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Porcelli L.,National Cancer Research Center Giovanni Paolo | Quatrale A.E.,National Cancer Research Center Giovanni Paolo | Mantuano P.,National Cancer Research Center Giovanni Paolo | Leo M.G.,Health-U | And 6 more authors.
Molecular Oncology | Year: 2013

Cancer cells may use PARP enzymes and Homologous Recombination to repair single and double strand breaks caused by genotoxic insults. In this study, the PARP-1 inhibitor Rucaparib was utilized to increase the sensitivity to chemoradiotherapy treatment in BRCA-2-deficient and -proficient pancreatic cancer cells. We used the pancreatic cancer cell lines, Capan-1 with mutated BRCA-2 and Panc-1, AsPC-1 and MiaPaCa-2 with BRCA-1/2 wild type. Cells were treated with Rucaparib and/or radiotherapy (4-10 Gy) plus Gemcitabine then the capability to proliferate was evaluated by colony formation, cell counting and MTT assays. Flow cytometry, immunocytochemistry and western blotting were utilized to assess cell response to Rucaparib plus irradiation. The antitumour effectiveness of combining the PARP-1 inhibitor before, together and after radiotherapy evidenced the first as the optimal schedule in blocking cell growth. Pre-exposure to Rucaparib increased the cytotoxicity of Gemcitabine plus radiotherapy by heavily inducing the accumulation of cells in G2/M phase, impairing mitosis and finally inducing apoptosis and authophagy. The upregulation of p-Akt and downregulation of p53 were evidenced in MiaPaCa-2 which displayed replication stress features. For the first time, the rationale of using a PARP inhibitor as chemoradiosensitizer in pancreatic cancer models has been hypothesized and demonstrated. © 2012 Federation of European Biochemical Societies.


Novello S.,University of Turin | Capelletto E.,University of Turin | Cortinovis D.,San Gerardo Hospital | Tiseo M.,University of Parma | And 5 more authors.
Translational Lung Cancer Research | Year: 2014

Introduction: The introduction of targeted therapies in non-small cell lung cancer (NSCLC) treatment has led to emerging toxicities, whose management and impact on quality-of-life (QoL) is not clearly defined. Aim of this Italian multicenter survey was to highlight any discrepancy between patients' and clinicians' perception of such toxicities in order to improve their management. Methods: From October 2013 to April 2014, 133 NSCLC advanced patients, treated with targeted therapies, were consecutively enrolled to assess toxicities and QoL with dedicated questionnaires. One hundred and sixteen patients were included in the final analysis, having attended three consecutive evaluations (T0, T1, T2), starting at least 15 days after the biological treatment. The survey required monthly compilation of both physicians and patients' questionnaires, basing adverse event evaluation on CTCAE version 4.0. Results: Most of the patients received either an EGFR-TKI or an anaplastic lymphoma kinase (ALK) inhibitor as targeted therapy (84.5% and 13.8%, respectively). At every checkpoint (T0, T1, T2) a significant difference in terms of perception of targeted therapies-related toxicities of any type and grade was described (P value =0.0001 in all cases). This difference was more pronounced for skin toxicity, fatigue and diarrhea. Furthermore, also the assessment of QoL revealed contrasting data between patients and clinicians, mainly QoL reported as good by the majority of patients and daily activities considered as slightly influenced by targeted therapies. Conclusions: In our knowledge, this is the first prospective survey in patients and doctors specifically designed for targeted therapies in advanced NSCLC. The results show an underestimation of toxicities by clinicians when compared with patients, the difference being greater for adverse events more strongly associated with daily life and QoL. Further studies are needed to confirm our first results. The discrepancy in perception of targeted therapies-related toxicities should be a result from which to start thinking about a new approach in their management. © Translational lung cancer research. All rights reserved.


Rossi A.,Sg Moscati Hospital | Torri V.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Garassino M.C.,Instituto Nazionale dei Tumori | Porcu L.,Irccs Instituto Of Ricerche Farmacologiche Mario Negri | Galetta D.,National Cancer Research Center Giovanni Paolo
Cancer Treatment Reviews | Year: 2014

