I will start with the program anyway so that we move ahead because I think we have quite a lot of good abstracts that have been submitted. So I would like to call the first speaker, which is actually the second speaker, which is Cynthia Guterio. You're going to go first? Okay. Which is, I'm sorry, Cynthia. So the first presentation will then be given by Dr. Oluwatomi Adeyoti, who is from the Central Michigan University and who will give a presentation on the outcomes and predictors of 30-day readmission for hyperthyroidism, a nationwide study. But that's the first one on my list. Is Dr. Oluwatomi here? Then I go to the second speaker on my list. I'm sorry, there's a lot of confusion here. But the second speaker on my list is Dr. Cynthia Citerio. Dr. Citerio, are you in the audience? Okay. What's your name? And you are not on my list. I suggest you just please come ahead. I hope your presentation is on the list then. I'm really sorry for this, ladies and gentlemen. But please go ahead. Joshua Stokar. You have Joshua's presentation? Okay, so hi everyone. My name is Joshua Stokar. I'm from Hadassah Medical Center in Hebrew University in Jerusalem, Israel. I'd like to thank the organizers for allowing me to present some of our work about the transcriptional changes in the thyroid relating to immune checkpoint inhibition. Let's go forward. Okay, nothing to disclose. The last decade or so has seen a revolution in cancer therapy in the form of the category of immune checkpoint inhibitors, starting with advanced melanoma patients, but receiving more and more indications for different types of cancer with great success. Some consider it a miracle in some cases. Just a brief reminder of the underlying mechanism. We have the immune checkpoint that normally allows for immune tolerance of autoantigens. The cancer cells can hijack the system to evade the immune system, and by inhibiting various immune checkpoints, for example, the CTLA-4 you see on the left, or the PD-1, PD-L-1 on the right, we can allow the immune system, the T-cells specifically, to remain active against tumor cells, and the Nobel Prize in Medicine was awarded for Han-Zhou and Allison for this discovery in 2018. Now, with this novel category of medications comes an interesting category of adverse events, and these are called immune-related adverse events, where the immune system attacks the different organ systems. Some of these can be endocrine systems, and the most common endocrine system involved is the thyroid. The most common clinical manifestation is hypothyroidism, but if we follow these patients carefully as we usually do, we usually see that the hypothyroidism is preceded by what is usually an asymptomatic phase of thyrotoxicosis, meaning there's destructive thyroiditis that then leads to usually permanent hypothyroidism requiring replacement therapy. Now, the incidence of this phenomenon is actually quite common, and depending on which treatment is being used and which cancer type, we see even more than 30% involvement of the thyroid, especially with the combination of different types of immune checkpoint inhibitors together. So the question we set out to explore is what causes this immune checkpoint inhibitor-induced thyroid dysfunction. Now, obviously, this is common sense, but also supported by data, the T-cells are involved, and this is work published in Thyroid in 2020 from a group from Mayo Clinic. You see the different populations of T-cells in the thyroids of patients with immune-related thyroid dysfunction versus those who did not have immune-related thyroid dysfunction. But perhaps the more basic question we wanted to examine is why is the thyroid being targeted more so than other organs by these immune-related adverse events. So one hypothesis can be that the thyroid perhaps expresses PD-L1, which would make it more common for these immune-related adverse events, but we already showed this was published. As you can see in B, the normal thyroid doesn't express any PD-L1 versus the control. Now, we do know that in cases of thyroiditis, for example, Hashimoto, and some cases of Graves' disease, we do see expression of PD-L1 in the thyroid, but we think this is a result of the inflammation and not the underlying cause. So we went one step back and asked ourselves, well, maybe the immune checkpoint inhibitors induce transcriptional changes in the thyroid even before thyroiditis occurs. So we used a mouse model, and you have to understand, as of yet, there isn't an established mouse model for immune-checkpoint-related thyroid dysfunction. The regular so-called lab mice, the C57 black or the 129 that we used here, don't develop thyroiditis when they are given immune-checkpoint inhibitors. But this was actually good for our purpose because we wanted to see what happens before or unrelated to the actual thyroiditis. So these