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Pancreatic Neoplasms: HELP
Articles by Nicola Silvestris
Based on 27 articles published since 2010
(Why 27 articles?)
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Between 2010 and 2020, Nicola Silvestris wrote the following 27 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Editorial Focus on pancreatic cancer. 2018

Silvestris, Nicola / Falconi, Massimo. ·Medical Oncology Unit and Scientific Directorate, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Pancreatic Surgery Unit, Pancreas Translational and Research Institute, Scientific Institute, San Raffaele Hospital, University Vita e Salute, Milan, Italy. ·Dig Liver Dis · Pubmed #30301604.

ABSTRACT: -- No abstract --

2 Review Moving the Target on the Optimal Adjuvant Strategy for Resected Pancreatic Cancers: A Systematic Review with Meta-Analysis. 2020

Galvano, Antonio / Castiglia, Marta / Rizzo, Sergio / Silvestris, Nicola / Brunetti, Oronzo / Vaccaro, Giovanni / Gristina, Valerio / Barraco, Nadia / Bono, Marco / Guercio, Giovanni / Graceffa, Giuseppa / Fulfaro, Fabio / Gori, Stefania / Bazan, Viviana / Russo, Antonio. ·Medical Oncology Unit, Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy. · Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II" of Bari, Viale Orazio Flacco, 65, 70124 Bari, Italy. · Department of Surgical, Oncological and Stomatological Sciences, University of Palermo, Palermo, Via del Vespro 129, 90127 Palermo, Italy. · Oncology Department, IRCCS Sacro Cuore Don Calabria Hospital, 37024 Negrar, Verona, Italy. · Department of Experimental Biomedicine and Clinical Neurosciences, School of Medicine, University of Palermo, Via del Vespro 129, 90127 Palermo, Italy. ·Cancers (Basel) · Pubmed #32110977.

ABSTRACT: Combination regimens have shown superiority over single agents in the adjuvant treatment of resected pancreatic cancer (PC), but there are no data supporting definition of the best regimen. This work aimed to compare the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel in PC patients. A meta-analysis was performed for direct comparison between trials comparing combination regimens and gemcitabine monotherapy. Subsequently, an indirect comparison was made between trials investigating the efficacy and safety of mFOLFIRINOX, gemcitabine+capecitabine, and gemcitabine+nab/paclitaxel because of the same control arm (gemcitabine). A total of three studies met the selection criteria and were included in our indirect comparison. Indirect comparisons for efficacy outcomes showed a benefit in terms of DFS (disease-free survival)/EFS (event-free survival)/RFS (relapse-free survival) for both mFOLFIRINOX versus gemcitabine+capecitabine (HR 0.69, 95% CI 0.52-0.91) and versus gemcitabine+nab/paclitaxel (HR 0.67, 95% CI 0.50-0.90). No significant advantage was registered for OS (overall survival). Indirect comparisons for safety showed an increase in terms of G3-5 AEs (with the exception of neutropenia) for mFOLFIRINOX versus gemcitabine+capecitabine (RR 1.24, 95% CI 1.03-1.50), while no significant differences were observed versus gemcitabine+nab/paclitaxel. According to our results, mFOLFIRINOX is feasible and manageable and could represent a first option for fit PC resected patients.

3 Review Systematic Review of Irreversible Electroporation Role in Management of Locally Advanced Pancreatic Cancer. 2019

Lafranceschina, Stefano / Brunetti, Oronzo / Delvecchio, Antonella / Conticchio, Maria / Ammendola, Michele / Currò, Giuseppe / Piardi, Tullio / de'Angelis, Nicola / Silvestris, Nicola / Memeo, Riccardo. ·Department of Emergency and Organ Transplantation, University "Aldo Moro" of Bary, 70124 Bary, Italy. stefano.lafranceschina@gmail.com. · Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II 2", 70124 Bari, Italy. dr.oronzo.brunetti@tiscali.it. · Department of Emergency and Organ Transplantation, University "Aldo Moro" of Bary, 70124 Bary, Italy. antodel88@libero.it. · Department of Emergency and Organ Transplantation, University "Aldo Moro" of Bary, 70124 Bary, Italy. maria_cont@hotmail.it. · Department of Health Science, General Surgery, Magna Graecia University, Medicine School of Germaneto, 88100 Catanzaro, Italy. michele.ammendola@libero.it. · Department of Health Science, General Surgery, Magna Graecia University, Medicine School of Germaneto, 88100 Catanzaro, Italy. currog@unime.it. · Department of Surgery, Hôpital Robert Debré, University of Champagne-Ardenne, 51100 Reims, France. tullio.piardi@gmail.com. · Department of Digestive and Hepato-Pancreato-Biliary Surgery, Henri Mondor University Hospital, AP-HP, Université Paris-Est Créteil (UPEC), 51 Avenue du Maréchal de Lattre de Tassigny, 94010 Créteil, France. nic.deangelis@yahoo.it. · Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II 2", 70124 Bari, Italy. n.silvestris@oncologico.bari.it. · Department of Biomedical Sciences and Human Oncology, University of Bari 'Aldo Moro', 70124 Bari, Italy. n.silvestris@oncologico.bari.it. · Department of Emergency and Organ Transplantation, University "Aldo Moro" of Bary, 70124 Bary, Italy. drmemeo@yahoo.it. ·Cancers (Basel) · Pubmed #31684186.

ABSTRACT: BACKGROUND: Ablative techniques provide in patients with locally advanced pancreatic cancer (LAPC) symptomatic relief, survival benefit and potential downsizing. Irreversible Electroporation (IRE) represents potentially an ideal solution as no thermal tissue damage occurs. The purpose of this review is to present an overview on safety, feasibility, oncological results, survival and quality of life improvement obtained by IRE. METHODS: A systematic search was performed in PubMed, regarding the use of IRE on PC in humans for studies published in English up to March 2019. RESULTS: 15 original studies embodying 691 patients with unresectable LAPC who underwent IRE were included. As emerged, IRE works better on tumour sizes between 3-4 cm. Oncological results are promising: median OS from diagnosis or treatment up to 27 months. Two groups investigated borderline resectable tumours treated with IRE before resection with margin attenuation, whereas IRE has proved to be effective in pain control. CONCLUSIONS: Electroporation is bringing new hopes in LAPC management. The first aim of IRE is to offer a palliative treatment. Further efforts are needed for patient selection, as well as the use of IRE for 'margin accentuation' during surgical resection. Even if promising, IRE needs to be validated in large, randomized, prospective series.

