L’infezione da SARS CoV-2 può coinvolgere vari organi e apparati, tra cui la tiroide, provocando la tiroidite subacuta (SAT). Dopo la prima descrizione della SAT causata dall’infezione da SARS-CoV-2 sono stati pubblicati numerosi altri casi e studi che abbiamo raccolto nel presente lavoro. Nei 69 pazienti inclusi abbiamo documentato aspetti tipici della SAT, quali la presenza di dolore al collo, tireotossicosi, elevazione degli indici di flogosi, classiche caratteristiche ecografiche e scintigrafiche e pronta risposta alla terapia antinfiammatoria e/o glucocorticoide praticata. La SAT da SARS-CoV-2 si caratterizza per una maggiore gravità, un più elevato tasso di ipotiroidismo rispetto alla SAT documentata nell’era pre-COVID-19 (36,5

Background: Treatment for Graves' hyperthyroidism (GH) in patients with Graves' orbitopathy (GO) remains a topic of debate. This study aimed to investigate the outcome of GO following glucocorticoids, depending on the chosen thyroid treatment. Methods: This retrospective cohort study included 49 consecutive patients with GH and moderate-to-severe, active GO, as defined by the European Group on Graves' Orbitopathy guidelines. Twenty-four patients were treated with radioactive iodine (RAI) and 25 with methimazole (MMI). All patients were administered intravenous methylprednisolone. Follow-up visits occurred at weeks 24, 48, and 72. The primary endpoint was the overall outcome of GO at week 24. Response was defined as a change in at least two of the following eye features: reduction ≥1 point in clinical activity score; proptosis reduction ≥2 mm; eyelid aperture reduction ≥2 mm; increase in eye ductions ≥8 degrees. Results: Follow-up duration was 72 weeks for both groups (interquartile range 66-72 for RAI and 48-72 for MMI). The proportion of responders for week 24 overall GO outcome was greater in RAI (54.1% vs. 16%; odds ratio [OR] 6.2 [confidence interval (CI): 1.6-23.6], p = 0.0075), but it increased in MMI at weeks 48 and 72, with no differences between groups. There was a trend indicating a better response in RAI regarding individual eye features. Improvement in GO-specific quality of life questionnaire at week 24 was trendily more pronounced in RAI (responders 50% vs. 28% in MMI; OR = 2.5 [CI: 0.7-8.4], p = 0.11), although results were similar in both groups at later time points. At week 24, only one patient (4%) in RAI and three (12%) in MMI experienced worsening of GO. Fifty-nine adverse events were recorded among 36 patients, with no differences between groups, except for infections, which were more frequent in RAI (53.8% vs. 15.3% in MMI; OR = 6.41 [CI: 1.7-23.9], p = 0.0056). Conclusions: RAI appears to be associated with an earlier response of GO to intravenous glucocorticoids. In the long term, a conservative approach also seems to be effective. RAI appears to be relatively safe when patients are concurrently treated with glucocorticoids. However, randomized clinical trials are necessary to confirm these findings.

Compared with methylprednisolone, a greater response of Graves’ orbitopathy (GO) at 24 weeks was reported in patients treated with sirolimus (rapamycin) for 12 weeks. We investigated whether serum levels of sirolimus at week-12 predict the outcome of GO at week-24. Retrospective investigation in 30 patients [males: 4; females: 26; age 61.3 (9.62) yr] with moderate-to-severe, active GO, treated with sirolimus (2 mg on day-one, followed by 0.5 mg QD for 12 weeks). Primary outcome: serum sirolimus at week-12 in week-24 GO responders vs nonresponders, assessed by a composite evaluation. Secondary outcome: establishment of a cut-off value of week-12 sirolimus concentrations predictive of response to treatment. At week-24, overall GO responders and nonresponders were 18 (60

