This is an ENDO 2023 Satellite CME Session, Symposium. And as you saw from the title, we're not going to need two hours because there are no controversies in Cushing syndrome, either in diagnosis or management for that matter. It's my pleasure to be your chair. I'm Maria Flacheau and you'll meet our superb faculty soon. But we're going to talk about individualized treatment for patients with Cushing's and also diagnosis of recurrence and everything else that you have questions for us, we'll ask a lot of time for questions at the end as a panel. The Endocrine Society is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. So you will get two hours of CME credits and they are PRA Category 1 and you'll also get AIBM maintenance of certifications. This program is provided by the Endocrine Society and CMM Global and is accredited by the Endocrine Society and supported by an unrestricted educational grant from Recordati Rare Diseases. Our faculty presenters, well-known international experts in Cushing's and in pituitary in general. It's my pleasure to introduce Dr. Irina Bankosh from Mayo Clinic, Dr. Beverly M.K. Biller from Harvard Medical School and Massachusetts General Hospital, and Dr. Michael Buchfelder from Neurosurgery University of Erlangen-Nuremberg, Germany. We'll talk a little bit about diagnosis but not in full detail, mostly about recurrence. We'll talk about role of medical therapy and you'll see several cases of either mild or severe Cushing's and then you can think about your cases of Cushing's at home and then come with your questions. And then we'll hear about the neurosurgical view. As you've seen, we have a neurosurgeon with us and we can't wait to ask him questions and then these are faculty disclosures and you all have them also in the printed material and online and you have seen them circulating. We'll all talk about off-label treatment. As you know, everything in Cushing's used to be off-label until 12 years ago. Now we have some treatments approved but not all of them and then you'll see for each of us the disclosures related to Cushing's for the last two years in detail, either for research to our institutions or scientific consulting directly to us or the institutions and you have the details here. So I wanted to have an introduction to try to convince for some of you that are not seeing so many patients with Cushing's why it's important and why we're here. Cushing's syndrome is associated with increased morbidity and mortality and we have taught our fellows this for many, many years. What I have thought was that over time we're actually doing a great job but this meta-analysis was published last year and if you are looking at the numbers both for Cushing's disease and for ectopic Cushing's, we can definitely see it's getting better compared with before but you can see that it's still very high 2.8 standard mortality ratio versus 3.3 for adrenal Cushing's and this excludes adrenal cancer. How about activity of disease? You can see that the active is 5.7 standard mortality ratio and remission is 2.28. So yes, it's improving but still significantly higher compared to the normal population and you also see that microadenoma is better than macro but not a huge difference. So the most common causes of death in Cushing's syndrome are cerebrovascular disease, infection and malignancy and the reason I'm talking to you about complications, we all know but we have to think about them when we're treating patients with Cushing's. So if we're treating a patient with Cushing's we have to address the comorbidities in the same time but also in choosing the personalized treatment for that particular patient, we are also thinking about the multiple systems affected by hypercortisolemia and as you can see here from neuropsychiatric dysfunction, musculoskeletal disorder, cardiovascular and thromboembolic disorders, we can talk about that for many hours, just about that and then metabolic disorders, immunodeficiency. I also wanted to point out and I think that's very important to highlight for patients that there are comorbidities that partly recover and you see this in blue and we have to focus on them specifically and then there are comorbidities that persist, doesn't mean we shouldn't try and this is even more important to treat the Cushing's but we have to think about all of these when we're choosing one treatment versus the other and also how aggressive would be in treating and controlling the cortisol as soon as possible. We have several guidelines on management of Cushing's syndrome. On the left you see the Endocrine Society Guidelines talking about Cushing's syndrome in general and on the right you see the Pituitary Society Consensus for Cushing's disease and I'm going to enlarge it to you just because it's newer, it has been published two years ago, more than 54 experts from all over the world have been part of it and I was lucky to be co-chair with Dr. Biller and as you can expect again no controversies and we all agreed immediately on everything but I wanted to point out that the persistent disease is the one and also recurrence are the one that if the surgeon and you'll see from Professor Buchfelder if the surgeon doesn't fix the problem immediately especially for Cushing's disease then it's when we have to think about all these other treatments and the other thing I wanted to point out was what's in green. Once we start a medication and you'll hear that's not as easy as it sounds, we have to determine if the patient is controlled, partial control or no control and then what do we do next? So just starting a medication for example after a failed surgery is not going to be enough, we have to closely monitor the patient and now it's my distinct pleasure to invite to the microphone Dr. Beverly Biller to talk about recurrent Cushing's disease and you'll have one question at the end and then we'll leave all the other questions for the panel after all the other talks. Thank you Beverly for accepting. Thanks so much for inviting me, I can't imagine anything more fun than a night of talking about Cushing's with these experts. So I'm gonna be talking about recurrent diagnosis. So just as a reminder, the recent Pituitary Society guidelines, which it was fun to share with Maria, summarized how to make the diagnosis of Cushing's initially and this is what it said, that after we exclude or stop exogenous glucocorticoids, remembering that they can come in any form, oral, inhaled, topical or injected, then the diagnostics tests you see listed here can be conducted. At least two late night salivaries or at least two 24-hour urines or a one milligram overnight dex test as the initial screening. We also have to consider the many causes of non-neoplastic hypercortisolism when interpreting the tests. But what we're here to talk about now is recurrent Cushing's and so my question for you to think about for a moment is do you think evaluation for recurrent Cushing's is any different than when we're first faced with a patient who might or might not have Cushing's? My answer is yes for several reasons. First of all, in patients with a history of proven Cushing's, I think we need to have a much lower threshold for making the diagnosis initially. These people actually had the condition. They were in remission and so we can move faster when we're trying to diagnose a recurrence. Another thing that I think is really interesting is that patients often tell us that the Cushing's is back and sometimes they can't even explain why exactly. Sometimes they talk about, oh, I have that brain fog again or I have that swelling around my ankles or I wake up at night like I used to and they often say like when I had it before and I think when we hear that, we need to take it seriously. We also should consider what is known about the sequence of test abnormalities when a patient develops recurrent Cushing's and that is what I'm going to be talking about. That is that the late night salivary becomes abnormal before the one milligram overnight dexamethasone suppression test which becomes abnormal before the 24-hour urine-free cortisol. So we need to bear that timing in mind and then there's one other difference of course which is that we don't need to spend time searching for the source. If the patient was in remission after pituitary surgery, that's where the problem is and we can move on to treating the patient. I'm gonna show you a couple of cases that I think are very illustrative. This was a 36-year-old woman who was diagnosed with Cushing's when she was pregnant, presenting with facial rounding, hypertension and fungal infections and her diagnosis was easy to make with elevated urine-free cortisol, a non-suppressed