Thank you for joining us today for the year in review for pituitary, gonadal, adrenal, and neuroendocrine tumors. My name is Diane Donegan. I am at Indiana University. I have a special interest in pituitary, and I'd like to thank you all for coming. It's great to see some new faces, some old faces, but all faces in one view makes a difference as well, so thanks for coming. So these are my disclosures. So classically, the year in review involves an overview of literature and for things that are going to be relevant to our disease state network, but I also wanted to give you an idea of what the disease state network has been doing over the last year, and there have been some changes in ACE, and so we have been trying to expand opportunities for education, for ways of advancing care for our patients, and some of this has been through a variety of different ways. Firstly, we have the disease state network blog, which is intended to be an informal way of providing information, somewhat conversational, so I would invite you to look at the website and see those that come up periodically. Also, it's a way to get involved, so if you have any comments or any concerns or areas that you would like addressed, please let us know. It's designed to be interactive. ACE has also had a variety of different podcasts, and so we've also tried to do more disease state network specific podcasts. You may have noticed that there was an adrenal incidentaloma one, and there will be another one coming up shortly about adrenal insufficiency. We've had some white papers or position statements. One, I think, was about 2020. It was reviewed last year, but there will be one coming up shortly, so look out for that too. But, of course, we're always looking for different ways for unique engagement with our community to make it really a community. So I'd also like to extend my gratitude to the team that's been helping us over the last year, as well as many other committees that has made this happen. So you will see some of them today. Adriana and Anne, thank you. Fadi had to leave, but he was here moderating a session earlier. So thank you to the team. But, of course, this is a community that we're trying to build, and so we want to hear about what you think is missing, what is underrepresented, what would you like to hear more about, but also how would you like to hear it. Our community has a lot of skills that we don't possess, so if there is something that you could contribute to, please reach out to us, and we'd be more than happy to get people involved. So back to the more formal way of reviewing the year, and I've been tasked with an overview of gonadal aspects. So as endocrinologists, we're always worried about whether the treatment we're providing is doing more harm than good. So this study looked at mortality trends over five decades in adult transgender people receiving hormone treatment. This was a retrospective cohort of transgender people who started hormone treatment between 1972 and 2018 at Amsterdam University Medical Centre, who were over 17 years of age. And after applying their exclusion criteria, they had 4,568 individuals, of whom about there was a two-fold greater amount of transgender women compared to transgender men, and the median follow-up for transgender women was 11 years. Whereas for transgender men, it was five years. And what they found was that there was a two-fold increase in mortality risk in transgender people compared to the general population. And so what these figures represent is that for transgender women and transgender men, you can see that the overall survival was lower compared to the general men or general population women, and that over the time period that they were followed up, 10.8% of the people who were followed up, 10.8% of transgender women died, and 2.7% of transgender men died. And when they looked at the most common causes for death, cardiovascular disease was the most common among transgender women. There is also HIV-related causes, lung cancer, and suicide. Whereas for transgender men, overall, these were non-natural causes. So while we can see that the causes of death weren't really related to treatment being provided, it is important to monitor, optimize, and when necessary, treat comorbidities. In particular, cardiovascular disease, tobacco use, HIV, and they remain important in the health care of transgender people. So where are there deficits in the care that we're providing? So where are there deficits in the care that we're providing? Well, knowing a little bit more about population-based data may help identify this. So changes in the size and demographic composition of transgender and gender non-binary population receiving care in an integrated health care system hope to provide some of this information. They looked at transgender and gender non-binary individuals who are a sizable minority of the population, and there are some reports that this is increasing. And to better assess this, the study group interrogated the study of transition outcomes and gender, a StrongHerb-based cohort, assessing Kaiser Permanente plans in Georgia and in