The insulin-like growth factor-1 receptor (IGF-1R) plays a role in the pathogenesis of Graves’ orbitopathy (GO). A possible protective role of autoantibodies against IGF-1R (IGF-1R-Abs) on GO has been suggested. We conducted a cross-sectional study to investigate IGF-1R-Abs in 147 consecutive Graves’ disease (GD) patients, with (n = 92) or without (n = 55) GO (primary outcome), their relationship with GO features and their effect on cell proliferation in primary cultures of orbital fibroblasts. Serum IGF-1R-Abs levels were higher (29.3 ng/mL, IQR 17.4–36.6) in patients without GO than in those with GO (19.8 ng/mL, IQR 11.2–29.8; Mann Whitney U 1819, P = 0.00509). The prevalence of IGF-1R-Abs levels above the previously established cut-off value of 55 ng/mL did not differ statistically between the two groups, despite a trend towards a greater prevalence in patients without GO (9 vs 3.2

The ongoing digital revolution in the healthcare sector, emphasized by bodies like the US Food and Drug Administration (FDA), is paving the way for a shift towards person-centric healthcare models. These models consider individual needs, turning patients from passive recipients to active participants. A key factor in this shift is Artificial Intelligence (AI), which has the capacity to revolutionize healthcare delivery due to its ability to personalize it. With the rise of software in healthcare and the proliferation of the Internet of Things (IoT), a surge of digital data is being produced. This data, alongside improvements in AI's explainability, is facilitating the spread of person-centric healthcare models, aiming at improving health management and patient experience. This paper outlines a human-centered methodology for the development of an AI-as-a-service platform with the goal of broadening access to personalized healthcare. This approach places humans at its core, aiming to augment, not replace, human capabilities and integrate in current processes. The primary research question guiding this study is: "How can Human-Centered AI principles be considered when designing an AI-as-a-service platform that democratizes access to personalized healthcare?" This informed both our research direction and investigation. Our approach involves a design fiction methodology, engaging clinicians from different domains to gather their perspectives on how AI can meet their needs by envisioning potential future scenarios and addressing possible ethical and social challenges. Additionally, we incorporate Meta-Design principles, investigating opportunities for users to modify the AI system based on their experiences. This promotes a platform that evolves with the user and considers many different perspectives.

Objectives: The pathogenesis of Graves’ orbitopathy (GO) remains to be fully elucidated. Here, we reviewed the role of genetics and epigenetics. Design: We conducted a PubMed search with the following keywords: GO, thyroid eye disease; or Graves’ ophthalmopathy; or thyroid-associated ophthalmopathy; and: genetic, or epigenetic, or gene expression, or gene mutation, or gene variant, or gene polymorphism, or DNA methylation, or DNA acetylation. Articles in which whole DNA and/or RNA sequencing, proteome, and methylome analyses were performed were chosen. Results: The different prevalence of GO in the two sexes, as well as racial differences, suggest that genetics play a role in GO pathogenesis. In addition, the long-lasting phenotype of GO and patient-derived orbital fibroblasts suggests a genetic or epigenetic mechanism. Although no genes have been found to confer a specific risk for GO, differential gene expression has been reported in orbital fibroblasts from GO patients vs control fibroblasts, suggesting that an epigenetic mechanism may be involved. In this regard, a different degree of DNA methylation, which affects gene expression, has been found between GO and control fibroblasts, which was confirmed by whole methylome analysis. Histone acetylation and deacetylation, which also affect gene expression, remain to be investigated. Conclusions: Although no pathogenic gene variants have been reported, epigenetic mechanisms elicited by an initial autoimmune insult seem to be needed for differential gene expression to occur and, thus, for GO to develop and persist over time.

Sirolimus was found to be associated with a better outcome of Graves’ orbitopathy (GO) at 24 weeks compared to methylprednisolone. We conducted a retrospective study to investigate its efficacy and safety over a longer period. Data from 40 consecutive patients with moderate-to-severe, active GO, 20 treated with sirolimus and 20 with methylprednisolone, were collected. Primary outcome: overall outcome (composite evaluation) of GO at 48 weeks. Secondary outcomes: (1) GO outcome at 24 weeks, and, at 24 and 48 weeks: (2) outcome of single eye features; (3) quality of life (GO-QoL); (4) TSH-receptor antibodies; (5) GO relapse at 48 weeks; (6) adverse events. The overall GO outcome at 48 weeks did not differ between the two groups (responders: 55