ACTH. The head MRI was non-diagnostic with maybe something on the right so she underwent inferior pituitary sinus sampling for ACTH and that centralized. So this was easy. As I said, she had clear clinical and biochemical features of Cushing's. The testing pointed to the pituitary so she underwent pituitary surgery by an expert pituitary surgeon and had an extremely low set of cortisol tests post-operatively. So she's in remission and she made a good clinical improvement. She was euthyroid, eugenital and had a normal growth hormone axis so the rest of her pituitary gland is intact and she was, of course, adrenally insufficient which lasted about a year and then she was able to be tapered off glucocorticoids and was eupituitary. Some years later, she moved away to Arizona across the country from Boston so we lost touch with her. Let me tell you about this patient. She was a 27-year-old woman who was diagnosed with Cushing's disease also after pregnancy in this case. In her case, though, she had a head MRI that was conducted after her ACTH was shown to be non-suppressed that showed a borderline macroadenoma at one centimeter. So she underwent pituitary surgery and in her case, the good news was that the levels fell to normal but the bad news was that they weren't frankly low. Nevertheless, she made a good clinical improvement over the next year, losing weight and all of her clinical features improved and I think you'll agree she looks markedly improved. So what are their chances of recurrence? It was interesting to me that one of the answers on the quiz question that Maria showed you was 7% chance. That's interesting to me because we actually published that a number of years ago, that it was a 7% chance of recurrence overall but the fact is we were wrong. It's higher than that and if you follow people for long enough, you will see more recurrences. Now, when I asked what are their chance of recurrence, my guess is that you probably thought, well, the woman on the left has a really low chance of recurrence and the woman on the right has a much higher chance of recurrence because there are data that support that someone profoundly adrenally insufficient post-operatively is less likely to recur and that a patient who just falls to normal and had a macro adenoma is much more likely to recur. These are the data about recurrent Cushing's after transfinodal surgery. First, the green bars are just showing you surgical remission rates by expert surgeons and it's somewhere between 70 to 90% which is terrific. But these series also publish their recurrence rates and although they ranged widely, they were as high as 27% and studies in the last decade have sometimes shown even higher rates of about a third. An important point to remember is that these are from the best centers. Surgeons who only place a small percent of patients in remission initially and have very high recurrence rates are not so likely to think about publishing their results. So there's publication bias that we're seeing the best possible results in the publications. And so these are the best results which means there may be even higher rates of recurrence worldwide. So what happened to these patients? Case one, did well for 20 years. And at the 21st year, she developed new diabetes, weight gain, hypertension and asked her local doctor in Arizona if she might have a recurrence. He told her no because Metformin was working well to control the diabetes. She was able to lose weight with diet and exercise and her serum cortisol was normal. She still had family in Boston so she asked if she could come for a second opinion and all of her urine-free cortisols were completely normal and she looked pretty healthy. But in fact, two thirds of her late night salivary cortisols were high. She had not had a head MRI in many years and with a non-suppressed ACTH, we decided to do that. And it turns out that now she has a macroadenoma, a lesion of 1.5 centimeters with the normal gland kind of pushed over there to the left and maybe some right cavernous sinus invasion. What about the other patient? Well, just two years after her surgery, she had recurrent symptoms and she is one of the people that thought it was back. She said, now I'm finding myself crying at nothing that should upset me. I'm much more moody and I've gained some weight back. She didn't look cushingoid though as I think you'd agree here. Her head MRI had not changed over two years and local serum cortisols were normal so she was told that she likely did not have a recurrence. Now you all know this. This is a pulsatile and diurnal pattern of cortisol secretion over a 24-hour period in a healthy person who was admitted to the research center and had blood drawn every 10 minutes for 24 hours. So it's 144 samples of cortisol. And we do the same protocol in a patient with Cushing's. This is what we see. Obviously the area under the purple curve is much higher than the area under the black curve of the normal person and it doesn't dip down into undetectable levels late at night. But the point is that if we sent the patient to the lab for a serum cortisol measurement, at any of the times I've circled in green, the levels are exactly the same. And both of these patients were told they didn't have a recurrence because they had a quote, normal cortisol. Another important point to make is that even though we spend time writing guidelines, they're not always being followed. And this is an interesting study from Australia where they looked at what was the initial testing done when someone was suspected to have Cushing's. And nearly 80% of the time, the test done was only a serum cortisol. So I think we as endocrinologists need to do a better job of educating our fellow physicians about screening tests. This patient though, the second patient, did have urine-free cortisols. One was just at the upper limit of normal and the other was about two-fold elevated. So why are they so different? Can this be the case that one is normal and one is elevated two-fold? So 24-hour urine-free cortisol, which gives us that area under the purple curve, the integrated assessment of cortisol secretion and is not impacted by changes in cortisol binding lobulin, is a very nice test in patients with mild to, sorry, moderate to severe Cushing's. But in patients who have early or mild Cushing's or cyclic Cushing's or who are recurring, it may not yet be abnormal. We have to be aware of a number of caveats and I'll mention a couple of those. This is a study that I really like that was conducted now many years ago by Veronica Merrick when she was at the NIH. She asked her colleagues at the NIH to please do a study with her and drink five liters of water in one day. So they agreed and you can see that their urine volume went up as you would expect. But the point is, so did the 24-hour urine-free cortisol. Most of the healthy volunteers had UFCs above that hatched bar at the bottom, which represents the normal range. Now, the patient I just presented did not have high urine volumes and her creatinines were normal, suggesting that she hadn't pooled two collections. So can she really have two values that are so different? We had the chance to answer the question, what is the within-patient variability of urine-free cortisol, when we were about to start a study looking at a new medication for Cushing's and were enrolling over 150 patients who were known to have Cushing's disease, in fact, many of them were recurring, and had a mean urine-free cortisol of at least 1.5 times the upper limit of normal. So we had a chance to compare four 24-hour urines that were collected at baseline. Four urines were collected over just two weeks with the patients getting the same written and verbal instructions on how to collect the samples. They were measured in duplicate by HPLC and Central Labs. And what I'm showing you here are the first and the second sample in each patient represented by a single dot. It's highly correlated, which is great news. The first sample and the second sample are correlated with an R-value of almost 0.8. And particularly we see that near where the axes merge, meaning the lower values, there's very tight correlation. But the higher the levels go, the more splay there is. So that we can pick out patients down near the bottom where their first and their second values are exactly one, or rather, three times the upper limit of normal. But we can also pick out some patients like this where they have very different first and second 24-hour urine-free cortisols. One sample is sitting on the upper limit of normal and the other is elevated about five-fold. And so we learned in this study that the within-patient variability across four