mice were injected with a non-small cell lung cancer tissue about two weeks before the treatment began. They were given immune-checkpoint inhibitor, anti-PD-1 or anti-PD-L1 antibodies, or vehicle control every three days, and then sacrificed a week later. And then the tissues were harvested, and we were obviously interested in the thyroid. So first of all, we see that the treatment did work. The tumors shrank in the two different treatment arms versus the control where the tumors continued to grow. So we know the treatment was working. And when we looked at the transcriptome in the thyroid, what was interesting, as you can see on the left in the principal component analysis plot, is that the groups differed not treatment versus control, rather anti-PD-1 versus all the rest. So the anti-PD-1 are the blue dots, and the control, red, and the PD-L1, green. You can see the main differentiating factor is anti-PD-1 versus all the rest. And this is reflected also in the numbers of genes that were up and down-regulated, where you see several hundred genes were up and down in anti-PD-1 versus control, versus only a few genes that were up and down-regulated in anti-PD-L1 versus control. So then we continue to analyze this more robust gene set, this transcriptome that seemed to be changing in the thyroid as a result of anti-PD-1 versus control. And you can see in the various forms in the two graphs how you have several hundred genes up and down-regulated, and they cluster together in different groups. And then we went on to use Ingenuity's pathway analysis tool to understand a little bit of the biology that's going on here. And some of the results are to be expected. We had changes in pathways and gene sets related to cell death, apoptosis, cell cycle, things that have to do with the mechanism of the immune checkpoint inhibition. Some results were more surprising, like this strong activation of the oxidative phosphorylation pathway that we don't yet understand. This is just a diagram of all the genes that were activated, up-regulated in the oxidative phosphorylation pathway. So we then asked ourselves, well, how do these changes compare to changes exhibited in other forms of immune thyroid dysfunction? So we went to the Gene Expression Omnibus, which is a publicly available database of genetic data, of transcriptomes, different experiments, and we found two gene sets to compare to. So we have our data set that's anti-PD-1 versus control, and then we have two other data sets. One is thyroiditis induced by a combination of cytokines, interferon gamma and IL-1 beta, and these are actually primary human thyroid cells, and a mouse model of Graves' disease. And what's good about this specific option in the IPA tool is it allows you to compare results from different platforms. It doesn't matter that these were done in different technologies, microarray or RNA-seq, or different, actually, human versus mouse, because it all converges on the same pathway analysis. So for example, you can see on the right-hand side in the diseases and functions category, apoptosis was activated in our gene set, anti-PD-1 versus control, as well as in the cytokine-induced thyroiditis, but was down-regulated in the Graves' disease mouse model, and this is to be expected. As we know, even though Graves' is immune-related, it doesn't destroy the thyroid, rather there's hyperplasia. But overall, we see that in the canonical pathways on the left, the anti-PD-1 versus control showed a unique transcriptional signature versus these two other models. We can't say that it was similar to any of the two. When we looked at who are the predicted regulators of these changes, also available in the IPA analysis tool, we see a whole list of cytokines that are predicted to be deactivated or down-regulated in anti-PD-1 versus control, whereas they were predicted to be activated in the other two models. So it seems very different. Now this may be surprising that cytokines would be predictably deactivated in what eventually leads to thyroiditis, but as I said, our model didn't include thyroiditis. We're just looking at the net effect of the checkpoint inhibition on the thyroid. We also think this may be compatible with results already published by a Japanese group in 2020 that examined the peripheral level of the blood level of various cytokines in patients with or without the immune-related thyroid dysfunction. What is notable is that, especially in the patients that suffered the immune-related thyroid dysfunction, many of the cytokines actually go down. They start high, and maybe this predisposes them to this phenomenon, but the treatment actually leads to a reduction in the level of these cytokines. So in conclusion, we found that immune checkpoint inhibition induced distinct transcriptional changes in the mouse thyroid, much more robustly in the