 It's my pleasure now to introduce Eric Mitra, who's a faculty member in the division of radiology and with nuclear medicine. So he's going to talk to us about diagnostic imaging for kidney cancer. So we had a lot of questions in the morning. Please make sure that you direct all of those questions to Eric at the end of his talk about any of the imaging modalities in addition to what he's going to tell us today. Thank you for coming, Eric. Okay, I'll put it back. Okay, I think we're all set. Well, thank you everyone for being here. My name once again is Eric Mitra. I'm from the department of radiology and I specialize in a sub-specialty called nuclear medicine. I'm going to be talking a little bit broadly about all sorts of different imaging modalities, but because of my bias and also because I think it's kind of the future of imaging, I'm going to particularly focus on some of the molecular imaging things. So I just wanted to get a raise of hands for how many people are familiar with nuclear medicine. Okay, good number. And how many people have heard the term molecular imaging? Okay, a little bit fewer. So that's fine. Even in our field, it's kind of definitely a novel area. So this is, I want to use this to introduce all these topics and then leave some time for questions as Dr. Srinivas was saying. And I want to thank her also for inviting me to give this talk. So once again, I'll go over some of the more standard modalities just to be complete, but really I'll spend the time, most of the time focusing on some of the more emerging technologies. So one of the most standard modalities that we have, of course, for imaging is the standard X-ray. It's still a very good workhorse for a lot of different things that we do. And one of the great things about it actually is that it has very low amount of radiation and it can quickly image all sorts of areas within the body. The downsides are that it really provides rather limited information. And typically if you see something abnormal on an X-ray, it means that the size of the abnormality has to be quite large for you to see it. So that means that things have already progressed to quite a degree. And so for that reason, as we're trying to move towards early cancer detection, the X-ray, which has again been around for a long time, isn't really the preferred modality. And so nowadays in addition to that is that it will typically require further evaluation with more advanced technologies such as CT scans, MRIs, and ultrasounds. One would be the next kind of more basic modality. Here the primary advantage is that it uses no radiation whatsoever. However, there are several disadvantages to it, is that it doesn't have very good depth penetration and so it's really only good for surface things. Although you can look deeper, but the more deeply you look within the body, the less information that you can really evaluate from it. So the ultrasound unlike any of the other modalities that I'm going to be discussing is very user-dependent. So depending on the quality of the technologist who's doing it, it can be a very good ultrasound and you get very interesting information from it, or it could be not very good and it's limited information. So now moving on to some of the more advanced technologies, but still ones that probably you're relatively familiar with, the CT scan or computed tomography, is essentially an X-ray, but that moves around the body in three dimensions, so providing these three dimensional views of the body. So the upper image there is a standard CT scan, or you can see that it's not too closed in, so most patients don't have any issues with claustrophobia related to that. And you can begin to see that the image quality that we can get from this with or without the use of iodinated contrast agent becomes quite good. Each slice within a CT scan is only one millimeter thick, so you can really slice through the body in very great detail and typically we can see things also up to about one millimeter in size. But again when we're talking about early cancer detection, believe it or not, one millimeter in size already means something on the order of 10 to 100,000 cells. So that's still quite an advanced situation. Was there a question? Each CT scan that you get can be different from the previous one. So that's a good question. What's that? Without growth. Yeah. So the question is, can sequential CT scans be different even if the actual body hasn't changed? And yeah, there's always a little bit of difference, so it goes back down to this resolution issue that we're talking about. So if you imagine one thing that's stable and then you slice it one way and then the next time you slice it slightly differently, it might look a little bit different. It could. Yeah. But within that small range, so typically we ignore things if they're only in that kind of one millimeter, two millimeter change. We often say exactly that in our reports that this could be due to technical differences is the jargon that we use. By the way, more and more that brings up a good point that all our imaging reports now will become available to you if it's not already available to you. So everything that the referring physician sees, you will also be able to see exactly. The other downsides listed there are it is quite high level amount of radiation depending on the type of CT scan that it's done and also it can be expensive. And if there are any issues with contrast, contrast is something that can cause an allergic reaction or other issues to those are some things to keep in mind as well, although most patients do just fine with it. Moving on to some of the most advanced technologies is magnetic resonance imaging. Having said that, this has been around now for many decades. The advantage to this is that it essentially combines the advantages of an ultrasound with an advantage of a CT scan. What I mean by that is that there's no radiation involved in an MRI scan. However, it has incredibly a good anatomical detail just like a CT scan did. However, there are many downsides to it as well that you can see. So it's not the ideal imaging modality for everything. First of all, it's probably the most expensive exam of all the ones that I've listed so far. You can see that the bore of the MRI scanner, unlike the CT scanner, is much smaller and it's longer. So it's essentially like going into this very closed area. And so if there are patients who have issues with claustrophobia, and I would even go so far as to say even if you don't