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Sant'Ambrogio di Torino, Italy

Bustreo S.,Citta della Salute e della Science Hospital | Osella-Abate S.,University of Turin | Cassoni P.,University of Turin | Donadio M.,Citta della Salute e della Science Hospital | And 6 more authors.
Breast Cancer Research and Treatment | Year: 2016

Although Ki67 index suffers from poor reproducibility, it is one of the most important prognostic markers used by oncologists to select the treatment of estrogen receptor (ER) positive breast cancer patients. In this study, we aim to establish the optimal Ki67 cut-offs for stratifying patient prognosis and to create a comprehensive prognostic index for clinical applications. A mono-institutional cohort of 1.577 human epidermal growth factor receptor 2 negative/ER+ breast cancer patients having complete clinical, histological, and follow-up data was collected. The 14 and 20 % Ki67 cut-offs were correlated to disease-free interval (DFI) and disease-specific survival (DSS). To create a comprehensive prognostic index, we used independent variables selected by uni/multivariate analyses. In terms of DFI and DSS, patients bearing tumors with Ki67 < 14 % proliferation index did not differ from those with Ki67 values between 14 and 20 %. Patients with tumor with Ki67 > 20 % showed the poorest prognosis. Moreover, to tumor size, the number of metastatic lymph nodes and Ki67 > 20 % was given a score value, varying depending on definite cut-offs and used to create a prognostic index, which was applied to the population. Patients with a prognostic index ≥3 were characterized by significant risk of relapse [DFI: Hazard Ratio (HR) = 4.74, p < 0.001] and death (DSS: HR = 5.03, p < 0.001). We confirm that the 20 % Ki67 cut-off is the best to stratify high-risk patients in luminal breast cancers, and we suggest to integrate it with other prognostic factors, to better stratify patients at risk of adverse outcome. © 2016 The Author(s) Source

Cossu I.,Laboratorio Of Oncologia | Bottoni G.,Nuclear Medicine Unit | Loi M.,Laboratorio Of Oncologia | Loi M.,University of Zurich | And 24 more authors.
Biomaterials | Year: 2015

Selective tumor targeting is expected to enhance drug delivery and to decrease toxicity, resulting in an improved therapeutic index. We have recently identified the HSYWLRS peptide sequence as a specific ligand for aggressive neuroblastoma, a childhood tumor mostly refractory to current therapies. Here we validated the specific binding of HSYWLRS to neuroblastoma cell suspensions obtained either from cell lines, animal models, or Schwannian-stroma poor, stage IV neuroblastoma patients. Binding of the biotinylated peptide and of HSYWLRS-functionalized fluorescent quantum dots or liposomal nanoparticles was dose-dependent and inhibited by an excess of free peptide. In animal models obtained by the orthotopic implant of either MYCN-amplified or MYCN single copy human neuroblastoma cell lines, treatment with HSYWLRS-targeted, doxorubicin-loaded Stealth Liposomes increased tumor vascular permeability and perfusion, enhancing tumor penetration of the drug. This formulation proved to exert a potent antitumor efficacy, as evaluated by bioluminescence imaging and micro-PET, leading to (i) delay of tumor growth paralleled by decreased tumor glucose consumption, and (ii) abrogation of metastatic spreading, accompanied by absence of systemic toxicity and significant increase in the animal life span. Our findings are functional to the design of targeted nanocarriers with potentiated therapeutic efficacy towards the clinical translation. © 2015 Elsevier Ltd. Source

Gori S.,Medical Oncology | Inno A.,Medical Oncology | Rossi V.,Medical Oncology | Turazza M.,Medical Oncology | And 17 more authors.
PLoS ONE | Year: 2016

