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With similar performances in predicting prognosis, the Turin proposal and HHG provided complementary results in identifying a larger group of 'intermediate prognosis' thyroid carcinomas, which require adequate treatment and follow-up.

Compliance with ethical standards-Conflict of interest: None.-Research involving human participants: All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Declaration of Helsinki and its later amendments or comparable ethical standards.

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Background: Two-thirds of patients with metastatic differentiated thyroid cancer (DTC) become refractory to radioactive iodine (RAIR). The inhibition of the MAP-kinase pathway that is activated in case of BRAFV600E mutation might increase RAI incorporation into metastatic foci and reverse the RAI refractoriness. MERAIODE is a prospective multicentric open-label phase II trial, using a one-stage Fleming design, evaluating the efficacy and tolerance of trametinib (a MEK inhibitor) and dabrafenib (a BRAF inhibitor) treatment followed by the administration of RAI in metastatic RAIR DTC patients. Methods: Patients with BRAFV600E mutated RAIR metastatic DTC with RECIST progression within 18 months prior to enrollment and no lesion > 3 cm were included. A baseline rhTSH-stimulated diagnostic whole body scan (dc WBS) was performed prior to treatment initiation. Patients were treated with dabrafenib (150 mg bid) and trametinib (2 mg per day) for 42 days. At day 28, a second rhTSH-stimulated dc WBS was performed. After 35 days, a therapeutic activity of RAI (5.5 GBq) was administered. Primary endpoint was objective response rate (ORR) at 6 months according to RECIST v1.1 (central review). Patients: Among the 24 patients (mean age 67 years, 15 females) with a BRAFV600E mutated RAI refractory papillary DTC included between March 2018 and January 2020 in 8 French centers from the TUTHYREF netwok, 24 patients were treated and 21 patients were evaluable for the principal outcome at 6 months. Results: Abnormal RAI uptake was present in only 1 of the 21 patients (5%; 95%CI 0-24%) on a RAI diagnostic whole body scan (dc-WBS) performed prior to treatment initiation, in 11 patients, 11/17 (65%; 95%CI 38-86) on a dc-WBS performed 4 weeks after dabrafenib-trametinib initiation and in 20/21 (95%; 95%CI 76-100) on the post-therapeutic WBS performed after 5.5 GBq of RAI. The RECIST 6-months tumor response (central review) was partial response (PR) in 38% (95%CI 18-61), stable disease (SD) in 52% (95% CI 30-74) and progressive disease (PD) in 10% (95% CI 1-30). The median change in the sum of target lesions was -22% (range: -79 to +46) at 6 months after baseline. The 6-month fluorodesoxyglucose metabolic PET response was PR in 11/17 (65% 95%CI 38-86), SD in 4/17 (23%) (95% CI 7-50) and PD in 2/17 (12%; 95% CI 1-36). Among the 15 patients without Tg antibodies, 7 (47%) patients had a decrease of serum thyroglobulin level on T4 treatment by more than 50%All patients experienced at least one grade 1-2 adverse event, mainly asthenia, nausea, fever, diarrhea and cutaneous eruption. Nine grade 3 toxicities occurred in 6 treated patients. No grade 4-5 adverse event occurred Conclusion: The association of dabrafenib and trametinib in BRAFV600E mutated patients is effective for restoring RAI uptake and is followed by a tumor control in 90% of patients and by tumor response in 38% with limited adverse events. (PHRC 2015, NCT 03244956)

Background: The aim of this study was to determine the frequency and characteristics of bone and joint complications, specifically bone fragility, joint replacement surgery, and arthropathy, in hereditary hemochromatosis (HH) and related factors. Methods: This study was a cross-sectional observational study of 93 patients with HH. Radiographs of the hands, wrists, knees, and ankles were scored for joint space narrowing, erosions and cysts, osteophytes, and chondrocalcinosis. Prevalent (vertebral and non-vertebral) fragility fractures were recorded and bone mineral density (BMD) was systematically evaluated by dual energy X-ray absorptiometry. Bone fragility was defined as (i) a T-score ⩽ −2.5 at any site with or without a prevalent fragility fracture, or (ii) a T-score between −1.0 and −2.5 at any site and a prevalent fragility fracture. Results: The mean age of the patients was 60.0 (11.2) years, and 58.0% of them were men. The frequency of radiographic MCP2–3 arthropathy was 37.6% (95% CI 0.28–0.48). Radiographic MCP2–3 arthropathy was independently associated with older age [OR 1.17 (1.09–1.26) per year, p < 0.0001], male sex [OR 3.89 (1.17–12.97), p = 0.027] and C282Y+/+ genotype [OR 4.78 (1.46–15.68), p = 0.010]. The frequency of joint replacement surgery was 12.9% (95% CI 0.07–0.21). The frequency of bone fragility was 20.4% (95% CI 0.13–0.30). Bone fragility was independently associated with hepatic cirrhosis [OR 8.20 (1.74–38.68), p = 0.008]. Discussion: Radiographic MCP2–3 arthropathy was found to occur in 37.6% of patients with HH. The association observed between this form of arthropathy and C282Y homozygosity, male sex, and older age suggests that demographic characteristics and genetic background are likely to be major determinants of this joint disorder and play a more important role than severity of iron overload. Bone fragility was observed in a fifth of the patients with HH, independently of genetic background and severity of iron overload, and was strongly associated with hepatic cirrhosis. Conclusion: Future investigations should focus on pathogenesis and early identification of patients at risk of developing bone and joint complications secondary to HH.