4 Review Prognostic Role of High-Grade Tumor Budding in Pancreatic Ductal Adenocarcinoma: A Systematic Review and Meta-Analysis with a Focus on Epithelial to Mesenchymal Transition. 2019

Lawlor, Rita T / Veronese, Nicola / Nottegar, Alessia / Malleo, Giuseppe / Smith, Lee / Demurtas, Jacopo / Cheng, Liang / Wood, Laura D / Silvestris, Nicola / Salvia, Roberto / Scarpa, Aldo / Luchini, Claudio. ·ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. ritateresa.lawlor@univr.it. · National Institute of Gastroenterology-Research Hospital, IRCCS "S. de Bellis", 70013 Castellana Grotte, Italy. ilmannato@gmail.com. · Department of Surgery, Section of Pathology, San Bortolo Hospital, 36100 Vicenza, Italy. alessia.nottegar@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. giuseppe.malleo@univr.it. · Cambridge Centre for Sport and Excercise Sciences, Anglia Ruskin University, Cambridge CB1 1PT, UK. Lee.Smith@anglia.ac.uk. · Primary Care Department, Azienda USL Toscana Sud Est, 58100 Grosseto, Italy. eritrox7@gmail.com. · Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN 46202, USA. liang_cheng@yahoo.com. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21231, USA. ldelong1@jhmi.edu. · Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, 70124 Bari, Italy. silvestrisnicola@gmail.com. · Department of General and Pancreatic Surgery, The Pancreas Institute, University and Hospital Trust of Verona, 37142 Verona, Italy. roberto.salvia@univr.it. · ARC-Net Research Center, University and Hospital Trust of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. aldo.scarpa@univr.it. · Department of Diagnostics and Public Health, Section of Pathology, University of Verona, 37134 Verona, Italy. claudio.luchini@univr.it. ·Cancers (Basel) · Pubmed #30669452.

ABSTRACT: This study aims at clarifying the prognostic role of high-grade tumor budding (TB) in pancreatic ductal adenocarcinoma (PDAC) with the first systematic review and meta-analysis on this topic. Furthermore, we analyzed with a systematic review the relationship between TB and a recently suggested TB-associated mechanism: the epithelial to mesenchymal transition (EMT). Analyzing a total of 613 patients, 251 of them (40.9%) with high grade-TB, we found an increased risk of all-cause mortality (RR, 1.46; 95% CI, 1.13⁻1.88,

5 Review Molecular profiling of pancreatic neuroendocrine tumors (pNETS) and the clinical potential. 2018

Camilli, Massimiliano / Papadimitriou, Konstantinos / Nogueira, Amanda / Incorvaia, Lorena / Galvano, Antonio / D'Antonio, Federica / Ferri, Jose / Santini, Daniele / Silvestris, Nicola / Russo, Antonio / Peeters, Marc / Rolfo, Christian. ·a Department of Oncology , University Campus Biomedico of Rome , Rome , Italy. · b Oncology Department , Antwerp University Hospital , Edegem , Belgium. · c Phase I-Early Clinical Trials Unit, Oncology Department , Antwerp University Hospital & Center for Oncological Research (CORE) , Antwerp , Belgium. · d Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology , University of Palermo , Palermo , Italy. · e Medical Oncology Department , Oncological institute Giovanni Paolo II , Bari , Italy. ·Expert Rev Gastroenterol Hepatol · Pubmed #29629846.

ABSTRACT: INTRODUCTION: Pancreatic neuroendocrine tumors (pNETs) represent a small part of pancreatic neoplasms, and the knowledge about their indolent clinical course remains a subject of investigation. They occur sporadically or as part of familial cancer syndromes and are classified by WHO in 3 categories. There is ongoing research to understand their molecular profiling and leading mutations. Areas covered: The aim of this review is to clarify the overall aspects of tumorigenesis, to expose the latest developments in understanding the course of the disease and the possible therapeutic implications of these. The review also discusses functional and non-functional pNETs and associated inherited syndromes as well as pNET molecular profiling and its possible guidance in the use of targeted therapy. Expert commentary: In the next decade, a more extensive application of new technologies will help improve quality of life and survival, individualizing treatment protocols and identifying which therapeutic strategy is more suitable for each kind of NET.

6 Review Mast cells and angiogenesis in pancreatic ductal adenocarcinoma. 2018

Longo, Vito / Tamma, Roberto / Brunetti, Oronzo / Pisconti, Salvatore / Argentiero, Antonella / Silvestris, Nicola / Ribatti, Domenico. ·Department of Medical Oncology, Hospital of Taranto, Taranto, Italy. · Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy. · National Cancer Institute "Giovanni Paolo II", Bari, Italy. · Medical Oncology Unit and Scientific Directorate, Cancer Institute "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124, Bari, Italy. · Medical Oncology Unit and Scientific Directorate, Cancer Institute "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124, Bari, Italy. n.silvestris@oncologico.bari.it. ·Clin Exp Med · Pubmed #29492715.

ABSTRACT: Mast cells are recognized as critical components of the tumor stromal microenvironment in several solid and hematological malignancies, promoting angiogenesis and tumor growth. A correlation between mast cells infiltration, angiogenesis and tumor progression has been reported for pancreatic ductal adenocarcinoma as well. Mast cells contribute to the aggressiveness of the pancreatic ductal carcinoma enhancing the expression of several pro-angiogenic factors such as vascular endothelial growth factor, fibroblast growth factor-2, platelet-derived growth factor and angiopoietin-1 as well as stimulating the pancreatic cancer cells proliferation by IL-13 and tryptase. The disruption of this pro-angiogenic and proliferative stimulation by inhibiting the mast cells migration and degranulation is under investigation as a potential therapeutic approach in pancreatic ductal adenocarcinoma patients. This review will summarize the literature concerning the mast cells infiltration in the pancreatic ductal adenocarcinoma analyzing its role in angiogenesis and tumor progression.

7 Review The role of inflammatory cytokines and tumor associated macrophages (TAMs) in microenvironment of pancreatic cancer. 2018

Farajzadeh Valilou, Saeed / Keshavarz-Fathi, Mahsa / Silvestris, Nicola / Argentiero, Antonella / Rezaei, Nima. ·Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran. · Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Students' Scientific Research Center, Tehran University of Medical Sciences, Tehran, Iran; Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran. Electronic address: m-keshavarz@student.tums.ac.ir. · Medical Oncology Unit and Scientific Directorate, National Cancer Institute IRCCS "Giovanni Paolo II", Bari, Italy; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Bari, Italy. · Medical Oncology Unit, National Cancer Institute IRCCS "Giovanni Paolo II", Bari, Italy; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Bari, Italy. · Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran; Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Sheffield, UK. Electronic address: rezaei_nima@yahoo.com. ·Cytokine Growth Factor Rev · Pubmed #29373197.

