Use of levothyroxine for euthyroid, thyroid antibody positive women with infertility: Analyses of aggregate data from a survey of European thyroid specialists (Treatment of Hypothyroidism in Europe by Specialists: An International Survey).

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.

Histology is more ιmportant than persistent anti-Tg antibodies for progression of differentiated thyroid cancer.

CONTEXT: Anti-thyroglobulin antibodies (anti-Tg), present in 20%-25% of differentiated thyroid cancer (DTC) patients, interfere with thyroglobulin measurements posing a challenge in the follow-up. OBJECTIVES: The aim of this study was to identify clinical-histological factors that may affect anti-Tg persistence and disease outcome in DTC with positive anti-Tg. METHODS: We retrospectively studied 234 DTC patients, with positive anti-Tg at diagnosis (females: 82.1%, age at diagnosis: 46.0 ± 14.4 yrs, median follow-up: 5 yrs (1.5-32 yrs). 221/234 (94.4%) received radioiodine (RAI) ablation. Patients were divided into two subgroups: those whose anti-Tg became undetectable (anti-Tg-NEG) and those whose anti-Tg remained positive (anti-Tg-POS) at the end of the follow-up period. RESULTS: Anti-Tg-POS patients (n = 80, 34.2%) compared to anti-Tg-NEG (n = 154, 65.8%) had more frequently lymph node infiltration (36.3% vs 20.1%, P = .01), extrathyroidal extension (ETE, 35.0% vs 22.1%, P = .04), poorly differentiated DTC and increased tumour size (P ≤ .004). They received higher total RAI dose (P < .001). In most cases, additional RAI administration and/or additional surgeries did not lead to anti-Tg elimination. These had more frequently structural disease persistence/progression compared to anti-Tg-NEG (remission: 78.8% vs 95.5%, persistence: 13.8% vs 3.9%, progression: 7.5% vs 0.6%, P < .001). In Kaplan-Meier analysis, the probability of disease progression was higher in anti-Tg-POS. In Cox proportional hazard analysis, the predictors of disease progression were size (P = .002) and ETE (P = .006). CONCLUSIONS: Worse histological features are more frequent in patients with anti-Tg persistence during follow-up. Further additional RAI administration and/or surgeries do not affect anti-Tg elimination in most cases. Anti-Tg persistence correlates with structural persistence although tumour size and extrathyroidal extension are the main predictors of disease progression.

Cortisol to Dehydroepiandrosterone Sulphate Ratio and Executive Function in Bipolar Disorder.

INTRODUCTION: Bipolar disorder (BD) is associated with impairment in cognitive domains such as verbal memory and executive functions. Very few studies have assessed dehydroepiandrosterone sulphate (DHEA-S) in BD and its relation to cognitive functioning despite evidence showing its regulatory effects on glucocorticoid action. The aim of our study was to explore the association of cortisol, DHEA-S, and cortisol to DHEA-S ratio with visuospatial memory and executive functioning in BD. METHODS: Cognitive performance of 60 bipolar I patients and 30 healthy subjects was evaluated by using Cambridge Neuropsychological Test Automated Battery tasks targeting visuospatial memory (spatial recognition memory) and executive functions (planning [Stockings of Cambridge; SOC] and attentional set shifting [ID/ED]). Morning serum cortisol and DHEA-S levels were measured in patients. Main effects of cortisol, DHEA-S, and cortisol/DHEA-S ratio for each neurocognitive task were explored in multiple regression analyses correcting for demographic and clinical parameters as well as treatment-related factors (current use of antipsychotic and mood stabilizer medication). RESULTS: Bipolar patients showed poorer performance than healthy subjects in planning and attentional set shifting but not in visuospatial memory. Cortisol to DHEA-S ratio predicted worse performance in planning (SOC). CONCLUSIONS: This is the first study to assess memory and executive function in BD in relation to DHEA-S and cortisol to DHEA-S ratio. We report an association of cortisol to DHEA-S ratio with worse performance in planning in bipolar I patients, which warrants further investigation.

