinoma to um certainly think about these things as well. Next slide please. And so just to sort of spearhead the discussion regarding low grade you tuc Next slide please. Okay again, with low grade disease. The good thing is that overall for purely low grade disease progression to either higher grade states or more invasive states tends to be relatively uncommon. However, recurrence is in fact a very common occurrence and bees in many cases can be considered like nuisance dreamers. Um, because of these tumors being relatively less aggressive than their higher grade counterpart, we often try our best to try and spare the kidney when appropriate. And these often include endoscopic means. In other words, going up with the scope, sometimes with a laser and basically trying to control the disease in that manner while without having to sacrifice the kidney as a whole. Now there are some patients that may benefit from still undergoing an afro, you direct me a removal of the kidney, but there certainly would be a handful of patients that we believed to be over treated. If you were to offer this to every patient who walked in the door would locate too. You see, and like I had indicated before, um, you know, it's, it's important to try and be as confident as we can with the diagnosis of low grade tumor because again, um, we found that there may be still areas of higher grade involvement for the bulk year tumors, perhaps below the surface, that you can't always get with the uterus coptic biopsy alone. And so at the end of the day, um, as a clinician, we think about a few different goals when it comes to managing low grade uT you see, this includes a as accurate grading as we can get b um, maintaining longer term kidney function. Inasmuch as we're able to. But then at the same time finally see making sure that we are also not curtailing oncological controls and making sure that we're trying to maximize the control of the cancer and as much as we're able with balancing these other considerations as well. Next slide please. And so in terms of options for managing low grade uT, you see, I've presented here a few that that we have in our wheelhouse as well as some investigational ones that are, that will be kind of opening up soon here at Hopkins as well. Um, classically we have surgical extra patient which again, could involve the removal of the whole kidney or perhaps uh, and and you order or perhaps even just the order alone based on the location of these tumors. But again, like I said, it's possible that some subset of patients with low grade disease maybe over treated with that type of an approach. As a result, endoscopic ablation has largely taken hold for low grade disease. Um, and this can be done with a your horoscope um, using a laser in in either either what we call a retrograde fashion. So going up from the bladder up the order and up to the kidney in that manner under anesthesia or something called an anti great approach which involves going through the back and what we would call it per catania slee, a blading these tumors. Um, and so those are a couple of different ways to access the kidney and and go down into the ureter and depending on the nature of the tumor or tumors, sometimes one or the other approach may be more appropriate. Um One thing I'm going to focus a little bit more on instagram slides is a recently FDA approved agent as of april of last year um called gel mido um which is basically a prelim arised form of hydrogel that is mixed with a special type of chemotherapy agent classically used for um non muslim invasive bladder cancer called me thomas and see. And this is like a topical agent that we've actually found to be helpful for patients who have low grade disease in in reducing their recurrences. And I'll talk a little bit more about that agent here momentarily. But johns Hopkins was involved in the initial trial and certainly we have it available at our disposal if we need to use it for the appropriately selected patient. And then finally, we do have other emerging techniques, including one that we will be opening up here at Hopkins. Hopefully in the in the near future. And I'll talk a little bit about that as well in the coming slides next slide please. And so, um so what I wanted to highlight in terms of kind of the the newest FDA approved approach to managing low grade disease is this agent that was developed by european pharma, which is again a marketed as jell Mido. And this is the trial that was published last year. Uh that was a phase three open label single arm trial that looked at the efficacy of this agent in particular for patients with low grade beauty. You see next slide please. And just about a little bit of background regarding this agent. Again, this is a hydrogel polymer that um it involves a process called reverse thermoregulation. So essentially this is a polymer that's mixed in with minimum efficiency and the the challenge anatomically when it comes to managing upper tract urethral carcinoma is um largely the fact that we don't have great ability to have contact of any topical agents with the urinary tract in the bladder. We have the benefit of having gravity dependence and the ability to hold one's bladder. And as a result, sometimes you can get really nice dwell times with these topical agents. However, in the upper urinary tract we don't have that luxury all the time. And so the idea behind it um combining this chemotherapy with the hydrogel is to allow it to increase its contact time with the with the urethane layer that dr Hoffman census was talking about earlier. Um and so this uh this semi solid. So this this agent essentially um at room temperature is a liquid. But then when, once it's exposed to heat, including body temperature, you actually form this semi solid gel that then stays in place for a longer period of time. And it's thought and generally over the course of about 4 to 6 hours um has has a slower dissolution process. And so that way you can maximize how much time the mind of licensee is in contact with us that you're trying to treat. Next slide, please. And so again, just very briefly regarding the trial itself. This included all patients, adults who had primary or recurrent biopsy, proven low grade ut You see anywhere from 5 to 15 millimeters in size regardless of the location, but primarily within the renal pelvis and Kelsey's uh the way that the treatments were administered were in this case in the trial. They use a retrograde approach, but essentially six weekly installations of this agent um with a with an appropriate well time um and essentially monitored for a complete response, which they looked at um 4 to 6 weeks following the completion of the initial therapy as dictated by a negative Butera Skopje cytology and in cases where it may have been indicated a biopsy as well. Next slide please. Um and so, and go ahead and just hit the next hit the next button. Okay, so, so in total the trial of crude 71 patients and per the defined criteria, there were actually 59% of patients who demonstrated a complete response, which was quite encouraging. And there was also a maintenance or a follow up period that was included in the trial as well, in which 41 patients had entered with a median follow up of 11 months and out by to about 12 months among the patients, who made who remained within the follow up period that that at least was captured at the time of the publication, 70% of patients have actually demonstrated a durable response, which again was really quite