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Pancreatic Neoplasms: HELP
Articles by Eithne Costello
Based on 58 articles published since 2009
(Why 58 articles?)
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Between 2009 and 2019, E. Costello wrote the following 58 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2 · 3
1 Review Therapeutic developments in pancreatic cancer: current and future perspectives. 2018

Neoptolemos, John P / Kleeff, Jörg / Michl, Patrick / Costello, Eithne / Greenhalf, William / Palmer, Daniel H. ·Department of General Surgery, University of Heidelberg, Heidelberg, Germany. john.neoptolemos@med.uni-heidelberg.de. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. joerg.kleeff@uk-halle.de. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. joerg.kleeff@uk-halle.de. · Department of Internal Medicine I, Martin-Luther-University Halle-Wittenberg, Halle (Saale), Germany. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. ·Nat Rev Gastroenterol Hepatol · Pubmed #29717230.

ABSTRACT: The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts.

2 Review Designing a bio-inspired biomimetic in vitro system for the optimization of ex vivo studies of pancreatic cancer. 2017

Totti, Stella / Vernardis, Spyros I / Meira, Lisiane / Pérez-Mancera, Pedro A / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Neoptolemos, John / Mantalaris, Athanasios / Velliou, Eirini G. ·Bioprocess and Biochemical Engineering Group (BioProChem), Department of Chemical and Process Engineering, University of Surrey, Guildford GU2 7XH, UK. · Biological Systems Engineering Laboratory (BSEL), Department of Chemical Engineering, Imperial College London, SW7 2AZ London, UK. · Department of Clinical and Experimental Medicine, University of Surrey, Guildford GU2 7XH, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool,Daulby Street, Liverpool L69 3GA, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool,Daulby Street, Liverpool L69 3GA, UK; NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool,Daulby Street, Liverpool L69 3GA, UK. · NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool,Daulby Street, Liverpool L69 3GA, UK. · Bioprocess and Biochemical Engineering Group (BioProChem), Department of Chemical and Process Engineering, University of Surrey, Guildford GU2 7XH, UK. Electronic address: e.velliou@surrey.ac.uk. ·Drug Discov Today · Pubmed #28153670.

ABSTRACT: Pancreatic cancer is one of the most aggressive and lethal human malignancies. Drug therapies and radiotherapy are used for treatment as adjuvants to surgery, but outcomes remain disappointing. Advances in tissue engineering suggest that 3D cultures can reflect the in vivo tumor microenvironment and can guarantee a physiological distribution of oxygen, nutrients, and drugs, making them promising low-cost tools for therapy development. Here, we review crucial structural and environmental elements that should be considered for an accurate design of an ex vivo platform for studies of pancreatic cancer. Furthermore, we propose environmental stress response biomarkers as platform readouts for the efficient control and further prediction of the pancreatic cancer response to the environmental and treatment input.

3 Review Reduced risk of pancreatic cancer associated with asthma and nasal allergies. 2017

Gomez-Rubio, Paulina / Zock, Jan-Paul / Rava, Marta / Marquez, Mirari / Sharp, Linda / Hidalgo, Manuel / Carrato, Alfredo / Ilzarbe, Lucas / Michalski, Christoph / Molero, Xavier / Farré, Antoni / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberà, Victor / Crnogorac-Jurcevic, Tatjana / Domínguez-Muñoz, Enrique / Muñoz-Bellvís, Luís / Alvarez-Urturi, Cristina / Balcells, Joaquim / Barneo, Luis / Costello, Eithne / Guillén-Ponce, Carmen / Kleeff, Jörg / Kong, Bo / Lawlor, Rita / Löhr, Matthias / Mora, Josefina / Murray, Lim / O'Driscoll, Damian / Peláez, Pablo / Poves, Ignasi / Scarpa, Aldo / Real, Francisco X / Malats, Núria / Anonymous6460850. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain. · National Cancer Registry Ireland, Cork, Ireland, and Institute of Health & Society, Newcastle University, UK. · Hospital Madrid-Norte-Sanchinarro, Madrid, Spain. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Technical University of Munich, Munich, Germany. · Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Barcelona, Spain. · Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Department of Surgery, 12 de Octubre University Hospital, Madrid, Spain. · The Royal Liverpool University Hospital, Liverpool, UK. · Centre for Public Health, Queen's University Belfast, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, UK. · Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Cirugía General y del Aparato Digestivo, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Gastrocentrum, Karolinska Institutet, Stockholm, Sweden. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. ·Gut · Pubmed #26628509.

ABSTRACT: OBJECTIVE: Studies indicate an inverse association between ductal adenocarcinoma of the pancreas (PDAC) and nasal allergies. However, controversial findings are reported for the association with asthma. Understanding PDAC risk factors will help us to implement appropriate strategies to prevent, treat and diagnose this cancer. This study assessed and characterised the association between PDAC and asthma and corroborated existing reports regarding the association between allergies and PDAC risk. DESIGN: Information about asthma and allergies was collated from 1297 PDAC cases and 1024 controls included in the PanGenEU case-control study. Associations between PDAC and atopic diseases were studied using multilevel logistic regression analysis. Meta-analyses of association studies on these diseases and PDAC risk were performed applying random-effects model. RESULTS: Asthma was associated with lower risk of PDAC (OR 0.64, 95% CI 0.47 to 0.88), particularly long-standing asthma (>=17 years, OR 0.39, 95% CI 0.24 to 0.65). Meta-analysis of 10 case-control studies sustained our results (metaOR 0.73, 95% CI 0.59 to 0.89). Nasal allergies and related symptoms were associated with lower risk of PDAC (OR 0.66, 95% CI 0.52 to 0.83 and OR 0.59, 95% CI 0.46 to 0.77, respectively). These results were supported by a meta-analysis of nasal allergy studies (metaOR 0.6, 95% CI 0.5 to 0.72). Skin allergies were not associated with PDAC risk. CONCLUSIONS: This study shows a consistent inverse association between PDAC and asthma and nasal allergies, supporting the notion that atopic diseases are associated with reduced cancer risk. These results point to the involvement of immune and/or inflammatory factors that may either foster or restrain pancreas carcinogenesis warranting further research to understand the molecular mechanisms driving this association.

