Good afternoon, everyone, and I welcome you now to our meeting about Cushing's syndrome. So the title is Zap It or Treat It, Surgical versus Medical Treatment in Cushing's Syndrome. My name is Richard Auchus. I'm from the University of Michigan, and I'm delighted to have with me today on our faculty, John Newell-Price, who's professor of endocrinology in the School of Medicine and Population Health at the University of Sheffield, also the president-elect of the Endocrine Society for next year, Eliza Geer, the medical director of the Memorial Sloan-Kettering Multidisciplinary Pituitary and Skull Base Tumor Center in New York, and then finally, Sasmita Sharma, who is the director of pituitary endocrinology at MedStar Washington Hospital Center and Georgetown University. I am required to show you our disclosures. All right, so I'm going to start with an overview of the clinical landscape of Cushing's syndrome. Now, Cushing's syndrome has protean manifestations, cardiovascular, thromboembolic, you can read the list here, but many, many things that make us consider this. But a lot of these things like obesity, diabetes, neuropsychiatric diseases are very common in the population. So we often are in a quandary about whether we should screen people or not, because is this a common presentation of a common disease or is this an uncommon presentation of something like Cushing's? But the bottom line is that you will never diagnose Cushing's syndrome if you don't screen patients. So I want to just go over who to screen and how to screen. Now, there are discriminatory features in Cushing's besides these, and these are the catabolic aspects of hypercortisolemia. Cortisol breaks down skin, muscle, and bone. So when you see muscle weakness or myopathy, osteoporosis, particularly unexplained osteoporosis, osteoporosis in an obese person, osteoporosis in the absence of hypogonadism, those are red flags. The wide, purple, non-blanching striae, not just flesh-toned stretch marks, but hemorrhage in new tissue so that they are non-blanching and really violaceous purple, not pink. And then easy bruising in the absence of anticoagulants and things like that. So there are other things that are good tip-offs. Dermal atrophy, disproportionate head and neck, that is the dorsal cervical and the supraclavicular fat pads, sleep disturbance, and unexplained hyperglycemia, hypertension, and bone loss, as I mentioned before. So the bottom line is that biochemical data, which we're going to get to next, are important for the evaluation and necessary, but they don't substitute for the history and physical. I think many of us really rely on that history and physical exam, thorough physical exam, before we decide whether to screen or not, regardless of what the complaint is. So in textbooks, people have the purple striae and so on, but the people you meet in the clinic look more like this. Now, you might not hand this person your card and say, I think you need an endocrinologist. She's only gained about five pounds. She doesn't have diabetes. Her hypertension is controlled with one medication, but you can't see her clavicles. And you can see the facial plethora here. So this is when we want to pick people up, when they have early manifestations, before they get the myopathy, before they get the osteoporosis, and those devastating manifestations. So some groups have looked at what predicts a positive screen for Cushing's. And in fact, if the reason for screening is just obesity or type 2 diabetes, those are actually negative predictive factors. But when you have unexplained osteoporosis, dorsal cervical fat pad, muscular atrophy, those are much more predictive. Now, purple striae didn't make it, but just because of the wide range, you see there's quite a lot more in the Cushing syndrome patients. And of course, you don't know who's doing this physical exam. So this is still important because the majority of these people actually do have Cushing's, but it just didn't reach statistical significance in this study. And then, of course, a positive screen predicts that you have Cushing's. So the principles of testing are three. Cortisol production is elevated. And that's why we do the 24-hour urinary-free cortisol. But this test is not always abnormal in Cushing's, and it varies with the assay. And that is because early in the development of hypercortisolemia, that extra cortisol is being shunted to cortisol metabolites, and you never see it in the urine. And cortisol is only spilled in the urine when the concentration exceeds the binding capacity of plasma. So the elevation has to be quite significant. It has to be elevated for a substantial period of time. When people have overt Cushing's, very severe Cushing's, it's a good barometer of how severe it is. Now, cortisol production is also not suppressible, and that's where we do the dexamethasone suppression test. And it is the most sensitive test for ACTH-independent disease, which we are not going to focus on today. And then finally, the cortisol diurnal rhythm is blunted, and this is where we do nocturnal serum or saliva cortisol and or cortisone. These are now routine tests that you probably all do in the clinic. So you have the clinical suspicion, and then you make sure that they don't have non-neoplastic hypercortisolemia, psychiatric disease, critical illness, or other conditions which would make you stop. Otherwise, you screen with one of these tests, and then if they're positive, there's endogenous Cushing's syndrome, you determine if it's ACTH-dependent or not, and that is what we're going to focus on today, the different forms of ACTH-dependent Cushing's pituitary or ectopic. So I'm going to transition with a case. This is a 64-year-old woman with Cushing's disease diagnosed in 2002. She had transphenoidal surgery, and she moved in 2006. She was told to get follow-up, but did not until 2014. She has multiple complaints, some nonspecific, some specific. She has several things on physical exam, like the plethora and the dorsal cervical and supercaloricular fat pads and the severe myopathy that are highly suggestive, and then her lab tests are all flamingly abnormal. And here's her MRI in 2006, and here's her MRI when she presented in 2014. So what do you do next? More tests? Intervention? I'm going to use that for you to think about while I turn the program over to Dr. Sharma now, who's going to talk about pituitary