encouraging. Next slide please. And overall, um, this actually was a pretty well tolerated agent. Um, you know, aside from even though you see here the numbers related to adverse events, we look specifically towards serious adverse events related to the study drug or procedure itself, which amounted to about 27%. Um, the main sort of concern that was found in the trial was a possibility of Euro Terek stenosis or narrowing basically from the use of this agent In about 44% of the, of the population. This tended to be usually a transient effect, but one that certainly would make us take a bit of a pause for patients who have solitary or single kidneys that we're treating. And so these are, that's what I would say would be kind of the main consideration when we're practically looking at the implementation of this agent. Uh, and there were no treatment related deaths next next slide please. Um and so so the benefit of this trial is that now it has introduced into our armamentarium, the first sort of FDA approved agent for the liberation of low grade U. T. U. C. And this offers a kidney sparing treatment in patients particularly with larger tumor burden or tumor volume of disease who may not be the best candidates for endoscopic ablation alone. And like I said, I have this agent fortunately available here at johNS Hopkins and we're offering it in our Jayhawk clinics next slide And uh and before I hand it over to DR Hoffman census, I'll just put in another plug for this. Um since we are opening up this trial here at UT at jOHns Hopkins as well. But there is another another agent that was developed initially in Israel that has been kind of investigated in in terms of ablation for focal ablation in prostate cancer but also actually investigated in UT you see as well with some encouraging preclinical and phase one um results. But this is called to CAd BTP or Penelope por fin vascular targeted photodynamic therapy. And essentially this is an an agent that's injected and um it's a photo sensitizing agent that actually accumulates within the vascular compartment of these of these tumors. And you activated endoscopic lee using a laser you try to oblate the tumors. And um at this specific wavelength 753 nanometers you induce the release of free radicals that ultimately amount to tumor necrosis and death. And so there's now an open phase three trial called the Unlighted Study next slide um that we're now in the process of undergoing regulatory review here at johNS Hopkins before it will be formally open to a cruel. But this is going to be another option that may be available for patients with low grade disease. In the trial, up to two tumors to different sites can be included anywhere from 5 to 15 millimeters in size. And we're also including patients who have a unit focal high grade tumors. Um, up to about a centimeter in size. Um, again, looking at the same sort of objective criteria that was reported in the in the Olympus trial, i. E. Complete response. And so hopefully soon to come on this. As soon as as soon as we're open will be eager to recruit appropriately selected patients for for this trial. Next slide. And so on that, I'll hand it over to Dr Hoffman sense. It's to talk about the other end of the spectrum which is higher a beauty, you see. Thanks dr Singh. But it's so exciting that just in the past couple of years we've we've seen so much attention and and you know, work that's really propelled upper tract epithelial cancer. It's hard to believe We actually have an FDA approved agent that's specific for upper tract epithelial cancer. This is a disease that that really um, you know, not a lot of people know about not only do we have an empty improved agents, specifically prolonged great disease, but other trials coming down the line. So really very exciting. So thank you. Yeah, I'm going to take over and talk about high grade upper tractors here. The old cancer. This is in fact a lot of times the disease that doctor single and I will take care of it together. Um, I think one of the the the great benefits of working in a place like johns Hopkins and being in these departments, you'll often hear that hear that were, you know, all have appointments in different departments and that's because we really do live in multiple worlds. Um, you know, I'm a medical oncologist. I use medicines for a living, but I certainly interact with and talk to our surgical colleagues and participating in their conferences and their workflows really often next slide. So when we see a patient with high grade upper tract disease, um we're also thinking about the co morbid renal function, cardiovascular issues and functional status that dr single mentioned earlier. But the other two things that we add in as I'm having, you know, conversations with patients and families um, well, ask about hearing loss as well as peripheral neuropathy, which is numbness and tingling in the fingers and toes. And I know that seems like some unusual questions to be asking somebody that has a high grade upper track your it's really old cancer. But the reason for that is because we're trying to make decisions as to whether or not a patient is um a candidate to get a drug called CISplatin. So as of today, in october 2021 CISplatin remains the most active agent and you're a filial cancer and is the primary first line treatment for patients who have metastatic disease of the bladder and upper tract as well as the agent that we preferentially used in the period operative setting, meaning before or after surgery for a high grade high risk cancer. Um and because this platinum is metabolized by as well as toxic to the kidneys because it needs to be given with a lot of intravenous fluids. We have to make sure that patients have very good kidney function, especially because at the end of their treatment, if they go forward with the surgery to remove the kidney, they will lose kidney function. Unfortunately, most of the time they have to have a good functional status because chemotherapy can make patients quite tired and because of neurologic toxicity, um, CISplatin based chemotherapy can cause hearing loss as well as neuropathy. Both of these things can be permanent. So it's an unfortunate um um um issue in the population of patients who have bladder and upper tractor epithelial cancers. A lot of our patients to have hearing impairment related to their disease and their treatment. This is something that we don't find satisfying at all and is one of the satisfying parts of our job that we continue to work on newer and better treatments where we don't have to think about these questions so often next slide. So we'll talk a little bit about preoperative chemotherapy. That means getting platinum based chemotherapy prior to a planned never redirect to me that would be done by dr singler one of his colleagues next slide. So this is a really busy slide. But the reason I put this up is because I wanted to show one of the things that we do in academic centers, especially when we have a disease that's quite rare, like upper trying to ethereal cancer. Um so, you know, different centers will see a different number of patients every year and treat those patients as part of their standard of care process. And in many academic centers, they've made the decision to at least think about our offer chemotherapy. Two patients that have high grade a protracted basilio cancer before they have an effort redirecting me. The reason that they do this is because we're extrapolating or kind of borrowing from the