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Pancreatic Neoplasms: HELP
Articles by Ivana Cataldo
Based on 14 articles published since 2010
(Why 14 articles?)
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Between 2010 and 2020, Ivana Cataldo wrote the following 14 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 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.

2 Review International Association of Pancreatology (IAP)/European Pancreatic Club (EPC) consensus review of guidelines for the treatment of pancreatic cancer. 2016

Takaori, Kyoichi / Bassi, Claudio / Biankin, Andrew / Brunner, Thomas B / Cataldo, Ivana / Campbell, Fiona / Cunningham, David / Falconi, Massimo / Frampton, Adam E / Furuse, Junji / Giovannini, Marc / Jackson, Richard / Nakamura, Akira / Nealon, William / Neoptolemos, John P / Real, Francisco X / Scarpa, Aldo / Sclafani, Francesco / Windsor, John A / Yamaguchi, Koji / Wolfgang, Christopher / Johnson, Colin D / Anonymous231183. ·Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: takaori@kuhp.kyoto-u.ac.jp. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Academic Unit of Surgery, University of Glasgow, Glasgow, United Kingdom. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. · Pancreatic Surgery Unit, Università Vita e Salute, Milano, Italy. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, United Kingdom. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Endoscopic Unit, Paoli-Calmettes Institute, Marseille, France. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan. · Division of General Surgery, Yale University, New Haven, CT, United States of America. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Surgery, University of Auckland, HBP/Upper GI Unit, Auckland City Hospital, Auckland, New Zealand. · Department of Advanced Treatment of Pancreatic Disease, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Surgery, The Johns Hopkins University, Baltimore, MD, United States of America. · University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom. ·Pancreatology · Pubmed #26699808.

ABSTRACT: BACKGROUND: Pancreatic cancer is one of the most devastating diseases with an extremely high mortality. Medical organizations and scientific societies have published a number of guidelines to address active treatment of pancreatic cancer. The aim of this consensus review was to identify where there is agreement or disagreement among the existing guidelines and to help define the gaps for future studies. METHODS: A panel of expert pancreatologists gathered at the 46th European Pancreatic Club Meeting combined with the 18th International Association of Pancreatology Meeting and collaborated on critical reviews of eight English language guidelines for the clinical management of pancreatic cancer. Clinical questions (CQs) of interest were proposed by specialists in each of nine areas. The recommendations for the CQs in existing guidelines, as well as the evidence on which these were based, were reviewed and compared. The evidence was graded as sufficient, mediocre or poor/absent. RESULTS: Only 4 of the 36 CQs, had sufficient evidence for agreement. There was also agreement in five additional CQs despite the lack of sufficient evidence. In 22 CQs, there was disagreement regardless of the presence or absence of evidence. There were five CQs that were not addressed adequately by existing guidelines. CONCLUSION: The existing guidelines provide both evidence- and consensus-based recommendations. There is also considerable disagreement about the recommendations in part due to the lack of high level evidence. Improving the clinical management of patients with pancreatic cancer, will require continuing efforts to undertake research that will provide sufficient evidence to allow agreement.

3 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.

4 Review Genetics and Epigenetics of Pancreatic Neuroendocrine Tumors and Pulmonary Carcinoids. 2015

Dreijerink, Koen M A / Derks, Jules L / Cataldo, Ivana / Scarpa, Aldo / Valk, Gerlof D / Speel, Ernst-Jan M. ·Department of Endocrine Oncology, University Medical Centre Utrecht, Utrecht, The Netherlands. ·Front Horm Res · Pubmed #26303708.

ABSTRACT: In this chapter, we give an overview of the genetic and epigenetic background of neuroendocrine tumors (NETs), in particular pancreatic and pulmonary NETs. Studying the mechanism of disease of the inherited syndromes that feature NETs has provided valuable insights that have revolutionized the therapeutic options for these tumor types: both inhibition of mTOR (mammalian target of rapamycin) signaling and inhibition of angiogenesis have become standard treatments. Although sporadic NETs harbor relatively few somatic gene mutations, these somatic mutations often affect genes that encode epigenetic regulators. Restoring the aberrant epigenetic characteristics may be an attractive approach for future treatment.

5 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.

6 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.

