I am delighted to see all of you here in the room, as well as welcoming those of you who are participating virtually in this wonderful session on Dilemmas in the Management of Pituitary Tumors. I'm Beverly Biller from Mass General Hospital in Boston, and I'd like my co-chair to introduce herself. Hi, everyone. I'm Flavia Amanda Costa Barbarosa from Federal University of Sao Paulo, It's an honor to be with you today. Super. Each of our three terrific speakers will talk for 20 to 25 minutes, after which you can come to the microphone if you'd like to ask questions for the remaining five minutes or so of their block of 30 minutes, or you can submit questions online, typing into your phone using the QR code that you just saw. So let's get started. It is my absolute delight to introduce a colleague who has been in my pituitary world for so many years, and that's Professor John Wass at Oxford, where he was head of the Department of Endocrinology for many years. He has published over 400 papers, and he has led many organizations as the president or chairperson, EFES, SFE, Pituitary Society, and he's received so many awards that I could take up his 25 minutes by telling you about every award, but I will just mention that he will be receiving an award at this very meeting for outstanding leadership from the Endocrine Society. But now it is time for him to tell us about discrepancies in growth hormone and IGF-1 in acromegaly. Professor Wass. Beverly, thank you very much indeed. That's very kind of you. And can I begin by thanking Nikki Karavitaki for the invitation to do this symposium? She's actually recovering in Birmingham from COVID, and I'd like to wish her well for a rapid recovery. And can I also please thank Beverly, who with her characteristic diligence and efficiency has put together this session and made sure that all the speakers interact. And as she says, it is absolutely lovely to be here. This is my first trip to the US for a couple of years now. And I actually think that endocrinologists can do things virtually, but actually it's much more fun. And I actually also think that it's much more likely to generate good ideas if we're reacting with each other face-to-face. And so it is a real pleasure to be here in Atlanta. This is my first trip to Atlanta. So I'm gonna talk a little bit about discordance of IGF-1 and growth hormone in acromegaly and really address the question, does it affect mortality? And that's the purpose of the talk. And the two ladies who are there, Dayakshi Abhiratne is from Sri Lanka, and she's been in Oxford for a year or so now, and has now gone back to Sri Lanka actually, but I'd like to say how much she has contributed to this project over the last year or so. And also on the right there, Sonia Jakubowska, who comes from Gdansk in Poland, and who's also been absolutely hugely wonderful in helping to put all these data together. And I'd like to commend these two people who I now consider our friends as well. No conflicts of interest. So the question is discordance of growth hormone and IGF-1 in acromegaly. And I think this is a well-recognized phenomenon. And when you read all the papers about it, basically everybody says, well, we don't really know what to do. Do you treat them for symptoms? Do you treat them at all if they haven't got any symptoms? And the question is, what do we do about it? And I think that there's been no really good data, and I think and hope that what we're going to describe today is going to be useful in that regard. And the question really is, does this affect mortality? Because we know from the previous papers that growth hormone and IGF-1 are high, that does affect mortality adversely. And does it affect morbidity? We've also looked at that, and you'll see those slides in a bit. And so those are the questions we asked now about a year ago. And what do we define of the cure of acromegaly? Well, it's very important that this has changed over the years with the changing sensitivities of the assays, the changing normal ranges, and so on. And so what we hope is that an IGF-1 is normal in an age and center related. And this is one of the problems with these analyses is that the IGF-1 assays are different in different laboratories, they're different normal ranges, and these normal ranges have changed over the years. And this is something which Peter Treanor has highlighted in the past. And it's something which I think is something which we need to be very careful about in interpreting the figures that we've got. And then over the years with Shlomo Melmed and Ken Ho and others, we've spent some time in various locations on the planet discussing normal growth hormone and normal IGF-1. And the level of growth hormone has come down. And in the olden days, a post-operative growth hormone of five was normal, then it was 2.5, and now it's one. So that has changed over the years as well. And I think that's an important consideration when we're analyzing the data. Now, these are slides which you'll be familiar with. This is Ian Holdaway in New Zealand, who back in 2008 and before that, actually, has done a whole load of work showing the importance of ambient growth hormone after treatment and its effect on mortality. And in the top half of this slide, you can see the various papers from people who've reported that if growth hormone is high, the mortality is up to doubled. And on the bottom half, Ian Kabirmaz, Brooke Schwering, and others have actually highlighted that if the growth hormone level's normal, then mortality becomes normal. But what we don't know, as I said, is what happens if growth hormone and IGF-1 are disparate. That means that one is high and one is normal, or the other way around. And this is IGF-1, and this is also Ian Holdaway's work, showing that if the IGF-1 is normal, then the mortality is normal, whereas if the IGF-1 standard deviation score is greater than two, mortality is significantly increased, and you can see that from that slide. And that's where we start this study. Now, I'd like to just take a brief look at the acromegaly register in the UK. I helped to start this back in 1997, and in its current form, it's been running since 2006. I, and then Peter Treynor, chaired it, and Peter Treynor got the Christie Hospital to academically support this, and it's been sponsored by various people, as you'll see in the next slide, since 2005. And the funding's come from the Clinical Endocrinology Trust, from Ibsen and Novartis over many years. We have a total of 3,563 patients, and that's a number who are deceased is 809. Those discharged, 52, lost to follow-up, 288, and move, 38, and unknown, two. And I have to say that running the acromegaly database has been, at times, a significant challenge, helping to help and get people to update their data, to fill in the bits of data that we need, and so on. But we have chased this very ardently, and I think we have a reasonably reliable database upon which to base various of our findings. And this next slide shows some of the papers that we've actually published in the past from 1997. And the first one is Paul Jenkins' paper on radiotherapy and acromegaly. And this was published in JCNM, and showed that, actually, growth hormone levels take a long time to come down. In 40%, even at 10 years, they're not normal. And so, also, that the higher the growth hormone ab initio, i.e., from the beginning of treatment with radiotherapy, the longer it takes to bring the growth hormone level down by radiotherapy, so that, I think, radiotherapy takes a long time, and is by no means always effective. In the second paper, Peter Bates showed a wide variation in surgical outcomes, and this was the first data in the UK showing how important it was that surgeons actually have experience. And we now have been around, actually, all the country's endocrine departments, and we've now delineated exactly how many surgeons there should be, and Brooke Schweringen has done a huge amount of really good work in this area as well. And I think this was the first time that, actually, people realized how important it was to get an experienced surgeon. And when I was going around in the UK, there was one surgeon who was done doing one microadenoma a year for Cushing's, and another area which the same surgical numbers were there. So it was one per year, and in one of these centres, the cure rate was zero. And so I think that it's really important that we actually are using surgical numbers to delineate the experience, and therefore, the outcome for the patient, which is hugely important. And then Trevor Howlett, who was in Leicester, did a whole series of studies and published this paper on medical treatment in acromegaly, and showing the outcomes, and showing, actually, that the response rate to somatostatin analogues wasn't as high as we'd previously thought. And there'd been other papers which have said that as well. So those are some of the things that we've done in the past. So there's been a little bit of publications, but no big studies that I can find. And this is Campano et al. this year, last year, showing in 90%... 