Microenvironment inflammatory infiltrate drives growth speed and outcome of hepatocellular carcinoma: a prospective clinical study

In HCC, tumor microenvironment, heavily influenced by the underlying chronic liver disease, etiology and stage of the tissue damage, affects tumor progression and determines the high heterogeneity of the tumor. Aim of this study was to identify the circulating and tissue components of the microenvironment immune-mediated response affecting the aggressiveness and the ensuing clinical outcome. We analyzed the baseline paired HCC and the surrounding tissue biopsies from a prospective cohort of 132 patients at the first diagnosis of HCC for immunolocalization of PD-1/PD-L1, FoxP3, E-cadherin, CLEC2 and for a panel of 82 microRNA associated with regulation of angiogenesis, cell proliferation, cell signaling, immune control and autophagy. Original microarray data were also explored. Serum samples were analyzed for a panel of 19 cytokines. Data were associated with biochemical data, histopathology and survival. Patients with a more aggressive disease and shorter survival, who we named fast-growing accordingly to the tumor doubling time, at presentation had significantly higher AFP levels, TGF-β1 and Cyphra 21-1 levels. Transcriptomic analysis evidenced a significant downregulation of CLEC2 and upregulation of several metalloproteinases. A marked local upregulation of both PD-1 and PD-L1, a concomitant FoxP3-positive lymphocytic infiltrate, a loss of E-cadherin, gain of epithelial-mesenchymal transition (EMT) phenotype and extreme poor differentiation at histology were also present. Upregulated microRNA in fast-growing HCCs are associated with TGF-β signaling, angiogenesis and inflammation. Our data show that fast HCCs are characterized not only by redundant neo-angiogenesis but also by unique features of distinctively immunosuppressed microenvironment, prominent EMT, and clear-cut activation of TGFβ1 signaling in a general background of long-standing and permanent inflammatory state

Antimicrobial stewardship in a Gastroenterology Department: Impact on antimicrobial consumption, antimicrobial resistance and clinical outcome

Background A major cause of the increase in antimicrobial resistance is the inappropriate use of antimicrobials. Aims To evaluate the impact on antimicrobial consumption and clinical outcome of an antimicrobial stewardship program in an Italian Gastroenterology Department. Methods Between October 2014 and September 2015 (period B), a specialist in infectious diseases (ID) controlled all antimicrobial prescriptions and decided about the therapy in agreement with gastroenterologists. The defined daily doses of antimicrobials (DDDs), incidence of MDR-infections, mean length of stay and overall in-hospital mortality rate were compared with those of the same period in the previous 12-months (period A). Results During period B, the ID specialist performed 304 consultations: antimicrobials were continued in 44.4% of the cases, discontinued in 13.8%, not recommended in 12.1%, de-escalated 9.9%, escalated in 7.9%, and started in 4.0%. Comparing the 2 periods, we observed a decreased of antibiotics consumption (from 109.81 to 78.45 DDDs/100 patient-days, p = 0.0005), antifungals (from 41.28 to 24.75 DDDs/100pd, p = 0.0004), carbapenems (from 15.99 to 6.80 DDDsx100pd, p = 0.0032), quinolones (from 35.79 to 17.82 DDDsx100pd, p = 0.0079). No differences were observed in incidence of MDR-infections, length of hospital stay (LOS), and mortality rate. Conclusions ASP program had a positive impact on reducing the consumption of antimicrobials, without an increase in LOS and mortality