California. So as you can see from the figure here, what we notice is that there is an increase in the number of transgender and non-gender binary individuals seeking care. And represented in the top line would be North California, the middle line South California, and Georgia is represented in green, and you can see that the numbers per 100,000 persons seeking care is increasing over time. And if we look at the changes in the proportion according to age group, you can see that both figures do show an increase in individuals of all age groups, but predominantly in the 18 to 25 year old age group. Not demonstrated in these figures here, it does show that the dominance of transgender women is declining, or another way of looking at it is that transgender men are increasingly seeking care. So the number of transgender and gender non-binary people seeking care has increased, particularly in the 18 to 25 year age group. However, this study couldn't say whether the proportion of individuals within the population are increasing, or is it just that they are more openly seeking care. So on to treatment. We're looking here at the pharmacokinetics of sublingual versus oral estrogen therapy for transgender women. And of course, oral estrogen is seen as a convenient and an affordable way of treating individuals, but is limited by its bioavailability and its risks, clotting risks. So sublingual therapy is seen as an attractive way of providing care. It can avoid first pass metabolism through transmucosal passive absorption, and therefore, as I mentioned, could avoid the potential complications seen with oral estrogen. So this study looked at the pharmacokinetics of oral and sublingual estrogen, which was assessed in 10 individuals, a small group, over an eight hour period. And in this figure here, you can see represented in kind of green and sort of a reddy brown, depending on which assay was used, whether it was liquid chromatography, mass spectrometry, or the immunoassay, oral estrogen increases in concentration in plateaus, whereas a sublingual estrogen has a peak, subsequently declines, and reaches then oral estrogen levels. And overall, there was a 1.8 time increase of area under the curve for estradiol using sublingual estrogen compared to oral estrogen. But the effect of this peak is not really known. And based on the pharmacokinetics that we can see here, multiple daily dosing is suspected when it's going to be used. So they concluded that sublingual compared to oral estrogen is associated with an increased area under the curve, but has different pharmacokinetics. And of course, further studies are required to determine the effect of this peak, and also to determine the optimal frequency of dosing. So what about for individuals that may experience some side effects to androgen deprivation therapy in patients being treated for prostate cancer? So in this study, they looked at novel liver-targeted testosterone therapy for sarcopenia in androgen deprivation therapy for men with prostate cancer. So of course, we know that androgen deprivation therapy plays a significant role in the treatment of prostate cancer, but it is associated with side effects such as a decrease in muscle mass, as well as a decrease in bone mass. And so liver-targeted testosterone treatment is oral delivery of small amounts of testosterone, which is not meant to increase peripheral testosterone levels. And so this was initially driven by a study that indicated that 40 milligrams of oral crystalline testosterone could lead to protein anabolism without an increase in serum testosterone levels, that is, serum mean testosterone levels. And in this study, they looked at individuals of the androgen deprivation therapy that were recruited for six months in a double-blind placebo-controlled study, 49 were randomized. Of note, 19 had acute androgen deprivation therapy, 30 had been on androgen deprivation therapy for some time. But you can see that the use of this liver-targeted testosterone therapy led to a significant increase in lean mass and a significant difference in bone mass content. And this occurred without transaminitis, without an increase in hemoglobin levels, or without a significant increase in the mean PSA level. However, five patients withdrew from the treatment group because their PSA levels had increased, and they had determined a significant increase to be greater than 50 percent from baseline or an increase greater than four nanograms per ml. So liver-targeted testosterone therapy is suggested to be a potential mechanism to decrease sarcopenia in those that have androgen deprivation therapy. The positive anabolic effects were demonstrated, but there were also reversible elevations in PSA that were seen. So we do see a lot of people that may be on testosterone therapy for reasons other than hypogonadism. And when you're asking them to stop their therapy, what could you counsel them about? When are they likely to expect an improvement or normalization in their testosterone levels? So this study was a nested sub-cohort runoff study of the T4-DM study and was able to provide some information regarding