collections was just over 50%. And that's the reason that the guidelines suggest getting at least two urine-free cortisols to give us some sense of the excess production of cortisol. So these patients had what I would consider very typical recurrences. They had mild clinical features, mild biochemical abnormalities. One had an unchanged head MRI and abnormal UFCs. One had normal UFCs and an abnormal head MRI, but a lot of her late-night salivaries were abnormal. Case two, as I mentioned, I think you would agree, had a high probability of recurrence because she had the large tumor and she didn't have adrenal insufficiency post-op. But what I think it's important for all of us to remember is that even patients without positive predictors may also recur. Which brings me to mention that late-night salivary cortisol is a very good test in this circumstance. It has high sensitivity and specificity. Patients like to do it because they can perform it at home, chewing on the cotton and then mailing it or bringing it into the lab. Just as with urine-free cortisol, we need to have them do at least two samples. The one time not to do this test is if someone is a shift worker, working at night rather than in the daytime. These are some really nice data that followed a cohort of patients. Some of them recurred and some of them stayed in remission. They had the patients collect multiple saliva, late night salivary samples, and then when they followed the patients over time, looked back to see what were the salivary tests in the patients who stayed in remission, and you see those on the left, and what were the salivary samples in the patients who recurred, and you can see there's quite a difference here. While not all of the samples are elevated, the patients with recurrence had the majority of their samples high. So the fact that there's an occasional sample that is not elevated shouldn't dissuade us from thinking that a patient might have a recurrence. If the majority is high, I think that's the answer. It's important to understand that recurrence can be many years after surgery. We looked across many series and saw that relapses can occur anytime between six months and 12 years, but in fact, since then, we've seen patients that recurred at 21 years and now 27 years, and I just heard yesterday that a patient that one of our surgeons operated on has now recurred at 28 years, so so far that's the record. So we need to keep in mind the sequence of hormone changes. The elevation of midnight cortisol usually precedes the elevation in overnight dex and 24-hour urine-free cortisol because losing diurnal variation is the first thing that happens. All post-op patients really need to be followed, and we cannot rely on urine-free cortisol alone. We need to use the other tests, and late-night salivary is the most sensitive test. So I'd like to conclude that we should have a lower threshold for diagnosing recurrence. We need to listen when the patient tells us, I think it's back, and according to the Pituitary Society guidelines about recurrent Cushing's, we should be thinking about using the tests that were abnormal at initial diagnosis, but also use late-night salivary tests, performing them at least annually and more frequently if the patient has symptoms. Dex suppression and urine-free cortisol take longer to become abnormal, so we have to bear that in mind. Most recurrences, or at least half of them, occur within the first five years, but plenty of them recur later, so patients really need lifelong monitoring. Thank you. Great, thank you so much. So we have time for one question now. You'll have more time at the end, so anybody that has any specific questions? If not, I would like to ask Dr. Biller, can you tell us how you set up the saliva cortisol test at your hospital, because we all had problems, and I talked to many colleagues, and even now some local labs, we send the patients and they say, what's that test? Yeah, yeah, thanks for asking me about that. When the first publications came out, Herschel Raff and Jay Finling were publishing about the high sensitivity and specificity of late-night salivary cortisol, we went to the lab at Mass General and said, we need you to add this test, and they said, well, we'll think about it and get back to you, and they got back to us and said no. And so we set up a contract with Herschel at his institution, and the samples had to get processed through the Mass General lab, and then would be shipped out to Wisconsin. And pretty soon, the lab saw how many samples we were sending, and we got another call, and they said, actually, I think we can do this now. So I would say, you have to push, and you have to show the lab that it's gonna be worth it, because you're gonna order enough that they wanna set it up. Great. Beverly, what is the place of the one milligram dexamethasone suppression in your follow-up, and if the patient had response to decimopressin before surgery, do you use it also within the follow-up? Yeah, thank you. Perfect question for the panel, Andrea, I said one question, but, because I think that's very important, and we should all discuss that. But we wanted to see what happened to that patient, so. Oh, you want me to tell you? You can say from there. Sure. Because I'm sure you are all curious what happened to that patient. Sure, I'll tell you what happened to the patients. So, the second patient, who had the recurrence, had a second surgery, which was not successful, because there was some invasion in the cavernous sinus. So we discussed with her all of the possible medical treatment options, which I think you're gonna hear about very soon. And she said, I'll think about it and call you back. And she called, and she reached our fellow who was taking care of her, and she told the fellow she was very excited to report that she was pregnant. So, this really changes things, because the choices are limited. There is no drug approved for someone who is pregnant with Cushing's. But the best safety data are available about metirapone, and that was started where we had to target her urine-free cortisol, of course, above the normal range for a non-pregnant patient, because it goes up in pregnancy, we were worried about the precursors proximal to the 11-beta-hydroxylase blockade. So, she went to the OBGYN weekly, actually, for measurement of potassium and blood pressure. And I'm happy to say that she delivered a healthy boy. The second patient decided to have a second transphenoidal. She was shocked that patients only spend 36 hours in the hospital now, because when she had her surgery 21 years ago, it was a week. And she did get placed in remission. Her diabetes and hypertension resolved. She came off all her medicines. However, she did develop pituitary hormone deficiencies, and is on hormone replacements. And this is the most recent picture I took. And if you're wondering why she's pulling on her shirt, she said, if you're gonna show this, make sure they can see I have clavicles again. Thank you. And now we'll hear from Dr. Ina Bankash about other cases that have been treated with medical therapy and the role of medical therapy in different cases of Cushing's. Thank you, Ina. Thank you. Well, I have only one objective, to hopefully discuss all available outpatient medical therapists for Cushing's syndrome. And I will start with my first case, who gave me an opportunity to discuss three of those medications, because she tried all three. So, she's a 29-year-old woman who presented initially with weight gain, irregular menses, and prediabetes. On physical exam, obese, and clearly has features of Cushing's syndrome. On hormonal workup, I think everyone would agree that it's this ACTH-dependent Cushing's syndrome was abnormal. One in eight milligram dexamethasone suppression test, high ACTH, high DHA sulfate, and her midnight salivary cortisol several times, as well as her 24-hour urine cortisols were elevated. So, that was her initial presentation years ago. At that time, MRI potentially showed a three millimeter lesion, but I had to use my imagination to see it. So, she did IPSS, and it clearly showed that that was pituitary source, so centralized, and she had pituitary surgery by one of our expert pituitary surgeons. She actually did not have a pituitary adenoma on pathology, despite the fact that our surgeon promised me that he found pituitary tumor and removed it. But, despite that, she was cured. So, I guess that pituitary tumor is somewhere in the tubes, because her cortisol the morning after surgery was very low, and ACTH dropped as well. She continued to have adrenaline insufficiency for 18 months. Eventually, she recovered, and her hydrocortisone was stopped. She