anti-PD-1 than the anti-PD-L1 versus control. We mentioned the different pathways that were activated and deactivated, oxidative phosphorylation. Don't know really why that was. When we compare this with other forms of immune thyroid dysfunction, this is a distinct signature with what seems to be a down-regulation of downstream effects of cytokines. We are aware that this poses more questions than answers, but we do think it justifies further research, perhaps using a combination of single-cell sequencing and, of course, thyroid histopathology to uncover what seems to be a very novel mechanism of immune checkpoint inhibitor-induced thyroid dysfunction. Thank you, and I'll take any questions. Thank you very much. Excellent presentation. Very exciting data. While people are still thinking about questions, I was wondering, you started the presentation with the remark that we don't know why the thyroid is so vulnerable. Did you have a chance to look at other tissues or other endocrine organs in your mice? Yes, that's a very good question. Thank you. We did collect other organs and we did the same RNA sequencing on those organs. We took the adrenal, we took the liver, some non-endocrine organs, and we're still analyzing that data, but that is the plan. Thank you. So, if there are no questions from the audience, thank you again for this presentation. To the second talk. So the next presentation will be given by Dr. Cynthia Quiterio from the Division of Metabolism, Endocrinology, and Diabetes from the Department of Internal Medicine at the University of Michigan, Ann Arbor. She will be presenting also on behalf of the co-authors a presentation on thyroglobulin structural requirements in protein trafficking for thyroid hormonogenesis. Hello, good morning. I'm going to talk about thyroglobulin trafficking that is required for the synthesis that are very important for this. So invertebrate thyroglobulin needs to be secreted to the thyroid follicular lumen to enable its iodination for the thyroid hormone synthesis. Indeed, thyroglobulin is the only precursor protein for thyroid hormone synthesis throughout vertebrate. And defective thyroglobulin or tissue secretion causes hypothyroidism. We know that a defining step in tissue secretion is export through the endoplasmic reticulum. However, tissue structural features needed to meet those endoplasmic reticulum quality control requirements remain poorly understood. Here is the primary structure of tissue. It is composed of region one, region two, region three, and a carboxy terminal cholinesterase like domain. Each engage in intradomain disulfide bonding. Two major surprises that recently emerged from the visualization of the 3D structure of tissue by Cryo-EM are the first identified long-range disulfide bond involving 16408-16608, which appears to tie a boundary between two halves of region one. And the second surprise is the apparent absence of an evolutionarily conserved disulfide bond between 16244 and 162455 in the cholinesterase-like domain, which is known to support the folding stability of the region one of tissue. Then to understand the cell biological importance of these findings, we employed site-directed mutagenesis to determine the impact of these structural features in protein folding and export of recombinant tissue expressed in cell culture. We utilized recombinant full-length tissue and introduced point mutations in these cysteines of interest, cysteine to alanine, created singles and double mutant, transfected 293 T cells, which do not endogenously express thyroglobulin, and analyzed tissue expression in the cell lysate and secretion to the media by Westenroth with anti-tissue antibody under non-reducing conditions and under reducing conditions. And we can see how is the expression and secretion of wild-type TG compared to each of the mutants. We repeated the experiment three times and calculated the recovery of TG and we found that mutation of 16408 and or 16608 impairs TG secretion. Then we turn our attention to 162444 and 162455 because these are involved in the disulfide bridge that is conserved in the cholinesterase family. As we can see here in the acetylcholinesterase structure, they are highlighted in red. So we utilize recombinant acetylcholinesterase with a MYC tag, create point substitution mutants, cysteine to alanine or cysteine to serine in our amino acids of interest. Again, transfected to 93T cells and analyzed expression and secretion by Western blots under non-reducing conditions and under reducing conditions. So we can see how the wild-type acetylcholinesterase MYC tag is well expressed and secreted. However, when we introduce the mutations, there is no secretion. We again repeated the experiment three times and calculated the ratio of secretion of acetylcholinesterase in the cell lysate divided by the expression of