the natural history of recovery following cessation of testosterone treatment. However, this testosterone treatment was testosterone undecanoate, not cypionate or enanthate that we may use more often. And you may recall from last year's PGA DSN year in review, we covered this study that was the T4-DM, where there were men that were recruited between 50 to 74 years of age to assess the effect of testosterone therapy for metabolic dysfunction in individuals that didn't have pathological hypogonadism, and they were treated for two years. They entered this runoff study three months after their last injection, be it of placebo or testosterone, and then were followed up every six weeks to assess their testosterone levels. Notably, prior to unblinding, patients were asked which treatment did they think they had received. So looking at these figures here, you can see that the serum testosterone, of course, was higher in the individuals that had received testosterone, but gradually declined and would appear to be less than those that had received placebo, when in actual fact the free testosterone was comparable because the sex hormone binding globulin was lower in those that had received testosterone therapy. And there was a gradual increase in LH and FSH, and so essentially recovery occurred 1.5 to 2 years after cessation of therapy. So it gives you some reference point of what to tell individuals, and that it does take time. Notably here you can see that those individuals that were receiving testosterone, only just over a third of individuals guessed right, whereas the majority, or two-thirds, thought they were on placebo or were unsure. So there's nothing so uncertain as a sure thing. So what about adding exercise to a hypocaloric diet? Could that possibly lead to a boost in testosterone? So some studies have indicated that weight loss through either diet or bariatric surgery can lead to an improvement in testosterone levels. So could exercise be an adjunct and lead to an increase in testosterone? So this systematic review and meta-analysis identified nine eligible studies that were included where they assessed a hypocaloric diet or hypocaloric diet plus exercise, and they looked to see what effect this had on serum testosterone. So regarding the effect on testosterone levels, unfortunately adding exercise did not have a significant effect on circulating mean testosterone levels. They noted a serious risk of bias and that the certainty in the data was moderate. So although exercise is crucial to health, the additive effect to a diet on testosterone levels, if anything at best, were small. So that's the gonadal urine review, and I will hand it over to my colleague. Thank you. So I'm going to be presenting the adrenal review today. I have nothing to disclose. I'm going to review five publications rather than six here in the interest of time and making sure that I don't go over, including Adrenal Incidental Oma, Adrenal Insufficiency, Pheochromocytoma, Primary Aldosteronism, and Congenital Adrenal Hyperplasia. So the first study entitled Plasma Steroid Profiling in Patients with Adrenal Incidental Oma. The objective was to establish the utility of LC-MS plasma steroid profiling with plasma metanephrines and adrenal lesion size to discern adrenal tumor type. So this was a retrospective cross-sectional study in patients from seven European tertiary care centers. Inclusion was just based on the incidental finding of adrenal mass, as well as available plasma for steroid profiling. The final population was comprised of 577 patients, including 19 with ACC, 104 with Autonomous Cortisol Secretion, or MAC, 312 with Non-Functioning Adrenal Incidental Omas, 65 with Primary Aldosteronism, and 77 with Pheochromocytoma. So measures of diagnostic performance were assessed for discriminating different subgroups of patients with Adrenal Incidental Oma. So this slide illustrates the plasma concentrations by steroid type by lesion type. And so as you can see, patients with Primary Aldosteronism in the fourth column here have the highest levels of aldosterone, 18-oxycortisol. They had three and a half to four times that of other groups. They also had significantly higher levels of 18-hydroxycortisol. Those patients with ACC were distinguished from all other groups, but by much higher levels of 11-deoxycortisol, 11-deoxycorticosterone, 17-hydroxyprogesterone, DHEAS, androstenedione, as well as progesterone. As expected, patients with pheochromocytoma had much higher levels of normetinephrine here, metinephrine, as well as methoxytyramine. So this slide illustrates the matrix that really compares the diagnostic performance of using a steroid panel versus using a steroid panel plus metinephrines, and the steroid panel, metinephrines, and adrenal lesion size. So as you can see, patients with ACC, 14 of the 19 patients were identified here, giving a sensitivity of 74%, 98% specific. When metinephrines were added, the sensitivity went up to 83%, and 100% sensitivity when adrenal lesion size was included here, with a 99% specificity. For patients with PA or primary aldosteronism, there was 83% sensitivity