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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.

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.

Introduction: Tyrosine kinase inhibitors represent a better treatment in patients with radioiodine-refractory differentiated thyroid cancer (RAI-R DTC). Lenvatinib is usually well-tolerated, but sometimes, it is associated with serious and even life-threatening side effects. The aim of this study was to evaluate the prevalence of and the potential risk factors for fistula and/or organ perforation in RAI-R DTC patients treated with lenvatinib. Methods: This study included data from advanced and progressive RAI-R DTC patients treated with lenvatinib from February 2011 to February 2020 who were followed up at a single center. The clinical-pathological features and the biochemical and morphological results of the patients were collected at the time of starting lenvatinib and during the follow-up. Results: Fourteen of 95 (14.7%) locally advanced or metastatic RAI-R DTC patients treated with lenvatinib developed a fistula or organ perforation. Nine of 14 (64.3%) patients had tumor infiltration of the trachea, bronchus, esophagus, pleura, or bladder. Five of 14 (35.7%) had a bowel perforation, but only 2 had preexisting diverticulosis. Evaluation of the risk factors for developing a fistula or organ perforation showed that the presence of tumor infiltration and the tumor histology (papillary and poorly differentiated vs. follicular and Hurthle thyroid cancer) were significantly correlated with the development of a fistula or organ perforation (p = 0.003 and p = 0.02, respectively). In the subgroup of patients with tumor infiltration, we found that the papillary thyroid cancer histotype was the only potential predictor of fistula development. External beam radiation therapy (EBRT), the starting dose of lenvatinib, and the duration of treatment were not relevant for the development of fistula. Conclusions: In metastatic thyroid cancer patients treated with lenvatinib, the presence of tumor infiltration and histological type should be considered as potential risk factors for the development of fistula or organ perforation, although they do not represent an absolute contraindication. Although EBRT and the presence of diverticulosis were not significantly associated with the development of fistula and organ perforation, they should be regarded as potential additional reasons for the development of these complications. According to our findings, there is no reason to start lenvatinib at a lower daily dose when tumor infiltration is present.

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.

Context Tumor capsule integrity is becoming a relevant issue to predict the biological behavior of human tumors, including thyroid cancer. Objective This work aims to verify whether a whole tumor capsule in the classical variant of papillary thyroid carcinoma (CVPTC) could have as a predictive role of a good outcome as for follicular variant (FVPTC). Methods FVPTC (n = 600) and CVPTC (n = 554) cases were analyzed. We distinguished between encapsulated-FVPTC (E-FVPTC) and encapsulated-CVPTC (E-CVPTC) and, thereafter, invasive (Ei-FVPTC and Ei-CVPTC) and noninvasive (En-FVPTC and En-CVPTC) tumors, according to the invasion or integrity of the tumor capsule, respectively. Cases without a tumor capsule were indicated as invasive-FVPTC (I-FVPTC) and invasive-CVPTC (I-CVPTC). The subgroup of each variant was evaluated for BRAF mutations. Results E-FVPTC was more frequent than E-CVPTC (P Conclusion En-CVPTC is less prevalent than En-FVPTC. However, it has good clinical/ pathological behavior comparable to En-FVPTC. This finding confirms the good prognostic role of a whole tumor capsule in CVPTC as well. New nomenclature for En-CVPTC, similar to that introduced for En-FVPTC (ie, noninvasive follicular thyroid neoplasm with papillary-like nuclear features; NIFTP) could be envisaged.