have issues with claustrophobia, it can be quite challenging to be in there. And when we talk about MRI, we talk about sequences. And so you have to acquire a number of different sequences to do a whole scan. Each of those sequences takes time. The radiologists or the technologists sitting out there just pushing buttons and it's like, oh, let's do this and let's do this and let's do that, but everything is adding up in time. So to get a very complete exam can often be at least half hour if not sometimes even over an hour. If you're good, then you might fall asleep in the scanner and that would be good. But on the other hand, then you might start twitching and cause motion. So it's hard to get around it. It is kind of loud. And there are restrictions because it's a very strong magnet. So if you have any metal or hardware or other things inside you that cannot be removed prior to the scan, then that would be a contraindication to getting the scan in the first place. So just one example of how this might be worked up. Again, an early imaging study would be an x-ray. And what we're looking at here are the two kidneys with contrast in it. And I don't know if you can tell, but what we're looking for is basically a normal filling which is what we see on this side. These are all the renal calices. And so this is where the contrast should be coming out. This side looks normal. This side, you can see that there's some in the top part of the kidney, but the entire bottom part of the kidney doesn't have contrast. So you might say, okay, that's something abnormal. And you might follow it up if you're not too concerned with an ultrasound. An ultrasound, again, would be a good first line study just to evaluate, kind of generally speaking, what's going on. Perhaps this was just an artifact that you saw on the x-ray and you want to confirm if that's real. And on ultrasound you can see, again, parts of the kidney that are more cystic and parts that are solid. So then you become concerned that there's something odd going on within one kidney. But really the answer starts to come when you do the CT scans or MRI scans, both of which are quite good for the evaluation of the kidney. And you can see, compared to the right kidney, which looked normal on the x-ray, the left kidney has this very large mass. And that was what was causing you to see this little bit of activity on the upper part and then the lower part doesn't have any activity because it's not functioning like normal kidney anymore. Any other questions about some of those more standard modalities before I move on to some of the more newer ones? So one of the first newer ones I want to talk about is positron emission tomography. How many people are familiar with that? It's called pet imaging. Okay, good. So pet imaging has been used clinically since the early 1990s and probably most of it has been since 2000. So it really has been around for quite a long time as well. So I'm glad that many people are aware of it. This looks like the CT scanners and the MRI scanners you saw before and part of it actually is a CT scanner as well. But the pet portion of it you have to keep in mind is completely different than anything we looked at before. And the major demarcation that we say there is that all the other modalities were anatomical based and this is functional based. So everything that you see on a PET scan you are actually looking at cells. And the way we look at those cells is we inject some radioisotope that's attached to a certain molecule and that molecule then homes in on a certain cellular mechanism. Okay, so it kind of begins to get into what we were talking about in the prior talk in terms of that was at the genomic level. Now we're talking about molecular and cellular level. And so the good thing about that is that the same scanner can be used to investigate all different types of cellular physiology within the body depending on which molecule you attach to that radioisotope and then inject. So that makes this very powerful because the same scanner can be bought by the hospital and you can come and get one scan done one day and then the next very next day you can come back and get injected with a different radioisotope and have a completely different scan essentially because we're looking at now new information. So in terms of cons for this is it too is a radiation exam because the radioisotope that we inject into you to evaluate is radioactive to begin with so that gives you radiation and then the CT scanner that I mentioned is embedded within this also gives you radiation. It also is relatively expensive and when we talk about kidney cancer in particular the primary cancer is not well evaluated by this because the main radioisotope that we use is actually cleared through the kidneys just normal clearance and so it causes a lot of uptake in the kidneys and so we can't really evaluate the kidney so well but for anything outside of it it works very well. So here's what we actually do just to give a small detail we inject you with the radioactivity it circulates around the body you wait about 60 minutes for it to go everywhere and then you're actually now the source of the radiation and the camera the pet camera is actually picking up where those molecules have gone to so that we can see what that mechanism is and it's a type of radioactive decay here that we're following. So here's what those images now look like this is from a standard FDG scan FDG is the standard isotope that's been used for the last 20 years or so for pet imaging but only over the last five years now we're beginning to see several more radiopharmaceuticals that are now available for pet imaging as well and each one again investigates very different types of physiology within the body but and just to orient you this is you know different slices through the body and this is what we call a maximum intensity projection image but basically what you're seeing is the distribution again of this tracer now the G in FDG stands for glucose so it's essentially a radioactive form of glucose and that's literally what we're looking at is what cells in your body are taking up sugar more than other cells in your body are and those cells that are cancerous because they're growing at a faster rate they tend to take up sugar more than other cells do and that's exactly how we can see so these areas that are marked with the arrows represent in this patient some areas of disease and so we know that those areas are abnormal because they're taking