looking at plasma steroid panel alone. When metinephrines were added, that sensitivity went up to 91, and slightly up when adrenal lesion size was looked at. They used an adrenal lesion size over four centimeters here. In terms of pheochromocytoma, the sensitivity with the steroid panel alone was only 66%, but went up to really 95% with using metinephrines, adding metinephrines, 97% when adrenal lesion size was added, with 99% specificity here. Those patients with ACS, a non-functional adrenal incidental omas, performed the poorest really here, and so steroid panel alone was 66%. When metinephrines were added, 71%. Not much change here when adrenal lesion size was added. And non-functional adrenal adenomas, 44% sensitivity when looking at the steroid panel alone, which increased to 69% and 71% with adrenal lesion size was added. So based on this, the authors concluded that among patients with adrenal incidental oma, the combination of using plasma steroid metabolomics with routinely available plasma-free metinephrines and data from imaging studies on adrenal lesion size may facilitate the identification of almost all clinically relevant adrenal tumors. So very clinically relevant here. So to move on, I'm gonna move on to the topic of adrenal insufficiency. This is a publication entitled The Biochemical Diagnosis of Adrenal Insufficiency with Modern Cortisol Assays. Reappraisal in the Setting of Opioid Exposure and Hospitalization. So we often are concerned about opioid exposure causing adrenal insufficiency in our patients. And this was a study from Mass General where their objectives were to examine the diagnosis of opioid-induced adrenal insufficiency and the diagnostic value of a morning plasma cortisol less than three. So twofold objectives in their study. This was a retrospective single center study at Mass General and they used the cutoff for adrenal insufficiency as a maximum stimulated cortisol of less than 14.7 micrograms per deciliter with analysis applying a standard cortisol of less than 18. And they used this because of the increasing specificity of cortisol assays. And specifically in their study, they used monoclonal antibody immunoassay that was validated at 14.7. So it is a data-driven cutoff that they used. And so of this, for this first cohort, there were 75 patients that had at least 30 days of opioid exposure and underwent Cortisone Stimulation Testing. And so the peak cortisol was less than 14.7, that cutoff, in only three patients. Whereas when they used the cutoff of less, this should be less than 18, apologize here, 14 patients met that cutoff. So using a cortisol of less than 14.7 opioid-induced adrenal insufficiency, it really is quite rare. The prevalence really using that cutoff was 4% versus 18% with the traditional cutoff of using 18. So the second part of this study was looking at the morning plasma cortisol. And this table really gives the test characteristics in terms of sensitivity and specificity using a morning plasma cortisol level in these patients who underwent a Cortisone Stim test who were both on and off opioids. And so as you can see, using a plasma cortisol, morning plasma cortisol of three, the sensitivity was very low, it was only 47.6%. As they used, they found that their cortisol level in this study of 12.6, the morning cortisol level, was 100% sensitive in diagnosing adrenal insufficiency. So 64% of hospitalized patients with a morning cortisol of less than three actually passed the Cortisone Stimulation Test. And so they concluded that the serum morning cortisol of less than three is not a valid diagnostic test for adrenal insufficiency in hospitalized patients whether or not they're receiving opioids. The next study that I'm gonna present is on primary aldosteronism, and it's entitled Adrenocorticotropic Hormone Stimulated Adrenal Venous Sampling Underestimates Surgically Curable Primary Aldosteronism, a Retrospective Cohort Study and Review of Contemporary Studies. So the purpose was to examine the impact of giving ACTH during AVS on lateralization. And it's well accepted that using ACTH to confirm cannulation of the adrenal vein or selectivity, there's no question or debate about that. But there has been a lot of controversy about using ACTH during AVS and very mixed studies on this. And so this was from the Brigham. It was a retrospective study, 340 patients with primary aldosteronism who underwent AVS single center protocol used sampling both pre and post ACTH bolus. They used it for pre for selectivity and then they used it during AVS as well. And so what they found is that the post ACTH bolus led to a decline in lateralization index in 58% of cases and 26% discordance between pre and post ACTH lateralization index. Nearly all discordance was due to unilateral disease being reclassified as bilateral disease post ACTH. So why is this clinically significant? Of course, the post ACTH lateralization index did not add really meaningful prognostic information beyond the pre lateralization index in this study. And when they looked at all the other studies in their review of contemporary studies, 10 of 11 recent studies