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Michele Caraglia, Daniele Santini, Monica Marra, Bruno Vincenzi, Giuseppe Tonini, and Alfredo Budillon

Bone metastases are common in patients with many types of cancer, especially breast and prostate cancer — in which the incidence is approximately 70% among patients with advanced metastatic disease. Aminobisphosphonates (NBPs) have entered clinical practice in the treatment of bone metastases from several neoplasms, including breast and prostate adenocarcinoma, as a result of their anti-resorption properties. However, evidence has accumulated on the direct anti-tumour effects of NBPs. This review describes the metabolic pathways that are putative molecular targets of NBPs and that are involved in the prenylation processes of several intracellular small GTP-binding proteins (ras family related proteins). The latter regulate the intracellular survival and proliferative pathways of tumour cells and could be the intracellular molecular targets of the NBPs responsible for the direct anti-cancer effects, even if definitive conclusions cannot be drawn at present. Different mechanisms have been reported to account for the anti-neoplastic action of NBPs, including: the induction of apoptosis; cell cycle perturbations; and anti-invasive, anti-migration and anti-angiogenic effects. Moreover, this review describes the most important clinical studies that demonstrate the activity of NBPs in preventing skeletal-related events induced by bone metastases. The main pharmacokinetic pitfalls of NBPs are described, and methods of overcoming these pitfalls through the use of liposome vehicles are proposed. Finally, the principal pre-clinical studies on the interaction between NBPs and other biological agents are also described; these studies may enable reductions in the in vivo NBP concentrations required to achieve anti-tumour activity. To date, however, the real molecular targets of NBPs are not completely known and new technological platforms are required in order to detect them and to develop new anti-cancer strategies based on the use of NBPs.

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Paola Sperone, Anna Ferrero, Fulvia Daffara, Adriano Priola, Barbara Zaggia, Marco Volante, Daniele Santini, Bruno Vincenzi, Giuseppe Badalamenti, Chiara Intrivici, Sabrina Del Buono, Silvia De Francia, Emmanouil Kalomirakis, Riccardo Ratti, Alberto Angeli, Luigi Dogliotti, Mauro Papotti, Massimo Terzolo, and Alfredo Berruti

Adrenocortical carcinoma (ACC) is a rare neoplasm characterized by poor prognosis. First-line systemic treatments in advanced disease include mitotane, either alone or in combination with chemotherapy. Studies evaluating second-line therapy options have obtained disappointing results. This trial assessed the activity and toxicity of gemcitabine plus metronomic fluoropyrimidines in heavily pretreated advanced ACC patients. From 1998 to 2008, 28 patients with advanced ACC progressing after mitotane plus one or two systemic chemotherapy lines were enrolled. They received a combination of i.v. gemcitabine (800 mg/m2, on days 1 and 8, every 21 days) and i.v. 5-fluorouracil protracted infusion (200 mg/m2/daily without interruption until progression) in the first six patients, or oral capecitabine (1500 mg/daily) in the subsequent patients. Mitotane administration was maintained in all cases. The rate of non-progressing patients after 4 months of treatment was 46.3%. A complete response was observed in 1 patient (3.5%); 1 patient (3.5%) obtained a partial regression, 11 patients (39.3%) obtained a disease stabilization and 15 patients (53.7%) progressed. Treatment was well tolerated, with grade III and IV toxicities consisting of leukopenia in six patients (21.4%), thrombocytopenia in one patient (3.5%), and mucositis in one patient (3.5%). Median time to progression and overall survival in the patient population were 5.3 (range: 1–43) and 9.8 months (range: 3–73) respectively. Gemcitabine plus metronomic fluoropyrimidines is a well-tolerated and moderately active regimen in heavily pretreated ACC patients.

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Nicola Viola, Laura Agate, Sonia Caprio, Loredana Lorusso, Alessandro Brancatella, Debora Ricci, Daniele Sgrò, Clara Ugolini, Paolo Piaggi, Paolo Vitti, Rossella Elisei, Ferruccio Santini, and Francesco Latrofa

The relevance of thyroid autoimmunity to the prognosis of papillary thyroid carcinoma is still unsettled. We decided to investigate the impact of thyroid autoimmunity on the prognosis of papillary thyroid carcinoma and the handling of TgAbs. We evaluated the clinical course of a large group of patients according to the presence (PTC-LT) or absence (PTC) of lymphocytic thyroiditis at histology. We studied 194 consecutive patients with a diagnosis of PTC and treated them with total thyroidectomy plus ¹³¹I ablation between 2007 and 2009. Median follow-up (with 25th–75th percentiles) was 84.0 (56.4–118.0) months. The remission criteria were: basal Tg < 0.2 ng/mL (or stimulated Tg: < 1), TgAbs < 8 IU/mL (otherwise ‘decreasing TgAb trend’, a decline of ≥20% in sequential TgAb measurements) and unremarkable imaging. PTC-LT and PTC patients had comparable treatment.TgAbs were detectable in 72.5% of PTC-LT and 16.5% of PTC patients. Time to remission was longer in the detectable than in the undetectable TgAb cohort (28.5 vs· 7.5 months (median); HR: 0.54, CI: 0.35–0.83, P = 0.005). When comparing PTC-LT to PTC patients, the difference was maintained in the detectable TgAb (29.3 vs 13.0 months; HR: 0.38, CI: 0.18–0.80; P = 0.01) but not in the undetectable TgAb cohort (7.7 vs 7.3 months; HR: 0.90, CI: 0.55–1.47; P = 0.68). Using the decreasing TgAb trend, the influence of detectable TgAbs on time to remission was abolished. Thyroid autoimmunity does not influence the prognosis of papillary thyroid carcinoma. A decreasing TgAb trend seems an appropriate criterion to establish the remission of papillary thyroid carcinoma.