Agnese Biagini

BRAF(V600E) mutation and outcome of patients with papillary thyroid carcinoma: a 15-year median follow-up study.

BACKGROUND The BRAF(V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinoma (PTC). The role of BRAF(V600E) mutation as a poor prognostic factor has been controversially reported in series with short-term follow-ups. In this study we verified the prognostic value of the BRAF(V600E) mutation in PTC patients with a long-term follow-up. METHODS We studied 102 PTC patients with a median follow-up of 15 yr. The BRAF(V600E) mutation was analyzed by PCR-single-strand conformational polymorphism and sequencing. The correlation between the presence/absence of the BRAF(V600E) mutation, clinicopathological features, and outcome of PTC patients were evaluated. RESULTS The BRAF(V600E) mutation was found in 38 of 102 (37.3%) PTC patients, and was significantly more frequent in patients older than 60 yr (P = 0.02), in advanced stages (P = 0.03), and in cases with vascular invasion (P = 0.02). At univariate analysis the worst outcome for PTC patients was significantly correlated with clinicopathological features (i.e. age, tumor size, extrathyroid extension, lymph node and distant metastases, advanced stage, vascular endothelial growth factor expression, and vascular invasion) and the BRAF(V600E) mutation (P < 0.002). However, at multivariate analysis only the BRAF(V600E) mutation showed an independent correlation with the worst outcome (P = 0.03). Moreover, the survival curves of PTC patients showed a lower percentage of survivors in the BRAF(V600E)-mutated group (P = 0.015). CONCLUSIONS In this study the BRAF(V600E) mutation correlated with the worst outcome for PTC patients, who were not only at a higher risk not to be cured but also for death. In particular, the BRAF(V600E) mutation was demonstrated to be a poor prognostic factor independent from other clinicopathological features.

Surgical Treatment of Low- and Intermediate-Risk Papillary Thyroid Cancer with Minimally Invasive Video-Assisted Thyroidectomy

BACKGROUND Minimally invasive video-assisted thyroidectomy (MIVAT) was introduced in the clinical practice to treat small benign thyroid nodules. This method has recently been demonstrated to produce the same completeness as a conventional thyroidectomy in patients with papillary thyroid cancer (PTC). The low number of treated cases and the limited follow-up of these patients represent the major limitations of these studies. OBJECTIVE The aim of the study was to compare the outcome of two groups of PTC patients, one treated with MIVAT and the other with conventional thyroidectomy, after a median follow-up of 5 yr. STUDY GROUP A total of 221 PTC patients were enrolled in this study according to the following criteria: 171 were treated with MIVAT (group A), and 50 were treated with conventional thyroidectomy (group B). RESULTS The outcome and the cumulative (131)I activity administered to achieve curative status were compared. After a mean follow-up of 3.6 +/- 1.5 yr (range, 1-8 yr; median, 5 yr), no differences were found between group A and group B. A similar rate of permanent hypoparathyroidism and/or nerve cord palsy was found in both groups. CONCLUSION We demonstrated that PTC patients operated on with MIVAT had a good outcome after 5 yr. This was similar to the outcome of patients treated with conventional thyroidectomy and the same degree of exposure to (131)I. These results, together with the evidence of a similar degree of completeness and rate of complications between the two surgical techniques, show that MIVAT is a valid option to treat low- and intermediate-risk PTC patients.

RET genetic screening of sporadic medullary thyroid cancer (MTC) allows the preclinical diagnosis of unsuspected gene carriers and the identification of a relevant percentage of hidden familial MTC (FMTC)

Objective  This study was aimed to demonstrate the clinical benefits of rearranged during transfection (RET) genetic screening in patients with apparently sporadic medullary thyroid cancer (MTC) not only to identify the hereditary nature of the disease in the index case but also to discover family members harbouring the same germline mutations (i.e. gene carriers) who are unaware of their condition.

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.

Twenty years of lesson learning: how does the RET genetic screening test impact the clinical management of medullary thyroid cancer?

Medullary thyroid carcinoma (MTC) is a rare disease that can be inherited or sporadic; its pathogenesis is related to activating mutations in the RET gene.

Anaplastic thyroid carcinoma: from clinicopathology to genetics and advanced therapies

Anaplastic thyroid carcinoma (ATC) is a rare malignancy, accounting for 1–2% of all thyroid cancers. Although rare, ATC accounts for the majority of deaths from thyroid carcinoma. ATC often originates in a pre-existing thyroid cancer lesion, as suggested by the simultaneous presence of areas of differentiated or poorly differentiated thyroid carcinoma. ATC is characterized by the accumulation of several oncogenic alterations, and studies have shown that an increased number of oncogenic alterations equates to an increased level of dedifferentiation and aggressiveness. The clinical management of ATC requires a multidisciplinary approach; according to recent American Thyroid Association guidelines, surgery, radiotherapy and/or chemotherapy should be considered. In addition to conventional therapies, novel molecular targeted therapies are the most promising emerging treatment modalities. These drugs are often multiple receptor tyrosine kinase inhibitors, several of which have been tested in clinical trials with encouraging results so far. Accordingly, clinical trials are ongoing to evaluate the safety, efficacy and effectiveness of these new agents. This Review describes the updated clinical and pathological features of ATC and provides insight into the molecular biology of this disease. The most recent literature regarding conventional, newly available and future therapies for ATC is also discussed.

How to manage patients with differentiated thyroid cancer and a rising serum thyroglobulin level.

Serum thyroglobulin (sTg) is the marker for monitoring persistence/recurrence of differentiated thyroid cancer, in patients without sTg antibodies. Patients with undetectable basal sTg or peak sTg <2 ng/mL are cured with low risk to recur. Newly detectable level of sTg indicates the recurrence. The significance of increasing sTg in patients treated with emithyroidectomy or total-thyroidectomy but not ablated with radioiodine is undefined. A doubling time <1 year may be a poor prognostic factor, but this is more relevant in cases with high levels of sTg. Because of its sensitivity, neck ultrasound should be performed at any visit, especially when an increased sTg is seen.

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.

Nuove indicazioni all’impiego del TSH umano ricombinante (rhTSH) e basse attività di 131I nella radioablazione del residuo tiroideo post-chirurgico

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

Il carcinoma tiroideo: nuove prospettive terapeutiche

SommarioLa maggior parte dei pazienti con carcinoma tiroideo guarisce con i trattamenti convenzionali (chirurgia e iodio radioattivo). Tuttavia, alcuni tumori tiroidei sono resistenti al radioiodio, perché perdono le caratteristiche della cellula follicolare da cui originano o perché 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. BRAFV600E 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.