up more of the FDG but I will point out that there are other areas within the body which also show up this this for instance is the right kidney and so that's what our job is as radiologists is to know you know which part of this is normal this is also a normal organ here called the brain so even though you're resting there the brain is constantly you know taking up sugar because it's constantly working and so it always appears hot yes yeah great question so the question was if there are other areas of injury or inflammation when within the body will those take up glucose and the answer is absolutely yes again that causes actually one of the main problems for this type of imaging is and when you read your reports you know we sometimes have to equivocate on that and say this could be cancer or this could be you know something completely benign and we hate to do that because it's two ends of the spectrum but you know we can only tell so much why you would use a PET scan because from what I understand that kidney cancer doesn't really light up like other cancers for instance if you had a on this on this modality you mean yeah if you had like a chest lymph node mm-hmm it wouldn't light up very much no that's actually not true the so again the primary tumor in the in the kidney because of the high background clearance from the normal clearance that you can't evaluate well but other areas you typically do see yeah it's good for anything other than within the kidney right and I'll show you at the next example actually can sometimes even be valid useful for the kidney area itself so you know it's always helpful when the what we call the arrow sign is there to help identify the abnormality but in this case there's this little bit of uptake here which you can see much better on the cross-sectional image and what this is actually is a patient who's had their primary kidney tumor removed and when that's happened on those other types of imaging whether it be ultrasound CT or MRI it's very difficult to evaluate that area because there's scar tissue there there's all sorts of other things from the surgery if they if you've had radiation then that causes changes so how do you know if some of those things are actual recurrence or is it just post surgical change and this what this is showing you is that there's very high uptake here and so that represents recurrence which you would not easily have been able to pick up on a non functional non metabolic type of study so to go back to your question about inflammation this brings up that same point in you and one of the reasons why we actually wait after doing surgery is because we know that it's going to be hot immediately after because it's just the inflammatory cells that are taking it up but if you wait three months then that should have died down and if you still see something hot then you know that that's likely to be recurrence and the other area that fdg pet or metabolic imaging as we call it is very useful is to evaluate response to therapy and so this is very important to everyone because once you're placed on some type of medication as we were talking about in the in the prior study some things work for someone and the same thing might not work for someone else and then how do you know that and how do you know that as soon as possible so that if it's not working you can switch to something that may work and so you can see in this patient which is an unfortunate person who has you know very widely metastatic disease that you can then at baseline see where all the sites of disease are and then nicely follow that after four weeks and after 16 weeks on the therapy and see things coming down and to even make this point stronger if you look on the cross-section because as I mentioned all our scanners now have pet portion and a CT portion together we do it together so here's the CT portion fused to the pet information and what you can see is that there's this lung nodule here that actually didn't change size even after four weeks on the therapy but you can see that the metabolic uptake here the amount of glucose that that is taking has reduced dramatically so if you were just doing a CT scan you might think that that person didn't respond at all when in fact they did respond very well to the medication so those are some of the ways that are very helpful for this type of modalities so then to kind of conclude I wanted to talk about some of the most emerging technologies which which you know goes from everything that I've mentioned before and then takes it to the next level so I have listed a number of different terms here and again I wanted to see a show of hands how many people are familiar with these terms so have you heard of personalized or precision medicine okay okay yeah so that's that's a very generic term but not at all limited to imaging but to kind of oncology in general and I would say medicine in general stanford is having a big push about personalized precision medicine really because it again is kind of the future molecular medicine ties into that so that yeah this is a good transition from the prior talk because again using all of that kind of genetic molecular data you can then personalize so that's what the the goal of it is in short is to tailor the therapy to a specific individual rather than just give the same thing to everyone one of the other things that pet and CT imaging already show you is that everything is kind of moving towards combined modality imaging so all those different ones that I mentioned you can think about them in the future as combining them together so one of the newest types of scanners that actually even stanford only we've only had one for one year and many places in the country don't even have one yet is a pet and mr so now you can combine those two things together and there's work going on within the department and other places where you can combine ultrasound and some of some other technologies that I haven't even mentioned and put those together to find information but the whole goal again is to really personalize this and make specific to the cancer and specific to the individual and so one way we can do this specific to pet is as I've been alluding to is that you can have different radio tracers rather than just fdg to give you new information and lastly but not in any way least is that once you have identified a specific molecular or cellular target that you can image the beauty of this entire system is that then you can also attach a therapeutic