 Our next presenter is Dr. Pital Sabir from the University of Arizona at Basin Tucson. She's an associate professor of medicine of radiology and is the section chief of nuclear medicine. Thank you very much. I will try to get the time back so I just do Camino. Okay, there you go. So I will not, first of all, I have a lot of disclosures in oncology. I don't have a disclosure on amyloidosis, so I don't have that slide. This kind of introduction already being told, so I'm not going to cover that, but we all know that it is not coming from sugar like the name. It is actually a precursor protein that's going to create a very stable structure. And depends on where it will be deposited, it will create a variety of diseases. So we're here to really speak about the way to delineate leichen amyloidosis that will come from the bone marrow, from TTR amyloidosis that will come from the liver predominantly. So this is an example of a normal staining and then a congo rates turning. And we all know that back in the days that that would what we do, if there would be already a suspicious like we're still before the elephant in the room, people will go through biopsy. And the goal today is to see how can we minimize that biopsy. So we all are well aware about the bone scan. And this is the bottom line. This is sort of the last chapter of that, the last page on that chapter that in order to delineate LA from TTR amyloidosis, we would basically exclude the monoclonal protein in the body. We will use PYP. If the uptake in the heart is either equal or above that of the bone, it will consider to be grade two or grade three, highly sensitive, highly specific. And also we can quantify it by putting a region of interest above the heart and compare it to the contralateral area if the ratio is above 1.5. This is actually ATTR amyloidosis. So that being said, we have multiple tracers. As you can see PYP, DPD, HMDP and MDP. For those that not doing oncology in the United States, MDP is actually the one that we do. So compared to the study was shown here before about the prevalence of incidental finding of ATTR, it will be really hard to do because we're not actually using routinely any of the other tracers we're using MDP. And PYP is the only tracer here that is FDA approved. That being said, let's start looking at why the guidelines are the way they are. So this is a small study that looked at, in 2005 already, looked at ATTR patient 15, AL patient 10 and then a control group. They did five minutes images, they did delay images at three hours and then they said any cardiac uptake, even if you see the heart a little bit, that would be considered to be positive. And you can definitely see that group A with ATTR was actually significantly higher in uptake than the rest of the groups and the nice thing about it that AL was equal to control and that was the sign that you can actually delineate those two diseases together. Interestingly enough, in this cohort, which is extremely small, there is no grade one. And we'll talk about the grades in a little bit later. And that's where I'm going into the oncology bone scans in the United States, which is MDP. And you can definitely see here that on a patient with ATTR, there is actually positive uptake in the heart. It's so positive that there is almost no uptake in the bones and that would be considered grade three uptake. However, you can see on AL that there is no uptake and what you see there, it's actually the sternum and the spine. And look at the oncology MDP tracer, it's negative on both ATTR and AL. So we don't have enough data, but the data we have on MDP shows that it is inferior and we'll speak about it at the end when we have shortage of PYP. So that being said, a very large study, 1200 patients with positive and negative. And you can see that among them, they had 538 ATTR, 181 AL, and obviously other kinds. And this is a very nice study because some of them had endomyocardial biopsy, the rest of them had either other biopsies or clinical determination of amyloidosis and the subtype of it. And they use, again, DPD, PYP, and HMDP. And you can see that they only did planar and we'll talk about that as well. That being said, they did multiple region under curbs. So the first one they took, the only patient that they actually did biopsy. And I said, we're going to call any little uptake in the heart. Grade one, two, three, we're going to call it positive. We want to call negative for the one that are absolutely negative on bone skin, planar only, again. That being said, now you have sensitivity of 99%, but specificity of 68%. To make it very clear, now we have patients that we think they have amyloidosis or not and we're going to call all of these patients, ATTR, whether it's true positive or false positive, and that's a problem. So they said, okay, let's see what's going on. Among the false positive, they saw that they had tons of patients of Lichen amyloidosis and ApoA1, sorry, amyloidosis. So that being said, let's take the entire cohort. They included all the 1200 patients now and now since specificity in the larger cohort ended up being 86, higher, not enough. So now they went and say, let's see what makes it... Why is it so important to increase the specificity to 100%? Because this is a patient that you may call grade one uptake and now you won't be able to differentiate between AL and ATTR and now those that need chemotherapy will not receive it