had her very first 24 urine cortisol one month afterwards, and continued with yearly assessments. So, so far, so good. But, four years after that pituitary surgery, successful pituitary surgery, she called back saying, I think Cushing's is back. Going back to what Dr. Billa was saying, we have to listen to our patients, because she was right. The Cushing's was back. And when she traveled again to see us, she actually had milder features of overt Cushing's. At that time, she also reported that her primary care physician at home diagnosed her with liver steatosis, and did a bone density, but that found low bone mass. And here is her hormonal workup. So, she has recurrent Cushing's syndrome. We did MRI of pituitary gland, and it was negative. So, what do we do now? As the consensus that Dr. Flesseriu and Dr. Billa co-authored, or co-chaired, I should say, there are four options for recurrent Cushing's disease. Repeat pituitary surgery, radiation therapy, medical therapy, or bilateral adenolectomy. So, some of these options are not the best choice for this patient. We actually did have a discussion with our pituitary surgeon, and she did not like her chances of cure with repeat pituitary surgery, which were definitely not 100%. Radiation therapy, we did not think was the best step. She did not have a visible culprit lesion, and she was really a big fan of medical therapy at that point. That's what she decided for. So, here's a list of outpatient medical therapy available for Cushing's disease. And out of these, we have two pituitary directed therapies, Coburglin and Pasteriotide. We have several stereogenesis inhibitors, and we have glucocorticoid receptor blocker. And these are available to prescribe, though quite a few of these are off-label. So, we'll try to go through all of these. How do we choose medical therapy? It's really patient preference, cost insurance coverage, degree of hypercortisol, concomitant comorbidities in medications that this patient has, and the side effect profile of the medications. I feel that it's the second thing that stops me the most, unfortunately, so far. So, after discussing all of this, she wanted to try Coburglin first. So, Coburglin is a pituitary directed drug, which is off-label for Cushing's disease, usually used starting at 0.5 milligrams. I would guess most of us rarely go to six milligrams each week, but when it was studied in this way, the authors did see up to 40% response rate, though not necessarily lasting. Considerations for starting Coburglin would be mild disease, especially if residual tumor is present, there is some potential for shrinkage. In pregnant women, this may be a good choice, though I just want to emphasize that no medications for Cushing's are approved for pregnancy. And I'm a bit biased, because we did some research on impulse control disorders, and I would not start Coburglin at anyone with already existing impulse control disorder, because that could be quite devastating. So, after discussion of all the options, this patient wanted to do Coburglin. Cost was a big thing for her, and she liked the idea of pituitary directed therapy. But unfortunately, we did not see any changes in the first three months she was on Coburglin, and we did not really want to continue, because she developed fatigue, headache, and nausea, and she clearly described temporal relationship to Coburglin. So, we decided to stop Coburglin, and had a discussion again about other options. So, her second choice was Passeriotide. It is approved for Cushing's disease, and usually used in mild disease as well. Data show that 50% of patients on Passeriotide demonstrate at least 50% reduction of 24-hour urine cortisol at six months. Maybe normalized, depending on how high it was in the first place, and up to 40%. But we are all aware about the main side effect, which is hyperglycemia, in addition to gastrointestinal symptoms and gallstones, especially with a longer-term therapy. If residual tumor is there, which this patient did not have a visible tumor, this would be another benefit, because there is some potential for shrinkage of the tumor, up to 20%. So, she initiated on Passeriotide. We were mindful of hyperglycemia, because her hemoglobin A1C was already slightly abnormal at 6.1%. She did experience some decrease in cortisol, from 2.5 times up and normal, to 1.2 times up and normal at three months. But her hemoglobin A1C went up to 7.8%, and she was not keen on having diabetes. So, we discontinued Passeriotide. So, we talked about, oof, I guess I don't have my highlighting thing. We talked about the Coberglin and Passeriotide. So, there are some other sterogenesis inhibitors that are available, Ketoconazole and Levoketoconazole. These two, one of them is approved for Cushing syndrome, Levoketoconazole, while Ketoconazole is not, and it's used off-label. There are some cost differences. As far as potency, these two medications were not compared head-to-head. But they could be successful in patients with Cushing syndrome. Some of the considerations here are hepatotoxicity. And remember, this patient already had significantly elevated liver enzymes and diagnosis of hepatic steatosis. So, I'm showing this just to mention that this would have been an option for someone without baseline abnormalities in liver function tests. One of the preferences for Levoketoconazole would be twice a day administration versus only four times daily administration for Ketoconazole for compliance issues. So, what other medications we have? Now, let's go to Metiropon and Esaladrastat. So, Metiropon is widely used in Europe, but not in the United States. It's not approved in the United States for Cushing syndrome. It is approved to be used for overnight Metiropon tests in adrenal insufficiency. It's 11-beta-hydroxylase inhibitor. It is quite, can be quite potent adrenal sterogenesis, especially if used at higher doses, let's say 1,000 milligrams every six hours. And it was shown to lead to normalization of urine-free cortisol in up to 50% of patients. Side effects, any sterogenesis inhibitor would cause adrenal insufficiency at high enough doses. So, adrenal insufficiency is a side effect, also gastrointestinal side effects and rarely hypertension and hypokalemia. I just would like to point out the recommendation from the Cushing's consensus that patients in need for rapid cortisol normalization, adrenal sterogenesis such as Oseladrastatum Metiropon would have the fastest action and should be considered. I'm not sure whether patients would be compliant with four times a day. I've never had a person on long-term therapy. I would say a person with Cushing's probably would do anything not to have Cushing's, but that's one of the considerations here because it needs to be used every six hours. So, what she decided on and it was approved for Cushing's at that time is Oseladrastatum. She started on Oseladrastatum two milligrams twice a day and those was gradually increased to five milligrams twice a day using 24-hour cortisols and midnight salivary cortisols and 2.5 months later, she did have a normal 24-hour cortisol and normal midnight salivary cortisol, but developed fatigue and arthralgia. So, at that time, her morning cortisol was borderline and we started her on hydrocortisone therapy. Oseladrastatum is approved for Cushing's disease. It's an 11-beta-hydroxylase inhibitors. It's the most potent adrenal sterogenesis inhibitor. Shows up to 81% rate of urinary-free cortisol normalization. So, what are the factors to consider for using combination therapy or to switch from one medical therapy to another? It's really clinical response and biochemical response, unless we are dealing with mifepristone. Biochemical response, 24-hour urine cortisol is what the consensus recommends. It is unclear yet how targeting diurnal secretion alone with morning cortisol and midnight salivary cortisol can help. I certainly do that. Change in treatment should be considered if cortisol level persistently is elevated after several months of maximum tolerated doses. And if it does not normalize bad response, so it's slightly lower, or if you see some clinical improvement, combination therapy can be considered. On the other hand, if there's clear resistance to treatment, despite dose escalation, we would switch to a different therapy. So, some more information on this patient. She continued on oseladrastatum and 20 milligrams hydrocortisone daily, so it really was a block-and-replace therapy for her. She did experience clinical improvement. Hyperglycemia went away. She lost 17 pounds. Her quality of life was not improved right away, but did improve after around four months of oseladrastatum hydrocortisone therapy. Six