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Sant'Ambrogio di Torino, Italy

Bologna C.,University of Turin | Buonincontri R.,University of Turin | Serra S.,Human Genetics Foundation HuGeF | Vaisitti T.,University of Turin | And 12 more authors.
Journal of Clinical Investigation | Year: 2016

Chronic lymphocytic leukemia (CLL) is a variable disease; therefore, markers to identify aggressive forms are essential for patient management. Here, we have shown that expression of the costimulatory molecule and microbial sensor SLAMF1 (also known as CD150) is lost in a subset of patients with an aggressive CLL that associates with a shorter time to first treatment and reduced overall survival. SLAMF1 silencing in CLL-like Mec-1 cells, which constitutively express SLAMF1, modulated pathways related to cell migration, cytoskeletal organization, and intracellular vesicle formation and recirculation. SLAMF1 deficiency associated with increased expression of CXCR4, CD38, and CD44, thereby positively affecting chemotactic responses to CXCL12. SLAMF1 ligation with an agonistic monoclonal antibody increased ROS accumulation and induced phosphorylation of p38, JNK1/2, and BCL2, thereby promoting the autophagic flux. Beclin1 dissociated from BCL2 in response to SLAMF1 ligation, resulting in formation of the autophagy macrocomplex, which contains SLAMF1, beclin1, and the enzyme VPS34. Accordingly, SLAMF1-silenced cells or SLAMF1lo primary CLL cells were resistant to autophagy-activating therapeutic agents, such as fludarabine and the BCL2 homology domain 3 mimetic ABT-737. Together, these results indicate that loss of SLAMF1 expression in CLL modulates genetic pathways that regulate chemotaxis and autophagy and that potentially affect drug responses, and suggest that these effects underlie unfavorable clinical outcome experienced by SLAMF1lo patients. Source

Morello F.,AO Citta della Salute e della Science | Piler P.,Masaryk University | Novak M.,Masaryk University | Kruzliak P.,Masaryk University
Biomarkers in Medicine | Year: 2014

Aortic dissection (AD) is a severe vascular disease associated with major morbidity and mortality. The diagnosis of AD requires the performance of urgent aortic imaging exams such as computed tomography angiography, but the decision to perform these exams now essentially relies on clinical judgment. Several studies have identified a range of potential biomarkers stemming from the aortic extracellular matrix (matrix metalloproteinases, TGF-β, soluble elastin fragments), vascular smooth muscle cells (smooth muscle myosin heavy chain, creatine kinase, calponin), coagulation (d-dimer, platelets) and inflammation (C-reactive protein), whose circulating levels increase in patients affected by AD. Biomarkers of AD could be potentially used to screen patients with compatible symptoms, to identify patients at higher risk of AD, to rule out AD in patients with non-high clinical probability of AD and/or to obtain prognostic stratification of affected patients. This review will summarize available data and discuss present and future perspectives of circulating biomarkers for the diagnosis and prognostic stratification of AD. © 2014 Future Medicine Ltd. Source

Cereda S.,San Raffaele Scientific Institute | Milella M.,Istituto Nazionale Tumori Regina Elena | Cordio S.,Struttura Complessa di Oncologia Medica Ospedale Garibaldi | Leone F.,University of Turin | And 16 more authors.
Cancer Chemotherapy and Pharmacology | Year: 2016

Purpose: Advanced biliary tract adenocarcinoma (BTA) is a rare tumor with a poor prognosis. Since no standard salvage chemotherapy regimen exists, we explored the activity of capecitabine alone or combined with mitomycin C. Methods: Patients aged 18-75 years and with KPS >50, with pathological diagnosis of BTA stratified based on site and stage of disease, were randomized to receive capecitabine 2000 mg/m2 day 1-14 alone (ARM A) or in combination with mitomycin C 6 mg/m2 day 1 (ARM B) as second-line therapy. Cycles were repeated in both arms every 3 weeks. Tumor assessment was performed every 2 months. The primary endpoint was the probability of being progression free at 6 months (PFS-6) from treatment start. According to the Fleming design, the study aimed to enroll 26 pts per arm. An exploratory endpoint was to assess thymidylate synthase (TS) and thymidine phosphorylase (TP) expression, as biomarkers predictive for clinical outcomes of capecitabine treatment. Results: Between October 2011 and 2013, 57 metastatic pts were enrolled: ARM A/B 28/29. Accordingly, 55 (26/29) pts were assessable for the primary endpoint: 2 (8 %) ARM A and 3 (10 %) ARM B pts were PFS-6. Main G3-4 toxicities were: hand-foot syndrome and transaminitis in 4/0 %, and thrombocytopenia, diarrhea and fatigue in 0/3 % of pts. No statistically significant correlation was found between TS or TP expression and pts' outcome. Conclusions: Since capecitabine yielded a disappointing outcome and the addition of mitomycin C did not improve the results, new therapeutic strategies need to be explored to improve survival in this disease setting. © 2015 Springer-Verlag Berlin Heidelberg. Source

Bulliard J.-L.,University of Lausanne | Garcia M.,Cancer Prevention and Control Program | Blom J.,Karolinska University Hospital | Senore C.,AO Citta della Salute e della Science | And 2 more authors.
European Journal of Cancer | Year: 2014

Participation is a key indicator of the potential effectiveness of any population-based intervention. Defining, measuring and reporting participation in cancer screening programmes has become more heterogeneous as the number and diversity of interventions have increased, and the purposes of this benchmarking parameter have broadened. This study, centred on colorectal cancer, addresses current issues that affect the increasingly complex task of comparing screening participation across settings. Reports from programmes with a defined target population and active invitation scheme, published between 2005 and 2012, were reviewed. Differences in defining and measuring participation were identified and quantified, and participation indicators were grouped by aims of measure and temporal dimensions. We found that consistent terminology, clear and complete reporting of participation definition and systematic documentation of coverage by invitation were lacking. Further, adherence to definitions proposed in the 2010 European Guidelines for Quality Assurance in Colorectal Cancer Screening was suboptimal. Ineligible individuals represented 1% to 15% of invitations, and variable criteria for ineligibility yielded differences in participation estimates that could obscure the interpretation of colorectal cancer screening participation internationally. Excluding ineligible individuals from the reference population enhances comparability of participation measures. Standardised measures of cumulative participation to compare screening protocols with different intervals and inclusion of time since invitation in definitions are urgently needed to improve international comparability of colorectal cancer screening participation. Recommendations to improve comparability of participation indicators in cancer screening interventions are made. © 2013 Elsevier Ltd. All rights reserved. Source

Balzarotti M.,Humanitas Cancer Center | Brusamolino E.,Humanitas Cancer Center | Angelucci E.,Uo Ematologia E Centro Trapianti Midollo Osseo Armando Businco Hospital | Carella A.M.,IRCCS AOU San Martino IST | And 22 more authors.
Leukemia and Lymphoma | Year: 2016

This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m2) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%; p = 0.002) and OS (two-year OS: 100% vs 76%; p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed. © 2016 Taylor & Francis Source

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