data um for how we treat your epithelial cancer of the bladder, same tissue type a couple inches down. So for patients with high grade muscle invasive bladder cancer, if we give CISplatin based chemotherapy for several cycles before going on to surgery to remove the bladder patients who have gotten that preoperative CISplatin based chemotherapy versus those that do not in a large prospective trial. Um They live longer and they do better now again, not everybody is a candidate for that medicine. But because in general up until now we haven't successfully run those large trials in upper tract disease. We extrapolated. We borrowed that same data and we utilize it for our patients and clinic. So what this is an example of is um just a slide showing that each one of these lines is a different academic center, a group of academic centers that looked at their patients that they treated with standard of care. Um Getting chemotherapy prior to never knew redirecting me or those patients for whatever reason, maybe they weren't offered or didn't want that chemotherapy or couldn't tolerate that chemotherapy before surgery. And what we see this um T T. Zero and zero. We talked about the T staging earlier. This is pathologic which means um the actual specimen in hand that the pathologist tells us about. T. Zero means no evidence of cancer in the primary specimen and zero means no evidence of cancer in lymph nodes. That each one of these retrospective studies where they looked back at their population of patients over time, those that got chemotherapy and those patients are represented by the top line. They had a higher rate of pathological we call down staging and no evidence of cancer. Um Compared to those patients who weren't able to get chemotherapy. And there were trends for survival benefit in those patients as well. So that's one of the ways that we can obtain what we call evidence. This is some of the literature. This is all the different references at the bottom of the slide that we as physicians can reference and tell our patients about is we're making these treatment decisions for rare diseases, like a protractor epithelial cancer. Next line. So what this slide is representing is for very small and is the number of patients in these clinical trials prospective meaning going forward in time clinical trials where patients were, where we discuss getting preoperative chemotherapy and then following those patients forward in time to understand number one, how did they tolerate the chemotherapy prior to Nefertiti redirected me And then to what was the rate of pcr pathologic complete response. And there's pretty much consistency across the board with these different studies. This pathologic complete response rate of 38% was a little bit higher. That was a different combination of medicines that we saw compared to these other um studies. But this is um some information again that we use to inform decisions and make clinical decisions when we're meeting with patients. Next slide. So again, one of the things that is a reality when we take care of your filial cancer and the upper track compared to patients who are getting chemotherapy for bladder cancer is that if we take an entire population of patients. So if we look at every single person that we need in clinic, um really about half 50-60% of those patients because of impaired functional status, because of, you know, bad cardiovascular disease, because of poor hearing or preexisting them disentangling or renal function disorders. They are not candidates to get that CISplatin chemotherapy. Um So already we have patients that maybe would see us together in clinic Doctor Single and I together we would have a conversation and decide for this patient. We're going to forgo the decision the discussion about preoperative chemotherapy because their candy function maybe isn't good enough for it. And they would move on straight to surgery with dr Simba. But we also know that following that kidney surgery, that treatment with curative intent to remove the kidney, that postoperative even less patients are good candidates to get that postoperative chemotherapy. So that's why our workflow. Is it to at least discuss that um the provision of chemotherapy before surgery. And that's one of the things that I think sets apart a multidisciplinary team of doctors who think about upper tract epithelial cancer for a living. That we have made a decision as a group, as a center, as physicians who care about the disease to at least have a conversation about it before. A final treatment recommendation is made based on the patient and based on the situation, we may not necessarily have a direct discussion with the patient because if the kidney function um is um if there's no reversible cause of a poor kidney function, then we may not um I want to use the time of the space to do that um and bring a patient in for a conversation that really is not suitable for them. Um but I think it is important that we have agreed to have this discussion and think about the use of chemotherapy prior to surgery next life. Um so this is an exciting clinical trial that was a few years in the making. This is called the E. A 81 92 schema. Um this clinical trial, the E. And the A stanford peacock akron. So um especially for rare cancers, the peacock and and cooperative group mechanism is very important. So what this is is a collection of academic medical centers that have decided to collectively work together to come to clinical trial answers for our patients and beauty too. Of a cog. And other cooperative groups. There's a Southwest oncology group, there's here's your oncology group. I almost think of these like professional sports leagues like the national Nathan american League almost. But this collective which is includes academic centers as well as community partners. So there's plenty of oncologists that are in the community trained in academic centers are interested in doing research. So some of these clinical trials that can be, you know done close to home. You don't need to come to an academic medical center to get these um access to these clinical trials. Um This this trial is just up and running and what this trial is trying to see is whether our Hopkins institutional standard and the standard and many centers across the country which is four cycles of em back which is accelerated and back accelerated means that we give that treatment every two weeks and the impact stands for a standard for drug chemotherapy regimen that we give the preoperative setting as well as a metastatic disease that stands for method truck state and lasting Adriamycin and CISplatin. Whether or not giving that medicine alone or giving that combination with an immunotherapy drug called your Value Man this is one of five checkpoint inhibitors that's FDA approved for your affiliate cancer. Be giving it together with them back. Does that improve something called event free survival. Which means that if the cancer comes back or where if the patient unfortunately winds up passing away from the cancer. Um so that's going to be a very large clinical trials. So patients for this study or um diagnosed and identified by urologists with hybrid upper tract epithelial cancer. And then they're if they're interested in participating in this study, the majority of those patients who have a good kidney function will be randomized. That means we don't get to choose and the patient doesn't get to choose into one of these two treatment arms and that's of course if they agree to involved in the clinical trial, we also have what's called an exploratory arm, this is much lower number of patients. 