years after surgery, so one year after oseladrastatum initiation, her MRI of pituitary gland continued to be negative, but now she expressed desire to conceive. So, at that time, we discussed bilateral adrenalectomy. We stopped oseladrastatum. Hydrocortisone was continued. Flucocortisone added. She's doing well with bilateral adrenalectomy. Would like to move on to case number two. Here is a 56-year-old woman with history of diabetes for many years, but based on what she was describing, maybe around six months or so prior to diagnosis of Cushing's, she noticed that she required more and more insulin. So now, at that time of diagnosis with Cushing's syndrome, which was done elsewhere, not at our institution, she was requiring 130 units of insulin per day. And again, her diabetes was controlled previously with metformin. And on physical exam, based on notes, it was evident that she did have clinical features of avert Cushing's syndrome. She was in wheelchairs. I'm assuming it was because of objective proximal myopathy. And she did have red-purple abdominal and axillary striae, skin thinning, and bruising. And her biochemical workup did show ACH-dependent Cushing's syndrome. Her MRI, which was available for my review as well, was negative for pituitary adenoma. And what the team recommended to her at that time was to proceed with IPSS to understand whether it's pituitary or ectopic and decide for the next step. But she deferred further workup, first because of pandemic. Then she said, well, she just, you know, is fine on medications. But she did ask for a second opinion with me, and that's how I saw her. When she was on mifepristone, 600 milligrams daily. And she described that she started mifepristone around five months prior to visiting with me. And she did experience clinical improvement. She lost 15 pounds. Her diabetes improved. She was still on the same dose of insulin, but her hemodialysis went from 10.3% to 7.7%. And she was feeling very unwell, extreme fatigue, apathy, arthralgias, and poor appetite. But no nausea, no vomiting, and no hypotension or orthostasis. So I guess, is it adrenaline insufficiency? Is it glucocorticoid withdrawal? Difficult to say with mifepristone. It is approved for hyperglycemia associated with Kersheng syndrome. It's a glucocorticoid receptor antagonist, also potent antiprogestin. It is used at doses anywhere between 300 and 1,200 milligrams a day. And efficacy can only be determined by changes in clinical parameters. Hyperglycemia, blood pressure, weight, which she did have those improvement in clinical parameters. We are not able to use ACH and cortisol levels in any biomaterial to evaluate efficacy. We would have to monitor for vaginal bleeding in women and for hypokalemia. So side effects, symptoms of adrenaline insufficiency and moderate to severe hypokalemia. So again, this just summarizes her case. She sort of heard what I had to say as far as what it could be. What can we do, decrease mifepristone or something else? She said she would like to try something else. So we stopped mifepristone and we started oselodrostat instead. We traded it to two milligrams twice a day and her 24-hour urine cortisol at that time on oselodrostat was normal. Her morning cortisol was low. We started hydrocortisone at that time in divided doses and she continues to feel unwell with fatigue and arthralgias. So now we have clearly treated adrenaline insufficiency. So I think at this point, it is clear that what she's experiencing is not adrenaline insufficiency that again is being treated by glucocorticoid withdrawal. And what I'm trying to illustrate with this table is just a difference between symptoms of glucocorticoid withdrawal that can occur at supraphysiological cortisol levels versus adrenaline insufficiency that is unreplaced. For example, all of you probably see patients on exogenous prednisone. And if we are to decrease prednisone 15 milligrams a day to prednisone 10 milligrams a day, which is still quite supraphysiological, many of our patients would complain of similar symptoms of arthralgias, myalgias, and fatigue. So this is a good parallel to what we would see in endogenous Cushing syndrome when we decrease maybe 24-urine cortisol to simplify it from 200 to 100. So we counseled our patient about glucocorticoid withdrawal. We thought it would help her to give more time to adjust to lower cortisol levels. So we increased her hydrocortisone to 40 milligrams for one week, and then eventually went down to 35, and then to 30, and she actually tolerated that much better. So in summary, we should consider patients' preferences, duration of therapy, cost, side effect profile, other comorbidities in medications when choosing medical therapy for Cushing syndrome. We should also consider the onset of action and potency of agent needed in relation to degree of hypercortisolism. We should organize appropriate biochemical and clinical monitoring in patients treated with medical therapy for Cushing syndrome, discuss glucocorticoid withdrawal symptoms, and the difference of glucocorticoid withdrawal and side effect to medication. And if you have a person with severe hypercortisol, as I just want to underline, it's a medical emergency. So fast-acting cortisol-lowering medication are required in those cases. Thank you. Thank you so much, Irina. So anybody that has questions, one question related to the cases that Irina presented, and then keep all the questions you have. We'll discuss them in the panel. If we're over time, we'll just get them and we'll answer you after that. Okay, go ahead. Thank you. I just had one question regarding all the studies that have been done. They have titrated the medications to normalize the urine-free cortisol. I have come across a few instances. You normalize the urine-free cortisol, but the salivary cortisol, the late night, is still abnormal. What do you do in those scenarios? Well, first I would say I agree that sometimes you normalize urine-free cortisol and patients still has Cushing's. So I personally, in my practice, do monitor midnight salivary cortisol. And I know that we probably have different ways we manage things. And I'm trying to make the midnight salivary cortisol normal. And what is actually happening at the pathophysiological level that we still have the midnight salivary cortisol abnormal? Yeah. But total cortisol. Well, it's, well, yeah. So I guess the way I'm imagining it is this way. So Cushing's is not a normal cortisol production that when we, which is, what is normal, right? When we sleep, cortisol is very low. And then we have the first peak in the morning and the second peak in the afternoon. In the Cushing's, if it's mild Cushing's, it's sort of like you lose, the first thing that happens, you lose the circadian production. So you have increased nocturnal production of cortisol with some abnormal production in the afternoon. And all the drugs that we currently have basically just decrease that threshold. They do not normalize circadian production. So depending on how low you go, you will cause adrenal insufficiency if you would also suppress midnight salivary cortisol. None of the medications we currently have restores circadian cortisol production. So this was a composite question. There were not really two, but that was not the one either. But that's a very good point. And we'll discuss in the panel because I think each of us are using it differently and also some of the starting doses could be different. Serena, can you show us a case with very severe Cushing's because that's going to be even more debatable how to manage. And I'm glad you're asking Maria because I prepared a case like this. So I did want to illustrate a case with very severe hypercortisolase when this was a medical emergency. And actually I'm glad to see some of our fellows who participated in the care of this patient if they remember. So this is a 57 year old woman with acute onset of symptoms, hypertension, hypokalemia, peripheral edema, 30 pound weight gain, facial rounding, hirsutism and progressive myopathy. I'm seeing as outpatient, she's in a wheelchair and she's very unwell. So this is a patient I transferred to the hospital from my clinic. Workup showed metastatic adrenal cortical carcinoma with multiple liver lesions and a 16 centimeter adrenal cortical cancer. And hormonal workup, we suspected Cushing's. Hormonal workup shows severe ACTH independent Cushing's syndrome but also severe androgen excess. ACTH was completely suppressed. She was not able to collect a 24 hour urine cortisol collection. It was possibly 11 hours from what she thought. And we did have multiple cortisols done in the hospital. It was 57 and 66 in the first day and then