4 Review New biomarkers and targets in pancreatic cancer and their application to treatment. 2012

Costello, Eithne / Greenhalf, William / Neoptolemos, John P. ·National Institute for Health Research Pancreas Biomedical Research Unit and Liverpool Cancer Research UK Centre, Department of Molecular, University of Liverpool, Liverpool, L69 3GA, UK. ·Nat Rev Gastroenterol Hepatol · Pubmed #22733351.

ABSTRACT: Late diagnosis of pancreatic ductal adenocarcinoma (pancreatic cancer) and the limited response to current treatments results in an exceptionally poor prognosis. Advances in our understanding of the molecular events underpinning pancreatic cancer development and metastasis offer the hope of tangible benefits for patients. In-depth mutational analyses have shed light on the genetic abnormalities in pancreatic cancer, providing potential treatment targets. New biological studies in patients and in mouse models have advanced our knowledge of the timing of metastasis of pancreatic cancer, highlighting new directions for the way in which patients are treated. Furthermore, our increasing understanding of the molecular events in tumorigenesis is leading to the identification of biomarkers that enable us to predict response to treatment. A major drawback, however, is the general lack of an adequate systematic approach to advancing the use of biomarkers in cancer drug development, highlighted in a Cancer Biomarkers Collaborative consensus report. In this Review, we summarize the latest insights into the biology of pancreatic cancer, and their repercussions for treatment. We provide an overview of current treatments and, finally, we discuss novel therapeutic approaches, including the role of biomarkers in therapy for pancreatic cancer.

5 Review Nanotechnology advances in upper gastrointestinal, liver and pancreatic cancer. 2012

Sykes, Paul D / Neoptolemos, John P / Costello, Eithne / Halloran, Christopher M. ·Liverpool Cancer Research UK Centre, Department of Molecular and Clinical Cancer Studies, University of Liverpool, Daulby Street, Liverpool, L69 3GA, UK. ·Expert Rev Gastroenterol Hepatol · Pubmed #22646256.

ABSTRACT: Cancers of the upper GI tract, liver and pancreas have some of the poorest prognoses of any malignancies. Advances in diagnosis and treatment are sorely needed to improve the outcomes of patients. Nanotechnology offers the potential for constructing tailor-made therapies capable of targeting specific cancers. The particles themselves may be endowed with multifunctional properties that can be exploited for both diagnosis and treatment. Although development of therapies is still in the early stages, the use of nanoparticles (NPs) is widespread in diagnostic applications and will probably involve all areas of medicine in the future. Research into NPs is ongoing for upper gastrointestinal, liver and pancreatic cancers, and their use is becoming increasingly popular as contrast media for radiological investigations. Although more sophisticated technologies capable of active targeting are still in the early stages of assessment for clinical use, a small number of NP-based therapies are in clinical use.

6 Review Pancreatic cancer in 2010: new insights for early intervention and detection. 2011

Costello, Eithne / Neoptolemos, John P. ·Liverpool CR-UK Centre, NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, Daulby Street, University of Liverpool, Liverpool, UK. ·Nat Rev Gastroenterol Hepatol · Pubmed #21293504.

ABSTRACT: Pancreatic cancer is usually detected at an advanced stage and responds poorly to treatment. In 2010 new insights were gained into understanding the complex biology of pancreatic cancer. Importantly, these insights offer novel opportunities for early diagnosis and treatment of this disease.

7 Review Pancreatic cancer: proteomic approaches to a challenging disease. 2009

Tonack, Sarah / Aspinall-O'Dea, Mark / Neoptolemos, John P / Costello, Eithne. ·Division of Surgery and Oncology, Royal Liverpool University Hospital, University of Liverpool, Liverpool, UK. ·Pancreatology · Pubmed #19657212.

ABSTRACT: PURPOSE OF REVIEW: To describe progress in the application of proteomic approaches to advance our understanding of the biology of pancreatic cancer as well as contribute potential protein biomarkers for this disease. RECENT FINDINGS: Here we review proteomic studies relating to pancreatic cancer that have been published in the past 12 months. We describe novel techniques for the simplification of complex protein samples, focusing particularly on emerging methods for reducing the complexity of blood. We provide examples, where possible, of the application of these novel technologies to pancreatic cancer research. SUMMARY: Both the range of proteomic-based approaches and their sensitivities for the detection of low-abundance proteins has increased. This provides promise that further research will yield insight into pancreatic cancer, including valuable information on proteins that may ultimately serve as biomarkers for pancreatic cancer.