90 patients, rather, of the importance of the cutoff for growth hormone and IGF-1, and this is something we may like to discuss later. And so what he showed was that there was a high discordance of patients if the growth hormone was taken as less than one, which is the current accepted normal range, I think, for people who've been treated with acromegaly to define them as cured. And high IGF-1 was predominant if the growth hormone was less than 2.5, but that's, I think, now an old-fashioned delineation of cure for acromegaly. And he also showed that using a mean of three growth hormone values lessened growth hormone discordance. And so the message there is that growth hormone and IGF-1 discordance depends on the growth hormone cutoff, and we use less than one, as you'll see in a minute. And then this is a paper from Zinaladeze, who showed or discussed the various causes of discordance, and there are quite a lot there, and I'm sure that that list is not comprehensive. And so altered growth hormone dynamics after surgery may be a problem. Too early post-operatives. Assay may be a problem, and we shouldn't be measuring IGF-1 until three months after the operation, as has been shown in Rotterdam by A.J. Vandalili and his team there. Inaccurate and less sensitive tests, I've talked a little bit about that, and Peter Treynor's work on IGF-1 assays. And then laboratory errors. Sometimes you find that your growth hormone patients suddenly are showing high IGF-1s, having previously been normal, and you worry that the laboratory is actually, there are errors in the laboratory methodology there, and I think that that's something which we sometimes seem to see with IGF-1 assays particularly. And then the cutoff points of growth hormone, I've mentioned how important they are and how they've changed over the years. And then concomitant medication like estrogen and so on. And so those are some of the factors that are involved. So what we did in the UK acromegaly database is that we selected four groups. This is very straightforward. With a normal growth hormone and IGF-1, we took IGF-1 cutoff as 1.3 of normal, which is what's been done in the literature. We took high growth hormone and high IGF-1 as the comparative group. And then we had two other groups, one with a high growth hormone and normal IGF-1, and the fourth with a normal growth hormone and high IGF-1. And we looked at those, as you'll see. Now we looked at patients who had simultaneous growth hormone and IGF-1 measured at the same time. And if it wasn't done at the same time, we didn't use those samples in our analyses. And so from that, we had 2,138 numbers out of a total of 3,500. And we had 41,331 person years follow up from 29 centers. And so there are a large number of centers involved all in the UK in this data. 50% of the patients were male with a mean age of diagnosis of 47.1. And what we showed was that the growth hormone and IGF-1 was normal in 1,210. The high growth hormone and high IGF-1, the cohort was 326. And the high growth hormone and normal IGF-1, the cohort was 429. And the normal growth hormone and high IGF-1 was 173. And it's interesting that in the analysis of the high growth hormone and normal IGF-1, the female to male ratio was 60 to 40. And the other way around was the case in the high growth hormone and normal IGF-1 the female to male ratio was 60 to 40. And so those are interesting facts. I don't think they affect the outcome. And then 173 with a normal growth hormone and high IGF-1. And the discordance rate, and this is something which is not new to those of you who know this literature, was a mean of 28.2% with a range of 5 to 47.4%. And this was quite a significant range. And what we found, which I won't show you the data on, is that the discordance rate was higher in the centers where they were returning more patients. I don't think that's relevant either to the outcome of this, but it was very variable in the various centers. And this is across, as I say, 29 centers in the UK. And the most discordant was growth hormone at 71%. So that was a variable discordance rate, but it certainly occurs at a significant percentage. And therefore, importantly, in the decisions to make for patients further treatment with discordant growth hormones, this is something which is a significant issue when we come to address patients who've had operations or are on treatment for various, by various means. When we looked at the mortality data, we actually took out the PEG-visceromotor patients, because obviously those will have a not suppressed growth hormone and a normal IGF-1. So this analysis took out about 70 patients who were on PEG-visceromotor in the UK at Cremegly database. And there were a total of 451 deaths, and the causes were available in 418. We're actually working in Scotland with Peter Trainor's help, who wears a kilt at the best of times. And basically, he is helping me with the mortality in Scotland. So 212 had both normal, 103 had both high, 105 had high growth hormone, and 38 had IGF-1 high. And the mean age at death was 73.4, plus or minus 10.8 years. And so these patients had a reasonable life expectancy on the whole. In the both discordant groups, there was a lower median survival. So at the bottom there, the normal was 41.8 years with a range of 37.7 to 45.8. And the discordant growth hormone patients had a lower life expectancy of 35.5. And you can see the confidence intervals there. And the IGF-1 discordant had a lower confidence, had a lower mortality, sorry, a higher mortality with the confidence intervals there. So the growth hormone and IGF-1 discordant groups were both had a lower median survival compared to the normal. And then we looked at age and gender adjusted hazard ratios. And these were higher in the higher group, growth hormone and IGF-1. And the growth hormone discordant group, it was 1.32 with a confidence interval of 1.03 to 1.68, and that was significant. And with the IGF-1 discordance, the adjusted hazard ratio was 1.53 with the confidence intervals of 1.06 to 2.2. Again, that was a significant difference. And so we're showing here that the growth hormone and IGF-1 groups both had a higher hazard ratio compared to the normal group. We also looked at comorbidities, and we looked at hypertension, myocardial infarction, heart failure, and arrhythmia. As I say, we've got the death certificates on most of these patients. We looked at respiratory deaths, COPD, sleep apnea, malignancy, breast and lung. And somebody working on this database because this came up in our meeting in Milan a week or two ago on breast cancer. But we've looked at that. We've looked at metabolic disease and neurological disease. And in terms of morbidity, the only difference that we found was that diabetes mellitus was higher in the IGF-1 high group compared to the normals as opposed to the growth hormone where there were no differences in morbidity. And here's the graph showing the survival. And you can see at the bottom there the survival of those who had growth hormone and IGF-1 that was high in the black. And at the top in blue is the patients who had normal growth hormone and IGF-1. And you can see there's a significant difference between those and that the growth hormone discordant and IGF-1 discordant come in the middle of those lines which actually show the importance of the growth hormone and IGF-1 being abnormal and that affecting mortality. So in summary, I think these are the first data which in a large group of patients with acromegaly show that discordance of growth hormone and IGF-1 are important. If one is normal, it's associated with a higher mortality than patients with both normal results. And I think that this probably means that we've got to take a slightly different attitude to patients who have a growth hormone that's higher than IGF-1 that's normal or vice versa and think about starting treatment in more than a routine way because I think that this means that hopefully if these data are confirmed that this is something which will affect our practice in the future. Thank you very much. Thank you. Thank you, John. That's quite a remarkable database. Very, very exciting data that you shared with us. If anyone has questions, you can step to the microphone and state your name and where you're from. Hi, Asher Grossman from, well, mainly from London. John, that was brilliant, fantastic. I just wonder whether the use of somatocetin analogs influence your results in any way based on the work of A.J. Vandaleli and others. Obviously, that can affect the concordance between GH levels and IGF-1. And were you able to analyze whether it had a specific effect on the discordance rates and the mortality? Okay, so that is a very important point. And we haven't been able to find a difference in this if you're on somatostatin analogs. And the other thing I thought following, so that's a no at the moment. And the second thing that's important is radiotherapy, because I was worried that there was more discordance in the radiotherapy patients and slightly because of Ariel Barkan's work, a slight, and I'm sorry, there wasn't. And so radiotherapy doesn't seem to affect it as far as we can tell. Very interesting, important points, thank you. Professor John Morasta, Manilka Sumanathilaka from Sri Lanka. In our limited series, this is pure anecdotal, we have about 100 patients. This discordance group is very much real. And what I see is that those with normal growth hormone and high IGF-1, they seem to have a lot of insulin resistance, acanthosis, more diabetes, they're