Subacute thyroiditis in the SARS-CoV-2 era: a multicentre prospective study.

OBJECTIVE: Many cases of subacute thyroiditis (SAT) have been described related to SARS-CoV-2 infection, but no prospective data about follow-up is known. This prospective, longitudinal, 3-year, multicentre study is aimed at exploring clinical peculiarities and outcome of SAT in relation to SARS-CoV-2 infection, ascertained with antibody dosage. METHODS: All patients receiving SAT diagnosis from November 2020 to May 2022 were enrolled. Data about anamnesis, physical examination, blood tests (TSH, freeT4, freeT3, thyroglobulin, anti-thyroid antibodies, C-reactive protein, erythrocyte sedimentation rate, complete blood count), and thyroid ultrasound were collected. At baseline, the presence of IgG against the SARS-CoV-2 spike protein or nucleocapside was investigated. Patients were evaluated after 1, 3, 6, 12 months. RESULTS: Sixty-six subjects were enrolled. At baseline, 54 presented with pain, 36 (67%) for at least 15 days. Serum SARS-CoV-2 IgG measurement documented that 7 out of 52 subjects (13.5%) had infection before SAT diagnosis (Covid+). No significant difference between Covid+ and Covid- groups was found at baseline except for respiratory symptoms and fever, more represented in Covid+ (p=0.039 and p=0.021, respectively). Among the 41 subjects who completed follow-up, Covid+ and Covid- did not differ for therapeutic approach to SAT or outcome, all having an improvement in neck pain, inflammation parameters, and ultrasound features. CONCLUSIONS: This is the first prospective study investigating any difference both at diagnosis and at follow-up between SAT presentation in patients with previous SARS-CoV-2 infection and those without. Our data demonstrate that SARS-CoV-2 does not impact on SAT onset, evolution and outcome.

Randomized double-blind placebo-controlled trial on levothyroxine and liothyronine combination therapy in totally thyroidectomized subjects: the LEVOLIO study.

OBJECTIVE: Despite having normal thyroid-stimulating hormone levels, many hypothyroid patients are dissatisfied with the treatment. The primary aim of this study was to evaluate the effect of twice-daily, combination therapy with levothyroxine (LT4) and liothyronine (LT3), at doses adapted according to TSH-level, on peripheral tissues as reflected by sex hormone binding globulin (SHBG) levels in totally thyroidectomized patients. Changes in other tissue markers and quality of life considering DIO2-rs225014 and MCT10-rs17606253 genetic variants were also assessed. DESIGN: Double-blind, randomized, placebo-controlled. METHODS: One hundred and forty-one subjects were randomized to LT4 + LT3 group (LT4 + LT3 in the morning and LT3 in the evening; n = 70) or placebo group (LT4 in the morning and placebo in the evening; n = 71). Pituitary-thyroid axis compensation was assessed after 6, 12, and 24 weeks. Clinical parameters, quality of life, and tissue markers (sex hormone binding globulin, serum lipids, bone markers) were evaluated at 12 and 24 weeks. DIO2 and MCT10 single nucleotide polymorphisms were genotyped. RESULTS: The LT4 + LT3 group was treated with mean daily LT3 doses of 5.00 µg, with a mean daily LT4 reduction of 15 µg. After 6 months of treatment, neither SHBG and other tissue markers nor quality of life differed significantly between groups. Combination treatment required greater dose adjustments than placebo (25% vs 54%, P < .001), due to thyroid-stimulating hormone reduction, without hyperthyroidism signs or symptoms. At the end of treatment, the LT4 + placebo group had significantly lower fT3/fT4 compared to the LT4 + LT3 group (0.26 ± 0.05 vs 0.32 ± 0.08, P < .001). No preference for combination therapy was found. Genetic variants did not influence any outcomes. CONCLUSIONS: Six months of combination therapy with twice-daily LT3 dose adapted according to TSH-level do not significantly change peripheral tissue response or quality of life, despite an increase in the fT3/fT4 ratio.

Long-Term Use of Temozolomide as Safe and Effective Therapy for an Aggressive Corticotroph Adenoma in a Very Old Patient.