we had 120s and 142. Cortisol 142 must be one of the highest I've seen. So what do we have here? We have an unrespectable adrenal cortical cancer with very severe Cushing's syndrome. Right away we started anticoagulation, antibacterial prophylaxis with Bectrim, aggressive hypokalemia and hypertension management. We did plan debulking surgery and chemotherapy but really what needed to happen first is management of severe hypercortisolase. So this gives me a chance to discuss Edamidate which is a medication we very rarely use and only in ICU. It is a sterogenesis inhibitor. It acts very quickly. And here's what happened. What you see here is on the bottom of the table you see cortisol levels at the time or right before she started Edamidate. Cortisol was 123. It was started at 0.02 milligrams per kilogram per hour. Cortisol did drop, especially after it was titrated to 0.04 milligrams per kilogram per hour and then we actually obtained metiropon that was urgently shipped to us. So we started metiropon and stopped Edamidate and transferred her back on the floor and she was actually controlled on metiropon afterwards. So this is my case of urgent medical therapy for hypercortisolase. Great, thank you. Before we move to hear from our expert surgeon, I would like to ask Dr. Biller if this patient will come now in the hospital, would you have to use ICU? I wasn't on the list of favorites from the hospital when we had to put patients in ICU for treatment of Cushing's. Yeah, it's a good question. It sounds like she was beautifully managed, so good job. That's a very challenging situation when someone is critically ill and actually in risk of dying from their Cushing's. I will say that it's hard to know what we would do now, but the fact that we have two really potent adrenal blocking drugs now does afford us potentially the possibility of getting rapid control of a patient like that without having to hospitalize them in the ICU. And that's a situation where I don't think we start low and go slowly. We work really quickly to escalate the doses of adrenal blocking drugs and try to get control. And that is one circumstance where, although I don't ordinarily use block and replace, I would because I want to escalate as quickly as I can to get the cortisol down and keep the patient safe with a little bit of glucocorticoids. So maybe we will be changing our paradigms because we have two very potent adrenal blocking drugs now. I agree, and that's probably what I would have done. And now let's see, because I want to talk more about the dosings, but let's see what an expert surgeon can actually do with a pituitary tumor. And Professor Buchfelder is going to present the neurosurgical view. Thank you, Dr. Flicerio. For primary and recurrent operations in Cushing's disease, we have now generally accepted standard procedures. If we see a microadenoma, we try to approach this and perform a selective adenomyctomy, including a small rim of normal pituitary tissue around the tumor. If we don't see it directly, then we cut the gland in parallel incisions and search in the depth of the pituitary for a tiny tumor. If we find nothing during this exploration, we can still do a partial or total hypophysectomy. In microadenomas with lateral inversion, we go as far parallel as possible and try to resect utmost tumor, even if it requires partially resecting some tissues of the cavernous sinus. And this provides excellent results in primary surgeries with up to, depending on the patients that are treated, up to 75 and 95% of remissions. But with increasing follow-up, even in the most experienced centers, recurrences occur, the patients redevelop the syndromes, and therefore we have to deal with recurrent disease as neurosurgeons. Thank you. And I would also like to show you a case to introduce the problem that we are faced with. A 22-year-old female was diagnosed with hypocortisism in March 2005. Very soon thereafter, she had, in another hospital, her first transphenyl surgery where a pituitary microadenoma was identified which expressed ACTH, and she ended up with remission of the disease. She was very happy. A few years, four years thereafter, she noted that something was not perfectly wrong. She had a re-evaluation. Recurrent disease was identified. She underwent another transphenyl surgery. Again, tiny portions of ACTH-secreting microadenoma were found and extracted, but she did not have another remission and was referred to us where we had this MRI, and this is a typical MRI with some cisternal herniation with a sequelae of the previous operations, and there is maybe some isometrical volume of the normal gland or of the cellular content, and we thought there is a tiny zone of lesser signal intensity which we used to indicate a re-operation, and this we did with all technical support that is available because we have to fight with the sequelae of the primary operations carrying the cisternal herniation, the tissue defects that the first surgeon did, the outlines of the yellow segmented portion is the signal intensity change in the cell as obtained from the MR images. The blue structure is the carotid artery, and we incised the gland, and this whitish, creamy tissue is typical pituitary adenoma that we found, and we excised it, and as you see, we went also through the normal gland and exposed the cavernous sinus, and fortunately, this re-resection of adenoma tissue was followed by another remission. 11 years ago, because I had this seminar, I phoned her up and said, can you give me a recent picture and allow me to show this in the seminar, and she also sent this last laboratory investigations of her midnight salivary cortisol. She is still okay. But it is not always like this. From a cumulative series of recent literature overview on the results of recurrent and persistent Cushing's disease, if we only look at the recurrent situations, 486 patient in 44 studies, 65% remitted, and the publication bias is that the best centers, those who have success, publish their results, and we can suppose that this is not representative for our entire countries. Many years ago, I was forced by my previous chairman to make drawings of the operations that we did of the initial and recurrent operations for Cushing's disease, and as you can see, there is a similarity. The recurrences were found in the, adjacent to the resection cavities of the primary initial operations, and this is some indication for us to search at first there where the initial tumor was and study exactly the operating reports of the initial surgery. So when we deal with recurrent Cushing's disease as neurosurgeons, we have no problems with the diagnosis since we have, as it was already pointed out, empirical confirmation from the first successful surgery. Frequently also the histology of ICTH secreting tumor is available, which defines the pathophysiology. But we have to find with the sequelae of prior surgery, scarring, tissue defects, cisternal herniation, particularly favorable if we have a target, if we have a positive MRI depiction of tumor on the MRI. And I think in this context, because the previous speakers haven't clarified the terminology, I would like to again review that elevated hormone levels in the ideal case by resection of a functioning tumor result in long-term normalization. Spontaneous cure occurs, but it's rather miraculous, a miracle, and not the rule. If we have normalized hormone secretion and the disease reappears, then we denote it as recurrence. But if not only recurrence, there's also persistence of the disease. Persistent disease of a patient who has never achieved as yet a perfect normalization. And I'll show you another case. A girl, seven years of age, had diagnosis of central hypercortisolism. She underwent a transfundal resection in another department. Some of you who have experience with radiology see the lesion that is American football-like between anterior and posterior lobes. It is likely not an adenoma, but a colloid cyst. This colloid cyst was resected. She had persistent disease. From the amorphous cell-less material, no histology could be obtained. She had a serotype, but refused to take it again, and they preferred to refer to us, who had overweight girl who had clinical signs of hypercortisolism. We performed a second transfundal surgery with all the scrutiny, but we found no circumscript adenoma. We didn't want to do a hypophysectomy in a child. The histology revealed Crook's cells, histological confirmation of active hypercortisolism, and she ended up with persistent disease. And according to the guidelines, of course, we are following the recommendations, we did reconfirm the central origin of the hypercortisolism by the venous-venous