Molecular alterations of the MAPK pathway are frequently observed in papillary thyroid carcinomas (PTCs). It leads to a constitutive activation of the signalling pathway through an increase in MEK and ERK phosphorylation. ERK is negatively feedback-regulated by Dual Specificity Phosphatases (DUSPs), especially two ERK-specific DUSPs, DUSP5 (nuclear) and DUSP6 (cytosolic). These negative MAPK regulators may play a role in thyroid carcinogenesis. MAPK pathway activation was analyzed in 11 human thyroid cancer cell lines. Both phosphatases were studied in three PCCL3 rat thyroid cell lines that express doxycycline inducible PTC oncogenes (RET/PTC3, H-RAS^V12 or BRAF^V600E). Expression levels of DUSP5 and DUSP6 were quantified in 39 human PTCs. The functional role of DUSP5 and DUSP6 was investigated through their silencing in two human BRAF^V600E carcinoma cell lines. BRAF^V600E human thyroid cancer cell lines expressed higher phospho-MEK levels but not higher phospho-ERK levels. DUSP5 and DUSP6 are specifically induced by the MEK-ERK pathway in the three PTC oncogenes inducible thyroid cell lines. This negative feedback loop explains the tight regulation of p-ERK levels. DUSP5 and DUSP6 mRNA are overexpressed in human PTCs, especially in BRAF^V600E mutated PTCs. DUSP5 and/or DUSP6 siRNA inactivation did not affect proliferation in two BRAF^V600E mutated cell lines, which may be explained by a compensatory increase in other phosphatases. In the light of this, we observed a marked DUSP6 upregulation upon DUSP5 inactivation. Despite this, DUSP5 and DUSP6 positively control cell migration and invasion. Our results are in favor of a stronger activation of the MAPK pathway in BRAF^V600E PTCs. DUSP5 and DUSP6 have pro-tumorigenic properties in two BRAF^V600E PTC cell line models.

Since 2009, thyroid imaging reporting and data systems (TI-RADS) have been playing an increasing role in the field of thyroid nodules (TN) imaging. Their common aims are to provide sonologists of varied medical specialties and clinicians with an ultrasound (US) based malignancy risk stratification score and to guide decision making of fine-needle aspiration (FNA). Schematically, all TI-RADSs scores can be classified as either pattern-based or point-based approaches. The main strengths of these systems are their ability (i) to homogenize US TN descriptions among operators, (ii) to facilitate and shorten communication on the malignancy risk of TN between sonologists and clinicians, (iii) to provide quantitative ranges of malignancy risk assessment with high sensitivity and negative predictive values, and (iv) to reduce the number of unnecessary FNAs. Their weaknesses are (i) the remaining inter-observer discrepancies and (ii) their insufficient sensitivity for the diagnosis of follicular cancers and follicular variant of papillary cancers. Most common pitfalls are degenerating shrinking nodules and confusion between individual and coalescent nodules. The benefits of all TI-RADSs far outweigh their shortcomings, explaining their rising use, but the necessity to improve and merge the different existing systems remains.

Understanding of changes in salivary and lacrimal gland functions after radioiodine therapy (131I-therapy) remains limited; and, to-date no studies have evaluated dose-response relationships between absorbed dose from 131I-therapy and dysfunctions of these glands. This study investigates salivary/lacrimal dysfunctions in differentiated thyroid cancer (DTC) patients six months after 131I-therapy, identifies 131I-therapy related risk factors for salivary/lacrimal dysfunctions, and assesses the relationships between 131I-therapy radiation dose and these dysfunctions. A cohort study was conducted involving 136 DTC patients treated by 131I-therapy of whom 44 and 92 patients received 1.1 and 3.7 GBq, respectively. Absorbed dose to the salivary glands was estimated using a dosimetric reconstruction method based on thermoluminescent dosimeters measurements. Salivary and lacrimal functions were assessed at baseline (T0, i.e., immediately prior to 131I-therapy), and 6 months later (T6) using validated questionnaires and salivary samplings, with and without stimulation of the salivary glands. Statistical analyses included descriptive analyses and random-effects multivariate logistic and linear regressions. There was no difference between T0 and T6 in the level of parotid gland pain, nor was there difference in the number of patients with hyposalivation, but there were significantly more patients with dry mouth sensation and dry eyes after therapy compared to baseline. Age, menopause, depression and anxiety symptoms, history of systemic disease, and not taking painkillers in the last 3 months were found to be significantly associated with salivary or lacrimal disorders. Significant associations were found between 131I-exposure and salivary disorders adjusted on the previous variables: e.g. per 1-Gy increase in mean dose to the salivary glands, OR=1.43 (95%CI 1.02-2.04) for dry mouth sensation, ß=-0.08 (95%CI -0.12;-0.02) mL/min for stimulated saliva flow, and ß= 1.07 (95%CI 0.42;1.71) mmol/L for salivary potassium concentration. This study brings new knowledge on the relationship between the absorbed dose to the salivary glands from 131I-therapy and salivary/lacrimal dysfunctions in DTC patients 6 months after 131I-therapy. Despite the findings of some dysfunctions, the results do not show any obvious clinical disorders after the 131I-therapy. Nevertheless, this study raises awareness of the risk factors for salivary disorders, and calls for longer follow-up. Clinical trials registration: number NCT04876287 on ClinicalTrials.gov.

Papillary thyroid cancer (PTC) often co-occurs with Hashimoto’s thyroiditis, an association that has long been reported in clinical studies, remaining controversial. Experimental evidence has recently shown that pre-existing thyroiditis has a beneficial effect on PTC growth and progression by a distinctive expansion of effector memory CD8 T cells. Although the link between inflammation and PTC might involve different components of the immune system, a deep characterization of them which includes T cells, B cells and tertiary lymphoid structures, Mye-loid cells, Neutrophils, NK cells and dendritic cells will be desirable. The present review article considers the role of the adaptive and innate immune response surrounding PTC in the context of Hashimoto’s thyroiditis. This review will focus on the current knowledge by in vivo and in vitro studies specifically performed on animals’ models; thyroid cancer cells and human samples including (i) the dual role of tumor-infiltrating lymphocytes; (ii) the emerging role of B cells and tertiary lymphoid structures; (iii) the role of myeloid cells, dendritic cells, and natural killer cells; (iv) the current knowledge of the molecular biomarkers implicated in the complex link between thyroiditis and PTC and the potential implication of cancer immunotherapy in PTC patients in the context of thyroiditis.

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. 17,247 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% (6,058 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 five 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 non-endocrine causes and despite the evidence of non-superiority 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.

Purpose: 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. Methods: 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”. Results: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96–0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55–0.91). Conclusions: Despite the lack of evidence, and contrary to guidelines’ recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.