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 to the stage, and we look forward to hearing his presentation on new biology of pheochromocytoma. 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, 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 if 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 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. Then we have some interesting paragangliomas that are actually located in the head and neck. We call them head and neck paragangliomas. 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 metoxytyramine, either in plasma or urine, and I will talk about it, what is actually going on, because, you know, the audience, especially for the practicing endocrinologists and other practicing healthcare professionals, so I will give you a little bit more towards 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 very 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 patients having benign tumors, so please remove it when you talk with the patients. 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 some, I put like 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 these are 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 the weight loss. I think the weight loss is very interesting. Maybe we will add weight loss 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. Even if pheochromocytoma paraganglioma do not continuously secrete catecholamines, they store a lot of catecholamines in storage vesicles and they can be released anytime, 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 that 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 cardiovascular events and mortality, that 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. And I put, you know, the pie chart, what they are presenting with, especially supraventricular tachycardia. This is typical because they are presenting with sustained hypertension, sustained tachycardia. And this is the most important, you know, for the patient with elevated catecholamine. So therefore outpatient management for these patients is definitely important. I would say this is very critical. And if you look at, you know, the receptors, for example, if you have alpha-adrenergic receptors and those receptors are affecting with catecholamines, of course it leads to hypertension. But if you look at the, for example, heart, we have some options, you know, how to treat with tachycardia. That 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 am 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 can be actually difficult to get DEMSR. And then you look at the biochemical diagnosis. In about 90s, you know, we improve, actually, understanding how we look at the catecholamines and the metabolites. And approximately in 2000, together, you know, 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 metanephrines and started using metanephrines, especially in the plasma. So when we developed the test for the measurement of plasma metanephrines and introduced it to everybody, so I think that that definitely improved the diagnosis. In 2011, we came up with the metoxythiramine, 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, you know, free metanephrines in urine. Because before we talk about the fractionated and because fractionated mean it, you know, so you needed to do the deconjugation, you know, to convert them into the free, just now we can measure, actually, free metanephrines in urine. But what is important that we are going further, actually, and this is especially, you know, related to metabolomics and metabologenomics, and I wanted to show here, you know, 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, they have. For example, if they have, for example, pathogenic mutation, because you know that many mutations are coming as a VUS, 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, you know, what is going on with these tumors. And from Dr. Gayi, there is some interesting, actually, 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, since you know that they are metabolized to methanephrines, or methoxytyramine, that is the enzyme which is called catecholamethyltransferase, and I mentioned something about the 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. So also what is important, that the catecholamines are released episodically, but the methanephrines are released continuously, so which is 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 as 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, you know, for the plasma. So if you have a choice, of course, you know, 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, everything that is two times above the upper reference limit. You know, 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%, ali je dvakrat više nekoliko of reference limits, that is somewhat 80%. Another scenario is that he has a pretest probability that he has a somewhat paraganglioma multiple chromocytoma. For example, who has incidentaloma. The probability is somewhat 5% to 7%, but this is a very different scenario, because if it is metanifrenza or methoxytyramine unloved sometimes prohibited prohibited prohibited different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different you can not finish the medication, over the antidepressants. You will not do clonidine's various tests if the patient is on antidepressants. I will not go into detail, because the pathophysiology is very complicated, but we will do clonidine's various tests and you can see that there is also sensitivity and specificity. The first time we asked about the modality of clonidine's various tests was, I think, in 2011 and in 2012. We used to work with patients where they had very high levels of plasmametanephrine. Now we knew they were convenient with life. You need to know this because it's going to be very important, it's very important for pediatric endocrinologists, for those endocrinologists who work with, for example, a young patient, and it is different to plasmametanephrine, it is not different to methoxytyramine or to plasmametanephrine. Now there's a new different thing that was prepared here, I think, two of those years and three of those years, which is prepared new today, that different clonidine's different tests have improved diagnostic accuracy and sensitivity is 94%. The specification remained real, i.e. around 97%. This is very important because it is for a patient who has slightly different plasma metanephrines. It's not for those patients who are prepared to have chromocytoma and paraganglioma, so be prepared for that to happen. Now, it's still new that we're talking about plasmametanephrine, that it's surfaced by air different different different different different different, that they are also different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different various various