BACKGROUND: Temozolomide (TMZ) is safe and effective in the treatment of aggressive pituitary adenomas (PAs). However, the optimal duration of TMZ therapy is still unknown. Moreover, data about administration of TMZ in elderly (≥65 years) people to treat aggressive PAs are scarce. We report the case of the oldest female patient undergoing the longest TMZ protocol described so far to treat an aggressive, initially silent corticotroph PA. CASE REPORT: The patient initially underwent partial surgical removal of the PA. Subsequent treatment with cabergoline was applied, but it was unsuccessful in controlling the growth of the residual tumor. Pasireotide and external radiation also showed to be ineffective; therefore, treatment with TMZ was started at the standard dose of 200 mg/m2/day for 5 days every 4 weeks for a total of 47 cycles. At the time of treatment's beginning, the patient was 83 years old. Radiological follow-up documented a progressive, remarkable reduction of the adenoma and the last imaging, after 39 cycles of TMZ, showed an intrasellar lesion with large areas of cystic degeneration. The patient also developed adrenal deficiency managed with glucocorticoid replacement. No major side effects were observed throughout the treatment, with exception of nausea, well controlled with anti-emetic medication. TMZ therapy was discontinued after 47 cycles; hormonal and imaging follow-up investigations documented sustained functional and dimensional response. CONCLUSIONS: Our case supports the long-term use of TMZ, confirming its safety and efficacy also for elderly patients.

Real-life use of BRAF-V600E mutation analysis in thyroid nodule fine needle aspiration: consequences on clinical decision-making.

PURPOSE: This study aimed to evaluate the real-life use of BRAF-V600E mutation analysis in washout liquid from thyroid nodule fine needle aspiration (FNA), and the consequences of genetic result on clinical decision-making. METHODS: We retrospectively considered subjects tested for BRAF-V600E among those attending the Endocrinology Unit of Modena for FNA between 2014 and 2018. Washing fluid was collected together with cytological sample and stored at -20 °C. If the clinician deemed it necessary, the sample was thawed, DNA extracted, and genetic test performed by high-resolution melting technique. We collected data on cytology according to the Italian Consensus for the cytological classification of thyroid nodules, type of surgery (when performed), histology, and adverse events. RESULTS: Out of 7112 subjects submitted to FNA, BRAF analysis was requested for 683 (9.6%). Overall, 896 nodules were analyzed: 74% were indeterminate at cytology, mainly TIR3A (low risk). Twenty-two nodules were mutant (BRAF+). Only 2% of indeterminate, mainly TIR3B, were BRAF+. Based on final histological diagnosis, BRAF test had high specificity (100%) but poor sensitivity (21%), also in indeterminate nodules. Mutant subjects underwent more extensive surgery compared to wild type (p = 0.000), with frequent prophylactic central lymph node dissection. One third had local metastases. Higher prevalence of hypoparathyroidism was found in BRAF+ compared to wild type (p = 0.018). CONCLUSIONS: The analysis of BRAF-V600E outside of gene panels has low sensitivity, especially in indeterminate nodules, and a positive result could lead to more extensive surgery with greater risk of hypoparathyroidism and questionable clinical utility.

Sexual Dysfunction: A Neglected and Overlooked Issue in Adult GH Deficiency: The Management of AGHD Study.

