Visceral adipose tissue adiponectin predicts excess weight loss after bariatric surgery in females with severe obesity.

OBJECTIVE: Bariatric surgery not always results in satisfactory excess weight loss (EWL) in severe obesity. Given the economic and clinical costs of bariatric surgery failure, defining predictors of successful EWL represents a relevant clinical issue for the health system to select patients benefiting from operation. METHODS: By ELISA and Western blot analyses, we assessed the predicting value of pre-operative adiponectin (APN) locally produced in abdominal visceral (VAT) and subcutaneous (SAT) adipose tissue versus plasma levels as a novel sex-linked biomarker of EWL at different time points of follow up (6-24 months) after bariatric surgery in 43 patients (56% females) affected by severe obesity undergoing a small pilot observational study. RESULTS: VAT-APN was lower in females and represented the only marker significantly correlated with EWL. In females, VAT-APN in the distribution upper quartile but not baseline BMI retained a statistically significant correlation with EWL at any time points (6-24 months) at multivariate analysis. The best VAT-APN cut-off value to predict 95% EWL at 12 months from surgery (98% accuracy, 100% sensitivity, 94% specificity, p = 0.010) was 5.1 µg/mg. CONCLUSIONS: In this very preliminary study, APN in VAT rather than its circulating or subcutaneous levels predicts EWL after bariatric surgery as an independent factor in the female sex only, thus contributing to identify those patients who could much benefit from surgery.

Intratumour microbiota modulates adrenocortical cancer responsiveness to mitotane.

The infiltrating microbiota represents a novel cellular component of the solid tumour microenvironment that can influence tumour progression and response to therapy. Adrenocortical carcinoma (ACC) is a rare and aggressive endocrine malignancy for which mitotane (MTT) treatment represents the first-line therapy, though its efficacy is limited to a therapeutic window level (14-20 mg/L). Novel markers able to predict those patients who would benefit from MTT therapy are urgently needed to improve patient's management. The aim of our study was to evaluate the presence of intratumoural bacterial microbiota DNA in 26 human ACC tissues vs 9 healthy adrenals; moreover, the association between the relative bacterial composition profile, the tumour mass characteristics and MTT ability to reach high circulating levels in the early phase of treatment, were explored. We found the presence of bacterial DNA in all adrenal samples from both tumours and healthy cortex specimens, documenting significant differences in the microbial composition between malignancy and normal adrenals: in detail, the ACC tissues were characterised by a higher abundance of the Proteobacteria phylum (especially the Pseudomonas and Serratia genera). In addition, the Proteobacteria's low abundance was negatively associated with tumour size, Ki67 and cortisol secretion. MTT levels reached higher levels at 9 months in ACC patients with high abundance of Proteobacteria, Pseudomonas and Serratia and with low abundance of Bacteroidota, Firmicutes and Streptococcus. These findings are the first indication that human ACCs are characterised by infiltrating bacteria and their specific abundance profile seems to influence the increase in circulating MTT levels at 9 months.

Prognostic Value of Microscopic Tumor Necrosis in Adrenal Cortical Carcinoma.

Adrenal cortical carcinoma (ACC) is an uncommon neoplasm with variable prognosis. Several histologic criteria have been identified as predictors of malignancy in adrenal cortical tumors. The Weiss score is the system most widely employed for diagnostic purposes, but also possesses prognostic value. We aim to determine the relative impact of each Weiss parameter on ACC patient survival. A multicenter retrospective analysis was conducted on a series of 79 conventional ACCs surgically treated at the Florence and Utrecht centers of the European Network for the Study of Adrenal Tumors (ENSAT). Weiss classification was recapitulated using principal component analysis (PCA). The Kaplan-Meier and Cox multivariate regression analyses were applied in order to estimate the prognostic power of Weiss versus other clinical parameters. PCA reduced the nine Weiss parameters to the best fitting 4-component model, each parameter clustering with a single component. Necrosis and venous invasion clustered together with the highest scores, thus establishing the most relevant component (Component 1) to explain Weiss distribution variability. Only Component 1 significantly predicted overall survival (OS, log-rank = 0.008) and disease-free survival (DFS, log-rank < 0.001). When considering the prognostic power of Weiss parameters, necrosis alone could independently assess OS (log-rank = 0.004) and DFS (log-rank < 0.001) at both the Kaplan-Meier and multivariate Cox regression analyses [hazard ratio (HR) = 7.8, 95% confidence interval [CI] = 1.0-63.5, p = 0.05, and HR = 12.2, 95% CI = 1.6-95.0, p = 0.017, respectively]. The presence of necrosis significantly shortened time to survival (TtS) and time to recurrence (TtR), 57.5 [31.5-103.5] vs 34 [12-78] months (p = 0.05) and 57.5 [31.5-103.5] vs 7 [1.0-31.5] months (p < 0.001), respectively. Our study suggests that, of the Weiss parameters, necrosis is the most powerful adverse factor and the best predictor of OS and DFS in ACC patients.