8 Clinical Trial Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial. 2018

Tatarian, Talar / Jiang, Wei / Leiby, Benjamin E / Grigoli, Amanda / Jimbo, Masaya / Dabbish, Nooreen / Neoptolemos, John P / Greenhalf, William / Costello, Eithne / Ghaneh, Paula / Halloran, Christopher / Palmer, Daniel / Buchler, Markus / Yeo, Charles J / Winter, Jordan M / Brody, Jonathan R. ·Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Department of Pathology, Anatomy, and Cell Biology, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Division of Biostatistics, Department of Pharmacology and Experimental Therapeutics, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA. · Institute of Translational Medicine, Cancer Research UK Liverpool Cancer Trials Unit, Liverpool, UK. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Ann Surg · Pubmed #27893535.

ABSTRACT: OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3-36.4 vs 10.9 months, CI: 7.5-14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6-14.6 vs GEM, 12.9 months, CI: 11.2-15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.

9 Clinical Trial Vandetanib plus gemcitabine versus placebo plus gemcitabine in locally advanced or metastatic pancreatic carcinoma (ViP): a prospective, randomised, double-blind, multicentre phase 2 trial. 2017

Middleton, Gary / Palmer, Daniel H / Greenhalf, William / Ghaneh, Paula / Jackson, Richard / Cox, Trevor / Evans, Anthony / Shaw, Victoria E / Wadsley, Jonathan / Valle, Juan W / Propper, David / Wasan, Harpreet / Falk, Stephen / Cunningham, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Wadd, Nick / Corrie, Pippa / Hickish, Tamas / Costello, Eithne / Campbell, Fiona / Rawcliffe, Charlotte / Neoptolemos, John P. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · Division of Molecular and Clinical Cancer Sciences, University of Manchester, Manchester, UK; Christie NHS Foundation Trust, Manchester, UK. · Centre for Cancer and Inflammation, Barts Cancer Institute, London, UK. · Hammersmith Hospital, London, UK. · Bristol Haematology and Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · Royal Marsden, Royal Marsden NHS Foundation Trust, London, UK. · Northern Centre for Cancer Care, Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middlesborough, UK. · Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Poole Hospital NHS Foundation Trust, Bournemouth University, Poole, UK. · Liverpool Cancer Research UK Cancer Trials Unit and LCTU-GCPLabs, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #28259610.

ABSTRACT: BACKGROUND: Erlotinib is an EGFR tyrosine kinase inhibitor that has shown a significant but only marginally improved median overall survival when combined with gemcitabine in patients with locally advanced and metastatic pancreatic cancer. Vandetanib is a novel tyrosine kinase inhibitor of VEGFR2, RET, and EGFR, all of which are in involved in the pathogenesis of pancreatic cancer. We investigated the clinical efficacy of vandetanib when used in combination with gemcitabine in patients with advanced pancreatic cancer. METHODS: The Vandetanib in Pancreatic Cancer (ViP) trial was a phase 2 double-blind, multicentre, randomised placebo-controlled trial in previously untreated adult patients (aged ≥18 years) diagnosed with locally advanced or metastatic carcinoma of the pancreas confirmed by cytology or histology. Patients had to have an Eastern Cooperative Oncology Group (ECOG) score of 0-2 and a documented life expectancy of at least 3 months. Patients were randomly assigned 1:1 to receive vandetanib plus gemcitabine (vandetanib group) or placebo plus gemcitabine (placebo group) according to pre-generated sequences produced on the principle of randomly permuted blocks with variable block sizes of two and four. Patients were stratified at randomisation by disease stage and ECOG performance status. All patients received gemcitabine 1000 mg/m FINDINGS: Patients were screened and enrolled between Oct 24, 2011, and Oct 7, 2013. Of 381 patients screened, 142 eligible patients were randomly assigned to treatment (72 to the vandetanib group and 70 to the placebo group). At database lock on July 15, 2015, at a median follow-up of 24·9 months (IQR 24·3 to not attainable), 131 patients had died: 70 (97%) of 72 in the vandetanib group and 61 (87%) of 70 in the placebo group. The median overall survival was 8·83 months (95% CI 7·11-11·58) in the vandetanib group and 8·95 months (6·55-11·74) in the placebo group (hazard ratio 1·21, 80·8% CI 0·95-1·53; log rank χ INTERPRETATION: The addition of vandetanib to gemcitabine monotherapy did not improve overall survival in advanced pancreatic cancer. Tyrosine kinase inhibitors might still have potential in the treatment of pancreatic cancer but further development requires the identification of biomarkers to specifically identify responsive cancer subtypes. FUNDING: Cancer Research UK and AstraZeneca.

10 Clinical Trial Gemcitabine and capecitabine with or without telomerase peptide vaccine GV1001 in patients with locally advanced or metastatic pancreatic cancer (TeloVac): an open-label, randomised, phase 3 trial. 2014

