Please welcome to the main stage, Dr. Oksana Hamidi. ♪ Good morning, everyone. Welcome to the last day of ACE 2022. My name is Oksana Hamidi, and I'm an assistant professor and adrenal endocrinologist at the University of Texas Southwestern Medical Center in Dallas, Texas. It's my absolute pleasure and privilege to present to you today's speaker. Dr. Patak doesn't really need an introduction, so that makes my job quite easy. So I'll keep it brief. So Dr. Patak is a tenured chief of the section of medical neuroendocrinology at the National Institutes of Health. He is recognized nationally and internationally for establishing a patient-oriented pheochromocytoma and periganglioma research program at the NIH. His laboratory has accumulated major findings in the field of pheochromocytoma and periganglioma. He has over 500 publications, and some of them are cited over 1,000 times. He's a strong advocate for patients and their families and has established an international symposium on pheochromocytoma, which is a series of conferences on major scientific and clinical updates in the field. Dr. Patak has received numerous awards for his clinical and scientific work, and I would like to congratulate Dr. Patak for being a recipient of the Science and Distinction Endocrinology Award at ACE 2022. So you knew all that. What you did not know about Dr. Patak is actually what he likes outside of medicine. He loves antique shows and antique in general, and he also loves epic music. Without further delay, I would like to welcome Dr. Patak on the stage, and we look forward to hearing his presentation on new biology of pheochromocytoma. Thank you. Thank you. Thank you. Ladies and gentlemen, good morning. First of all, it's really a great pleasure and honor to be here today, and I would like to thank the American Association of Clinical Endocrinologists for the invitation, as well as the Program Committee, Nominating Committee, as well as PGAN, the Disease State Network, for having me here today. I also would like to thank Oksana for a very nice and very kind introduction, and as you heard, I will talk a little bit about the pheochromocytoma and paraganglioma, which is my favorite topic. I wanted to say that the results I'm going to present today came not only from NIH, but also those results came as well from other scientists outside, for example, NIH in the U.S., as well as outside the U.S., and we would not have those results. It would not be very good participation of many patients. As you know, the title of my talk is New Biology of Pheochromocytoma. I have no relevant financial relation to disclose, and when we talk about the pheochromocytoma and paragangliomas, I have to say that those are neuroendocrine tumors that synthesize, metabolize, and release catecholamines, as well as their metabolites. When we talk about the incidence, the incidence increase for these tumors, and it's about eight cases per one million per year, and doubled approximately from 1995 to 2015. Of course, you know, somebody would say how it is possible. Of course, you know, we have a better CT and MRI, as well as functional imaging, but there is also something that we feel that actually the number of these tumors is increasing, and we are working actually on these causes. When we talk about the pheochromocytoma, everybody knows that those tumors are actually sitting in the adrenal gland, and everything that is outside the adrenal gland is called paraganglioma. And then we have some interesting paragangliomas that are actually located in the head and neck. We call them head and neck paragangliomas. And as you may know, those tumors are usually benign, and they hardly metastasize. The current biochemical diagnosis of these tumors is actually based on the measurements of catecholamine metabolites, and we talk about the metanephrines, as well as metoxythiramine. Either in plasma or urine, and I will talk about it, what is actually going on, because, you know, the audience is, especially for the practicing endocrinologists and other practicing healthcare professionals, so I will give you a little bit more towards, you know, the diagnosis and how we work with these patients, rather than to go into a very complicated scenario about transcriptomic proteomics and other aspects of pheochromocytoma paraganglioma. These tumors are growing, you know, very actually slowly. The doubling time is approximately five to seven years. And when we look at the pheochromocytoma paraganglioma, it's a very strong hereditary component. It's expected to be approximately 35%, with the new genes that was discovered, and I will tell you something about the new genes. It would be approximately 38%, and the same number would be for somatic mutation. So there is a very important genetic component for pheochromocytoma and paraganglioma. And now all the pheochromocytoma and paraganglioma are considered to have the metastatic potential, which is definitely very interesting, because we are not anymore talking about pheochromocytoma, like having, you know, patients having benign tumors. So please remove it, you know, when you talk with the patients. You know, we don't have something like benign pheochromocytoma. The pheochromocytoma can become actually malignant even after 10, 15, 20 years, and unfortunately there is no cure for a metastatic disease. When we talk about the pheochromocytoma, paraganglioma, we know the catecholamine concentration in these tumors are extremely high, and that can be released actually any time, and creating, you know, some, I put like, you know, the volcano, and that can erupt any time. We talk about, for example, the storms, attacks, and spells. But the new studies are showing, and this is really very new studies that came up actually a few weeks ago, that paroxysmal hypertension palpitation as well as diaphoresis are characteristic of pheochromocytoma. It's not sustained hypertension. It's not, for example, tachyarrhythmia and other symptoms and signs, but these are the most important right now based on large number of patients. Of course, somebody mentioned yesterday about, you know, the weight loss. I think the weight loss is very interesting. Maybe we will add weight loss, you know, to patients with pheochromocytoma paraganglioma, but more studies are actually needed because we are not absolutely sure how everything works because, as you know, if you have increased catecholamines, you are actually