Stimulated Expression of CXCL12 in Adrenocortical Carcinoma by the PPARgamma Ligand Rosiglitazone Impairs Cancer Progression.

Adrenocortical carcinoma (ACC) is a rare malignancy with poor prognosis when metastatic and scarce treatment options in the advanced stages. In solid tumors, the chemokine CXCL12/CXCR4 axis is involved in the metastatic process. We demonstrated that the human adrenocortex expressed CXCL12 and its cognate receptors CXCR4 and CXCR7, not only in physiological conditions, but also in ACC, where the receptors' expression was higher and the CXCL12 expression was lower than in the physiological conditions. In a small pilot cohort of 22 ACC patients, CXCL12 negatively correlated with tumor size, stage, Weiss score, necrosis, and mitotic activity. In a Kaplan-Meier analysis, the CXCL12 tumor expression significantly predicted disease-free, progression-free, and overall survival. In vitro treatment of the primary ACC H295R and of the metastatic MUC-1 cell line with the PPARγ-ligand rosiglitazone (RGZ) dose-dependently reduced proliferation, resulting in a significant increase in CXCL12 and a decrease in its receptors in the H295R cells only, with no effect on the MUC-1 levels. In ACC mouse xenografts, tumor growth was inhibited by the RGZ treatment before tumor development (prevention-setting) and once the tumor had grown (therapeutic-setting), similarly to mitotane (MTT). This inhibition was associated with a significant suppression of the tumor CXCR4/CXCR7 and the stimulation of human CXCL12 expression. Tumor growth correlated inversely with CXCL12 and positively with CXCR4 expression, suggesting that local CXCL12 may impair the primary tumor cell response to the ligand gradient that may contribute to driving the tumor progression. These findings indicate that CXCL12/CXCR4 may constitute a potential target for anti-cancer agents such as rosiglitazone in the treatment of ACC.

Circulating Fascin 1 as a Promising Prognostic Marker in Adrenocortical Cancer.

Fascin-1 (FSCN1) is an actin-bundling protein associated with an invasive and aggressive phenotype of several solid carcinomas, as it is involved in cell cytoskeleton rearrangement and filopodia formation. Adrenocortical carcinoma (ACC) is a rare endocrine malignancy characterized by poor prognosis, particularly when metastatic at diagnosis. Radical resection is the only therapeutic option for ACC patients in addition to the adjuvant treatment with mitotane. Novel specific biomarkers suggestive of tumor progression to refine diagnosis and prognosis of patients with advanced ACC are urgently needed. ACC intratumoral FSCN1 has previously been suggested as a valid prognostic marker. In the present study, we identified FSCN1 in the bloodstream of a small cohort of ACC patients (n = 27), through a specific ELISA assay for human FSCN1. FSCN1 can be detected in the serum, and its circulating levels were evaluated in pre-surgery samples, which resulted to be significantly higher in ACC patients from stage I/II and stage III/IV compared with nontumoral healthy controls (HC, n = 4, FI: 5.5 ± 0.8, P<0.001, and 8.0 ± 0.5, P < 0.001 for stage I/II and stage III/IV group vs HC, respectively). In particular, FSCN1 levels were significantly higher in advanced stage versus stage I/II (22.8 ± 1.1 vs 15.8 ± 1.8 ng/ml, P < 0.005, respectively). Interestingly, circulating levels of pre-surgical FSCN1 can significantly predict tumor progression/recurrence (Log rank = 0.013), but not the overall survival (Log rank=0.317), in patients stratified in high/low PreS FSCN1. In conclusion, these findings-though very preliminary-suggest that circulating FSCN1 may represent a new minimally-invasive prognostic marker in advanced ACC, in particular when measured before surgery enables histological diagnosis.