obese. And the other way around, they seem to have fatty liver disease, low IGF-1 and high growth hormone. So have you looked at those factors, the insulin resistance factor, HOMA-IR, or the fatty liver, the presence or the absence of fatty liver disease? Okay, I think that's very interesting. We haven't obviously done that because those data aren't available on the acromegaly database, but certainly a subsequent study could look at that in a smaller cohort of patients. I think that's an important point which we should take further. Thank you. I think that she's working on it, so we can share your data. Okay, well, we must liaise with Dayakshi then. Yes. If she's in Colombo as well. Yes. Very good. Gérald Ravrault from Lyon, France. Very nice presentation, thank you. Do you have the chance to see, to evaluate how long the patient were on this discordance stage? You know, it's at certain time point, but do you know that you have some patients with this discordance for years? Yeah. And the impact of the therapeutic strategy for each patient? Yeah. So that's something which we haven't looked at, but I think we could and probably should look at it because the question is, if they're discordant once, are they likely to carry on being discordant? That's your point. And I think that's a very interesting thing which we actually haven't looked at, but we will do. Thank you. Ken Ho from Sydney. John, fabulous data. The ratio between growth hormone and IgM1 will be different between men and women. So do your survival data fall in accordance with a gender difference in survival? Okay, that's very important. And we haven't actually, because for another talk I'm doing in a day or so, I've looked at that as well. And the answer is that there doesn't seem to be a discordance in survival data with women versus men. Actually, women tend to be diagnosed later, as you know, but there doesn't seem to be a survival difference in women versus men. Because the data in the literature, Ken, as you know, are that women have bigger tumours at presentation and they take longer to present their age. I'll show you the data on some tomorrow, actually, from our database, which we've analysed specially. But basically, the women tend to be diagnosed later. Thank you. Very important point. Thank you. Vygursky, Washington. Do you have anything in your database related to patient-reported outcomes and functionality? Not particularly. No, not specifically. So, quality of life hasn't been assessed, actually, and it's an important topic. And since it was founded in 1997, it's become an even more important topic with all the work that Susan Webb has done. But we don't have any data on that, no. Very important point. I think beyond mortality, that's… Yeah, yeah, yeah, no, sure, absolutely. Because endocrinologists tend to be obsessed with numbers and not the quality of life so much, and I think that's an important point. We have one question here. Do you always do OGTT even if GH is suppressed? So, in Oxford, the practice is that we do an OGTT usually at diagnosis. And if there's any doubt, then we'll do an OGTT, but otherwise we rely on growth hormone and IGF-1 on its own. So, we don't often do an OGTT unless there's doubt about what the state of the patient is. John, I wonder if you can continue discussing the difference between men and women. So, the diabetes, for example. Can you just talk more about that? Speculate, maybe, what you think is happening? Okay. So, I mean, one of the things is, why is the diagnosis of acromegaly later in women than it is in men? And there's an overlap of symptoms of the menopause and things, which is the mean time when they tend to present. I wonder whether that's partly related. We don't quite know exactly why they tend to be diagnosed late. And then the disparity with growth hormone and IGF-1 may be related to estrogen, I think. So, if the growth hormone is high, that may be estrogen. So, those are a few speculations, but I think they're important points, actually. So, another question I have is that you have a fantastically large database, and the number of patients lost to follow-up was impressively small. But I wonder if you, at 282, I think, I wonder if you know anything about them, the reasons that they were lost to follow-up. Is there anything we could learn from that group? We haven't analyzed. That's an important point. We haven't analyzed it specifically. You know, patients may go abroad and things like that, but I haven't analyzed that specifically. Yeah, whether there was any one typical reason. Yeah. Okay. Go ahead. Heaney. Hi, John. John, I'm curious, what implications do you think this has, if any, for the patients we treat with therapies such as pegvisimone, where, I guess, potentially, we could be masking the patients who have, you know, the IGF-1-Gase discordance? I think that's a good thing, actually, because I think that, basically, what we don't know is what the right criteria are for pegvisimone-treated patients, and what we're talking about is a normal IGF-1. So, we haven't analyzed those yet, but I think it's an important aspect to do. But we haven't got quite enough patients to do it in, at the moment, I would say. But I think that's an important point, because that's a question that hangs over this study, which is, what about the pegvisimone-treated patients? I agree. Thanks, Heaney. Awesome investigation. Congratulations. I come from Quito, Ecuador. My question is, have you identified any relation between Gase or IGF-1, and the complications? For example, if GH-1 or IGF or G8 is a better, have a better relation with a tunnel carpal syndrome, or with cardiovascular complications, for example? Yes, we haven't looked at that, but perhaps we could have a discussion afterwards, because I think it sounds important and interesting. Very good discussion. Thank you very much. Yes, I'm going to ask you one last question. Oh, go on. One last question. Going to your conclusions, you talked about how it may need to change how we think clinically in terms of when we jump into treatment. Do you now think of both of these hormones in the same category as dating perhaps earlier treatment, or do you think of one above the other? How do we address that? Okay, that's interesting. Because there are some places that only measure IGF-1, and I've never just done that. I always measure both, but there's one place in Holland, for example, that just measures IGF-1, I think. I think they are both important, and I think that this, in a way, shows that they are both important, and you've got to respond to both values, actually. That's my sense of it, anyway. That may be rather idiosyncratic, but it would be interesting to hear other views later. Oh, looks like there's one more. Yes, I think it's the last one. Do you suggest a more conservative approach in terms of dosage for these patients with GHD in order to ensure IGF-1 and GH in normal levels? I don't think so. Yes. I think this is related to how do you think about over-treatment and driving things too low? Okay. Well, we don't have any data on that. It's very interesting. I think that, you know, because the work in Boston actually has shown how important growth hormone deficiency is in acromegaly, and how important it is to treat it from the symptomatic point of view, and so we haven't addressed that, but I think it's an interesting point. So maybe both normal is the best way to go. Yeah. Okay. Thank you so much, Professor Wass. Now, Dr. Athanasios Fontes from University Hospital of Athens, Georgios Gymnathas is going to present how to manage Nelson syndrome. Thank you very much, Dr. Kostopoulos. I would like to thank the organizing committee at the Endocrine Society for the honor to talk today about the management of Nelson syndrome. I have nothing to disclose. Nelson syndrome is a potentially severe complication in patients with Cushing's disease treated with bilateral adenolectomy. Its prevalence varies significantly between studies influenced mainly by the diagnostic criteria, the length of the follow-up, and the potential referral bias. However, in a recent systematic review of 36 studies, and followed up for a median period of seven years, a mean prevalence of 26% of Nelson syndrome was reported. There is no consensus about the definition of Nelson syndrome and the diagnosis mainly based on three main axes, the audiographic evidence of corticotoftumor growth, or recurrence, and the diagnosis of acute myelodysplasia. The diagnosis of acute myelodysplasia is the three main axes, the audiographic evidence of corticotoftumor growth, or recurrence, the increased plasma ACTH levels, and the development of a skin pigmentation. A recent expert concessions recommended that the primary criteria for the diagnosis of Nelson should be the audiographic evidence of corticotoftumor progression, or recurrence, while progressive increase of ACTH plasma levels, and the skin pigmentation should be considered non-mandatory secondary criteria. Although more than 60 years have passed since Don Nelson described the first patient with Nelson syndrome, the pathogenesis of the syndrome remains unknown. There are two suggested theories. According to the first, Nelson represents a national history of corticotoftumor programmed to behave aggressively from the outset, while according to the