surgery and Cushing's disease. Thank you, Dr. Arcus. So we'll talk about pituitary surgery and Cushing's disease next. So transphenoidal surgery is the first-line therapy for Cushing's disease. However, it is critical that surgery is performed by an experienced pituitary surgeon with a multidisciplinary team. So here are three scenarios. In an MRI-positive case, you see a clear microadenoma on the MRI. The surgeon would resect around the pseudocapsule, the pseudocapsule being the compressed anterior pituitary tissue around the tumor, leading to complete resection of the tumor. In an MRI-negative case, complete resection of the gland is absolutely necessary, and in some cases, they may need to section through the pituitary gland to identify the tumor and then resect it. If the tumor is not found, in some cases, subtotal hyperplasectomy may be needed to give the patient the best chance for remission. And then in the macular genoma, the tumor is clearly visible, of course, but it is important to inspect the dura and the cavernous sinus for any signs of invasion. So if you look at the ratio for remission rates, this is a systematic review looking at studies, more recent studies on the topic. The remission rates are anywhere from 65 to 98 percent. Higher for microadenomas, 80 to 98 percent, and lower for macroadenomas, about 45 to 68 percent. If you look at recurrence rates, these are anywhere from 5 to 66 percent, and this truly depends on the duration of follow-up. In these studies, varying anywhere from 2 to 16 years, and you can see that the highest recurrence rates are in those studies with the longest follow-up. So recurrence can happen even 20 years down the road, and it is really important to follow these patients long-term. Most of these published reports are from tertiary referral centers, so in the hands of an experienced surgeon, and therefore even these underestimate the overall rate of recurrence. If you look at the individual surgical techniques, so endoscopic versus microscopic, the remission rates are similar, with a slight trend of higher remission for a macroadenoma with endoscopic approach potentially related to the wider surgical view that is seen there with better visualization of the optic protuberance and the cavernous sinus in that approach. So how do we define remission? Well, these patients with prolonged hypercortisolism, in them the normal corticotropes are suppressed, so if we resect the ACT8-secreting pituitary tumor, the patient should develop adrenal insufficiency, which the patient that Dr. Aukus described did not. And so what we are looking for is during the first week of surgery, you want to see a low fasting serum cortisol, less than two micrograms per deciliter, low UFC, low ACTH, and in cases with mild or cyclical cushings, one may need to assess their diurnal rhythm as well. However, there is no absolute determinant of postoperative long-term remission. The postoperative testing varies between centers as well. Some centers like to hold glucocorticoid replacement until testing is completed, while others discharge the patient on replacement doses of glucocorticoid and complete testing as outpatient. Postoperative serum cortisol less than one microgram per deciliter in the study predicted remission with a positive predictive value of 96%, so pretty good. However, other studies have shown that even an undetectable cortisol does not rule out late recurrence. So here is data from the NIH group. The diamonds are all the patients with recurrence. The dashed line is the one microgram per deciliter for cortisol, and you can see there are patients even whose post-op cortisol level was less than one, but still later on recurred. And therefore, all patients with Cushing's disease need to be followed long-term. Can we predict remission in these patients? So smaller size of tumor microadenoma, lack of tumor invasiveness, so no dural or cavernous sinus invasion, ability to identify the tumor preoperatively as well as intraoperatively, confirming it on pathology as an ACT abstaining pituitary adenoma, and surgical expertise all predict a better surgical outcome. If we look at surgical morbidity, again, in the hands of an experienced pituitary surgeon, the complication rates will be lower. But overall, new onset hypopituitarism is seen in about 10% of patients. Permanent DI, 2% to 4% of patients. If we compare between the two approaches, similar complication rates with slightly higher CSF leak in endoscopic approach and a slightly higher transient DI in microscopic approach. One also has to remember that if we compare post-transfronoidal surgery for Cushing's disease patients compared to non-functioning pituitary adenoma, we see higher rates of venous thromboembolism with Cushing's disease and slightly higher rates of transient DI or hyponatremia also in Cushing's disease patients. Overall, though, the preoperative mortality is low. So if the patient has not gone into remission after TSS, what can be the reasons? So first, we need to assess if we made the diagnosis correctly, reassess the preoperative biochemical data, the IPSS data, make sure we have the correct diagnosis. It's possible that the resection was of an abnormal tissue which was not even an adenoma, or it may have been a pituitary incidentaloma that did not stain for ACTH. Dual adenomas have been reported. And in those cases, early repeat TSS with complete exploration of the gland again is recommended. Other possibility can be incomplete resection of an intracellular ACTH-staining pituitary adenoma. In that case, again, early repeat surgery to look for the residual tumor may be considered. Or if there is presence of local dural invasion, carinocinus invasion, adjunct medical or radiation therapy would be recommended. So if it is clear that patient has persistent hypercortisolism, repeat early TSS, so within first few weeks of the first TSS, should be considered. And this is because post-op scarring is minimal. The surgeon knows exactly where the tumor is, and the surgery is less difficult. But it is important to wait for the cortisol levels to plateau to identify these cases with delayed remission. And remember, mild or sigmoid Cushing's disease may not have marked post-op hypercortisolism. As we follow these patients, late night salivary cortisol is the most sensitive test to assess for recurrence. And if we do see that the patient has