7 Article Radiofrequency ablation for locally advanced pancreatic cancer: SMAD4 analysis segregates a responsive subgroup of patients. 2018

Paiella, Salvatore / Malleo, Giuseppe / Cataldo, Ivana / Gasparini, Clizia / De Pastena, Matteo / De Marchi, Giulia / Marchegiani, Giovanni / Rusev, Borislav / Scarpa, Aldo / Girelli, Roberto / Giardino, Alessandro / Frigerio, Isabella / D'Onofrio, Mirko / Secchettin, Erica / Bassi, Claudio / Salvia, Roberto. ·General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. salvatore.paiella@aovr.veneto.it. · General and Pancreatic Surgery Department, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · Department of Pathology and Diagnostics, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · Gastroenterology B Department, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · ARC-Net Research Centre, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. · HPB Unit, Casa di Cura Pederzoli, Via Monte Baldo, Peschiera del Garda, Verona, Italy. · Department of Radiology, Pancreas Institute, University of Verona Hospital Trust, Policlinico GB Rossi, Piazzale L.A. Scuro, 10, 37134, Verona, Italy. ·Langenbecks Arch Surg · Pubmed #28983662.

ABSTRACT: PURPOSE: SMAD4 mutational status correlates with pancreatic ductal adenocarcinoma (PDAC) failure pattern. We investigated in a subset of locally advanced patients submitted to radiofrequency ablation (RFA) whether the assessment of SMAD4 status is a useful way to select the patients. METHODS: Clinical, radiological, and follow-up details of patients submitted to RFA for locally advanced pancreatic cancer (LAPC), in whom cytohistological material was available at our institution, were retrospectively retrieved. SMAD4 expression was evaluated by immunohistochemistry (IHC) and considered "negative" or "positive." The survival analysis was conducted using Kaplan-Meier and Cox proportional hazards models. RESULTS: The study population consisted of 30 patients. Thirteen patients (43.3%) received RFA upfront, whereas 17 (56.7%) after induction treatments. SMAD4 was mutant in 18 out of 30 patients (60%). The overall estimated post-RFA disease-specific survival (DSS) was 15 months (95% CI 11.64-18.35). The estimated post-RFA DSS of patients with wild-type and mutant SMAD4 was 22 and 12 months, respectively (log-rank p < 0.05). At the multivariate analysis, SMAD4 was the only independent predictor of survival (p = 0.05). The pattern of failure was not associated with SMAD4 status (p = 0.4). CONCLUSIONS: Within patients undergoing RFA for LAPC, SMAD4 analysis could segregate a subgroup of subjects with improved survival, who likely benefited from tumor ablation.

8 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.

9 Article UCP2 inhibition induces ROS/Akt/mTOR axis: Role of GAPDH nuclear translocation in genipin/everolimus anticancer synergism. 2017

Dando, Ilaria / Pacchiana, Raffaella / Pozza, Elisa Dalla / Cataldo, Ivana / Bruno, Stefano / Conti, Paola / Cordani, Marco / Grimaldi, Anna / Butera, Giovanna / Caraglia, Michele / Scarpa, Aldo / Palmieri, Marta / Donadelli, Massimo. ·Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: ilaria.dando@univr.it. · Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. · Applied Research on Cancer Centre (ARC-Net) and Department of Diagnostics and Public Health, University of Verona, Verona, Italy. · Food and Dug Department, University of Parma, Parma, Italy. · Department of Pharmaceutical Sciences, University of Milan, Milan, Italy. · Biochemistry Department, Universidad Autónoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain. · Department of Biochemistry, Biophysics and General Pathology, University of Campania "L. Vanvitelli", Naples, Italy. · Department of Neuroscience, Biomedicine and Movement, Biochemistry Section, University of Verona, Verona, Italy. Electronic address: massimo.donadelli@univr.it. ·Free Radic Biol Med · Pubmed #28962872.

ABSTRACT: Several studies indicate that mitochondrial uncoupling protein 2 (UCP2) plays a pivotal role in cancer development by decreasing reactive oxygen species (ROS) produced by mitochondrial metabolism and by sustaining chemoresistance to a plethora of anticancer drugs. Here, we demonstrate that inhibition of UCP2 triggers Akt/mTOR pathway in a ROS-dependent mechanism in pancreatic adenocarcinoma cells. This event reduces the antiproliferative outcome of UCP2 inhibition by genipin, creating the conditions for the synergistic counteraction of cancer cell growth with the mTOR inhibitor everolimus. Inhibition of pancreatic adenocarcinoma cell growth and induction of apoptosis by genipin and everolimus treatment are functionally related to nuclear translocation of the cytosolic glycolytic enzyme glyceraldehyde 3-phosphate dehydrogenase (GAPDH). The synthetic compound (S)-benzyl-2-amino-2-(S)-3-bromo-4,5-dihydroisoxazol-5-yl-acetate (AXP3009), which binds GAPDH at its redox-sensitive Cys152, restores cell viability affected by the combined treatment with genipin and everolimus, suggesting a role for ROS production in the nuclear translocation of GAPDH. Caspase-mediated apoptosis by genipin and everolimus is further potentiated by the autophagy inhibitor 3-methyladenine revealing a protective role for Beclin1-mediated autophagy induced by the treatment. Mice xenograft of pancreatic adenocarcinoma further confirmed the antiproliferative outcome of drug combination without toxic effects for animals. Tumor masses from mice injected with UCP2 and mTOR inhibitors revealed a strong reduction in tumor volume and number of mitosis associated with a marked GAPDH nuclear positivity. Altogether, these results reveal novel mechanisms through which UCP2 promotes cancer cell proliferation and support the combined inhibition of UCP2 and of Akt/mTOR pathway as a novel therapeutic strategy in the treatment of pancreatic adenocarcinoma.

