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Cosimo Durante, Giuseppe Costante, and Sebastiano Filetti

The demography of differentiated thyroid cancers (DTCs) has changed considerably since the 1990s, when the vast majority of these tumors were clinically evident at the time of diagnosis, and many were associated with regional lymph node involvement. Today's DTCs are more likely to be small, localized, asymptomatic papillary forms that are discovered incidentally, during neck imaging procedure performed for other reasons or during postoperative assessment of a gland removed for benign nodular goiter. The tools available for diagnosing, treating, and monitoring DTCs have also changed and their diagnostic capacities have increased. For these reasons, DTC treatment and follow-up paradigms are being revised to ensure more appropriate, cost-effective management of the current generation of DTCs. This review examines some of the key issues in this area, including the assessment of risks for disease recurrence and thyroid cancer-related death, the indications for postoperative ablation of the thyroid remnant with radioactive iodine and TSH-suppressive doses of levothyroxine, the pros, cons, and rationales for the use of various follow-up tools (serum thyroglobulin assays, neck ultrasound, 2-[18F]fluoro-2-deoxyglucose–positron emission tomography, and whole-body 131I scintigraphy), and temporal strategies for maximizing their efficacy. An algorithm is presented for individualized, risk-tailored management of DTC patients.

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Cosimo Durante, Houda Boukheris, Clarisse Dromain, Pierre Duvillard, Sophie Leboulleux, Dominique Elias, Thierry de Baere, David Malka, Jean Lumbroso, Joël Guigay, Martin Schlumberger, Michel Ducreux, and Eric Baudin

Survival of metastatic gastroenteropancreatic well-differentiated endocrine carcinoma (GEP WDEC) is not well characterized. We evaluated the long-term outcome and prognostic factors for survival in 118 patients with distant metastases from GEP WDEC. Inclusion criteria were 1) pathological review by a single pathologist according to the present WHO criteria, 2) absence of previous therapy apart from surgery, 3) complete morphological evaluation within 3 months including somatostatin receptor scintigraphy, and 4) follow-up at Gustave-Roussy Institute until death or study's end. Clinical, biological marker, and pathological parameters were analyzed in univariate and multivariate statistical models. Survival after the first complete imaging work-up of the metastatic disease was determined using Kaplan–Meier method. Overall, survival for 5 years after the diagnosis of metastatic disease was 54%. In multivariate analysis, age (hazard ratio (HR): 1.05, 95% confidence interval (CI): 1.01–1.08, P=0.01), the number of liver metastases (HR: 3.4, 95% CI: 1.4–8.3, P=0.01), tumor slope (HR: 1.1, 95% CI: 1.0–1.1, P=0.001), and initial surgery (HR: 0.3, 95% CI: 0.1–0.8, P=0.01) were predictive of survival. Five-year survival was 100%, 91% (95% CI, 51–98%), 62% (95% CI, 37–83%), and 9% (95% CI, 6–32%) when patients had 0, 1, 2, 3 or more poor prognostic features respectively. This study enables the stratification of metastatic GEP WDEC patients into distinct risk groups. These risk categories can be used to tailor therapeutic approaches and also to design and interpret clinical trials.

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Catia Mio, Elisa Lavarone, Ketty Conzatti, Federica Baldan, Barbara Toffoletto, Cinzia Puppin, Sebastiano Filetti, Cosimo Durante, Diego Russo, Arturo Orlacchio, Antonio Di Cristofano, Carla Di Loreto, and Giuseppe Damante