ABSTRACT: Pancreatic cancer is considered as one of the most lethal types of cancer due to its poor prognosis and lack of effective therapeutic approaches. Although many studies have been done on pancreatic cancer, the current treatment methods did not exhibit successful results. Hence, novel strategies are needed for treatment of pancreatic cancer. The microenvironment of pancreatic cancer contains many factors such as inflammatory cytokines and tumor associated macrophages (TAMs), which influence the tumor's status. These factors can be upregulated and consequently lead to exacerbation of tumor progression. Understanding the role of pro- and anti-inflammatory cytokines and the function of TAMs in the pancreatic cancer microenvironment might lead to development and improvement of novel strategies in the diagnosis and treatment of pancreatic cancer and may result in promising treatments for this type of cancer.

8 Review Second-line chemotherapy for advanced pancreatic cancer: Which is the best option? 2017

Aprile, Giuseppe / Negri, Francesca V / Giuliani, Francesco / De Carlo, Elisa / Melisi, Davide / Simionato, Francesca / Silvestris, Nicola / Brunetti, Oronzo / Leone, Francesco / Marino, Donatella / Santini, Daniele / Dell'Aquila, Emanuela / Zeppola, Tea / Puzzoni, Marco / Scartozzi, Mario. ·Department of Oncology, University and General Hospital, Udine, Italy; Department of Oncology, San Bortolo General Hospital, ULSS8 Berica, East District, Vicenza, Italy. Electronic address: giuseppe.aprile@aulss8.veneto.it. · Medical Oncology, University Hospital, Parma, Italy. · Medical Oncology Unit, National Cancer Institute IRCCS "Giovanni Paolo II", Bari, Italy. · Department of Oncology, University and General Hospital, Udine, Italy. · Medical Oncology, University of Verona, Italy. · Medical Oncology, Candiolo Cancer Institute, FPO, IRCCS, University of Torino (TO), Italy. · Department of Medical Oncology, University Campus Bio-Medico, Roma, Italy. · Department of Oncology, University Hospital, Cagliari, Italy. ·Crit Rev Oncol Hematol · Pubmed #28602164.

ABSTRACT: Despite recent biological insight and therapeutic advances, the prognosis of advanced pancreatic cancer still remains poor. For more than 15 years, gemcitabine monotherapy has been the cornerstone of first-line treatment. Recently, prospective randomized trials have shown that novel upfront combination regimens tested in prospective randomized trials have resulted in improved patients' outcome increasing the proportion of putative candidate to second-line therapy. There is no definite standard of care after disease progression. A novel formulation in which irinotecan is encapsulated into liposomal-based nanoparticles may increase the efficacy of the drug without incrementing its toxicity. NAPOLI-1 was the first randomized trial to compare nanoliposomal irinotecan and fluorouracil-leucovorin (5-FU/LV) to 5-FU/LV alone after a gemcitabine-based chemotherapy. This review focuses on the current data for the management of second-line treatment for metastatic pancreatic adenocarcinoma, presents the most interesting ongoing clinical trials and illustrates the biologically-driven future options beyond disease progression.

9 Review Multimodal treatment of resectable pancreatic ductal adenocarcinoma. 2017

Silvestris, Nicola / Brunetti, Oronzo / Vasile, Enrico / Cellini, Francesco / Cataldo, Ivana / Pusceddu, Valeria / Cattaneo, Monica / Partelli, Stefano / Scartozzi, Mario / Aprile, Giuseppe / Casadei Gardini, Andrea / Morganti, Alessio Giuseppe / Valentini, Vincenzo / Scarpa, Aldo / Falconi, Massimo / Calabrese, Angela / Lorusso, Vito / Reni, Michele / Cascinu, Stefano. ·Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: dr.oronzo.brunetti@tiscali.it. · Department of Oncology, Azienda Ospedaliero-Universitaria Pisana, Pisa, Italy. Electronic address: e.vasile@ao.pisa.toscana.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: francesco.cellini@uniroma3.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: cataldo.ivana@gmail.com. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: oncologiamedica2reparto@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy. Electronic address: aprile83@gmail.com. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: partelli.stefano@hsr.it. · Medical Oncology Unit, University of Cagliari, Cagliari, Italy. Electronic address: marioscartozzi@gmail.com. · Department of Medical Oncology, University and General Hospital, Udine, Italy; Department of Medical Oncology, General Hospital of Vicenza, Vicenza, Italy. Electronic address: aprile.giuseppe@aoud.sanita.fvg.it. · Medical Oncology Unit, IRCCS, Meldola, Italy. Electronic address: casadeigardini@gmail.com. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. Electronic address: alessio.morganti2@unibo.it. · Radiation Oncology Department, Gemelli ART, Università Cattolica del Sacro Cuore, Roma, Italy. Electronic address: vincenzo.valentini@unicatt.it. · ARC-NET Research Centre, University of Verona, Verona, Italy. Electronic address: aldo.scarpa@univr.it. · Pancreatic Surgery Unit, Pancreas Translational and Clinical Research Centre, San Raffaele Scientific Institute, 'Vita-Salute' University, Milan, Italy. Electronic address: falconi.massimo@hsr.it. · Radiology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: acalabrese22@gmail.com. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. Electronic address: vito.lorusso@oncologico.bari.it. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milan, Italy. Electronic address: reni.michele@hsr.it. · Modena Cancer Center, Policlinico di Modena Università di Modena e Reggio Emilia, Italy. Electronic address: cascinu@yahoo.com. ·Crit Rev Oncol Hematol · Pubmed #28259290.

ABSTRACT: After a timing preoperative staging, treatment of resectable pancreatic adenocarcinoma (PDAC) includes surgery and adjuvant therapies, the former representing the initial therapeutic option and the latter aiming to reduce the incidence of both distant metastases (chemotherapy) and locoregional failures (chemoradiotherapy). Herein, we provide a critical overview on the role of multimodal treatment in PDAC and on new opportunities related to current more active poli-chemotherapy regimens, targeted therapies, and the more recent immunotherapy approaches. Moreover, an analysis of pathological markers and clinical features able to help clinicians in the selection of the best therapeutic strategy will be discussed. Lastly, the role of neoadjuvant treatment of initially resectable disease will be considered mostly in patients whose malignancy shows morphological but not clinical or biological criteria of resectability. Depending on the results of these investigational studies, today a multidisciplinary approach can offer the best address therapy for these patients.

