PurposeTreatment-resistant depression (TRD) is most commonly defined as depression that has not responded to two different pharmacological agents used for an adequate period of time. We explored the views of European specialists via survey, regarding the use of thyroid hormone (TH) in euthyroid patients with TRD as part of ‘Treatment of Hypothyroidism in Europe by Specialists: An International Survey’ (THESIS).MethodsThe question “Thyroid hormones may be indicated in biochemically euthyroid patients with treatment resistant depression” was posed to specialists from 28 countries.Results5695 valid responses were received following 17,232 invitations (33.0% response rate; 65% female, 90% endocrinologists). 348 (6.1%) stated that TH may be indicated in biochemically euthyroid patients with TRD. This view was more common in males (p<0.01), respondents who saw ≥100 patients with hypothyroidism per year (p<0.01), respondents who worked in private practice (p=0.05) and respondents who were not members of international specialist associations (p=0.05). Geographical variation existed with respondents in Eastern Europe significantly more likely to use TH in TRD (p<0.01). Linear regression showed a statistically significant reduction in the use of TH for TRD with increasing gross national income (F-statistic=7.35, CI -0.15 - -0.02, p=0.01). TH in TRD was recommended in psychiatry guidelines but not endocrinology guidelines.ConclusionWhile there is limited evidence for their use, over 6% of respondents stated that TH may be indicated in TRD. Due to the risk of iatrogenic thyrotoxicosis and increased morbidity the use of TH should be addressed in relevant endocrinology guidelines and consensus should be reached between specialties.

Background: In prolactinoma diagnosis, current guidelines recommend prolactin (PRL) assessment, considering values exceeding 200 ng/mL highly suggestive of prolactinoma. However, subtler hyperprolactinemia is more common, and to rule out potential prolactinomas, pituitary resonance magnetic imaging (MRI) studies are necessary. These present limitations in terms of availability, costs, and delays in diagnosis. We aimed to evaluate the screening utility of the metoclopramide (MCP) test in identifying patients with moderate hyperprolactinemia for whom MRI studies might be unnecessary. Methods: We retrospectively selected patients with moderate hyperprolactinemia, with an MCP test and a pituitary MRI within the same assistance, and with no interfering pharmacological treatment. Increases in PRL (Delta PRLMax) and thyrotropin (Delta TSHMax) after MCP infusion were compared according to MRI findings: patients with microadenoma (<10 mm; n = 23), with macroadenoma (>= 10 mm; n = 5), or without adenoma (n = 39). Results: Delta PRLMax exceeds baseline PRL capability to identify patients with an adenoma (area under the curve = 0.872 vs 0.776). Delta PRL(Max )below 220% identifies 100% of these patients with 71% of specificity. This screening would have avoided 42% of MRI, resulting in a cost savings of 34%. Analysis of Delta TSHMax only slightly increased specificity when considered as a secondary criterion. Test duration can be shortened to 30 min without compromising its screening capability. Conclusions: A short MCP test is a useful and cost-effective screening tool to avoid unnecessary MRI. Its simplicity allows its performance in almost any clinical facility to easily rule out prolactinoma in an important percentage of patients, something of upmost importance especially in regions where MRI facilities or their access are limited.

OBJECTIVE:The generally good prognosis of low- and intermediate-risk differentiated thyroid cancer (DTC) underscored the need to identify those few patients who relapse. DESIGN:Records of 299 low- or intermediate-risk DTC patients (mean follow-up 8.2 ± 6.2 years) were retrospectively reviewed. The sample was classified following the American Thyroid Association (ATA) dynamic risk stratification (DRS) system. PATIENTS AND MEASUREMENT:After classifying patients according to DRS at the first visit following initial therapy (FU1), structural recurrence occurred in 2/181 (1.1%), 5/81 (6.2%) and 13/26 (50.0%) with excellent, indeterminate and biochemical incomplete response to treatment, respectively. All relapses but one happened within 5 years from FU1. Univariate analysis comparing excellent, indeterminate and biochemical incomplete with structural incomplete responses at the end of the follow-up, identified tumour size (p < .001), T status (<0.001), positive lymph nodes (N) (p < .01), multifocality (p < .004), need of additional radioactive iodine (RAI) (p < .0001) and first DRS status (p < .0003) as risk factors of recurrence. In the multivariate analysis, only RAI remained statistically significant (p < .02). Comparison between excellent and indeterminate with biochemical and structural incomplete responses, identified tumour size (p < .0004), T (p < .01), N (p < .0001), bilaterality (p < .03), first DRS status (p < .0001) and RAI (p < .001) as recurrence risk factors. T (p < .01) and first DRS (p < .0006) were confirmed in the multivariate analysis. CONCLUSIONS:Patients with DTC classified as low- or intermediate-risk of recurrence with excellent response to treatment at FU1 rarely develop structural disease and this occurs almost exclusively in the first 5 years. Initial DRS status is an accurate tool for determining the risk of recurrence.