10 Article Pancreatic undifferentiated carcinoma with osteoclast-like giant cells is genetically similar to, but clinically distinct from, conventional ductal adenocarcinoma. 2017

Luchini, Claudio / Pea, Antonio / Lionheart, Gemma / Mafficini, Andrea / Nottegar, Alessia / Veronese, Nicola / Chianchiano, Peter / Brosens, Lodewijk Aa / Noë, Michaël / Offerhaus, G Johan A / Yonescu, Raluca / Ning, Yi / Malleo, Giuseppe / Riva, Giulio / Piccoli, Paola / Cataldo, Ivana / Capelli, Paola / Zamboni, Giuseppe / Scarpa, Aldo / Wood, Laura D. ·Department of Diagnostics and Public Health, Section of Pathology, University of Verona, Verona, Italy. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. · ARC-Net Research Center, University of Verona, Verona, Italy. · National Research Council, Neuroscience Institute, Aging Branch, Padua, Italy. · Institute for Clinical Research and Education in Medicine (IREM), Padua, Italy. · Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands. · Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. · Sacro Cuore Don Calabria Hospital, Negrar, Verona, Italy. · Department of Oncology, Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA. ·J Pathol · Pubmed #28722124.

ABSTRACT: Undifferentiated carcinoma of the pancreas with osteoclast-like giant cells (UCOGC) is currently considered a morphologically and clinically distinct variant of pancreatic ductal adenocarcinoma (PDAC). In this study, we report clinical and pathological features of a series of 22 UCOGCs, including the whole exome sequencing of eight UCOGCs. We observed that 60% of the UCOGCs contained a well-defined epithelial component and that patients with pure UCOGC had a significantly better prognosis than did those with an UCOGC with an associated epithelial neoplasm. The genetic alterations in UCOGC are strikingly similar to those known to drive conventional PDAC, including activating mutations in the oncogene KRAS and inactivating mutations in the tumor suppressor genes CDKN2A, TP53, and SMAD4. These results further support the classification of UCOGC as a PDAC variant and suggest that somatic mutations are not the determinants of the unique phenotype of UCOGC. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

11 Article Fhit down-regulation is an early event in pancreatic carcinogenesis. 2017

Fassan, Matteo / Rusev, Borislav / Corbo, Vincenzo / Gasparini, Pierluigi / Luchini, Claudio / Vicentini, Caterina / Mafficini, Andrea / Paiella, Salvatore / Salvia, Roberto / Cataldo, Ivana / Scarpa, Aldo / Huebner, Kay. ·ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. matteo.fassan@unipd.it. · Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Via Gabelli 61, 35121, Padua, Italy. matteo.fassan@unipd.it. · ARC-NET Research Centre, Department of Diagnostics and Public Health, University of Verona, Verona, Italy. · Comprehensive Cancer Center, Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA. · Department of Diagnostics and Public Health, Surgical Pathology Unit, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, Santa Chiara Hospital, Trento, Italy. · Department of Surgery, Unit of General Surgery B, University and Hospital Trust of Verona, Verona, Italy. ·Virchows Arch · Pubmed #28289900.

ABSTRACT: Aberrant Fhit expression characterizes a large proportion of primary pancreatic ductal adenocarcinomas (PDACs), but fragmentary information is available on Fhit expression during the phenotypic changes of pancreatic ductal epithelium during multistep transformation. We assessed Fhit expression by immunohistochemistry in two different multistep pancreatic carcinogenic processes: pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasia (IPMN). We considered 105 surgically treated PDACs/IPMNs and selected 30 samples of non-neoplastic pancreatic parenchyma, 50 PanIN lesions, 30 IPMNs, 15 IPMNs with associated invasive carcinoma, and 60 adenocarcinomas. Normal pancreatic ducts and surrounding acinar cells consistently showed moderate to strong Fhit immunoreactivity. Significant down-regulation of Fhit expression was observed in association with increasing severity of dysplastia/neoplastia in both carcinogenic processes. This was further confirmed by studying multiple lesions obtained from the same surgical specimen. Of 60 PDACs, only 14 showed Fhit expression comparable to normal pancreatic ductal epithelium, while the remainder (77%) showed clearly negative or reduced Fhit expression. This study demonstrates that Fhit down-regulation is an early event in both multistep carcinogenic processes leading to PDAC.

