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La sopravvivenza del paziente con carcinoma tiroideo peggiora in presenza di metastasi a distanza. L’osso, dopo il polmone, rappresenta la sede di metastatizzazione piu frequente e il suo interessamento puo incidere negativamente anche sulla qualita di vita del paziente, causando dolore, fratture e/o compressione del midollo spinale. La gestione dei pazienti con metastasi ossee deve essere discussa in ambito multidisciplinare per garantire una diagnosi precoce, una precisa definizione dell’estensione di malattia e il miglior trattamento possibile. La fattibilita di terapie locali (chirurgia, radioterapia esterna, terapie percutanee) va sempre verificata con i rispettivi specialisti di riferimento. Le terapie farmacologiche con agenti anti-riassorbitivi possono essere utilizzate allo scopo di stabilizzare le lesioni e prevenire gli eventi correlati alla presenza delle lesioni come il dolore osseo e le fratture patologiche. Infine, ove indicato, occorre identificare il trattamento sistemico piu indicato (terapia radiometabolica con 131I o inibitori delle tirosin-chinasi). La discussione del singolo caso nell’ambito di un gruppo multidisciplinare oncologico risulta imprescindibile per l’ottimale gestione del paziente con metastasi ossee.

PurposeSevere acute respiratory syndrome coronavirus 2 (SARS-Cov-2) is challenging health systems all over the world. Cancer patients have a higher risk of being infected by SARS-Cov-2 and higher coronavirus disease 2019 (COVID-19) severity and mortality. Up to date, there were no data about COVID-19 in patients with thyroid cancer (TCs). The aim of the study was to describe the prevalence of COVID-19 in a well-characterized series of TC patients evaluated for the persistence of the neoplastic disease from March to September 2020; as secondary objective, we looked for the COVID-19 disease severity in a subgroup of multimetastatic TC patients.MethodsWe evaluated 1464 patients affected by persistent TC: 67 patients who were taking multikinase inhibitors (MKIs) and 1397 under active surveillance for a persistent but stable disease. During the clinical evaluation, all patients were specifically investigated about a positive history of Sars-Cov-2 infection.ResultsSARS-Cov-2 infection was identified in 4/1464 (0.3%) cases of patients affected by TC. We identified three cases among patients under active surveillance (0.2%), and one case among patients treated with MKI systemic therapy (1/67, 1.5%). This patient was taking vandetanib for metastatic medullary thyroid cancer (MTC), when he came to our attention referring severe fatigue, dyspnea for light physical activities. He presented a mild COVID-19 and he received exclusively supportive care. After a multidisciplinary consultation, we decided against the discontinuation of vandetanib. After 2 months from the infection, he did not present any signs of active infection, and the MTC metastatic disease was stable.ConclusionsWe showed that COVID-19 is not more frequent in TC patients than in general population, although a relatively higher prevalence in the group of TC patients treated with MKIs. A single patient with advanced TC and SARS-Cov-2 infection during MKIs treatment had a mild COVID-19 and did not require the discontinuation of MKI therapy. In cases of more severe COVID-19, an accurate evaluation from a multidisciplinary team would consider risks and benefits in taking the decision to continue or stop MKI treatment.

In the last decade, multikinase inhibitors (MKIs) have changed the paradigm of treatment of advanced and progressive thyroid cancer. Compared with the traditional treatment with chemotherapy and radiotherapy, these new drugs have shown a good efficacy in controlling the neoplastic disease, and also a different toxicity profile compared to traditional chemotherapy, milder but still present and involving mainly the nutritional profile. Weight loss, nausea, anorexia, stomatitis, diarrhea may be associated with malnutrition and cancer-related cachexia. The latter is characteristic of the advanced cancer stage and may be present before starting MKIs, or may develop afterwards. Adverse events with nutritional impact may cause a significant impairment of quality of life, often requiring dose reduction and sometimes drug discontinuation, but with a lower efficacy on the neoplastic disease. The aim of this paper was to discuss the role of nutritional therapy in advanced thyroid cancer and the importance of prevention, early recognition and careful management of malnutrition and cachexia during systemic therapy with MKIs.