selective sampling of ICTH secreting of the drainage of the pituitary, as in the red bars you see on the left and right side, high ICTH levels in the cavernous sinuses in the drainage of the pituitary, and much lower levels in the peripheral catheter, so that the central origin of the hypercortisolism was confirmed. Should we do a third transfundal surgery after two unsuccessful operations? The pediatric endocrinologist gave her MITO-10. And after four months of MITO-10, these ICTH levels that were 100 picogram per millimeter increased to 245, but we thought in May 2019 that the hypo-intense zone has a little bit expanded, is more pronounced, and we operated her again. We found this time ACTH-segreting adenoma and achieved a remission. The postoperative cortisol was low, ACTH also, and also her I found up recently, and she's still four years after this surgery in remission and in need for hydrocortisone replacement. When we deal with this recurrent Cushing's disease as neurosurgeons, we like all technical gadgets which are available to date. Navigation, to see the position of the carotid artery which is also adherent in the scar, the endoscope for enhancing visualization, the Doppler probe with which we can verify exact position of the carotid artery. So why don't we avoid the scarring and the delayed reoperation and reoperate any time immediately if we have not achieved a remission? Because we need some time to reaffirm the diagnosis and because of the observation that in Erlangen, in most of the centers and also in studies, there is a unexplainable, miraculous delayed remission of the transplant surgery. In this study, hypercortisolemic patients spontaneously went into delayed hypocortisolemic states, or eucortisolemic. This occurred in every 20th patient, and they denote also that the delayed remission, delayed recurrence after remission was, or recurrence in this delayed remission was much higher than in the patients who had severe hypercortisolism that necessitated replacement therapy immediately after the surgery. The consensus on diagnosis and management of Cushing's disease guideline uptight recommends also radiotherapy. Talks about radiotherapy, which can be used in cases of persistent hypercortisolism after incomplete corticotroph tumor resection, and says that stereotactic radiosurgery is more convenient, but avoiding optic chiasm exposure is crucial. The disadvantage from this radiosurgery, from the classical radiosurgery is that it requires a target, and the lack of this target is the problem for the surgeon and also for the radiosurgeon. If you find a target, the results of radiosurgery are quite remarkable. They start after 12 months, they are delayed, but after five years, in this study, 77% of the patients achieved a remission. I think it is good news that even if we can't identify a target, how will sell a stereotactic radiosurgery for functioning adenomas, offers an alternative treatment. These authors saw urinary free cortisol normalization in 70% of the cases, after a median of 10 months. You see that the success rate is dose dependent in margin doses between 12 and 16 grace, 60% of the patients remitted. If the doses were very high, 25 to 30 grace, 72% of the patients. At least this is an alternative option. Unfortunately, also the number of hypopituitarism, the rate of hypopituitarism is dosage dose dependent. So, I already come to the summary of my short contribution. Repeat surgery, I would have liked to show you that it should be considered in real recurrences of Cushing's disease, month to years after initial remission. These operations are difficult, they should be performed in experienced centers. Particularly in patients in whom we have a target, suspicious tumor is suggested by the MR, and the tumor seems resectable. The results are quite favorable. In persistent disease, the situation is more difficult. A reoperation may be considered if the initial surgeon was less experienced. The mass effect can be relieved, or radiotherapy at least facilitated. If the distance between the upper tumor margins and the visual pathways is crucial. And in contrast to surgery, radiotherapy does not produce immediate remission. Hypercortisolism instead declines progressively over years. Thank you very much. Thank you. We have time for one question. So, we have with us one of the most expert surgeons in the world for Cushing's disease, and he told us he cannot cure all the cases. So, that's the surgeon you want to send patients to. One question, go ahead, sorry. Please introduce yourself. Dr. Richard Levy, Chicago. I'm curious, do you chase down erosion into the sphenoid sinus with surgery, or do you leave that as a target for radiotherapy or something else? If the tumor goes into the cavernous sinus, or sphenoid sinus. Sphenoid. But the sphenoid with the endoscope, we can almost deal with. I think the inferior clival and sphenoid sinus invasion is much easier for us to deal with than the cavernous sinus, because in the cavernous sinus sits the carotid artery, and if a previous surgery has been performed with the scarring, it's really very difficult to dissect it. Thanks. So, Michael, can you show us the data, because you have participated in all the clinical trials with us. So, it's one of the surgeons that actually likes to work with endocrinologists, so you know. And especially for the long term, we get these questions for all our colleagues, and including for our patients, if they are not treated with pituitary directed cases, and as you've seen, patients switch from one to the other, as you need in our cases, how do we monitor, when do we do the MRI, and what do we see shorter and long term? I believe that, of course, it is very interesting for you, what happens with the tumor if you treat in the periphery, if you treat the adrenal glands. And in the studies, this has been extensively investigated by central MR image reading, which is labor intensive and requires a lot of resources. Thank you for doing it for us. For example, when the effect of mifepristone on the pituitary tumor was assessed, you see that there were non-visible tumors, negative MRIs, but also some micro adenomas and macro adenomas. And by segmenting these tumors, you see these red outlines, the evolution of the tumor could be readily compared, and the segmented portions in a three-dimensional fashion, superimposed between the initial scans and the last follow-up. And as you see in this study, four minor volume changes that did not lead to discontinuation of the treatments were rather reassuring for you. And similarly, in the liver ketoconazole trial also, most of the tumors stable, three increased creases, very minor, and one decrease, and again, no discontinuation on basis of the MRI, even with the utmost scrutiny of image evaluation. Slightly different was it in the oscillator start trial, where 40% had a 20% increase, but 30%, a decrease, a similar decrease, most of the tumors were stable, and 20% is just the minimal recognizable size change. Then, if it would be transferred to the diameter of the tumor, would only make a difference of one or 1.5 millimeter. Great. Depending on the size of the tumor, of course. Thank you so much. So now we'll all send our MRIs to you. Thank you. So now we'll start the panel portion. So I'm not going to ask you to stop after one question, so we'll have more time. Professor Lacroix is not here, but that was a very good question. And while you're preparing for other questions, I want you to ask my colleagues, because we all know that CRH doesn't exist anymore. So what's your experience with the small pressing test, and do you use it to determine recurrence that's used mostly in France and Canada? Have you used it for recurrence, the small pressing test? Beverly, and then Irina. Not for recurrence, no. Initial evaluation. Or during IPSS. Irina? So we do use vasopressin for IPSS. We actually don't have vasopressin set up in our endocrine testing center. But if we did, I would also use it for initial diagnosis only. Okay. Yes, I was happy to hear that you don't have it that we have when I visited. But that's a different question. While you are preparing for other questions, I want you to ask Beverly, because in the case that Irina showed us, she started with two milligram ocilodacet twice a day. And the patient had, and I'm not saying that was the reason, but the patient had symptoms of either adrenosufficiency or withdrawal. What's usually the dose you are starting on for patients with mild disease? Thanks, yeah. Well, certainly the instructions are to start with 2BID. But a lot of patients we see have very mild Cushing's. And if a patient is diagnosed when they have very