Dedicated neck 18 F-FDG PET/CT: An additional tool for risk assessment in thyroid nodules at ultrasound intermediate risk.

BACKGROUND: Several ultrasound (US) risk stratification systems have been proposed for the assessment of thyroid nodules, and their performance was shown as good. However, the rate of nodules assessed at intermediate risk is not negligible and whether they should be submitted or not to further examination is still under debate. The present study aimed to evaluate the reliability of 18 F-FDG PET/CT in stratifying the risk of malignancy in these lesions. METHODS: Two institutions participated to this retrospective study in which a dedicated 18 F-FDG PET/CT was proposed to patients having a thyroid nodule with US assessment of EU-TIRADS 4 or 5. 18 F-FDG PET/CT did not influence the diagnostic and therapeutic decision. Histology was the gold standard for all patients. RESULTS: Ninety-three patients were included for the study with 48 EU-TIRADS 4 and 45 EU-TIRADS 5 nodules. Of these, 26 underwent thyroidectomy following FNAC suspicious for or consistent with malignancy, 38 for inconclusive cytology, 27 because of large goitre and 2 for high-risk lesion at US. At histology, 35 carcinomas and 58 benign lesions were found. Cancer prevalence was 16.7% in EU-TIRADS 4 and 60% in EU-TIRADS 5. Overall, 18 F-FDG PET/CT was positive in 33/35 cancers (94.5% sensitivity) and negative in 31/58 benign lesions (53.4% specificity). When considering only EU-TIRADS 4, 18 F-FDG PET/CT was positive in 7/8 cancers and negative in 20/40 benign lesions; among these, there were 36 cases with FNAC indication according to dimensional cut-off (ie >1.5 cm), and 18 F-FDG PET/CT showed 85.7% sensitivity and 41.4% specificity. CONCLUSIONS: 18 F-FDG PET/CT may have a role in stratifying the cancer risk of thyroid nodules with an intermediate ultrasound assessment. More specifically, thyroid lesions classified as EU-TIRADS 4 and with no 18 F-FDG uptake could be ruled out from further examination, similar to other anamnestic and clinical suspicious factors of patients. Further prospective and cost-effectiveness studies are needed.

RAGE polymorphisms and oxidative stress levels in Hashimoto's thyroiditis.

BACKGROUND: Polymorphisms of the receptor for advanced glycation end products (RAGE) gene have been studied in various autoimmune disorders, but not in Hashimoto's thyroiditis. Also, increased oxidative stress has been described in patients with Hashimoto's thyroiditis. The aim of this study was to investigate the possible role of two common RAGE polymorphisms (-429T>C, -374T>A) in Hashimoto's thyroiditis; in parallel, we studied oxidative stress levels. MATERIALS AND METHODS: A total of 300 consecutive euthyroid women were examined and classified into three groups: Hashimoto's thyroiditis with treatment (n = 96), Hashimoto's thyroiditis without treatment (n = 109) and controls (n = 95). For a rough evaluation of oxidative stress, total lipid peroxide levels in serum were measured. The -429T>C AluI and -374T>A MfeI polymorphisms of RAGE were studied in genomic DNA. RESULTS: Significant association of the RAGE system with Hashimoto's thyroiditis was found only with regard to the prevalence of the -429T>C, but not with -374T>A polymorphism. The levels of oxidative stress were significantly elevated in Hashimoto's thyroiditis patients under treatment. Further analysis demonstrated that an oxidative stress cut-off value of 590 µmol/L is associated with an increased risk of progression of Hashimoto's thyroiditis from euthyroidism to hypothyroidism; this risk is further increased in carriers of the RAGE -429T>C polymorphism. CONCLUSIONS: Our findings indicate that both examined risk factors may be implicated in the occurrence of Hashimoto's thyroiditis, but this covers only a fraction of the pathophysiology of the disease.