10 Review Angiogenesis in pancreatic ductal adenocarcinoma: A controversial issue. 2016

Longo, Vito / Brunetti, Oronzo / Gnoni, Antonio / Cascinu, Stefano / Gasparini, Giampietro / Lorusso, Vito / Ribatti, Domenico / Silvestris, Nicola. ·Department of Medical Oncology, Hospital of Taranto, Taranto, Italy. · Medical Oncology Unit, Cancer Institute "Giovanni Paolo II", Bari, Italy. · Department of Medical Oncology, Hospital "Vito Fazi" of Lecce, Lecce, Italy. · Medical Oncology Unit, University of Modena, Modena, Italy. · Scientific Direction, Cancer Institute "Giovanni Paolo II", Bari, Italy. · Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy. · National Cancer Institute "Giovanni Paolo II", Bari, Italy. ·Oncotarget · Pubmed #27462915.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early loco-regional spread and distant metastases at diagnosis, leading to dismal prognosis with a 5-year overall survival rate moderately over than 5%. This malignancy is largely resistant to chemotherapy and radiation, but the reasons of the refractoriness to the therapies is still unknown. Evidence is accumulating to indicate that the PDAC microenvironment and vascularity strongly contribute to the clinical features of this disease. In particular, PDAC is characterized by excessive dense extracellular matrix deposition associated to vasculature collapse and hypoxia with low drug delivery, explaining at least partly the low efficacy of antiangiogenic drugs in this cancer. Strategies aimed to modulate tumor stroma favoring vasculature perfusion and chemotherapeutics delivery are under investigation.

11 Review Neoadjuvant multimodal treatment of pancreatic ductal adenocarcinoma. 2016

Silvestris, Nicola / Longo, Vito / Cellini, Francesco / Reni, Michele / Bittoni, Alessandro / Cataldo, Ivana / Partelli, Stefano / Falconi, Massimo / Scarpa, Aldo / Brunetti, Oronzo / Lorusso, Vito / Santini, Daniele / Morganti, Alessio / Valentini, Vincenzo / Cascinu, Stefano. ·Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. Electronic address: n.silvestris@oncologico.bari.it. · Medical Oncology Unit, 'Mons R Dimiccoli' Hospital, Barletta, Italy. · Radiation Oncology Department, Policlinico Universitario Campus Bio-Medico, Rome, Italy. · Medical Oncology Department, IRCCS San Raffaele Scientific Institute, Milano, Italy. · Medical Oncology Clinic, AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · ARC-NET Research Centre, University of Verona, Italy. · Pancreatic Unit, Department of Surgery, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Medical Oncology Unit, National Cancer Research Centre "Giovanni Paolo II", Bari, Italy. · Medical Oncology Unit, University Campus Biomedico, Roma, Italy. · Radiation Oncology Center, Dept. of Experimental, Diagnostic and Specialty Medicine - DIMES, University of Bologna, Italy. ·Crit Rev Oncol Hematol · Pubmed #26653573.

ABSTRACT: Treatment of pancreatic ductal adenocarcinoma (PDAC) is increasingly multidisciplinary, with neoadjuvant strategies (chemotherapy, radiation, and surgery) administered in patients with resectable, borderline resectable, or locally advanced disease. The rational supporting this management is the achievement of both higher margin-negative resections and conversion rates into potentially resectable disease and in vivo assessment of novel therapeutics. International guidelines suggest an initial staging of the disease followed by a multidisciplinary approach, even considering the lack of a treatment approach to be considered as standard in this setting. This review will focus on both literature data supporting these guidelines and on new opportunities related to current more active chemotherapy regimens. An analysis of the pathological assessment of response to therapy and the potential role of target therapies and translational biomarkers and ongoing clinical trials of significance will be discussed.

12 Review Robotic radiosurgery in pancreatic cancer: A systematic review. 2015

Buwenge, Milly / Cellini, Francesco / Silvestris, Nicola / Cilla, Savino / Deodato, Francesco / Macchia, Gabriella / Mattiucci, Gian C / Valentini, Vincenzo / Morganti, Alessio G. ·Milly Buwenge, Francesco Deodato, Gabriella Macchia, Department of Radiation Oncology, Università Cattolica del Sacro Cuore, 86100 Campobasso, Italy. ·World J Gastroenterol · Pubmed #26309369.

ABSTRACT: AIM: To present a systematic review of techniques and clinical results. METHODS: A systematic review of published literature was performed. Only studies reporting patient outcome after radiosurgery (single fraction) delivered with robotic devices [i.e., robotic radiosurgery (RRS)] have been analyzed. RESULTS: A total of 96 patients from 5 studies were included. The studies are characterized by small series and different methods in terms of dose, target definition, combination with chemotherapy and/or standard fractionated radiotherapy and evaluation modalities. Preliminary results are positive in terms of tumor response (ORR = 56%) and local control of the tumor (crude rate of local progressions: 19.5%). Results for median overall survival (11.4 mo) seem comparable with the ones of prolonged chemoradiation (range: 8.6-13.0 mo). However, gastrointestinal toxicity seems to be the main limitation of RRS, especially at the duodenal level. CONCLUSION: RRS allows for local treatment in a shortened time (1 fraction) compared to traditional treatments (about 1 mo), providing the possibility for an easy integration with systemic therapies. Preliminary results did not show any outcome differences compared to standard chemoradiation. Thus, further efforts to reduce gastrointestinal toxicity are strongly needed.

13 Review MicroRNA in pancreatic adenocarcinoma: predictive/prognostic biomarkers or therapeutic targets? 2015

Brunetti, Oronzo / Russo, Antonio / Scarpa, Aldo / Santini, Daniele / Reni, Michele / Bittoni, Alessandro / Azzariti, Amalia / Aprile, Giuseppe / Delcuratolo, Sabina / Signorile, Michele / Gnoni, Antonio / Palermo, Loredana / Lorusso, Vito / Cascinu, Stefano / Silvestris, Nicola. ·Medical Oncology Unit, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Surgical, Oncological and Oral Sciences, Section of Medical Oncology, University of Palermo, Palermo, Italy. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medical Oncology, University Campus Bio-Medico, Rome, Italy. · Department of Medical Oncology, San Raffaele Scientific Institute, Milan, Italy. · AOU Ospedali Riuniti, Polytechnic University of the Marche Region, Ancona, Italy. · Clinical and Preclinical Pharmacology Laboratory, National Cancer Research Centre, Istituto Tumori Giovanni Paolo II, Bari, Italy. · Department of Medical Oncology, University Hospital of Udine, Udine, Italy. · Department of Medical Oncology, Hospital of Taranto, Taranto, Italy. ·Oncotarget · Pubmed #26259238.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a tumor with a poor prognosis, short overall survival and few chemotherapeutic choices. MicroRNAs (miRNAs) are non-coding, single-stranded RNAs of around 22 nucleotides involved in the pathogenic mechanisms of carcinogenesis and metastasis. They have been studied in many tumors in order to identify potential diagnostic, prognostic or therapeutic targets. In the current literature, many studies have analyzed the role of miRNAs in PDAC. In fact, the absence of appropriate biomarkers, the difficultly of early detection of this tumor, and the lack of effective chemotherapy in patients with unresectable disease have focused attention on miRNAs as new, interesting advance in this malignancy. In this review we analyzed the role of miRNAs in PDAC in order to understand the mechanisms of action and the difference between the onco-miRNA and the tumor suppressor miRNA. We also reviewed all the data related to the use of these molecules as predictive as well as prognostic biomarkers in the course of the disease. Finally, the possible therapeutic use of miRNAs or anti-miRNAs in PDAC is also discussed. In conclusion, although there is still no clinical application for these molecules in PDAC, it is our opinion that the preclinical evidence of the role of specific miRNAs in carcinogenesis, the possibility of using miRNAs as diagnostic or prognostic biomarkers, and their potential therapeutic role, warrant future studies in PDAC.

