Barbi S.,University of Verona |
Cataldo I.,University of Verona |
De Manzoni G.,University of Verona |
Bersani S.,University of Verona |
And 6 more authors.
Journal of Experimental and Clinical Cancer Research | Year: 2010
Background. PIK3CA is one of the genes most frequently mutated in human cancers and it is a potential target for personalized therapy. The aim of this study was to assess the frequency and type of PIK3CA mutations in gastric carcinoma and compare them with their clinical pathological correlates. Methods. We analysed 264 gastric cancers, including 39 with microsatellite instability (MSI), for mutations in the two PIK3CA hotspots in exons 9 and 20 by direct sequencing of DNA obtained from microdissected cancer cells. Results. The cases harbouring mutations were 42 (16%). All were heterozygous missense single base substitutions; the most common was H1047R (26/42; 62%) in exon 20 and the second was Q546K (4/42; 9.5%) in exon 9. All the mutated MSI cases (8/39) carried the H1047R mutation. No other association between PI3KCA mutations and their clinical pathological covariates was found. A metanalysis of the mutations occurring in the same regions presented in 27 publications showed that ratio between exon 20 and exon 9 prevalences was 0.6 (95% CI: 0.5 -0.8) for colon, 1.6 (95% CI: 1.1 -2.3) for breast, 2.7 (95% CI: 1.6 -4.9) for gastric and 4.1 (95% CI: 1.9 -10.3) for endometrial cancer. Conclusions. The overall prevalence of PIK3CA mutations implies an important role for PIK3CA in gastric cancer. The lack of association with any clinical-pathological condition suggests that mutations in PIK3CA occur early in the development of cancer. The metanalysis showed that exon-selectivity is an important signature of cancer type reflecting different contexts in which tumours arise. © 2010 Barbi et al; licensee BioMed Central Ltd.
Differential activity of nivolumab, pembrolizumab and MPDL3280A according to the tumor expression of programmed death-ligand-1 (PD-L1): Sensitivity analysis of trials in melanoma, lung and genitourinary cancers
Carbognin L.,University of Verona |
Pilotto S.,University of Verona |
Milella M.,Regina Elena Cancer Institute |
Vaccaro V.,Regina Elena Cancer Institute |
And 11 more authors.
PLoS ONE | Year: 2015
Background: The potential predictive role of programmed death-ligand-1 (PD-L1) expression on tumor cells in the context of solid tumor treated with checkpoint inhibitors targeting the PD-1 pathway represents an issue for clinical research. Methods: Overall response rate (ORR) was extracted from phase I-III trials investigating nivolumab, pembrolizumab and MPDL3280A for advanced melanoma, non-small cell lung cancer (NSCLC) and genitourinary cancer, and cumulated by adopting a fixed and random-effect model with 95% confidence interval (CI). Interaction test according to tumor PD-L1 was accomplished. A sensitivity analysis according to adopted drug, tumor type, PD-L1 cut-off and treatment line was performed. Results: Twenty trials (1,475 patients) were identified. A significant interaction (p<0.0001) according to tumor PD-L1 expression was found in the overall sample with an ORR of 34.1% (95% CI 27.6-41.3%) in the PD-L1 positive and 19.9% (95% CI 15.4-25.3%) in the PD-L1 negative population. ORR was significantly higher in PD-L1 positive in comparison to PD-L1 negative patients for nivolumab and pembrolizumab, with an absolute difference of 16.4% and 19.5%, respectively. A significant difference in activity of 22.8% and 8.7% according to PD-L1 was found for melanoma and NSCLC, respectively, with no significant difference for genitourinary cancer. Conclusion: Overall, the three antibodies provide a significant differential effect in terms of activity according to PD-L1 expression on tumor cells. The predictive value of PD-L1 on tumor cells seems to be more robust for anti-PD-1 antibody (nivolumab and pembrolizumab), and in the context of advanced melanoma and NSCLC. © 2015 Carbognin et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Gaviraghi M.,University of Verona |
Gaviraghi M.,Siena Biotech Spa |
Tunici P.,Siena Biotech Spa |
Valensin S.,Siena Biotech Spa |
And 9 more authors.
