 All right, so thanks Kim for having me here and the organizers So I'm going to talk over the next probably 20 minutes or hopefully less about pet Which I know there's a lot of excitement about So I'm going to talk a little bit about what is pet and I'm going to try not to get too technical But I think you know again There are a lot of misconceptions about what is pet and what it can do how it works things like that So I do you know want to just mention a little bit of science behind it I will talk about what could pet tell us so what are kind of what's the promise of pet and I'll give a few examples and kind of review the evidence hopefully pretty concisely So this is a nice slide showing kind of the evolution of technology over the past Over 40 years and you can see from left to right in terms of CT and pet both The resolution has gotten a lot better over the years And then it's only really the last maybe 10 or 15 years where it's gotten to the point where we can Start to be able to use it For different purposes. So what are the potential advantages of pet CT over just say CT alone or other imaging? And I think the advantages are really that it marries both structure and function So structure is in terms of the CT having a very high spatial resolution being able to look at different types of tissues bone Fat air other things like that and then the pet on top of that adds the function So we can characterize lesions, you know How are they say taking up sugar or doing other types of things depending on what kind of tracer you're using and then that may allow You to better detect lesions or at least to maybe better separate out which lesions are lesions to be worried about and which lesions Are lesions you should not be worried about So this is a nice slide kind of showing that marriage so on the top Row you have a pet scan and it's black and white. You'll notice you have a CT in the middle row And these are different views kind of a frontal view a side view and then the last column is a patient lying on his or her back With their belly button pointing towards the ceiling And as you can see at the bottom the pet CT marriage, you know So you first take the they first take the pet scan And they colorize it and then they overlay the the CT on top and that gives a lot more information than just one Or another alone and then they can kind of play with the different features back and forth So so so on the topic of pet being kind of a functional type of an imaging What what types of things are unique to cancer? What how does cancer function different from normal cells? And so this is a this is a classic slide First published by Hannah Hannon Weinberg in 2000 I believe that's now been updated in 2011 and these are showing some some kind of cardinal features of cancer or hallmarks of cancer biology So these are things like deregulating cellular energetics So so that means cancer takes up glucose more than normal tissues things like evading gross suppressors You know other things inducing angiogenesis, which we all know is very important in in kidney cancer And then sustaining proliferative signaling and of course avoiding immune destruction, which is being increasingly recognized now is important in kidney cancer so since since I think especially Fdg pet is so misconstrued. I do want to just talk about a few basic basic principles And so to do that I'll have to talk about a little science But also to note when most people say pet They don't they don't say Fdg pet They don't say floating sodium fluoride pet or some other kind of pet They just say pet and usually what they mean is Fdg pet which is basically looking at sugar and how the tumor takes up sugar And so this is a kind of a cartoon that has a lot of science in it But basically you can break this down very simply What it amounts to is what you're looking at is a cell membrane so so of the say a cancer cell There are glucose transporters in that cell membrane. So sugar flows from a gradient, you know into the cell And what's unique to cancer cells is the cancer cell is relatively inefficient So it doesn't go towards that bottom pathway that's in the mitochondrion It just kind of cycles back and forth and so in doing so takes up a lot of sugar relative to normal cells And we could take advantage of that with Fdg pet imaging So this is a slide showing Fdg So kind of a sugar like substance flowing through the same sugar Transporter that that sugar would and normally sugar these these arrows here These arrows here are showing different kind of enzymes that convert the sugar into all different types of things But the cell can't get rid of the Fdg so it can't flow back out It also can't flow down into other pathways So that Fdg is then trapped and we can take advantage of that to do imaging And so what we see is this the this Fdg that's trapped in cells This is where it gets a little bit complicated because you can imagine if a patient has one or several Tumors in their body. What are you really looking at? Are you looking at all of the tumors? How do you how do you kind of quantify that? And so what is commonly used is an SUV max it's called and that's Again, I'm sorry to have to to mention these kind of technical terms But that is one voxel and a voxel is like a pixel so a pixel is two-dimensional It's a square a voxel is three-dimensional It's a cube and so it's the cube in the tumor that has the brightest intensity So what you're doing then is you're boiling this whole tumor down to one little point That's the very brightest spot And that's the most common measurement called SUV max. There are other ways of of looking at this So so one of my colleagues at Wisconsin likes to say images are just more than one number In fact, they're very complex the data that comes out of these PET scans is just enormous And so one of the reasons why we use SUV max is it's very nice You have one point that you boil everything down to but the disadvantage of that is you don't really capture all of the features of this Lesion so think about this lesion, you