14 Review Clinical application of microRNA testing in neuroendocrine tumors of the gastrointestinal tract. 2014

Vicentini, Caterina / Fassan, Matteo / D'Angelo, Edoardo / Corbo, Vincenzo / Silvestris, Nicola / Nuovo, Gerard J / Scarpa, Aldo. ·ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy. · ARC-Net Research Centre, University and Hospital Trust of Verona, Verona 37134, Italy. matteo.fassan@gmail.com. · Medical Oncology Unit, National Cancer Institute "Giovanni Paolo II", Bari 70124, Italy. · Comprehensive Cancer Centre, Ohio State University, Columbus, OH 43210, USA. ·Molecules · Pubmed #24566314.

ABSTRACT: It is well documented that dysregulation of microRNAs is a hallmark of human cancers. Thus, this family of small non-coding regulatory molecules represents an excellent source of sensitive biomarkers. Unique microRNAs expression profiles have been associated with different types and subsets of gastrointestinal tumors including gastroenteropancreatic neuroendocrine tumors (GEP-NETs). GEP-NETs are a heterogeneous group of epithelial neoplasms with neuroendocrine differentiation. At present, early detection and surgical resection of GEP-NETs represent the best chance for a cure. Thus, clinically useful biomarkers for GEP-NETs that strongly correlate with early detection are urgently needed. The purpose of this review is to summarize the role of miRNAs in GEP-NET carcinogenesis and their possible use as novel diagnostic, prognostic and predictive biomarkers.

15 Review Target therapies in pancreatic carcinoma. 2014

Silvestris, Nicola / Gnoni, Antonio / Brunetti, Anna Elisabetta / Vincenti, Leonardo / Santini, Daniele / Tonini, Giuseppe / Merchionne, Francesca / Maiello, Evaristo / Lorusso, Vito / Nardulli, Patrizia / Azzariti, Amalia / Reni, Michele. ·Medical Oncology Unit, National Cancer Research Centre - Istituto Tumori Giovanni Paolo II, Viale Orazio Flacco, 65, 70124 Bari, Italy. n.silvestris@oncologico.bari.it. ·Curr Med Chem · Pubmed #23992319.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) occurs in the majority of cases with early locoregional spread and distant metastases at diagnosis, leading to dismal prognosis and limited treatment options. Traditional cytotoxic chemotherapy provides only modest benefit to patients with PDAC. Identification of different molecular pathways, overexpressed in pancreatic cancer cells, has provided the opportunity to develop targeted therapies (monoclonal antibodies and small-molecule inhibitors) and peculiar new class of taxanes with a crucial therapeutic role in this cancer setting. A phase III trial has shown that erlotinib in combination with gemcitabine was clinically irrelevant and skin toxicity can be a positive prognostic factor. Moreover, the combination of cetuximab or erlotinib with radiotherapy in advanced pancreatic cancer has shown to be synergistic and a reversal of radio-resistance has been suggested by inhibition of VEGF/EGFR pathway. To overcome EGFR-inhibition therapy resistance several alternative pathways targets are under investigation (IGF- 1R, MMPs, Hedgehog proteins, m-TOR, MEK, COX-2) and provide the rationale for clinical use in phase II/III studies. Also nab-paclitaxel, a new taxanes class, uses high pancreatic albumin-binding protein SPARC levels to act in cancer cells with a less toxic and more effective dose with respect to classic taxanes. Understanding of molecular pathogenesis of pancreatic adenocarcinoma continues to expand. However, many promising data in preclinic and phase I/II trials did not yield promise in phase III trials, suggesting that identification of predictive biomarkers for these new agents is mandatory. The knowledge of biologic and molecular aspects of pancreatic cancer can be the basis for future therapeutic developments.

16 Review Carcinogenesis of pancreatic adenocarcinoma: precursor lesions. 2013

Gnoni, Antonio / Licchetta, Antonella / Scarpa, Aldo / Azzariti, Amalia / Brunetti, Anna Elisabetta / Simone, Gianni / Nardulli, Patrizia / Santini, Daniele / Aieta, Michele / Delcuratolo, Sabina / Silvestris, Nicola. ·Medical Oncology Unit, Hospital Vito Fazzi, Lecce 73100, Italy. n.silvestris@oncologico.bari.it. ·Int J Mol Sci · Pubmed #24084722.

ABSTRACT: Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy.

17 Review Combined modality treatments in pancreatic cancer. 2012

Lombardi, Lucia / Troiano, Michele / Silvestris, Nicola / Nanni, Luciano / Latiano, Tiziana Pia / Di Maggio, Gabriele / Cinieri, Saverio / Di Sebastiano, Pierluigi / Colucci, Giuseppe / Maiello, Evaristo. ·Oncology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy. ·Expert Opin Ther Targets · Pubmed #22443336.

ABSTRACT: INTRODUCTION: Of all the carcinomas, pancreatic carcinoma (PC) has the highest mortality rate, with a 1- and 5-year survival rate of 25% and less than 5% respectively. This is regardless of the stage at diagnosis. AREAS COVERED: In this review relevant literature assessing the evidence regarding preoperative and adjuvant chemoradiotherapy (CRT) is discussed. Furthermore, new therapeutic approaches are summarized, while the future direction regarding the multimodality approach to PC is also discussed. EXPERT OPINION: The role of combined-modality therapy for PC is continuously evolving. There have been several recent developments, as well as the completion of major, multi-institutional clinical trials. One of the challenges for the busy clinician is to appreciate the variation in staging, surgical expertise, and application of either definitive CRT or neo-adjuvant CRT for local and/or borderline disease.

18 Review Targeting EGFR in bilio-pancreatic and liver carcinoma. 2011

Fratto, Maria Elisabetta / Santini, Daniele / Vincenzi, Bruno / Silvestris, Nicola / Azzariti, Amalia / Tommasi, Stefania / Zoccoli, Alice / Galluzzo, Sara / Maiello, Evaristo / Colucci, Giuseppe / Tonini, Giuseppe. ·Medical Oncology, University Campus Bio-Medico, Rome. ·Front Biosci (Schol Ed) · Pubmed #21196353.

