Objective: Many patients with adrenocortical carcinoma (ACC) suffer from tumor recurrence despite radical surgery. Evidence on the post-operative use of mitotane is controversial and no predictors of response are available. We aimed to assess whether adjuvant mitotane treatment may prolong survival in patients with non-metastatic ACC following complete resection and whether ACC patients at high risk of recurrence may benefit from treatment. Design and methods: We retrospectively reviewed data from 152 non-metastatic ACC patients followed at the San Luigi Gonzaga Hospital: 100 patients were treated with adjuvant mitotane and 52 patients were left untreated following surgery. We assessed a number of potential predictive factors of recurrence and death. Mitotane effect was explored stratifying patients by staging (stage I–II vs stage III), hormone secretion (yes vs no) and Ki67 index. Results: The non-treated group had a higher risk of recurrence (HR: 2.79, 95%CI: 1.58–4.91; P < 0.001) than mitotane-treated group, while overall survival was not significantly different between groups. Hormone secretion, elevated Weiss score and elevated Ki67 index confer a higher risk of both recurrence and death and stage III ACC of death. Adjuvant mitotane treatment reduced significantly the risk of death in patients with elevated Ki67 index (P = 0.005) and in patients with stage III ACC (P = 0.02). Conclusions: Adjuvant mitotane may prolong recurrence-free survival in radically resected ACC patients with acceptable toxicity and may also prolong overall survival in a subgroup of ACC patients at high risk of recurrence.

Mitotane is used as a post-operative adjuvant treatment for patients with adrenocortical carcinoma. Monitoring of plasma mitotane concentrations is recommended, but we do not know what impact target concentrations have on patient outcome. To answer this question, we retrospectively analyzed patient records in the Lysosafe Online^® database (HRA Pharma, France) for patients who were treated for ≥6 months and who had ≥3 measurements of plasma mitotane levels during follow-ups at 11 tertiary centers in Italy from 2005 to 2017. We identified 110 patients treated with adjuvant mitotane for a median of 46 months (IQR, interquartile range, 28–62) with a median maintenance dose of 2.0 g/day (IQR 1.5–2.5). Achievement of target mitotane concentrations (≥14 mg/L) required a median of 8 months (IQR 5–19). Female sex was associated inversely with the dose, while body mass index (BMI) was correlated positively. Multivariate analysis showed that the Ki67 index and time to achieve the target range of plasma mitotane were independent predictors of recurrence-free survival (RFS). In a separate multivariate model, considering only the maintenance phase (month 7 to month 36, M7–M36) of treatment, the time in the target range of plasma mitotane was associated with a significantly lower risk of recurrence (Hazard Ratio, HR = 0.93; 0.88–0.98, p < 0.01). The prognostic implications of the time in target range and the time needed to reach target mitotane concentrations support the use of mitotane monitoring and may inform practice.

Objective: Microvascular damage is an early pathogenetic event in systemic sclerosis (SSc). The receptor activator of nuclear factor-κB ligand (RANKL)/RANK/osteoprotegerin (OPG) system is involved in vascular biology. Our aim was to assess OPG and soluble RANKL (sRANKL) serum levels in patients with SSc and healthy controls.Methods: Sixty patients with SSc (median age 58, range 31–72 yrs) and 60 healthy subjects matched for age, sex, and menopausal status were recruited. Serum OPG, sRANKL, soluble vascular cell adhesion molecule (sVCAM; marker of endothelial activation/injury), and bone turnover markers were measured. Bone mineral density in patients was assessed and cardiovascular/coronary risk was estimated.Results: OPG was similar in the 2 groups, while sRANKL and sRANKL/OPG ratio was higher in patients (p = 0.01 for both). sVCAM was markedly higher in patients (p < 0.001). OPG levels correlated positively with age in both patients (Spearman R = 0.50, p < 0.001) and controls (R = 0.56, p < 0.001). In patients, OPG was lower in men and higher in those with active ulcers or calcinosis. sRANKL levels were higher in patients treated with platelet aggregation inhibitors, and correlated negatively with densitometric measures. 25-hydroxyvitamin D levels were significantly lower in patients (p < 0.001). In patients, OPG levels correlated positively with cardiovascular and coronary risk (R = 0.28, p = 0.05 and R = 0.34, p < 0.01, respectively) and were higher in patients with hypertension and left ventricular hypertrophy. sVCAMlevels correlated positively with cardiovascular and coronary risk (R = 0.27, p = 0.06, and R = 0.38, p < 0.01, respectively).Conclusion: Higher sRANKL levels and sRANKL/OPG ratio in patients with SSc are likely to be a consequence of altered bone microenvironment. We show a dissociation between the well established marker of endothelial activation/injury, sVCAM, and the alleged marker of vascular damage, OPG, in patients with SSc. Further studies are needed to better ascertain the relationships of the RANKL/RANK/OPG system with the progression of macro- and microvascular damage.