Middleton, Gary / Silcocks, Paul / Cox, Trevor / Valle, Juan / Wadsley, Jonathan / Propper, David / Coxon, Fareeda / Ross, Paul / Madhusudan, Srinivasan / Roques, Tom / Cunningham, David / Falk, Stephen / Wadd, Nick / Harrison, Mark / Corrie, Pippa / Iveson, Tim / Robinson, Angus / McAdam, Karen / Eatock, Martin / Evans, Jeff / Archer, Caroline / Hickish, Tamas / Garcia-Alonso, Angel / Nicolson, Marianne / Steward, William / Anthoney, Alan / Greenhalf, William / Shaw, Victoria / Costello, Eithne / Naisbitt, Dean / Rawcliffe, Charlotte / Nanson, Gemma / Neoptolemos, John. ·University of Birmingham, Edgbaston, Birmingham, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. · Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester UK. · Weston Park Hospital, Sheffield Teaching Hospital NHS Foundation Trust, Sheffield, UK. · St Bartholomew's Hospital, Barts Health NHS Trust, West Smithfield, London, UK. · Northern Centre for Cancer Care, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Freeman Hospital, Newcastle upon Tyne, UK. · Guy's Hospital, Guy's and St Thomas' NHS Foundation Trust, London, UK. · Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Nottingham, UK. · Norfolk and Norwich University Hospital, Norfolk and Norwich University Hospital NHS Foundation Trust, Norwich, UK. · The Royal Marsden, The Royal Marsden NHS Foundation Trust, London, UK. · Bristol Haematology And Oncology Centre, University Hospital Bristol NHS Foundation Trust, Bristol, UK. · The James Cook University Hospital, South Tees Hospitals NHS Foundation Trust, Middleborough, UK. · Mount Vernon Hospital, The Hillingdon Hospitals NHS Foundation Trust, Northwood, UK. · Addenbrookes Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK. · Southampton General Hospital, University Hospital Southampton NHS Foundation Trust, Southampton, Hampshire, UK. · Conquest Hospital, East Sussex Healthcare NHS Trust, The Ridge, St Leonards-on-Sea, East Sussex, UK. · Peterborough City Hospital, Peterborough and Stamford Hospitals NHS Foundation Trust, Edith, Cavell Campus, Peterborough, UK. · Belfast City Hospital, Belfast Health and Social Care Trust, Belfast, UK. · University of Glasgow, Beatson West of Scotland Cancer Centre, Glasgow, UK. · Queen Alexandra Hospital, Portsmouth Hospitals NHS Trust, Cosham, Portsmouth, UK. · Royal Bournemouth Hospital, The Royal Bournemouth and Christchurch Hospitals NHS Foundation Trust, Bournemouth, UK. · Glan Clwyd Hospital, University Health Board, Rhyl, Denbighshire, UK. · Abderdeen Royal Infirmary, NHS Grampian, Aberdeen, UK. · Leicester Royal Infirmary, University Hospitals of Leicester NHS Trust, Leicester, UK. · St James University Hospital, The Leeds Teaching Hospital Trust, Beckett Street, Leeds, UK. · Liverpool Cancer Research UK Cancer Trials Unit and GCLP Facility, University of Liverpool, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. ·Lancet Oncol · Pubmed #24954781.

ABSTRACT: BACKGROUND: We aimed to assess the efficacy and safety of sequential or simultaneous telomerase vaccination (GV1001) in combination with chemotherapy in patients with locally advanced or metastatic pancreatic cancer. METHODS: TeloVac was a three-group, open-label, randomised phase 3 trial. We recruited patients from 51 UK hospitals. Eligible patients were treatment naive, aged older than 18 years, with locally advanced or metastatic pancreatic ductal adenocarcinoma, and Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned (1:1:1) to receive either chemotherapy alone, chemotherapy with sequential GV1001 (sequential chemoimmunotherapy), or chemotherapy with concurrent GV1001 (concurrent chemoimmunotherapy). Treatments were allocated with equal probability by means of computer-generated random permuted blocks of sizes 3 and 6 in equal proportion. Chemotherapy included six cycles of gemcitabine (1000 mg/m(2), 30 min intravenous infusion, at days 1, 8, and 15) and capecitabine (830 mg/m(2) orally twice daily for 21 days, repeated every 28 days). Sequential chemoimmunotherapy included two cycles of combination chemotherapy, then an intradermal lower abdominal injection of granulocyte-macrophage colony-stimulating factor (GM-CSF; 75 μg) and GV1001 (0·56 mg; days 1, 3, and 5, once on weeks 2-4, and six monthly thereafter). Concurrent chemoimmunotherapy included giving GV1001 from the start of chemotherapy with GM-CSF as an adjuvant. The primary endpoint was overall survival; analysis was by intention to treat. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN4382138. FINDINGS: The first patient was randomly assigned to treatment on March 29, 2007, and the trial was terminated on March 27, 2011. Of 1572 patients screened, 1062 were randomly assigned to treatment (358 patients were allocated to the chemotherapy group, 350 to the sequential chemoimmunotherapy group, and 354 to the concurrent chemoimmunotherapy group). We recorded 772 deaths; the 290 patients still alive were followed up for a median of 6·0 months (IQR 2·4-12·2). Median overall survival was not significantly different in the chemotherapy group than in the sequential chemoimmunotherapy group (7·9 months [95% CI 7·1-8·8] vs 6·9 months [6·4-7·6]; hazard ratio [HR] 1·19, 98·25% CI 0·97-1·48, p=0·05), or in the concurrent chemoimmunotherapy group (8·4 months [95% CI 7·3-9·7], HR 1·05, 98·25% CI 0·85-1·29, p=0·64; overall log-rank of χ(2)2df=4·3; p=0·11). The commonest grade 3-4 toxic effects were neutropenia (68 [19%] patients in the chemotherapy group, 58 [17%] patients in the sequential chemoimmunotherapy group, and 79 [22%] patients in the concurrent chemoimmunotherapy group; fatigue (27 [8%] in the chemotherapy group, 35 [10%] in the sequential chemoimmunotherapy group, and 44 [12%] in the concurrent chemoimmunotherapy group); and pain (34 [9%] patients in the chemotherapy group, 39 [11%] in the sequential chemoimmunotherapy group, and 41 [12%] in the concurrent chemoimmunotherapy group). INTERPRETATION: Adding GV1001 vaccination to chemotherapy did not improve overall survival. New strategies to enhance the immune response effect of telomerase vaccination during chemotherapy are required for clinical efficacy. FUNDING: Cancer Research UK and KAEL-GemVax.