Multiple Endocrine Neoplasia 2 (MEN2) is a hereditary cancer syndrome for developing medullary thyroid cancer (MTC) due to germline mutations of RET gene. Subjects harboring a germline RET mutation without any clinical signs of MTC are defined as gene carriers (GCs), for whom guidelines propose a prophylactic thyroid surgery. We evaluate if active surveillance of GCs, pursuing early thyroid surgery, can be safely proposed and if it allows safely delaying thyroid surgery in children until adolescence/adulthood. We prospectively followed 189 GCs with moderate or high risk germline RET mutation. Surgery was planned in case of: elevated basal calcitonin (bCT) and/or stimulated CT (sCT), surgery preference of subjects (or parents, if subject less than 18 years old), other reasons for thyroid surgery. Accordingly, at RET screening, we sub-grouped GCs in subjects who promptly were submitted to thyroid surgery (Group A, n = 67) and who were not (Group B, n = 122). Group B was further sub-grouped in subjects who were submitted to surgery during their active surveillance (Group B1, n = 22) and who are still in follow-up (Group B2, n = 100). Group A subjects presented significantly more advanced age, bCT and sCT compared to Group B. Mutation RETV804M was the most common variant in both groups but it was significantly less frequent in Group A than B. Analyzing age, bCT, sCT and genetic landscape, Group B1 subjects differed from Group B2 only for sCT at last evaluation. Group A subjects presented more frequently MTC foci than Group B1. Moreover, Group A MTCs presented more aggressive features (size, T and N) than Group B1. Accordingly, at the end of follow-up, all Group B1 subjects presented clinical remission, while 6 and 12 Group A MTC patients had structural and biochemical persistent disease, respectively. Thank to active surveillance, only 13/63 subjects younger than 18 years at RET screening have been operated on during childhood and/or adolescence. In Group B1, three patients, while actively surveilled, had the possibility to reach the age of 18 (or older) and two patients the age of 15, before being submitted to thyroid surgery. In Group B2, 12 patients become older than 18 years and 17 older than 15 years. In conclusion, we demonstrated that an active surveillance pursuing an early thyroid surgery could be safely recommended in GCs. This patient-centered approach permits postponing thyroid surgery in children until their adolescence/adulthood. At the same time, we confirmed that genetic screening allows finding hidden MTC cases that otherwise would be diagnosed much later.

Differentiated thyroid cancers (DTC) are commonly and successfully treated with total thyroidectomy plus/minus radioiodine therapy (RAI). Medullary thyroid cancer (MTC) is only treated with surgery but only intrathyroidal tumors are cured. The worst prognosis is for anaplastic (ATC) and poorly differentiated thyroid cancer (PDTC). Whenever a local or metastatic advanced disease is present, other treatments are required, varying from local to systemic therapies. In the last decade, the efficacy of the targeted therapies and, in particular, tyrosine kinase inhibitors (TKIs) has been demonstrated. They can prolong the disease progression-free survival and represent the most important therapeutic option for the treatment of advanced and progressive thyroid cancer. Currently, lenvatinib and sorafenib are the approved drugs for the treatment of RAI-refractory DTC and PDTC while advanced MTC can be treated with either cabozantinib or vandetanib. Dabrafenib plus trametinib is the only approved treatment by FDA for BRAFV600E mutated ATC. A new generation of TKIs, specifically for single altered oncogenes, is under evaluation in phase 2 and 3 clinical trials. The aim of this review was to provide an overview of the current and future treatments of thyroid cancer with regards to the advanced and progressive cases that require systemic therapies that are becoming more and more targeted on the molecular identity of the tumor.

Context 18F-fluoro-2-deoxy-D-glucose positron emission tomography–computed tomography ([18F]-FDG-PET/CT)–positive metastatic lesions in radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) have a poor prognosis and lenvatinib represents the best therapy. Objective We investigated the role of [18F]-FDG-PET/CT in the evaluation of metabolic response and prediction of the outcome of RAI-R DTC patients treated with lenvatinib. Methods Patients (n = 33) with progressive metastatic RAI-R DTC who were treated with lenvatinib were investigated at baseline and during follow-up with biochemical (thyroglobulin and thyroglobulin antibodies), morphological (whole-body CT scan) and metabolic ([18F]-FDG-PET/CT) evaluation. Results Nineteen (57.6%) patients showed the greatest metabolic response at the first [18F]-FDG-PET/CT scan, performed after 4 weeks of lenvatinib, while 5/33 (15.1%) patients had this response later. Moreover, 66.7% of patients had both a metabolic response at the first [18F]-FDG-PET/CT scan and a morphological response at the first CT scan. We observed a correlation between the metabolic response at [18F]-FDG-PET/CT scan performed after 4 weeks of treatment and the biochemical response at the same time in 60.6% of patients. The median overall survival (OS) was significantly longer in patients with either a metabolic response at last [18F]-FDG-PET/CT (40.00 vs 8.98 months) or a morphological response at last CT scan (37.22 vs 9.53 months) than in those without response. Moreover, the OS was longer in patients with a metabolic response at [18F]-FDG-PET/CT performed after 4 weeks of treatment (36.53 vs 11.28 months). Conclusions Our data show that [18F]-FDG-PET/CT can early predict the response to lenvatinib and correlates with the OS of RAI-R DTC patients treated with this drug.