29 patients versus over 200 patients. Um for patients that are interested in participating in this clinical trial but unfortunately don't have an adequate kidney function to safely receive that impact chemotherapy. So we have an arm for those patients as well. Next slide. Excellent. So what about postoperative chemotherapy? Next line. So for postoperative chemotherapy we actually have thanks to our colleagues in europe, a completed randomized phase three clinical trial in a protracted epithelial cancer. It's hard for me to believe that we can actually say that that's true. But our colleagues in europe led by Allison brutal have done really a miraculous and a very important job I think really. Number one is just shedding light on the fact that upper tractor epithelial cancer isn't it? Is it is a disease. Um And the fact that a clinical trial that is this large that was done was actually completed I think is um they've they've done so much I think to help all of our patients with the disease um to really bring focus to it. So in this clinical trial in part based on kind of standard workflows in europe instead of having conversations about chemotherapy. Prior to surgery, patients were seen by doctors like dr singular first and then sent to medical oncology to have a conversation about chemotherapy. So for those patients that had high risk to us meaning T. Two, which is invasion into the muscle layer of the ureter or the renal pelvis or to T four which is kind of tumor extending beyond the tissues or any evidence of link nodes that were invaded by cancer. Those patients were then randomized to what at time at that time was the standard of care which is observation alone, meaning getting a follow up CT scan as well as Dr. Singla and other colleagues looking inside the bladder doing assist Oscar P because patients with upper tractor at the odd little cancer can sometimes get occurrences that dropped into the bladder over time. So part of our standard of care is that we do a CT scan as well as the cyst ask api and the chemotherapy arms of those patients were randomized to get chemotherapy. That chemotherapy arm um was then assigned based on kidney function. So, patients had good kidney function that resist putting candidates. They were given what is the standard of care which is his button and Jim cited bean and if they did not have adequate kidney function there. So good chemotherapy candidates, they could still be in the trial but instead they got cargo planning, which is a medicine that is reasonable medication but may not be as good as as planned. Um And so um patients that had a G. F. Are less than 30. So that means that patients who had poor kidney function after surgery But whether or not that it was because they came to surgery with poor kidney function or in surgery, they had good kidney function but lost that kidney function after surgery. Those patients were not in this clinical trial. So that's a group of patients that maybe we're not served by that study. Um Next line. So this was a really important study and um an outcome. These are the three year disease free survival estimates. So, um this is an updated data that was presented at the U. S. Co. Um But this giving this chemotherapy for patients who were not candidates. Um they did not get chemotherapy prior to surgery is standard of care based on this information, which is that getting chemotherapy after surgery improves disease free survival, sorry, dog wants to participate um improves disease free survival. Which is really, really important. Um Looking at long term again following these patients over time, um there was a numerical improvement in um metastases free survival um as well as overall survival, which means numerically patients live longer getting this chemotherapy. Um and that chemotherapy arm is in the red versus their surveillance or just observation along arm in blue. Um, but at the end of the day, looking at the three year long term estimates, it was unclear and it didn't mean what we call statistical survival benefit. Um Despite that, I think a lot of us still believe in this state and will offer chemotherapy to our patients who've had an effort to direct me for high grade protractor available cancer and have high risk features like positive disease next one. Um This um um this just shows that the patients who got CISplatin and genocidal bean um may have had more benefit from their chemotherapy versus those that type of carbon platinum genocidal bean. Um to the left of the of the of the long line here, these are the patients that are benefiting from treatment to the right, those are the patients that may have not benefited from the treatment. So it looks like across the board that was probably benefit based on whether or not there were positive margins like no positive or the stage. But in general um this recapitulated what we previously kind of believed about the chemotherapy, which is that CISplatin is probably superior to carbon Platten but we will certainly have conversations with selected patients about carbo planting next time. Um So this is some exciting um um data um this is another large randomized clinical trial um that change standard of care. So when we have conversations with our patients about different clinical trials, um you know, we have smaller clinical trials that may be what we call pilot studies, meaning that Maybe it's, you know 10 patients or 20 patients in the study were really trying to understand a certain molecular pathway or you know, a type of resistance or you know some safety information um and that is compared to a clinical trial like this one which is very large. We see the numbers and is here is 353 versus 356 patients. So what this was was a clinical trial for patients that had had surgery. Either in effort to redirect to me or a radical systemic to me had their bladder removed. Um They could have had preoperative chemotherapy. So this is partly based chemotherapy. And despite that chemotherapy had high risk disease meaning lymph node positive disease or disease into the beyond the muscle layer of the bladder of the ureter. Or they could be patients that maybe we're never going to be candidates for that chemotherapy and didn't have it. So in this clinical trial half of the patients with that high risk disease state where previously the standard of care was observation alone. A ct scan and the systolic api for patients with upper tract disease. Half of them received the volume model which is an immunotherapy systemic checkpoint inhibitor goes through the I. V. FDA approved for advanced your theoretical cancer but not in the postoperative setting. And the other half were followed with just imaging alone. Um The patients who had the volume and we're also followed the standard of care imaging And as I pointed out the bottom that patients with upper tract epithelial cancer were included in this study. It was about 80% almost 80% bladder cancer and then about 20% upper tract epithelial cancer. So we um thank the authors of the study for having the forethought to include a separate group with upper tract epithelial cancer next line. And this is an important trial again. So these are called Kaplan Meier curves. Um Looking at two different outcomes in this study. Um This study looked at disease free survival as well as overall survival. Um This top slide is looking at what's called the intention