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Donatella Treppiedi, Genesio Di Muro, Giusy Marra, Anna Maria Barbieri, Federica Mangili, Rosa Catalano, Andreea Liliana Serban, Emanuele Ferrante, Marco Locatelli, Andrea Gerardo Antonio Lania, Maura Arosio, Anna Spada, Erika Peverelli, and Giovanna Mantovani

Cushing’s Disease (CD) is a rare endocrine disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary tumor. Pasireotide is the only pituitary-targeted drug approved for adult patients. Nevertheless, many side effects are encountered and a curative therapy is still challenging. Ubiquitin Specific Peptidase 8 (USP8) plays a crucial role in the modulation of corticotroph cells growth and ACTH secretion. Here, we explored the anticancer potential of the USP8 inhibitor RA-9 in USP8-wild type human tumor corticotroph cells and murine AtT-20 cells. Our results showed that RA-9 causes cell proliferation decrease (-24.3±5.2%, P<0.01) and cell apoptosis increase (207.4±75.3%, P<0.05) in AtT-20 cells, as observed with pasireotide. Moreover, RA-9 reduced ACTH secretion in AtT-20 cells (-34.1±19.5%,P<0.01), as well as in AtT-20 cells transfected with USP8 mutants, and in 1 out of 2 primary cultures in vitro responsive to pasireotide (-40.3±6%). A RA-9 mediated decrease of pERK1/2 levels was observed in AtT-20 cells (-52.3±13.4%, P<0.001), comparable to pasireotide, and in primary cultures, regardless of their in vitro responsiveness to pasireotide. Upregulation of p27 was detected upon RA-9 treatment only, both in AtT-20 cells (167.1±36.7%, P<0.05) and 1 primary culture tested (168.4%), whilst pCREB level was similarly halved in AtT-20 cells by both RA-9 and pasireotide. Altogether, our data demonstrate that RA-9 is efficient in exerting cytotoxic effects and inhibitory actions on cell proliferation and hormone secretion by modulating the expression of pERK1/2, pCREB and p27. Inhibition of USP8 might represent a novel strategy to target both USP8-wild type and USP8-mutated tumors in CD patients.

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Olimpia Alice Manzardo, Miriam Cellini, Rita Indirli, Alessia Dolci, Paolo Colombo, Flaminia Carrone, Elisabetta Lavezzi, Giovanna Mantovani, Gherardo Mazziotti, Maura Arosio, and Andrea Gerardo Antonio Lania

TNM 8th edition introduces changes in the staging of patients with differentiated thyroid carcinoma (DTC). This study aims at assessing the value of TNM 8th edition in predicting response to therapy and structural recurrence of DTC. Four hundred and eighty DTC patients were retrospectively evaluated by 7th and 8th editions of TNM staging system in relationship with risk stratification, response to therapy and recurrence of disease as defined by 2015 ATA guidelines. As compared to the 7th edition, TNM 8th led to downstage 136 patients (28.3%), with 97.5% of patients falling into lower stages (I–II) and only 2.5% remaining in higher stages (III–IV) (P < 0.001). Patients who were downstaged in stages I–II by TNM 8th were classified more frequently at intermediate-high risk (P < 0.001), had more frequently structural incomplete response to therapy (P = 0.009) and had higher risk of structural recurrence (P = 0.002) as compared to patients who were in the same TNM stages but were not downstaged. Specifically, the risk of structural recurrence was significantly higher in patients in whom the downstaging was induced by changes in tumour classification (hazard ratio (HR) 6.18, 95% CI 2.20–17.40; P = 0.001) but not in those who were downstaged for the increase in age cut-off (HR 2.80, 95% CI 0.86–9.19; P = 0.09). In conclusion, TNM 8th edition did not show reliability in predicting aggressiveness of DTC. In fact, the downstaging of DTC patients especially when performed due to changes in tumour classification may overlook patients predisposed to structural recurrence, potentially causing uncertainty in the therapeutic decision-making at the time of disease’s diagnosis.