12 Article Whole-genome landscape of pancreatic neuroendocrine tumours. 2017

Scarpa, Aldo / Chang, David K / Nones, Katia / Corbo, Vincenzo / Patch, Ann-Marie / Bailey, Peter / Lawlor, Rita T / Johns, Amber L / Miller, David K / Mafficini, Andrea / Rusev, Borislav / Scardoni, Maria / Antonello, Davide / Barbi, Stefano / Sikora, Katarzyna O / Cingarlini, Sara / Vicentini, Caterina / McKay, Skye / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / McLean, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Wilson, Peter J / Anderson, Matthew J / Fink, J Lynn / Newell, Felicity / Waddell, Nick / Holmes, Oliver / Kazakoff, Stephen H / Leonard, Conrad / Wood, Scott / Xu, Qinying / Nagaraj, Shivashankar Hiriyur / Amato, Eliana / Dalai, Irene / Bersani, Samantha / Cataldo, Ivana / Dei Tos, Angelo P / Capelli, Paola / Davì, Maria Vittoria / Landoni, Luca / Malpaga, Anna / Miotto, Marco / Whitehall, Vicki L J / Leggett, Barbara A / Harris, Janelle L / Harris, Jonathan / Jones, Marc D / Humphris, Jeremy / Chantrill, Lorraine A / Chin, Venessa / Nagrial, Adnan M / Pajic, Marina / Scarlett, Christopher J / Pinho, Andreia / Rooman, Ilse / Toon, Christopher / Wu, Jianmin / Pinese, Mark / Cowley, Mark / Barbour, Andrew / Mawson, Amanda / Humphrey, Emily S / Colvin, Emily K / Chou, Angela / Lovell, Jessica A / Jamieson, Nigel B / Duthie, Fraser / Gingras, Marie-Claude / Fisher, William E / Dagg, Rebecca A / Lau, Loretta M S / Lee, Michael / Pickett, Hilda A / Reddel, Roger R / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Epari, Krishna / Nguyen, Nam Q / Zeps, Nikolajs / Falconi, Massimo / Simbolo, Michele / Butturini, Giovanni / Van Buren, George / Partelli, Stefano / Fassan, Matteo / Anonymous201184 / Khanna, Kum Kum / Gill, Anthony J / Wheeler, David A / Gibbs, Richard A / Musgrove, Elizabeth A / Bassi, Claudio / Tortora, Giampaolo / Pederzoli, Paolo / Pearson, John V / Waddell, Nicola / Biankin, Andrew V / Grimmond, Sean M. ·ARC-Net Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona 37134, Italy. · Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona 37134, Italy. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden, Glasgow G61 1QH, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow G31 2ER, UK. · The Kinghorn Cancer Centre, Cancer Division, Garvan Institute of Medical Research, University of New South Wales, 384 Victoria St, Darlinghurst, Sydney, New South Wales 2010, Australia. · Department of Surgery, Bankstown Hospital, Eldridge Road, Bankstown, Sydney, New South Wales 2200, Australia. · South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales, Liverpool, New South Wales 2170, Australia. · QIMR Berghofer Medical Research Institute, Herston Road, Brisbane 4006, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, St Lucia, Brisbane, Queensland 4072, Australia. · Department of Surgery, Pancreas Institute, University and Hospital Trust of Verona, Verona 37134, Italy. · Medical Oncology, University and Hospital Trust of Verona, Verona, Italy. · Department of Pathology, General Hospital of Treviso, Department of Medicine, University of Padua, Italy. · Department of Medicine, Section of Endocrinology, University and Hospital Trust of Verona, Verona, Italy. · The University of Queensland, School of Medicine, Brisbane 4006, Australia. · Pathology Queensland, Brisbane 4006, Australia. · Royal Brisbane and Women's Hospital, Department of Gastroenterology and Hepatology, Brisbane 4006, Australia. · Institute of Health Biomedical Innovation, Queensland University of Technology, Brisbane, Australia. · School of Environmental &Life Sciences, University of Newcastle, Ourimbah, New South Wales 2258, Australia. · Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Centre for Cancer Bioinformatics, Peking University Cancer Hospital &Institute, Beijing 100142, China. · Department of Surgery, Princess Alexandra Hospital, Ipswich Rd, Woollongabba, Queensland 4102, Australia. · Department of Anatomical Pathology. St Vincent's Hospital, Sydney, New South Wales 2010, Australia. · Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow G4 OSF, UK. · Department of Pathology, Queen Elizabeth University Hospital, Greater Glasgow &Clyde NHS, Glasgow G51 4TF, UK. · Department of Molecular and Human Genetics, Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, MS226, Houston, Texas 77030-3411, USA. · Michael E. DeBakey Department of Surgery and The Elkins Pancreas Center, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411, USA. · Children's Hospital at Westmead, Westmead, New South Wales 2145, Australia. · Children's Medical Research Institute, The University of Sydney, Westmead, New South Wales 2145, Australia. · Department of Surgery, Royal North Shore Hospital, St Leonards, Sydney, New South Wales 2065, Australia. · University of Sydney. Sydney, New South Wales 2006, Australia. · Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales 2050, Australia. · School of Medicine, Western Sydney University, Penrith, New South Wales 2175, Australia. · Department of Surgery, Fremantle Hospital, Alma Street, Fremantle, Western Australia 6160, Australia. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia 5000, Australia. · School of Surgery M507, University of Western Australia, 35 Stirling Highway, Nedlands, Western Australia 6009, Australia. · St John of God Pathology, 12 Salvado Rd, Subiaco, Western Australia 6008, Australia. · Bendat Family Comprehensive Cancer Centre, St John of God Subiaco Hospital, Subiaco, Western Australia 6008, Australia. · University of Melbourne Centre for Cancer Research, University of Melbourne, Melbourne, 3010, Victoria, Australia. ·Nature · Pubmed #28199314.