presenting with the constipation. But the weight loss may be related, for example, to metastatic disease. So even if pheochromocytoma paraganglioma do not continuously secrete catecholamines, they store a lot of catecholamines in storage vesicles, and they can be released any time, especially if there is, for example, some physical or psychological stress or tumor manipulation. Thus, most pheochromocytomas and paragangliomas need to be treated in certain way because they are producing norepinephrine and epinephrine. So the patient needs to be on the blockade, and we put the patients on, for example, alpha blockade. And if they have, for example, tachycardia, they have to be put on the beta blockade. What is important, the patient needs to be put on the blockade not only if they go to surgery. That is obvious, although there are some articles, they are not absolutely in favor of that, but the patient, they have to be put on the blockade at the initial diagnosis of pheochromocytoma. I don't want to go into that, but at least the U.S. law and everything, you know, when you are responsible for the patient, from the beginning, when you diagnose pheochromocytoma, paraganglioma, you have to do something with the patient if you have, for example, metanephrine or catecholamine secreting tumors. We talk about the cardiovascular events and mortality. This is the cause of death approximately in 70% of patients. 20% of patients are presenting with tachyarrhythmia, and approximately 90-95% are presenting with hypertension, whether it's episodic or sustained hypertension. I put the pie chart of what they are presenting with, especially supraventricular tachycardia. This is typical because they are presenting with sustained hypertension, sustained tachycardia. This is the most important for the patient with elevated catecholamines. Therefore, outpatient management for these patients is definitely important. I would say this is very critical. If you look at the receptors, for example, if you have alpha-adrenergic receptors, and those receptors are affecting these catecholamines, of course it leads to hypertension. But if you look at the, for example, heart, we have some options how to treat with tachycardia. It can be really complicated. We usually use the beta-blockers. I very often use those beta-blockers. They are specific for the heart, for the beta-1 adrenergic receptors, for example, atenolol or metoprolol. I'm not using propranolol because propranolol is also affecting, for example, the brain. We are using calcium channel blockers. But there are some patients that are presenting with very complicated, difficult situation. For example, if you treat them with chemotherapy, if you treat them with radiotherapy, sometimes they can have a very high increase in catecholamines. And those patients can present, for example, with the aseptic myocarditis and other problems. And you cannot manage them with, for example, calcium channel blockers, alpha-blockers, even if they are in the intensive care unit. So we came with the new concept, and I don't want to go so much into this new concept, but using, for example, medication which is called ivabredine that is affecting the HCN channel. And I can tell you, honestly, we have several patients. We treated them at the ICU, especially those that they have a problem with tachycardia and failing heart. And this medication is really working very well because it's affecting the sinoatrial node. And, of course, there is something which blocks catecholamine synthesis, which is very good. It's called DEMSR, and it decreases, actually, the amount of catecholamines. The problem with DEMSR, it's available in the United States. It's not so much available in Europe. But the cost of the DEMSR is a little bit high. So for the patients that they have a problem with insurance, it can be actually difficult to get DEMSR. And then you look at the biochemical diagnosis. In about the 90s, we improved, actually, understanding how we look at the catecholamines and the metabolites. And approximately in 2000, together with the other scientists, and especially I have to give credit to Dr. Eisenhofer, Dr. Landers, and others, we actually put a better understanding how actually catecholamines are metabolized into the methanephrines and started using methanephrines, especially in the plasma. So when we developed the test for the measurement of plasma methanephrines and introduced it to everybody, so I think that that definitely improved the diagnosis. In 2011, we came up with the methoxytyramine, which is very good, and especially in some patients with hereditary pheochromocytoma and paraganglioma. Graham Eisenhofer, Dr. Landers just introduced, and it was approximately 2018, how to measure free methanephrines in urine. Because before we talk about the fractionated, and because fractionated means that you need to do the deconjugation to convert them into the free, just now we can measure actually free methanephrines in urine. But what is important is that we are going further actually, and this is especially related to metabolomics and metabologenomics. I wanted to show here, for example, some of these tumors are related to the Krebs cycle because there are some genes, at least eight genes, that are actually relevant to pathogenesis, pheochromocytoma, paraganglioma, and we can measure actually those metabolites, and those metabolites are very important. Just now we measured about eight metabolites, and the ratio of those metabolites can predict what the patients have. For example, if they have, for example, a pathogenic mutation, because you know that many mutations are coming as a BUS, which means variant unknown significance, and those metabolites are very important. And you will hear about it in the future, I promise you that we will actually look at the urine, we will look at the plasma, and from the metabolomics we will be able actually to see what is going on with these tumors. And from Dr. Gayi, there is some interesting study looking at SDHB, which means succinate dehydrogenase sapunate B, pheochromocytomas, paragangliomas, and they look at the polyamine pathway and our expression, why it's important, because they found actually that the signaling pathway that can be affected actually with some drugs and it can be promising. So metabolomics are not only promising related to genetics, but also to future therapeutic options. And I will talk also