Breast, colorectal and lung cancers represent the three most incident forms of cancer worldwide. Among these three "big killers", lung cancer is considered the one with the worst prognosis due to its high mortality even in early stages. Due to their more favorable prognosis, breast and colorectal cancers might appear to have benefited from major advances. Most oncologists who are faced with metastatic non-small cell lung cancer (NSCLC) find the reported results very frustrating when compared with those for metastatic breast (MBC) and colorectal cancers (MCRC). The aim of this analysis was to quantify and compare the relative magnitude of overall survival (OS) improvements in the first-line approaches in metastatic NSCLC, MBC and MCRC through the analysis of the main landmark meta-analyses and randomized clinical trials (RCTs) of commercially available drugs. Five items were considered and analyzed for each cancer. Moreover we evaluated the real clinical impact of the results reported by each item on the entire population; for each "big killer" an overall hazard ratio (HR) was estimated: 0.88 (95%+ CI: 0.72-1.07) for MBC, 0.94 (95%+ CI: 0.82-1.07) for MCRC, and about 0.80 (95%+ CI: 0.73-0.90) for advanced NSCLC. We showed that, in the last decades, these three tumors had important and constant OS improvements reached step by step. The relative magnitude of OS improvement seems higher in metastatic NSCLC than MBC and MCRC. © 2013 Elsevier Ltd.


Pinto R.,National Cancer Research Center Giovanni Paolo | De Summa S.,National Cancer Research Center Giovanni Paolo | Petriella D.,National Cancer Research Center Giovanni Paolo | Tudoran O.,Oncology Institute Prof Dr Ion Chiricuta | And 3 more authors.
Cancer Biomarkers | Year: 2014

Advances in our understanding of the molecular basis of tumors, as well as in the technology of DNA analysis, are rapidly changing the landscape of these diseases. Traditional approaches such as sequencing methods and arrays have too many limits. These have been overcome by the advent of next generation sequencing (NGS) methods which facilitate and accelerate the analysis of multiple genes and samples. These technologies allow new applications in molecular biology and medicine, for example precise analysis of RNA transcripts for gene expression; profiling of small RNAs, DNA methylation patterns and histone modification analysis; identification of splicing isoforms and of DNA regions that interact with regulatory proteins; pharmacogenomics studies and so on. In this review we describe recent applications of NGS in genomics, transcriptomics and epigenomics for a better comprehension of solid tumor metabolisms. © 2014 - IOS Press and the authors.


PubMed | University of Molise, National Cancer Research Center Giovanni Paolo and University of Bari
Type: Comparative Study | Journal: La Radiologia medica | Year: 2016

This study prospectively evaluated whole-body magnetic resonance/diffusion-weighted imaging with body signal suppression (WB-MR/DWIBS) reliability compared to (18)F-FDG PET/CT in the treatment response assessment of classic Hodgkin lymphomas (HL) and aggressive non-Hodgkin lymphomas (aNHL).Twenty-seven consecutive patients were prospectively enrolled at the time of diagnosis. Eighteen (11 HL and seven aNHL) were considered for the analysis. They received chemo/radiotherapy as induction and completed post-treatment evaluation performing both (18)F-FDG PET/CT and WB-MR/DWIBS. The revised response criteria for malignant lymphomas were used to assess the response to treatment. We evaluated the agreement between the two methods by Cohens K test. Post-therapy WB-MR/DWIBS sensitivity, specificity, PPV, NPV and accuracy were then calculated, considering the 12 months of follow-up period as the gold standard.By using an evaluation on a lesion-by-lesion basis, WB-MR/DWIBS and (18)F-FDG PET/CT showed an overall good agreement (K = 0.796, 95% IC = 0.651-0.941), especially in the evaluation of the nodal basins in aNHL (K = 0.937, 95% IC = 0.814-1). In reference to the revised response criteria for malignant lymphomas, the two methods showed a good agreement (K = 0.824, 95% IC = 0.493-1). Post-therapy sensitivity, specificity, PPV, NPV and accuracy of WB-MR/DWIBS were 43, 91, 75, 71 and 72%, respectively.WB-MR/DWIBS seems to be an appropriate method for the post-treatment assessment of patients affected by HL and aNHL. The small discrepancies between the two methods found within HL could be due to the biological and metabolic behavior of this group of diseases. Larger prospective studies are necessary to better define the role of WB-MR/DWIBS in this setting of patients.


Niro A.,University of Bari | Strippoli S.,National Cancer Research Center Giovanni Paolo | Alessio G.,University of Bari | Sborgia L.,University of Bari | And 2 more authors.
American Journal of Ophthalmology | Year: 2015

