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Antonino Belfiore, Dario Giuffrida, Giacomo L. La Rosa, Orazio Ippolito, Giovanna Russo, Antonio Fiumara, Riccardo Vigneri and Sebastiano Filetti

Abstract.

In order to evaluate the risk of malignancy of cold thyroid nodules occurring in young as compared with adult patients, we studied a consecutive series of 2327 patients with a solitary cold thyroid nodule over a 6-year period. None of these patients had been previously irradiated in the neck or head. Fine needle aspiration of the nodule and cytologic examination were carried out in all patients and, on the basis of this evaluation and clinical examination 391 patients were selected for surgery; 109 patients were 4–20 years old and 2218 patients were older than 20 years. Malignancy was found in 11 (10.1%) and in 112 (5.0%) of cold thyroid nodules occurring in young and adult patients, respectively. The annual incidence of cold thyroid nodules in the population of the area studied was 5.2 vs 55.9 (per 105 inhabitants) in the young and in the adult group, respectively, and the annual incidence of thyroid cancer was 0.53 vs 2.82 (per 105 inhabitants) in the young and in the adult patients, respectively. The present study indicates, therefore, that in the absence of head or neck irradiation, cold thyroid nodules are much less frequent in young age, but that the malignancy rate of cold nodules occurring in young patients is 2-fold higher than in adults patients

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Cosimo Durante, Giovanni Tallini, Efisio Puxeddu, Marialuisa Sponziello, Sonia Moretti, Claudia Ligorio, Antonio Cavaliere, Kerry J Rhoden, Antonella Verrienti, Marianna Maranghi, Laura Giacomelli, Diego Russo and Sebastiano Filetti

Objective

Tyrosine kinase inhibitors (TKIs) are evaluated for treatment of radioiodine refractory thyroid cancer. Their effects in this setting are based on blockade of proangiogenic signaling mediated by receptors for vascular endothelial growth factors (VEGFs) and platelet-derived growth factors (PDGF). Most TKIs also block other cancer-relevant kinases, such as B-type Raf kinase (BRAF), which are constitutively activated in approximately half of papillary thyroid carcinomas (PTCs), but the impact of these effects is not clear.

Design

The aim of our study was to investigate the impact of BRAF V600E on proangiogenic gene expression and microvascular features of PTCs.

Methods

mRNA levels for VEGFA, VEGF receptors, and coreceptors (VEGFRs 1, 2, and 3, neuropilin-1), and PDGF receptor β (PDGFR β or PDGFRB) were measured with real-time PCR in BRAF V600E (n=55) and wild-type BRAF (BRAF-wt; n=35) PTCs. VEGF and VEGFR protein expression and microvessel densities (MVD) and lymphatic vessel densities (LVDs) were assessed by immunohistochemistry in 22 of the 90 PTCs (including 11 BRAF V600E cases). Angiogenic gene expression was also studied in vitro after induction/silencing of the BRAF V600E mutation in thyrocyte lines.

Results

Transcript levels of proangiogenic factors were significantly lower in BRAF V600E PTCs versus BRAF-wt PTCs (P<0.0001), but MVD and LVDs were not significantly different. VEGFA mRNA levels in thyroid cell lines decreased when BRAF V600E mutation was induced (P=0.01) and increased when it was silenced (P=0.01).

Conclusions

Compared with BRAF-wt PTCs, those harboring BRAF V600E exhibit downregulated VEGFA, VEGFR, and PDGFR β expression, suggesting that the presence of BRAF mutation does not imply a stronger prediction of response to drugs targeting VEGF and PDGFB signaling pathways.

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Deborah Cosentini, Giuseppe Badalamenti, Salvatore Grisanti, Vittoria Basile, Ida Rapa, Sara Cerri, Andrea Spallanzani, Paola Perotti, Emanuela Musso, Marta Laganà, Vittorio D Ferrari, Gabriele Luppi, Alberto Dalla Volta, Lorena Incorvaia, Sandra Sigala, Antonio Russo, Marco Volante, Massimo Terzolo and Alfredo Berruti

Objective

Temozolomide has shown a significant anti-proliferative activity on adrenocortical cancer (ACC) cells in vitro.