about the microenvironment, but at the end of my talk. So when we talk about, you know, the catecholamines, as you know that they are metabolized to methanephrines, or methoxytyramine, that is the enzyme which is called catecholamethyltransferase, and I mentioned something about methoxytyramine, which is very important, because it's important for SDHX, you know, succinate dehydrogenase gene mutation, especially for SDHB. So why we are actually preferring the methanephrines over the catecholamines, because the importance is that only about 70% of your chromocytomas, paragangliomas, actually release catecholamines from their storage, and approximately, you know, 70% of those catecholamines, they are released from the storage into cytoplasm, they are metabolized by catecholamethyltransferase. So you will never see patients with elevated catecholamines, but practically everybody will have elevated methanephrines. Also, what is important, that the catecholamines are released episodically, but the methanephrines are released continuously, which is a very important advantage of methanephrines, so you don't have to have the patients during the spells or during the certain situation. So today, we abandon, actually, measurement of catecholamines. Of course, at the NIH, because we are a clinical research institution, we are measuring catecholamines, but to be honest with you, you don't have to measure catecholamines. You can only and only measure methanephrines. About, you know, the mass spec, and how we actually approach those catecholamines and methanephrines, as well as methoxytyramine, what is better? You know, should we measure everything in the plasma? Should we measure in the urine? If you look at the specificity, it's practically the same, but the sensitivity is slightly higher for the plasma. So if you have a choice, of course, I would suggest to measure plasma methanephrines, but there is no problem if you use, for example, urine metabolites. That would not be a problem except for methoxytyramine, but I will mention it later on. So there is no consensus, as I said, you know, whether to measure plasma or urine metabolites, but what is important is everything that is two times above the upper reference limit. And I had some talks, and maybe for some of you, you know, in the past I always say three times above the upper reference limit, but we are doing better because we are using mass spec and everything, and there is no interference with some, for example, drugs, so it's about two times above the upper reference limit, and it's worrisome. And this is interesting, pre- and post-test probability, how actually those metabolites can actually help you. For example, if you have a patient with hypertension or with some symptoms and signs that could be suggested for catecholamine access, there is usually a low likelihood that the patient may have, actually, the pheochromocytoma or paraganglioma. And if you look at, you know, how the metabolites are elevated, if it is only one time above the upper reference limit, you can actually see that that would be approximately the chance to have, you know, pheoparaganglioma 10%. But if they are two times above the upper reference limit, the chance is approximately 80%. The other scenario is that there is pre-test probability having pheochromocytoma paraganglioma high. For example, somebody has an incidentaloma, and the probability is approximately five to seven percent. And of course, that makes a little bit, you know, different scenario, because if these, the metanephrines or metoxythiramine is elevated to one time above the upper reference limit, it's already 50% chance the patient will have pheo-paraganglioma, but if it is two times above the upper reference limit, it's almost 100%. It really depends on the scenario. So, these and other results strongly support that plasma metanephrines and metoxythiramine can be or can do better, especially in those patient than when you have, you know, high likelihood to have the pheochromocytoma or paraganglioma. Of course, you know, some results are in the gray zone, between the upper reference limit and two times above the upper reference limit, and of course, you know, the gray zone is coming if you have a patient, for example, on some medication. Sometimes you can stop medication, sometimes you cannot stop the medication, but let's say you will be able to stop the medication, then you can do, for example, clonidine suppression test, or even if you cannot stop the medication, it's except for actually antidepressants. You will never do clonidine suppression test if the patient is on antidepressant. I will not go into the details, because the pathophysiology is very complicated, but you will do, you know, the clonidine suppression test, and you can see that the sensitivity is specificity, but the first time when we introduced the modified clonidine suppression test, it was, I think, 2011, 2012, you know, we actually working with patients, and they had, you know, quite high elevation of plasmamethanephrines. Just now, we know that they are age-related upper reference limit. You should know about those, because they will be very important, especially for pediatric endocrinologists. Now, for those endocrinologists working, you know, with, for example, younger patients, and it's related to normetanephrine. It's not related to metoxythiramine or the metanephrine, and there is new study that was published just now, you know, maybe two weeks ago and three weeks ago, that newly published data shows that age-related cutoff improves, actually, diagnostic accuracy, and the sensitivity is 94%. The specificity stays the same. It's approximately 97%, and it's very important, because it's for the patient that have a slightly elevated metanephrines, okay? It's not for those patient that you know, a priori, that they may have your chromocytoma and paraganglioma, so keep it in mind that something like that exists. And so, what is new, actually, that we talk about to, about metanephrines to fault above the upper reference limit. They are also age-related upper reference limit. We talk about that, the introduction of urinary-free metanephrines, and remember, the measurement of urinary dopamine and metoxythiramine is useless, absolutely useless, you know, for the diagnosis of your chromocytoma paraganglioma. And you look at the genetics, what we knew at the beginning, in the 90s, pretty much, not so