know, it may have spots that are brighter than others it may have Different nests of cells that are behaving differently, you know, some are good some are bad for other Lack of a better way to kind of explain it So there have been other ways of kind of quantifying and describing What you get when you get a PET scan? So one of those is SUV peak where you actually take some diameter around the the brightest voxel So the SUV max so like one centimeter around and you quantify that you can also quantify the whole thing in terms of the total Brightness say and you can do measurements. So this is a list, you know Just all kinds of possibilities just showing that SUV max is what is commonly used And if you're an oncologist or other doctor were to get a PET scan chances are what would be in the report is An SUV max it would say this is this is something that looks like a tumor here And this is its SUV max. It's you know seven or whatever it is For now these other measurements are being looked at for research purposes But aren't really aren't really a standard of care But as as bioinformatics gets better and things like that I think that the field of of PET research may move to looking at some of these other other things because they may be more important and may not You know, I guess for lack of a better way of putting it may better describe the tumor burden and the patient's body Then just boiling each tumor down to one little point so So if you look up in an NCCN guidelines or you look in and different guidelines and recommendations medic Medicare's recommendations for example They do not routinely mention the use of PET scans and kidney cancer And so these are some of the reasons why most PET tracers including FDG are eliminated by the kidney So you have you know what you can see is the FDG kind of flowing down the track From the kidney into the bladder and so on and so forth out the body Also early investigation seemed to indicate that primary kidney tumors so tumors within the kidney had relatively low sugar uptakes So it didn't seem to be kind of useful there So FDG PET didn't really seem to add a lot to just conventional CT imaging for example for looking at renal masses when they kept looking at it It looked like FDG PET performed a little bit better for detection of distant metastasis So it was fairly specific meaning that if it was a if it was a positive FDG PET you could kind of believe that that result So in the next part of the talk I'm going to talk a little bit about what FDG PET could tell us And I'm going to argue a lot of this is is still a work in progress But I think there's a lot of hope As the as the technology advances and maybe new tracers are used We could have some some real use from PET So the first area where I think PET may be useful is better characterization of small renal masses So basically differentiating malignant malignant from benign small renal masses and I I'm sorry I missed Dr. Smith's talk Did she talk about About gerontuximab or Okay, all right, so I'll talk a little bit about what's you know, maybe the most promising tracer gerontuximab um The second area where I think PET could maybe tell us something useful is we know that there are patients at high risk of recurrence And we know that because of different features when Dr. Ampersad takes him to surgery when he looks in the pathology may make them more likely to recur So if they're t3 t4 if you know if they have other high grade, you know those kinds of things What we think those patients are probably more likely to recur But we can't see the disease on our conventional imaging So maybe we could see that better on PET and then the key is if we see it Hopefully we can also treat it and have good tools that To treat it to to improve outcomes for patients And so I think it's important to know both of those things have to be true um And then the third thing which is something that's near and dear to my heart is in patients with metastatic kidney cancer. Can we improve prognostication? Or prediction so prognosticating how long patients may live which is important for a lot of a lot of things But also predicting when therapies might work or or even just treatment monitoring our our treatments working or not Current prognostication systems as I imagine was discussed this morning Rely really on clinical factors. So things like laboratory values the patient's performance status um But maybe pet should be in there And I'll show you a little bit of the data around that the other problem is that standard radiographic methods So ct are a little bit problematic in kidney cancer Without getting into it too much there are Some situations where we see that the tumor is growing On ct scans and so conventional research methods of measuring the tumors might say this patient is progressing When in fact the tumors are changing in their characteristics of taking up different Different ib contrast and we think no maybe they're dying in the middle or or something like that And there are other there are other scenarios where we can't where we can't really evaluate patients So for example a patient who has tumors only in the bone tumors in the bone are very Hard to measure and hard to kind of quantify. So maybe that's a situation where pet could be useful over ct or say bone scan So without further ado, I'll get into the first One of these which is characterization of small renal masses and this is I think one of the most exciting Uses of pet. So this is gerin tuxamab. So cg 250 which is labeled with iodine So this is a monoclonal antibody So an antibody that recognize what's called carbonic and hydrase nine on the cell membrane Of specifically clear cell kidney cancer. So keeping in mind there are other histologies or types or flavors of kidney cancer It's you know, it's specific for clear cell kidney cancers And so keep in mind that in terms of interterminate renal masses if you think about it about half are clear cell renal cancer But then the other half are made up of some with limited malignant potential So things