demonstrated similar results. So the authors concluded that ACTH stimulation during AVS can underestimate surgically remediable primary aldosteronism and thereby lead to fewer patients referred for potentially curative surgery. So something to keep in mind when we're referring patients on for AVS. So ACTH again should be limited primarily to enhancing selectivity is what they concluded. The next study is on pheochromocytoma and this is a correlation between plasma catecholamines, weight and diabetes in pheochromocytoma and paraganglioma. Their objective of this study was to evaluate the relationships between plasma catecholamines, body weight and A1C. And so this was a retrospective cohort over 10 years at a tertiary hospital. This is from the University of Pennsylvania. And they looked at 360 total patients with either pheochromocytoma or paraganglioma. Their median age was 59 years and 54% of them were female. So what they found is that they looked, the main outcomes was weight over the entire course of the study in hemoglobin A1C and found that both plasma norepinephrine and normetinephrine directly correlate with hemoglobin A1C and inversely correlate with weight in patients with pheochromocytoma and paraganglioma. And these graphs just illustrate this. It was norepinephrine and its metabolite normetinephrine that had the strongest correlation with A1C here. So when these levels were very high, the A1C was high and when the tumor was removed, the A1C declined. And with that removal of tumor, in addition, post-resection, there were decreased normetinephrine levels that correlated with the improving A1C despite an increase in body weight. And that's significant and clinically relevant because although these studies have shown that A1Cs improve after removal of pheochromocytoma or paraganglioma, it wasn't a specific relationship between the catecholamine or its metabolite hadn't really been shown. And so persistently elevated catecholamines and decreased weight were seen in those patients with metastatic recurrent disease. And this graph really illustrates this, is that this graph shows the percent weight change over the entire course of the study in the different subgroups. So those who had surgery, no surgery, metastatic disease, non-metastatic. And then they looked at elevated norepinephrine and normetinephrine versus normal normetinephrine and norepinephrine. And these were, just to clarify this, this was the final endpoint of the study. It was the last time point that they looked at, most strongly correlated with the trajectory of the weight change over the course of the study. And so what we see here is these patients with elevated norepinephrine and normetinephrine over the trajectory of the study. So this is at the final time point experience weight loss. And those were the patients with metastatic recurrent disease. Whereas those patients who normalized, who had a normalization of their levels after resection actually gained weight. So this was significant again. And I think more studies will be done on looking at this relationship and how this plays out in terms of A1C and different effects of these catecholamines. So I'm actually gonna skip over this study. In the interest of time and to present the last study is on congenital adrenal hyperplasia. And this actually is an interesting study from Korea where they looked at adrenal morphology as an indicator of long-term disease control in adults with classic 21-hydroxylase deficiency. The objective was to evaluate the relationship between adrenal morphology and disease control status in patients with CAH. And as we know, it's difficult to monitor these patients because of different clinical and laboratory settings. And there are no current guidelines on whether to image patients with CAH. So this is an interesting study to look further into this. It was a retrospective cross-sectional study with 90 adult patients with classic 21-hydroxylase deficiency and 270 age- and sex-matched healthy controls. They assessed adrenal volume, width, and tumor presence using abdominal CT and evaluated correlations of adrenal volume and width with hormonal status. So this is what they did in terms of looking at image analysis. They looked at adrenal morphology assessed according to limb width, number one, and they looked at, here in A and B, we see the limb width just to orientate use of vertebral body, the aorta here, the diaphragmatic cruise, right, the IVC, and two nice plump adrenal glands here. And so in terms of measuring the width of the limbs, they looked at the widest portion of the limb in each, both the lateral and medial gland, the limbs here, of both glands, and then averaged them to come up with the limb width. So here we have a limb width of 6.91 here, and this, where's my cursor here, oh, 6.91. And so hypertrophy was defined as a limb width of greater than or equal to five millimeters. Normal width was two to five, and hypertrophy was less than two. So this patient has a hypertrophied medial limb here in A, in panel A, and in panel B, tiny little gland here is seen here right near the liver, and this width was 