Clinical and treatment-related predictors of cognition in bipolar disorder: focus on visual paired associative learning.

Bipolar disorder (BD) is associated with impairment in cognitive domains such as verbal memory and executive functions. However, visual paired associative learning (PAL) has been far less researched. Neurocognitive dysfunction in BD patients has been related to several clinical factors, but data on the effect of medication are relatively scarce and inconsistent. The aim of our study was to explore the effect of clinical and treatment-related parameters on executive functions and visual memory/learning, including PAL, in BD. Cognitive performance of 60 bipolar I patients and 30 healthy subjects was evaluated by using CANTAB battery tasks targeting spatial recognition memory, PAL and executive functions (set shifting, planning, inhibitory control). Bipolar patients showed poorer performance in PAL, set shifting, planning and inhibitory control than healthy subjects; however, only differences in PAL and planning survived correction for multiple comparisons. Number of previous manic episodes and illness duration predicted worse performance in set shifting and PAL, respectively, whereas current treatment with valproate predicted better performance in PAL. This is one of the first studies to assess clinical and treatment-related predictors of PAL in BD. We report a possibly beneficial effect of valproate on PAL, which warrants further investigation.

Papillary thyroid carcinomas in patients under 21 years of age: clinical and histologic characteristics of tumors ≤10 mm.

OBJECTIVE: To compare clinical and histologic characteristics of papillary thyroid carcinomas (PTCs) ≤10 mm in patients ≤21 years old with larger ones and with microcarcinomas in adults. STUDY DESIGN: Retrospective study of patients with PTC diagnosed between 1983 and 2012. Medical records were reviewed and information about age, sex, tumor size, intra/extrathyroid extension, lymph node, and distant metastases were collected. RESULTS: Patients ≤21 years old (n = 93) and adults (n = 1235) with PTC were identified. Among the former, 34 had PTC ≤10 mm (37.4%) and among the latter, 584 had papillary thyroid microcarcinoma (PTM) (47.3%), P = .082. Patients with tumors ≤10 mm less frequently had extrathyroidal extension and lymph node metastases compared with larger tumors (8.8% vs 33.3%, P = .017, and 60.0% vs 95.2%, P = .001, respectively). The percentage of PTC ≤10 mm increased with age (7.1%, 32.0%, and 48.1% in age groups ≤15, 15-18, and >18 to ≤21 years old, respectively; P = .016). Mean tumor size was larger (6.8 ± 2.7 vs 5.8 ± 2.8 mm, P = .030), and lymph nodes metastases were more frequent (41.2% vs 18.6%, P = .003) in patients ≤21 years of age compared with adults with PTM. The frequency of multifocal cancers decreased between 1983-1992, 1993-2002, and 2003-2012 (66.7%, 53.6%, and 27.1%, respectively, P = .019). CONCLUSIONS: The frequency of PTC ≤10 mm is low in children, increases in adolescents, and reaches that of adults at 18-21 years of age. Mean tumor size is larger and metastases to regional lymph nodes more frequent in comparison with PTM in adults. Whether their treatment and follow-up could be based on guidelines used for PTM in adults is questionable.

Volumetric bone mineral density and bone geometry assessed by peripheral quantitative computed tomography in women with differentiated thyroid cancer under TSH suppression.