mild Cushing's, I don't think we're in a rush. It's kind of the opposite extreme to the critically ill patient that Irina presented. So if someone has mild Cushing's, I want them to be able to tolerate the medicine and not stop it because of side effects. So I will start as low as one milligram BID. And then of course, if they're not controlled, we move up to two and so on. So I would not do that in someone who's seriously ill with very high values. But in a patient with mild Cushing's, I start with a lower dose. I agree. And now I start with a lower dose in many patients. So let's get Professor Strasburger the chance of asking a question. And then I have other questions in mind for you. Thank you. This is a completely different topic. And first of all, I would like to thank all you four experts for sharing with us these very educative cases and sharing your insights. I get a bit of a stomach ache when I see a patient who clearly has ACTH-dependent Cushing's. And in the end, we end up with steroidogenous inhibitor drugs because it just indicates that we couldn't localize and or remove the tumor. So my question to all four of you is, what is your current experience with and what is your future hope for functional imaging? I can start and then I can let my colleagues. In US, what you are referring to, the great PET with methionine is not possible yet. We had Mark Cornell visiting us trying to set it up. You are welcome to try. Maybe other centers can do it, but it's not FDA approved and it's almost impossible. So without that functional imaging, I wouldn't count on any other imaging besides the MRIs that we have. And I can say that I have long-term experience with medical therapy. So we had in the studies patients for over six and seven years that are on steroidogenesis inhibitors in several of the studies. I have patients that are on glucocorticoid receptor blockers also for long-term. Again, to begin with, we didn't start in patients with large microadenomas. So these were the patients that went to repeat surgery, irradiation, but in some patients, and as Andre Lacroix had the case that he presented that the tumor grew. In another study, Jay Findling had a case that ended up being carcinoma. I also had a case that was posted was pituitary carcinoma that they grew. But I don't think per se we have a concern. However, going back to your question, I would be happy to have more imaging and better imaging, but if you remember in all the guidelines we said, we still need the data. There are very few cases and who's reading them is the Cambridge group that they have one of the best software and people that are doing analyzing from all over the world. So I'm not sure even if we get the meta-INN scans, who's going to read them to be able to see a one millimeter tumor so then Michael can cure the patient. But I want to see if you have better imaging or better experience than that. No, we're in the same circumstance. It's not available, but I would love to have better imaging. Go ahead, yes. For the surgeons, Christian, it's, I think, crucial because the results are so clearly dependent on whether a tumor can be depicted or not. Also from the psychological conviction of the surgeon. If you know that a tumor is there, you make your utmost efforts to get it. I'm hoping that they will develop another radiopharmacon, which is available more widely and not in only the centers that have a cyclotron within reach. Yeah, so it has to be, for now, 15 minutes from the center. So that's why it's almost impossible. Go ahead. Yes, by just commenting the extension of this, that if you are not able to localize a tumor with a 1.5 texla, you can go for a three texla MRI also. Sometimes that is more helpful in localizing the tumor. And another thing is that recently we have evolved with a CRH scan that we published last year that CRH scan for localizing the pituitary corticotropinomas. So I think that will be another useful modality for that. However, this facility may not be available at most of the places. But this we've already published. Okay, thank you for your comment. Go ahead, sorry, I should have switched earlier. Let go back and forth, yes. No worries, thank you very much. Elizabeth van Rossum, Rotterdam, the Netherlands. First of all, thank you so much for this very excellent case presentations. I was wondering, in the recent years, our new data that cortisone in saliva in a skull pair, they have high diagnostic accuracy for initial diagnosis of Cushing's. I was wondering whether you have some experience already with recurrent Cushing's, how the diagnostic accuracy is there. So cortisone rather than cortisol. Yeah, I haven't seen much data about that. I think it's particularly useful because you can look at whether patients are taking exogenous Cushing's. That's one good way to help figure that out. But no, I have not seen any data in recurrent Cushing's and would welcome it. So for recurrence, I haven't seen anything better determined for recurrent, for initial diagnosis though. For most patients with adrenal adenoma, it's a paper a few weeks ago that I have not seen it until I was asked to write a commentary on it last week. So it seems it correlates very well with the overnight dex. So the cortisone is better than the cortisol. But I think for recurrence, we don't have the test that would be the gold standard. So we think salivary is better. Beverly showed that it's better. But as you see, not all of them were high either. So which one you would consider? I think that for severe disease, both cortisol and cortisone are clearly better than what you have seen in most patients and most times. For recurrence, I don't know. Yes, okay, thank you so much. Khaled Baga from Qatar. Thank you for excellent presentations. For osteoarthritis, do you usually use block and replacement therapy? And if we will use replacement, at what point do you start your replacement with hydrocortisone? I can start because Irina already showed some cases and I think she chose the cases that were the most difficult. So one, to show us how great medicine is at Mayo Clinic, but also from the teaching point of view. I have to say that most of the patients with the exception of severe Cushing's, with osteoarthritis or levoketoconazole or other drugs, I do not use block and replace. In some patients, for example, and we didn't have time to talk and I'm really curious to hear from my colleagues, I start, for example, osteoarthritis at night. I start with lower doses to avoid adrenal insufficiency or withdrawal and don't ask me how I make the diagnosis because I don't have an answer for you. And then slowly, because in my mind, the patient had Cushing's for five years, I'm not in a rush to fix it within weeks. So I go slowly up on the doses. And then, yes, when it was COVID, I used more block and replace, but otherwise, for many, many patients, I'm able to adjust doses accordingly and I use block and replace if they are sick, but sometimes it's not even block and replace because then I stop the osteoarthritis and give them steroids. If they have surgery, I stop it again and sometimes I give them a little bit of steroids, but not long-term block and replace. I have very few patients. And I like to use higher dose of night. As you've seen from many, many talks at this meeting, chronotherapy is very important for Cushing's. Do we know how? And it was a good question to Irina. Do we know how the drug would work to actually decrease the cortisol at night much better? No, but if the patient has insomnia, for example, I increase the dose at night and sometimes the patients get better. So higher dose at night in general and then it allows me to decrease the dose in the morning and to avoid some of the symptoms. But let's hear from Beverly also because Irina told us. Very similar, actually. The reason I don't use block and replace in most patients, unless I'm in a rush and they're really ill, is that I think we, or I'll just say I, am bad at glucocorticoid replacement. We don't have any biochemical marker to tell us how to adjust the dose the way we do with TSH for primary hypothyroidism or something. And so it's all clinical judgment. And the concern is the patients end up getting more than physiologic replacement. So then we're creating iatrogenic Cushing's on top of blocking their cortisol excess endogenously. So I generally don't do that, except in the circumstances similar to what Maria has outlined.

Cushing Syndrome

diagnosis

management

individualized treatment

recurrence monitoring

pituitary directed therapies

sterogenesis inhibitors

glucocorticoid receptor blockers

combination therapy

functional imaging

medication dosing

ongoing research