The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether “Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions”. Of 17,232 invitations 5695 responses were received (33

Background: Hypothyroidism is common, however, aspects of its treatment remain controversial. Our survey aimed at documenting treatment choices of European thyroid specialists and exploring how patients' persistent symptoms, clinician demographics, and geo-economic factors relate to treatment choices.Methods: Seventeen thousand two hundred forty-seven thyroid specialists from 28 countries were invited to participate in an online questionnaire survey. The survey included respondent demographic data and treatment choices for hypothyroid patients with persistent symptoms. Geo-economic data for each country were included in the analyses.Results: The response rate was 32.9% (6058 respondents out of 17,247 invitees). Levothyroxine (LT4) was the initial treatment preferred by the majority (98.3%). Persistent symptoms despite normal serum thyrotropin (TSH) while receiving LT4 treatment were reported to affect up to 10.0% of patients by 75.4% of respondents, while 28.4% reported an increasing such trend in the past 5 years. The principal explanations offered for patients' persistent symptoms were psychosocial factors (77.1%), comorbidities (69.2%), and unrealistic patient expectations (61.0%). Combination treatment with LT4+liothyronine (LT3) was chosen by 40.0% of respondents for patients who complained of persistent symptoms despite a normal TSH. This option was selected more frequently by female thyroid specialists, with high-volume practice, working in countries with high gross national income per capita.Conclusions: The perception of patients' dissatisfaction reported by physicians seems lower than that described by hypothyroid patients in previous surveys. LT4+LT3 treatment is used frequently by thyroid specialists in Europe for persistent hypothyroid-like symptoms even if they generally attribute such symptoms to nonendocrine causes and despite the evidence of nonsuperiority of the combined over the LT4 therapy. Pressure by dissatisfied patients on their physicians for LT3-containing treatments is a likely explanation. The association of the therapeutic choices with the clinician demographic characteristics and geo-economic factors in Europe is a novel information and requires further investigation.

BACKGROUND:Treatment of simple goiter (SG) growing over time with thyroid hormone (TH) therapy is discouraged by international guidelines. PURPOSE:To ascertain views of European thyroid specialists about TH treatment for euthyroid patients with growing SG and explore associations with management choice. METHODS:Online survey on the use of TH for growing SG among thyroid experts from 28 European countries. RESULTS:The response rate was 31.5% (5430/17,247). Most respondents were endocrinologists. Twenty-eight percent asserted that TH therapy may be indicated in euthyroid patients with a growing SG. National and regional differences were noted, from 7% of positive responses in The Netherlands to 78% in Czech Republic (p < 0.0001). TH was more frequently prescribed by respondents over 40 years old (OR 1.77, 2.13, 2.41 if 41-50, 51-60, >60, respectively), and working in areas of former iodine insufficiency (OR 1.24, 95% CI 1.03-1.50). TH was less frequently prescribed by endocrinologists (OR 0.77, 95% CI 0.62-0.94) and respondents working in Southern Europe (OR 0.40, 95% CI 0.33-0.48), Northern Europe (OR 0.28, 95% CI 0.22-0.36) and Western Asia (OR 0.16, 95% CI 0.11-0.24) compared to Western Europe. Associations with respondents' sex, country, availability of national thyroid guidelines, and gross national income per capita were absent or weak. CONCLUSIONS:Almost a third of European thyroid specialists support treating SG with TH, contrary to current guidelines and recommendations. This calls for urgent attention.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract Background Prolactinoma is the main cause of hyperprolactinemia once physiological and pharmacological causes are excluded. Prolactin (PRL) and thyrotropin (TSH) response to dopaminergic antagonists has been previously used in prolactinoma diagnosis. Current guidelines only recommend baseline PRL concentration in diagnosis, considering values exceeding 250 ng/mL highly suggestive of prolactinoma. However, subtler hyperprolactinemia is much more frequent, and magnetic resonance imaging (MRI) studies are necessary to detect potential prolactinomas. Our aim was to examine the utility of a metoclopramide (MCP) stimulation test as a screening tool to evaluate the need for pituitary MRI studies in patients with moderate hyperprolactinemia. Methods We retrospectively selected 67 moderate hyperprolactinemia patients (<250 ng/mL), with a MCP test and a pituitary MRI within the same assistance. We excluded patients with pharmacological treatments affecting dopaminergic axis. According MRI results we classified them in patients with microadenoma (<10 mm; n=23), with macroadenoma (≥10 mm; n=5) or without adenoma (n=39). Maximum relative increases over baseline concentrations were calculated for PRL (ΔPRLMax) and TSH (ΔTSHMax). The Research Ethic Committee approved the study. Results ΔPRLMax exceeds baseline PRL capability to identify patients with an adenoma (AUC=0.8718 vs 0.7756). ΔPRLMax below 220% identifies 100% of these patients with 71% of specificity (Table 1). Screening with MCP test would have avoided 42% of MRI, resulting in 34% costs saving. Analysis of TSH response only slightly increased the specificity when considered as a secondary criterion. Test length can be reduced from 60 to 30 minutes without losing screening capability. Conclusions A shortened MCP test is a useful and cost-effective screening tool to avoid unnecessary MRI. Its simplicity allows its performance in almost any clinical facility, allowing to easily rule out prolactinoma in an important percentage of patients, something of upmost importance specially in regions were MRI facilities are scarce.