OBJECTIVE: TSH suppression therapy in patients with differentiated thyroid cancer (DTC) has been associated with adverse effects on areal bone mineral density (aBMD) only in postmenopausal women. The purpose of study was to examine the effect of TSH suppression therapy on skeletal integrity using peripheral quantitative computed tomography (pQCT) at the radius and tibia in pre- and postmenopausal women with DTC and controls. STUDY DESIGN AND PATIENTS: Subjects included 80 women with DTC (40 pre- and 40 postmenopausal) and 89 (29 and 60, respectively) controls. pQCT was performed at the radius and tibia, Dual-energy X-ray absorptiometry (DXA) at the hip and lumbar spine, while samples were taken for calciotropic hormones and bone markers. RESULTS: No differences were observed concerning aBMD by DXA. In premenopausal women, there were no significant differences concerning vBMD, while cortical thickness was higher at the radius in patients with DTC (P < 0·01) compared with controls. In postmenopausal women with DTC trabecular bone mineral content (BMC), area and vBMD were lower at the radius (all P < 0·05), while at the tibia trabecular BMC and vBMD were lower at the mixed transition zone (14% from the distal end, P < 0·05) compared with controls. Cortical thickness was lower at the radius (P < 0·01) in postmenopausal patients compared with controls. Serum CTX was higher in postmenopausal women with DCT (P < 0·01), while in premenopausal patients, parathyroid hormone (PTH) was lower (P = 0·01) compared with controls. CONCLUSIONS: TSH suppression therapy is associated with higher bone resorption only in postmenopausal women; this adversely affects trabecular and cortical bone properties especially at nonweight-bearing sites such as the radius.

Primary Hyperparathyroidism in MEN2 Syndromes.

One of the components of trethe classical form of MEN2 syndromes is primary hyperparathyroidism (PHP). It occurs in 20-30% of the typical MEN2A syndrome. The prevalence is more rare in gene carriers as these frequently have familial MTC only. PHP is diagnosed more frequently in association with the exon 11, codon 634 mutation of the ret gene-so there is phenotype/genotype correlation. The clinical manifestations of PHP in MEN2 are usually mild and the peak age of diagnosis after the 3rd decade. The treatment is surgical excision of the enlarged gland(s). Although there can be multigland disease in the parathyroids, it is frequently the case that both hyperplasia and adenoma may coexist, or even a single adenoma may be found during the investigation and finally during the operation. Patients with MEN2 syndromes should be screened for PHP with serum calcium measurements. The intensity of the screening should be higher in those carrying the ret mutations most frequently associated with this manifestation.

Outcomes of adrenal-sparing surgery or total adrenalectomy in phaeochromocytoma associated with multiple endocrine neoplasia type 2: an international retrospective population-based study.

BACKGROUND: The prevention of medullary thyroid cancer in patients with multiple endocrine neoplasia type 2 syndrome has demonstrated the ability of molecular diagnosis and prophylactic surgery to improve patient outcomes. However, the other major neoplasia associated with multiple endocrine neoplasia type 2, phaeochromocytoma, is not as well characterised in terms of occurrence and treatment outcomes. In this study, we aimed to systematically characterise the outcomes of management of phaeochromocytoma associated with multiple endocrine neoplasia type 2. METHODS: This multinational observational retrospective population-based study compiled data on patients with multiple endocrine neoplasia type 2 from 30 academic medical centres across Europe, the Americas, and Asia. Patients were included if they were carriers of germline pathogenic mutations of the RET gene, or were first-degree relatives with histologically proven medullary thyroid cancer and phaeochromocytoma. We gathered clinical information about patients'RET genotype, type of treatment for phaeochromocytoma (ie, unilateral or bilateral operations as adrenalectomy or adrenal-sparing surgery, and as open or endoscopic operations), and postoperative outcomes (adrenal function, malignancy, and death). The type of surgery was decided by each investigator and the timing of surgery was patient driven. The primary aim of our analysis was to compare disease-free survival after either adrenal-sparing surgery or adrenalectomy. FINDINGS: 1210 patients with multiple endocrine neoplasia type 2 were included in our database, 563 of whom had phaeochromocytoma. Treatment was adrenalectomy in 438 (79%) of 552 operated patients, and adrenal-sparing surgery in 114 (21%). Phaeochromocytoma recurrence occurred in four (3%) of 153 of the operated glands after adrenal-sparing surgery after 6-13 years, compared with 11 (2%) of 717 glands operated by adrenalectomy (p=0.57). Postoperative adrenal insufficiency or steroid dependency developed in 292 (86%) of 339 patients with bilateral phaeochromocytoma who underwent surgery. However, 47 (57%) of 82 patients with bilateral phaeochromocytoma who underwent adrenal-sparing surgery did not become steroid dependent. INTERPRETATION: The treatment of multiple endocrine neoplasia type 2-related phaeochromocytoma continues to rely on adrenalectomies with their associated Addisonian-like complications and consequent lifelong dependency on steroids. Adrenal-sparing surgery, a highly successful treatment option in experienced centres, should be the surgical approach of choice to reduce these complications.