Design

On the basis of these results the drug was prescribed as second/third line in advanced metastatic ACC patients in four referral centers in Italy.

Methods

We retrospectively collected anagraphic, clinical and pathological data of patients with advanced ACC with disease progression to standard chemotherapy plus mitotane who were treated with temozolomide at the dose of 200 mg/m2/die given for 5 consecutive days every 28 days. The primary endpoint was the disease control rate, defined as objective response or disease stabilization after 3 months. Secondary endpoints were overall survival (OS), progression-free survival (PFS) and drug safety.

Results

Twenty-eight patients have been included in the study. Ten patients (35.8%, 95% CI: 17.8–53.8) obtained a disease control from temozolomide treatment. In particular, 1 patient had a complete response, 5 patients a partial response and 4 patients stable disease. Median PFS was 3.5 months and median OS was 7.2 months. Disease response was more frequently observed in patients with methylation of O6-methylguanine-DNA methyltransferase (MGMT) gene. Temozolomide therapy was well tolerated and most toxicities were limited to grade G1–2 according to WHO criteria.

Conclusion

Temozolomide was found active in the management of advanced ACC patients. The disease control rate obtained, however, was short-lived and the prognosis of treated patients was poor.

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Marco Bonomi, Valeria Vezzoli, Csilla Krausz, Fabiana Guizzardi, Silvia Vezzani, Manuela Simoni, Ivan Bassi, Paolo Duminuco, Natascia Di Iorgi, Claudia Giavoli, Alessandro Pizzocaro, Gianni Russo, Mirella Moro, Letizia Fatti, Alberto Ferlin, Laura Mazzanti, Maria Chiara Zatelli, Salvo Cannavò, Andrea M Isidori, Angela Ida Pincelli, Flavia Prodam, Antonio Mancini, Paolo Limone, Maria Laura Tanda, Rossella Gaudino, Mariacarolina Salerno, Pregnolato Francesca, Mohamad Maghnie, Mario Maggi, Luca Persani and Italian Network on Central Hypogonadism

Objective

Isolated hypogonadotropic hypogonadism (IHH) is a rare disorder with pubertal delay, normal (normoosmic-IHH, nIHH) or defective sense of smell (Kallmann syndrome, KS). Other reproductive and non-reproductive anomalies might be present although information on their frequency are scanty, particularly according to the age of presentation.

Design

Observational cohort study carried out between January 2008 and June 2016 within a national network of academic or general hospitals.

Methods

We performed a detailed phenotyping of 503 IHH patients with: (1) manifestations of hypogonadism with low sex steroid hormone and low/normal gonadotropins; (2) absence of expansive hypothalamic/pituitary lesions or multiple pituitary hormone defects. Cohort was divided on IHH onset (PPO, pre-pubertal onset or AO, adult onset) and olfactory function: PPO-nIHH (n = 275), KS (n = 184), AO-nIHH (n = 36) and AO-doIHH (AO-IHH with defective olfaction, n = 8).

Results

90% of patients were classified as PPO and 10% as AO. Typical midline and olfactory defects, bimanual synkinesis and familiarity for pubertal delay were also found among the AO-IHH. Mean age at diagnosis was significantly earlier and more frequently associated with congenital hypogonadism stigmata in patients with Kallmann’s syndrome (KS). Synkinesis, renal and male genital tract anomalies were enriched in KS. Overweight/obesity are significantly associated with AO-IHH rather than PPO-IHH.

Conclusions

Patients with KS are more prone to develop a severe and complex phenotype than nIHH. The presence of typical extra-gonadal defects and familiarity for PPO-IHH among the AO-IHH patients indicates a common predisposition with variable clinical expression. Overall, these findings improve the understanding of IHH and may have a positive impact on the management of patients and their families.