and now it's a problem. So that being said, they said, okay, let's increase the specificity by going into only calling the one that we biopsy, we know for sure, with the verification of truth that grade two and grade three now would be considered ATTR only. And now they had 91% sensitivity, 87% specificity. Again, not enough. So they started looking at the entire cohort, the same concept now sensitivity decrease because again, you do have some overlap when the cohort is high, but specificity again, 97%. Again, may not be enough. So let's look at the role of the monoclonal study. I'm not going to spend much time. This is on the agenda of today, but what they did, they basically said, let's take all our cohort that we know have AL and then they saw that 99% of the Leichen amyloidosis actually had some kind of monoclonal in their either urine or blood. So when they excluded this population, they actually find that this is where they're going to increase their specificity. The interesting part was they said, you know, out of ATTR amyloidosis in their population, 19% also had detectable monoclonal protein. So you can already understand you're going to compromise your sensitivity. So now when they included all of it, wheat grade 2 and grade 3, specificity became 100%, but look what happened to the sensitivity. But it's okay because before everybody would go to biopsy. Now you can find some subpopulation that you can exclude biopsy because now you know that if they're going through these parameters, they're going to have 100% specificity with positive predictive value of 100% to have ATTR amyloidosis in the best way to delineate the two. So they concluded that the only people that would actually benefit from PYP bone scan would be patient with negative monoclonal need to have, again, you need to think about, like I would say now, use that term, the elephant in the room, and then have positive echo, cardiac MR and grade 2 and grade 3 apoptic scintigraphy. Pay attention that the semi-quantitation is only included here, which is essentially visualization and not the quantitation. So let me show you the quantitation. Extremely small study, but very robust because they had 12 patients of AL and then out of the TTR amyloidosis, they divided them almost equally to the wild type and demutate. They use PYP and basically they did images at one hour, followed by spect, if needed, compared to the protocol today that when you have a spect CT, you do it anyway. And they looked at cardiac retention. They looked to see how it's washing out from the system. And then they actually saw that on the semi-quantitation, they had two patients, again with false positive, that they called ATTR whether they had actually lichen amyloidosis, but they went into the quantitation, they only had one ATTR false negative. So this is where they increase the sensitivity in that cohort to 97% and specificities remain 100%. And you can see the delineation that when you have region of interest on the counts and you have extra counts on the heart and you compare that to the contralateral lung on basically away from the sternum, you can actually see that everything that is 1.5 and above in ratio would be very, very specific for the delineation of TTR from lichen amyloidosis. So a multi-sensual trial, look at multiple, and again you can still see the tracers. We don't have MDP, the oncology tracer that we use here in the United States. So you can see that the variety of studies and again specificity and sensitivities are very high. Again, they didn't certify those studies, whether they use monoclonal search or not, but they did mention that in that paper. So going back into the guidelines that was done by ASNAC and also I took some from up to date, but you guys saw that lines on all of the presentation. So first of all, do you have any clinical features of amyloidosis? If the answer is yes, you have to exclude monoclonal antibody by blood and urine. And if it's yes, you have to understand that you cannot go through the ATTR pathway, the traditional images now. You have to go by hematology referral biopsy because you can actually have either ATTR and Lichen as you saw in the study and you have to go into a different path. If the answer is no, now you can actually perform PYP bone skin. YPYP FDA approval here. We cannot bill for the rest of them. And if there is basically grade two or grade three, now you know it's highly specific for TTR amyloidosis. If it's zero, you're basically going into different approach. Maybe it's early, maybe it's not amyloidosis, but then if it's grade one, it's equivocal and biopsy would be needed anyway. So going into the... I won't go into all the protocols, but this is for you to see if you have an institution that has spec CT. This is what we recommend and I'll explain why. So the finding would be either by semi-quantitation, as you can see here, negative will have absolutely no uptake. Grade one will be uptake that is slightly there, less than the ribs, two equal to the ribs, above the ribs and actually decrease in the bone itself. So the uptake is predominantly in the heart. And then you have the quantitation which you do the circle. There is no really mentioning of the size that you want, but you want to get a good size around the heart. Copy, paste it to the other side. The technologies are doing that for us. And then you want to make sure it doesn't sit on the sternum, obviously, because