1.96 millimeters, so less than two, so hypertrophy or atrophy there. They then looked also at the presence very carefully for the presence of an adrenal mass in each gland, and here's two well-circumscribed masses, and also for the presence of gross fat, indicating a myelolipoma. And then lastly, they did adrenal volume by manual segmentation, so the radiologists manually segmented carefully each gland here, and then used a computer-based program to look at, that computed the volume to look at volumetry. And so what they showed was that 17-hydroxyprogesterone and androstenedione had the highest levels in those patients with adrenal hypertrophy. So here we go, so patients with hypertrophy here in the first bar, very high, 17-OHP. Those with hypertrophy or atrophy had very low levels, and the same with androstenedione. The next slide shows just a table that really correlates, that shows the correlation of adrenal volume and width with hormonal status in patients with 21-hydroxylase deficiency. So as you can see, adrenal volume correlated positively, both adrenal volume and width with ACTH, 17-hydroxyprogesterone, 11-beta-hydroxytestosterone, as well as DHEAS. So patients with hypertrophy or atrophy had 17-OHP levels and androstenedione levels that were less than those with hypertrophy and normal glance. And 50% of these patients with hypertrophy or atrophy showed normal 17-OHP levels indicating overtreatment. So when we see this, to see this correlation visually was very helpful, but we wanna be clear as clinical endocrinologists when we see this to be aware of overtreatment of these patients. So in conclusion, adrenal volume and width by CT reflect disease status control in patients with 21-hydroxylase deficiency. Adrenal volume and width may be reliable quantitative parameters for monitoring patients with classic 21-hydroxylase deficiency. So thank you very much, and I'm gonna hand it over to Adriana, who's gonna be presenting on the pituitary update. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. Thank you. So what we see more often in any clinic, especially general endocrinology clinic, is prolactin-secreting tumors. This article comes from Italy, and in essence, they looked at 27 patients with pituitary macroadenomas secreting prolactin. It was a retrospective study, however these patients all had a very thorough evaluation at baseline, at three months, and at 12 months post-treatment, and so on. They were all treated with cabergoline, and the authors chose a cutoff of 50% of greater in terms of tumor shrinkage at 12 months as the main outcome here. And the calculation of the tumor size is based on these two diameters measured in the sagittal view. Now, the tumor shrinkage, when they calculated that, you subtract the post-treatment size from the baseline size, so there is a little bit of a mistake in that formula, I'm sorry. So in terms of prediction model, they chose a stepwise backward selection approach to predict their main outcome, and they put in there multiple variables, both clinical, radiological, biochemical, cabergoline dose, and so on. And the only predictor they found for shrinkage at 12 months was the degree of shrinkage at three months post-cabergoline treatment. And the area under the curve for the optimal cutoff that they identified was very good, 0.97. The cutoff was 30% shrinkage at three months. So in other words, nobody that achieved a meaningful 50% or more shrinkage at 12 months had less than 30% shrinkage at three months. And in fact, for those followed later, nobody who didn't have shrinkage up until a 12-month point had significant shrinkage afterwards. This table looks at those patients that underwent surgery versus those that underwent medical therapy. And most of the surgically treated patients after 12 months of cabergoline did so because of the suboptimal tumor shrinkage response. There was few for preference. And really, you don't see any significant differences between the two groups other than the tumor shrinkage, which was pretty much how the groups were created. But what I want to show you is the prolactin here. The average prolactin at three months is similar in the two groups. And the degree of prolactin normalization is around 50% for both groups. And then if you look below at the 12-months data, it has gone up a little to 60%. So what this is telling us that we've all seen it in our patients, right? There are those cases of discordant biochemical and radiological response. And you have to look at all the facets of this problem when you're trying to predict or to discuss with your patient what kind of response they had to the treatment that you're prescribing. And for those that you are referring to surgery, this second paper might be relevant. This comes from the Mayo Clinic. And it's a meta-analysis of surgical outcomes and medically failed prolactinoma. So these were patients treated either with bromocriptin or cabergoline. And 84% of them did not achieve prolactin normalization. The remainder had intolerance to the medicine. So most of them were non-responders to cabergoline or bromocriptin. I'm going to show you