acetylcholinesterase in the cell lysate. And we found that disruption of 162444, 162455 blocks the secretion of acetylcholinesterase. However, when we take a look at this image from electrodensity map of bovine tissue by cryo-EM, we do not see the disulfide between 162444, 162455. So what we did is utilize truncated cytoglobulin that only expressed the secretory keldomain. And again, we generalize the systems of interest. And we express again in cell capture, analyzed by Western blot under non-reducing conditions and under reducing conditions. And when we calculated the ratio of cholinesterase-like domain secreted to the media divided by the cholinesterase-like expressed in the cell lysate, we found that abolition of these systems, 2444, 2455 prevents the secretion of the tissue secretory keldomain. Next, we repeated this set of experiments in the full length cytoglobulin, again creating singles and double mutants in our systems of interest, analyzed expression and secretion by Western blot under non-reducing and under reducing conditions. And again, we found that disruptions of these systems in TG blocks TG secretion. We know that in a number of patients suffering from congenital hypothyroidism, as well as in the Koch congenital goiter mouse, cytohormone synthesis is inhibited because of mutations in the keldomain that block TG export from the endoplasmic reticulum. So we wanted to compare how our keldouble mutant looks compared to the keldcog mutant. As we can see here, after expression of these constructs, the intracellular pattern of misfolding is similar in the double mutant and in the keldcog mutant. And this pattern of misfolding disappear under reducing conditions. So mutation of this disulfide bond of interest causes the same pattern of intracellular misfolding than the pathogenic Koch mutation, which produces hereditary hypothyroidism. We can see in this 3D structure representation of the homodimeric bovine TG, that this disulfide bond in the keldomain, the keldomain is there in yellow, is far away from the region one that is represented in green. And we can see that the other system that we were studying, 408608, faces an interior cleft of the TG dimer. Then disruption of these cysteines in the keldomain, cysteine 2444 and cysteine 2455, may help to unbuild the keldomain structure in such a way that no longer provides proper contact to the region one. In summary, we found that loss of the cysteine 2444, 2455 disulfide bridge behaved similarly to the defective folding observed in the TG Koch mutation, whereas no pathogenic mutations have been reported affecting the long-range disulfide bond in TG in region one. Mutagenesis of cysteine 2444, cysteine 2455 blocks TG secretion, and the lack of detection of this disulfide bridge in the TG cryo-EM structure is likely due to its prior radiolysis by the electron beam that occurs in the cryo-EM. Together, these results highlight the importance of the keldomain structure in the maturation and secretion of thyroglobulin. I'd like to thank the NIDDK for my K01 and for my mentors at O1 that are supporting this research. Our collaborators, Kim Koyoko, Oliver Clark, my student, Bahabana Rahesh, my mentor, Peter Alban, the Endo Society for this Outstanding Abstract Award, and of course, thanks to all of you for your attention. Thank you very much. Excellent presentation and very well explained. So when there are no questions, I was wondering, so you clearly show the importance of this cysteine 2444 and 4055, could you speculate why no pathogenic or human mutations have been identified because we screen all patients or most, in a lot of countries, we screen those patients with congenital hypothyroidism? Is there another reason? Yeah, so we calculated that about one in 200 people have a mutation in TG. However, not all of us are screened because for developing this disease, congenital hypothyroidism, you need to have two mutations. So maybe it's because not all of us are screened and so perhaps with time, it will appear, but definitely it is predicted to be pathogenic. And in, let's say, SNP databases, for example, or large TWAS studies, I know some polymorphisms in the TG gene in itself have been related to thyroid function. Is it also in this position? Yes, we have, for example, the Shinomat, that database where we can find all kind of variations in the TG gene. However, not in this exact position, but maybe it's a question of time. With time, it will appear. Yeah, and would you expect to see some effect of heterozygous mutation? Maybe that, let's say, subjects could have a slightly higher TSH because they secrete less thyroglobulin or so? Yes, so nowadays we are also having our mice model to study what's the effect of mutations in only one allele of thyroglobulin. Yeah, and definitely they can show some effect that perhaps will not develop into