Background Limited data suggest that treatment with statins is associated with a reduced risk of Graves’ orbitopathy (GO) in patients with Graves’ disease (GD), attributed to the anti-inflammatory rather than to the hypolipemic effects of these medications. The aim of the present study was to investigate whether there is an association between high cholesterol and GO. The primary outcome was the relation between GO and low-density lipoprotein (LDL)-cholesterol. The secondary outcomes were the relation between severity or activity [the clinical activity score (CAS)] of GO and LDL-cholesterol. Methods We conducted a cross-sectional investigation in consecutive patients with GD who came to our observation to undergo radioiodine treatment, a stratification aimed at forming two distinct groups of patients under the same conditions. We enrolled 250 patients, 133 with and 117 without GO. Ophthalmological assessments and serum lipids measurements were performed. Results In multivariate analyses with correction for the duration of hyperthyroidism, a variable that differed between patients with respect to the presence or absence of GO, a correlation between the presence of GO and both total (P=0.01) and LDL-cholesterol (P=0.02) was observed. In patients with hyperthyroidism lasting <44 months, total and LDL-cholesterol were higher (P=0.01 and P=0.008, respectively) among GO patients. In this subgroup, based on the presence/absence of GO, we established cut-off values for total (191 mg/dl) and LDL-cholesterol (118.4 mg/dl), above which an increased risk of GO was observed (total cholesterol RR: 1.47; P=0.03; LDL-cholesterol RR: 1.28; P=0.03). GO severity and CAS did not correlate with serum lipids. However, CAS was found to be higher (P=0.02) in patients with high total cholesterol. When the analysis was restricted to untreated GO patients, we found a correlation between CAS and both total (P=0.04) and LDL-cholesterol (P=0.03), after adjustment for GO duration. Conclusions In patients with a short duration of hyperthyroidism, total and LDL-cholesterol correlate with the presence of GO, suggesting a role of cholesterol in the development of GO. Depending on GO duration, total and LDL-cholesterol correlate with GO activity, suggesting a role of cholesterol in the clinical expression of GO.

Background and aim: Recent preclinical studies have confirmed that inhibiting the MAP kinase pathway can induce the re-differentiation of radioiodine (RAI)-refractory (RAIR) follicular cell thyroid cancers (TCs). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myo-inositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells. Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into two groups: (1) a control group in which patients are treated with KIs (subgroup a: trametinib plus dabrafenib; subgroup b: lenvatinib); (2) a group in which patients (divided into the two subgroups) are treated with the same KIs in addition to MI. After 30 days of MI treatment, all patients, treated with levothyroxine (L-T4) at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). On day 35, the patients will be subjected to whole-body scintigraphy, with hybrid imaging where possible (SPECT/CT), after the administration of diagnostic activity (185–222 MBq of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0); after 30 days of MI therapy; and then on days 31, 32, 33, 34, and 35 after MI therapy. Quality of life (QoL) will be assessed at the beginning of the MI treatment and at the end of its administration. The primary endpoint is the restoration of 123-I uptake in RAIR-TC patients already on KI therapy alone and on KI therapy plus MI. The restoration of 123-I uptake in target lesions will be evaluated. Conclusions: MI may have a synergistic effect at the cellular level, and the possible increase in the re-differentiation of RAIR-TC in patients treated with KIs plus MI may have great clinical relevance. The re-uptake of RAI will be evaluated as the primary endpoint, and Tg values and QoL will be evaluated as the secondary endpoints. The main limitation of this study is that we do not investigate any clinical effects. We will have to postpone the clinical analysis to a later date after the administration of RAI for therapeutic purposes.

Background and aim: Recently pre-clinical studies have confirmed that the inhibition of the MAP kinase pathway can induce re-differentiation of radioiodine refractory(RAIR) follicular-cell thyroid cancers (TC). The aim of this trial is to investigate whether the combination of kinase inhibitors (KIs) with myoinositol (MI) can induce or potentiate the re-uptake of RAI in cancer cells Overview and methods: This is an open label, non-pharmacological, multicenter, randomized pilot study. Patients will be divided into 2 groups: a) a control group in which patients are treated with KIs (T plus D or L); b) a group, in which patients are treated with the same KI and in addition with MI. After 30 days of MI treatment, all patient, treated with L-T4 at a semi-suppressive dosage as per clinical practice, will be stimulated with recombinant human TSH (rhTSH) (days 31 and 32). Then at day 35 patients will be submitted to whole-body scintigraphy, with hybrid imaging where possible (SPECT/TC), after administration of the diagnostic activity (185-222 MBq) of 123-I in accordance with the SNMMI/EANM guidelines. Blood samples will be collected before starting MI therapy (day 0), after 30 days of MI therapy and then at days 31, 32, 33, 34 and 35 after MI therapy. QoL will be assessed at beginning of the MI treatment and at the end of its administration. The primary endpoint is to evaluate the restoration of the 123 uptake in RAIR follicular cell-derived TC patients already on KIs therapy alone and on KIs therapy plus MI. Restoration of the 123 uptake will be evaluated in target lesions. Conclusions: The study evaluates the possible re-differentiation of RAIR cell-derived TC in patients treated with KIs plus MI. The re-uptake of iodine will be evaluated as the primary end point, and Tg values and QoL will be evaluated as the secondary end points. The main limitation of the study is that we do not investigate any clinical effects. We will have to post-pone the clinical analysis to a later date after the administration of RAI for therapeutic purposes.