Differential transcriptional and protein expression of thyroid-stimulating hormone receptor in ovarian carcinomas.

OBJECTIVE: Thyroid-stimulating hormone (TSH) regulates normal thyroid function by binding to its receptor (thyroid-stimulating hormone receptor -TSHR) that is expressed at the surface of thyroid cells. Recently, it has been demonstrated that TSHR is abundantly expressed in several tissues apart from the thyroid, among them the normal ovarian surface epithelium. The role of TSHR expression outside the thyroid is not completely understood. The current study examines possible alterations of TSHR expression in ovarian carcinomas and its implication in ovarian carcinogenesis. MATERIALS AND METHODS: Quantitative real-time polymerase chain reaction and immunohistochemistry analysis of TSHR expression were performed in 34 ovarian carcinoma specimens and 10 normal ovarian tissues (controls). RESULTS: Significant reduction in TSHR messenger RNA (mRNA) expression was detected in ovarian carcinomas (mean [SD]: 0.518 [0.0934] vs normal, 49.4985 [89.1626]; P < 0.001, Mann-Whitney U test), whereas TSHR protein levels were significantly increased (percentage of positive cells: cancer, 73.55% [20.09%], vs normal, 54.54% [21.14%]; intensity: cancer, 2.52 [0.508], vs normal 1 [0]; P = 0.012, Mann-Whitney U test). No significant differences in TSHR mRNA were found according to history of thyroid disease. CONCLUSIONS: Our study describes for the first time alterations in TSHR expression both at mRNA and protein levels in ovarian carcinomas. The discrepancy between the decreased levels of the TSHR mRNA and the increased protein expression has already been described in thyroid carcinomas and might be due to alterations in its degradation by the ubiquitin system or other unknown mechanisms. Further analysis could elucidate the role of these findings in ovarian carcinogenesis.

Does the presence of thyroid antibodies affect the course and outcome of pregnancy in type 1 diabetic women?

OBJECTIVE: The aim of the study was to evaluate the significance of the presence of thyroid peroxidase autoantibodies (anti-TPO Abs) in type 1 diabetes mellitus (DM1) pregnant women relative to the course of pregnancy and, especially, with regard to metabolic control, thyroid function, maternal complications and neonatal outcome. METHODS: In a prospective observational study of 91 DM1 women with singleton pregnancies, anti-TPO, anti-thyroglobulin, thyroid-stimulating hormone (TSH), and free thyroxine index (T4/thyroid binding capacity) were measured in each trimester. At each visit, HbA1c, body mass index, and units of insulin per kilogram were recorded, as were complications and pregnancy outcome. RESULTS: Twenty-one (27%) of the 78 women who met the inclusion criteria presented with positive anti-TPO Abs. There were no differences regarding glycemic control (HbA1c) or insulin dose. First-trimester TSH levels were significantly higher in the anti-TPO-positive group than in the anti-TPO-negative group. Finally, no differences were observed regarding diabetic or obstetric complications and neonatal outcome. CONCLUSION: One fourth of DM1 pregnant women presented with positive anti-TPO Abs. However, the presence of anti-TPO Abs does not seem to be related with worse metabolic control or adverse pregnancy outcome. Further investigation is needed; meanwhile, the effort for early treatment of thyroid dysfunction and strict metabolic control in all DM1 women should be continued.

Two rare cases of benign struma ovarii with malignant recurrence.