recurred, again, repeat TSS should be considered, especially if there is visible recurrent tumor on MRI. The tumor usually recurs at the site of the initial tumor. And if there is no visible tumor on MRI, even then, repeat TSS can be considered. But again, it should be in the hands of an experienced pituitary surgeon, and only after we have confirmed that the initial diagnosis was correct, so by pathology or by IPSS. Remission rates after repeat TSS do tend to be slightly lower, so 40% to 86%. And higher complication rates as well, so hypopituitarism mean rate of up about 38%, permanent DI up to 24%. I want to briefly talk about radiosurgery. So primarily, this is used as an adjunct treatment for residual or recurrent disease after surgery. Remission of hypercortisolism after radiation therapy takes time, and we have to remember that we will need concomitant medical therapy during that time. We have two major categories, conventional radiation therapy and stereotactic radiosurgery. The stereotactic radiosurgery is in a single session, while conventional radiation therapy is several fractions over six weeks. And the decision to choose which type depends on how large the residual volume of the residual tumor is, proximity to the optic apparatus, and irregular geometry as some of the factors. Our three types of radiosurgery being gamma knife, linear accelerator, and proton beam. So looking at the efficacy rates, these are just the largest studies, more recent studies on each of these, the lower three being radiosurgery. So for gamma knife, 200 plus patients, remission rate, hormonal remission rate reported about 80%. So 11% of these patients were on medications. Mean time to remission, about 14 months, and tumor control in gamma knife is excellent. In other radiosurgery as well, linear accelerator and proton beam, hormonal remission rates of about 60%. Mean time to remission, anywhere from 16 months to 30 months. Tumor control rates, again, anywhere from 85 to 100% in these studies. If you look at safety and complication data, main side effect to watch out for is hypopituitarism. And again, this can be seen in both modalities with slightly lower rates with stereotactic radiosurgery. This can happen even 10 to 15 years down the road, so need to be monitored. Other more rare side effects, but still need to be counseled for, is cranial neuropathy, CVA, secondary intracranial tumors, cognitive impairment, seizures, and hemorrhage. So in summary, transplanoidal surgery by an experienced pituitary surgeon with a multidisciplinary team is needed for treatment of Cushing's disease. We are looking for hypocortisolism to predict remission, but there is no single determinant of long-term remission, and all patients with Cushing's disease need long-term follow-up. Late-night salivary cortisol is our most sensitive marker for recurrence, and if that happens, consider early repeat transplanoidal surgery, especially with visible tumor. If surgery is not possible or is unsuccessful, medical therapy, radiation therapy, or bilateral adrenalectomy may be considered as adjunct therapy. Thank you. Thank you, Dr. Sharma. Okay, so moving on from surgery and radiation, I'm now delighted to pass the baton to Dr. Eliza Geer to discuss medical therapy and Cushing's disease. Great, thank you. I want to thank the Endocrine Society for sponsoring this event and Dr. Aukus for inviting me to talk, so I will be discussing medical therapy for Cushing's. I just want to start by reminding everyone that we have multiple outcomes to consider when we're treating our patients with Cushing's, not just biochemical control, but the many clinical outcomes that I'm showing here on the slide. These are our targets for medical therapy. We have pituitary directed targets, adrenal stratagenesis inhibitors, and a glucocorticoid receptor blocker. So I'm gonna start from the top down with the pituitary. So cabergoline has been in use off-label for Cushing's disease for many years. We don't have clinical trial data, but we have several small retrospective and prospective studies showing that overall, patients achieve a normal UFC in about 25 to 40% of the time. Various doses have been used. We don't have predictive factors for who might respond, and there's a variable time to reach a response. On the plus side with cabergoline, this is an oral therapy. It's a tumor directed therapy. We may consider it for pregnancy. Please note it's not FDA approved for pregnancy, but it has been used during pregnancy. On the downside, we don't have clinical trial data. It's not FDA approved for Cushing's. There is a risk for impulse control disorders. It's unlikely to be effective with severe disease, and we do see treatment escape in about 40% of patients. So you can see the UFCs over time in this small cohort of 18 patients, and you can see that seven of them escape treatment. Next, we have Passyriotide. We have both the SUBQ and the LAR form approved. SUBQ Passyriotide was FDA approved in 2012 after this study in the New England Journal was published that showed that 25% of patients achieved a normal UFC. These were the patients that were randomized to the higher dose of treatment, which was 900 micrograms SUBQ twice per day. It was associated with clinical benefit as well. You can see here as the UFC decreases in blue, we're seeing improvements in weight as well as improvements in quality of life scores. This is a tumor directed therapy. So patients with a visible tumor show that there was a 44% decrease in those tumors in the patients getting the higher dose. And the GI side effects are similar to first-generation SRLs, but this is different than the first-generation SRLs because it acts on SSTR5, which causes hyperglycemia in 40% of patients and diabetes in 20% of patients. The LAR form was approved in 2018 after a clinical trial showed that 40% of patients achieved a normal UFC. These are similar with the LAR versus SUBQ. Again, we're seeing a lot of hyperglycemia and we are seeing that patients with mild disease have a higher response rate than the patients with more severe disease. So on the plus side, this is tumor directed. So we may see some tumor shrinkage. Again, patients with mild disease, we're seeing about 50% of them are gonna respond to Passyriotide. And we also see an early response. So if patients respond, they tend to respond within the first three months. So we can consider a short trial of