that we would worry less about papillary and chromophobe Histologic types, but also benign tumors oncocytoma. So there is a concern for overtreatment of small renal masses specifically some renal masses that are greater than or sorry less than or equal to four centimeters. So we know that patients who have you know Especially full nephrectomy or even partial nephrectomy are at risk for chronic kidney disease and then for cardiovascular disease So maybe we can differentiate Amongst these different categories of interterminate renal masses with something like gerontuximab And so again, I don't want to I don't want to bore you with too much biology But this is I think a nice cartoon just showing one of the pathways That's really central in kidney cancers. And that's the von Hippel Lindau tumor suppressor gene So what you can see on the left here is that in conditions where there's normal oxygen levels in the tissue The vhl Von Hippel Lindau tumor suppressor basically marks this thing called the hif one alpha hypoxia inducible factor one alpha for degradation and it's degraded Now in clear cell kidney cancer what happens is in a large majority of cases that vhl is inactivated for some reason Maybe a mutation As a consequence, it doesn't inactivate that hif one alpha that goes to the nucleus of the cell And sets off this whole signaling cascade where there's growth factor overexpression of a lot of different things Vegef which I imagine you all are familiar with but also carbonic anhydrase nine So this is something that's kind of specific for kidney cancer based on the biology of kidney cancer And specifically clear cell kidney cancer the most common type So this was an important trial that came out relatively recently where they were looking at this This compound so gerontuximab the antibody again against ca nine Took about 200 patients with complete data Sites all over the u.s. And these were patients who were going to go to surgery For renal mass and what they did is in these patients they did a pet ct with gerontuximab And then they also did a contrast enhanced ct and so what they were asking is Is the pet ct better than the regular ct? And their standard of truth then it was surgery so in these trials It's always important you have to have some kind of gold standard You're trying to you're trying to say gerontuximab pet is better. Well, what's the what's the gold standard that you're looking against? So the sensitivity and specificity for clear cell kidney cancer was pretty good 86 so these mean Kind of the confidence you can get for ruling in or out the diagnosis of clear cell kidney cancer Positive and negative predictive value So again different ways of kind of looking at that were fairly good The criticisms were though that these patients were actually not just patients with small renal masses, which is you know What I think this could be used most for Only 52 percent. So only about 100 of those had pretty small renal masses 20 percent had really large renal masses where they would have just got an nephrectomy as standard of care Other things that are important to note and this is the case for a lot of pet compounds. So I just I just mentioned this here All pet compounds are not the same. They have different features They have different half-lifes as far as how long they last in the body. They have different technical specifications So a scanner may be optimized for the most common type fdg, but it may not do very well with With this gerontuximab So there's really a trial needed in patients with small renal masses to kind of sort this out and patients who are going to go Not just patients who are who are uh candidates for surgery So I do want to show you a few pictures because I think this is pretty neat. So this is this is a sample image. So Thinking about what's the standard of truth or the gold standard The patient had a one centimeter mass. It was clear cell kidney cancer on surgery And this is what it looked like on non contrast ct. This is what it looked like on The gerontuximab pet. So it was it was positive. This is what it looked like On a fusion. So in this case Both the contrast enhanced ct And the pet fusion would have picked this patient's uh, this patient's kidney cancer up Now contrast this with this scenario. So this is a patient with a 1.8 centimeter Oncositoma so so meaning a benign type of a tumor in the kidney At an effrectomy so and my errors. I realize uh have moved here but um You see the mass there in in the kidney seen on on a contrast enhanced ct Um And it would have been worrisome. It was positive. So so worrisome based on contrast enhanced ct But on the pet ct it did not up up take the gerontuximab So this may have in this case may have saved the patient from surgery now In this case, of course, the patient did get surgery as the standard truth But in in clinical care, this is a scenario where where the gerontuximab might have been helpful So scenario two. So what about surveilling patients who are high risk? um I'm not going to go through the evidence because I think that A lot of it's retrospective and not a lot of it's not that great But I'll just sum it up by saying that a lot of different guidelines whether you want to look at the nccn The american urologic association the european urologic association Basically say that the the role of pet for follow-up of rcc remains to be determined And I think the main concern is is false positives So if if you do a pet scan, you know, maybe it picks up some lung nodules that weren't otherwise seen But maybe it makes you more worried about lung nodules that are nothing in the first place And that's the real concern. I think there So i'm going to move right into the the third kind of area where I think pet may be useful And this is looking at response to therapy. So specifically tyrosine kinase inhibitors So drugs like sutent drugs like seraphonib And so uh, these aren't meant to be read But just to show you there at least seven trials that were summarized in or in a nice review that came out earlier