to treat population. So that means essentially all the patients um that were enrolled into the clinical trial. Um As you can see those that were received the volume and versus in the green line versus those that received the placebo had a much longer and statistically significant improvement in disease free survival meaning how long they live without evidence of the cancer coming back. Which is really important. Especially as the volume. That tends to be a very well tolerated treatment. And this um impact was even more profound in those patients whose tumors had this expression of PD. L. One which is the target for the volume app. And that's something that we look at in our tumor specimens when we're making some treatment decisions in the later line setting next line. So another important pathway especially in upper track to ethereal cancer is the F. G. F. R. Or fabric lies growth factor pathway. So um some of the patients or families that are on the call today may have had something called next generation sequencing down in the past. Um And that's where a tumor is sent sometimes to a commercial entity like terrorists or like Tempest or like foundation medicine or internally sequenced. And so what you're we as physicians and what may be your doctors at home we're looking for is a mutation or fusion or a change in the pathway of F G F. R. This is pretty common in your ethereal cancer. I think probably Dr single has seen a lot more of this than I have because it's so much more common in low grade bladder cancer. Um But in high grade upper tract epithelial cancer, we can see that change of that mutation in about 20 to 30% of patients. So what does that mean? It means that an FDA approved drug called Earth if it needed as well as other drugs that are in development um are in our toolkit that we can use for patients that have metastatic epithelial cancer where their tumor has that change or mutation. So that's important because if we identify who those patients are, that means that they could potentially get to benefit from this targeted agent. Um And we can also then identify those patients who maybe wouldn't get a benefit may only have side effects, but unlikely to have a response. So um this is important technology as well as an important FDA approved drug and pathway next line. And the reason I'm bringing that up in this context is because this is another large randomized phase three trial where patients postoperative um are, you know, offered enrollment into this trial looking at upper tract epithelial cancer because it's more common in upper tract disease. This trial is trying to enroll 85% with upper tract disease or muscle invasive bladder cancer that had this change of mutation. And this is a clinical trial where half the patients are planned to get um um F G F. R. Targeted therapy or um follow up with policy bell alone next slide. Um so finally, you know, one population because dr single and I see a lot of patients with upper trying to epithelial cancer. There is a special population of patients where they have very, very poor kidney function. Um, so maybe that's a creatinine clearance of, you know, 15 or less. Or or or maybe they have one kidney. So your ethereal cancer is a disease that unfortunately can recur in different places that you're feeling them. As I mentioned, the beginning of the talk is this continuous kind of, you know, tissue lining of the bladder, the your orders and the pelvis. And you know, to have an upper tract epithelial cancer on one side. You know, unfortunately part of the reason that the surveillance includes, you know, cT scans and CISA CISA SKA, please excuse me, is because those tumors can develop on the other side. Um so this is a special population of patients, many of whom will seek out, you know, carrot academic centers because they've been told that the best true standard really is to have that can be removed. But understandably that's a whole lifestyle change to go on human analysis that not many patients we're interested in or at least want to see if there's a treatment that could delay that. Um so we do have a clinical trial in development and hopefully this will be something that we could um kind of give more public information about. Maybe the next time we're invited back by dr McConkey and colleagues your slide. So what about resources? I bet that for the patients and the families who were on the call when they or somebody that they loved was diagnosed with a protracted epithelial cancer. And maybe the first time that they've ever heard of this entity. And because it's so rare and because the best information you can probably find about it is tied in with bladder cancer. One of the things that we thought as a group was important was to really put information good information into the, you know, into the web about this so that this wouldn't be such an isolating diagnosis. Um so we've worked hard to make our Greenberg bladder cancer Institute upper tract epithelial cancer website. There's also other groups that are that are dedicated to this as well. So of course our partners that weakened the bladder cancer advocacy network as well as Euro today and others I think are doing their best to shed light on this rear but really important topic. Next one. And um this is our team, you know when we say multidisciplinary and when patients meet with Dr Singleton, i it's really not just us, it's this collective team of, you know, doctors that we work with um together. You know, sometimes we present cases in tumor board to get more of a collective information. All of the pathology is reviewed by specialized genital urinary, you know, pathologists who for a living, you know, look at um second opinion slides and slides from, you know, Hopkins. Um you know, these doctors really are so important and like certainly people that you might not necessarily meet but really important people in terms of the multidisciplinary program, we have specialized radiologists that are really um you know, our partners and looking on the, you know at the order at the lymph nodes around it um in the renal pelvis which is so important as well as our scientific team that help us answer, ask and answer really important scientific questions about the best diagnosis and treatment modalities for upper tract disease. So I think we've reached the end of our slides and I think we have some time for discussion. Thank you so much for everybody who tuned in today. Thanks to both of you. You have several questions in the question answer. I will go ahead and start at the top. So curt's asks. And patients who ultimately undergo bilateral never you direct me uh for you t you see, what are the criteria for renal transplantation? Hamish? Yeah I'm happy to uh I'm happy to address that. So um you know when it comes to these kidney transplants um you know the main concern that we have is the need for lifelong immuno suppression. So basically the immune system is sort of kept quiescent in order to uh in order to make sure that there's no rejection of the transplanted kidney. But the problem is that, you know the reason for concern from a cancer perspective is that the immune system also has has an important role in sort of fending off tumor cells at the same time. And so for patients who have a history of cancer, typically there's there's a mandated waiting period which can be anywhere from 2 to 5 years of basically being disease free depending on the type of cancer and also how aggressive the cancer was at the outset before they