ABSTRACT: The key role of epidermal growth factor receptor(EGFR) in tumorigenesis has been demonstrated in several cancer types, so recent clinical trials have investigated their activity/efficacy in different settings. Two different types of EGFR-targeted agents were developed: monoclonal antibodies such as cetuximab and panitumumab, and tyrosine kinase inhibitors, such as gefitinib and erlotinib. In this review, we summarize the preclinical rational of potential activity and the most important clinical trials evaluated anti-EGFR targeted agents in non-colorectal digestive cancer, both in monotherapy and in combination with other chemotherapeutic or targeted agents. Patient selection by use of biologic markers will identify which patients are more likely to respond, contributing to the successful use of these agents.

19 Clinical Trial Optimal control of nausea and vomiting with a three-drug antiemetic regimen with aprepitant in metastatic pancreatic cancer patients treated with first-line modified FOLFIRINOX. 2013

Silvestris, Nicola / Brunetti, Anna Elisabetta / Russano, Marco / Nardulli, Patrizia. ·Medical Oncology Unit, National Cancer Institute "Giovanni Paolo II", Viale Orazio Flacco, 65, 70124, Bari, Italy, n.silvestris@oncologico.bari.it. ·Support Care Cancer · Pubmed #23975230.

ABSTRACT: -- No abstract --

20 Article Gene Expression Comparison between the Lymph Node-Positive and -Negative Reveals a Peculiar Immune Microenvironment Signature and a Theranostic Role for WNT Targeting in Pancreatic Ductal Adenocarcinoma: A Pilot Study. 2019

Argentiero, Antonella / De Summa, Simona / Di Fonte, Roberta / Iacobazzi, Rosa Maria / Porcelli, Letizia / Da Vià, Matteo / Brunetti, Oronzo / Azzariti, Amalia / Silvestris, Nicola / Solimando, Antonio Giovanni. ·Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, 70124 Bari, Italy. · Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy. · Experimental Pharmacology Laboratory, IRCCS Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy. · Department of Internal Medicine II, Interdisciplinary Center for Clinical Research Laboratory, University Hospital of Würzburg, 97080 Würzburg, Germany. · Medical Oncology Unit, The Hospital Mons. R. Dimiccoli, 76121 Barletta (Bat), Italy. · Scientific Direction, IRCCS Cancer Institute "Giovanni Paolo II", 70124 Bari, Italy. · Department of Internal Medicine II, Interdisciplinary Center for Clinical Research Laboratory, University Hospital of Würzburg, 97080 Würzburg, Germany. antonio.solimando@uniba.it. · Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine 'G. Baccelli', University of Bari Medical School, 70124 Bari, Italy. antonio.solimando@uniba.it. ·Cancers (Basel) · Pubmed #31277479.

ABSTRACT: Over the past several years there has been much debate with regards to the prognostic and clinical significance of pancreatic ductal adenocarcinoma (PDAC) with lymph nodes metastasis. The PDAC gene expression knowledge and the biologic alterations underlying the lymph node involvement convey a clinical implication in dealing with the theranostic window. To this end, we provide an original bioinformatic dissection of the gene expression differences of PDAC according to the nodal involvement from a large public available dataset. Comprehensive transcriptomic analysis from 143 RNA-seq patient's derived samples indicated that WNT increased activation and a peculiar immune microenvironment identify subjects with nodal involvement. In frame of this thinking, we validated the WNT pathway role in increasing the likelihood of lymphatic dissemination in vitro. Moreover, we demonstrated for the first time in a PDAC model the potential therapeutic window that XAV-939-a specific WNT pathway inhibitor-has in re-educating a tumor-permissive immune system. Finally, we outline the potential implication on bystander molecular drivers exerted by WNT molecular inhibition, providing a picture of the proteomic oncogenic landscape changes elicited by XAV-939 on PDAC cells and their clinical implication. Our findings hold the promise to identify novel immune-based therapeutic strategies targeting WNT to enhance PDAC cytotoxicity and restore anti-PDAC immunity in node-positive disease.

21 Article The Italian Rare Pancreatic Exocrine Cancer Initiative. 2019

Brunetti, Oronzo / Luchini, Claudio / Argentiero, Antonella / Tommasi, Stefania / Mangia, Anita / Aprile, Giuseppe / Marchetti, Paolo / Vasile, Enrico / Casadei Gardini, Andrea / Scartozzi, Mario / Barni, Sandro / Delfanti, Sara / De Vita, Fernando / Di Costanzo, Francesco / Milella, Michele / Cella, Chiara Alessandra / Berardi, Rossana / Cataldo, Ivana / Santini, Daniele / Doglioni, Claudio / Maiello, Evaristo / Lawlor, Rita T / Mazzaferro, Vincenzo / Lonardi, Sara / Giuliante, Felice / Brandi, Giovanni / Scarpa, Aldo / Cascinu, Stefano / Silvestris, Nicola. ·1 Medical Oncology Unit, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. · 2 Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · 3 Molecular Diagnostics and Pharmacogenetics Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italy. · 4 Functional Biomorphology Laboratory, IRCCS-Istituto Tumori, Bari, Italy. · 5 Medical Oncology Unit, Hospital of Vicenza, Vicenza, Italy. · 6 Medical Oncology Unit, Sant'Andrea Hospital, University of Rome La Sapienza, Rome, Italy. · 7 Medical Oncology Unit, University Hospital of Pisa, Pisa, Italy. · 8 Medical Oncology Unit, Scientific Institute of Romagna for the Study and Treatment of Cancer (IRST), Meldola, Italy. · 9 Medical Oncology Unit, University of Cagliari, Cagliari, Italy. · 10 Medical Oncology Unit, ASST Bergamo Ovest, Treviglio, Italy. · 11 Medical Oncology Unit, IRCCS Foundation Polyclinic San Matteo, Pavia, Italy. · 12 Medical Oncology Unit, II University of Naples, Naples, Italy. · 13 Medical Oncology Unit, Careggi University Hospital, Florence, Italy. · 14 Medical Oncology Unit, "Regina Elena" National Cancer Institute, Rome, Italy. · 15 Gastrointestinal Medical Oncology and Neuroendocrine Tumors, European Institute of Oncology (IEO), Milan, Italy. · 16 Medical Oncology Unit, Polytechnic University of the Marche, "Ospedali Riuniti Ancona," Ancona, Italy. · 17 Department of Pathology and Diagnostics, University of Verona Hospital Trust, Policlinico GB Rossi, Verona, Italy. · 18 Medical Oncology Unit, University Campus Biomedico, Rome, Italy. · 19 Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy. · 20 Medical Oncology Unit, IRCCS "Casa Sollievo della Sofferenza" Foundation, San Giovanni Rotondo, Italy. · 21 Arc-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · 22 Hepato-Biliary-Pancreatic Surgery, University of Milan, Istituto Nazionale Tumori, Fondazione IRCCS, Milan, Italy. · 23 Medical Oncology Unit, IRCCS Veneto Institute of Oncology (IOV), Padua, Italy. · 24 Hepatobiliary Surgery Unit, IRCCS A. Gemelli Polyclinic Foundation, Catholic University of the Sacred Heart, Rome, Italy. · 25 Oncology Unit, Department of Experimental, Diagnostic and Specialty Medicine, Sant'Orsola-Malpighi Hospital, University of Bologna, Bologna, Italy. · 26 Medical Oncology Unit, Modena Cancer Center, University Hospital of Modena, Modena, Italy. · 27 Scientific Direction, IRCCS Cancer Institute "Giovanni Paolo II" of Bari, Bari, Italy. ·Tumori · Pubmed #30967031.

