No abstract

Thyroid cancer is rare, but it is the most frequent endocrine malignancy. Its prognosis is generally favorable, especially in cases of well-differentiated thyroid cancers (DTCs), such as papillary and follicular cancers, which have survival rates of approximately 95% at 40 years. However, 15-20% of cases became radioiodine refractory (RAI-R), and until now, no other treatments have been effective. The same problems are found in cases of poorly differentiated (PDTC) and anaplastic (ATC) thyroid cancers and in at least 30% of medullary thyroid cancer (MTC) cases, which are very aggressive and not sensitive to radioiodine. Tyrosine kinase inhibitors (TKIs) represent a new approach to the treatment of advanced cases of RAI-R DTC, MTC, PDTC, and, possibly, ATC. In the past 10 years, several TKIs have been tested for the treatment of advanced, progressive, and RAI-R thyroid tumors, and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC and vandetanib and cabozantinib for MTC. The objective of this review is to present the current status of the treatment of advanced thyroid cancer with the use of innovative targeted therapies by describing both the benefits and the limits of their use based on the experiences reported so far. A comprehensive analysis and description of the molecular basis of these therapies, as well as new therapeutic perspectives, are reported. Some practical suggestions are given for both the choice of patients to be treated and their management, with particular regard to the potential side effects.

Context The dramatic rise in the incidence of thyroid cancer over the last 30 years is largely attributable to the increasing diagnosis of papillary microcarcinomas (mPTCs). Current guidelines endorse an observational management approach in properly selected cases. Objective To evaluate the feasibility of active surveillance in mPTC in Italy, its impact on real life, and to identify risk factors of progression. Design and setting In 2014 we started a prospective–observational study of active surveillance in mPTC patients. Patients Included patients demonstrated a single Thy4 or Thy5 thyroid nodule, with largest diameter ≤1.3 cm, and no suspicious laterocervical lymph nodes by neck ultrasonography. Of 185 eligible subjects, 50.3% (93/185) enrolled in the observational management protocol while the others opted for surgery and were excluded from this analysis. Intervention Enrolled patients were followed with neck ultrasound at 6- to 12-month intervals. Disease progression was defined as the appearance of abnormal lymph nodes or nodule enlargement during follow-up. In these cases, patients were directed to surgery. Results Three patients (3/93, 3%) showed clinical progression and required surgery. Another 19 patients (19/93, 20%) decided to transition to surgical intervention even though there was no evidence of disease progression. All operated patients had excellent response to initial treatment despite the delayed surgery. Conclusions Within an Italian medical context, active surveillance appears to be a feasible and safe alternative to immediate surgery in healthy mPTC patients. Only 3% of mPTC demonstrated disease progression during a median follow-up of 19 months (range 6–54) and importantly demonstrated excellent outcomes after surgical intervention in a short-term follow-up.

Aims To evaluate the patients' perceptions of telemedicine visits during COVID-19 lockdown and their level of anxiety about COVID and diabetic foot (DF). Methods In May 2020, we contacted by phone all the patients who underwent in March and April to remote monitoring visits for DF during the lockdown for COVID-19, with a structured interview, focusing on their perceptions about telemedicine service for DF and on the anxiety toward COVID and DF. Results We analyzed 257 remote monitoring visits in 211 patients. Two hundred and six patients answered the follow-up interview; 177 patients (85.9%) remembered the monitoring visit, 140 (67.9%) the health care professional and 181 patients (87.9%) the reason of contact; 169 patients were alone during the visit, 37 with a relative. Patients judged useful both the monitoring during pandemic (4.35 ± 0.28 on a maximum of five) and the possibility to continue after the lockdown (4.34 ± 0.23 on a maximum of five). Eventually, we observed that DF patients were more worried by DF than by COVID on a scale from 0 (not fear at all) to 5 (terrified) (4.79 ± 0.05 vs. 3.27 ± 1.03, p < 0.05). This difference was higher in previously ulcerated patients (4.84 ± 0.03 vs. 3.03 ± 1.13, p < 0.05) and even more in amputees (4.93 ± 0.03 vs. 2.73 ± 1.21, p < 0.05). Conclusions DF patients appreciated televisits during lockdown and the continuation of this service after its end. In this context DF prevails on COVID in the worries of patients, especially if they are recurrent ones. Keywords Diabetic foot • COVID • Follow-up • PandemicThis article belongs to the topical collection Health Education and Psycho-Social Aspects, managed by Massimo Porta and Marina Trento.

