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Maria Chiara Zatelli, Mariella Minoia, Chiara Martini, Federico Tagliati, Maria Rosaria Ambrosio, Marco Schiavon, Mattia Buratto, Fiorella Calabrese, Erica Gentilin, Giorgio Cavallesco, Lisa Berdondini, Federico Rea, and Ettore C degli Uberti

Bronchial carcinoids (BCs) are rare tumors originating from endocrine cells dispersed in the respiratory epithelium. It has been previously demonstrated that everolimus, or RAD001, an mTOR inhibitor, has potent antiproliferative effects in human endocrine tumors. Our aim was to evaluate the possible antiproliferative effects of everolimus in human BCs in primary culture. We collected 24 BCs that were dispersed in primary cultures, treated without or with 1 nM–1 μM everolimus, 10 nM SOM230 (pasireotide, a somatostatin receptor multiligand), and/or 50 nM IGF1. Cell viability was evaluated after 48 h, and chromogranin A (CgA) as well as vascular endothelial growth factor (VEGF) secretion was assessed after 8 h incubation. Somatostatin receptors, mTOR, and AKT expression were investigated by quantitative PCR. We found that in 15 cultures (67.5%), everolimus significantly reduced cell viability (by ∼30%; P<0.05 versus control), inhibited p70S6K activity (−30%), and blocked IGF1 proliferative effects. Everolimus also significantly reduced CgA (by ∼20%) and VEGF (by ∼15%) secretion. Cotreatment with SOM230 did not exert additive effects on cell viability and secretory activity. AKT expression was similar in responder and nonresponder tissues, while mTOR expression was significantly higher in the responder group, which was characterized by higher CgA plasma levels and bigger tumors with higher mitotic index and angiogenesis. Our data demonstrate that everolimus reduces VEGF secretion and cell viability in BCs with a mechanism likely involving IGF1 signaling, suggesting that it might represent a possible medical treatment for BCs.

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Chiara Borga, Carlo Alberto Dal Pozzo, Elisabetta Trevellin, Francesca Bergamo, Sabina Murgioni, Anna Caterina Milanetto, Claudio Pasquali, Umberto Cillo, Giada Munari, Chiara Martini, Eugenio De Carlo, Vittorina Zagonel, Vincenza Guzzardo, Gianmaria Pennelli, Angelo Paolo Dei Tos, Roberto Vettor, and Matteo Fassan

The knowledge of the molecular landscape of ileal neuroendocrine tumors (NETs) is affected by the lack of systematic studies investigating intra-tumoral heterogeneity. In this study, intra-tumoral heterogeneity was investigated in 27 primary ileal G1-NETs and their matched nodal and liver metastases in order to assess the tumor grading, the expression status of two somatostatin receptor isoforms (i.e. SSTR2A and SSTR5) and mTOR signaling dysregulation (ph-mTOR, ph-p70S6K, ph-4EBP1, PTEN and miR-21). Among the 27 G1 primary tumors, 4 shifted to G2 in the matched liver metastasis. Although mTOR activation was pretty consistent between primary and secondary malignancies, mTOR effectors (ph-p70S6K and ph-4EBP1) were overexpressed in matched liver metastases, whereas PTEN expression profile changed in only two cases. MiR-21 was significantly up-regulated in the metastatic setting. Although SSTRs expression was present in most of the primary tumors and matched metastasis, we found SSTR5 expression to be significantly increased in liver metastases. Notably, SSTRs expression was heterogeneous within the same lesions in most of the lesions. Overall, despite primary and metastatic ileal NETs show a similar molecular landscape, tumor grading and mTOR signaling pathway may diverge in the metastatic setting, thus affecting prognosis and treatment.

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Massimo Terzolo, Giuseppe Reimondo, Paola Berchialla, Emanuele Ferrante, Elena Malchiodi, Laura De Marinis, Rosario Pivonello, Silvia Grottoli, Marco Losa, Salvatore Cannavo, Diego Ferone, Marcella Montini, Marta Bondanelli, Ernesto De Menis, Chiara Martini, Efisio Puxeddu, Antonino Velardo, Alessandro Peri, Marco Faustini-Fustini, Patrizia Tita, Francesca Pigliaru, Giulia Peraga, Giorgio Borretta, Carla Scaroni, Nicoletta Bazzoni, Antonio Bianchi, Alessandro Berton, Andreea Liliana Serban, Roberto Baldelli, Letizia Maria Fatti, Annamaria Colao, Maura Arosio, and for the Italian Study Group of Acromegaly

It is debated if acromegalic patients have an increased risk to develop malignancies. The aim of the present study was to assess the standardized incidence ratios (SIRs) of different types of cancer in acromegaly on a large series of acromegalic patients managed in the somatostatin analogs era. It was evaluated the incidence of cancer in an Italian nationwide multicenter cohort study of 1512 acromegalic patients, 624 men and 888 women, mean age at diagnosis 45 ± 13 years, followed up for a mean of 10 years (12573 person-years) in respect to the general Italian population. Cancer was diagnosed in 124 patients, 72 women and 52 men. The SIRs for all cancers was significantly increased compared to the general Italian population (expected: 88, SIR 1.41; 95% CI, 1.18–1.68, P < 0.001). In the whole series, we found a significantly increased incidence of colorectal cancer (SIR 1.67; 95% CI, 1.07–2.58, P = 0.022), kidney cancer (SIR 2.87; 95% CI, 1.55–5.34, P < 0.001) and thyroid cancer (SIR 3.99; 95% CI, 2.32–6.87, P < 0.001). The exclusion of 11 cancers occurring before diagnosis of acromegaly (all in women) did not change remarkably the study outcome. In multivariate analysis, the factors significantly associated with an increased risk of malignancy were age and family history of cancer, with a non-significant trend for the estimated duration of acromegaly before diagnosis. In conclusion, we found evidence that acromegaly in Italy is associated with a moderate increase in cancer risk.