Mitotane is the main option of treatment for advanced adrenocortical carcinoma (ACC). However, limited evidence is available regarding the impact of plasma mitotane levels on patient outcome. To address this question, we retrospectively analyzed patients with advanced ACC treated with mitotane for ≥3 months, with ≥3 measurements of plasma mitotane reported in the Lysosafe Online^® database (HRA Pharma, France), followed at 12 tertiary centers in Italy from 2005 to 2017. We identified 80 patients, initially treated with mitotane alone (56.2%) or plus chemotherapy (43.8%). The preference toward combination therapy was given to de novo stage IV ACC and younger patients. After the first line of treatment, 25% of valid cases experienced clinical benefit (14.5% objective response, 10.5% stabilization of disease) and 75% progression, without differences between the groups of treatment. Patients with progression had a lower time in the target range (TTR) of plasma mitotane and an unfavorable outcome. Death occurred in 76.2% of cases and multivariate analysis showed that clinical benefit after first treatment and longer TTR were favorable predictors of overall survival (OS). In conclusion, the present findings support the importance of mitotane monitoring and strengthen the concept of a therapeutic window for mitotane.

Objective: Glucocorticoids (GCs) at pharmacological doses stimulate bone resorption. Mechanisms of this action are unclear. The osteoclastogenic cytokine interleukin (IL)-6 acts through an oligomeric receptor consisting of two subunits, gp80 (or IL-6 receptor α, IL-6Rα) and gp130; both exist in membrane and soluble forms. Soluble IL-6Rα (sIL-6Rα) enhances, while sgp130 inhibits IL-6 signalling. In vitro, GCs enhance many effects of IL-6 by up-regulation of IL-6Rα. The aim of the present study was to assess acute changes of IL-6 system in the peripheral blood of patients given high-dose GCs. Subjects and methods: Serum levels of IL-6, sIL-6Rα, sgp130 and bone turnover markers were assessed before and each day during treatment in 24 multiple sclerosis (MS) patients undergoing high-dose (prednisolone, 15 mg/kg per day), short-term (3 to 5 days) intravenous GC therapy for relapse at the Regional Multiple Sclerosis Centre. Results: An immediate and marked fall of osteocalcin and an early increase of C-terminal telopeptide of type I collagen were already noticed at day 2 (P < 0.001 and P < 0.02, respectively); both became more apparent in the subsequent days. IL-6 was always below or near the detection limit of our ELISA. sgp130 showed a slight increase. sIL-6Rα significantly increased, peaking at day 4 (P < 0.01). However, inter-individual variability of response was noticed. Four patients showed a slight decrease, while no change was observed in one patient and an increase was noticed in the remaining nineteen (maximum change ranging from +10% to +67% with respect to baseline). In these patients, a significant increase of sIL-6Rα/sgp130 ratio was apparent. No correlation was found between bone turnover markers and any measured component of the IL-6 system. Conclusions: sIL-6Rα and sIL-6Rα/sgp130 ratio are precociously increased in the peripheral blood of the vast majority of patients given high-dose, intravenous GCs. The increase of systemically available sIL-6Rα conceivably results in the enhancement of IL-6-dependent osteoclastogenesis. The role of such a mechanism in the bone loss observed in inflammatory and immune-mediated diseases (where abundancy of IL-6 in the bone microenvironment is expected) requires further investigation.