second, the loss of the negative glucocorticoid feedback on the hypothalamus after the adrenalectomy leads to subsequent increase in CRH production and corticotofneoplasia. Many studies have assessed the potential predictive factors for the development of Nelsons, and the most consistently identified is a higher levels of ACTH after the bilateral adrenalectomy. However, a specific cutoff has not been defined yet. We have four main options for the management of Nelsons. The pediatric surgery, radiotherapy, which can be other primary loss or adjuvant treatment, active surveillance, and medical therapy. However, the data that are available on outcomes of patients with Nelsons are very limited, and this is because Nelson is a very rare condition, and we have available only studies with small sample size and usually from one center. There is a wide heterogeneity in the monitoring approaches, the definition of the recurrence of Nelsons, the length of the follow-up, and the imaging modalities used in each study. In some of them, already recurrent tumors are included in the analysis, so this makes the interpretation of the results more difficult, and we should not forget the potential referral bios of the reporting centers. In order to elucidate the outcomes of patients with Nelsons after primary management, we performed a retrospective cohort study of patients with Nelsons from 13 UK pediatric centers. The criteria we used for the Nelson syndrome diagnosis was imaging, evidence of adenoma growth, or identification of new tumor if previously the imaging was negative, biochemical criteria, gradually increasing monitoring and morning ACTH levels, and or lack of ACTH suppressions two hours after the morning glucocorticoid dose, clinical criteria, which was the development of skin pigmentation. A total number of 68 patients were included in our studies, and as expected, most of them were females, and the median age of diagnosis of Cushing's was 30 years. 30 patients were treated for their Cushing's with surgery and bilateral adenolectomy. Eight of them had two surgeries, and one patient had three surgeries before proceeding to bilateral adenolectomy. 17 patients were treated with pediatric surgery, radiotherapy, and bilateral adenolectomy. One had three courses, sorry, three courses of radiotherapy. Another patient had two courses. One patient had two surgeries before the radiotherapy, and another patient had two surgeries, followed by radiotherapy, and then two further surgeries. Two patients received radiotherapy and finally an adenolectomy, and 19 patients had an adenolectomy as a primary treatment. The median age of diagnosis on Nelsons was 42 years, and the diagnosis was made based on imaging and biochemical clinical criteria in 53 patients, while in 40 patients the diagnosis was based only on biochemical and clinical criteria. The median interval between the time of adenolectomy and the Nelson diagnosis was three years. With regard to the primary management of the Nelsons, 10 patients were treated with pediatric surgery, 22 only with radiotherapy as a primary treatment. 18 patients received surgery and adenosine radiotherapy, 16 were observed, and two received bacilliotide under clinical trial. The median clinical follow-up was 16 years, and the median imaging follow-up was 13 years. During this follow-up, 18 patients developed further tumor progression, and as you can see on the left top of the Kaplan-Meier analysis, the 10-year tumor progression free survival for these patients was 62%. There was a statistical significant difference in these survival rates according to the type of the primary management, with patients treated with pediatric surgery without or with radiotherapy having the best optimal control, with survival of 80 and 81% respectively. We also performed a sample analysis according to the criteria we used for the diagnosis of the Nelson syndrome, and as you can see on the left of the Kaplan-Meier analysis, the 10 years tumor progression free survival for the group of patients that Nelson was diagnosed based on biochemical and clinical criteria and imaging was 65%. In this group, there was not a statistical significant difference according to the type of the primary management, and those that the diagnosis was based on your biochemical and clinical criteria, the 10-year tumor progression free survival was 50%. We did not perform any further analysis according to the primary management because the number of the patients was small. Pediatric surgery is the first line treatment in cases of Nelson syndrome, and traspinolder root is a preferred approach, but this depends on the tumor localization and the direction of its growth. There are some other studies, a few other studies that include more than 10 cases, and they assess the outcomes of patients treated with pediatric surgery as a primary management, and as you can see, the recurrence rates are similar to the UK Nelson study, 15 to 20%. Small tumor size and no extracellular extension has been associated with long-lasting remission. Radiotherapy is also another approach. It can be used as primary or as adjuvant treatment. As primary treatment is mainly considering patients that are not candidates for surgery due to the tumor location or significant comorbidities. Conversional radiotherapy was used mainly before 2000, and in our study, in the UK Nelson study, patients that were treated with conversional radiotherapy had a 10-year tumor progression free survival of 52%. However, it should be noted here that four of these patients have already been treated with another course of radiotherapy for the treatment of their cushiness. With regard to stereotactic radiosurgery, the available stats that we have have given promising results regarding the recurrence rates between 0 to 16%. However, this result should be interpreted with caution because these stats are few, they have small sample size, and we should not forget that there is potential selection bias. Radiotherapy as adjuvant treatment is mainly used in cases of incomplete tumor excision in order to control tumor growth, and in the UK Nelson study, the 10-year tumor progression free survival of the patients that were treated with this approach was 81%. In another study assessing the outcomes of these patients with treated with surgery and adjuvant radiotherapy, a particular tumor progression of 14% was found during a median follow-up of 17 years. However, this was an already recurrent tumor. Active surveillance is mainly considered in patients with small tumors that do not cause mass effects or vital sizing structures. In the UK Nelson study, the 10-year tumor progression free survival of these patients was 51%, and in the majority of cases, active treatment was finally needed. In another study, a particular tumor progression of 85.7% was found during a small median period of follow-up of 2.5 years, and it should be noted here that these seven patients, the six of the seven patients that had tumor progression finally received active treatment with surgery or radiotherapy, while the seventh developed a massive pituitary hemorrhage. With regard to medical therapy, we do not have any established medical therapy for the control of ACTH or tumor growth in patients with Nelsons. There are several types of pharmacotherapy that have been proposed, and the data on their effectiveness are limited and inconclusive. Dopamine agonists, and especially carbergolin, are being used of label in patients with Cushing's. Corticosteroids express type 2 dopamine agonist receptors, and the use of dopamine agonists leads to inhibition of ACTH and secretion and potentially tumor secretions. There are some reports demonstrating effectiveness of carbergolin and vermocryptin in patients with Nelsons. Sodium valproate, which is an inhibitor of gamma-aminobutyric acid, we have taken of the hypothalamus, leading to decreased CRH release, was used in the past, but the available reports have showed an inconclusive effectiveness. And serotonin agonist, and especially cyproheptadine was used in the past. There was a potential, that caused a potential suppression of ACTH secretion. However, the use of this agent has been abandoned nowadays due to lower effectiveness. We should not forget about the peroxon-proliferator-activated gamma-receptor agonists, and especially, particularly, rosiclitazone. There are some in vitro studies that showed that rosiclitazone had an antiproliferative and pro-apoptotic effects on tumor ACTH secreting cells. However, these results have not been replicated in patients with Nelsons, and rosiclitazone is not used anymore. Finally, somatostatin analogs. Chondrocortopinomas express subtype 2 and mostly subtype 5 somatostatin receptors, and there are some case reports of octeotide decreasing ACTH levels and controlling tumor volume. Nowadays, pasireotide is under investigation, but pasireotide is approved for the treatment of patients with Cushing's disease. It causes ACTH inhibition and potential tumor size reduction. However, it is associated with high rates of hyperglycemia. There are some case reports that show the effectiveness of pasireotide in reducing ACTH levels in Nelsons patients, and there's also a small case series, including seven patients that were treated with pasireotide, and ACTH reduction developed in