these conclusions as graphs. The first conclusion of this meta-analysis was that overall, at last follow-up, and this was about 14 months median later after surgery, 38% of patients maintained prolactin normalization. So that's surgery as second-line therapy after dopamine agonist did not achieve this. If we're going to split them up in macro and micro prolactinoma, we see that macro prolactinoma remission is pretty low. So if the patient with macro prolactinoma did not achieve remission as a result of maximal dose cabergoline, for example, it's very unlikely they're going to do so after surgery. For micro prolactinomas, a little different is about 66% of them did. Post-operative dopamine agonist use was encountered in 46% of these patients, and they were those who didn't normalize prolactin as a result of surgery, or those who did but afterwards they underwent recurrence of their hyperprolactinemia, and those represent about 16%. So with this article, I would like to kind of emphasize the need to follow up these patients that you send to surgery in an attempt to improve prolactin control, because they still might need dopamine agonist. The third article is in acromegaly and comes from Sweden, is a nationwide population-based study where they had almost 1,300 patients that were diagnosed over the course of 30 years, starting 1987 and followed up for 12 years, and they were compared with general population in Sweden to calculate incidence ratios and mortality ratios for non-pituitary tumors. So for malignancies, there was an increase in observed malignancies in the acromegaly patients, 186 versus expected 144, which was noted in both women and men. As one might expect, colorectal and anal malignancies were increased, about 50% above expected. So kidney and ureter malignancies were increased about four times from what's expected, and these were symptomatic tumors, not incidentally detected, advanced. No other cancer made it there from a statistical standpoint, and they only had three cases of thyroid cancer observed over 30 years. Twenty-three patients with acromegaly had multiple malignant tumors. How about benign tumors? Significant increase versus general population, in particular in men, about three times, and in women about twice. And what you see listed there are those that were actually found to increase. So colorectal and anal tumors, other gastrointestinal tumors, benign, melanocytic nevi, nasal polyps and lipomas. When the authors took into consideration benign brain tumors, there was an increase in incident ratio for all tumors three times above general population, and this was very significant in those that underwent radiation, so that went to 4.5. Incidents of malignant tumors did not change over the three decades that were studied here, and mean age at cancer diagnosis was around 66. Mean time from the acromegaly diagnosis to cancer diagnosis was around 6.5 years, but as you can see from the Kaplan-Meier curve, it could happen any time during the acromegaly patient lifetime. Mortality due to malignancies was similar to the general population and similar in both genders. One might think that with being aware of something and more cancer screening, maybe malignancies are detected at an earlier stage. Well, the authors specify that in Sweden, for general population, the screening for colon cancer starts at age 60 with a fecal-to-occult blood test, and only those patients who have a positive test go on to have a colonoscopy, and the situation is no different for acromegaly patients. So personalized cancer surveillance programs for acromegaly are needed, and in this country we need to figure out the way with regional or national databases to find out what's going on. The last two papers I have about novel studies and novel therapies in acromegaly and Cushing, and I just wanted to show how much progress we've made here. Obviously this is not the—there is no time to go over this incredible increase in the landscape of medications from octreotide in 1988, first approved for acromegaly, and then we had two additional somatostatin receptor ligands, SRL, approved in 2007 and 2014, and we have a pegvisoman, which is a grofomol receptor antagonist, and in 2020 oral octreotide was approved by the FDA. This year the Empowered Study was published in Lancet, and this was an open-label study that included patients previously controlled, biochemically controlled, either on octreotide or landreotide long-acting, and you can see there the inclusion criteria in terms of almost perfect IGF-1 level and grofomol profile. 