much, about a few genes, right now, as you see, there are many, many genes, and we have approximately 25 genes that are related to pathogenesis of these tumors. And we have several clusters, and we identify, it was actually multi-institutional study in 2017, three clusters, but really, from these three clusters, two clusters are main, you know, so one is related to Krebs cycle, and one is related to kinase signaling, Krebs cycle number one, kinase signaling number, actually, two. There is also a new gene, just now, when we discover, you know, at the NIH, we published a few months ago, SSUCLG2, that converts, actually, succinyl coenzyme A to succinate, is again, you know, in the Krebs cycle. It's a very interesting gene, because it's the one that actually leads to generation of GTP in the Krebs cycle. I will not go into details, but I will tell you that this is interesting, how nature is working, because, you know, it's in the Krebs cycle. Everything that is in Krebs cycle is worrisome, and this gene, also, is worrisome, because, you know, those patients, as you see, are presenting, you know, with metastatic disease. They have a typical noradrenergic phenotype. Everything that is in the Krebs cycle is noradrenergic. Everything that is in kinase signaling is adrenergic, okay? And so, and this is very nicely fit, actually, with the cluster, cluster one. So, when we are talking about cluster one, it's cluster one and cluster one A, and one B, one A is Krebs cycle. Now, representing Krebs cycle, one B representing hypoxia signaling pathway. So, what is important is, actually, tumors are extra adrenal. They have, as I said, noradrenergic biochemical phenotype, or mixed phenotype, with noradrenergic and dopaminergic. They are highly metastatic aggressive. There are some new data, few weeks ago, published, especially, you know, from Australian and from some other colleagues, that, for example, if the patient have a SDHA, they have a high, actually, likelihood to get metastatic. This is about 70%. I always say A as an awful, you know, the B as a bad, because, you know, bad is approximately 40%, before we said, you know, the SDHB is the worst one. I am telling you, it's not the worst one. SDHA is the worst one. But the good thing is, for SDHA, that there is low penetrance, because almost non-existing. I never had two family members that would have, actually, SDHA, and feel chromocytoma, compared to, for example, SDHB and D and C. It's approximately 20%. The surveillance is very important from Australian colleagues. The paper came just now, a few weeks ago. Surveillance, surveillance, surveillance. I can guarantee you, if you get the tumor early enough, we can treat those patients, and we can help them. If we don't get those patients, you know, early enough, it can be problematic, and it can be, actually, disaster for the patients. So just remember that, especially if you have, for example, careers, if you know something that the patient has, for example, family history of those genes, especially related to cluster one, fewer chromocytomas, paragangliomas. So what is new in genetics? Hereditary, I told you, 35%. Somatic mutation, 40%. With the new gene, it would be 80%. So we are there, you know? So it's 80%, which is, it is huge, huge, huge. So we are moving, or I predict we will be moving to measure all the genes in the tumor first, and go to blood, versus we are measuring blood, and going sometimes, you know, to the tumor in the future. The life penetrance for SDHB is very high. It's about 40, 45%, compared to what I told you about SDHA, which is non-existing, almost. And males are doing worse, you know, than females, which is interesting. Primary SDHB, fewer chromocytoma, four centimeter, is associated with metastatic disease. I would say about 3.5 centimeter, but I go through what was published just now, recently, because I promised that that would be update of what is new in fewer chromocytoma, paraganglioma, but I stick with our, all the data, that it's approximately 3 to 3.5 centimeter. And SDHB-related kidney cancer, to some of you, when I gave, for example, grand rounds, I always say between 10 to 14%. There is new study, very good study, that is showing it's only 2.5%, which is definitely great. And children are doing much better than adult, in terms of survival, if they have SDHB, including metastatic disease. The last one is about neurofibromatosis, which is cluster two. Now, before, we saw that, you know, they are related to metastatic disease in 2 to 5%, and just now, it's approximately 7, 7.3%. So, what is new, actually, in genetics? We talk about the successibility genes, I can skip it. All patients with identified predisposing mutation, or hereditary syndrome, should receive, of course, you know, surveillance, we talk about it. There are some guidelines about the SDHA, no, I mean, SDHX, and that should start, you know, for the patient between age six to 10, and that would be for the SDHB, and between 10 to 15 for SDHA and CND. And they should have, actually, annual follow-up, and usually, I suggest the imaging every two to three years. VHL should start at the age four to five years, and followed by annual metanephrine measurements, and then, if they would be positive, then to go to imaging. It's a little bit different from SDHX, and neurofibromatosis should start between also age four to five, and follow with metanephrine measurement, but here, you know, every three years. About, you know, overall metastatic disease, you know, if we take the cluster one, and we talk about the cluster one, if I take all of them, including hypoxia, signaling pathway, it would be approximately, you know, the metastatic disease into 20 to 30%, but for the cluster two, kinase signaling between two and seven percent. So there are some new data that suggest, you know, the patient can go to metastatic disease, so what is related to metastatic disease is, of course, we talk about SDHB, and just newly, SDHA, high norepinephrine, and dopamine, and, of course, survival demonstrated a combination with the age and metastasis, so, and we actually talk about it, or I mention something, but if I put all the risk factors together, you know, elevated succinate, because succinate is oncometabolite or fumarate, and we talk about the mutations, we talk about the biochemical phenotype, I think that the size matter, and I stay behind that, because my 20 or over 20 experience working