this therapy and clinical trial data has shown clinical improvement. On the downside, we're seeing hyperglycemia and diabetes, which we need to screen for, GI side effects, cholelithiasis, and it's not an oral therapy, it's an injected therapy. I'm showing the doses that are used here. Again, patients need to monitor their finger sticks. We need to monitor the QTC interval and gallbladder ultrasound if clinically indicated. So next I'll discuss our straight agenesis inhibitors starting with ketoconazole. So we've been using this off-label in the US for many years. Again, we don't have clinical trial data with ketoconazole, but we do have this large French retrospective study that looked at 200 patients treated with ketoconazole and show that overall, about half of the patients achieved a normal UFC. There were mild increases in LFTs in 13.5% and major increases in 2.5%. The reasons for withdrawal in this study were lack of efficacy in about a quarter of patients and AEs and also about a quarter of patients. The AEs that were most commonly seen were LFT increases in 15% and GI complaints in 13%. On the plus side, this is an oral therapy. It's twice daily, very familiar. It's been in use for many years because it inhibits multiple enzymes along the straight agenesis pathway. We don't see precursor buildup and it is approved by the EMA for Cushing syndrome. On the downside, we don't have clinical trial data. It's not FDA approved for Cushing's. We do need to monitor LFTs and because of 17 alpha hydroxylase inhibition, men can develop hypogonadism and patients need gastric acid. So no proton pump inhibitors or H2 blockers. We start at 200 once or twice per day. Again, we must monitor liver function and with any straight agenesis inhibitor, we need to monitor for adrenal insufficiency. Levoketoconazole is the enantiomer of ketoconazole, which is a racemic mixture and it's the hand of the molecule that is more potent. We have several clinical trials that have been published starting with SONIX, which was an open label study. It showed that after dose titration period, 81% of patients had a normal UFC. The primary endpoint of the study was a normal UFC after six months of maintenance without a dose increase during that six months and 31% of patients achieved that primary endpoint, which was significant. We're seeing clinical improvements with improvements in acne, keratotism and edema, as well as improvements in glycemic control, cholesterol and weight. Logix was the second phase three trial. It was randomized withdrawal also met its primary endpoint. And we also have long-term data on levoketoconazole in the SONIX extension study. And we're seeing that over time, 41% of patients are maintaining a normal UFC and that's associated with clinical improvements and no new safety signals. And this was FDA approved in 2021. So on the plus side, levoketoconazole, we have some familiarity because we're familiar with ketoconazole. It's more potent than ketoconazole. We're seeing, we have clinical trial data showing that there are clinical improvements. In women, it may lower androgens, which might be beneficial. In men, it may be a precursor accumulation. There may be less liver toxicity compared to ketoconazole, but we don't really know because we don't have head-to-head data on that. On the downside, there's a lot of drug-drug interactions we need to check for. We need to monitor liver enzymes. Patients need stomach acid for it to work. And we need to monitor the QTC and men may develop hypogonadism. We start at 150 twice per day. We titrate according to the biochemical and again, monitoring LFTs. And again, we must be careful we don't over-treat our patients and cause adrenal insufficiency. Metaripone is the next adrenal stratagenesis inhibitor I'm gonna discuss. And it's used off-label in this country and it's approved in Europe. We don't have published clinical trial data, but we have this large retrospective UK study that looked at 195 patients with Cushing syndrome and found that 43% of these patients achieved a normal UFC. There were AEs in about a quarter of patients, mostly GI and dizziness, usually with initiation of drug and these symptoms were most often reversible. There was a clinical trial that was conducted by Lynette Nieman and presented at Endo. It's not been published yet, but in this study of 50 Cushing syndrome patients, almost a half, 47% achieved a normal UFC and it was associated with clinical improvements. On the plus side, there's rapid onset. This is an oral therapy. It's been in use for many years. We may consider it for pregnancy, but note it's not FDA approved for pregnancy. There have been published case reports, however, of successful pregnancies with patients taking metaripone. On the downside, it has a short half-life. So we need to give it three or even four times a day. There can be precursor buildup because it inhibits the final step in cortisol synthesis, 11 beta hydroxylase. So we can have some buildup of the mineralocorticoid and androgen precursors. It's also not FDA approved for Cushing syndrome. So finally, we have oselodristat, which is very similar to metaripone. It's an 11 beta hydroxylase inhibitor. It also inhibits aldosterone synthase. This is the most potent adrenal stratagenesis inhibitor. We have several trials that have been published. Link two was a phase two study. We have two phase three studies, link three and link four. And you can see here that this medication is resulting with a high rate of UFC normalization. In all these studies, the rates vary a bit on the protocol and the cohort, but we're seeing that overall 70 to 80% of patients are achieving a normal UFC. These studies have also shown clinical improvements in most cardiovascular and metabolic parameters. And I'm showing on the right clinical signs and symptoms improving. And you can see that they improve in the setting of partial or complete control of UFC. And this was approved in 2020. So on the plus side, oselodristat is very potent. It's an oral therapy given twice per day. We're seeing long-term sustained control and clinical improvements. We have very good clinical trial data on this medication. On the downside, because it predominantly inhibits the final step of cortisol synthesis, we may see a precursor buildup with androgen and mineralocorticoid effect. We have to be very careful not to over-treat our patients. In link