The pyridobenzoxazepine compound, 5-(4-methylpiperazin-1-yl)-8-chloro-pyrido[2,3-b][1,5]benzoxazepine (JL13), has been developed as a potential antipsychotic drug. We tested the hypothesis that JL13 is efficacious in both dopaminergic and glutamatergic animal models of schizophrenia. We investigated JL13 for its efficacy to prevent cocaine- and ketamine-induced hyperlocomotion and MK-801-induced deficits in prepulse inhibition (PPI) of the startle reflex. Male Swiss mice received injections of JL13 (0.1-10 mg/kg) and were tested in the open field for basal locomotion. In separate experiments, the animals received injections of JL13 (0.1-3 mg/kg) followed by cocaine (10 mg/kg), ketamine (60 mg/kg), or MK-801 (0.5 mg/kg) and were tested in the open field for hyperlocomotion. In addition, it was also tested if JL13 prevented MK-801-induced disruption of PPI. Only the highest dose of JL13 impaired spontaneous locomotion, suggesting its favorable profile regarding motor side effects. At doses that did not impair basal motor activity, JL13 prevented cocaine-, ketamine-, and MK-801-induced hyperlocomotion. Moreover, JL13 prevented MK-801-induced disruption of PPI. Extending previous findings, this study shows that JL13 exerts antipsychotic-like activity in both dopaminergic and glutamatergic models. This compound has a favorable pharmacological profile, similar to second-generation antipsychotics.

Patients with advanced progressive metastatic medullary thyroid cancer (MTC), show poor prognosis and few available systemic therapeutic options. After the loss of clinical benefit with other tyrosine kinase inhibitors (TKI), we evaluated the use of lenvatinib as salvage therapy. Ten patients who experienced the loss of clinical benefit after treatment with at least one previous TKI, were treated with lenvatinib. We assessed patient’s response immediately before, at the first (first-EV) and last (last-EV) evaluation, after the beginning of treatment. At first-EV, one patient died, while all the remaining 9 showed a stable disease (SD) in the target lesions. At last-EV, SD was still observed in seven patients, while partial response (PR) and progressive disease (PD), in one patient each. Conversely, analyzing all target and non-target lesions, at first-EV, we observed PR in one patient and SD in eight patients. At last-EV, PR was shown in two patients and SD was shown in seven. Bone metastases showed stable disease control at both first-EV and last-EV in only approximately 60% of cases. Tumor markers (CTN and CEA) decreased at first-EV, while they increased at last-EV. Seven patients experienced at least one dose reduction during treatment with lenvatinib. In this real-life clinical experience, lenvatinib showed interesting results as salvage therapy in patients with advanced progressive metastatic MTC patients. Its usefulness could be effective in patients without any other available treatment, because previously used or unsuitable, especially with negative RET status with no access to the new highly selective targeted therapies.

For women with previous gestational diabetes (GDM), international guidelines recommend 75 g oral glucose tolerance test (OGTT) at 4-12 weeks after delivery to assess glucose tolerance, considering their increased risk of type 2 diabetes. We evaluated prevalence of postpartum impaired glucose regulation (IGR) and identified associated risk factors.We retrospectively collected data from 749 women with previous GDM (IADPSG criteria) who underwent postpartum OGTT for type 2 diabetes screening between 2011 and 2019. IGR was identified according to ADA criteria.Prevalence of IGR was 12.7%, lower in women with pre-pregnancy normal weight, higher in women with family history of type 2 diabetes and in those treated with insulin during pregnancy. Prevalence of IGR raised with increasing number of altered glucose values at OGTT performed during pregnancy for GDM screening. HbA1c and triglycerides measured during the third trimester of pregnancy were higher in women with postpartum IGR. At postpartum screening, women with IGR had higher BMI, waist, blood pressure. At multivariate logistic regression analysis, family history of diabetes (OR 2.21; 95% CI: 1.33-3.69; p 0.01) and presence of all three glucose values exceeding threshold at OGTT during pregnancy (OR 2.89; 95% CI: 1.42-5.86; p 0.01) were independently associated with IGR.In women with GDM, persistence of IGR in the immediate postpartum period is associated with family history of diabetes and the presence of all three glucose values exceeding diagnostic threshold for GDM at OGTT in pregnancy, suggesting that these women should undergo specific diabetes monitoring and prevention programs.

Simple Summary In the last decades, many researchers produced promising data concerning genetics and tumor microenvironment of poorly differentiated thyroid cancer (PDTC) and anaplastic thyroid cancer (ATC). They are trying to tear the veil covering these orphan cancers, suggesting new therapeutic weapons as single or combined therapies. Abstract PDTC and ATC present median overall survival of 6 years and 6 months, respectively. In spite of their rarity, patients with PDTC and ATC represent a significant clinical problem, because of their poor survival and the substantial inefficacy of classical therapies. We reviewed the newest findings about genetic features of PDTC and ATC, from mutations occurring in DNA to alterations in RNA. Therefore, we describe their tumor microenvironments (both immune and not-immune) and the interactions between tumor and neighboring cells. Finally, we recapitulate how this upcoming evidence are changing the treatment of PDTC and ATC.