all of them during a 28-week period. There was no significant change in tumor volume, and six patients developed hyperglycemia. In some patients, some patients will develop further particular tumor progression, even after primary management, and identification of predictive factor is challenging. In this patient, management is individualized, tailored to previously offered treatments, and due to the SCART 11 literature, is not evidence-based. In the UK Nelson study, we tried to assess multiple parameters to find potential predictor factors for further particular tumor progression after the primary treatment, and as you can see, neither sex, age at Cushing's or Nelson's diagnosis, size of adenoma at Cushing's diagnosis, presence of predatory tumor on imaging prior to the adenolectomy, internal between the adenolectomy and Nelson's diagnosis of three years above or below, the mode of primary management of Nelson's and diagnosis of Nelson's based on imaging criteria were not predictors of particular tumor progression. However, what we found was that the mode of management of Cushing's before the diagnosis of Nelson's was a significant factor predicting particular tumor progression after primary treatment. Specifically, we found that patients that were treated with surgery, adiotherapy, and adenolectomy for their Cushing's had a hazard ratio of 4.6 compared to those that were treated only with surgery and adenolectomy. This finding remained even when we adjust findings according to the type of the primary management for the Nelson's, and when we focused only on patients that diagnosis were based on imaging and biochemical clinical criteria. This finding possibly reflects that a tumor, corticot of tumor that is aggressive from the outset and receive complex treatment for the Cushing's probably will behave aggressively and as tumor during Nelson's syndrome. However, this remains to be elucidated. With regard to regarding management of recurrent Nelson's, we have extremely limited studies assessing outcomes. Stereotactic surgery halted tumor progression in a very small study of four patients, and as you can see in the UK Nelson study, different approaches were employed and with varying results. However, the numbers are too small in order to make robust conclusions. A small subset of patients will develop aggressive Nelson and their corticot of tumor will demonstrate multiple growths despite the previous treatment modalities. Aggressive Nelson is associated with poor prognosis and increased mortality, and malignant transformation of the corticot of adenoma can also occur. Identification of predictive factor for the malignant transformation is not possible due to the rarity of this phenomenon. In the UK Nelson study, 18 patients had recurrent Nelson's and three of them developed further tumor progression and two had malignant transformation of their tumor. The patients with pituitary carcinoma developed spinal metastasis seven and 14 years after diagnosis of Nelson's, and three patients died during the follow-up due to the causes that were directly related to Nelson's syndrome. They all had an enlarging mass into their brain, and in one patient household also had spinal metastasis. The management of aggressive Nelson is individualized. We use any option that we have in our hands, alone or in combination. There are some reports of temozolomide being effective in aggressive cases of Nelson's but not in all of them, and there are also reports of several of some types of chemotherapy alone or in combination or together with temozolomide. In conclusion, pituitary surgery combined or not with radiotherapy offers the most optimal tumor control. Radiotherapy alone should be considered mainly patients that are not surgical candidates. Observation should be used or considered in small lesions that do not cause mass effects to vital surrounding structures, but we should give these patients other close follow-up for a timely detection. Yeah, yes, please. Yeah, it does not go back. So observations should be considered in patients with small lesions that do not cause mass effects to vital sardine structures, but we should keep our patient in close follow-up for timely detection of further tumour progression and potentially appropriate treatment. We don't have an established medical therapy. Pancreatitis is under investigation now. However, we should use medical therapy when all the other treatments have failed. In a small subset of nursing patients, we develop further tumour growth and in some cases an aggressive behaviour. In these cases, an individualised management tailored to previous treatments should be considered and the temozolomide should be also considered in cases of aggressive nurses. We definitely need further studies to facilitate the development of evidence-based management pathways. At this point, I would like to thank all my colleagues from 13 UK veterinary centres that participate in the UK Nelson study and of course Dr Nick Karabitaki, who was the lead investigator of the study. I would like also to thank the healthcare professionals involved in the care of the patients, the Clinical Endocrinology Trust that funded the study and the University of Birmingham that had the responsibility for the study. I would like to thank you all. We have one question here. You already said that, but do you recommend a specific monitoring protocol to look for Nelson syndrome? Yes. Given that the median diagnosis of Nelson is mainly through the first three years, most doctors and investigators suggest that we should do an MRI scan 6-12 months after a veterinary dialectomy and then annually for the first three years and then according to the levels of ACTH, plasma ACTH, we can extend this period every two years and we should measure ACTH levels for the first three years every six months and then annually. Thank you. You mentioned the median of three years. What was the longest you saw it happen? I think it was 32 years. 32 and had the patient been followed in that interval or was it that they hadn't? Yeah, there was a period of 14-15 years of loss to follow-up in the first three years but then it was followed. Thank you. Let's go to the microphone. Thank you. That was super and I think it's a really important study. Two things. Number one, I don't think we know how and when to monitor ACTH post bilateral adrenalectomy because Xavier Botania said that early rises in ACTH were predictive of Nelson's development and I don't think we've studied that. So I think our protocol in Oxford is to measure it at three months and then six months and see whether it's going up, but I think that's probably more frequent than most and I'd be interested in your comments on when we should measure ACTH postoperatively. And then the second thing is radiotherapy and when we're doing that. Are we doing that at the time of hypophysectomy or the time of bilateral adrenalectomy or when? Because the old prejudice that radiotherapy was helpful has come out as being useful in that study. So for the first part of the question, I think that we should measure ACTH according to the data we have three to six months after the bilateral adrenalectomy and then every six months for the first three years and then only if we don't have diagnosed patients. For the second question with regard to radiotherapy, the studies that we have in our hands are not inclusive whether radiotherapy is prophylactic or not for the development of Nelsons. There are studies that support this and there are some other studies that do not. So I don't think that we have available data to say whether actually we should perform prophylactic radiotherapy in pituitary after the adrenalectomy just for a prophylactic reason. We don't have it. Thank you. Thank you. Manil Kasumanathilaka from Sri Lanka. Very interesting. I was thinking, even Professor Johan who asked us questions, did you look at or were you not having the KI-67 index and the P53 immunohistochemistry of these tumours? If they are high and positive, whether you could decide on some of these factors in radiotherapy, early radiotherapy? Unfortunately, we do not have the tissue for the samples for these patients in order to check the molecular KI-67 and P53. But usually most of the centres, they do that. Yeah, we are trying to get them, but we didn't have them for the studies. That's something we are planning to do if we find the tissue. Thank you. Asad from Alexandria, Egypt. Very informative presentation. Do you think in your study, did you find any correlation between the plasma ACTH and survival? My question is that does high ACTH can be detrimental to health despite normal glucocorticoids? What do you think about that? We did not make any investigation regarding ACTH levels and the survival or the tumour growth because there were 13 different centres with different laboratories and when ACTH was measured was according to the local team decision and whether it was measured under the morning glucocorticoid dose or 20 hours after the previous dose. And in some centres they also do the measurement of ACTH levels two hours after the morning glucocorticoid dose. So we did not make any analysis according to the ACTH results. That's why I did not mention anything about that. Do you think that high ACTH can be bad for the health despite normal