11 Article Pancreatic cancer and autoimmune diseases: An association sustained by computational and epidemiological case-control approaches. 2019

Gomez-Rubio, Paulina / Piñero, Janet / Molina-Montes, Esther / Gutiérrez-Sacristán, Alba / Marquez, Mirari / Rava, Marta / Michalski, Christoph W / Farré, Antoni / Molero, Xavier / Löhr, Matthias / Perea, José / Greenhalf, William / O'Rorke, Michael / Tardón, Adonina / Gress, Thomas / Barberá, Victor M / Crnogorac-Jurcevic, Tatjana / Muñoz-Bellvís, Luís / Domínguez-Muñoz, Enrique / Balsells, Joaquim / Costello, Eithne / Yu, Jingru / Iglesias, Mar / Ilzarbe, Lucas / Kleeff, Jörg / Kong, Bo / Mora, Josefina / Murray, Liam / O'Driscoll, Damian / Poves, Ignasi / Lawlor, Rita T / Ye, Weimin / Hidalgo, Manuel / Scarpa, Aldo / Sharp, Linda / Carrato, Alfredo / Real, Francisco X / Furlong, Laura I / Malats, Núria / Anonymous2321201. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center CNIO, Madrid, Spain. · Centro de Investigación Biomédica en Red en Oncología (CIBERONC), Enfermedades Hepáticas y Digestivas (CIBERHD), and Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. · Research Program on Biomedical Informatics (GRIB), Hospital del Mar Research Institute (IMIM), Universidad Pompeu Fabra (UPF), Barcelona, Spain. · Department of Surgery, Technical University of Munich, Munich, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain. · Hospital Universitaru Vall d'Hebron, Exocrine Pancreas Research Unit and Vall d'Hebron Research Institute (VHIR), Barcelona, Spain. · Universitat Auntònoma de Barcelona, Campus de la UAB, Barcelona, Spain. · Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet and University Hospital, Stockholm, Sweden. · Department of Surgery, University Hospital 12 de Octubre, Madrid, Spain. · Department of Molecular and Clinical Cancer Medicine, The Royal Liverpool University Hospital, Liverpool, United Kingdom. · Centre for Public Health, Queen's University Belfast, Belfast, United Kingdom. · Department of Medicine, Instituto Universitario de Oncología del Principado de Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany. · Laboratorio de Genética Molecular, Hospital General Universitario de Elche, Elche, Spain. · Centre for Molecular Oncology, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. · General and Digestive Surgery Department, Hospital Universitario de Salamanca, Salamanca, Spain. · Department of Gastroenterology, Hospital Clínico Universitario de Santiago de Compostela, Santiago de Compostela, Spain. · Department of Gastroenterology, Hospital del Mar/Parc de Salut Mar, Barcelona, Spain. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, Halle, (Saale), Germany. · Cancer Data Registrars, National Cancer Registry Ireland, Cork, Ireland. · ARC-Net Centre for Applied Research on Cancer, Department of Pathology and Diagnostics, University Hospital Trust of Verona, Verona, Italy. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet and University Hospital, Sweden. · Hospital Madrid-Norte-Sanchinarro and Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Rosenberg Clinical Cancer Center, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA. · Institute of Health and Society, Newcastle University, Newcastle upon Tyne, United Kingdom. · Department of Oncology, Hospital Ramón y Cajal, Madrid, Spain. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · PanGenEU Study Investigators (Additional file 1: Annex S1). ·Int J Cancer · Pubmed #30229903.

ABSTRACT: Deciphering the underlying genetic basis behind pancreatic cancer (PC) and its associated multimorbidities will enhance our knowledge toward PC control. The study investigated the common genetic background of PC and different morbidities through a computational approach and further evaluated the less explored association between PC and autoimmune diseases (AIDs) through an epidemiological analysis. Gene-disease associations (GDAs) of 26 morbidities of interest and PC were obtained using the DisGeNET public discovery platform. The association between AIDs and PC pointed by the computational analysis was confirmed through multivariable logistic regression models in the PanGen European case-control study population of 1,705 PC cases and 1,084 controls. Fifteen morbidities shared at least one gene with PC in the DisGeNET database. Based on common genes, several AIDs were genetically associated with PC pointing to a potential link between them. An epidemiologic analysis confirmed that having any of the nine AIDs studied was significantly associated with a reduced risk of PC (Odds Ratio (OR) = 0.74, 95% confidence interval (CI) 0.58-0.93) which decreased in subjects having ≥2 AIDs (OR = 0.39, 95%CI 0.21-0.73). In independent analyses, polymyalgia rheumatica, and rheumatoid arthritis were significantly associated with low PC risk (OR = 0.40, 95%CI 0.19-0.89, and OR = 0.73, 95%CI 0.53-1.00, respectively). Several inflammatory-related morbidities shared a common genetic component with PC based on public databases. These molecular links could shed light into the molecular mechanisms underlying PC development and simultaneously generate novel hypotheses. In our study, we report sound findings pointing to an association between AIDs and a reduced risk of PC.