Lenvatinib is a small oral molecule able to inhibit three of the extracellular and intracellular molecules involved in the modulation of angiogenesis and lymphangiogenesis: vascular endothelial growth factor receptor 1–3, fibroblast growth factor receptor 1–4, and platelet-derived growth factor receptor alpha. Since it is also able to inhibit the REarranged during Transfection oncogene and the protooncogene c-KIT, this drug can also be used to control tumor cell proliferation. The maximum tolerated dose, as demonstrated in Phase I studies, is 25 mg daily. The drug is rapidly absorbed with maximum concentrations achieved within 3 and 5 hours after administration in fasting and nonfasting treated patients, respectively. The most common adverse events, reported in Phase I study and confirmed in the subsequent Phase II and III studies, are hypertension, proteinuria, and gastrointestinal symptoms such as nausea, diarrhea, and stomatitis. In Phase I studies, efficacy of lenvatinib in solid tumors was demonstrated, and these encouraging results have led to the development of a Phase II study using lenvatinib in advance radioiodine-refractory differentiated thyroid cancer (DTCs) patients. Since an overall response rate of 50% was reported, this study also confirmed the efficacy of lenvatinib in DTCs patients with an acceptable toxicity profile. Recently, a Phase III study in patients with DTCs (SELECT study) demonstrated the lenvatinib efficacy in prolonging progression-free survival with respect to the placebo (18.3 vs 3.6 months; P<0.001). Although there was no statistically significant difference in the overall survival of the entire group, this result was observed when the analysis was restricted to both the follicular histotype and the group of senior patients (>65 years). The study confirmed that the most common side effects of this drug are hypertension, diarrhea, decreased appetite, weight loss, nausea, and proteinuria. In this review, we report the results of the main studies on lenvatinib efficacy in patients with advanced and progressive thyroid cancer, mainly in DTCs but also in medullary and anaplastic thyroid cancer. We also compared the efficacy of lenvatinib with that of other tyrosine kinase inhibitors, mainly sorafenib, already tested in the same type of patient population.

To our knowledge, this is the first study analyzing a possible involvement of RET, BRAF and RAS oncogene mutations in PTC/MTC. These data clearly suggest that the classical activating mutations of the oncogenes commonly involved in the pathogenesis of PTC and MTC may not be responsible for their simultaneous occurrence.

Long-term outcomes are similar in DTC patients treated with 1.1 GBq (30 mCi) ¹³¹I and prepared either with rhTSH or endogenous TSH. It is of interest that serum thyroglobulin at first control after ablation can have a prognostic role.

Anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC) are very aggressive cancers whose histological diagnosis is not always straightforward. Clinical, pathological and genetic features may be useful to improve the identification of these rare histotypes. In the present study the clinical, pathological and genetic features of two groups of ATC (n=21) and PDTC (n=21) patients were analyzed. Clinical data were retrieved from a computerized database. The oncogenic profiles were studied using the Sanger sequencing method of a selected series of oncogenes and/or tumor suppressor genes known to be altered in these tumors. The presence of macrophages in both series of tissues was evaluated by immunohistochemistry. Patients with ATC were older and affected by a more advanced disease at diagnosis than those with PDTC. The median survival was significantly shorter in ATC compared with PDTC patients (P=0.0014). ATC showed a higher prevalence of TP53 and TERT mutations (10/21, 47.6% and 9/21, 42.8%, respectively) while TERT and BRAF mutations were the most prevalent in the PDTC group (7/21, 33.3% and 4/23, 19% respectively). Genetic heterogeneity (i.e., >2 mutations) was more frequent in ATC (10/21, 28.6%) compared with in PDTC (3/21, 4.7%) (P=0.03). Macrophages were more frequently present in ATC, particularly in those cases with TP53 mutations. In conclusion, these data indicate that ATC and PDTC may be characterized by different clinical, pathological and genetic profiles. In particular ATC, but not PDTC, were positive for TP53 and PTEN alterations. Complex mutations were also found in ATC but not in PDTC. Moreover, genetic heterogeneity was more frequent in ATC than PDTC. Finally, TP53 mutation and the accumulation of several mutations correlated with a shorter survival time.