glucocorticoids? This is a very good question and it's a very big talk. High ACTH levels can have a negative psychological impact in some patients due to the pigmentation and also there are increased risk for developing adrenal rest tumours. So I think that if we have a patient that have high ACTH level without a particular tumour in the MRI or growth of a tumour we should not just ignore that. Thank you for your great beautiful talk. Fukuoka from Kobe, Japan. So I'm wondering about if we treat some steroidogenesis inhibitor and a complete suppression of cholesterol using the broken liposome thing for a long time very frequently we see the Nelson syndrome. So I think maybe only the cholesterol suppression is not enough to induce the Nelson syndrome. Maybe another factor is including the bilateral adrenalectomy instead of the suppression of cholesterol. So how do you think of the tumour genesis of Nelson syndrome? It's only for the suppression of cholesterol or including another tumour genesis? If I understood the question right you think whether the CRH increased secretion is the only reason of tumour? So if we treat cholesterol suppression by the medicary so it also induces CRH but it doesn't... If the increased ACTH and decreased CRH secretion was the only cause of the tumour growth then we should see Nelson syndrome in all patients that have Cushing's and bilateral adrenalectomy but we don't see that. As you can see we see that in 26% of the cases so it cannot be just it. It cannot be just only the increased ACTH level and decreased CRH levels that cause the tumour growth. And I'm also wondering how frequently including the USP8 mutant in these groups? We have not looked at it in our study but there is a study from Germany published in 2018 in the European Journal that showed that USP8 mutations cannot drive the Nelson syndrome progression. Okay, thank you. Sorry, I will... Always the same question. Do we really know that bilateral adrenalectomy will increase the risk of malignancy or tumour progression but did you have a chance from your retrospective analysis to see what was the growth curve of the particular tumour before bilateral adrenalectomy? Because in my experience we already have this nasty tumour that we treat with bilateral adrenalectomy just to save the patient but the tumour was already growing before. I'm not sure about this. We looked at the patients after the diagnosis of Nelson syndrome You are not able to... That's a good point. We can do that but for this study we just look at the time of diagnosis. We have one question here. Have you not said that the aggressive behaviour of the tumour during the follow-up depends on the initial signs No. There was no correlation between the size of the abnormal and the further tumour progression. Hi, Diane Donagan from Indianapolis. I was wondering if we're looking at trying to decipher if CRH is going to be a stimulant. Has anybody thought about using the CRH antagonist that they're using for congenital adrenal hyperplasia as a one way of maybe deciphering if it's going to inhibit growth or play a part? There are many reports about the CRH antagonist It can be a good clinical trial but according to my knowledge Do you see Nelson syndrome in Addison patients with chronic ECG elevation? To my limited experience I have not seen one and I don't think that every professional can answer this question I don't think that we can see Nelson syndrome in Addison patients The thing is that in Addison the levels are high in the morning but when they take the morning glucose dose it goes down very quickly This clearly is a topic that we all struggle with so thank you for sharing your data. Thank you. And now it's my pleasure to introduce the last speaker Dr. Grace Avila She went to medical school in Albania and then trained both in Munich and Paris and she is now head of the Endocrine Clinic at Medical University of Vienna where she focuses on pituitary research and I've had the great pleasure of collaborating with her on a number of projects over the years so it's a real pleasure to introduce her and we are waiting for the newly fixed pointer and slide changer which is about to be delivered and then we can hear a bit about how to manage and monitor Cushing's after radiation therapy Take it away. Thank you very much for the invitation and for this difficult topic and I'd first like to start with the recent guidelines of the Pituitary Society Radiotherapy, as we all know is recommended as a second line treatment for patients who are not cured after pituitary surgery or for patients who relapse In very few cases this might also be a primary therapy in patients who have not surgical tumors or who are not a good candidate for surgery Very good candidates for this type of therapy are patients with aggressive tumors who are in such a location that are not very good treatable by surgery so this we should keep in mind all the time when we discuss about radiotherapy How is it performed? There are two types There is stereotactic radiosurgery and the conventional radiotherapy Stereotactic radiosurgery uses different techniques that have one thing in common They are able to deliver a very high dose of radiation in a short period of time in one session or sometimes in a few sessions These use very steep dose gradients and allow a high anatomical selectivity thereby targeting the target issue and sparing the surrounding critical structures In the case of conventional radiotherapy, lower doses of radiation are used and they are given in a few sessions, several times per week usually over a period of time about 5-6 weeks Actually, all the literature that we have nowadays is based on mainly retrospective studies using these techniques In the real world, these techniques have evolved so much during the time and nowadays the machinery we have available is a lot more accurate and allows actually better targeting and better sparing of the critical structures What is the benefit of the radiotherapy? Actually, it is a dual benefit both on ACTH secretion and on tumor growth We should always keep in mind the fact that this is a slowly proceeding event So radiotherapy is not the modality of choice when we have a severe hypercortisolism a patient having several problems and we need to reduce cortisol immediately We can offer radiotherapy to these patients but parallel to steroid synthesis inhibitors or parallel to bilateral adrenalectomy as we have done in the last 10-20 years but this doesn't have a rapid effect Usually 50% of patients are in admission at about 2 years and the long-term success rates vary between 50% to 70% or 80% and it is generally accepted that 2 third of patients receiving either conventional radiotherapy or serotactic radiotherapy will be in remission in the long term What about side effects? Actually, this is the only part I am going to discuss side effects in this talk Hypopituitarism occurs in 14-62% of the patients When discussing about Cushing's we should keep in mind that these patients have hypopituitarism to start with anyway Hypocortisolism, also in the absence of a mass effect, induces a suppression of the gonadotrop axis of the somatotrop axis and also of the hypothalamic pituitary thyroid axis So some of these axes may recover after surgery but some may not All studies show that radiotherapy induces an additional 25% increase in at least one pituitary deficiency in the long term So it adds on to the pituitary deficiency potential that these patients have to start with There is also a very small potential for other complications, cerebrovascular complications and for example cranial neuropathy like optic nerve pulse etc. which are observed in about 3% of the patients in the long term Now, how efficacious is stereotactic radiosurgery and there are many studies with a low sample size This is the biggest international multicenter study that was published in 2017 in JCM and has been our reference in the last years It studied retrospectively 278 patients which had a mean follow-up of 5.6 years with a range of 6 months to 20.5 years Meantime, the cortisol normalization was 14.5 months and I would like to make a point here These 14.5 months are actually quite well reproducible in all studies, whatever the sample size was. So when it comes to Cushing's radiotherapy achieves quicker an effect as in other tumors We all actually have about 10 times more patients with acromegaly in our clinics than those with Cushing's and those centers that use radiotherapy very often they also use it 10 times more in acromegaly, so we're used to expect a long effect coming after many years etc In patients with Cushing's it comes quicker so please take care not to miss it. What about recurrence? Recurrence is also a topic which is seen in all studies. In this study it occurred in 80% of patients with initial cortisol normalization and similar data come also from studies with a smaller sample size. So what happens is that in this study the initial cumulative control, so the control rate was 59% of the patients were in remission 2 years after radiosurgery 77% were in remission 5 years after radiosurgery and 10 years and later on 80% of these patients were in remission Nevertheless, several years afterwards there was a relapse and this is the reason why the durable cumulative control rate is 48% at 