Bioscience Reports | Year: 2011
Pancreatic cancer stem-like cells are described by membrane expression of CD24, CD44 and ESA (epithelial-specific antigen) and their capacity to grow as spheres in a serum-free medium containing well-defined growth factors. The capacity of a panel of four pancreatic cancer cell lines (PANC-1, CFPAC-1, PancTu-1 and PSN-1) to form spheres was tested. All cell lines with the exception of PancTu-1 developed spheres. Phenotypically, the sphere-growing cells showed an increased in vitro invasion capability. Both gene and protein expressions of markers of metastases [CXCR4 (CXC chemokine receptor 4), OPN (osteopontin) and CD44v6] and components of active hedgehog pathway signalling were assessed. Spheres clearly demonstrated increased expression of the above-mentioned markers when compared with their adherent counterpart. With the aim of identifying a minimum set of markers able to separate cells that have the capacity to form spheres from those incapable of forming spheres, a PCA (principal component analysis) of the multidimensional dataset was performed. Although PCA of the 'accepted' sternness genes was unable to separate sphere-forming from sphere-incapable cell lines, the addition of the 'aggressiveness' marker CD44v6 allowed a clear differentiation. Moreover, inoculation of the spheres and the adherent cells in vivo confirmed the superior aggressiveness (proliferation and metastasis) of the spheres over the adherent cells. In conclusion, the present study suggests that the sphere-growing cell population is not only composed of cells displaying classical stem membrane markers but also needs CD44v6-positive cells to successfully form spheres. Our results also emphasize the potential therapeutic importance of pathways such as CXCR4 and hedgehog for pancreatic cancer treatment.
Boninsegna L.,University of Verona |
Panzuto F.,University of Rome La Sapienza |
Partelli S.,University of Verona |
Capelli P.,University of Verona |
And 6 more authors.
European Journal of Cancer | Year: 2012
Introduction: Malignant pancreatic neuroendocrine tumours (PNENs) are generally associated with a good prognosis after radical resection. In other pancreatic malignancies predictors of recurrence and the role of lymph node ratio (LNR) are well known, but both have been scarcely investigated for malignant PNETs. Methods: The prospective database from the surgical Department of Verona University was queried. Clinical and pathological data of all patients with resected malignant PNET between 1990 and 2008 were reviewed. Univariate and multivariate analysis were performed. Results: Fifty-seven patients (male/female ratio = 1) with a median age of 58 years (33-78) entered in the study. Twenty-nine (51%) patients underwent pancreaticoduodenectomy and 28 (49%) distal pancreatectomy. Postoperative mortality was nil with a 37% morbidity rate. There were 36 (63%) patients with lymph node metastases (N1). Of these, 23 (64%) had a lymph node ratio (LNR) >0 and ≤0.20 and 13 (36%) had a LNR >0.20. The median overall survival and the median disease free survival (DFS) were 190 and 80 months, respectively. Recurrent disease was identified in 24 patients (42%) with a 2 and 5-year DFS rate of 82% and 49%, respectively. On multivariate analysis, LNR >0.20 (HR = 2.75) and a value of Ki67 >5% (HR = 3.39) were significant predictors of recurrence (P < 0.02). Conclusions: After resection for malignant PNETs, LNR and a Ki67 >5% are the most powerful predictors of recurrence. The presence of these factors should be considered for addressing patients to adjuvant treatment in future clinical trials. © 2011 Elsevier Ltd. All rights reserved.
Scarpa A.,University of Verona |
Scarpa A.,Center for Applied Research on Cancer |
Mantovani W.,University of Verona |
Capelli P.,University of Verona |
And 8 more authors.
Modern Pathology | Year: 2010
Pancreatic endocrine tumors are rare diseases and devising a clinically effective prognostic stratification of patients is a major clinical challenge. This study aimed at assessing whether the tumor-node-metastasis (TNM)-based staging and proliferative activity-based grading recently proposed by the European NeuroEndocrine Tumors Society (ENETS) have clinical value. TNM was applied to 274 patients with histologically diagnosed pancreatic endocrine tumors operated from 1991 to 2005, with last follow-up at December 2007. According to World Health Organization (WHO) classification, 246 were well-differentiated neoplasms (51 benign, 56 uncertain behavior, 139 carcinomas) and 28 poorly differentiated carcinomas. Grading was based on Ki67 immunohistochemistry. Survival analysis not only ascertained the prognostic value of the TNM system but also highlighted that in the absence of nodal and distant metastasis, infiltration and tumor dimensions over 4 cm had prognostic significance. T parameters were then appropriately modified to reflect this weakness. The 5-year survival for modified TNM stages I, II, III and IV were 100, 93, 65 and 35%, respectively. Multivariate analysis identified TNM stages as independent predictors of death, in which stages II, III and IV showed a risk of death of 7, 29 and 58 times higher than stage I tumors (P<0.0001). Ki67-based grading resulted an independent predictor of survival with cut-offs at 5 and 20%. In conclusion, WHO classification assigns clinically significant diagnostic categories to pancreatic endocrine tumors that need prognostic stratification by applying a staging system. The ENETS-TNM provides the best option, but it requires some modifications to be fully functional. The modified TNM described in this study ameliorates the clinical applicability and prediction of outcome of the ENETS-TNM; it (i) assigns a risk of death proportional to the stage at the time of diagnosis, and (ii) allows a clinically based staging of patients, as the T parameters as modified permit their clinical-radiological recognition. Ki67-based grading discerns prognosis of patients with same stage diseases. © 2010 USCAP, Inc. All rights reserved.