this year And what's key about these trials is each one of them had relatively few patients The largest number of patients had the largest, uh trial that is had 44 patients and they arranged down to having 10 patients Um, and if you look, uh, most of the drugs studied either sutent or seraphonib sometimes a combination They had different timing Most of them were looking after one cycle of sutent. So that's usually about six weeks But others looked at at different time points And they did use mostly suv max, but some used uh, some used some other features as well So they're in other words, these were a little bit heterogeneous small trials Different designs. So sometimes when that's the case, it's hard to draw firm conclusions Um, so I'm just going to show you the the very largest trial and just kind of talk about the top line results So this was the one with 44 patients These were previously untreated patients who had metastatic clear cell kidney cancer Treated with sutent and what they did is they did this fdg pet imaging at baseline They did an early time point at four weeks and they did a late time at 16 weeks And what they were really hoping to see is that uh responses at either four weeks So it's a change from baseline at four weeks or change it from baseline at 16 weeks Would correlate with either overall survival or with progression free survival um, and interestingly The response at four weeks did not correlate with any outcomes But on the other hand progression at 16 weeks did predict an inferior survival They also find a finding that's been found in other trials, which is that a high suv max at baseline. So a lot of Lighting up bright, um very intensely and number of pet positive lesions predicted for inferior survival So, um I'm going to try to show you some more pictures because I think this this makes it more interesting So what you see here is a patient, uh, who's kind of falls into that camp So a patient who at baseline had lesions and you can see the little arrowheads Pointing out some different lesions the patient had a response after four weeks of therapy And then after 16 weeks of therapy had new lesions Indicating progression and then this is just picking out one lesion on a cross-sectional imaging show it how showing how it Decreased an uptake from baseline to four weeks This slide isn't isn't necessarily meant to be read but just showing you kind of the The differences and things that were shown in the different trials Um, so in some trials early assessment of response by fdg pet Could predict both progression free survival and overall survival whereas in that largest trial it couldn't Um in one trial trial high baseline Fdg pet uptake so so being really bright at baseline seemed to indicate the disease was more aggressive And then the last one is as dr. Rathmill and colleagues trial So this was looking at patients interestingly prior to to kidney surgery or removing the primary tumor And they did show that lower baseline uptake Were more likely to respond to seraphina, which was an interesting finding That was in patients with clear cell kidney cancer not in the non clear cell subtypes So um in the next slide one of the last slides I'm just going to look toward the future and I we can make a list of you know Tens of hundreds of different pet tracers that have been looked at in cancer But these are a couple that I picked out that I think are interesting just because they may or may not be specific to kidney cancer So one if you remember back to that hallmarks of cancer Diagram one thing that may be unique to kidney cancer is this tumor hypoxia effect And so they've looked at this compound That's usually abbreviated f myso or something else because it's unpronounceable Um And they showed that pfs, but not overall survival was shorter in those who had more hypoxia meaning low oxygen levels In the tumor versus those who had higher oxygen levels This is another uh type of pet so looking at again if you remember back to that hallmarks of cancer diagram Looking at tumor proliferation And this is the group that I worked with at the University of Wisconsin Looking at basically a labeled thymidine. So so a compound that's used in d and i synthesis when cells are proliferating They're needing a lot of this compound is kind of the raw materials And so they're turning over a lot of this Um And so what what we showed in this study is that we could characterize or quantify changes During suten exposure and during withdrawal And so if you keep in mind suten is given on a 4-2 schedule So it's given for four weeks on two weeks off We showed that veg f is associated with that flare and in an exploratory analysis patients who had less clinical benefit Appeared to have a large withdrawal flare and so i'll show you a little picture of that So this hopefully you're able to see but versus baseline This patient had a decrease in intensity in this particular lesion From here to here the patient had their plan two week holiday of suten which is in the you know the fda approved Package and the patient had a large withdrawal flare this patient did not do as well as patients who had less of a flare So just indicating that this may be a tool to to sort out or tease out biology and see how each tumor is acting So in conclusion, I would say that pet is very promising I think though, there's a lot of a lot of work to be done Jiren tuximab I think it is important and may eventually play a role in management of small renal masses ftg pet ct though Really isn't a standard for surveillance after nephrectomy It may be in the future may be useful for evaluating response to targeted therapy So drugs like suten, affinitor so on and so forth But I think we're still a long way from qualifying it as an actual biomarker for response And you know, lastly, I'd say there's lots or more room for research new tracers some of which I showed you and new methods To to make things better for our patients and and better help with management decisions So thanks for your attention and happy to take any questions