Summary: Struma ovarii is an ovarian teratoma that comprises 2-5% of all ovarian teratomas. Malignant transformation of struma ovarii occurs in less than 5% of all cases, and metastatic disease is even rarer. We report two cases initially diagnosed with benign struma ovarii that presented malignant transformation, specifically highly differentiated follicular carcinoma of the ovary (HDFCO), some years after the first diagnosis. Case 1 concerns a 37-year-old female featuring HDFCO of the right ovary with multiple metastatic foci, who was diagnosed with benign struma ovarii 14 years ago. Case 2 concerns a 26-year-old female diagnosed with HDFCO of the left ovary. This patient was initially diagnosed with benign struma ovarii 6 years ago that recurred 4 years after the diagnosis. Both patients were treated with surgery, adjunctive total thyroidectomy, and radioactive iodine (131I) therapy. Learning points: Malignant transformation of struma ovarii is very rare (<5%). Diagnosis of HDFCO without extra ovarian dissemination is difficult due to the resemblance of its histological appearance with normal thyroid tissue. There is no consensus on the postoperative treatment of malignant struma ovarii (MSO). Clinical and histological features of MSO should be assessed for the postoperative treatment decisions. TSH suppression and thyroglobulin level measurements are necessary for patient follow-up.

Patients' Persistent Symptoms, Clinician Demographics, and Geo-Economic Factors Are Associated with Choice of Therapy for Hypothyroidism by European Thyroid Specialists: The "THESIS" Collaboration.

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.

A study of ERα PvuII polymorphism in female patients with acute stroke: no associations with disease severity and early outcome.

Several studies have examined the association of the PvuII polymorphism of the estrogen receptor alpha gene with the risk of stroke. Data linking the polymorphism with the severity and outcome of cerebrovascular disease are lacking. In this study, we evaluated 285 postmenopausal Caucasian patients suffering an acute stroke, hospitalized in two tertiary hospitals over a period of 2 years, and searched for associations between the PvuII polymorphism and the one-month outcome and the neurological severity on admission. The prevalence of CC genotype was 21%, CT 50% and TT 29%. Estradiol levels were higher with increasing frequencies of the C allele (p = 0.04). There was no difference in the short-term functional outcome and mortality and the neurological severity on admission among the three genotypes. We did not find a significant association of the PvuII polymorphism with intracerebral hemorrhage and classical stroke risk factors. An association of the CC genotype with venous thromboembolism history was recorded (p 0.05). There was no association between the PvuII polymorphism and stroke severity and short-term outcome in the studied female stroke population. It is possible that the long-term estrogenic action, reflected by the genetic polymorphism, is not a major determinant of disease severity and prognosis in older age.

Metastatic medullary thyroid carcinoma (MTC): disease course, treatment modalities and factors predisposing for drug resistance.