146 patients with acromegaly entered the running phase, and this lasted 26 weeks, and all these patients received oral octreotide, and then of them, 92 patients were then randomly assigned either to continue the oral octreotide or to go back to their injectable somatostatin receptor ligand, so whatever they were on before, and the primary response was to assess non-inferiority throughout the randomized treatment phase by looking at time-weighted average IGF-1 levels, and this was attained, achieved, 91 percent of patients in the oral octreotide group, and of course we expected 100 percent in the ISRL. So adverse events, 35 percent in the oral octreotide group and 41 in the ISRL, no significant difference. There are the similar oral side effects that you would expect with octreotide and landreotide in general, and of course for oral octreotide, there are no side effects from the injections themselves. This study also incorporated some patient-reported outcomes and symptoms, but was not really powered. These were secondary endpoints, and they weren't really powered for statistical comparison. What you see in the upper graph, you see at the end of randomized phase, those patients in orange represent injectable group, and the ones in blue, the oral group, and there are no significant differences there in terms of the main symptoms that you would expect in patients with acromegaly, joint pain, swelling, perspiration, and so on. Now in the lower part, in purple, you see the baseline symptoms at the beginning, right? They were coming off their injectable SRLs, and then in green, the same patients at the end of the run-in phase, after they have taken oral octreotide for 26 weeks. You see that there were some differences in favor of oral octreotide in terms of swelling of extremities and fatigue. Of course, further work has to be done, and this is a very active research field with regards to patient-reported outcomes. For Cushing's, it's no less exciting. We didn't have any medication that was approved by the FDA up until December 2012, when the first cortisol receptor blocker, remifepristone, were approved, and then the multiligand SRL passereotide. In the last two years, we have two steroidogenesis inhibitors that were approved, ocilodrostat and levokitocornazole. All the steroidogenesis inhibitors that we have used, FDA-approved or not, are very nicely represented here in also new paper that came out in the last year, and it's helpful from a physiopathological standpoint to always go back to that. The last article is a randomized trial of ocilodrostat for treatment of Cushing's disease that I'll link for, that was just published in JCM, 73 adults with Cushing's disease. They were randomized either to two milligrams of ocilodrostat twice daily or placebo for two weeks. The titration was based on urinary free cortisol measurement and tolerability. After 12 weeks, they all received ocilodrostat in a 36-week open-ladable treatment period. The primary endpoint was normalization of mean urinary free cortisol at 12 weeks as it compared with placebo, and the key secondary endpoint was percent of patients achieving this at the end of the additional 36 weeks of the next phase that was the open-label phase. The first endpoint, ocilodrostat arm, 77% normalization of urinary free cortisol at 12 weeks versus 8% in the placebo arm. What you can see in the panel below the B figure in the dark bars, you can see the percent of patients that normalized their urinary free cortisol at each week when the measurement was taken on. This is a medicine that works fast, and many patients don't need too high doses, and titration has to be taken into account. The possible adrenal insufficiency factor has to be taken into account, so don't move too fast with the titration. In terms of the randomized period, you see here how nicely placebo and ocilodrostat separate, and then at the end of 48 weeks, 81% of patients had normal urinary free cortisol. With that, I am going to finish my presentation. Thank you. I'm going to invite my colleagues back on the podium, and please approach the microphones if you still have time and if you have any questions for us. Thank you. No questions. Go ahead. There was, I think a week or two weeks ago, there was the ISE, the auspices of the ISE, there was a talk about Cushing, and one of them, it was a combination of Oxford and France, and the idea was that even though there is normalization of the UFCs with ocilodrostat, apparently it's not enough for a cure, and they suggested that salivary cortisols should be measured too. Do you have any data on the salivary cortisols with ocilodrostat? Very good point. So obviously we can measure late night salivary cortisols, and although urinary free cortisol has been the main measurement in all the studies that were done with all the Cushing medications, it is difficult to normalize the diurnal variation of the cortisol with medical treatment. So as far as I know with ocilodrostat, this was not published in terms of the findings, and there is just one paper that is older that looked at pasireotide LAR and how some patients had both urinary free cortisol and salivary cortisol normalization, and how that impacted the core mobility. So yeah, it would be nice if we were able to normalize the... So the last piece was the one who actually suggested that you should actually measure both to make sure that this is a cure. But it's not very often that the normalization happens. In my experience, I don't know about you. No. Yeah, no, I agree. It's pretty tough. Yeah. Any other questions? Okay. Well, enjoy the rest of the beautiful evening in San Diego.

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