you're going to have false positive areas. So three options. One, not suggestive when the score is zero or less than 1.5, and then you have strongly suggesting when it's two, three, and above 1.5, anything in between that is equivocal. As an imager, I don't like to give you equivocal data. I will try to do everything I can to say yes, no, and if I say I don't know, I'll tell you why. So let's go over some cases. This is a no-brainer. Across the street you see Grade 3. You don't even need the quantitation. So this is another case. And you can actually see the uptake. You can see where is the most deposit of essentially the calcium. That's what we see here. And there you know there is probably a TTR. This is an interesting case because this is a Grade 0, maybe Grade 1, and you know there is a little bit of uptake there that someone can come and say, you know, I don't know actually to exclude or not, but then when you look at a region of how you have 1.1, that, sorry, that's sort of fluctuating. That being said, now it goes into the equivocal, right? If you look at ASNAC, it's like, what do you do with that? Are you guys going to take him for a biopsy according to the recommendations? So here you go. There is a speck. There is still some uptake there, right? But there is another problem. How do you exclude? So this is where the speck CT is extremely important because when you fuse them together, you just see that this is in fact blood pool uptake. Those people may have more stasis in their blood. It's going to take a long time to completely excrete the tracer. The uptake isn't the blood pool. It's going to run along the myocardium, and therefore this should not be called equivocal. It should come and say in the report, not suggestive of cardiac amyloidosis, ATTR amyloidosis. Another grade one and another example of 1.1 and another, essentially you can see speck only that there is uptake predominantly in the blood pool, but obviously your confidence is increasing when you fuse it to a CT image. And for those that understand you can see that I really blacked out that image to be able to show the blood pool because look at the ribs and look at the spine how intense it is. So I just try to show it. But that in a non-expert eyes may go into the equivocal and that may actually send you to a different workup protocol. So another thing, this is actually minimally positive. So this is an interesting case that I just came across not too long ago. If you look at that you can definitely say grade two. It's there, there is uptake, you can't argue with that. But then when you look at the uptake and the ratio it's 1.4, it doesn't reach the threshold. Is that one of the false negative that that study showed? Maybe. But the problem is that if you look at the uptake on the upper picture you have there you see that it's predominantly in the blood pool. But then when you look at other cross-section you see that there is some uptake in the lateral wall in the basal aspect. And then you don't really know what to do with that because according to the recommendation this is highly suggestive. According to quantitation it's a so-so. And also the spectcity doesn't show much of uptake where it's supposed to be and therefore this would have to go into the other way of workup because this is not as specific and that will be on the discrete of the referring physician. So the challenges, we know that we have again and again shortage of PYP. It's hard to get it, we don't have enough kits and we need to sort of fight for it. And then I always get the question can I use the outer bone scan and the answer for that question is probably not because data is not supporting it. Now if it would be positive it's probably very positive but if it's negative it's probably not sensitive Another thing, as mentioned again and again there is lack of knowledge among physicians. We don't get enough of this compared to what we see. And if we get them I have no clinical history to know what I'm looking at because nobody told me what happened so far so I'll know if I'm looking at the correct workflow of what I see because positive bone scan can also be shown sometimes on Leichen amyloidosis. As you could see great overlapping and as I said outreach is extremely important. So I don't have time to speak and I'm really going to give a tip of the iceberg but we do have amyloidosis beta sheet proteins that are specific for those proteins on the PET CT side compared to the bone scan and it's mainly for TTR because we are tracing the calcium extracellular calcium deposit here we have a specific tracer that goes into this beta amyloid. So those are the three approved tracers that you can see and when you look at the data this is an example of a non-FDA approved but this is the C11 Pittsburgh B compound that you can actually see that there is correlation between mortality, prognosis and the increased uptake the quantitation, the SUV max of the PET. That being said this is very promising and that probably holds true for other tracers this is the tracer that you are all familiar with and you can see that Li-Chen it will show uptake and ATTR and non-cardiac negative group will show washout and it seems to be that the future goes into combination of both to predict some AL and delineated from ATTR. Not very cheap method though not cheap at all. With that I will say thank you very much and I would be happy to join the panel later. Thank you.