PURPOSE: MTC has varying clinical course. In cases with metastatic disease (meta-MTC) further therapeutic modalities (locoregional and/or Tyrosine-Kinase-Inhibitors, TKIs) are needed. Clinical features, disease progression, response to therapy and possible factors predisposing to TKIs response-resistance in meta-MTCs were investigated. METHODS: Out of 338 MTC patients 54 had meta-MTC and were followed for 0.7-46 years (median 10.5); therapeutic interventions and response to therapy were recorded retrospectively. RESULTS: Of 54 meta-MTC patients, 34/54 were men, 44/54 sporadic (age-at-diagnosis 47 ± 17.4 years, range: 5-78). Distant metastases at diagnosis were present in 12/54 (≥2 loci in 8/12), 7/12 received TKIs; During follow-up metastases occurred in 42/54 (within 0.6-25 years from diagnosis, median 5 yrs). Locoregional therapies were administered to 44/54 (81.5%) and TKIs to 40/54 (74.1%). Vandetanib was administered in 30 patients (24 as first-line therapy). The median progression-free-survival, PFS) was 48 months (range 4-120), partial response (PR): 26.7%, stable disease (SD): 23.3%, progressive disease (PD): 50.0%, cancer-specific survival: 44.8%, (16 in ongoing-therapy). More favorable disease course was recorded in familial-MTC compared to sporadic (p = 0.02) and in those patients with serious-adverse-events (SAEs) under treatment (p = 0.027). Those with biochemical progression under vandetanib, later showed more frequently structural progression (p = 0.007). Ten patients received cabozantinib (8/10 as second-line therapy, median PFS:11 months (3-36 months), 8/10 died). Three RET-mutant patients received selpercatinib; all showed PR. Within the total follow-up period, the response to therapy was: PR: 8/54 (14.8%), SD: 15/54 (27.8%), PD: 31/54 (57.4%), cancer-specific survival 46.3%. Mortality was higher in older patients (≥60 years) compared to younger ones (<60 yrs) (83.3 vs 45.2%, p = 0.021). Outcome was better in familial-MTC vs sporadic (PR: 50 vs 6.8%, SD: 20 vs 29.5%, PD: 30 vs 59.1%, p = 0.007). CONCLUSIONS: Meta-MTCs treatment results in disease stabilization in 42.6% during a median 10.5 year follow-up. Combination of locoregional and systemic therapies may result in more favorable PFS. Family history, younger age, SAEs may predict better response; biochemical escape under TKI needs to be followed-up closely as it may indicate disease progression.

High-Dose Intravenous Steroid Treatment Seems to Have No Long-Term Negative Effect on Bone Mineral Density of Young and Newly Diagnosed Multiple Sclerosis Patients: A Pilot Study.

High-dose intravenous steroid treatment (HDIST) represents the first choice of treatment for multiple sclerosis (MS) relapses. Chronic oral glucocorticoid (GC) administration correlates with bone loss whereas data regarding HDIST in MS are still conflicting. Twenty-five newly diagnosed MS patients (NDMSP) (median age: 37 years) were prospectively studied for the effects of HDIST on bone mineral density (BMD) and bone metabolism. Patients received 1000 mg methylprednisolone intravenously every day for 5 days followed by oral prednisolone tapering over 21 days. Bone metabolism indices were determined prior to GC, on days 2, 4, 6, and 90, and at months 6, 12, 18, and 24 post GC therapy. Femoral, lumbar-spine BMD, and whole-body measurement of adipose/lean tissue were assessed prior to GC-administration and then every six months. Ten patients completed the study. N-terminal-propeptide-procollagen-type-1 and bone-specific alkaline phosphatase showed a significant increase at day-90 (p < 0.05). A transient non-significant fall of BMD was observed at 6 months after GC-administration, which subsequently appeared to be restored. We conclude that HDIST seems not to have long-term negative effects on BMD, while the observed transient increase of bone formation markers probably indicates a high bone turnover phase to GC-administration. Additional prospective studies with larger sample size are needed.

Characteristics of specialists treating hypothyroid patients: the "THESIS" collaborative.

Introduction: Thyroid specialists influence how hypothyroid patients are treated, including patients managed in primary care. Given that physician characteristics influence patient care, this study aimed to explore thyroid specialist profiles and associations with geo-economic factors. Methods: Thyroid specialists from 28 countries were invited to respond to a questionnaire, Treatment of Hypothyroidism in Europe by Specialists: an International Survey (THESIS). Geographic regions were defined according to the United Nations Statistics Division. The national economic status was estimated using World Bank data on the gross national income per capita (GNI per capita). Results: 5,695 valid responses were received (response rate 33·0%). The mean age was 49 years, and 65·0% were female. The proportion of female respondents was lowest in Northern (45·6%) and highest in Eastern Europe (77·2%) (p <0·001). Respondent work volume, university affiliation and private practice differed significantly between countries (p<0·001). Age and GNI per capita were correlated inversely with the proportion of female respondents (p<0·01). GNI per capita was inversely related to the proportion of respondents working exclusively in private practice (p<0·011) and the proportion of respondents who treated >100 patients annually (p<0·01). Discussion: THESIS has demonstrated differences in characteristics of thyroid specialists at national and regional levels, strongly associated with GNI per capita. Hypothyroid patients in middle-income countries are more likely to encounter female thyroid specialists working in private practice, with a high workload, compared to high-income countries. Whether these differences influence the quality of care and patient satisfaction is unknown, but merits further study.