Purpose To report the clinical features and management of mitogen-activated protein kinase kinase inhibitor-associated ocular side effects in 4 patients with advanced melanoma and a review of literature. Design Interventional case series. Methods Four patients with advanced cutaneous melanoma were treated with a mitogen-activated protein kinase kinase (MEK) inhibitor as single therapy or together with a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor. All patients underwent ophthalmologic examinations at regular intervals or as needed, including visual acuity, intraocular pressure, external eye examination, and funduscopy. When pathologic findings were found, patients underwent visual field examination, optical coherence tomography (OCT), and/or fluorescein angiography. Ocular toxicity was assessed and handled according to the Common Terminology Criteria for Adverse Events. Results Ocular adverse events appeared early in the treatment. In 3 patients OCT revealed subfoveal neuroretinal elevation, often asymptomatic, also after discontinuation and re-starting of MEK inhibitor. Vascular injury appeared in 2 patients, in 1 case associated with a visual field defect reduced after discontinuation of the drug and use of systemic therapy. In 1 case an inflammatory reaction was observed in the anterior chamber. Visual symptoms were usually mild and short-lived. Conclusions MEK inhibitor as a single agent or in combination with BRAF inhibitor induces transient retinopathy with time-dependent recurrence and usually mild visual symptoms. Vascular injuries can be observed and their management is essential in clinical practice. It is important to investigate all previous ocular disorders, systemic conditions, and pharmacologic interactions of MEK inhibitor that could facilitate the onset of associated ocular effects. © 2015 by Elsevier Inc. All Rights Reserved.


Malfettone A.,National Cancer Research Center Giovanni Paolo | Silvestris N.,Medical Oncology Unit | Saponaro C.,National Cancer Research Center Giovanni Paolo | Ranieri G.,Interventional Radiology Unit | And 6 more authors.
Journal of Cellular and Molecular Medicine | Year: 2013

Tryptase(+) mast cells (MCs), abundant in the invasive front of tumours, contribute to tissue remodelling. Indeed, protease-activated receptor-2 (PAR-2) activation by MC-tryptase is considered an oncogenic event in colorectal cancer (CRC). Recently, we have suggested NHERF1 as a potential new marker in CRC. In this study, we aimed to determine the distribution of tryptase(+) MCs and PAR-2 and to examine the relationship between PAR-2 and NHERF1, investigating their reputed usefulness as tumour markers. We studied a cohort of 115 CRC specimens including primary cancer (C) and adjacent normal mucosa (NM) by immunohistochemical double staining, analyzing the protein expression of MC-tryptase, PAR-2 and cytoplasmic NHERF1. MC density was higher in NM than in C. Tumours with high TNM stage and poor grade showed the highest MC density. A higher PAR-2 immunoreactivity characterized tumours most infiltrated by MCs compared with samples with low MC density. Furthermore, PAR-2 overexpression was associated with advanced TNM stage, poor grade and lymphovascular invasion (LVI). A positive correlation existed between tryptase(+) MC density and PAR-2 expression. Cytoplasmic NHERF1 was higher in C than in NM and overexpressing tumours resulted associated with nodal and distant metastases, poor grade and LVI. PAR-2 correlated with cytoplasmic NHERF1 and the PAR-2(+)/cytoplasmic NHERF1(+) expression immunophenotype identified tumours associated with unfavourable prognosis and aggressive clinical parameters. Our data indicate that the high density of tryptase(+) MCs at invasive margins of tumours was associated with advanced stages of CRC and was strongly correlated with PAR-2 expression. © 2013 The Authors. Journal of Cellular and Molecular Medicine Published by Foundation for Cellular and Molecular Medicine/Blackwell Publishing Ltd.


Bellizzi A.,University of Bari | Greco M.R.,University of Bari | Rubino R.,University of Bari | Paradiso A.,National Cancer Research Center Giovanni Paolo | And 4 more authors.
International Journal of Oncology | Year: 2015

Triple negative breast cancer (TNBC) patients cannot be treated with endocrine therapy or targeted therapies due to lack of related receptors. These patients overexpress the epidermal growth factor receptor (EGFR), but are resistant to tyrosine kinase inhibitors (TKIs) and anti-EGFR therapies. Mechanisms suggested for resistance to TKIs include EGFR independence, mutations and alterations in EGFR and in its downstream signalling pathways. Ligand-induced endocytosis and degradation of EGFR play important roles in the downregulation of the EGFR signal suggesting that its activity could be regulated by targeting its trafficking. Evidence in normal cells showing that the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) can associate with EGFR to regulate its trafficking, led us to hypothesize that NHERF1 expression levels could regulate EGFR trafficking and functional expression in TNBC cells and, in this way, modulate its role in progression and response to treatment. We investigated the subcellular localization of NHERF1 and its interaction with EGFR in a metastatic basal like TNBC cell model, MDA-MB-231, and the role of forced NHERF1 overexpression and/or stimulation with EGF on the sensitivity to EGFR specific TKI treatment with gefitinib. Stimulation with EGF induces an interaction of NHERF1 with EGFR to regulate its localization, degradation and function. NHERF1 overexpression is sufficient to drive its interaction with EGFR in non-stimulated conditions, inhibits EGFR degradation and increases its retention time in the plasma membrane. Importantly, NHERF1 overexpression strongly sensitized the cell to the pharmacological inhibition by gefitinib of EGFR-driven growth, motility and invadopodia-dependent ECM proteolysis. The further determination of how the NHERF1-EGFR interaction is regulated may improve our understanding of TNBC resistance to the action of existing anticancer drugs.