with these tumors, I can tell you, if you actually miss the size of the tumor, you know, regardless whether the patient has this and that, you know, those patients will go into, actually, complicated situation, they develop metastatic disease. Whether, you know, there is mechanistic theory of cancer, you know, that was introduced many, many years ago, which I still believe it, you know, because those tumors are shedding a lot of cells, or maybe, you know, some other mutations that are actually occurring, we don't know, but definitely size matters. There are also some other risk factors, like ATRX or telomerase, you know, so I will not go into that, but, you know, if you find, you know, or pathologists will call you that this, in the tumor they found, you know, the mutation, ATRX mutation, which is definitely very, very worrisome, because those patients are not doing very well. This is the new study showing, you know, what is actually related to risk factors for pheochromocytoma, paraganglioma. We went through everything, but I wanted to say, and it was also published maybe about two weeks ago, or one week ago, about the metoxythiramine, if metoxythiramine is elevated at least, you know, one time above the upper reference limit, because the upper reference limit is about 20, 22, it depends, you know, which lab, and it's here, you know, it's 45, you know that the patient is actually in complicated scenario. So when we have metoxythiramine elevated with everything, you know, it's not the definitely good scenario. And, you know, we also put together something about, you know, the adipose tissue, brown adipose tissue, and I see patients with metastatic disease, or even, you know, with the pheochromocytoma, paraganglioma, that's a huge, you know, with activation of brown adipose tissue, those patients are usually not doing very well. So it's something that a priori, I know those patients will be problematic and difficult. Then we look at the imaging signatures, you know, so we are using just now the DOTATATE, and you heard about the DOTATATE, you know, quite a lot, and it's very interesting, actually, using, you know, new functional imaging. But we will be moving to alpha emitters as well, because there are many patients that they have bone metastatic lesions, whether it's, for example, Xofigo, because approximately 80, 90% of those patients, they have bone lesions, and bone lesions will be very nicely actually affected by, or treated by Xofigo. We have also the astatine DOTATATE that is sort of maybe promising for those that are failing, for example, DOTATATE. We will be using, you know, those, the other options, you know, using, for example, alpha emitters. So the imaging concept, you know, I don't have to go through that, because it's, of course, the obvious, you know, coming from anatomic imaging to functional imaging. But what is important for functional imaging that we can touch the tumors from this stance. It's like in vivo histology. You don't have actually to do anything with the tumors, you don't do, like, you know, the biopsy, anything, and you still know about those tumors quite a lot. You have to find, you know, very good radiopharmaceuticals, and I put, you know, some examples, like about proliferation, mitochondrial dysfunction, which is hot topic just now, angiogenesis apoptosis. We can measure already hypoxia, which is very important, because, you know, for example, when you treat a tumor, you always go where the hypoxia is the highest. You know, so, and it's very important, you know, where to actually, or which part of the tumor to remove, but I don't have a time, actually, to go into details. And of course, you know, Pheo was born to be imaged, because there are some specific transporters, as well as very interesting receptors. For example, norepinephrine transporter system, which is, you know, pretty obvious to you, because you know about the MIBG, and you can use it not only for the imaging, but also for the therapy, because it's like paired. They have the same target. They work like sister and brother, and it's very, actually, very useful. And the same is, for example, for dotatate, where they use the gallium dotatate scan, or whether you are using, for example, the lutetium for the treatment. So, we are coming to the concept of theranostics. Everybody knows about theranostics, you know, put together, you know, the diagnostics and therapeutics, and it was actually introduced by John Farnam-Counsel to combine, actually, diagnostic and therapeutic approaches, and I think it's wonderful, wonderful approach. So, sometimes you are hearing, or at your hospitals, you are not only using gallium dotatate, you are using copper dotatate, you know? So, without, actually, discussion with endocrinologists and other healthcare professionals, at least, you know, my experience when I talk, you know, with several endocrinologists from different hospitals, and everybody is confused by what is going on. I can tell you, just preliminary data shows that it's pretty much the same, but there are some little bit differences. Both, they are actually approved by FDA, but, you know, the path length, you know, is, for the positrons, it's a little bit better for the dotatate, versus, you know, copper dotatate, but the copper dotatate has better half-life. Why it's important for the half-life? Because you can do the dosimetry. So, what is actually, in the future, what we have to look at, you know, to measure the dosimetry, and to see, you know, how much, actually, the patient can get, in terms of therapeutic options. So, if what is new, actually, here in the imaging, so, I only just wanted to say that the dotatate would be definitely used, you know, for cluster one. Tumors, if they cannot be used, the fluorodopa will be, you know, second option. For metastatic disease, it's definitely the dotatate. For a patient with head and neck paraganglioma, also the dotatate. And for the patient with sporadic pheochromocytoma, we released this study just, you know, a few weeks ago, it's definitely, you know, the dopa, it's not dotatate. You know, it's definitely dopa. But, of course, dopa is not so much available, but overall, if I put together everything, dotatate is still the winner, you know, compared, you know, to other function imaging approaches. And when we are actually treating the patients, you know, whether we are using Azedra, or, for example, Lutathera, you can