 Hello, good morning. Terry asked me to briefly mention some of the tumors that we discussed in June and speak only about one, although in the small group sessions we may speak about all of them. Always show my favorite slide, that we're a little slow, 4,600 years old. And in June, what I spoke about with Mark was MSI analysis and mismatch repair protein, even though his took chemistry for systematic screening of LYNS syndrome in all resected colorectal cancers on our main campus. And the uptake is exceedingly good, at least 80% make it to genetics clinics. We also spoke about a slower implementation of the same types of analysis for LYNS syndrome screening for all endometrial cancers, because it is a component. The uptake's a little less 64%. And there are challenges, including, unlike colon, many different pathology labs doing it. This will probably be solved when everything will be sent into our central lab. We also discussed the integration of genetic countsness in now over 25 non-genetic specialty clinics on our main campus and the regional practice. And a prototype of a family-enter cancer family history tool. Today, Kate Nathanson from Penn and I are gonna speak about routine screening for heritable neuroendocrine tumors. And we will look at fulcrum acytoma. We could have picked medullary thyroid cancer, but this one's slightly more exciting, as our prototype. So fuels come from the adrenal medulla, and that means they're from neurocrest. So neuroendocrine tumors in general come from neurocrest. This one, in particular, can secrete catecholamines, and I don't think I have to tell this group that if it's not recognized, bad things happen. This is just a picture, an MRI, to show those who don't quite know where the adrenals are. And that's an axial view, and that's the big purple arrow. Now periganglia can be anywhere, so they're along the periganglia chain and can be sympathetic or parasympathetic. So this one happens to be in the thorax. Now we learned in med school the famous 10% rule. 10% are genetic or heritable, 10% are bilateral, 10% are malignant. Now we thought this was gospel until we started, meaning the world of we started looking into it and the first genes appeared, and does it really matter? Well, so much for the 10% rule, so let me tell you. To fast forward, a lot of work, probably over the last 10 to 15 years, many consortia, and we have a population-based registry, show that up to 30%, sometimes more of all fields and periganglia presentations have a genetic etiology, and those are some, but not all of the known genes. So many genes, neuroendocrine tumors. So in theory, this is the ideal when you go through a germline mutation analysis. I've added in all the genes, they're actually 10. I didn't even put NF1 because we have found that in the presence of, that NF1 fields do not present unless they have physical stick length of which hopefully we can actually recognize. And every gene has other features, other tumors, or different presentations. For example, let's say SDHB. There is a high malignancy rate depending who you believe between 14 and 30%, whereas in some of the other malignancies rarely ever seen. For rat, you have to worry about medullary thyroid cancer, and so on and so forth, VHL, renal tumors. SDHB and D, they are renal tumors. So it does affect management. Well, what have we done? We have admitted genetic counselors in endocrinology and endocrine surgery clinics. In the literature, so that's all we've done, PEN has PEN NETs with a little bit more systematic. In the literature, SDHB immunohesity chemistry is said to be able to pick up those with germline SDHB, C, and D mutations, but not in the other syndromes that I showed you. A recent paper also showed this might be true for SDHA. This is routinely implemented at PEN NET, and Kate tells me that their uptake is very, very good. However, our clinical pathologists, why not slouches, get very inconsistent results. So if you ask them to read SDHB staining, it's all over the place. It's not correlated with any germline mutation. When we do Western blots and I give it to my lab to read it blindly, it can't predict presence of Epsom, but this needs to be worked out. It looks like a very reasonable screening tool. And so with that, I will start well within my time. Eight minutes. Nope, we speak on each and every half. Please add in. Can you increase it from 60% to 95%? So we're, this is actually inherited mutations. Right. So we have not gone back and re-sequenced the tumor. There are actually several issues about them. I'm sorry, there's several, Karis can talk about what her experience is. So this is actually something that we're in the process of doing. We've actually got funding to do this, but the PGLs actually tend to get embolized before they get removed, so that it can be very difficult to actually get decent tissue out to do them. And then the Pheos obviously can be relatively small or problematic, but actually, at least at Penn, we're in the process of collecting fresh frozen tissue. There are some studies, Karis may talk about that, that have shown these mutations in otherwise barat, somatic mutations in otherwise germline, negative patients. Correct. All of them, I'm not sure. I guess your question is, can we use somatic sequencing to enhance the positively in the germline? One of it's obviously technical issues, and we have that too. And poking Pheos with a fine needle, of course it's not a good idea, if surgeons hate that. We also worry about somatic mutations, although I have to admit, we have looked at that with my collaborator, Hunmut Neumann, and the somatic mutation frequency, meaning truly a second somatic hit, is variable, so it could infect fool, as is the somatic or germline. This is also a complicated area, just to point out, because the issue of some of these mutations are imprinted, and nobody's actually been ever been able to figure out what the imprinted tissue is. So they clearly only affects its ability when inherited from the father, but no one's determined what the tissue is that's infecting that. And so it's a complicated sort of somatic issue. And that's SDHD, especially. And AIC, because they are in the same imprinting, and that's a very neat little paper in HMG. So can I ask both of you to maybe describe, and I should have asked this and we'll ask it of all the speakers in this session, could you describe what the collaborative opportunities might be for those around the table and in the room, in terms of maybe expanding or building on your work? Yeah, so Kate and I, Matt, Kalki and the father have started talking offline before this, so we thought that we need to bring it to a group because these are not exactly common tumors. We talk as broadly as forming a net net N-A-T-N-E-T, for things like this are the quick rapid screens, like screening for germline syndromes, studying the uptake all the way, all the way to treatment consortia, because this has been an amazing field from nobody cared about it, to we know all these molecular pathways and lots of pathway directed therapy coming up, and might I say for people with germline disease, we really should be thinking of prevention. And I think actually there are a lot of concoctions, Matt, Murray and I actually also as part of this and put together a group to A-C-M-G to develop genetic testing guidelines for these patients, there are no published genetic testing guidelines, there are no surveillance guidelines for patients at risk, and actually one of the issues that we run into, and I'm sure both of you run into, is how do you manage these patients after the diagnosis, should it be the same for the different mutations? So I think there are a lot of opportunities to develop sort of best practice guidelines here in many different venues, and I think what Karris is emphasizing is also multi-institutional targeted therapy trials for patients with metastatic disease, particularly as many of them have inherited mutations. The other thing that I just mentioned that directly raises the surveillance piece is that Josh Schiffman at Primary Children's Hospital in the Huntsman Cancer Institute has in fact instituted a surveillance protocol, particularly for the Paragane Leoma families, and preliminary results are very encouraging that in fact there's a high degree of preventability, which is another one of those gospel axioms that you can't do anything about it that appears to be about to get an X through it. So I think that that would be definitely something that needs to be considered in the overall consortium approach, and would be a likely collaborative. I agree, and that's something that Karris and I have certainly talked about, and I think the other thing that I know Josh has done is the issue of implementation of rapid full body MR as a screening toll for patients with these diseases. And that's actually something that is very hard to get paid for because of the CPT codes, and something that's actually much quicker, much less, shall we say, invasive, and should be, is in fact cheaper than with the standard screening that we employ. And so I think there are a lot of venues to really translate this and different avenues which larger groups are needed to be able to move this forward. And of course, underlying all this is rarely said, is that we would like to study the cost, true cost effectiveness as well. Something you guys are very, very good at.