ABSTRACT: The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling.

13 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous171184 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

14 Article Combined inhibition of IL1, CXCR1/2, and TGFβ signaling pathways modulates in-vivo resistance to anti-VEGF treatment. 2016

Carbone, Carmine / Tamburrino, Anna / Piro, Geny / Boschi, Federico / Cataldo, Ivana / Zanotto, Marco / Mina, Maria M / Zanini, Silvia / Sbarbati, Andrea / Scarpa, Aldo / Tortora, Giampaolo / Melisi, Davide. ·aDigestive Molecular Clinical Oncology Research Unit bLaboratory of Oncology and Molecular Therapy, Department of Medicine cDepartment of Computer Science dSection of Anatomy and Histology, Department of Neurological, Neuropsychological, Morphological and Movement Sciences eARC-Net Research Centre and Department of Pathology and Diagnostics, Università degli studi di Verona fMedical Oncology Unit, Azienda Ospedaliera Universitaria Integrata, Verona, Italy. ·Anticancer Drugs · Pubmed #26473526.

ABSTRACT: Resistance of tumors to antiangiogenic therapies is becoming increasingly relevant. We recently identified interleukin-1 (IL1), CXC receptors (CXCR)1/2 ligands, and transforming growth factor β (TGFβ) among the proinflammatory factors that were expressed at higher levels in murine models resistant to the antivascular endothelial growth factor (anti-VEGF) antibody bevacizumab. Here, we hypothesized that the combined inhibition of these proinflammatory signaling pathways might reverse this anti-VEGF resistance. Bevacizumab-resistant FGBR pancreatic cancer cells were treated in vitro with bevacizumab, the recombinant human IL1 receptor antagonist anakinra, the monoclonal antibody against TGFβ receptor type II TR1, and a novel recombinant antibody binding CXCR1/2 ligands. The FGBR cells treated with these agents in combination had significantly higher levels of E-cadherin and lower levels of vimentin, IL6, phosphorylated p65, and SMAD2, and showed significantly lower migration rates than did their controls treated with the same agents without bevacizumab or with a single agent bevacizumab as a control. Consistently, the combination of these agents with bevacizumab reduced the FGBR tumor burden and significantly prolonged mice survival compared with bevacizumab in monotherapy. Tumors from mice receiving the combination treatment showed significantly lower expression of IL6 and phosphorylated SMAD2, higher expression of E-cadherin and lower levels of vimentin, and a significantly lower infiltration by CD11b cells compared with bevacizumab-treated controls. This study suggests that inhibition of IL1, CXCR1/2, and TGFβ signaling pathways is a potential therapeutic approach to modulate the acquired resistance to anti-VEGF treatment by reversing epithelial-mesenchymal transition and inhibiting CD11b proangiogenic myeloid cells' tumor infiltration.