12 Article S100A8 and S100A9 proteins form part of a paracrine feedback loop between pancreatic cancer cells and monocytes. 2018

Nedjadi, Taoufik / Evans, Anthony / Sheikh, Adnan / Barerra, Lawrence / Al-Ghamdi, Suliman / Oldfield, Lucy / Greenhalf, W / Neoptolemos, John P / Costello, Eithne. ·King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, P. O. Box 9515, Jeddah, 21423, Saudi Arabia. nedjadita@ngha.med.sa. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, The University of Liverpool, Liverpool, UK. · King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard-Health Affairs, P. O. Box 9515, Jeddah, 21423, Saudi Arabia. ·BMC Cancer · Pubmed #30558665.

ABSTRACT: BACKGROUND: The secretion of soluble factors enables communication between tumour cells and the surrounding microenvironment and plays an important role in oncogenesis. Pancreatic ductal adenocarcinoma (PDAC) is characterised by a highly reactive microenvironment, harbouring a variety of cell types, including S100A8/S100A9-expressing monocytes. S100A8/S100A9 proteins regulate the behaviour of cancer cells by inducing pre-metastatic cascades associated with cancer spread. The aim of this study was to examine how S100A8/A9 proteins mediate tumour-stroma crosstalk in PDAC. METHODS: Cytokine profiling of pancreatic cancer cell-derived conditioned media was performed using Bio-Plex Pro 27 Plex Human Cytokine assays. Protein expression and activation of downstream signalling effectors and NF-κB were assessed by western blotting analysis and reporter assays respectively. RESULTS: Stimulation of cultured pancreatic cancer cells with S100A8 and S100A9 increased the secretion of the pro-inflammatory cytokines IL-8, TNF-α, and FGF. S100A8, but not S100A9 induced PDGF secretion. Conversely, pancreatic cancer cell-derived conditioned media and the individual cytokines, TNF-α and TGF-β induced the expression of S100A8 and S100A9 proteins in the HL-60 monocytic cell line and primary human monocytes, while FGF and IL-8 induced the expression of S100A9 only. S100A8 and S100A9 activated MAPK and NF-κB signalling in pancreatic cancer. This was partially mediated via activation of the receptor of advanced glycosylation end-product (RAGE). CONCLUSION: S100A8 and S100A9 proteins induce specific cytokine secretion from PDAC cells, which in turn enhances the expression of S100A8/A9. This paracrine crosstalk could have implications for PDAC invasiveness and metastatic potential.

13 Article Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma. 2018

Mahajan, Ujjwal Mukund / Langhoff, Eno / Goni, Elisabetta / Costello, Eithne / Greenhalf, William / Halloran, Christopher / Ormanns, Steffen / Kruger, Stephan / Boeck, Stefan / Ribback, Silvia / Beyer, Georg / Dombroswki, Frank / Weiss, Frank-Ulrich / Neoptolemos, John P / Werner, Jens / D'Haese, Jan G / Bazhin, Alexandr / Peterhansl, Julian / Pichlmeier, Svenja / Büchler, Markus W / Kleeff, Jörg / Ganeh, Paula / Sendler, Matthias / Palmer, Daniel H / Kohlmann, Thomas / Rad, Roland / Regel, Ivonne / Lerch, Markus M / Mayerle, Julia. ·Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Institute of Pathology, Faculty of Medicine, LMU Munich, Munich, Germany. · Department of Medicine III, University Hospital, LMU Munich, Germany. · Department of Pathology, University Medicine Greifswald, Greifswald, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of General, Visceral, and Transplant Surgery, Ludwig-Maximilians-University Munich, Munich, Germany. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther University Halle-Wittenberg, Halle, Germany. · Institute of Translational Medicine, University of Liverpool, Liverpool, UK; Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, UK. · Department of Community Medicine, University Medicine Greifswald, Greifswald, Germany. · Center for Translational Cancer Research (TranslaTUM), Technische Universität München, Munich, Germany. · Department of Medicine II, University Hospital, LMU Munich, Germany; Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. Electronic address: julia.mayerle@med.uni-muenchen.de. ·Gastroenterology · Pubmed #30092175.

ABSTRACT: BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

14 Article Intratumoural expression of deoxycytidylate deaminase or ribonuceotide reductase subunit M1 expression are not related to survival in patients with resected pancreatic cancer given adjuvant chemotherapy. 2018

Elander, N O / Aughton, K / Ghaneh, P / Neoptolemos, J P / Palmer, D H / Cox, T F / Campbell, F / Costello, E / Halloran, C M / Mackey, J R / Scarfe, A G / Valle, J W / McDonald, A C / Carter, R / Tebbutt, N C / Goldstein, D / Shannon, J / Dervenis, C / Glimelius, B / Deakin, M / Charnley, R M / Anthoney, A / Lerch, M M / Mayerle, J / Oláh, A / Büchler, M W / Greenhalf, W / Anonymous1351258. ·Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. · Cross Cancer Institute and University of Alberta, Edmonton, Canada. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Glasgow Royal Infirmary, Glasgow, UK. · Austin Health, Melbourne, VIC, Australia. · Prince of Wales hospital and Clinical School, University of New South Wales, Sydney, NSW, Australia. · Nepean Cancer Centre and University of Sydney, Camperdown, NSW, Australia. · The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · University Hospital, North Staffordshire, Staffordshire, UK. · Freeman Hospital, Newcastle upon Tyne, UK. · St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital of the Ludwig-Maximilians-University Munich, Munich, Germany. · The Petz Aladar Hospital, Gyor, Hungary. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. greenhaf@liv.ac.uk. ·Br J Cancer · Pubmed #29523831.