see when we are using Lutathera, the dotatate, is, you know, the stabilization of the disease. So response is about 90%, when we look at the Azedra, it's 90% as well. So how we are actually approaching the patients, we released this paper approximately four months ago, four, five months ago. And, you know, if they have actually, the problem is coming if the imaging are the same. You know, all, you know, MIBG as well as dotatate, everything is the same, all the same number of regions. You look at the patient. If the patient has very good bone marrow, and the patient is younger, I would go with the Azedra. If the patient has, you know, the bone marrow that is affected, or older patients, I would go more to Lutathera. You have to think about it before you send the patient, you know, somewhere, because you are actually deciding about, you know, the patient's life. So, about, you know, what is new, you know, so after Lutathera, we see some increasing in catecholamines. There are some endocrine abnormalities about two-thirds of patients. We think that you can use the concomitant use of the colsomatostatin analog with the PRRT. I am not in favor to use the PRRT. Patient is, for example, failing, you know, and you give the patient chemotherapy, don't do it. And if you do it, you have to have at least two, three months or maybe more, because the patients will go into very complicated scenario with bone marrow suppression. And KI-67 is very important. A priori, high KI-67 will move you into a category that the patient may not respond very well. We have the program just now at ENIH, so having the patients treated with some underclinical trials. The one of this clinical trial is Belzotifan, when we actually discovered the HIF-2-alpha mutation some years ago, and I would say how the HIF-2-alpha mutation is participating in pathogenesis of these tumors. I think that definitely contributed to the trial with the Belzotifan, that is worthwhile trial. I think that that will be very good, not only for pheoparaganglioma, you have renal cell carcinoma, you have gist, and you have, for example, neuroendocrine tumors, that that would be good, but also something that is related to HIF-2-alpha. For example, I show you here some retinal changes. They are coming in patients with a certain type of syndrome. We will have also, or we are open, temozolomide, temozolomide with olaparib. I don't have a time to go into the details, but it's new to clinical trial that is especially for patient with SDHX, because those patients are creating a lot of NAD, and the NAD actually is feeding so-called PARP, and PARP is repairing DNA, so you have to have something to counteract and use, for example, olaparib. And then we have Lutathera using, and this is the first trial ever worldwide, that is looking at the patient with progressive disease. Not only the patient with metastatic disease, they have a stable disease, but metastatic disease that is progressing. What is actually happening? The data are actually very promising. And what is the future? We will look at the immunotherapy, microenvironment. We will look at, of course, some single-cell sequencing, metabologenomics. I mentioned something. We will look at the new cell membrane targets that would be actually very important, and of course, artificial intelligence. And my last slide is about the immunotherapy. I am big believer, different type of immunotherapy. Please, this is my personal view. Systemic immunotherapy is wonderful, and what was discovered is absolutely phenomenal, but it's sometimes actually failing. And you know, it's approximately 20, 15% of patients are treated well. Intratumoral therapy is very good because actually put together the innate immunity and adaptive immunity together, and we develop the new, actually, approach and new, I would say, cocktail, which is called MBTA. I don't have a time to go there, but if we do the intratumoral immunotherapy, especially for fewer that is immunogenically cold, so that we are activating first the innate immune cells. Innate immune cells swallow the tumor cells, express the antigens, go to actually the lymph nodes, and they give the signal to, for example, T-cells, and those soldiers, the T-cells, go to the tumor. So we don't need to know anything about the antigen. We don't need, actually, to do very complicated study to find the antigen, which usually in 95%, you will never find in the solid tumor at the present time. And we did, you know, experimental studies on our animals. You know, I will not go into details, but I will show you that here, you know, when we treated, for example, those animals and they had liver lesions, they responded extremely, extremely well. It will be very important to put together vaccines. We already have some vaccines, and we can actually treat those tumors that are either hiding themselves, or they are difficult, you know, to reach them. For example, glioblastoma. We can actually use this vaccine subcutaneously, and we eradicate glioblastoma in the brain, as well as, you know, pancreatic cancer that is shielded, actually, by, of course, the fibrous tissue and by fibroblast. So we will see what will happen, but I think that in the future of the immunotherapy is definitely, to my best knowledge and to my personal view, using this type of approach. So finally, I would like to thank everybody who participated in those studies. Not, of course, you know, it's related to NIH, but many co-investigators and collaborators. And I would like to also thank my wife, Michaela. She's sitting, I see her there. You know, she's sitting here. So she's very good and support, you know, of my work, and exceptional support. And because, you know, all these studies are keeping me a little bit away, you know, I could count how many Saturdays, Sunday I spent at home. But this is why we have here some new family member. So I will actually, that's, I can tell you it helps. You know, it's very good therapy, okay? So thank you so much. And once again, I would really thank, you know, to Ace, you know, for the invitation. It's really great honor. Thank you so much. We have some time for questions. I wanted to actually thank Dr. Pacek for such a wonderful presentation and hear these great updates in the field of pheochromocytoma and paraganglioma. You can go ahead. Giuseppe Barbicino from Boston. Thank you for that wonderful lecture. This is a kind of a theoretical question. SDH enzymes