2 years, 62% at 5 years and 64% after the 10th year and this is a recent meta-analysis showing actually remission rates in different patient groups treated with stereotactic radiosurgery and different follow-ups and these remission rates range actually till above 80%. Are there any predictors of remission and I would like to bring here an older but very nice paper from South France that showed already in 2009 that low tumor volume and low initial UFC are actually predictors of remission. So uncured patients had higher tumor volume to start with and higher UFC to start with. This larger study published in JCM 2017 found out that the radiation dose actually was important. The lower the marking dose and the lower the maximum radiation dose were, the higher was the likelihood that these patients were having durable control of hypercortisolism. We should keep in mind that the last one was actually a multicenter study so it might be difficult to reach actually the statistical significance in UFC when it's measured with different assays in different countries and different clinics. So in general, all these data show the same thing. The smaller the tumor is, the smaller the radiation dose is going to be and this would increase the likelihood that these patients will be in remission in the long term. And there was also another study I think from the group of Katznelson that showed that the sooner we perform radiosurgery, the better the outcome is. What about the follow-up of these patients? And I would like to bring here up the Delphi survey of many experts here in the group, also chaired by our chair, Everly Biller, that recommends the follow-up intervals in patients after treatment for Cushing's syndrome. And these are the data on patients who have received radiotherapy. And depending on whether they are in hypo or hypercortisolism, and depending on whether they need a medical therapy for this, the recommended follow-up intervals vary between four and 24 months. How do we manage these patients in the practical, in the daily practice? And actually, we are all endocrinologists and we always discuss about Cushing's and remission rates and tumor size, et cetera. And this is actually only one of the tasks we have when we treat these patients. So we need to monitor HPA axis activity, to diagnose and then treat not only hyper, but also hypocortisolism. And of course, to keep an eye on tumor size. And in our daily practice, this is only one of the four pillars we have to take care of when we deal with these patients. We have to monitor all other pituitary axis, diagnose and treat pituitary deficiencies. The third pillar is the comorbidities. And most of us are also internal medicine doctors and we do this in our daily practice. And we diagnose, manage or prevent also metabolic, cardiovascular and other comorbidities these patients have. Last but not least, keep an eye on potential side effects of radiotherapy. And I'd like to start how we work on these four pillars in the daily clinical practice, starting with a female patient that was diagnosed about three years ago with Cushing's disease. And her UFC to start with was above 1,700 microgram per 44 hours. And you see on your right hand side, the dynamic T1 sequences, and they show actually delayed compress in the left anterior side, adjacent to the left cavernous sinus. And also the post-contrast sequence shows reduced compress enhancement. So there was an adenoma. She received a transphenoidal surgery in December, 2019, and histology showed a corticotroph adenoma with MIB1 index still 15%. And there was an infiltration of the left cavernous sinus wall. So this was the worst histology I had seen in these patients in the last years, but post-op she was in remission and she remained in remission for about eight months and she received hydrocortisone for about eight months. And in the summer of the following year, she had actually a huge stressful situation. The local bank in the county where she lived, where all her savings and her business was actually was bankrupted. And at the same time, she received this recurrence. So she said her diabetes hypotension started again. UFC was very high. And we performed this MRI scan and couldn't actually, we were not sure whether these were post-op changes or whether there was a residual tumor there. So our surgeons performed a second surgery, this time exploring the whole pituitary, taking biopsies from the whole pituitary and they couldn't find anything there and were sure the tumor was not anymore inside the pituitary, but apparently this cavernous sinus invasion was the problem. She was started on ketoconazole and this was the therapy she received at the times of therapy for pituitary deficiencies, hypertension, diabetes, for her severe depression psychosis. The pituitary board recommended fractionated radiotherapy of the left cavernous sinus. And this was performed at the end of the year. She received 30 units over 42 days, a cumulative doses of 54 grays. And she actually experienced it very, very well. Although she was on ketoconazole, she had just mild nausea and mild fatigue during all these times and went to the radiotherapy department and also to us and came all the time. And she was actually doing quite well. I have summarized this case, showing her UFC to start with, the remission after the first surgery, the relapse eight months later, the good effect of ketoconazole and of radiotherapy. And it was actually a very difficult to treat case because she lived about one and a half hours away from Vienna, but had a very dedicated house doctor, for example, who called in May 21 and saying that the patient is having just hypoglycemia on metformin and she hasn't seen this anymore. That was the point when we reduced her ketoconazole from two tablets to one. And at the very end, we managed to stop ketoconazole about 13 or 14 months after radiotherapy. And she's now in remission. How do we treat the comorbidities at the same time? So here I have made a summary of the treatment plan that she received. She was doing very well and always coming with her blood pressure values and with her blood sugar values of the last week. So I was actually able to recommend changes of therapy without waiting for these serum cortisol and UFC levels, which usually take a while to come in our center. So we managed to stop hypertension therapy already very early and diabetes therapy was also stopped in May 21. And with the time, we did some prevention tests and she was started on a setting for hyperlipidemia. And we also diagnosed a growth hormone deficiency with a GHRG test. And she started on growth hormone replacement and the gonadotrop axis is not being replaced because of her age. So this is just a practical case how we manage these patients. Now we are in a session on dilemmas and I would go through two of these pillars that we work on with the HPA axis activity being actually the main dilemma that we have in the management of these patients. And when I discuss with colleagues all over the world, I also see that many have different protocols of treating patients, not only after radiotherapy, but also after curative surgery. So what is our aim? Of course, to achieve your cortisolism and how we define this. And that's also a point of dilemma. Is this a normal UFC or is this a normal circadian rhythm? Actually, no patient under cushion therapy is going to have a normal circadian rhythm to start with. And it is actually good if they manage to have it at some point ever. So for patients on concomitant medical therapy, we measure morning serum cortisol and we aim also normal serum cortisol at 8 a.m. and a normal UFC. But we use UFC to quantify this degree of hypercortisolism, but actually a nice paper from Northern Germany has shown that this is not so accurate. And actually we should ask our patients to bring two UFCs and only the average is going to tell us what's actually the real thing. And for those of you who take part in clinical studies like us, you know that for clinical studies, we actually need usually three UFCs at a single time point. What, how we treat or what do we aim to monitor in patients who are not receiving any concomitant therapy? This is easier. So patients who are not receiving any therapy for hyper or hypocortisolism, there we want a normal morning cortisol. I usually perform a dexamethasone suppression test and this is the next test we are going to perform also in the case that I showed. And of course we target a normal UFC and we also target a normal late night salivary cortisol, which we actually cannot target in patients receiving medical therapy. So here is actually the cortisol curve, the daily curve in patients with untreated Cushing's disease and in patients receiving steroid synthesis inhibitors. So we aim to lower this hypercortisolism, but we cannot reach this circadian rhythm and they have low cortisol in the morning, low in the evening. We cannot aim to achieve low salivary midnight cortisol because this would mean that they will be low in the morning also and in adrenal insufficiency. So this is a good option for intermediary cases when we are within the treatment, but surely not a long life ideal solution. The block and replace approach is actually a very, very good solution in many patients, but not very commonly used in