ABSTRACT: BACKGROUND: Deoxycytidylate deaminase (DCTD) and ribonucleotide reductase subunit M1 (RRM1) are potential prognostic and predictive biomarkers for pyrimidine-based chemotherapy in pancreatic adenocarcinoma. METHODS: Immunohistochemical staining of DCTD and RRM1 was performed on tissue microarrays representing tumour samples from 303 patients in European Study Group for Pancreatic Cancer (ESPAC)-randomised adjuvant trials following pancreatic resection, 272 of whom had received gemcitabine or 5-fluorouracil with folinic acid in ESPAC-3(v2), and 31 patients from the combined ESPAC-3(v1) and ESPAC-1 post-operative pure observational groups. RESULTS: Neither log-rank testing on dichotomised strata or Cox proportional hazard regression showed any relationship of DCTD or RRM1 expression levels to survival overall or by treatment group. CONCLUSIONS: Expression of either DCTD or RRM1 was not prognostic or predictive in patients with pancreatic adenocarcinoma who had had post-operative chemotherapy with either gemcitabine or 5-fluorouracil with folinic acid.

15 Article Expression of dihydropyrimidine dehydrogenase (DPD) and hENT1 predicts survival in pancreatic cancer. 2018

Elander, N O / Aughton, K / Ghaneh, P / Neoptolemos, J P / Palmer, D H / Cox, T F / Campbell, F / Costello, E / Halloran, C M / Mackey, J R / Scarfe, A G / Valle, J W / McDonald, A C / Carter, R / Tebbutt, N C / Goldstein, D / Shannon, J / Dervenis, C / Glimelius, B / Deakin, M / Charnley, R M / Anthoney, Alan / Lerch, M M / Mayerle, J / Oláh, A / Büchler, M W / Greenhalf, W / Anonymous1151214. ·From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. · The Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Cross Cancer Institute and University of Alberta, Alberta, Canada. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, Scotland, UK. · Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Austin Health, Melbourne, Australia. · Prince of Wales hospital and Clinical School University of New South Wales, New South Wales, Australia. · Nepean Cancer Centre and University of Sydney, Sydney, Australia. · The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden. · University Hospital, North Staffordshire, UK. · Freeman Hospital, Newcastle upon Tyne, UK. · St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Medicine II, University Hospital of the Ludwig-Maximilians-University, Munich, Germany. · The Petz Aladar Hospital, Gyor, Hungary. · From the Cancer Research U.K. Liverpool Cancer Trials Unit, University of Liverpool, Liverpool, UK. greenhaf@liv.ac.uk. ·Br J Cancer · Pubmed #29515256.

ABSTRACT: BACKGROUND: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy. METHODS: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA). RESULTS: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009). CONCLUSION: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine.

16 Article Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives. 2018

Molina-Montes, E / Gomez-Rubio, P / Márquez, M / Rava, M / Löhr, M / Michalski, C W / Molero, X / Farré, A / Perea, J / Greenhalf, W / Ilzarbe, L / O'Rorke, M / Tardón, A / Gress, T / Barberà, V M / Crnogorac-Jurcevic, T / Domínguez-Muñoz, E / Muñoz-Bellvís, L / Balsells, J / Costello, E / Huang, J / Iglesias, M / Kleeff, J / Kong, Bo / Mora, J / Murray, L / O'Driscoll, D / Poves, I / Scarpa, A / Ye, W / Hidalgo, M / Sharp, L / Carrato, A / Real, F X / Malats, N / Anonymous601079. ·Spanish National Cancer Research Center (CNIO), Genetic and Molecular Epidemiology Group, Madrid, and CIBERONC, Spain. · Karolinska Institutet and University Hospital, Gastrocentrum, Stockholm, Sweden. · Technical University of Munich, Department of Surgery, Munich, Germany. · University of Heidelberg, Department of Surgery, Heidelberg, Germany. · Hospital Universitari Vall d'Hebron, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, and CIBEREHD, Spain. · Hospital de la Santa Creu i Sant Pau, Department of Gastroenterology, Barcelona, Spain. · University Hospital 12 de Octubre, Department of Surgery, Madrid, Spain. · Royal Liverpool University Hospital, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK. · Hospital del Mar-Parc de Salut Mar, Barcelona, Spain. · Queen's University Belfast, Centre for Public Health, Belfast, UK. · Instituto Universitario de Oncología del Principado de Asturias, Department of Medicine, Oviedo, and CIBERESP, Spain. · University Hospital of Giessen and Marburg, Department of Gastroenterology, Marburg, Germany. · General University Hospital of Elche, Molecular Genetics Laboratory, Elche, Spain. · Barts Cancer Institute, Centre for Molecular Oncology, Queen Mary University of London, London, UK. · University Clinical Hospital of Santiago de Compostela, Department of Gastroenterology, Santiago de Compostela, Spain. · Salamanca University Hospital, General and Digestive Surgery Department, Salamanca, Spain. · Martin-Luther-University Halle-Wittenberg, Department of Visceral, Vascular and Endocrine Surgery, Halle (Saale), Germany. · National Cancer Registry Ireland and HRB Clinical Research Facility, University College Cork, Cork, Ireland. · ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital Trust of Verona, Verona, Italy. · Madrid-Norte-Sanchinarro Hospital, Madrid, Spain. · Newcastle University, Institute of Health and Society, Newcastle upon Tyne, UK. · Ramón y Cajal University Hospital, Department of Oncology, IRYCIS, Alcala University, Madrid, and CIBERONC, Spain. · Spanish National Cancer Research Centre (CNIO), Epithelial Carcinogenesis Group, Madrid, Universitat Pompeu Fabra, Departament de Ciències Experimentals i de la Salut, Barcelona, and CIBERONC, Spain. ·Int J Epidemiol · Pubmed #29329392.