four, there were hypocortisolism-related AEs in 27% of patients and in link three in 51% of patients. So these are higher rates than we're seeing with other therapies and other trials because it's a very potent medication. We start at two milligrams twice per day. And if it's a mild Cushing's patients, even lower than that. Again, we need to monitor for adrenal insufficiency. These precursor buildup signs and symptoms and also the QGC length. So finally, we have a glucocorticoid receptor blocker, which is mifepristone. And this was approved in 2012 to treat hyperglycemia due to Cushing's. This does not lower cortisol levels. It blocks the receptors, so levels go up. So we don't look at cortisol at all. We look at clinical outcomes. You can see that from this study of 50 patients with Cushing's syndrome, there were clinical improvements. You can see the area under the curve of the oral glucose tolerance test improved with treatment. You can see the body weight decreased with treatment. Side effects include nausea, fatigue, and hypokalemia. We do need to monitor the endometrial lining in women with a uterus because they can develop benign cystic dilatation due to progesterone receptor antagonism. On the plus side, this is a rapid onset daily oral medication. There's a wide dose response with very high doses and no apparent toxicity. We do see clinical improvements and it's available for all forms of Cushing's. On the downside, there are a lot of drug-drug interactions. Patients can develop hypokalemia. Again, we need to monitor and do a uterine ultrasound and biopsy if there's any vaginal bleeding in women. And we only have clinical outcomes to look at, no cortisol levels. We start at 300 milligrams per day. Patients need to have hyperglycemia to be eligible to get this medication. And again, it's clinical monitoring on this therapy. So some general considerations during medical therapy. One, for patients with Cushing's disease, we need to monitor the tumor, especially if we're using a therapy that's not a tumor-directed therapy. The recommendations are to do a pituitary MRI six to 12 months after starting treatment. And after that, depending on the clinical scenario, we do track the ACTH. We know that plasma ACTH is pulsatile and has a short half-life. But if we see a progressive increase, that could indicate tumor growth. We need to monitor our treatment response by these many clinical outcomes I'm showing here, as well as the 24-hour UFC and everyone except patients on mifepristone. And the rate of titration really depends on the scenario, the severity of Cushing's, the drug we're using, the rate of change in cortisol that we're seeing, the tolerability and the clinical changes. We need to be very careful about adrenal insufficiency. We should educate our patients. They should get injectable glucocorticoid, should be aware of signs and symptoms of adrenal insufficiency. And we follow the morning serum cortisol and everyone except those on mifepristone. We should manage our patients' expectations and let them know they will experience glucocorticoid withdrawal symptoms as we lower their cortisol levels, and we should counsel them about that. And it's very important to stay up-to-date on changes in other therapies, not just adding a medication, but also withdrawing other medications that can affect the metabolism of these therapies. So in summary, we have many factors to consider when we're treating our patients, tumor size, severity of disease, comorbidities, patient wishes and treatment goals, availability, prior and current treatments. And so in summary, we've seen a lot of progress in the 10 plus years, past 10 plus years. We now have four FDA approved therapies and two additional therapies available in Europe. These can be used as monotherapy or in combination. We know that these therapies are not disease modifying, but if patients have additional surgery or radiation, we may need to change the dose or the treatment. This is an individualized, personalized care for our patients, and we have new therapies and developments so stay tuned in the coming years for even more options. Well, thank you, Dr. Geer for that excellent handling of a complex topic that as you said, is evolving even as we speak. Okay, so our last speaker is John Newell-Price from University of Sheffield. Rich, thank you very much for the introduction and thank you for the invitation. So let's move to the final talk on bilateral adrenolectomy. And really the first thing to consider is the technique. So there are two main techniques. The first is a retroperitoneal technique, and you can see in the top left that there is a patient laid on the table. And this really allows access to both adrenal glands without having to turn the patient. Now, the alternative technique is the transabdominal laparoscopic technique. And you can see here both the approach from the right and the left. But what this means is that in the middle of the operation, the patient has to be turned from one side to the other. It really shouldn't matter. The key requirement here is having an expert surgeon. And the key requirement for whether the patient should undergo a bilateral adrenolectomy is a expert multidisciplinary team making that decision and discussing the risks and benefits with the patient. And the choice of the approach, whether it's from the back or actually the transabdominal approach really should be up to the surgeon. And that will depend on their expertise and also on some patient factors. So for example, depending on the body habitat of some patients, it may be more suitable to go through the back compared to the transabdominal approach. And then finally, it's important that the aim of this operation is to remove both adrenal glands completely. And this means that the serum cortisol after the operation should be very, very low, at least less than 1.8 micrograms per deciliter, but actually even lower than that in the vast majority of cases. So what are the indications, the pros and the cons? Well, the indications really are if the patient's failed pituitary surgery or failed medical therapy, either from an incomplete response or if the patient is intolerant of that treatment. In around about 10% of patients who've got ACTH-dependent disease, you can't actually find the source of ACTH. And they may be treated with medical treatment, but there's also the option of using bilateral