may be eligible. And there's some stringent criteria that are provided by the essentially the transplant guidelines that are put forth from the general surgery team. And there's a there's a coordinated effort to kind of make sure that it's rigorously followed. But in general um you know having had a history of U. T. U. C. And undergoing bilateral mastectomies wouldn't exclude you from necessarily being eligible for a transplant in the future. But there is again that mandated period along with other criteria from a health standpoint that would have to be met in order to be eligible to receive a kidney transplant in the future. So Karen socks a has a two part question for both of you. So the first part is standard of care for patients with high grade upper tractor theo cancer, all the surgery. Or is there a medical treatment options Maybe nervous? You can take part one. So so in this day and age technically, you know, the gold standard would be to would be actually surgical removal. Um Now, you know, like dr Hoffman since it's had had indicated there is a lot of compelling evidence that that often can be preceded by chemotherapy. Uh that being said uh you know we uh like like we kind of indicated earlier in the talk there are a number of factors also that make us concerned about patients eligibility to undergo that type of involved surgery. And so for patients who are making more elderly or who have other comorbidities or in whom we're worried about their kidney function. We do sometimes try alternative approaches where we spare the kidney and they simply just trying to blade these tumors similar to some of the methods we use for low grade disease. But using a laser and uh with with sort of limited success. There has been some series published regarding the use topical agents like BCG, which is, which is a form of an immune modulated therapy that has been utilized for non muslim base of bladder cancer. That have also been applied to the upper urinary tract as well for higher grade disease in those settings. You know, the problem again is that the dwell time is a little bit limited. So the amount of actual time that these agents can be in contact with the tumors is limited by the anatomy of the upper urinary tract. And so that's why newer agents are I definitely needed for higher grade disease. And I think a better understanding of how we can spare the kidneys in patients who have higher tumors that are higher grade, upper in the upper urinary tract within the renal pelvis. What have you are still in need of kind of these these alternative forms of management. So, dr Hoffman census, would you like to comment on the question of whether there's a treat medical treatment option? Yeah. You know, I think that this is a tough conversation that you know that we have with patients that there are some that um for whatever disease that we might be treating, you know, based on comorbidities or personal belief that a patient may not want to pursue that kind of aggressive standard of care, which is definitely really direct to me. Um, we certainly believe in the use of chemotherapy, you know, prior to surgery. And I think that this is a place where, you know, conversations about individualizing treatment can be had. Understanding that for going standard of care treatment is certainly a meaningful thing. But at the end of the day, we certainly have these conversations and honestly, um, recognizing that, you know, we as the doctors and the patients at the other side of the table, if we're having a conversation where nobody thinks that that any of these, you know, decisions really are are great decisions, you know, deciding between multiple different things. That is where these ideas about better treatment options and clinical trials coming to play really. And I think a lot of us when we develop these studies think about that individual patient, that discussion that feeling that that this just isn't good enough when we all agree this just isn't good enough. And that's why, you know, the clinical trial that I mentioned in development and others exists. And that's why I think that I am here and I think dr single is as well because even though this is the current standard, I don't think anybody thinks that that that is good enough. And um, and so we're hoping that maybe someday we may have discussions about, you know, topical therapy for, for high grade disease. It's so interesting that that you're done. Um, that that that technology exists. And I think thinking about utilizing that kind of technology and maybe others for high grade localized disease would be important, but certainly not standard at the moment. Thank you. So next question Dermish in patients who develop upper tract subsequent to suspect a me for bladder cancer are the upper track us genetic clones of the previous Lord crack tracked. Uh, that's, you know, a very insightful question. Um, you know, in the last few years there have been several concerted efforts to try and understand what what's termed essentially clonal relatedness essentially of bladder cancer tumors and an upper track your three little cancer tumors. And without sort of, you know, I think that by itself could deserve a whole talk on its own. But the sort of short summary of it is that um, so upper track and lower tract tumors or bladder cancers, they've been noted to share a substantial overlap in genomic alterations. Um, it's just that the frequencies of these mutations differ between the two and so, um, there there is evidence that suggests that in patients who may have had initially an upper tract tumor that later developed a lower tract tumor within the bladder. There's a likely relationship between those two tumors and it may just be simply that um, tumors from above have in an integrated manner come down to the bladder, below and seeded the bladder. And that wait. Now, the the interesting question is, is post here, which is in patients who have had a cyst ectomy before who developed an upper tract recurrence. Is it that this is related to the initial tumor or is it something called the field cancer Ization effect, which is essentially that the whole you're a helium may be predisposed in some manner to forming tumors. And that this de novo tumor was bound to sort of occur just by virtue of being um kind of subjected to forming your thyroid cancers. And I think we're still learning a little bit more exactly on what that relationship looks like. But there's I think there's enough evidence to suggest that there's certainly some form of relationship genomic lee between upper and lower urinary tract tumors. But I think that there's still still more evidence to be uh I guess more more data to be sort of learned from in terms of how, how related these are to one another biologically and does the timing of one's recurrence make a difference in terms of how they are related. Thank you. It's a very good question. Here's another one also from Garmisch is left mastectomy done concurrently, not for your directory. And if so, what template? So I would say that um, you know, lymphatic ectomy should be considered a standard as part of an effort. You directed me 100%. Um, you know, I think the exception to that would be if you're doing it for lower risk disease. Um, so for someone who has low grade ut you see maybe you can exclude uh the lymphatic to me. But again, with the caveat that, You know, knowing that there's an upgrading of about 50% from retrospective series that you would be sort of potentially rolling the dice