Anaplastic thyroid carcinoma (ATC) is an extremely aggressive thyroid cancer subtype, refractory to the current medical treatment. Among various epigenetic anticancer drugs, bromodomain and extra-terminal inhibitors (BETis) are considered to be an appealing novel class of compounds. BETi target the bromodomain and extra-terminal of BET proteins that act as regulators of gene transcription, interacting with histone acetyl groups. The goal of this study is to delineate which pathway underlies the biological effects derived from BET inhibition, in order to find new potential therapeutic targets in ATC. We investigated the effects of BET inhibition on two human anaplastic thyroid cancer-derived cell lines (FRO and SW1736). The treatment with two BETis, JQ1 and I-BET762, decreased cell viability, reduced cell cycle S-phase, and determined cell death. In order to find BETi effectors, FRO and SW1736 were subjected to a global transcriptome analysis after JQ1 treatment. A significant portion of deregulated genes belongs to cell cycle regulators. Among them, MCM5 was decreased at both mRNA and protein levels in both tested cell lines. Chromatin immunoprecipitation (ChIP) experiments indicate that MCM5 is directly bound by the BET protein BRD4. MCM5 silencing reduced cell proliferation, thus underlining its involvement in the block of proliferation induced by BETis. Furthermore, MCM5 immunohistochemical evaluation in human thyroid tumor tissues demonstrated its overexpression in several papillary thyroid carcinomas and in all ATCs. MCM5 was also overexpressed in a murine model of ATC, and JQ1 treatment reduced Mcm5 mRNA expression in two murine ATC cell lines. Thus, MCM5 could represent a new target in the therapeutic approach against ATC.

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Antonella Verrienti, Giovanni Tallini, Chiara Colato, Amélie Boichard, Saula Checquolo, Valeria Pecce, Marialuisa Sponziello, Francesca Rosignolo, Dario de Biase, Kerry Rhoden, Gian Piero Casadei, Diego Russo, Michela Visani, Giorgia Acquaviva, Marco Ferdeghini, Sebastiano Filetti, and Cosimo Durante

Advanced medullary thyroid cancers (MTCs) are now being treated with drugs that inhibit receptor tyrosine kinases, many of which involved in angiogenesis. Response rates vary widely, and toxic effects are common, so treatment should be reserved for MTCs likely to be responsive to these drugs. RET mutations are common in MTCs, but it is unclear how they influence the microvascularization of these tumors. We examined 45 MTCs with germ-line or somatic RET mutations (RETmut group) and 34 with wild-type RET (RETwt). Taqman Low-Density Arrays were used to assess proangiogenic gene expression. Immunohistochemistry was used to assess intratumoral, peritumoral and nontumoral expression levels of VEGFR1, R2, R3, PDGFRa, PDGFB and NOTCH3. We also assessed microvessel density (MVD) and lymphatic vessel density (LVD) based on CD31-positive and podoplanin-positive vessel counts, respectively, and vascular pericyte density based on staining for a-smooth muscle actin (a-SMA), a pericyte marker. Compared with RETwt tumors, RETmut tumors exhibited upregulated expression of proangiogenic genes (mRNA and protein), especially VEGFR1, PDGFB and NOTCH3. MVDs and LVDs were similar in the two groups. However, microvessels in RETmut tumors were more likely to be a-SMA positive, indicating enhanced coverage by pericytes, which play key roles in vessel sprouting, maturation and stabilization. These data suggest that angiogenesis in RETmut MTCs may be more intense and complete than that found in RETwt tumors, a feature that might increase their susceptibility to antiangiogenic therapy. Given their increased vascular pericyte density, RETmut MTCs might also benefit from combined or preliminary treatment with PDGF inhibitors.

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Livia Lamartina, Giorgio Grani, Emanuela Arvat, Alice Nervo, Maria Chiara Zatelli, Roberta Rossi, Efisio Puxeddu, Silvia Morelli, Massimo Torlontano, Michela Massa, Rocco Bellantone, Alfredo Pontecorvi, Teresa Montesano, Loredana Pagano, Lorenzo Daniele, Laura Fugazzola, Graziano Ceresini, Rocco Bruno, Ruth Rossetto, Salvatore Tumino, Marco Centanni, Domenico Meringolo, Maria Grazia Castagna, Domenico Salvatore, Antonio Nicolucci, Giuseppe Lucisano, Sebastiano Filetti, and Cosimo Durante