adrenolectomy. And in young women particularly, if they're seeking to get pregnant and they've failed the first line treatments, then bilateral adrenolectomy means that their Cushing's would be controlled. And it means they won't be on medications that would be contraindicated in the time of pregnancy. And finally, if someone's got terribly severe Cushing's, this can be a life saving operation, removing the adrenals, lowering the cortisol immediately, and really making sure the Cushing's is treated as quickly and as efficiently as possible. What about the pros and cons? Well, so the pros are clearly the immediate control of the hypercortisolemia and the life-saving aspect, but also you not infrequently see an improvement in the overall condition of the patient beyond what you achieve with medical therapy. And I'm gonna come back to that at the end of the talk. But in terms of the cons, they are of course on lifelong adrenal replacement therapy. There's the risk of adrenal crisis. And we've just heard from Alonza Geer that one really needs to make sure the patients know about that. And maybe the development of adrenal rest tissue. And there's the aspect and the things that we really worry about in terms of Nelson syndrome or corticotrophic tumor progression. So what about the outcomes? Well, the biochemical outcomes are very, very good. In the right hands, there's almost 100% of patients will have a very low serum cortisol because the bilateral adrenalectomy is a highly successful operation if done by the right people. And in the long-term, interestingly, between two to even up to 30%, there may be some cortisol secretion because of the development of adrenal rest tissue driven by the high levels of ACTH. And in only around about less than 2%, there's an overt return to the cushion. So this is some data from a very large series analyzed by Martin Rinki's group some 10 years ago. In terms of the perioperative management, it's essential the patients get hydrocortisone at stress doses, there's a gradual taper, and then flutocortisone will be added when the daily dose of hydrocortisone is reduced down to 30 milligrams a day or less. And then one adjusts the dose as you would do for someone with adrenal insufficiency. But education of the patients about the risks of adrenal insufficiency, making sure they're carrying steroid warning cards, access to hydrocortisone, and we certainly provide patients with an emergency hydrocortisone injection pack. We feel that's very important. In terms of the complications, they're few. The morbidity can be associated particularly with thromboembolic events. And in fact, the mortality of the operation, again, is low, higher in patients with ectopic disease than Cushing's disease, mainly because more of the patients with ectopic will have had more severe disease. And in terms of the long-term complications, well, these are really divided into those associated with adrenal crises. So around about nine per 100 patient years, patients will suffer from adrenal crises. So it's not an insignificant number, and that's why it's so important to educate the patients. But the one thing we really consider is about Nelson syndrome or corticotrophic tubal progression, and that may not necessarily need immediate treatment. There may be a small increase in a small tumor that can be monitored. And for that reason, we recommend doing an MRI scan three months after the bilateral adrenalectomy, then yearly for the first three years, and then individualizing the follow-up of that. The risk of Nelson syndrome after bilateral adrenalectomy has had two large meta-analyses published in 2021. This is one from Oscar Rangston's group, and you'll see that the prevalence is around about 38% in the long-term follow-up of patients. So, you know, 38% of patients having had bilateral adrenalectomy will end up developing Nelsons or corticotrophic tumor progression with a mean onset at around about four years. So what are the predictors for that? Well, in this analysis, the factors that were not associated with development were age, bilateral adrenalectomy as primary treatment, previous radiotherapy, or previous pituitary surgery. But in another large analysis, Martin Ranke in Munich led, in fact, younger age was associated with development. So there is some debate about the aspects of age. And the factors which do appear to be associated with development are a high plasma ACTH in the postoperative period, and if there's tumor visible on the MRI scan. So that MRI scan that Dr. Arcus showed at the beginning of this session, that would have a very high risk for tumor progression if that patient underwent a bilateral adrenalectomy. What about the long-term outcomes? Well, in nearly everyone, there's an improvement in a lot of the features of Cushing's, and it is extremely effective treatment for that. I just want to focus now on this study, which is a really interesting study that came out from Anton Tabaran in Bordeaux and other colleagues in France just a few months ago. And this was to look at the evidence of persistent mild hypercortisolemia in patients who are medically treated for Cushing's disease. So these are just Cushing's disease patients. And they compared those patients who are on medical treatment to those who had undergone successful pituitary surgery, who were in surgical remission, and those patients who had had bilateral adrenalectomy. Now, the numbers of patients were relatively few on medical treatment. I list this here. They were on heterogeneous treatments, and the total number is shown here. So these are a heterogeneous group of medical therapies. And what they did is to look at the concentration of cortisol in the hair, which is a little bit like the HbA1c for Cushing's. By measuring the incorporation of cortisol in the hair, one can get an idea of what the prevailing level of cortisol is on the general level in that patient. And the first thing to say is, if you look at the hair cortisol in the patients who are on medical treatments compared to those who have had successful surgery, you'll see that it is significantly higher. Interestingly, the patients who had bilateral adrenalectomy, it was also higher. And I'll come back to that right at the end. If one looks at the hair cortisone, that's cortisol is converted to cortisone by 11 beta-HSD type 2 in the hair follicle, you'll see that actually the discrimination is