on some patients. And so I routinely would plan to do the lymphatic neck to me at the time. Uh there is some potential added morbidity of doing that. It adds to the actual procedure as well. But I think that from a cancer perspective, there are if it's that have been shown in a number of retrospective series with respect to the actual template itself. To me, it depends entirely on the location of the primary tumor. So if it's in the renal pelvis or in the upper portion of the urinary tract, I usually do a retro paired and its lateral retro peritoneum lymph node dissection templates. Basically I try to dissect the lymph nodes around the island and the great vessel, depending on what side of the body you're on up down to the level of the pelvic inlet. Um if there's tumor involvement in the lower part of the, of the ureter, uh then I usually try to do a pelvic lymph node dissection. So just the just the pelvic nodes, but leave the stuff up above and if it's uh some patient who may have multifocal involvement and we're really concerned for high risk disease. I may try to get nodes in both areas. Thank you. So Saleh would like to know most of what is addressed in these seminars Internal theater binary system. What are diagnostic techniques and treatments for growths on the interior bladder wall? Anyone of you want to take a whack at that one. The only comment I suppose. You know, I mean I think when we think about your epithelial cancers, you know dr Hoffman sense that this was kind of discussing the anatomy of the urethra liam being the inner lining of the bladder and the and the year the kidney. Um You know, if we're talking about like a mass that maybe on the outside of the bladder um that sort of raises the suspicion that it may not be of your ethereal origin and maybe something else. Um You know, for example, like an adenocarcinoma, Rakell. Adenocarcinoma is something that would be maybe still pertinent to urology. Um As far as diagnostic techniques. Um you know, if it is in such a location oftentimes um it may be amenable to a perk you tania's biopsy that we may engage some of our interventional radiology colleagues for. Um Alternatively, um you can sometimes do laproscopic die diagnostic procedure. So um insert a scope and try and see if you can visualize uh you know an area of question and try to sample the tumor in that way. But you know, in those cases we start to think about maybe non neurologic reasons for why there may be a tumor in that type of location outside of the bladder itself. Thank you. I agree. Uh So is adjuvant radiation therapy used for t vote for any N. M zero U. T. You see I can take a step with that one and then we'll see what dr has to say. So I way I think I'm not a surgeon and I'm not a radiation oncologist. Um but the way I think about those modalities of treatment is that we use surgery for in general for tumors that can be completely removed with the goal of cure and that we can use radiation sometimes for the same reason. But oftentimes we may be using it as an adjunctive treatment or for almost like a spot welding treatment. So for some of our patients that even have metastatic disease, we can use radiation as a tool if someone has a great response to treatment the pain at one site. If you can kind of imagine boy if I can fire beams at one site and make that site go away. You know, that patient may certainly feel better. So there's different ways that you can use the tool of radiation. Um We're fortunate in our tumor board that we do have radiation oncologists that specialize in your skeletal cancer. To weigh in on these cases. I would say the current data, probably especially in a patient that had preoperative chemotherapy. Um and has a T. Four tumor that's lived through CISplatin based chemotherapy that we will likely have a discussion about as of an immunotherapy that the volume map study that I showed that was published in the new England Journal of Medicine. I think that we do certainly think about postoperative radiotherapy. But oftentimes those are reserved for other patients that have positive margins, meaning that there was a microscopic or even a microscopic focus of tumor that could not be respected by a surgeon. Um or in a patient where their first postoperative cat scan really is concerning for lymph nodes that are already back on the scan. So again, if that area can be kind of encapsulated in a small um kind of focus that radiation maybe it's more that we use with the hope that despite that early evidence of recurrent disease that we could still delay metastatic recurrence or hopefully, you know, still um potentially offer that patient a chance of cure. Dr singler anything dan. I agree completely with Dr Hoffman census and it's a great testament to the value of multidisciplinary care for this disease. Um you know, I agree we wouldn't necessarily routinely use adjuvant radiation. But if we do have some concern that surgically there was grossly uh you know that there was say, you know, positive margin or that we believe diseases likely left behind, we have to be a little careful. Um certainly if if we think it's at the level of the bladder. Um you know, there are some side effects related to radiation as well. Um you know, if you're trying to irradiate the bladder. And so those would be cases where, you know, maybe our threshold would be a little higher to offer radiation if it's in the sort of the renal fossa, so where the kidney was removed, um, you know, maybe there could be more benefit to it. But again, I would in my practice prison, I prefer to reserve it for cases in which we either see on postoperative imaging some persistence or if if we are grossly concerned that there may have been some some cancer left behind that, you know, maybe you'll be able to kind of sort of prolong the biology by, by offering radiation in those areas. Thank you Tracy Horgan has her hand up or has had her hand up, she still on the zoom Wasim can you give her permission to ask a question line? Yeah, sure. Maybe while we're waiting for Tracy Leslie asks, how do you remove a euro to but keep the kidney also a very excellent question. So, um, so, again, I think the 1st 1st, it's important to recognize that, um, that, you know, we do this operation, but it has to be in selected patients. So, patients who have a tumor within the last part of the order, um, would be kind of the best candidates. Um, but we would have to ensure that there's no evidence of tumors above that area or within the kidney for fear of, you know, leaving something behind the way to do so is actually you can technically remove a segment of your order and get it all the way down to the bladder. And basically, we do something called the original re implant, where the remaining section where that we believe to be uninvolved with cancer can then be sewn back into the bladder at a different portion of the bladder. Uh, it becomes a little bit more challenging as you get tumors involved in the earlier, higher up with within the order. And so those are situations where sometimes we have to become a little more creative, um, if we're trying to really make, uh, make a diligent effort to save the kidney. So there will be cases in which sometimes you have to sort of reconstruct the bladder or potentially do other maneuvers in the operating room in order to make the residual ureter reach the bladder. Since that's usually the limiting factor. Um, you know, if we start to see tumors kind of higher up in the order and it looks like it's not