hypothyroidism immediately, but yes, some defect. Thank you. So if there are no questions for the audience, thank you again. Thank you. And we move to the next speaker, which is Dr. Alessandro Brancatella from the University of Pisa in Italy. And Dr. Brancatella, on behalf of the co-authors, will share with us his abstract on steroid treatment in the management of destructive thyrotoxicosis induced by PD-1 blockade. Thank you. I wish to thank, first of all, the Endocrine Society for the opportunity of presenting our results. This is my disclosure. Thyrotoxicosis is the most common endocrine adverse event in patients treated with anti-PD-1 or anti-PD-L1 drugs. And it is estimated that up to 50% of patients treated with these drugs may experience thyrotoxicosis, especially in the early months of treatment. In a previous study, we observed that thyrotoxicosis induced by PD-1 or PD-L1 can be classified in two different types according to the presence or absence of a thyroid uptake at scintigraphy. A type one with a normal uptake at scintigraphy as shown in panel A. And a type two with an absent uptake at scintigraphy as shown in panel B. The two graphs show the natural time course of 3T4 on the left and 3T3 on the right in patients with a normal uptake at scintigraphy, the dot line, and in patients with absent uptake at scintigraphy, the continuous line. And while in patients with a normal uptake, 3T4 and 3T3 remain increased during the follow-up, in patients with an absent uptake, 3T4 and 3T3 normalize spontaneously in a few weeks. In addition, in the previous study, we decided to treat some of the patients with the most severe forms of thyrotoxicosis using methimazole. And we observed that while in patients with a normal uptake, methimazole was effective in normalizing thyroid levels in a few weeks, this treatment was ineffective in patients with an absent uptake, the continuous line. Current guidelines and expert opinion do not recommend any treatment for destructive thyroiditis induced by PD-1 or PD-L1 blockade. Nevertheless, in some cases, destructive thyroiditis may be particularly severe and long-lasting, and a severe thyrotoxicosis can be potentially harmful in patients with a poor performance status and comorbidities. The aim of the present study is to evaluate if steroids are useful in the management of the severe forms of destructive thyrotoxicosis induced by PD-1 or PD-L1 blockade in patients with a poor performance status. We chose steroids because these drugs are commonly used in other settings of destructive thyroiditis, for example, subacute thyroiditis and type 2 amiodarone-induced thyrotoxicosis, as well as in the management of other immune-related adverse events. From January to June 2020, 34 patients were referred from the oncology and pneumology units to the endocrinology unit of University Hospital of Pisa because of destructive thyrotoxicosis, according to the scintigraphy image, due to anti-PD-1 or anti-PD-L1 treatment. And then we decided to treat four of these patients with oral prednisone at a dosage of 25 milligram daily, tapered to discontinuation in three weeks, because of a poor performance status and an enlarged thyroid volume. And then we compared the course of thyrotoxicosis of these subjects to that of eight patients who experienced destructive thyrotoxicosis in the same period who matched thyroid volume at the onset. We chose thyroid volume as the matching criteria because in the previous study, we ordered patients with a destructive thyrotoxicosis according to the thyroid volume. Patient one in the box had the smallest thyroid volume, patient 15 the largest. And we observed that both 3T4 and TSH normalized quickly in patients with a minimum thyroid volume, for example, patient one, compared to patients with a largest thyroid volume as patient 15. And then we concluded that thyroid volume is the only determinant of the severity and duration of the destructive thyrotoxicosis induced by PD-1 or PD-L1 blockade. In this table, we reported the baseline characteristics of the present study. The levels of 3T4 and 3T3 were very high in both groups, treated and treated with steroids, with no difference in the levels, confirming that an increased thyroid volume is the main determinant on the severity of thyrotoxicosis in these patients. The two graphs show the time course of 3T4 and 3T3 in patients treated with steroids, the dot line, and in patients who left untreated, the continuous line. And while in patients treated with steroids, the levels of thyroid hormone normalized in a few days, in a few weeks, the levels of thyroid hormone in untreated subjects normalized in more than 100 days. And indeed, the median time to remission of thyrotoxicosis was 25 days in patients treated with steroids and 120 days in untreated patients. Moreover, steroids were also useful in improving