Fine epitope mapping within the pathogenic thyroglobulin peptide 2340-2359: minimal epitopes retaining antigenicity across various MHC haplotypes are not necessarily immunogenic.

We have previously reported that the 20-mer peptide p2340 (amino acids 2340-2359), of human thyroglobulin (Tg) has the unique feature that it causes experimental autoimmune thyroiditis (EAT) in mouse strains bearing high-responder (HR) or low-responder (LR) MHC haplotypes in Tg-induced EAT. In this study, we have employed fine epitope mapping to examine whether this property of p2340 is the result of recognition of distinct or shared minimal T-cell epitopes in the context of HR or LR MHC class II molecules. Use of overlapping peptides showed that a core minimal 9-mer epitope (LTWVQTHIR, amino acids 2344-2352) was recognized by p2340-primed T cells from both HR (H2(k,s) ) and LR (H2(b,d) ) strains, whereas a second 9-mer epitope (HIRGFGGDP, amino acids 2350-2358) was antigenic only in H2(s) hosts. Truncation analysis of LTWVQTHIR and HIRGFGGDP peptides delineated them as the minimal epitopes recognized by p2340-primed T cells from the above strains. Subcutaneous challenge of all mouse strains with the 9-mer core peptide LTWVQTHIR in adjuvant elicited specific lymph node cell proliferative responses and mild EAT only in HR hosts, highlighting this sequence as a minimal pathogenic Tg peptide in EAT. The 9-mer peptide HIRGFGGDP was not found to be immunogenic in H2(s) hosts. These data demonstrate that minimal T-cell epitopes, defined as autoantigenic in hosts of various MHC haplotypes, are not intrinsically immunogenic. Activation of naive autoreactive T cells may require contributions from flanking residues within longer peptide sequences encompassing these epitopes.

Perchlorate and thiocyanate exposure and thyroid function in first-trimester pregnant women from Greece.

OBJECTIVE: Thyroid hormone, requiring adequate maternal iodine intake, is critical for neurodevelopment in utero. Perchlorate and, less so, thiocyanate decrease uptake of iodine into the thyroid gland by competitively inhibiting the sodium/iodide symporter (NIS). It remains unclear whether environmental perchlorate exposure adversely affects thyroid function in first-trimester pregnant women. DESIGN: Cross-sectional. PATIENTS: 134 pregnant women from Athens, Greece, at mean ± SD 10·9 ± 2·3 weeks' gestation. MEASUREMENTS: Urinary iodide, perchlorate, and thiocyanate and thyroid function tests were measured. RESULTS: The median urinary iodide was 120 µg/l. Urinary perchlorate levels were detectable in all women: median (range) 4·1 (0·2-118·5) µg/l. Serum thyroperoxidase antibodies (TPO Ab) were detectable in 16% of women. Using Spearman's rank correlation analyses, there was no correlation between urinary perchlorate concentrations and serum TSH, although inverse correlations were seen between urine perchlorate and free T3 and free T4 values. In univariate analyses, urine thiocyanate was positively correlated with serum TSH, but was not associated with serum free T3 or free T4. Urine perchlorate was positively correlated with gestational age. In multivariate analyses adjusting for urinary iodide concentrations, urine thiocyanate, gestational age, maternal age and TPO Ab titres, urine perchlorate was not a significant predictor of thyroid function. CONCLUSIONS: Low-level perchlorate and thiocyanate exposure is ubiquitous, but, in adjusted analyses, is not associated with alterations in thyroid function tests among mildly iodine-deficient Greek women in the first trimester of pregnancy.