CONTEXT: Although sexuality influences well-being and quality of life (QoL), studies on sexual dysfunction (SD) in adult growth hormone deficiency (AGHD) patients are lacking. OBJECTIVE: To investigate the prevalence of SD in AGHD patients grouped according to recombinant human growth hormone (r-hGH) therapy. DESIGN: Prospective, cross-over, 24 months, monocentric study. SETTING: Real-life clinical setting in a tertiary, endocrinological center. PATIENTS: 83 AGHD patients (31 women, 52 men, mean age 56.3 ± 14.7 years) were enrolled according to stringent criteria. INTERVENTIONS: Patients already on long-term r-hGH therapy (Group 1, n = 32) vs untreated (Group 2, n = 51). MAIN OUTCOME MEASURES: Serum hormones, QoL Satisfaction in Hypopituitarism (QLS-H) and QoL Assessment of GHD in Adults (QoL-AGHDA) questionnaires for QoL, Index for Erectile Function-15 (IIEF-15) in men, and Female Sexual Function Index (FSFI) in women for SD. RESULTS: The overall prevalence of SD was 71.2% (60% men, 89% women). All IIEF-15 scores were lower (P = 0.001) and erectile dysfunction was more prevalent in Group 2 (75%) than Group 1 (35%). IGF-1 was correlated to scores of all IIEF-15 domains, particularly with that of erectile function (EF) (R2=0.123, P = 0.019). EF domain score correlated with QLS-H (P < 0.005) and QoL-AGHDA (P = 0.001). Despite the high prevalence of female SD also in untreated AGHD women, FSFI scores did not correlate with IGF-1 levels and QoL scores. CONCLUSIONS: SD is highly prevalent in AGHD patients, especially in those untreated. SD represents an overlooked and neglected issue in AGHD, regardless the contribution of sexual life on QoL. The evaluation of sexual function should be integrated in the global assessment of AGHD patients.

ESE audit on management of Adult Growth Hormone Deficiency in clinical practice.

Guidelines recommend adults with pituitary disease in whom GH therapy is contemplated, to be tested for GH deficiency (AGHD); however, clinical practice is not uniform. AIMS: 1) To record current practice of AGHD management throughout Europe and benchmark it against guidelines; 2) To evaluate educational status of healthcare professionals about AGHD. DESIGN: On-line survey in endocrine centres throughout Europe. PATIENTS AND METHODS: Endocrinologists voluntarily completed an electronic questionnaire regarding AGHD patients diagnosed or treated in 2017-2018. RESULTS: Twenty-eight centres from 17 European countries participated, including 2139 AGHD patients, 28% of childhood-onset GHD. Aetiology was most frequently non-functioning pituitary adenoma (26%), craniopharyngioma (13%) and genetic/congenital mid-line malformations (13%). Diagnosis of GHD was confirmed by a stimulation test in 52% (GHRH+arginine, 45%; insulin-tolerance, 42%, glucagon, 6%; GHRH alone and clonidine tests, 7%); in the remaining, ≥3 pituitary deficiencies and low serum IGF-I were diagnostic. Initial GH dose was lower in older patients, but only women <26 years were prescribed a higher dose than men; dose titration was based on normal serum IGF-I, tolerance and side-effects. In one country, AGHD treatment was not approved. Full public reimbursement was not available in four countries and only in childhood-onset GHD in another. AGHD awareness was low among non-endocrine professionals and healthcare administrators. Postgraduate AGHD curriculum training deserves being improved. CONCLUSION: Despite guideline recommendations, GH replacement in AGHD is still not available or reimbursed in all European countries. Knowledge among professionals and health administrators needs improvement to optimize care of adults with GHD.

The Added Value of Operator's Judgement in Thyroid Nodule Ultrasound Classification Arising From Histologically Based Comparison of Different Risk Stratification Systems.

Objective: Several ultrasound classifications for thyroid nodules were proposed but their accuracy is still debated, since mainly estimated on cytology and not on histology. The aim of this study was to test the diagnostic accuracy and the inter-classification agreement of AACE/ACE-AME, American Thyroid Association (ATA), British Thyroid Association (BTA), and Modena Ultrasound Thyroid Classification (MUT) that stratifies malignancy risk considering also the clinician subjective impression. Methods: A prospective study collecting thyroid nodule features at ultrasound and histological diagnosis was conducted. Ultrasound features were collected following a preformed checklist in candidates for surgery because of indeterminate, suspicious, or malignant cytology. All the nodules, besides the cytologically suspicious one, were blinded analyzed. MUT score was applied prospectively, and the others retrospectively. Sensitivity, specificity, diagnostic cut-off value, and accuracy of each classification were calculated. The overall agreement between classifications was tested by Bland-Altman, and agreement between single nodule analysis by different classifications by Weighted Cohen's Kappa. Results: In classifying a total of 457 nodules, MUT has the highest accuracy (AUC 0.808) and specificity (89%), followed by ATA and BTA, and finally by AACE/ACE-AME. ATA, BTA, and MUT are highly interchangeable. Considering agreement between single nodule analyses, ATA and BTA had the best (κ = 0.723); AACE/ACE-AME showed slight agreement with BTA (κ = 0.177) and MUT (κ = 0.183), and fair agreement with ATA (κ = 0.282); MUT had fair agreement with both ATA (κ = 0.291) and BTA (κ = 0.271). Conclusion: Classifications have an acceptable overall diagnostic accuracy, improved using a less rigid system that takes into consideration operator subjective impression.