the thyrotoxicosis-related signs. Indeed, the heart rate that was increased in all patients normalized more quickly in patients treated with steroids compared to those who left untreated. Finally, given the concern on the potential reduction of the antitumoral efficacy of the immunotherapy in patients treated with steroids, we evaluate the progression-free survival of the patients in the two groups. And we did not observe any difference in patients treated with steroids compared to those who left untreated. In conclusion, our preliminary data suggests that in patients with a poor performance status experiencing a severe destructive thyrotoxicosis induced by PD-1 or PD-L1 blockade, a short period of administration of oral prednisone is effective in obtaining a quick reduction of the levels of thyroid hormones and related symptoms. Further studies, prospective and randomized, investigating a larger cohort of patients are required to identify patients who may benefit mostly from this treatment and to establish the duration and the appropriate dosage of steroid. A special thanks to my supervisor, Professor Latrofa, to all my colleagues, and to you for your attention. Thank you. Thank you very much. Excellent presentation. I see a question from Dr. Celli. Yeah, it's easier. Congratulations, Francesco Celli-Richmond. I have a couple of questions to ask. You say that the major predictor is volume of thyroid. In your population, can you stratify or give us a glimpse whether it's nodular thyroid disease or diffuse volume? And then also, did you take in consideration, I mean, those patients are inoplastic patients, so presumably they had lots and lots and lots of CT scans with contrast. Do you have any information on that? That was great, thank you. Thank you very much for the question. Yes, in the previous study, we better characterized the neck ultrasound characteristics of the patients included in the study, and we did not observe any difference in the course of the destructive tyrotoxicosis according to the presence or absence of tyrod nodules. In addition, we evaluated the iodine, the level of iodine in this patient that was particularly high, given the high number of CT scan, but the levels of iodine did not modify the course of tyrotoxicosis in the different groups. Thus, at the end of our analysis, we find only the thyroid volume as the main determinant of the severity of tyrotoxicosis. Thank you. So, there are more questions? Thanks a lot. Asad from Alexandria, Egypt. What's the percentage of your patient developed hypothyroidism following the hyperthyroid stage, and did the steroid influence this natural course? Thank you. Yes, thank you for the question. We evaluated this aspect in our study. The rate of hypothyroidism in the two groups treated with steroid and untreated subjects were similar. About 60% of the patients developed permanent hypothyroidism in both groups. The only difference is that the patients treated with steroids, given the more quickly course of evolution of the tyrotoxicosis to hypothyroidism, developed hypothyroidism earlier compared to those untreated. But the rate of hypothyroidism was the same. Thank you. If there are no further questions, thanks again for this excellent presentation. And we move to the next presentation that will be given by Dr. George Kahaly on behalf of Horizon Therapeutics. And Dr. Kahaly will talk on taprotumimab, a markedly improved disease-related quality of life lessons learned from true randomized placebo-controlled clinical trials. Dr. Kahaly. Yeah, thank you so much, Chairman. Dear colleagues, it will be a pleasure. I'm looking for the slides, waiting for the slides. However, I may continue. It will be a pleasure to actually introduce you to the effect of taprotumimab within two randomized trials on the quality of life. More than this, I would also differentiate between those factor leading to improvement of quality of life versus deterioration of the quality of life. Thank you so much. So having solved this technical problem, I would like to introduce you to my co-authors. These are the co-authors of the abstract and their corresponding disclosures. And this is my disclosure. Okay. So, dear colleague, thyroid R disease cause inflammation and expansion of orbital muscle and fat tissue, leading to orbital pain, redness, and often proptosis, also called eye bulging, and diplopia, or double vision. Taprotumimab, a fully human monoclonal insulin-like growth factor one, receptor inhibitory antibody, demonstrated improvement in proptosis, diplopia, and inflammation in phase two and three clinical trial. A large significant improvement in quality of life, measured by the disease-specific Graves' orbitopathy quality of life questionnaire, which has been introduced by our group, the European Group on Graves' Orbitopathy, abbreviated EUGOGO, was also