ABSTRACT: INTRODUCTION: Exocrine pancreatic cancers include common type pancreatic ductal adenocarcinoma and cystic neoplasms, which account for 85% and 10% of cases, respectively. The remaining 5% are rare histotypes, comprising adenosquamous carcinoma, acinar cell carcinoma, signet ring cell carcinoma, medullary carcinoma, pancreatoblastoma, hepatoid carcinoma, undifferentiated carcinoma and its variant with osteoclast-like giant cells, solid pseudopapillary carcinoma, and carcinosarcoma. Due to their low incidence, little knowledge is available on their clinical and molecular features as well as on treatment choices. The national initiative presented here aims at the molecular characterization of series of rare histotypes for which therapeutic and follow-up data are available. METHODS: A nationwide Italian Rare Pancreatic Cancer (IRaPaCa) task force whose first initiative is a multicentric retrospective study involving 21 Italian cancer centers to retrieve histologic material and clinical and treatment data of at least 100 patients with rare exocrine pancreatic cancers has been created. After histologic revision by a panel of expert pathologists, DNA and RNA from paraffin tissues will be investigated by next-generation sequencing using molecular pathway-oriented and immune-oriented mutational and expression profiling panels constructed availing of the information from the International Cancer Genome Consortium. Bioinformatic analysis of data will drive validation studies by immunohistochemistry and in situ hybridization, as well as nanostring assays. CONCLUSIONS: We expect to gather novel data on rare pancreatic cancer types that will be useful to inform the design of therapeutic choices.

22 Article CAFs and TGF-β Signaling Activation by Mast Cells Contribute to Resistance to Gemcitabine/Nabpaclitaxel in Pancreatic Cancer. 2019

Porcelli, Letizia / Iacobazzi, Rosa Maria / Di Fonte, Roberta / Serratì, Simona / Intini, Angelica / Solimando, Antonio Giovanni / Brunetti, Oronzo / Calabrese, Angela / Leonetti, Francesco / Azzariti, Amalia / Silvestris, Nicola. ·Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. porcelli.letizia@gmail.com. · Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. rosamaria.iacobazzi@gmail.com. · Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. difonte.roberta@gmail.com. · Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. simonaserrati@hotmail.com. · Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. angelicaintini@gmail.com. · Department of Biomedical Sciences and Human Oncology, Section of Internal Medicine 'G. Baccelli', University of Bari Medical School Bari, 70124 Bari, Italy. antoniogiovannisolimando@gmail.com. · Medical Oncology Unit, Ospedale Mons. R. Dimiccoli, 76121 Barletta (Bat), Italy. dr.oronzo.brunetti1983@gmail.com. · Radiology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. acalabrese22@gmail.com. · Dipartimento di Farmacia-Scienze del Farmaco, University of Bari, 70125 Bari, Italy. francesco.leonetti@uniba.it. · Experimental Pharmacology Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. a.azzariti@oncologico.bari.it. · Medical Oncology Unit and Scientific Direction, IRCCS Istituto Tumori "Giovanni Paolo II", 70124 Bari, Italy. n.silvestris@oncologico.bari.it. ·Cancers (Basel) · Pubmed #30866547.

ABSTRACT: Tumor⁻stroma interactions are of key importance for pancreatic ductal adenocarcinoma (PDAC) progression. Our aim was to investigate whether cancer associated fibroblasts (CAFs) and mast cells (MC) affected the sensitivity of PDAC cells to gemcitabine/nabpaclitaxel (GEM/NAB). For this purpose, the combination cytotoxicity and the effect on tumor invasion and angiogenesis were evaluated with or without a conditioned medium from the mast cell line HMC-1 (human mast cell line-1 cells) and CAFs. Beside the clinical outcome of a homogenous population of PDAC patients, receiving GEM/NAB, was correlated to the circulating levels of mast cell tryptase and to a panel of inflammatory and immunosuppressive cytokines. CAFs neither affected drugs' cytotoxicity nor the inhibition of angiogenesis, but promoted tumor cell invasion. The MC instead, caused resistance to drugs by reducing apoptosis, by activating the TGF-β signalling and by promoting tumor invasion. Indeed, the inhibition of TβRI serine/threonine kinase activity by galunisertib restored drugs cytotoxicity. Moreover, MC induced the release of TGF-β1, and increased expression of PAR-2, ERK1/2 and Akt activation. Accordingly, TGF-β1, tryptase and other pro-inflammatory and immunosuppressive cytokines increased in the unresponsive patients. In conclusion, MC play a pivotal role in the resistance to GEM/NAB. A correlation between high level of circulating pro-inflammatory/ immunosuppressive cytokines and unresponsiveness was found in PDAC patients.

23 Article Systemic Chemotherapy for Advanced Rare Pancreatic Histotype Tumors: A Retrospective Multicenter Analysis. 2018

Brunetti, Oronzo / Aprile, Giuseppe / Marchetti, Paolo / Vasile, Enrico / Casadei Gardini, Andrea / Scartozzi, Mario / Barni, Sandro / Delfanti, Sara / De Vita, Fernando / Di Costanzo, Francesco / Milella, Michele / Cella, Chiara Alessandra / Berardi, Rossana / Cataldo, Ivana / Scarpa, Aldo / Basile, Debora / Mazzuca, Federica / Graziano, Giusi / Argentiero, Antonella / Santini, Daniele / Reni, Michele / Cascinu, Stefano / Silvestris, Nicola. ·Medical Oncology Unit, Sant'Andrea Hospital, University of Rome La Sapienza, Rome. · Medical Oncology Unit, Azienda Ospedaliero-Universitaria Pisana, Pisa. · Department of MedicalOncology, Istituto Scientifico Romagnolo per lo Studio e Cura dei Tumori (IRST) IRCCS, Meldola. · Medical Oncology Unit, University of Cagliari, Cagliari. · Medical Oncology Unit, ASST Bergamo Ovest, Treviglio. · Medical Oncology Unit, Fondazione IRCCS Policlinico San Matteo, Pavia. · Medical Oncology Unit, II University of Naples, Naples. · Medical OncologyUnit, Azienda Ospedaliero-Universitaria Careggi, Florence. · Medical Oncology 1, IRCCS Regina Elena National Cancer Institute, Rome. · Division of Gastrointestinal and Neuroendocrine Tumors, IEO, Milan. · Medical Oncology Unit, Università Politecnica Marche - Ospedali Riuniti Ancona, Ancona. · Department of Pathology and Diagnostics, University of Verona, ARCNET, Verona. · Department of Medical Oncology, University and General Hospital, Udine. · Scientific Direction, Cancer Institute "Giovanni Paolo II," Bari. · Medical Oncology Unit, University Campus Biomedico, Rome. · Department of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan. · Modena Cancer Center, University of Modena and Reggio Emilia, Azienda Ospedaliera-Universitaria di Modena, Modena, Italy. ·Pancreas · Pubmed #29771769.