isotope to that same molecule and then actually treat that same tumor type the same thing that you're using to image you can then treat as well so this is something that's called theranostics it's another term I should have thrown in there and that's a combination of therapy and diagnostics so come together so this is another great area so I just wanted to give you a couple of examples and I don't mean to get into hardcore biology here but just to give you an idea of where some of this might go so the fdg molecule that I've already talked about over here is actually enters through the glucose pathway so as I mentioned it's basically a radioactive glucose it enters through this specific transporter and then it's basically showing you this side of the equation within the cell called glycolysis so that's the sugar being taken up and used for energy well many cancers actually you know thrive even if you take away the sugar and so for a long time now people have considered what other are some of the alternatives and one of the key things that have come out from that is this molecule called glutamate it's an amino acid in your body uses lots of amino acids to help build structures within your body but this amino acid plays very important roles also in this energy balance within the cell and also on this side of the equation which is actually showing the reduction of free radicals within the cell so all of this is very important for the cell maintaining what we call homeostasis and then being able to grow now for a cancer cell it's the opposite we want to disrupt their homeostasis and prevent them from growing but it all comes back to the same biology and understanding it so where I'm going with this is then if you can then radio label this glutamate molecule just like you radio labeled glucose then you would be able to begin to see what's going on on this side of the equation for the cells which gives you very different information and furthermore if you can then develop chemotherapy that blocks the production of the glutamate within the cell then it would completely stop all of this mechanism and throw off the redox reduction within the cell all of which could be very beneficial and this is not science fiction there is a radioisotope that is now has been made to that's labeled glutamate there's even one that labels this one which is called glutamine it's a precursor to glutamate and there's a new chemotherapy that's now in phase one trials that actually blocks the conversion of glutamine to glutamate and we were actually at stanford participating in that so all of this is you know very relevant to what's going on the key is to then see how well does it work in different cancer types and how well would it work in specific individuals to go back to this idea of personalized medicine this is just a short list of some of the recent articles that have come out to show you you know how much work has been going on into these ideas of glutamate glutamine imaging and using this across a different a variety of different types of cancers that you can see listed there so a couple of examples of what oh sorry you have a question it's really the same it's really the same yes glucose well that gets into a very very confusing and debatable area yeah so as a general statement it's true that glucose is used by cells for growth but it becomes a very different statement to say that the more sugar I consume that you're feeding the tumor cells and actually this complicated diagram I have here may explain partly why because it's not just the glucose the cell has many different pathways for it to grow so if you reduced the sugar on one side if you I mean if you look you have to look at these things in a very simplified way otherwise it just you know becomes overwhelming so if you just look at it as a simple equation that way even if you reduce the the sugar on one side that's exactly what I'm saying is the cell may just up regulate the glutamate uptake in production and overcome that you know potentially what was the relationship between body mass index and metastasis and it turns out the heavier you are the longer you live it turns out so as a result it wasn't the case that you need to go on and slim down it seems like the metastasis slows down the more you weigh so the obvious relationship isn't always in place you know it's good to be it's good to be it's good to be thin in general so that you don't get this stuff but once you've got it exactly what happens is not clear yeah it's a it's a very complicated area and it goes to this idea of you know is it correlation or causation what is the true linking it's very challenging okay so I was just going to show you some images so this glutamate molecule that we are now beginning to study just as one example it's called fspg we initially did studies actually in brain cancer and this was sort of just chosen I to be honest randomly but you can see how well nicely these images are if you actually focus on the right side you can see the fdg images the ones you you've been looking at so far showing several patients with brain cancer and I know you're not too used to looking at these but on this patient you can see it a little bit here and on these two patients you actually can't see it at all this is just normal brain remember I mentioned that the brain always takes up a lot of glucose and now compare that to these fspg images first of all there's very low background uptake in the brain because it doesn't normally have circulation there and then you can just see these very small tumors which are about a millimeter in size just over a millimeter really standing out so it's really dramatic but even more than the dramaticness of the picture keep in mind that again you're looking at very different aspects of the biology so we're that's the real point I want to make so again you're using the exact same scanner and these literally in many patients were done one day apart from each other but you're now getting very different information now about what's going on with the glutamate molecule in the cell rather than what's going on with glucose and we also did some studies with had a neck cancer sorry so this was a patient with a nasal cancer and these were other patients with screma-silcarcinoma but again you can see just how much more clearly you can see it on the fspg scan compared to the fdg scan this even has potential implications for radiation treatment planning for instance because you can nicely see the boundaries of the