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

Abstract Background In this study, we used targeted next-generation sequencing (NGS) to investigate the genetic basis of congenital hypothyroidism (CH) in a 19-year-old Tunisian man who presented with severe hypothyroidism and goiter. Case presentation The propositus reported the appearance of goiter when he was 18. Importantly, he did not show signs of mental retardation, and his growth was proportionate. A partial organification defect was detected through the perchlorate-induced iodide discharge test. NGS identified a novel homozygous mutation in exon 18 of the SLC26A7 gene (P628Qfs*11), which encodes for a new iodide transporter. This variant is predicted to result in a truncated protein. Notably, the patient's euthyroid brother was heterozygous for the same mutation. No renal acid–base abnormalities were found and the administration of 1 mg of iodine failed to correct hypothyroidism. Conclusions We described the first case of goitrous CH due to a homozygous mutation of the SLC26A7 gene diagnosed during late adolescence.

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

Background The massive vaccination campaign against COVID-19 has granted a high level of protection against the severe forms of the disease at the price of some mild adverse events. Objective To underline that COVID-19 vaccination can induce a transient enlargement of lymph-node metastases in differentiated thyroid cancer patients. Case presentation We describe the clinical, laboratory, and imaging features of a 60-year-old woman affected by paratracheal lymph-node relapse of Hurtle Cell Carcinoma who came to our attention after full COVID-19 vaccination because of neck swelling and pain. In April 2021, after 5 years of stable structural disease, the patient presented an enlargement of the metastatic lymph node, associated with a rise of serum thyroglobulin (from 4.6 to 14.7 pg/mL). Anti-inflammatory treatment was started and pain and swelling remitted after 15 days. At the subsequent evaluation, at neck ultrasound, the right paratracheal lesion was smaller and thyroglobulin dropped to 3.9 pg/mL. Conclusions We report the case of an enlargement of metastatic lymph node from differentiated thyroid cancer after COVID-19 vaccination. We warn clinicians to identify features of inflammatory response due to COVID-19 vaccination in order to prevent unwarranted surgical treatment.

Breakdown of self-tolerance to thyroid antigens (thyroperoxidase, thyroglobulin and the thyrotropin-receptor) is the driver of thyroid autoimmunity. It has been suggested that infectious disease might trigger autoimmune thyroid disease (AITD). Involvement of the thyroid has been reported during severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection, in the form of subacute thyroiditis in subjects with mild coronavirus disease 19 disease (COVID-19) and of painless, destructive thyroiditis in hospitalized patients with severe infection. In addition, cases of AITD, both Graves' disease (GD) and Hashimoto's thyroiditis (HT), have been reported in association with (SARS-CoV-2) infection. In this review, we focus on the relationship between SARS-CoV-2 infection and occurrence of AITD. Nine cases of GD strictly related to SARS-CoV-2 infection and only three cases of HT associated to COVID-19 infection have been reported. No study has demonstrated a role of AITD as a risk factor for a poor prognosis of COVID-19 infection.

Laboratory, imaging, and pathological features of Graves’ disease (GD), although well characterized, have been barely correlated each other. Aim of the study was to link laboratory and ultrasound characteristics of GD with its pathological features. We correlated laboratory and ultrasound data at the time of diagnosis in 28 consecutive GD patients who underwent thyroidectomy with their pathological features, i.e., lymphocytic infiltration and follicular hyperplasia (both classified as mild or severe). Thyroid volume correlated positively with the levels of FT4 (P = 0.002, r2 = 0.42), FT3 (P = 0.011, r2 = 0.22), autoantibodies to thyroglobulin (TgAbs) (P = 0.016, r2 = 0.32), autoantibodies to thyroid peroxidase (TPOAbs) (P = 0.011, r2 = 0.34) and the extent of lymphocytic infiltration (P = 0.006 comparing mild to severe lymphocytic infiltration) but not with the levels of autoantibodies to the thyrotropin receptor (TRAbs) and to follicular hyperplasia. Compared to subjects with mild lymphocytic infiltration, those with severe lymphocytic infiltration showed higher levels of TgAbs (316 vs 0.0 IU/mL, P < 0.0001) and TPOAbs (295 IU/mL vs 14 IU/mL, P < 0.0001) and similar levels of TRAbs (7.5 vs 13 IU/mL, P = 0.68). Compared to patients with mild, those with severe follicular hyperplasia had similar levels of TgAbs (76 vs 30 IU/mL, P = 0.31) and TPOAbs (251 IU/mL vs 45 IU/mL, P = 0.26) but higher levels of TRAbs (39 vs 7.2 IU/mL, P < 0.001). In GD, TgAbs and TPOAbs levels correlate with the extent of lymphocytic infiltration, TRAbs levels with the degree of follicular hyperplasia. Thyroid volume, the main factor influencing the severity of hyperthyroidism, is related to lymphocytic infiltration and not to follicular hyperplasia.

Context:Serum thyroglobulin (Tg) is a highly sensitive and specific tumor marker, employed in post-operative management of patients with differentiated thyroid carcinomas. Tumor shrinkage of radioiodine-refractory thyroid cancer (RAIR-DTC) treated with multitarget kinase inhibitors as lenvatinib, expressed according to the Response Evaluation Criteria in Solid Tumors (RECIST), is also associated with a drastic reduction of Tg levels. However, interference caused by circulating thyroglobulin autoantibodies (TgAb) represents the main limitation in the clinical use of Tg.Objective:To evaluate if in RAIR-DTC TgAb could be considered a surrogate marker of Tg in monitoring response to treatment with lenvatinib.Design:We retrospectively evaluated patients who had started lenvatinib and correlated serum Tg and TgAb with the radiological response across visits.Setting:University of Pisa, Italy.Patients:We selected 9/97 RAIR-DTC patients with detectable TgAb.Intervention:None.Main Outcome Measures:None.Results:Tg values correlated neither with TgAb title nor with radiological response across visits. Greater decreases in TgAb titer correlated with favorable radiological response to lenvatinib after 1 month (Spearman's correlation = 0.74, P = .021) and 6 months (correlation = 0.61, P = .079). According to RECIST, patients with partial response showed a ∼10-fold greater decrease in TgAb compared to those with stable disease at 1 month (median TgAb decrease: -142 vs -14 IU/mL, P = .01) and those with progressive disease at 6 months (median TgAb decrease: -264 vs-24 IU/mL, P = .04).Conclusion:TgAb evaluation may represent a reliable surrogate marker for Tg trend in evaluating response of RAIR-DTC to treatment with lenvatinib. A multicentric study would be useful to confirm our results.

CONTEXT:Prognosis is excellent for papillary thyroid carcinoma (PTC), noninvasive follicular thyroid neoplasia with papillary-like nuclear features (NIFT-P), and follicular thyroid carcinoma (FTC) but is poor for poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC). Among PTCs, the prognosis is more favorable for follicular (FV-PTC) and classic (CV-PTC) than for tall cell (TCV-PTC), and solid (SV-PTC) variants.OBJECTIVE:To associate histotypes and variants of thyroid carcinoma with ultrasound and cytological features.METHODS:Histology of 1018 benign tumors and 514 PTC (249 CV, 167 FV, 49 TC, 34 SV, and 15 other variants), 52 NIFT-P, 50 FTC, 11 PDTC, and 3 ATC was correlated with fine-needle aspiration biopsy categories (Italian classification: TIR1, TIR2, TIR3A, TIR3B, TIR4, and TIR5) and ultrasound features at the Endocrinology Unit, University Hospital of Pisa. In total, 1117 patients with thyroid nodule(s) who underwent thyroidectomy were included.RESULTS:Of PTC, 36.3% had indeterminate cytology (TIR3A or TIR3B), 56.6% were suspicious for malignancy or malignant (TIR4 or TIR5); 84.0% FTC and 69.3% NIFT-P were TIR3A or TIR3B; 72.5% FV-PTC and 73.6% SV-PTC were TIR3A or TIR3B; 79.9% CV-PTC and 95.9% TCV-PTC were TIR4 or TIR5. The association of a hypoechoic pattern, irregular margins, and no microcalcifications was more frequent in TCV-PTC than in CV-PTC (P = .02, positive predictive value = 38.9%; negative predictive value = 85.5%).CONCLUSION:At cytology, most FTC, NIFT-P, FV-PTC, and SV-PTC were indeterminate, most CV-PTC and TCV-PTC were suspicious for malignancy or malignant. Ultrasound can be helpful in ruling out TCV-PTC.