similar between those on medical treatment for Cushing's compared to successful surgery and those patients who've had bilateral adrenalectomy. If one then looks at the salivary cortisol and the salivary cortisone, here the salivary cortisol, here the late night salivary cortisone, you'll see that the patients on treatment, medical treatment for Cushing's, compared to those successfully treated has significantly higher late night salivary cortisol or cortisone, indicating that although they were on what was thought to be effective treatment, there was still abnormalities in the circadian rhythm. And that was rather unsurprisingly not the case in bilateral adrenalectomy because most of these patients would be on hydrocortisone with lower doses that would have then come out of the system by the late night. However, I think the important aspect was in the Cushing's medically treated group, their clinical score was worse than those people from successful surgery. And for those patients who are antihypertensive, it was higher for those who were on higher cortisol. So in conclusion, it's often regarded as a last resort, but really the immediate and long-term outcomes are favorable. You need to make sure the patients are warned about the risks of long-term therapy. There's a debate about pituitary radiotherapy to reduce the risk of Nelson's, but actually it can be considered before the last resort. And in some patients it can be transformative therapy. Thank you. Well, thank you very much, John, for that excellent coverage of bilateral adrenalectomy. So there were several questions about which tests to do first, which treatment is preferred, which radiotherapy is the best. The answer is there's no answer to any of those questions because it depends on the clinical situation. But I will tell you how I approach screening. So if someone comes to me and I think about hypercortisolism, if I'm thinking about ACTH-dependent disease, I usually start with some saliva cortisols and an ACTH measurement. If someone is sent to me for an incidental adrenal modules, I measure an ACTH and I do an overnight dexamethasone suppression test. I start with a 24-hour urine if somebody has florid Cushing's, and I know already that they've got Cushing's. And I'm trying to gauge how severe it is, particularly if they may be a possible candidate for a clinical trial. Otherwise, I usually make the diagnosis on those other tests. So now I wanna start with Dr. Sharma. So there were a couple of questions about DVT, venous thromboembolism prophylaxis, testing post-operatively, giving glucocorticoids, do the glucocorticoids interfere with the testing? So could you just review your perioperative management strategies in terms of both treatment and testing, particularly with an idea about how are you gonna tell if they're in remission and how are you going to prevent venous thromboembolism? Sure, thank you, Dr. Aukes. I'll start with perioperative remission assessment. And so again, the approaches are different. In our center, we withhold glucocorticoid treatment and assess cortisol levels in which we are measuring for the first 24 to 48 hours, at least every 12 hour ACTH and cortisol measurements and we are checking UFC as well. There are centers where we would put on glucocorticoid replacement and then retest as an outpatient. And in that scenario, you would withhold hydrocortisone for 24 hours prior. So if the test is being done on a Monday morning, the last dose would be Sunday morning and then you can check just like you would do for an ACTH stimulation test. If you are trying to measure a UFC, one could transition the patient from hydrocortisone to a physiological dose of dexamethasone and measure UFC. But usually, so for our center, we are measuring, withholding glucocorticoids and measuring levels. And if it is a center where you're discharging on glucocorticoid replacement, then the preferred would be hydrocortisone and hold for 24 hours. For perioperative venous thromboembolism risk, I think we don't have still clear guidelines on who should be on DVT prophylaxis or not. And so I think there is a shown that the increased thrombotic risk is present even after persists after surgery. There are studies in non-functioning pituitary adenoma surgeries comparing to Cushing's disease up to at least three months, maybe potentially longer, the venous thromboembolic risk persists. So my approach is that if the hypercortisolism is severe enough that, and especially if they're immobile, their physical activity is also decreased, I do put patients on DVT prophylaxis preoperatively, especially if their UFCs are high enough that I'm thinking even about PCP prophylaxis. In those patients, I do end up starting DVT prophylaxis. Now this is, I don't think from any guidelines, this is what just learning anecdotally from patients I've started doing. Postoperatively, if the patient, that is still variable, I do patient to patient depending on their risk for, again, DVT. Mostly I have not discharged patients postoperatively on DVT prophylaxis. If they didn't have a PE or DVT, I did have one patient who had a pulmonary embolism, right, going into surgery, we delayed surgery for three to four weeks to try and get that stable before the surgery was done. And that patient, of course, went home on anticoagulation. So that would be my approach for perioperative management of that. The issue of, oh, did I? Yeah, the issue of anticoagulation is very controversial and I think there's no consensus on that right now. John or Eliza, do you have anything you want to add to that? We do anticoagulate patients. We do it for six weeks postoperatively. There are other centers who do it for even longer. I think there is a clear association, but what dose we should use and how long we do it is neatly established. Right, okay. So Dr. Geer, there's questions about combination medical therapy. Are you a fan of that? Are there triggers that would make you consider that? And if so, what's an example of what you would do with combination therapy? So certainly it can be done. We consider it for the very severe Cushing's patients. I see it's encountering a lot of patients with cancer, Cushing's from cancer. So in those patients, definitely we consider it. You know, it really depends on the clinical situation, of course, but you want to consider combining therapies that have different modes of action. So maybe a