ABSTRACT: OBJECTIVES: Two issues were put forth by clinicians in the management of the advanced stages of rare variants of pancreatic ductal adenocarcinoma and other exocrine histotypes with peculiar clinical and pathological features: Do chemotherapy regimens recommended in pancreatic ductal adenocarcinoma patients have a clinical activity in rare pancreatic tumors? Or should other chemotherapy combinations be considered in this subset of patients? METHODS: We conducted a multicenter retrospective study that collected data from 2005 to 2016 at 14 Italian cancer centers with the aim to evaluate tumor response and time to progression for first- and second-line and overall survival. RESULTS: Of approximately 4300 exocrine pancreatic cancer patients, 79 advanced cases affected by rare histological types were identified, with pancreatic acinar cell cancer (n = 23), pancreatic adenosquamous cancer (n = 16), and mucinous cystic neoplasm with an associated invasive mucinous cystadenocarcinoma (n = 15) most represented. Survival analyses for each subgroup in relation with the different chemotherapy regimens showed the lack of statistical significance correlations. CONCLUSIONS: Because of the lack of clinical trials in patients affected by these rare pancreatic histotypes, only their molecular classification would help clinicians in future therapeutic choice.

24 Article Immunological mutational signature in adenosquamous cancer of pancreas: an exploratory study of potentially therapeutic targets. 2018

Silvestris, Nicola / Brunetti, Oronzo / Pinto, Rosamaria / Petriella, Daniela / Argentiero, Antonella / Fucci, Livia / Tommasi, Stefania / Danza, Katia / De Summa, Simona. ·a Medical Oncology Unit and Scientific Directorate , Istituto Tumori "Giovanni Paolo II" , Bari , Italy. · b Medical Oncology Unit , Hospital of Barletta , Barletta , Italy. · c Pharmacogenetics and Molecular Diagnostic Unit , Istituto Tumori "Giovanni Paolo II" , Bari , Italy. · d Medical Oncology Unit , Istituto Tumori "Giovanni Paolo II" , Bari , Italy. · e Histopathological Unit , Istituto Tumori "Giovanni Paolo II" , Bari , Italy. ·Expert Opin Ther Targets · Pubmed #29561217.

ABSTRACT: OBJECTIVES: Adenosquamous cancer of pancreas (ASCP) is a rare variant of pancreatic adenocarcinoma (PDAC). It is characterized by poor prognosis and lacks of literature data supporting the choice of systemic therapies. The role of immunotherapy for this malignancy is still unknown. In this study, we evaluated any differences between immune-related genes of PDAC and its adenosquamous variant with the aim to characterize these histothistotypes and eventually identify potential biomarkers useful for an immune-therapy approach in ASCP. METHODS: We compared the mutational status of a customized gene panel, including 41 genes involved in immunity checkpoint, inflammation and control of leukocytes, B and T cells proliferation of PDAC and ASCP. Moreover, we evaluated the immunohistochemical expression of programmed death ligand 1 (PD-L1). RESULTS: We observed a status of 'hypermutation' of genes included in our panel in ASCP (22/41 mutated genes). Furtheremore, PD-L1 was found to be expressed in about 15% of the squamous component of ASCP tissue. CONCLUSION: Due to genetic characteristics and to PD-L1 expression in ASCP compared to PDAC tissue, we can conclude that ASCP presents a potential sensitivity to immunological therapy.

25 Article Angiogenesis in adenosquamous cancer of pancreas. 2017

Silvestris, Nicola / Danza, Katia / Longo, Vito / Brunetti, Oronzo / Fucci, Livia / Argentiero, Antonella / Calabrese, Angela / Cataldo, Ivana / Tamma, Roberto / Ribatti, Domenico / Tommasi, Stefania. ·Medical Oncology Unit and Scientific Directorate, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. · Molecular Genetics Laboratory, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. · Medical Oncology Unit, Hospital "S. G. Moscati" of Taranto, 74010, Taranto, Italy. · Medical Oncology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. · Histopatology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. · Radiology Unit, IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. · ARC-Net Research Centre, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124, Bari, Italy. · IRCCS Istituto Tumori "Giovanni Paolo II", 70124, Bari, Italy. ·Oncotarget · Pubmed #29221165.

ABSTRACT: Adenosquamous carcinoma of the pancreas (ASCP) is an uncommon variant of exocrine pancreatic malignancies, characterized by a histological admixture of adenomatous and squamous cell elements. This cancer is characterized by a poorly differentiated histology and a poorer clinical outcome compared to pancreatic ductal adenocarcinoma (PDAC). Unlike PDAC, that is characterized by a low microvascular density (MVD) and collapsed vasculature, no data are available about angiogenesis in ASPC. Immunohistochemical evaluation of MVD and trypatse-positive mast cells (MCs) were performed on a single case of ASCP compared to PDAC. Moreover, the levels of angiopoietin-1 and -2 (Ang-1, Ang-2), receptor tyrosine kinase with immunoglobulin and epidermal growth factor homology domain-2 (Tie-2), vascular endothelial growth factor A (VEGFA), hypoxia-inducible factor 1 alpha (HIF1A), miR-21-5p, miR-181a-5p, miR-122-5p, and miR-27a-3p were evaluated by real-time PCR. Higher number of tryptase-positive MCs and MVD are observed in the ASCP case compared to PDAC one. Lower levels of miR-122-5p and higher expression of VEGFA, HIF1A and Ang-2 genes were observed in ASCP. Furthermore, lower Ang-1 and Tie-2 transcript levels and higher increases of miR-21-5p, miR27a-3p and miR-181a-5p levels were found in the rarest form of pancreatic carcinoma. Our data demonstrate an important angiogenic activity in ASCP with a putative role of miR-21-5p, miR-181a-5p, miR-122-5p and miR-27a-3p in the regulation of this process.

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