ABSTRACT: Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

17 Article Transcriptional variations in the wider peritumoral tissue environment of pancreatic cancer. 2018

Bauer, Andrea S / Nazarov, Petr V / Giese, Nathalia A / Beghelli, Stefania / Heller, Anette / Greenhalf, William / Costello, Eithne / Muller, Arnaud / Bier, Melanie / Strobel, Oliver / Hackert, Thilo / Vallar, Laurent / Scarpa, Aldo / Büchler, Markus W / Neoptolemos, John P / Kreis, Stephanie / Hoheisel, Jörg D. ·Division of Functional Genome Analysis, German Cancer Research Centre (DKFZ), Heidelberg, Germany. · Genomics and Proteomics Research Unit, Luxembourg Institute of Health, Luxembourg City, Luxembourg. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Pathology and Diagnostics, Università di Verona, Verona, Italy. · National Institute for Health Research, Pancreas Biomedical Research Unit and the Liverpool Experimental Cancer Medicine Centre, Liverpool, United Kingdom. · Life Sciences Research Unit, University of Luxembourg, Luxembourg City, Luxembourg. ·Int J Cancer · Pubmed #28983920.

ABSTRACT: Transcriptional profiling was performed on 452 RNA preparations isolated from various types of pancreatic tissue from tumour patients and healthy donors, with a particular focus on peritumoral samples. Pancreatic ductal adenocarcinomas (PDAC) and cystic tumours were most different in these non-tumorous tissues surrounding them, whereas the actual tumours exhibited rather similar transcript patterns. The environment of cystic tumours was transcriptionally nearly identical to normal pancreas tissue. In contrast, the tissue around PDAC behaved a lot like the tumour, indicating some kind of field defect, while showing far less molecular resemblance to both chronic pancreatitis and healthy tissue. This suggests that the major pathogenic difference between cystic and ductal tumours may be due to their cellular environment rather than the few variations between the tumours. Lack of correlation between DNA methylation and transcript levels makes it unlikely that the observed field defect in the peritumoral tissue of PDAC is controlled to a large extent by such epigenetic regulation. Functionally, a strikingly large number of autophagy-related transcripts was changed in both PDAC and its peritumoral tissue, but not in other pancreatic tumours. A transcription signature of 15 autophagy-related genes was established that permits a prognosis of survival with high accuracy and indicates the role of autophagy in tumour biology.

18 Article A metabolomics-based biomarker signature discriminates pancreatic cancer from chronic pancreatitis. 2018

Costello, Eithne. · ·Gut · Pubmed #28539352.

ABSTRACT: -- No abstract --

19 Article Lack of Association for Reported Endocrine Pancreatic Cancer Risk Loci in the PANDoRA Consortium. 2017

Campa, Daniele / Obazee, Ofure / Pastore, Manuela / Panzuto, Francesco / Liço, Valbona / Greenhalf, William / Katzke, Verena / Tavano, Francesca / Costello, Eithne / Corbo, Vincenzo / Talar-Wojnarowska, Renata / Strobel, Oliver / Zambon, Carlo Federico / Neoptolemos, John P / Zerboni, Giulia / Kaaks, Rudolf / Key, Timothy J / Lombardo, Carlo / Jamroziak, Krzysztof / Gioffreda, Domenica / Hackert, Thilo / Khaw, Kay-Tee / Landi, Stefano / Milanetto, Anna Caterina / Landoni, Luca / Lawlor, Rita T / Bambi, Franco / Pirozzi, Felice / Basso, Daniela / Pasquali, Claudio / Capurso, Gabriele / Canzian, Federico. ·Department of Biology, University of Pisa, Pisa, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, S. Andrea Hospital, "Sapienza" University of Rome, Rome, Italy. · Pancreatic and Digestive Endocrine Surgery, Department of Surgery, Oncology and Gastroenterology -DiSCOG, University of Padova, Padua, Italy. · Institute of Translational Medicine, Cancer Research UK Liverpool Cancer Trials Unit, Liverpool, United Kingdom. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Gastroenterology and Research Laboratory, Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Medicine - DIMED, University of Padova, Padua, Italy. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, United Kingdom. · Division of General and Transplant Surgery, University of Pisa, Pisa, Italy. · Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, University of Pisa, Pisa, Italy. · Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. · University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom. · The Pancreas Institute, Department of Surgery, University and Hospital Trust of Verona, Verona, Italy. · Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy. · Department of Laboratory Medicine, University-Hospital of Padova, Padua, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. f.canzian@dkfz.de. ·Cancer Epidemiol Biomarkers Prev · Pubmed #28765340.

ABSTRACT:

20 Article A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk. 2017

Gomez-Rubio, P / Rosato, V / Márquez, M / Bosetti, C / Molina-Montes, E / Rava, M / Piñero, J / Michalski, C W / Farré, A / Molero, X / Löhr, M / Ilzarbe, L / Perea, J / Greenhalf, W / O'Rorke, M / Tardón, A / Gress, T / Barberá, V M / Crnogorac-Jurcevic, T / Muñoz-Bellvís, L / Domínguez-Muñoz, E / Gutiérrez-Sacristán, A / Balsells, J / Costello, E / Guillén-Ponce, C / Huang, J / Iglesias, M / Kleeff, J / Kong, B / Mora, J / Murray, L / O'Driscoll, D / Peláez, P / Poves, I / Lawlor, R T / Carrato, A / