Vincenzo Marotta

Detection of RET/PTC, TRK and BRAF mutations in preoperative diagnosis of thyroid nodules with indeterminate cytological findings

Background  Fine‐needle aspiration biopsy (FNAB) is the primary means to distinguish benign from malignant nodules and select patients for surgery. However, adjunctive diagnostic tests are needed because in 20–40% of cases the FNAB result is uncertain.

The Primary Occurrence of BRAFV600E Is a Rare Clonal Event in Papillary Thyroid Carcinoma

CONTEXT BRAF(V600E) is considered a primary event, a negative prognostic marker, and a site for pharmacological intervention in papillary thyroid carcinoma (PTC). We asked whether BRAF(V600E) can occur as a subclonal event in PTC and whether this and other oncogenes can coexist in the same tumor. STUDY DESIGN We determined by pyrosequencing the percentage of mutant BRAF, NRAS, and KRAS alleles in a series of conventional PTC. We also analyzed the BRAF mutation status in PTC cell clones in culture. RESULTS BRAF(V600E) alleles were present in 41 of 72 PTC (56.9%) in the range 44.7 to 5.1% of total BRAF alleles. In four PTC samples, mutant BRAF alleles were about 50%, being therefore compatible with a clonal heterozygous mutation. In 27 PTC samples, BRAF(V600E) alleles were in the range of 25 to 5.1%. This finding was confirmed after exclusion of the presence of a large contamination by lymphoreticular cells and by the analysis of PTC cells selected by laser capture. Analysis of clones derived from a single cell confirmed the presence of two distinct PTC populations with wild-type or mutated BRAF. Simultaneous subclonal BRAF and KRAS mutations were demonstrated in two PTC. CONCLUSIONS These data demonstrate that clonal BRAF(V600E) is a rare occurrence in PTC, although frequently this cancer consists of a mixture of tumor cells with wild-type and mutant BRAF. These results suggest that BRAF mutation in PTC is a later subclonal event, its intratumoral heterogeneity may hamper the efficacy of targeted pharmacotherapy, and its association with a more aggressive disease should be reevaluated.

Thyroid Nodules Treated with Percutaneous Radiofrequency Thermal Ablation: A Comparative Study

PURPOSE Percutaneous radiofrequency thermal ablation (RTA) was reported as an effective tool for the management of thyroid nodules (TNs). The aim of this study was to investigate the effects of RTA and to establish whether they were treatment-related by comparison with a matched, untreated control group. PATIENTS AND METHODS The study population included 40 patients with compressive TNs: 22 had nontoxic TNs, and 18 had toxic TNs and were treated with methimazole. In all patients, a fine-needle aspiration cytology was performed to exclude a thyroid malignancy. STUDY DESIGN Twenty patients were treated with RTA (group A), and 20 others did not receive any treatment (group B). At baseline, age, gender, and TN features did not differ significantly between groups. All patients were clinically, biochemically, and morphologically evaluated at baseline and after 1, 3, 6, and 12 months. RESULTS TN volume significantly decreased in group A (1.8 ± 0.3 ml at 12 months vs. 13.3 ± 1.8 ml at baseline; P < 0.0001) and remained stable in group B [11.7 ± 1.5 ml at 12 months vs. 11.2 ± 1.5 ml at baseline; P = not significant (NS)]. At 3-, 6-, and 12-month evaluations, TN volume was significantly lower in group A than in group B (P < 0.005). At the end of the follow-up, pressure symptoms were improved in all patients in group A but persisted unchanged in group B. In group A, hyperthyroidism completely recovered in 40% and improved in 40% of patients with toxic TNs, whereas it persisted in all patients with toxic TNs in group B. RTA was safe and well tolerated in all patients. CONCLUSIONS RTA induced a marked TN volume shrinkage resulting in parallel improvement of pressure symptoms. In most patients with toxic TNs, hyperthyroidism significantly improved as well. RTA may represent a valid therapeutic approach in patients with TNs not receiving conventional treatments.

Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET

Radioactive iodine is a crucial tool for treatment of differentiated thyroid cancer (DTC). In 5% of cases, DTCs lose I‐131 avidity and assume an aggressive behaviour. Treatment options for iodine‐refractory DTC are limited. We report the experience of off‐label use of the tyrosine kinase inhibitor sorafenib for treatment of advanced iodine‐refractory DTC.

High Growth Rate of Benign Thyroid Nodules Bearing RET/PTC Rearrangements

CONTEXT Benign thyroid nodules display a broad range of behaviors from a stationary size to a progressive growth. The RET/PTC oncogene has been documented in a fraction of benign thyroid nodules, besides papillary thyroid carcinomas, and it might therefore influence their growth. OBJECTIVE The aim of the present work was to evaluate whether RET/PTC in benign thyroid nodules associates with a different nodular growth rate. STUDY DESIGN In this prospective multicentric study, 125 subjects with benign nodules were included. RET rearrangements were analyzed in cytology samples; clinical and ultrasonographic nodule characteristics were assessed at the start and at the end of the study. RESULTS RET/PTC was present in 19 nodules. The difference between the mean baseline nodular volume of the RET/PTC- and RET/PTC+ nodules was not significant. After 36 months of follow-up, the RET/PTC+ group (n = 16) reached a volume higher than the RET/PTC- group (n = 90) (5.04 ± 2.67 vs. 3.04 ± 2.26 ml; P = 0.0028). We calculated the monthly change of nodule volumes as a percentage of baseline. After a mean follow-up of 36.6 months, the monthly volume increase of nodules bearing a RET rearrangement was 4.3-fold that of nodules with wild-type RET (1.83 ± 1.2 vs. 0.43 ± 1.0% of baseline volume; P < 0.0001). CONCLUSIONS Benign thyroid nodules bearing RET rearrangements grow more rapidly than those with wild-type RET. Searching for RET rearrangements in benign thyroid nodules might be useful to the clinician in choosing the more appropriate and timely therapeutic option.

Limitations of Chromogranin A in clinical practice

Context: Usefulness of circulating Chromogranin A (CgA) for the diagnosis of neuroendocrine tumors (NEN) is controversial. The aim of the present study was to assess the actual role of this marker as diagnostic tool. Methods: Serum blood samples were obtained from 42 subjects affected with NEN, 120 subjects affected with non-endocrine neoplasias (non-NEN) and 100 non-neoplastic subjects affected with benign nodular goitre (NNG). Determination of CgA was performed by means of immunoradiometric assay. Results: The CgA levels among NEN-patients were not significantly different from NNG and non-NEN subjects. The Receiver operating characteristic (ROC) curves analysis failed to identify a feasible cut-off value for the differential diagnosis between NEN and the other conditions. Conclusion: Serum CgA is not helpful for the first-line diagnosis of NEN.

BRAF mutation positive papillary thyroid carcinoma is less advanced when Hashimoto's thyroiditis lymphocytic infiltration is present

Concomitant papillary thyroid cancer (PTC) and Hashimotos thyroiditis (HT) is a frequent occurrence. Whether these two conditions are linked and whether PTC with concurrent HT has distinct clinicopathological characteristics are still debated issues. Lymphocytic infiltration is abundant in HT and might be relevant in the pathogenesis and progression of PTC. BRAFV600E mutation is associated with a more advanced PTC at diagnosis; however, its role in the clinicopathological characteristics of PTC with concurrent HT is unknown.

Hepatic arterial embolization in patients with neuroendocrine tumors

Liver metastases occur in 46-93% of patients with neuroendocrine neoplasms (NENs). Presence and extension of liver metastases are considered important prognostic factors, as they may significantly impair the patient’s quality of life, because of either tumor bulk or hormonal hypersecretion. Therapies for NEN liver metastases include surgical resection, liver transplantation, chemotherapy and biotherapy. Surgery is the gold standard for curative therapy, but in most of NEN patients with liver metastases, when surgery can not be applied, minimally invasive therapeutic approaches are adopted. They include trans-arterial embolization (TAE), trans-arterial chemoembolization (TACE), radiofrequency thermal ablation and new emerging techniques.TAE is based on selective infusion of particles in the branch of the hepatic artery supplying the tumor lesions. The goal of TAE is to occlude tumor blood vessels resulting in ischemia and necrosis. Many reports have shown that TAE can reduce tumor size and hormone output, resulting in palliation of symptoms without the use of cytotoxic drugs, resulting in better tolerability. This review will focus on TAE performance and safety in NEN patients with liver metastases.

Impact of long-acting octreotide in patients with early-stage MEN1-related duodeno-pancreatic neuroendocrine tumours

Somatostatin analogues (SSA) represent one of the main therapeutic option in patients affected with functioning well‐differentiated neuroendocrine tumours (NETs). There are no studies specifically focusing on NETs associated with Multiple Endocrine Neoplasia type 1 (MEN1).

The evolving field of kinase inhibitors in thyroid cancer

Most of the genetic events implicated in the pathogenesis of thyroid cancer (TC) involve genes with kinase activity. Thus, kinase inhibitors (KIs) are very relevant in this field. KIs are considered the most suitable treatment for patients with iodine-refractory differentiated TC; these patients comprise the subgroup with the poorer prognosis. To date, only sorafenib has been approved for this indication, but promising results have been reported with several other KIs. In particular, lenvatinib has demonstrated excellent efficacy, with both progression-free survival and objective tumour response being better than with sorafenib. Despite being considered to be well tolerated, both sorafenib and lenvatinib have shown a remarkable toxicity, which has led to dose reductions in the majority of patients and to treatment discontinuation in a significant proportion of cases. The role of KIs in differentiated TC may be revolutionised by the finding that selumetinib may restore a clinical response to radioactive iodine (RAI). Vandetanib and cabozantinib have been approved for the treatment of advanced, progressive medullary TC (MTC). Nevertheless, the toxicity of both compounds suggests their selective use in those patients with strong disease progression. Treatment with the mTOR-inhibitor everolimus, alone or in combination with somatostatin analogues, should be studied in metastatic MTC patients with slow progression of disease, these representing the vast majority of patients. KIs did not significantly impact on the clinical features of anaplastic TC (ATC).