A common immune-related adverse event (irAE) with immune checkpoint inhibitors (ICIs) is thyroid dysfunction (TD-irAEs). The clinical presentation can be varied, and its association with prognosis remains unclear. We investigated the characteristics of TD-irAEs and their association with clinical outcomes among cancer patients treated with ICIs in a real-life setting. Response to treatment was assessed using RECIST v1.1. We calculated the probability of recurrence and survival associated with TD-irAEs using multivariable-adjusted regression and Cox proportional hazards models. In this single-center retrospective analysis, we included 238 patients (72% male) with a median age of 69.5 years. Primary tumors were melanoma (23.1%), lung (60.5%), or urothelial cancer (16.4%), treated with atezolizumab (23.1%), pembrolizumab (44.5%), ipilimumab (0.4%), and/or nivolumab (25.6%). Seventy (29%) patients developed TD-irAEs in a median time of 69 days (41-181). The incidence of TD-irAEs with combination therapy was higher than with monotherapy (67% vs 6.3%, P = 0.011). TD-irAE patients showed a higher objective response rate (ORR) than those without TD-irAEs (60% vs 42.3%, P = 0.013) and longer overall survival (OS) 45 vs 16 months, P < 0.006. Patients who developed TD-irAEs had a relative reduction of 77% (OR 0.23, 95% CI 0.11-0.47) in the risk of progression and of 47% in the risk of mortality (HR 0.53, 95% CI 0.36-0.80), independent of age, sex, primary tumor, or ICI regimen. TD-irAEs occur in nearly 30% of our patients receiving ICIs. In our analysis, TD-irAEs appeared to be associated with higher ORR and longer OS and showed a reduction in the risk of progression and mortality.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

OBJECTIVES:The use of levothyroxine (LT4) treatment aiming to improve fertility in euthyroid women with positive thyroid peroxidase antibodies (TPOAb) is not supported by the available evidence. The aim of the study was to document the use of LT4 by European thyroid specialists in such patients. DESIGN:The data presented derive from Treatment of Hypothyroidism in Europe by Specialists, an International Survey (THESIS), a questionnaire conducted between 2019 and 2021 to document the management of hypothyroidism by European thyroid specialists. Here, we report the aggregate results on the use of LT4 in infertile, euthyroid women with positive TPOAb. RESULTS:A total of 2316/5406 (42.8%) respondents stated that LT4 may be indicated in TPOAb positive euthyroid women with infertility. The proportion of those replying positively to this question varied widely across different countries (median 39.4, range 22.9%-83.7%). In multivariate analyses males (OR: 0.8; CI: 0.7-0.9) and respondents >60 years (OR: 0.7; 0.6-0.8) were the least inclined to consider LT4 for this indication. Conversely, respondents managing many thyroid patients ("weekly" [OR: 1.4; CI: 1.0-1.9], "daily" [OR: 1.8; CI: 1.3-2.4]) and practicing in Eastern Europe (OR: 1.5; CI: 1.3-1.9) were most likely to consider LT4. CONCLUSIONS:A remarkably high number of respondents surveyed between 2019 and 2021, would consider LT4 treatment in TPOAb positive euthyroid women with infertility. This view varied widely across countries and correlated with sex, age and workload, potentially influencing patient management. These results raise concerns about potential risks of overtreatment.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Introduction The percentage of patients diagnosed with pheochromocytoma and paraganglioma (altogether PPGL) carrying known germline mutations in one of the over fifteen susceptibility genes identified to date has dramatically increased during the last two decades, accounting for up to 35-40% of PPGL patients. Moreover, the application of NGS to the diagnosis of PPGL detects unexpected co-occurrences of pathogenic allelic variants in different susceptibility genes. Methods Herein we uncover several cases with dual mutations in NF1 and other PPGL genes by targeted sequencing. We studied the molecular characteristics of the tumours with co-occurrent mutations, using omic tools to gain insight into the role of these events in tumour development. Results Amongst 23 patients carrying germline NF1 mutations, targeted sequencing revealed additional pathogenic germline variants in DLST (n=1) and MDH2 (n=2), and two somatic mutations in H3-3A and PRKAR1A. Three additional patients, with somatic mutations in NF1 were found carrying germline pathogenic mutations in SDHB or DLST, and a somatic truncating mutation in ATRX. Two of the cases with dual germline mutations showed multiple pheochromocytomas or extra-adrenal paragangliomas - an extremely rare clinical finding in NF1 patients. Transcriptional and methylation profiling and metabolite assessment showed an “intermediate signature” to suggest that both variants had a pathological role in tumour development. Discussion In conclusion, mutations affecting genes involved in different pathways (pseudohypoxic and receptor tyrosine kinase signalling) co-occurring in the same patient could provide a selective advantage for the development of PPGL, and explain the variable expressivity and incomplete penetrance observed in some patients.