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th–75th percentiles) was 84.0 (56.4–118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise ‘decreasing TgAb trend’, a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35–0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18–0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55–1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.

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

Abstract Fine-Needle Aspiration Biopsy (FNAB) guides surgical treatment of thyroid nodules which, according to the Italian classification, are classified as TIR 1/1C, TIR 2, TIR 3A, TIR3B, TIR4 or TIR5, which correspond to Thy I, Thy II, Thy III, Thy IV, Thy V and Thy VI categories of the Bethesda System. TIR 3 identifies the follicular pattern, which is typical of both benign and malignant lesions. Surgery is usually recommended for TIR 3B, TIR 4 and TIR 5 nodules. The latest histopathological classifications of thyroid cancers have introduced significant changes. While the follicular (FV-PTC) and classical variants (CV-PTC) of papillary thyroid carcinoma and the minimally invasive follicular thyroid carcinoma (FTC) are characterized by a good prognosis and require a less aggressive treatment, the poorly differentiated thyroid carcinoma (PDTC), the anaplastic thyroid carcinoma (ATC), the tall cell (TC-PTC) and the solid variants (SV-PTC) and other variants have a worse prognosis. In addition, thyroid ultrasound often identifies thyroid nodules <1 cm, which are usually characterized by an indolent behavior and active surveillance may be advised. We retrospectively analyzed consecutive histopathological records of 1117 patients (for a total of 1668 nodules, of which 650 malignant) who underwent surgery in 2017, and who had previously undergone FNAB and thyroid ultrasound (available for 390 nodules), in order to characterize echographic and cytological features useful to identified aggressive variants among TIR4-5 nodules and malignant lesions among TIR3B nodules. Of the 566 PTC, 18.7% were TIR3A, 20.7% TIR 3B and 51.6% TIR4-5, while of 50 FTC 42.0% were TIR3A, 42.0% TIR3B and 6.0% TIR4-5. Of the 11 PDTC 54.5% had been diagnosed as TIR 3B. Of the 249 classic variant of PTC, 0.8% had resulted TIR3A, 14.1% TIR3B and 79.9% TIR4-5. Among 49 tall cell variant, none had resulted TIR3A, 2% had been diagnosed as TIR3B and 95.9% as TIR4-5. Of the 219 follicular variant of PTC 42.0% had resulted TIR3A, 39.7% TIR3B and 12,3% TIR4-5. Among 34 SV-PTC, 32.4% had been diagnosed as TIR3A, 41.2% TIR3B and 0.6% TIR4-5. Blurred margins were the only feature associated with malignancy (p=0.034) in TIR3B nodules. The coexistence of hypoechogenicity and blurred margins in absence of microcalcifications were more common in tall cell variant (7/28) compared to classic variant (10/120) of PTC (p= 0.021). A significant number of PDTC and SV-PTC were diagnosed as TIR3. Among TIR3B nodules, irregular margins correlate with malignancy. Coexistence of irregular margins with a hypoechoic pattern in absence of microcalcifications is helpful in identifying TIR4/TIR5 nodule which turn out TC-PTC. In conclusion, among TIR3B, TIR4 and TIR5 nodules, ultrasound helps to identify aggressive variants and therefore to choose the extent of surgical treatment and, when <1 cm, to confidently advise active surveillance. Presentation: Saturday, June 11, 2022 1:00 p.m. - 3:00 p.m.

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