going to be a situation that's going to be easily repaired. Oftentimes, we, we tend to prefer just removing the kidney in those cases. Um, but but there are certainly ways to remove portions of the ureter and then basically re implant, uh, the, the tumor or reconstruct the order in some way to make it reach. Thank you Tracy. Are you with us? I want to ask your question. Okay. Okay. Um, I asked for a new but still still sorry about that. She may have stepped out. So Debbie baldwin would like to know something. She's lost one kidney to U. T. U. C. And now experiencing low grade beauty. You see in the surviving kidney recently underwent a second round of gel mido, curious to know your recommendations re frequency of you to read apostrophes given the risks. Happy to take that one as well. So, yeah, so generally I would say three month intervals is kind of uh, inappropriately accepted standard for those situations. Typically, if, you know, if we make a decision to move forward with the L mido, it would be the course of six kilometer treatments over the course of six weeks. And then the initial sort of your arthroscopy look would be at about 4 to 6 weeks after the completion of the of that course. And that's similar to the protocol that was published in that phase three trial that was presented and then thereafter. Um, I usually certainly at least for the first year would continue at three month intervals. Um, and then as as we get further out, uh, in terms of kind of longer term surveillance, um, sometimes we can start to relax that interval a bit a bit more. Thank you. So finally, one last question from Stephanie cooper Greenberg, often bladder cancer is misdiagnosed as a urinary tract infection, especially in women. His upper tract disease also misdiagnosed. And what are the signs that one may have upper track your theory? Do you need you want to take that? Sure. So thanks Stephanie for the question. Yeah. Unfortunately, I think that we do sometimes see patients that um also, you know, initially present with these, you know, irritated your urinary symptoms, your epithelial cancers will bleed and that blood inside the urinary system is very irritating. Um and um and that blood isn't always visible to the naked eye. So that's called microscopic he materia or you can have grocery material, which means that you can actually see blood in the bowl. Um and actually there are some patients where they even do get to a urologist and well look inside the bladder, don't really see any evidence of tumor and may or may not have the capability to go up into the upper tract or maybe are able to go there. And the tumor is so tiny or so, you know, far up into the pelvis. That is really, really hard to see. Um You know, dr single is the one with the expertise that actually does these, you know, these biopsies. But I would say that the for the majority of symptoms are pretty similar um to bladder cancer. So, um, frequency, urgency going the bathroom a lot when you have to go. You have to go and seeing blood in your room. Dr singler anything. Dad, I think maybe I agree with Dr Hoffman census. Um You know these I think compared to bladder cancer may be even more challenging to diagnose because the uh UTI type symptoms can be sometimes more prevalent with bladder tumors for obvious reasons. Whereas in the upper urinary track sometimes you don't always have that ability. Um And unless you're seeing blood or unless you're having flank pain from obstruction or if you have sort of a microscopic assessment of the urine that indicates that there's some blood may not always get you know a thorough evaluation which it would include a Sista ska P. Plus. Again our current gold standard right now for imaging would be a C. T. You're a gram. Um And so in many cases, you know, if if you don't pick it up from either those subtle symptoms or a CT scan done for another reason you may you may potentially miss the diagnosis and then you know, the sensitivity for CTE programs also like I mentioned earlier in the talk is a bit limited sometimes for U. T. U. C. As well. Um And so keeping a low threshold to to look up with the scope um you know and keeping kind of a high suspicion based on risk factors etcetera is an important way to kind of make sure we're not missing potential patients with with you t. You see. So while you were answering that question, two more questions came up. I think we'll draw a hard line in the sand after these two. Let our good doctors go back to their work. But Kathleen han um maybe some relation to know han what is the best way to find you? T you see when the patient has suspicious cytology for over two years, All this negative except for suspicious and murder one one. and actually I think I maybe I'll combine this. I believe. I see the next question in there also asks, is blue light available for you tea, you see. So um so you know, if if we find that there's a suspicious cytology um you know that could mean that it could come from anywhere in the urinary tract uh and so in and of itself, that should, at the very least by Asus tosca p evaluation. So looking at least in the urethra and the bladder. Um You know, in those cases if if we're not able to grossly see a tumor, usually we would try this blue light technique which is an installation of an agent called Hexham in electrolytic acid in the bladder. And that's supposed to preferentially be taken up Um more or less by by by bladder tumors. And sometimes you can get better detection of things like carcinoma in side to that you can ordinarily get with the naked eye about 25% chance of finding something. Uh using that technique more so invisible white light alone. But even in those cases there's benefit to getting these original washes where you're able to try and sometimes um with the risk of potentially contaminating your cytology specimens, try and actually selectively get a sample of urine from the left, the original orifice, or the part that drains from the urine into the bladder, and then one from the right side as well, and try to keep that separate from the sample safe from the bladder itself. Now, let's say we're in a situation where nothing shows up in the bladder and you do have one side that has a selective psychology that's positive. Next step typically would be to try and actually visualize that the upper urinary tract that would be kind of our gold standard way of making a diagnosis is with the urine horoscope and essentially biopsy any suspicious appearing areas if there's no obvious tumor that appears um in the event, that there could be some C. I. S. Unfortunately at the moment, there isn't a there isn't a in an analog of blue light in the upper urinary tract. Um, and I think that, you know, absolutely would be uh something of interest for future research efforts. Um, you know, again, for some of the an atomic limitations for instilling topical agents into the upper urinary tract for therapeutic purposes in a likewise manner. There are the same types of limitations for for diagnostic purposes as well. Um And so I think there's certainly some more work to be had from a technological standpoint, but absolutely, A very insightful question. Absolutely. And I wanted to thank both of our doctors for giving us a fantastic presentation and Q and A. Today and encourage all of you to come back next time and join us. Uh, thank you very much for being with us today. Take care. Have a good evening. Take care, everyone. Thank you.
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