Background: Lenvatinib, a multikinase inhibitor, is for progressive radioiodine-refractory-differentiated thyroid cancer (RR-DTC) patients. However, there are a lot of drug-related adverse events (AEs) that can affect the quality of life (QoL) of patients. The aims of this study were (a) to evaluate, and compared with other series, the safety of lenvatinib used in RR-DTC patients enrolled in an Italian expanded access program (EAP), and (b) to evaluate their QoL during treatment with lenvatinib. Methods: To evaluate the safety, we recorded and graded all AEs during the 6 months of lenvatinib treatment in 39 RR-DTC patients. We compared the safety profile of lenvatinib observed in our patients with that reported in the study of (E7080) levatinib in differentiated cancer of the thyroid (SELECT) and tumeurs thyroidiennes refractaires (TUTHYREF) network studies. Moreover, we evaluated the QoL in our series by using the European Organization for Research and Treatment (EORTC) Quality of Life Questionnaire-Core 30 and the pain visual analogue scale (VAS). Results: The most frequent AEs among our 39 RR-DTC patients were hypertension (80.5%), fatigue (58.3%), diarrhea (36.1%), stomatitis (33.3%), hand/foot syndrome (33.3%), and weight loss (30.5%). The most prevalent grade 3/4 AE was hypertension (25%). When compared with previous studies (i.e., SELECT and TUTHYREF), a significantly lower percentage of our patients experienced diarrhea, nausea, proteinuria, and weight loss. No statistically significant differences in the QoL of our patients evaluated before, during, and at the end of follow-up (6 months after starting the therapy) were found. However, a slight improvement of the general health and emotional and cognitive status associated with a slightly worsening of physical role and social functioning was observed during these 6 months. Pain, dyspnea, insomnia, and constipation moved toward better values, while fatigue, nausea and vomiting, appetite loss, and diarrhea worsened. By comparing the pain VAS, an overall reduction of the level of pain was found. Conclusions: The safety profile of the drug was similar to that already reported with some differences in the prevalence and severity of the AEs. Regarding the QoL, the EAP showed a trend of improvement of the global health status and a reduction of symptoms correlated to the disease. The clinical impact of fatigue, anorexia/weight loss and stomatitis, mainly due to the drug itself, continues to represent the major issue in the management of these patients.

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.

Background. Multiple endocrine neoplasia type 2 (MEN2) is a hereditary cancer syndrome caused by RET proto-oncogene mutation. Two different clinical variants of MEN2 are known (MEN2A and MEN2B): medullary thyroid carcinoma (MTC) almost always present and associated with pheochromocytoma (Pheo), and primary hyperparathyroidism (HPTH) in MEN2A and with Pheo and other nonendocrine diseases in MEN2B. Case Report. A 7-year-old girl, previously treated for a pelvic plexiform neurofibroma, arrived at our observation with a peculiar MEN2B syndrome and with HPTH. The neck ultrasound showed bilateral thyroid nodules, local lymph node lesions, and a suspicious left hyperplastic parathyroid. The CT scan showed a megacolon and described the persistence of the pelvic tumor. A new RET germline deletion in exon 11 (c.1892_1899delCGAGCT; p.Glu632_Leu633del) was found. She underwent total thyroidectomy, central compartment and latero-cervical lymph node dissection, and neck exploration for primary HPTH. The histology confirmed bilateral MTC, multiple lymph node metastases, a hyperplastic parathyroid, and a parathyroid adenoma. Conclusions. This is the first case of a complex syndrome characterized by peculiar features of MEN2B, without Pheo but with a pelvic plexiform neurofibroma and with HPTH, which is typical of MEN2A. A “de novo” new germline RET deletion located in exon 11 was found.