tumor-directed therapy like Pastry Type of Coberglyne with Adrenal Stratagenesis Inhibitor. So that can often be done. So really, you know, if we're able to achieve a good clinical response and normal UFCs and ideally normal salivary cortisols, but that often doesn't happen on one therapy, then we don't need another therapy. But if that's not possible, or if there's tolerability, we may consider adding a second one. So there isn't really one way to do it, but we do think about these different targets with the tumor and the adrenal, but you can give two adrenal-directed therapies together as well too. So that's also been done. So I don't know how, I mean, it really, yeah. I mean, there's more to be said, but it depends on the patient, but they are, in severe cases, combination therapies is definitely useful. Right, yeah. So I think some of the newer medications have, are very potent. And so drugs like osteologist and mispristone don't usually have to do that, but there might be a reason if there's an adverse event. I think the adrenal cancer patients is another group where we used god-awful doses of medication when they have very, very severe Cushing's. Yeah, I mean, that, I have used osteologist in combination for ACC or ectopic Cushing's patients, but otherwise, very low doses of osteologist for your typical pituitary Cushing's patient usually are highly effective. Right, okay. John, with bilateral adrenalectomy, yes, as you clearly said, the goal is to remove all of it, to remove all the adrenal tissue, but do you ever do a staged operation? You know, it's a big deal for somebody who's very debilitated to have both adrenals removed. They can't lay on either side and so on. Do you ever take one out at a time, not because you want to see if there's remission after one, but just because the morbidity might be lower? It's been done occasionally, but most of the time we aim to do both adrenals at the same setting. And do you think between the retroperitoneal and the abdominal, which one do you think is less morbid in that regard, that you're less likely to need to do one at a time? Yeah, I think it depends on the patient. So our surgeon can go both ways and he chooses the way he goes depending on the body habitus. So if there's a lot of truncal obesity, then although the patient's got to be lying prone on the table, it may be easy to approach from the back. But of course, if there's a lot of fat in the back compartment or the patient's very big, it may be difficult to approach from the back. So it does depend. Okay. I don't think one has an advantage necessarily over the other. There is the advantage of not having to turn the patient mid-operation. And that comes back to your point about, well, do you take one out rather than two? In fact, there was a vogue in Holland about 25 years ago to take out one adrenal and irradiate the pituitary. And that was quite effective. So there are alternative ways of doing it. Okay. So there was one other question about adrenalectomy about how do you monitor for adrenal rest tissue development? So you're going to monitor the 9 a.m. or 8 a.m. cortisol pre or hydrocortisone. And if you start to see a cortisol rising, then you almost certainly have developed some adrenal rest tissue. But in most cases, the levels come up. They still are too low. You need to remain some substitution therapy. I've had several patients who over the years have actually come off all substitution therapy. I've not had a single patient who's redeveloped cushions. Okay. All right. There's a question about if somebody has established cardiovascular disease or atrial fibrillation, are there contraindications to certain medical therapies or are they all fair game? Is there any issue there? I mean, we need to monitor the QTC with Passyriotide, with levoketoconazole, with oselodristat. So obviously we're going to do that anyway. You know, with Coburgly, and there's obviously the valvulopathy issue, which maybe has been put to rest at lower doses, maybe not, but we still think about that. So I wouldn't say there's an absolute contraindication, but we're certainly doing ECGs on these patients. Right. And then last question for Dr. Sharma, there was a question about negative MRI. You talked about exploring the entire adrenal gland. When do you say just take out the whole pituitary? Or never? That would be pretty drastic. I am more amenable to taking out the adrenal glands than the entire pituitary. So I think in that case though, if the MRI is negative, I think there are newer techniques coming out. We can look into higher resolution MRIs. I think the best localizing tool is an experienced neurosurgeon better than any imaging study. So even in a negative MRI, there can be intraoperatively, they can localize the tumor. And so I think paying attention to the preoperative testing, if you have confidence on that and the diagnosis for a pituitary source of ACTH is correct, then we are looking at our neurosurgeon to try and see if we can localize the tumor. Look at slightly additional sites. Sometimes the tumor can be in the cavernous sinus, sometimes in the sphenoid sinus. So looking at those areas and the pituitary being completely taken out would be further out. We could put them, these tumors are gonna grow. So if we really can't localize and intraoperatively we attempt a surgery and we can't localize, then we could put them on medical therapy and follow imaging and see if the tumor is growing. But that total hypothysectomy would be pretty drastic. Yeah, well, I think there are imaging agents, nuclear imaging agents that are coming out labeled amino acids and things like that. So that's a possibility. I mean, we have done it once in a while in a post-menopausal woman who's really debilitated and failed prior surgeries. Not a lot that you have to replace in that person. So, but never cause DI if you're gonna do that, no matter how aggressive you are. Okay, but you're right, there's other options. I think we're out of time. I think I wanna thank my colleagues for a fantastic section. I wanna thank the audience for their questions and for their attention. And I will adjourn the session now. And I hope you've all enjoyed this and good night, everybody. Bye, thank you. Bye, thanks.

Cushing's syndrome

screening

diagnosis

treatment options

biochemical data

surgical treatment

medical treatment

severity of disease

multidisciplinary approach