IntroductionThe dynamic risk stratification (DRS) is a relatively new system in thyroid cancer that considers the response to primary treatment to improve the initial risk of recurrence. We wanted to validate DRS system in a nationwide multicenter study and explore if the incorporation of BRAFV600E into DRS helps to better categorize and predict outcomes.Materials and methodsRetrospective study of 685 patients from seven centers between 1991 and 2016, with a mean age of 48 years and a median follow-up time of 45 months (range 23-77). The overall BRAFV600E prevalence was 53.4%. We classified patients into four categories based on DRS (‘excellent’, ‘indeterminate’, ‘biochemical incomplete’, and ‘structural incomplete’ response). Cox regression was used to calculate adjusted hazard ratios (AHR) and proportions of variance explained (PVEs).ResultsWe found 21.6% recurrences and 2.3% cancer-related deaths. The proportion of patients that developed recurrence in excellent, indeterminate, biochemical incomplete and structural incomplete response to therapy was 1.8%, 54%, 91.7% and 96.2% respectively. Considering the outcome at the end of the follow up, patients showed no evidence of disease (NED) in 98.2, 52, 33.3 and 25.6% respectively. Patients in the structural incomplete category were the only who died (17.7%). Because they have similar outcomes in terms of NED and survival, we integrated the indeterminate and biochemical incomplete response into one unique category creating the 3-tiered DRS system. The PVEs of the AJCC/TNM staging, ATA risk classification, 4-tiered DRS, and 3-tiered DRS to predict recurrence at five years were 21%, 25%, 57% and 59% respectively. BRAFV600E was significantly associated with biochemical incomplete response (71.1 vs 28.9%) (HR 2.43; 95% CI, 1.21 to 5.23; p=0.016), but not with structural incomplete response or distant metastases. BRAF status slightly changes the AHR values of the DRS categories but is not useful for different risk grouping.ConclusionsThis is the first multicenter study to validate the 4-tiered DRS system. Our results also show that the 3-tiered DRS system, by integrating indeterminate and biochemical incomplete response into one unique category, may simplify response to therapy keeping the system accurate. BRAF status does not provide any additional benefit to DRS.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Background and aims: Patients' response to treatment in differentiated thyroid cancer (DTC) is classified ac-cording to serum thyroglobulin concentrations (Tg), usually using the American Thyroid Association guidelines and considering potential interfering anti-thyroglobulin antibodies (Ab-Tg). We aim to evaluate the clinical implications of changing Tg and Ab-Tg quantification method. Material and methods: Tg and Ab-Tg were quantified in 82 serum samples (60 from DTC patients) by Elecsys and Access immunoassays. Results: Elecsys immunoassay rendered higher values of Tg than Access: mean bias 5.03 ng/mL (95%CI:-14.14-24.21). In DTC patients, there was an almost perfect agreement for response classification (kappa index = 0.833). Discrepancies appeared in patients with undetermined response, with a more tendency to subclassifi-cation with Access. Ab-Tg showed a poor correlation (r = 0.5394). When Elecsys cut-off was reduced to 43 IU/ mL, agreement for positive/negative classification improved from a kappa index of 0.607 to 0.650. Prospective study with personalized follow-up showed that only 6.3% of Tg results required an analytical confirmation, being confirmed 93% of them. Conclusions: Despite the biases observed, clinical impact of an analytical change is minimal in patients' man-agement. However, cautious and personalized follow-up period after the change is still mandatory, especially in patients with Tg levels between 0.2 and 1 ng/mL.