HAND-FOOT SYNDROME IN SORAFENIB AND LENVATINIB TREATMENT FOR ADVANCED THYROID CANCER.

OBJECTIVE: The aim of this study was to assess the clinical impact of hand-foot syndrome (HFS) during treatment with two multikinase inhibitors, sorafenib and lenvatinib, in a large group of patients with advanced thyroid cancer. Moreover, we looked for possible associations between HFS occurrence and clinical and pathological features. METHODS: We retrospectively evaluated 239 patients with advanced thyroid cancer: 165 treated with lenvatinib and 74 with sorafenib. Statistical analysis was performed to verify which features could be correlated with HFS development. RESULTS: HFS was observed in 35/74 (47.4%) and in 43/165 (26.7%) patients treated with sorafenib or lenvatinib, respectively. The median latency from the drug beginning and HFS appearance was 27 days for sorafenib and 2.9 months for lenvatinib. G3/G4 toxicity was observed in 16/35 (45.7%) patients treated with sorafenib and only in 3/43 (7%) treated with lenvatinib. Drug dose reduction due to HFS was required in 19/74 (25.7%) and 3/165 (1.8%) patients treated with sorafenib and lenvatinib, respectively. HFS occurrence was significantly associated with a longer duration of therapy in both groups. CONCLUSIONS: HFS was a frequent adverse event during both lenvatinib and sorafenib therapy, with a higher frequency and toxicity grade during sorafenib treatment. HFS was the most frequent reason for drug reduction or discontinuation in patient treated with sorafenib. Early diagnosis of HFS is important to allow early intervention, possibly in a multidisciplinary setting, and to avoid treatment discontinuation, which is highly relevant to obtain the maximum effectiveness of systemic therapy.

Pros and cons of an aggressive initial treatment with surgery and radioiodine treatment in minimally invasive follicular thyroid carcinoma.

BACKGROUND: Currently, surgery alone is the gold standard treatment for minimally invasive follicular thyroid cancer (mi-FTC). CASE PRESENTATION: A case of a mi-FTC diagnosed in 1994 was treated with total thyroidectomy and radioiodine (RAI) ablation, according to the therapeutic algorithm used at that time. Nevertheless, he had a recurrence with distant metastasis after 24 years from the initial treatment. CONCLUSION: Total thyroidectomy and RAI ablation might have delayed the development of distant metastasis but they were not sufficient to avoid disease recurrence. Certainly, remnant ablation simplified the follow-up and the monitoring of serum thyroglobulin allowed the early detection of the biochemical recurrence, but didn't change the outcome of the disease. Moreover, because of this early detection the patient was exposed to useless biochemical and imaging examinations. The aim of this report is to discuss the pros and cons of an aggressive treatment of a patient with mi-FTC.

Prevalence and Risk Factors of Developing Fistula or Organ Perforation in Patients Treated with Lenvatinib for Radioiodine-Refractory Thyroid Cancer.

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.

Whole Tumor Capsule Is Prognostic of Very Good Outcome in the Classical Variant of Papillary Thyroid Cancer.

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 < .001). No differences were found between En-FVPTC and En-CVPTC or between Ei-FVPTC and Ei-CVPTC. After 18 years of follow-up, a greater number of not-cured cases were observed in Ei-CVPTC with respect to Ei-FVPTC, but not in En-CVPTC to En-FVPTC. Multivariate clustering analysis showed that En-FVPTC, En-CVPTC, and Ei-FVPTC have similar features but different from I-FVPTC and I-CVPTC and, to a lesser extent, from Ei-CVPTC. A total of 177 of 614 (28.8%) cases were BRAFV600E mutated, and 10 of 614 (1.6%) carried BRAF-rare alterations. A significantly higher rate of En-CVPTC (22/49, 44.9%) than En-FVPTC (15/195, 7.7%) (P < .0001) were BRAFV600E mutated. 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.

Thyroid Cancers: From Surgery to Current and Future Systemic Therapies through Their Molecular Identities.

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.

[18F]-FDG-PET/CT Correlates With the Response of Radiorefractory Thyroid Cancer to Lenvatinib and Patient Survival.

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.

Thyroid cancer and COVID-19: experience at one single thyroid disease referral center.

PURPOSE: Severe 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. METHODS: We 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. RESULTS: SARS-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. CONCLUSIONS: We 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.

Safety and Quality-of-Life Data from an Italian Expanded Access Program of Lenvatinib for Treatment of Thyroid Cancer.

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.