observed in these trials. So the objective of this present work was to assess factors that influence improvement in quality of life with taprotumimab. This shows you again the improvement obtained, or seen, in quality of life in the pooled phase two and three trials with taprotumimab. For those who are not familiar with this issue, the disease-specific quality of life questionnaire includes two subscales that measure visual functioning, abbreviated VF, dealing with severity of the disease, diplopia, visual equity, and proptosis, and a more psychosocial subscale dealing with the psychosocial effect due to change physical appearance, abbreviated AP. And to make the whole story short, if you go from the left to the right, you may observe that in this paper published in the Lancet, you have a major improvement of overall quality of life on the left, and a major improvement of the two subscales, VF and AP, in patients on taprotumimab in blue in contrast to those on placebo. So to the methodology of the present work, we were relying on two randomized double mask placebo-controlled trials. The patient received infusion of taprotumimab or placebo once every three weeks, so a total of eight infusions. And the quality of life disease, the questionnaire, was evaluated at baseline at six, 12, and 24 weeks. The pool trial data from 84 taprotumimab patients and 87 placebo patients, this is one of the largest trials in patients with thyroid disease, was examined in a mixed effect model to identify the key variables contributing to quality of life improvement. So in detail, we looked at the dependent variables, of course the quality of life, in total the appearance and the visual function subscales, and the independent variables were demographic, sex, age, treatment, diplopia, proptosis, and orbital pain, spontaneous and gaze evoked orbital pain. And finally, the variability between the subjects was tested over the 24 weeks period. Now to the results. We will start with factors influencing overall quality of life. And you're looking at the busy slide with many sentences. A few words are printed in bold, telling you these are the relevant factors, the significant factors observed in the study. For example, those with a positive coefficient, like sex, 7.2, are actually positively influencing quality of life. Those with a minus sign are actually minus or deteriorating quality of life. The corresponding comments are the following. Male patients had better score, meaning that female were less happy with the treatment, and complaining more. This is our experience. Higher scores were found with teprotumumab over time. This is fine, with a coefficient of 6.2, meaning that the drug is helping the patients. Orbital pain, and this is the novelty here, highly correlated with lower worse quality of life score, with a negative coefficient of minus 31. What does this mean? Activity of disease has a major impact, and the symptom of activity have a major impact on thyroid artery disease. Quality of life improvement was smaller in those with concomitant gaze-evoked orbital pain than those without. Quality of life was lower in the presence of proptosis, but also new, diplopia produced more negative quality of life than proptosis, with a negative coefficient of minus 4.1. We did observe an interaction between proptosis and orbital pain. Gaze-evoked orbital pain and proptosis were found to interact significantly. What does this mean? Meaning that the larger proptosis is associated with worse appearance quality of life, but those with concomitant pain show less improvement. In other words, the larger the proptosis, the lower the quality of life. But this does not hold true in patients with concomitant pain. You don't see this positive correlation in patients with orbital pain, meaning that orbital pains appear to be a stronger driver for worse quality of life, and is accentuated by proptosis. Now let's turn our attention to the subscales, the visual function subscale. Again, the same sort of tables with the words written in bold. Treatment, pain, and diplopia, and the corresponding comment. Better visual function score were found with teprotumor map treatment over time, with a positive coefficient of 8.5. Spontaneous pain was associated with worse quality of life, with a negative coefficient of minus 6.66, and higher severity and presence of diplopia correlated with worse quality of life. This is the second subscale, appearance score, more psychosocial subscale. And again, you are looking at the major comments, the major factors, which is sex, with a positive coefficient of 14, and orbital pain with a negative coefficient of minus 38. In detail, quality of life score were better in older versus younger patients. More importantly, male and older age were associated with better quality of life, meaning that younger patients and