are present throughout the body, but germline mutations in these genes only manifest themselves in parasympathetic and sympathetic tissue. The question is, why is that? Oh, that is a phenomenal question. And I can tell you, I don't have an answer. If I would have an answer, I think I would be listed as a Nobel Prize winner. You know, so definitely, because it's, you know, I think that the chromaffin cells, however, I think that the chromaffin cells are actually more susceptible to sort of hypoxia and increase the succinate compared to other cells. So I think that there is a combination of other events that those cells, you know, how they are actually sensitive, you know, so they may actually be attacked, you know, with these actually events. And then, you know, so they develop into, for example, the tumor cells, you know, but the mechanism is very complicated and nobody knows right now. I wish to answer the question better, but I really don't know. Go ahead, Ever. Hey, I'm a first year fellow at UNC. Thank you for this great talk. Thank you. Really interesting and complicated topic. My question for you is, in those patients who have SDHB positive few chromocytoma, with evidence of oligometastases that's slowly progressing, who fail radionuclide therapy, what are your thoughts on using tyrosine kinase inhibitors in those patients who fail radionuclide therapy? That's a very interesting question. So I will tell you. So if they fail, if they have a oligometastatic disease, I would still think about a surgery, but let's say surgery is not the option, okay? So tyrosine kinase inhibitors, I know that there is a study that was published recently from Europeans that they are actually claiming that the tyrosine kinase inhibitors, for example, sonatabase, can be actually good. I don't have a very good experience because those patients are doing very well for the first six months. They have a honeymoon, okay? And then they are in very good mood. Everything is fine, they're responding, but then everything actually starts being much, much worse. So I'm not in favor of tyrosine kinase inhibitors If I can give you some advice, I would always go with temozolomide or temozolomide with capcitabine or try maybe the olaparib. If the lesion is, however, growing very fast, you always go with CVD. CVD, very old, but 70, 80% of those that have SDHB, and I promise, will respond to CVD. Thank you very much. Go ahead with your question. I'm Lilavivart, Sumter, South Carolina. Excellent review. Thank you. As a clinical endocrinologist, we've seen a lot of people referring for episodic hypertension. And my question is that, I really recently encountered cases where have this episodic hypertension elevated catecholamine, but negative metanephine and so on and so forth. As a compulsive behavior, we continue to work up and then do all the scan, everything, all negative. And the answer did not come out until we asked, what happened to your life in the past? Do you have anything hidden, agenda you never tell anybody? And it turned out to be that the case where a patient had unexpressed PTSD and the patient responded after that secret came out, the episodic hypertension subsiding, of course, along with the SSRI. My question is, how many of those people that come in presenting with episodic hypertension are the true Theo and how many of them are actually PTSD? Yeah, we did not look at the PTSD, but you know, those patients have something which is called pseudo-theochromocytoma usually, and it's not only PTSD, but there are other reasons for that, that they have, for example, episodic increase in catecholamines. Once I see that they have episodic increase of catecholamines and they don't have a increased metanephrine, there is no theochromocytoma, I can tell you honestly. So I would not go actually into 10,000 imaging studies like the function imaging or even a CT and MRI, but as I said, five to 10%, approximately, I see it more in women than, for example, in male. Those that they have episodic hypertension, I can tell you, it's about 45% to 50% that a patient with theochromocytoma have episodic hypertension, and approximately the same number they have, they have a so-called sustained hypertension, which gives you the number 90, 95%, what I mentioned before. Sometimes it's good to give them a little bit different medication, or you can do also the clonidine suppression test, but it's a little bit complicated with clonidine suppression test, and we don't have the time, but I will be happy to talk to you later on about that. Thank you for your talk. I'm Sarah Awad, I'm a clinical endocrinologist from Queen's University in Ontario, Canada. I actually have a clinical question for you. I'm early in my career, I've seen seven fails that I can think of in the last few years I've started. Very interestingly, I had a 32-year-old gentleman that was three years ago when I started who came in with typical hypertensive crisis, theochromocytoma, left adrenalectomy, cured. I'm still following this full genetic workup, negative for any hereditary theochromocytoma. I'm still following them yearly just in case of recurrence, which I'm not sure how long I'm gonna keep doing as my practice grows. Last year, he called me having some of these similar episodes, workup was negative for failed serum metanephrines and adrenals MRI. Recently, things got worse, repeated everything, his meta is like 10 times upper limit of normal. The interesting part of his presentation is when he gets hypertensive crisis, he's bradycardic to 30. None of which of my patients I've seen previously or I've read, I've learned from some case reports they can get sinus node dysfunction. So I'm wondering if that tells you anything about the tumor biology and if there's anything else I should be doing. He is getting an MIBG scan. Interestingly, his MRI is still negative for recurrence. So I just wanna know if there's anything I'm missing or I should be doing, because I've never heard or learned that brady can be a presentation of FAO. There is one missing information I would like to know from you. Tell me. The results of catecholamines, because you said the metanephrines are 10 times above the upper limit. The normeta actually, it was very isolated normeta. So I only do plasma fractionated metanormeta at my center. His normeta was more than 7.5, the upper limit of normal and our center is 0.9. So I didn't ask for dilution, it was