Background There are no validated predictive markers for lapatinib and capecitabine in patients with trastuzumab-resistant HER2 positive metastatic breast cancer. Methods Data of 148 consecutive patients treated with lapatinib and capecitabine from March 2007 to December 2013 were collected from 13 Italian institutions. Estimates of progression-free survival (PFS) and overall survival (OS) were obtained with the Kaplan-Meier method and compared with logrank test. The association of clinicopathological variables and the outcome was studied by binary logistic regression analysis and Cox proportional hazard analysis. Results At a median follow-up of 41 months, median PFS and OS were 7 and 21 months, respectively. Patents with a PFS longer than 7 months had a significantly longer OS, compared with patients with a PFS equal to or shorter than 7 months (36 vs 15 months; p<0.001). Multivariate analysis revealed the benefit of lapatinib-based therapy in terms of PFS and OS was significantly associated with time-to-progression (TTP) on prior first-line trastuzumabbased therapy. In particular, each additional month on first-line trastuzumab based therapy was associated with a reduction in hazard of progression and death after the initiation of lapatinib-based therapy of 2% and 4%, respectively. Conclusions A longer TTP to first line trastuzumab seems to predict a prolonged PFS and OS with subsequent lapatinib and capecitabine. © 2016 Gori 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. Source

Parri M.,Externautics | Pietrovito L.,University of Florence | Grandi A.,Externautics | Campagnoli S.,Externautics | And 14 more authors.
Angiogenesis | Year: 2014

Angiopoietin-like (ANGPTL) proteins are secreted proteins showing structural similarity to members of the angiopoietin family. Some ANGPTL proteins possess pleiotropic activities, being involved in cancer lipid, glucose energy metabolisms, and angiogenesis. ANGPTL7 is the less characterized member of the family whose functional role is only marginally known. In this study, we provide experimental evidences that ANGPTL7 is over-expressed in different human cancers. To understand the role played by ANGPTL7 in tumor biology, we asked whether ANGPTL7 is endogenously expressed by malignant cells or in response to environmental stimuli. We found that ANGPTL7 is marginally expressed under standard growth condition while it is specifically up-regulated by hypoxia. Interestingly, the protein is secreted and partially associated with the exosomal fraction, suggesting that it could be found in the systemic circulation of oncologic patients and act in an endocrine way. Moreover, we found that ANGPTL7 exerts a pro-angiogenetic effect on human differentiated endothelial cells by stimulating their proliferation, motility, invasiveness, and capability to form capillary-like networks while it does not stimulate progenitor endothelial cells. Finally, we showed that ANGPTL7 promotes vascularization in vivo in the mouse Matrigel sponge assay, thereby accrediting this molecule as a pro-angiogenic factor. © 2014 Springer Science+Business Media Dordrecht. Source

Martinello R.,Candiolo Cancer Institute IRCCs | Martinello R.,University of Turin | Milani A.,Candiolo Cancer Institute IRCCs | Geuna E.,Candiolo Cancer Institute IRCCs | And 5 more authors.
Expert Opinion on Investigational Drugs | Year: 2016

Introduction: ErbB2 overexpression and/or gene amplification is present in 20% of all breast cancers and characterizes an aggressive form of this disease. Despite the availability of several active drugs that have yielded substantial survival improvements, most patients with ErbB2-positive metastatic disease will develop tumor progression, either because of primary or acquired resistance. Therefore, research has focused on drugs that can more efficiently interfere with ErbB2 and with other members of the epidermal growth factor receptor family. Areas covered: This review focuses on those investigational drugs that inhibit ErbB2 tyrosine kinase activity (TKIs) for treating breast cancer. Expert opinion: ErbB-targeting TKIs show encouraging activity in patients with ErbB-positive tumors that are resistant to conventional ErbB-therapies (mostly trastuzumab), confirming pre-clinical observations. Efficient interference with the ErbB-network signaling implies also a potential use in ErbB2-normal tumors, where the phenotype is sustained by ErbB-aberrant signaling. Finally, early data suggests that ErbB-targeting TKIs could be active in treating patients with activating ErbB2 mutations. Ongoing and future research efforts should elucidate what is, according to the peculiarities of these compounds, their positioning in the treatment of women with breast cancer. © 2016 Informa UK Limited, trading as Taylor & Francis Group. Source

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