De novo Lesions Frequently Develop in Adult Normal Thyroid Over Almost Six Years.

Purpose: In order to understand how thyroid abnormalities emerge over time in adults, we evaluated incidence of thyroid diseases in healthy subjects, after almost 6 years from a previous negative ultrasound. Methods: Anamnestic and physical data were collected. Ultrasound neck evaluation was performed by an experienced endocrinologist, recording detailed thyroid and nodules characteristics. Nodules were classified according to American Thyroid Association classification for prediction of cancer risk. Serum samples were collected for subsequent evaluations (TSH, free thyroid hormones, calcitonin, anti-thyroid antibodies). Anamnestic, clinical, sonographic, and serological characteristics were analyzed with logistic regression analysis for subjects with nodules vs. those without. Results: One hundred and eleven subjects were enrolled (43M, 68F). Half of them developed nodules, mainly smaller than 1 cm and without suspicious characteristics. Ninety-seven percent were euthyroid. Only 4% had serological diagnosis of thyroiditis. Incidence of thyroid diseases was higher in women, especially nulliparous. Comparing clinical characteristics of subjects with and without nodules, the only statistically significant difference concerned thyroid volume adjusted for body weight or surface (p < 0.05), but not residual volume excluding nodules. Multivariate logistic regression analysis showed that female gender, higher BMI-adjusted thyroid volume and residual thyroid volume excluding nodules, nulliparity, age, and fT3 increase the risk of developing nodules. Conclusions: These results demonstrate that adult thyroid tissue undergoes changes that are already detectable by US after almost 6 years. Half of the enrolled subjects developed de novo nodules or colloid cysts of poor clinical relevance.

High-Resolution Melting Is a Sensitive, Cost-Effective, Time-Saving Technique for BRAF V600E Detection in Thyroid FNAB Washing Liquid: A Prospective Cohort Study.

OBJECTIVE: The diagnostic accuracy of thyroid fine needle aspiration biopsy (FNAB) can be improved by the combination of cytological and molecular analysis. In this study, washing liquids of FNAB (wFNAB) were tested for the BRAF V600E mutation, using the sensitive and cost-effective technique called high-resolution melting (HRM). The aim was to demonstrate the feasibility of BRAF analysis in wFNAB and its diagnostic utility, combined with cytology. DESIGN: Prospective cohort study. METHODS: 481 patients, corresponding to 648 FNAB samples, were subjected to both cytological (on cells smeared onto a glass slide) and molecular analysis (on fluids obtained washing the FNAB needle with 1 ml of saline) of the same aspiration. BRAF V600E analysis was performed by HRM after methodological validation for application to wFNAB (technique sensitivity: 5.4%). RESULTS: The cytological results of the FNAB were: 136 (21%) nondiagnostic (THY1); 415 (64%) benign (THY2); 80 (12.4%) indeterminate (THY3); 9 (1.4%) suspicious for malignancy (THY4); 8 (1.2%) diagnostic of malignancy (THY5). The BRAF V600E mutation was found in 5 THY2, 2 THY3, 6 THY4 and 6 THY5 samples. Papillary carcinoma diagnosis was histologically confirmed in all BRAF+ thyroidectomized patients. BRAF combined with cytology improved the diagnostic value compared to cytology alone in a subgroup of 74 operated patients. CONCLUSIONS: HRM was demonstrated to be a feasible method for BRAF analysis in wFNAB. Thanks to its sensitivity and cost-effectiveness, it might be routinely used on a large scale in clinical practice. In perspective, standby wFNAB samples could be analyzed a posteriori in case of indeterminate cytology and/or suspicious findings on ultrasound.