clearly high. And his meta and 3-methoxytyramine is normal. He's healthy otherwise, he's 35 now. His full genetic workup is negative. So I'm kind of also concerned. I'm like, what am I missing here? This is the first recurrence that I see. But again, I'm still early in my career and I just wonder if there's anything else missing or I should be doing something else. He's getting an MIBG this week. So the normetanephrine is elevated, you said. By definition, elevation seven times above the upper reference limit is pheochromocytoma or paraganglioma, by all means. I have never seen anybody, the exception, there are two exceptions. One exception, I would like to know what is the kidney function of the patient. And what the patient is, what is the patient doing? What is his job? Health, something in IT, so very difficult. So because they can be, sometimes patients are injecting, for example, catecholamines. I know, you will tell me your patient is not doing that. You never know. You would be surprised. I had like three patients at the NIH. I would never guess that those patients would be injecting. And in that scenario, because they have elevated this way, normetanephrine, and you cannot find the tumor you have to measure catecholamines, and try to do it at the same time. And then write me and we will talk about it. And if it is this way, because it may be, I'm not saying it is, but sometimes you would be surprised. There are only very few scenarios you can get, this kind of actually, I would say scenario. It's very, very rare, but sometimes as physicians, especially working with something which is rare, and the experience is a little bit limited, we can be fooled in certain way. And patients are very sophisticated and very smart, some of them. So I would like to see what the catecholamines will show. Here is the definitely situation when I would measure catecholamines. So the 24-hour urine, you mean? You can measure 24 hours, the urine, but you can measure if the patient, which most likely would not be able to do it, and the patient has, for example, hypertensive crisis, which is almost impossible to get the patient somewhere to the hospital or to your practice, and to measure simultaneously catecholamines and metanephrines and to see what's going on, which is almost impossible because they will tell you at home or at work or somewhere else. Yeah, and I did ask him, and I'm pretty sure I trust the patient because you also have a vibe from patients and you know where they're coming from and their family status and all that stuff. So I don't think he does inject anything. But I think what my also other question is, how would you explain the hypertensive crisis with the bradycardia at the same time? So he would go to 200. You could only explain it if the patient would have elevated catecholamines, extremely high hypertension, and the hypertension would actually cause counteracting the heart rate, which would be the bradycardia. So we could see that. And it's happening. It's definitely happening, and we see it from time to time. But although all inpatient, that they have a very high blood pressure because they have to counteract this, otherwise they would fall apart. They would not be doing so well. I can tell you, I have about 10 patients from Canada and they all ask, always complicated. So it will be number 11, number 11, okay? But I cannot wait, and you know my address definitely, or you can find me, or I can talk to you later on. I will be happy to help because I like very complicated and challenging cases. One more question. Does marijuana impact? Yes, absolutely. That's the only thing he does, smokes marijuana once a week. You see, you see. Okay, I told you. I told you there is something. Marijuana is known, you know, that increased catecholamines quite a lot. But that much? It depends, you know, how much you are taking and what kind of marijuana. You know, I'm not expert for marijuana, you know. So I would admit it if I had some, you know. So, but I did not, but definitely it depends which one and what are the doses. But I can tell you that sometimes can increase quite a lot. Okay. It's known. We'll touch base after. Thank you. Thank you. We are in California, so we can do different kinds of experiments here. Yeah, oh, that's good. You know, we don't stay for longer. The patient I have exactly the same thing. She went to emergency room with episodic hypertension, BP systolic over 200, invariably over 200. She got dizzy and she had bradycardia. Amazing. Yeah, yeah. And those episodes have been coming very frequently. It did not stop until I asked her, say, what is your secret in the past that you did not tell anybody? Yeah, yeah. And what happened that she was driving a car and her daughter four years old in the back seat. Yeah. And then her daughter called, say, mama, mama, there's a bug on my shoulder. She turned around looking at her daughter and lost control of the car, hit the tree and pass out. And the only time that she came up awake in the emergency room, I asked her, say, what happened? She say, when she woke up in the emergency room, the first question she asked, what happened to my daughter? And of course, the emergency room tell her, say, sorry, your daughter didn't make it. But there is, you know, really a component of pseudo-ferochromocytoma. Sometimes we don't know exactly what is going on. It's typical for females between 45 to 55, 58 years old. I can tell you, I don't know anything about your patient. I just telling you, you know, what, you know, what is my experience. She's close to 80 years old. Yeah, yeah, I see, yeah. Amazing. And did she never, I asked her, say, did you talk about this thing? No, she never reviewed her story to anybody until I asked her. Yeah, yeah. And she does respond to SSRI. So, amazing, I think. Yeah, there are some, yeah, some good responses, you know, for something else that we would expect, like alpha blockers, beta blockers. They don't, they respond to something else. But I think all those scans that you mentioned on, did not show up. I expect it, you know, yeah. We are nearly out of time. So I would like to take a few seconds to thank Dr. Pacek for such a wonderful presentation. Thank you, everyone. Thank you, thank you. Thank you. Thank you. Thank you.

Dr. Patak

pheochromocytoma

paraganglioma

research program

early diagnosis

plasma metanephrines

genetics

imaging techniques

DOTATATE

immunotherapy