Background: Our previous retrospective study demonstrated that the absence of tumor capsule or, if present, its invasion were independent risk factors for the persistence of the disease (OR 6.75, CI 1.97-23.08 and OR 7.89, CI 1.78-34.94, respectively) in papillary thyroid cancer (PTC). This data was confirmed also analyzing separately the most frequent PTC variants [follicular variant (FVPTC) and classical variant (CVPTC)]. Moreover, we demonstrated that the absence of tumor capsule was significantly more frequent in FVPTC BRAF V600E mutated than FVPTC wild-type for BRAF gene or with rare-BRAF mutations (e.g., BRAF K601E, BRAF V600_K601delinsE). These data confirmed the importance of the integrity of the tumor capsule in FVPTC which led in 2016 to the definition of a new thyroid neoplasm entity named NIFTP. According to these retrospective data, we have assumed that the integrity of the tumor capsule in CVPTC could have a prognostic role similar to that confirmed in the NIFTP group. Methods: we have prospectively collected data of patients (pts) underwent total thyroidectomy or lobectomy for encapsulated-CVPTC (E-CVPTC) or NIFTP. In both cases the tumor was accurately analyzed by the pathologists according to the criteria used for the NIFTP (in particular with one capsule sample every 1 mm). All pts performed at least one clinical control and neck US within 6 months from surgery. Results: From January 2018 to June 2019, 144 E-CVPTC and 177 NIFTP were prospectively collected. 83/144 (57.6%) E-CVPTC and 106/177 (59.8%) NIFTP cases were included. The others were excluded due to the presence of other thyroid tumors associated in the same gland. No differences in epidemiological and pathological features were found between E-CVPTC and NIFTP except for the tumor size, significantly bigger in NIFTP than E-CVPTC [22±16mm (2-68) vs 8±11mm (1-80), p Conclusions: These prospective data demonstrated that NIFTP and E-CVPTC have a similar clinical behavior in a short-term follow-up, thus suggesting that the presence of an intact tumor capsule is predictive of a good outcome. A longer follow up is needed to confirm these initial interesting findings.

To compare the epidemiological, clinical, and pathological features of follicular (FVPTC) and classical (CVPTC) variants of papillary thyroid cancer and to correlate their outcomes according to different features. Retrospective analysis of FVPTC and CVPTC patients selected at the moment of surgical treatment from 1999 to 2004, with a median follow-up of 15 years. Several significant differences were found between FVPTC and CVPTC such as the mean age at diagnosis, the presence of tumor capsule, the presence of thyroid capsule invasion, the presence of perithyroid soft tissue invasion, the lymph node metastases, the multifocality and bilaterality. At the end of follow-up only 9% (77/879) patients were not cured. However, a statistically significant lower percentage of persistent disease was found in the FVPTC than in the CVPTC group (3% vs. 14.5%, respectively, p

Introduction: Medullary thyroid cancer (MTC) arises from C cells secreting calcitonin. In familial MTC cases, a germline RET mutation is discovered in 98% of cases. Nowadays, an early diagnosis and radical surgery are the only curative approach. However, thyroidectomy in children is associated with a higher rate of surgical adverse events, compared to surgery in adults. The best clinical approach in patient harboring germline RET mutation (gene carriers, GC) is still undefined. Methods and materials: since 1994 to 2018 we identified 174 GC by RET screening. 56 GC underwent total thyroidectomy and lymph node dissection for the evidence of high calcitonin levels at the first clinical evaluation, whereas 27 GC underwent surgery for high stimulated calcitonin levels during the active surveillance (median 16 months, range 13-118). 90 GC are still in follow up. Results: In the group of 27 GC patients who underwent surgery during the active surveillance, 15 GC had only C cells hyperplasia (CCH) foci and 12 were affected by MTC. These carcinomas were all confined to the thyroid, without any lymph node and distant metastasis. All these patients are still in clinical remission, after a median follow-up of 4 years (range 1-11). At time of the surgery, the patients affected by MTC were significantly older than patients harboring only CCH (median 49 vs 30 years old, respectively). Among these 27 GC, 7 were diagnosed as GC when they were younger than 18 years (median 7 years old, range 2-18) and they underwent surgery after a median period of 3 years (range 1-10 years), when they were all older than 7 years. In this group, 6 of 7 were affected by CCH and only one case by a microMTC. There were not any persistent surgical adverse events and all of them are still in clinical remission. 41 of 90 GC, who are still in active surveillance, were younger than 18 years at time of RET screening: nowadays, 10/41 are older than 18 years and 15/41 are older than 14 years, all with calcitonin still in the normal range. Conclusions: we demonstrated that the calcitonin-based thyroidectomy is a safe approach in GC. Intriguingly, this approach seems to be interesting especially in children in order to perform still an early and safe surgery but when they are older, possibly adults.