tumor better than it getting obscured by the fdg uptake and then relevant to this talk I'm happy to be able to show one image really from a patient actually with kidney cancer and this is the so far we've only done one patient at Stanford this is the fdg image from that patient you can see it's relatively recent and again to kind of just orient you that essentially most of what you're seeing on the scan is normal so there's a normal lot of normal biodistribution in the brain these are the salivary glands and mouth area the heart always has a not actually not always but often can have very prominent uptake this is the liver spleen bowel this is kidney the other kidney was removed and this is clearance into the bladder from the kidney so the only sort of little bit of abnormalities are these things here in the chest and maybe that one so now if you compare that to the fspg image you can again see a lot of those similar normal areas such as the liver the kidney this is actually the pancreas always lights up heavily on the scan and then the bladder but then you can see all these other areas you know that you couldn't see these are all metastasis yeah these are all metastasis and even when i went back now seeing the fspg scan to look on the fdg scan to see if maybe i missed something that was subtle i still couldn't see it here's some cross-sectional images to make this point so this is the thing in that left chest on fdg you can barely see it above the background and here it stands out we use these suv values called standardized uptake values so for fdg it was four for fspg it was 16 here's an example i specifically chose to show that some areas are similar actually so on the right side of the chest this one had nsv of five versus nsv of four with fspg so actually a little bit lower and one more example here in the abdomen this is a mesent a nodule in the mesentery and this has nsv that i basically couldn't i couldn't see it this is one example that i was just mentioning that even when i went back i couldn't i couldn't see any uptake on CT scan it does look abnormal but i wouldn't have picked it up on the fdg but you know any person could pick up this nodule right here on fspg with value of 10 yes well we we hope so the question was will we be using fspg more often as we go into the future yeah so it's a very good question what is the criteria to use it or not so radiopharmaceuticals are actually mandated by the fda just like drugs are although it doesn't really make sense in many ways that's how they are treated so we have to essentially go through the same very long rigorous pathway that that drugs do in that we have to you know get initial regulatory approvals just to even do these scans to to try it and to show that oh there is some benefit as there clearly is and then you have to do more patients and larger studies larger studies to really document then you have to do a ton of safety profiling and all of that and then submit all that to the fda and then they will approve it even then there are many tracers who have gone through that enormously long pathways which can take years but are still not used because then then the next step is that insurance companies have to actually believe in it and approve it for use because especially new tracers are quite expensive just because they're not manufactured regularly so there's a lot of different hurdles but it all boils down to the biology and proving that it actually does work and work better the other answer to your question actually is that fdg while it's not good for everything actually is remarkably well for a lot of different things so if you use that as your benchmark or your standard to try to overcome it's quite a high benchmark yeah okay and then in the last minute or so I just wanted to mention one other thing so that it's not so again that you get the picture that this is not just a small area it's a really really booming area and probably new radiopharmaceuticals just at stanford we have something like 20 or 30 different ones that we're trying now and across the world probably over at least over a hundred another common one that's been looked at quite a bit is things that will help evaluate angiogenesis. Angiogenesis is the development of blood vessels into tumors so if you same same story as glutamate is if you could block that then that would help prevent the growth of the tumor cells but equally if you could image that then you could know you know a patient who has high uptake of glutamate would potentially be a good person to put on a therapy that blocks glutamate a person who has high uptake of an angiogenesis tracer would presumably have good response to an anti angiogenesis agent so this is where it ties into this concept of personalized medicine so that we can do a scan on you identify if you would or would not be a good candidate for something and then as I mentioned follow response at an early time point to see you know just after a few weeks is it working or is it not. So these are some examples of this tracer in this case you have to look a little bit harder in compares into fdg but again you can see that you you can see certain things on on this tracer called fpp rgd2 for angiogenesis that you can't see on the comparative fdg image here's perhaps an even more clear example again from brain cancer of a patient who has does have some abnormality on the fdg scan i wouldn't have called this negative but it's much much easier to see on the angiogenesis tracer but even perhaps more important than that is that this is that patient showing before the chemotherapy with an anti angiogenesis agent called avastin versus after and if again if you look at these suv values they've actually gone down and other patients that we've scanned using the same protocol have not gone down after using avastin for the same amount of time and so what we're finding is that those patients who have a reduction of the angiogenesis with the agent as you would as you would kind of normally think through that means that that's working and that's why you have a reduction in angiogenesis and so they in fact in the outcome studies are doing better and other patients who didn't respond in this way they didn't do as well so that's kind of a big overview of a lot of different imaging modalities and and novel techniques is going to be a lot more to come from from this area and it's really again going to tie into this concept of personalized medicine which is I think great for everyone so thank you very much