A New MEN2 Syndrome with Clinical Features of Both MEN2A and MEN2B Associated with a New RET Germline Deletion.

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.

No difference in the outcome of metastatic thyroid cancer patients when using recombinant or endogenous TSH.

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.

Active Surveillance in Papillary Thyroid Microcarcinomas is Feasible and Safe: Experience at a Single Italian Center.

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.

Twenty-Five Years Experience on RET Genetic Screening on Hereditary MTC: An Update on The Prevalence of Germline RET Mutations.

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 "de novo" 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-phenotype is confirmed; d) by RET screening, some VUS can be found but their pathogenic role must be demonstrated before screening the family.

Fifty Years After the First Description, MEN 2B Syndrome Diagnosis Is Still Late: Descriptions of Two Recent Cases.

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.

KIF5B/RET Rearrangement in a Carcinoma of the Thyroid Gland: A Case Report of a Fatal Disease.

Background: The diffuse sclerosing variant of papillary thyroid cancer (DSV-PTC) is a rare variant of papillary thyroid cancer (PTC) with different clinicopathological features compared with conventional PTC. Case: An advanced DSV-PTC was diagnosed in a 39-year-old man. The radioiodine posttherapeutic whole-body-scan showed only an uptake in the central neck, whereas the computerized tomography showed multiple latero-cervical and mediastinum lymph node metastases, a single and spiculated lung lesion and multiple bilateral cerebellum metastases. The patient died after 6 months from the initial diagnosis. The histological revision of the thyroid tumor confirmed the diagnosis of DSV-PTC, and its molecular analysis revealed a KIF5B/RET rearrangement that, until now, was described only in a minority of lung adenocarcinoma. Other 18 cases of DSV-PTC were then studied for the presence of KIF5B/RET rearrangement, but all of them were negative. Conclusions: This was a case of DSV-PTC positive for KIF5B/RET rearrangement, but considering that this alteration has been described only in lung adenocarcinoma and that the clinical course was more typical of lung carcinoma, we cannot completely rule out the possibility that this was a metastatic lesion from a lung tumor mimicking a DSV-PTC. As an alternative, we can also hypothesize that this was a case of fusion of two tumoral tissues deriving from a DSV-PTC and a metastasis of a KIF5B/RET positive lung adenocarcinoma. The question of whether the molecular findings, particularly when specifically reported only in some subtypes of human tumors, can overcome the morphological diagnosis is a matter of discussion.

Protein kinase inhibitors for the treatment of advanced and progressive radiorefractory thyroid tumors: From the clinical trials to the real life.

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.

Postoperative Thyroglobulin and Neck Ultrasound in the Risk Restratification and Decision to Perform 131I Ablation.

Context: There is much debate surrounding the choice of which patient should be submitted to postsurgical remnant radioiodine remnant ablation (RRA), particularly in low-risk (LR) and intermediate-risk (IR) differentiated thyroid cancer (DTC). Objective: The aim of this study was to evaluate the role of postoperative high-sensitive thyroglobulin (Tg) on L-thyroxine (LT4-HSTg) and postoperative neck ultrasound (US) in risk restratification and decision to perform RRA. Patients: We evaluated 505 patients with LR or IR DTC 3 to 4 months after total thyroidectomy (TTx). All patients underwent RRA and a posttherapeutic whole body scan (ptWBS). Results: After TTx, 29.7% DTC patients had LT4-HSTg <0.1 ng/mL (Group A) and could be restratified as cured: 1 of 150 had lymph node metastases (LN mets) detected by neck US but negative at ptWBS. 56.8% DTC patients had LT4-HSTg between 0.1 and ≤1 ng/mL (Group B) and could be restratified either as cured or not cured. In this group, 15 of 287 (5.2%) had metastases but only 7 were detected by ptWBS; 13.5% DTC patients had LT4-HSTg >1 ng/mL (Group C) and could not be considered as cured by definition. LN mets were present in 11 of 68(16.2%) cases, all detected by neck US. No correlation was found with the presence of metastases and serum LT4-HSTg values or with the level of risk. Conclusions: LT4-HSTg measured 3 to 4 months after TTx is important in the risk restratification of DTC patients but is less relevant than neck US in the decision to perform RRA.

Lenvatinib and other tyrosine kinase inhibitors for the treatment of radioiodine refractory, advanced, and progressive thyroid cancer.

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.

Treatment of advanced thyroid cancer with targeted therapies: ten years of experience.

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.

Minimally invasive video-assisted thyroidectomy versus conventional thyroidectomy in pediatric patients.

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.