Objective: Tyrosine kinase inhibitors (TKIs) are used for the treatment of metastatic differentiated (DTC), poorly differentiated (PDTC) and medullary (MTC) thyroid cancer. Several adverse events (AEs) have been reported in almost all patients (pts) treated with TKIs. One of the less known AE related to the use of these drugs is the primary adrenal insufficiency (PAI). Methods: We analyzed the basal and stimulated adrenal function, ACTH levels, adrenal antibodies and electrolytes levels in 82 thyroid cancer pts treated with TKIs (vandetanib and cabozantinib in MTC pts, lenvatinib and sorafenib in DTC and PDTC pts) and we correlated these results with the clinical-pathological features of our pts. Results: In our series, 25/82 (30.5%) pts showed a PAI after stimulation test with a progressive ACTH increase in 14/25 (56%) pts. Thirteen/25 (52%) pts with PAI were DTC, 8/25 (32%) pts were MTC and 4/25 (16%) pts were PDTC. Sixteen/25 (64%) pts were treated with lenvatinib, 8/25 (32%) were treated with vandetanib and 1/25 (4%) was treated with cabozantinib at the time of stimulation test. In 5/25 (20%) pts PAI occurred within 12 months from the TKIs treatment initiation, in 9/25 (36%) within 36 months and in 11/25 (44%) after 36 months of treatment. Eighteen/25 pts with PAI were older than 55 years. Twenty/25 (80%) of these pts were treated with cortisone acetate replacement therapy with the improvement of fatigue in a small part of these while other 5 pts were untreated due to the mild degree of PAI and the absence of specific symptoms (i.e fatigue). Moreover, in our pts the evaluation of adrenal antibodies was negative and the electrolytes levels were in the normal range. We also correlated the presence of PAI with the clinical-pathological features of our pts but we didn’t observe any significant correlation. Conclusions: We observed that PAI, mainly subclinical, can occur during TKIs treatment in thyroid cancer pts. The appearance of fatigue, the typical symptom of PAI, could be multifactorial in these pts due also to the direct effect of TKIs treatment. Thus, in these cases is very difficult to recognize the cause of fatigue and to decide the appropriate treatment (cortisone acetate replacement therapy vs TKIs dose reduction). Moreover, the time of PAI appearance is variable since it can be early (36 months) after TKIs treatment initiation and the adrenal function must be monitored during all TKIs treatment period. More studies are needed to know the pathophysiology of this “adverse event” during TKIs treatment and to improve the acknowledgments regarding the differential diagnosis and treatment of these pts, regardless of symptoms.

Objective: At present, recombinant TSH cannot be used for the treatment of metastatic differentiated thyroid cancer patients. The aim of this study was to evaluate if the type of TSH stimulation, recombinant or endogenous, had an impact on the outcome of these patients. Design and methods: We compared the outcome of two propensity score-matched groups of metastatic patients, stimulated by either only recombinant TSH (n = 43) or only endogenous TSH (n = 34). Results: As expected from the matching procedure, the clinical–pathological features and the cumulative 131-I activities administered to the two groups were very similar. After 4 years of follow-up, 4% of patients were cured, 3% had biochemical disease and 93% had structural disease. However, 91% of patients obtained a clinical benefit from this therapy in terms of stabilization of the disease or complete remission or partial response. When considering the two groups separately, we did not find any difference in their outcome. When considering the response to 131-I therapy of the single type of metastases, 8% of lymph node metastases and 8% of lung metastases disappeared but none of the bone metastases. The response to 131-I therapy of the single type of metastases was similar when we looked at the two groups separately. Conclusions: This study shows (i) an overall clinical benefit of the 131-I therapy, since the majority of patients remained affected but with a stable disease, and (ii) that the preparation with either recombinant or endogenous TSH has no impact on the 131-I therapy efficacy and the outcome of our two groups of patients.

Background: Pathogenic germline mutations affecting the RET proto-oncogene underlie the development of hereditary medullary thyroid carcinoma (MTC). The aims of this study were to evaluate the prevalence of germline RET mutations in a large series of MTC, collected over the last 25 years, and to reappraise their clinical significance. Methods: We performed RET genetic screening in 2031 Italian subjects: patients who presented with sporadic (n = 1264) or hereditary (n = 117) MTC, plus 650 relatives. Results: A RET germline mutation was found in 115/117 (98.3%) hereditary and in 78/1264 (6.2%) apparently sporadic cases: in total, 42 distinct germline variants were found. The V804M mutation was the most prevalent in our cohort, especially in cases that presented as sporadic, while mutations affecting cysteine residues were the most frequent in the group of clinically hereditary cases. All M918T mutations were &ldquo, de novo&rdquo, and exclusively associated with MEN2B. Several variants of unknown significance (VUS) were also found. Conclusions: a) RET genetic screening is informative in both hereditary and sporadic MTC, b) the prevalence of different mutations varies with V804M being the most frequent, c) the association genotype&ndash, phenotype is confirmed, d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

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.

Background Multiple endocrine neoplasia type 2B (MEN 2B) is a very rare syndrome characterized by a very peculiar phenotype with mucosal neuromas, marfanoid habitus, and bumpy lips associated with medullary thyroid cancer (MTC) and pheochromocytoma (PHEO). Although the syndrome was first described 50 years ago, it is still diagnosed too late, when the MTC is metastatic and frequently when the PHEO has already developed. Case presentations We report on two cases of MEN 2B that were diagnosed too late, preventing a cure. The cases involve two females who were 25 and 12 years old. Both were previously treated for congenital skeletal abnormalities; however, despite their bumpy lips and mucosal neuromas, MEN 2B syndrome was not recognized. When they arrived at our center for both the presence of thyroid nodules and elevated serum calcitonin values, the MTC was already metastatic, and the older patient had already developed a bilateral PHEO. After 3 years and 1 year of follow-up, the two patients are still alive but with persistent structural and biochemical disease. Discussion These two cases show that knowledge of this syndrome is still insufficient and that the lack of knowledge impairs the ability to obtain an early diagnosis and cure. Because most patients with MEN 2B have no familial history, the only way to ensure a timely diagnosis is to recognize the MEN 2B phenotype on a clinical basis.

The last ten years have been characterized by the introduction in the clinical practice of new drugs named tyrosine kinase inhibitors for the treatment of several human tumors. After the positive conclusion of two international multicentric, randomized phase III clinical trials, two of these drugs, sorafenib and lenvatinib, have been recently approved and they are now available for the treatment of advanced and progressive radioiodine refractory thyroid tumors. We have been involved in most clinical trials performed with different tyrosine kinase inhibitors in different histotypes of thyroid cancer thus acquiring a lot of experience in the management of both drugs and their adverse events. Aim of this review is to give an overview of both the rationale for the use of these inhibitors in thyroid cancer and the major results of the clinical trials. Some suggestions for the management of treated patients in the real life are also provided.

L’ablazione con radioiodio (RRA) in pazienti con carcinoma differenziato della tiroide a rischio basso/intermedio e un argomento di acceso dibattito sia per l’attivita di 131I che per la modalita di preparazione [ipotiroidismo vs eutiroidismo con TSH umano ricombinante (rhTSH)]. Recentemente e stato dimostrato che la percentuale ablativa era simile in pazienti preparati con rhTSH o in ipotiroidismo e trattati con alte o basse attivita di 131I. E stato inoltre dimostrato che la modalita di preparazione alla RRA non determinava alcuna differenza nello stato finale di malattia a 10 anni dal trattamento, eliminando cosi ogni esitazione sull’affidabilita della RRA con rhTSH e basse attivita di 131I.

Background: No long-term follow-up data are available for differentiated thyroid carcinoma (DTC) patients prepared with either exogenous or endogenous TSH and treated with low-activity (1.1 GBq [30 mCi]) radioiodine (131I). Aim: The aim of this study was to evaluate the 10-year follow-up of DTC patients who underwent remnant ablation with 1.1 GBq 131I after l-T4 withdrawal, recombinant human TSH (rhTSH) administration, or both. Patients: A total of 159 DTC patients treated with total thyroidectomy and 1.1 GBq (30 mCi) of 131I for remnant ablation and stimulated with rhTSH and/or endogenous TSH were separated into ablated (n = 115) and not ablated (n = 44) patients and prospectively followed-up for at least 10 years. In addition, we evaluated several features that could correlate with the final status of patients. Results: During the follow-up, 4 of 115 (3.5%) ablated patients showed a recurrence and 1 was successfully cured. Among not ablated patients, 16 of 44 (36.4%) had a persistent disease. At the end...

Thyroid cancer typically has a good outcome following standard treatments, which include surgery, radioactive iodine ablation for differentiated tumours and treatment with thyrotropine hormone-suppressive levothyroxine. Thyroid cancers that persist or recur following these therapies have a poorer prognosis. Cytotoxic chemotherapy or external beam radiotherapy has a low efficacy in these patients. 'Target therapy' with tyrosine kinase inhibitors (TKIs) represent an important therapeutic option for the treatment of advanced cases of radioiodine refractory (RAI-R) differentiated thyroid cancer (DTC), medullary thyroid cancer (MTC) and possibly for cases of poorly differentiated (PDTC) and anaplastic thyroid cancer (ATC). In the last few years, several TKIs have been tested for the treatment of advanced, progressive and RAI-R thyroid cancers and some of them have been recently approved for use in clinical practice: sorafenib and lenvatinib for DTC and PDTC; vandetanib and cabozantinib for MTC. The objective of this overview is to present the current status of the treatment of advanced DTC, MTC, PDTC and ATC with the use of TKIs by describing the benefits and the limits of their use. A comprehensive analysis and description of the molecular basis of these drugs and the new therapeutic perspectives are also reported. Some practical suggestions are also given for the management to the potential side-effects of these drugs.

Evidence for an increased prevalence of BRAF(V600E) mutations has been documented in recent decades. The aim of this study was to evaluate the prevalence of both RET/PTC rearrangements and BRAF(V600E) mutations in an Italian cohort of papillary thyroid carcinoma (PTC) patients followed at the Endocrine Units of Pisa, Milano, and Perugia from 1996-2010.In total, 401 PTC patients were examined and grouped according to the time of surgery: group 1, 1996-2000; group 2, 2001-2005; and group 3, 2006-2010. Patients were analyzed for clinical, pathological, and molecular features. In parallel, the molecular characteristics of 459 PTC from Sicily were studied.The genetic profiles of the three groups were significantly different (P0.0001). In particular, the frequency of RET/PTC rearrangements decreased from 1996-2010, occurring in 33 of 100 (33%) of the patients in group 1, 26 of 148 (17%) in group 2, and 15 of 153 (9.8%) in group 3. The incidence of BRAF(V600E) mutations increased over the same period, from 28% in group 1 (28 of 100) to 48.9% in group 2 (73 of 148) and 58.1% in group 3 (89 of 153). A consistent increase in BRAF(V600E) prevalence was observed in the Sicilian group (P0.0001). Moreover, a statistically significant increase in the mean age at diagnosis and decrease in tumor size over the study period was observed.The genetic profile of PTC changed over the last 15 yr, with a significant decrease in the prevalence of RET/PTC rearrangements and an increase in BRAF(V600E) mutations. In addition, the mean age at diagnosis increased and tumor size decreased over the study period.

We present the case of a male patient who presented with what appeared to be sporadic medullary thyroid cancer (MTC) but, with RET genetic screening that revealed a germline Ser891Ala mutation, was actually a familial case. He was initially treated with surgery that was ineffective in obtaining cure of disease, as one could expect since several lymph node metastases were already present at the time of diagnosis. After 2 years of good health and stable disease, because of the development of a severe diarrhea, the patient was enrolled in a clinical phase II trial with motesanib, the first tyrosine kinase inhibitor tested in MTC patients. Unfortunately, after a few months, the drug had to be discontinued because of the development of drug-related side effects. After a 7-year period of stabilization of the disease, a rapid growth of lung and lymph node lesions was observed and the patient was treated with vandetanib. After a few weeks of therapy, he developed severe erythroderma related to sunlight exposure. The drug was stopped followed, 2 weeks later, by complete resolution of the skin lesions. The drug was restarted at a lower dose, and a balance between tumor growth control and the side effects was attained. The patient is still receiving vandetanib and his quality of life remains good.