various various various different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different different they are very metastatic and aggressive, there have been some new cases for a few weeks now, especially from Australia and some other colleagues that, for example, when a patient has SDHV they actually have a high chance of getting metastatic issues, that's about 70%, I always say A as dangerous, you know B as dangerous, because you know dangerous is around 40% before when we said that SDHV is the best, I tell you that it is not the best, SDHV is the best but the good thing is for SDHV that it is difficult to penetrate because actually non-existent, I never had two families that had SDHV and pheochromocytoma before, when SDHV and DNC is around 20%. Surveillance is very important from Australian colleagues and before that he came a few weeks and surveillance, surveillance, surveillance I can discover to you that if you get a tumor enough we can teach those patients and we can help them when we can't get enough of those patients it can be problematic and it can actually matter to the patients so wait for it especially if you have, for example career when you know something that the patient for example the important importance of those genes, specially relevant to classic 1 Fiochromocytomas Paragangliomas. So what's new? In genetics, hereditary I told you 35%, somatic mutation 40%, with the new gene we would be 80%, so we are there, so 80%, which is big, big, big, so we can imagine that we introduce all the genes in the tumor first and we go to the cow before we introduce the cow and sometimes we go to the tumor in the future. Life penetration for SDHB it's very high, it's exactly 40-45%, exactly like what he told you about SDHA, which is exactly non-existent, and months happen terribly, which are interesting. First SDHB Pheochromocytoma 4 cm is associated with metastatic deity. I can say about 3-3.5 cm, but I will go before to present what was created, because I spoke that it will be an update, what is new in Pheochromocytoma paraganglioma, but I become with all the data that are exactly 3-3.5 cm. And SDHB-connected because of the king, for some of you, when I created for example Grand Rounds, I always say before 10 to 14%. There's a new study, a very good study, that shows it's only 2.5%, which is certainly great. And babies happen much better than most when they have SDHB, given the metastatic deity. The last one is about neurofibromatosis, which is before we saw them being exemplary to metastatic disease, it is 2-5% and now it is 7-7.3% before. So what is new in genetics, we can say about the succession of genes, I can not say it. 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One of those clinical foundations is Belsutifon, when we knew some years before the HIV2 alpha mutation was created, and I would say how the HIV2 alpha mutation was created to support the pathogenesis of those tumors. I think it was definitely needed on the foundation with Belsutifon, which is the world foundation. 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So we don't need to know anything about the antigen. We don't have to make a bigger question to meet about the antigen, which in 95% we can never find for the tumor, in time. And we know we did our questions. On the greens, I won't go into the details, but I will show that here, when we did the greens, for example the greens, because they did the greens, they changed very, very well. It should be very important to get the vaccines together. We probably already have vaccines, and probably those tumors those who help first or those who cannot contribute. For example, glioblastoma. We can probably use this vaccine cutaneously and the glioblastoma will originate in the eye, and the pancreatic tumor, which is a victim of fibrous tissue and fibrosis. So we'll find what's going on, but I think immunotherapy is my best science, and in his eyes originally this type of gathering. So finally, I want to thank everyone who owes these studies, not only at NIH, but to the other studies, and to the following. I would also like to thank my daughter Michaela. I see him there. Here. I am very well and provide my work and a special service, because all these studies make me listen a little. I know how many dark days I've spent in housewifery, but that's why I have a new family. So I can say that it will help. Very good therapy. Okay? Thanks a lot and thanks again for the offers for taking me. You're very welcome. Thank you very much. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. Thank you for our questions. 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My question for those of you who have SDHB without the chromocytoma is positive, what it means for oligometastases who are afraid of radio-nuclide therapy. What are the thoughts of those who are afraid of radio-nuclide therapy with tyrosine-kinesin inhibitors? Very interesting question. If they are afraid of radio-nucleate therapy for oligometastases, then I still have a question about radio-nucleate. But my radio nuke question is not an option. With the tyrosine kinesin inhibitors, I know that a PIME company was created in the European Union, in which the tyrosine kinesin inhibitors, for example, with addiction therapy, it can be really good. I am not so well understood because people do very well in their first seven months. I understand very well, everything is fine, but then everything starts much worse. So I don't understand tyrosine kinesin inhibitors. If I could help a little, it would always be with temozolom, bissitabine, or laparip. If the condition starts very badly, it always starts with CVD. CVD is very bad but 70-80% of those in SDHB and I hope they go back to CVD. Thank You. Thank you for your question. 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matter what's the matter what's the matter what's the matter So I just do plasma fractional meta-nor-meta in my center, nor-meta is over 7.5, at normal base, and my center is 0.9 So I didn't ask for a dilution, it must have been high, and meta-t and 3-methoxytyramine are normal He is otherwise strong, he is 35 years old, all genetic work is negative So I'm a little curious what's the question what's the question what's the question what's the question what's the question what's the question what's the question what's the question What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter what's the matter what's the matter what's the matter what's the matter what's the matter what's the matter what's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the matter What's the 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Dr. Oksana Hamidi

Dr. Patak

pheochromocytoma

paraganglioma

research

awards

patient-oriented research program

diagnostic tests

plasma metanephrines

catecholamines