the daily practice. So we give a steroid synthesis inhibitor in a high dose to maintain low levels. And in addition, we add hydrocortisone, for example, limiting the daily physiology. I have practiced this, I'm a big fan of the block and replace approach, but I have practiced this in the long term only with drugs which do not have side effects or have very mild side effects like oselotrostat. And this is an approach which doesn't come in question or in many cases, but it's very good in some cases. Not to forget are the comorbidities. So we're dealing with a huge clinical spectrum of comorbidities, cardiovascular, metabolic, reproductive system, musculoskeletal, neuropsychiatric complications, but also acute ones like thromboembolic events or infections. And this is actually what we have to think of and target all the time, especially for patients in hypercortisolism or in patients where this degree of hypercortisolism changes through the time. Then we have to change all the time the therapies we give for diabetes or for hypertension, et cetera, for not risking that patients get hypoglycemia or hypotension. And in this very nice management review published in the European Journal of Endocrinology, we have shown how to assess for these cardiovascular risk factors and how to manage them and which targets we want to achieve. And we shouldn't forget then other comorbidities. And this is an individualized management approach about thromboembolic risk in certain patients, depending on the degree of hypercortisolism, on the interventions used and on the comorbidities they have. We have to prevent and test for infections. And again, some patients are more prone than the others. Not to forget the vertebral fractures. Many patients have them to start with. The long-term risk for osteoporosis and therapy. It's myopathy, which gets better when we substitute the growth hormone deficiency. Cognitive problems for which we unfortunately cannot do much at the time. And of course, anxiety, depression and psychosis are also important comorbidities that can be very well treated. At the very end, I would like to bring a second example from our practice, which is actually a fully different side of the medal compared to the first case. And this is a female patient. When she was 45 years, she was diagnosed with Cushing's disease with an endocellular microadenoma and received a transgenital surgery and was in remission for a very long time, for 16 years. Afterwards, she had mild disease recurrence. She had only hypertension and her UFC was 145. And this is the MRI scan that we had. So after contrast, we see reduced contrast enhancement on the right side. And just on your right-hand side, you see the T2 correlates. The Pituitary Board decided to treat this patient with a radiotherapy surgery. So she received a gamma 9 with 18 grays at the border, 36 centrally with a radiation time of 37 minutes. And this is one of the most remarkable cases I have seen. And I'm very, very happy with the way she developed. She is now over 70. She comes once per year in our department. This was a time in 2010, we didn't have such great access nowadays. So she didn't receive any medical therapy and her UFC just gradually reduced over time. I mean, she had a mild Cushing to start with, but her UFC reduced gradually over time. So she didn't get any Cortisol Withdrawal Syndrome. She didn't get any adrenal insufficiency. We performed two CRH tests in the last four years and she's still doing great. And I hope she will not have another relapse. So taken together, radiosurgery is an effective treatment modality in patients with Cushing's up to 70% long-term success rate and a very short mean time to Cortisol normalization of 14.5 months. The main side effect is hypopituitarism. Management of these patients includes four pillars, monitoring and treating HPA axis activity and tumor size, treating other pituitary functions, comorbidities and other rare potential side effects. It is very important to practice an individualized and patient-tailored follow-up after radiotherapy as I showed with these two very different cases. Thank you very much. That's the very end. I'd like to thank my department and our great surgeons and neurosurgeons I'm very lucky to work with. Thank you. Thanks so much for that great tour. I like the four pillars. That's especially good. It looks like there are already questions. Monica? Hi, Monica Gadelha from Brazil. Nice talk, Grace, as usually. Thanks so much. I was wondering if in your daily practice, do you usually stop the medications before radiotherapy? And like acetoconazole, pasiriotide or zilodrostate, and if you can comment also on acromegaly because this is always in our board meetings, we have this huge discussion. So I would appreciate if you can give some help on this controversy. Thanks very much, Monica. I didn't go on this question. This is a dilemma, you're fully right. But because of time, I didn't go into this topic. Well, there is no literature on patients with pasiriotide and radiotherapy. So I cannot comment on that. There is some controversial literature on ketoconazole and radiotherapy. And there are also, I mean, ketoconazole stops the adrenal synthesis, but there are some papers showing an apoptotic effect at the level of the corticotroph cells. So I have also experienced patients in ketoconazole who achieved remission for years on ketoconazole only and were adrenal insufficient. So it has a central effect also. The literature is not concordant. So there are this year recent guidelines from the Society of, I think, Neuroradiotherapy, Neurosurgical. They recommend to stop the medication in secreting P3 tumors in general. Exactly. But this is mainly based from data with somatostatin receptor ligands in acromegaly. The data on OncoShix don't speak for, don't speak against. And these recommendations say in the case of Cushing's, you may, you should stop the therapy if this is doable. So if someone has a severe Cushing's, like, for example, the lady we had, we just couldn't stop the therapy because she was really psychotic at the time, for example. So the recommendations are stop the therapy if you can afford it. And if it's a pituitary targeted therapy. So in the case of osteoarthrostat, this is not a pituitary targeted therapy. So I do not see why we should stop this therapy. Myself, I have a very, very, I have another opinion on the topic because we also have data on aggressive pituitary tumors. And aggressive pituitary tumors are a bit different. So the lower this, the higher this proliferation rate it is, yeah. Also different is the effect of radiotherapy. So gamma knife is ideal for adenomas, low proliferative rate, yeah. And a conventional radiotherapy is better for patients with a high proliferation rate, yeah. Now we have this excellent survey of the European Society of Endocrinology on aggressive pituitary adenomas. And they show that aggressive pituitary adenomas do better when they receive temozolomide in addition to radiotherapy at the same time. Because some centers experience this with other brain tumors and have used this. So I'm not sure whether we should stop radiotherapy, we should stop medical therapy when we practice radiotherapy in patients with a high proliferation index. Okay, thank you so much. You're welcome. Hi, I'm Mark Mowat from Chicago. I'm intrigued by the high recurrence rate after radiotherapy. It's very similar to what it is after surgery. So what you know about the biology of how radiotherapy damages the pituitary tumor and then you have a normal level, why should there be any recurrence? How do you explain that? Well, excellent question. I mean, I can only hypothesize because there is surely no data on this. I was also surprised by the rate, but maybe I haven't worked as long for seeing remission rates coming after 16 years. Well, the potential. I would say, I would hypothesize on two different mechanisms. First is there are still some remaining cells, some remaining corticotroph cells they're producing some ACTH, but these are at a very, very low level. And the huge reduction in ACTH leads then to adrenal insufficiency, et cetera. And these cells take a while till they proliferate and initiate cushing. The second hypothesis might be a development of a new cushing disease in a patient who has the potential to develop a new cushing. For example, like the lady we had after 16 years, this could be a second tumor, which is usually theoretically possible. And if it's the same site, we have also had some reports on tumors appearing in different pituitary lobes after many years. So I would say both theories are possible, but that's just assumption. Manilka Sumanathilaka. Sorry, can I? Very quick one. The follow-up, do you think, I just remembered there's some reports to say activation of P53 with radiotherapy. So whether this question could, what do you think of that? Could be, but this huge amount of years is like, hard to tell. Thanks so much to all the presenters and the audience here for engagement. Thank you.

Nelson syndrome

Cushing's disease

bilateral adrenalectomy

corticotroph tumor growth

plasma ACTH levels

skin pigmentation

pediatric surgery

radiotherapy

tumor progression-free survival

adjuvant radiotherapy

hypopituitarism

HPA axis activity

evidence-based management pathways