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; P65 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.

La maggior parte dei pazienti con carcinoma tiroideo guarisce con i trattamenti convenzionali (chirurgia e iodio radioattivo). Tuttavia, alcuni tumori tiroidei sono resistenti al radioiodio, perche perdono le caratteristiche della cellula follicolare da cui originano o perche originano dalle cellule C (carcinoma midollare della tiroide). Fino al 2011 nessuna terapia efficace era approvata per il trattamento di queste neoplasie. Di recente, una nuova classe di farmaci, gli inibitori tirosino-chinasici, che agiscono sul prodotto degli oncogeni che determinano lo sviluppo tumorale (es. BRAF V600E e RET) e sui recettori che favoriscono la proliferazione dell’endotelio vascolare (es. VEGFRs), ha offerto nuove prospettive terapeutiche per i pazienti con malattia avanzata e in progressione.

Background Minimally invasive video-assisted thyroidectomy (MIVAT) proved to be safe and effective in the treatment of both benign and malignant disease. The aim of the present study is to compare MIVAT approach with conventional approach for total thyroidectomy in a group of 99 pediatric patients operated in the Department of General Surgery of the University of Pisa between March 2007 and July 2012. Patients A total of 99 pediatric patients under the age of 18 years with thyroid disease referred to our Department to undergo total thyroidectomy. Patients were divided into two groups according to the surgical technique performed: 34/99 (34.3%) patients (MIVAT group [MG]) and 65/99 (65.7%) patients, (conventional group [CG]) who underwent total thyroidectomy, respectively, with MIVAT approach and conventional approach. Results In MG mean operative time for total thyroidectomy was 40 ± 6.57 minutes (range 30–60 min); postoperative hospital stay was 1 day for 18 patients (53%), 2 days for 12 patients (35.25%), 3 days for 4 patients (11.8%); transient hypoparathyroidism (hypoPTH) was observed in 12 cases (35.3%) and permanent hypoPTH in 2 cases (5.9%); transient postoperative unilateral vocal cord palsy was observed in 2 patients (5.9%). In CG mean operative time for total thyroidectomy was 49.3 ± 12.9 minutes (range 30–80 min); postoperative hospital stay was 1 day for 16 patients (24.6%), 2 days for 40 patients (61.5%), 3 days for 8 patients (12.3%), and 4 days for 1 patient (1.6%); transient hypoPTH was observed in 23 cases (35.4%) and permanent hypoPTH in 4 cases (6.1%), who needed therapy with calcitriol and calcium carbonate; transient postoperative unilateral vocal cord palsy was observed in 4 patients (6.1%). There were no cases of permanent vocal cord paralysis in both groups. The correlation between two groups of patients showed that mean operative time was significantly lower in MG ( p = 0.0007). Conclusion Pediatric patients of MG showed a significantly lower operative time and postoperative hospital stay with respect to pediatric patients of CG if compared with conventional technique. This result with the evidence of similar degree of completeness and rate of postoperative complications make MIVAT a valid option for the treatment of pediatric patients when performed by a well-trained staff in a third referral center.

CONTEXT:For many years, total thyroidectomy (TTx) and radioiodine remnant ablation (RRA) represented the initial treatment of differentiated thyroid cancer (DTC). There is currently much debate surrounding the clinical impact of RRA, particularly in low (LR) and intermediate (IR) risk DTC.OBJECTIVE:To evaluate the role of postoperative High-Sensitive Thyroglobulin on L-thyroxine (LT4-HSTg) and postoperative neck ultrasound (nUS) in risk re-stratification and decision to perform RRA.PATIENTS:505 patients with LR or IR DTC were evaluated 3-4 months after TTx. All patients underwent RRA and a post-therapeutic whole body scan (ptWBS).RESULTS:After TTx, 29.7% DTC patients had LT4-HSTg