female patients were not happy, less happy with the treatment, and complaining more than older one and male patients. And gaze evoked orbital pain with a negative coefficient of minus 38. Diplopia and proptosis individually and significantly correlated with lower quality of life. Dear colleague, to summarize, this analysis indicates that improvement in orbital pain, novelty, diplopia, novelty, and proptosis drive improvement in quality of life in patients with thyroid R disease treated with teprotumormab. We may conclude and state that orbital pain improvement is an important determinant for better quality of life in this patients with thyroid R disease. And we do know that orbital pain is specific sensitive for the activity of the disease, for the inflammatory stage of the disease. So the conclusion we may draw here after actually performing these randomized double prime trial, is that you don't have to treat only severity, reduce proptosis, but you have to stabilize activity of the disease. You have to decrease inflammation because then the patients will be more satisfied and well, of course, happy with the treatment. I thank you so much. Thank you very much, Dr. Kahali. Excellent presentation. Perhaps I could start with a question. I was wondering with regard to the relation that you showed with age and appearance. Do you think that's a psychological component or could it be that there's also a difference in the effect of the drug based on age? Good point. So, two questions and a clear answer. No, this has nothing to do with the drug, the effect on age. In our experience, we see a thousand patients a year with eye disease. We have been treating also patients with separatumumab. And to be clear, males are more satisfied with their appearance than females. Well, this is actually the story everywhere. Females are more complaining. Males are fine if they don't have double vision, if they can read and drive. And this is not the case with females. Thank you for a terrific talk. Did you compare, since you say that the pain and inflammation is most important, the quality of life of patients on separatumumab versus steroids? Yeah, very good point. Thank you, Yaron. Good to see you. Yeah, quality of life is becoming actually one of the major factors when you are performing clinical trials and when you send your papers for review in the best journals. This is one of the major factors the reviewers and the journals are requesting. So, yes, quality of life is indeed important, and we have been surprised how actually positive or how major the improvement of quality of life was obtained in patients on tepramatumumab. So, just to give you an idea, the European Group of Graves' Obitopathy, I'll make it short, requests six-point improvement when you treat the patients. And we do see this when you are giving steroids. Ten points, this is a so-called relevant answer. We obtained 20 points with tepratumumab, and on a score of 100 points. So, 20, one-fifth improvement after eight weeks of tepratumumab, which I have to admit was much higher, more impressive than with steroids. This is the answer. Thank you very much. There's one more question. Thank you for an excellent presentation. My name is Elio Monsur. I'm a fellow from the University of Florida, and I wanted to ask, in these patients on tepratumumab, despite having good quality of life and orbital ocular outcomes, were you able to adjust seeing the patients who developed diabetes and how that impacted their quality of life in the questionnaire? Yeah, good questions. We had the largest group included in the phase two trials at my institution. And of these patients included in my institution, we had two patients who had type 2 diabetes. So, we did observe an exacerbation actually of blood sugar, but this was feasibly actually adjusted with medication, either with metformin or other medication. We didn't have to give insulin. I was also the largest site in the phase three trial, and we didn't have any problems. I have also patients with type 1 diabetes. So, this is not a major request or a major, how would you say, complication. If you are able to deal with diabetes, and I presume that all endocrinologists should be able to deal with this. Thank you very much. Thank you. I think that's a very nice last conclusion. Thank you again. Can we move to the first speaker on my list? Is Dr. Adeyoti in the audience? If not, I think I saw six presentations on the list. Unfortunately, I have only five. Is there another speaker who is expecting to present but not called upon the stage by me? If not, I'm again apologizing for all the confusion and thank all the speakers for their excellent talks.

thyroid disease

30-day readmission

hyperthyroidism

transcriptional changes

immune checkpoint inhibition

thyroglobulin

protein trafficking

thyroid hormoneogenesis

steroids