PubMed | National Cancer Research Center Giovanni Paolo and University of Bari
Type: Case Reports | Journal: American journal of ophthalmology | Year: 2015

To report the clinical features and management of mitogen-activated protein kinase kinase inhibitor-associated ocular side effects in 4 patients with advanced melanoma and a review of literature.Interventional case series.Four patients with advanced cutaneous melanoma were treated with a mitogen-activated protein kinase kinase (MEK) inhibitor as single therapy or together with a v-raf murine sarcoma viral oncogene homolog B1 (BRAF) inhibitor. All patients underwent ophthalmologic examinations at regular intervals or as needed, including visual acuity, intraocular pressure, external eye examination, and funduscopy. When pathologic findings were found, patients underwent visual field examination, optical coherence tomography (OCT), and/or fluorescein angiography. Ocular toxicity was assessed and handled according to the Common Terminology Criteria for Adverse Events.Ocular adverse events appeared early in the treatment. In 3 patients OCT revealed subfoveal neuroretinal elevation, often asymptomatic, also after discontinuation and re-starting of MEK inhibitor. Vascular injury appeared in 2 patients, in 1 case associated with a visual field defect reduced after discontinuation of the drug and use of systemic therapy. In 1 case an inflammatory reaction was observed in the anterior chamber. Visual symptoms were usually mild and short-lived.MEK inhibitor as a single agent or in combination with BRAF inhibitor induces transient retinopathy with time-dependent recurrence and usually mild visual symptoms. Vascular injuries can be observed and their management is essential in clinical practice. It is important to investigate all previous ocular disorders, systemic conditions, and pharmacologic interactions of MEK inhibitor that could facilitate the onset of associated ocular effects.


Strippoli S.,National Cancer Research Center Giovanni Paolo | Lorusso V.,National Cancer Research Center Giovanni Paolo | Albano A.,National Cancer Research Center Giovanni Paolo | Guida M.,National Cancer Research Center Giovanni Paolo
BMC Complementary and Alternative Medicine | Year: 2013

Background: Rhabdomyolysis is an uncommon side effect of trabectedin which is used for the second line therapy of metastatic sarcoma after anthracycline and ifosfamide failure. This side effect may be due to pharmacokinetic interactions caused by shared mechanisms of metabolism involving the cytochrome P450 (CYP) system in the liver. Here, for the first time in literature, we describe the unexpected onset of heavy toxicity, including rhabdomyolysis, after the fourth course of trabectedin in a patient with retroperitoneal liposarcoma who at the same time was taking an alternative herbal medicine suspected of triggering this adverse event.Case presentation: This is the case of a 56 year old Caucasian man affected by a relapsed de-differentiated liposarcoma who, after the fourth cycle of second-line chemotherapy with trabectedin, complained of sudden weakness, difficulty walking and diffuse muscle pain necessitating complete bed rest. Upon admission to our ward the patient showed grade (G) 4 pancytopenia and a marked increase in liver lytic enzymes, serum levels of myoglobin, creatine phosphokinase (CPK) and lactate dehydrogenase. No cardiac or kidney function injuries were present. Based on these clinical and laboratory features, our conclusive diagnosis was of rhabdomyolysis induced by trabectedin.The patient did not report any trauma or muscular overexertion and no co-morbidities were present. He had not received any drugs during treatment with trabectedin, but upon further questioning the patient informed us he had been taking a folk medicine preparation of chokeberry (Aronia melanocarpa) daily during the last course of trabectedin and in the 2 subsequent weeks.One week after hospitalization and cessation of intake of chokeberry extract, CPK and other markers of myolysis slowly returned to standard range, and the patient noted a progressive recovery of muscle strength.The patient was discharged on day 14 when a blood transfusion and parenteral hydration gradually lowered general toxicity. Progressive mobilization of the patient was obtained as well as a complete normalization of the laboratory findings.Conclusions: The level of evidence of drug interaction leading to the adverse event observed in our patient was 2 (probable). Thus our case underlines the importance of understanding rare treatment-related toxicities such as trabectedin-induced rhabdomyolysis and the possible role of the drug-drug interactions in the pathogenesis of this rare side effect. Furthermore, this report draws attention to a potential problem of particular concern, that of nutritional supplements and complementary and alternative drug interactions. These are not widely recognized and can cause treatment failure. © 2013 Strippoli et al.; licensee BioMed Central Ltd.

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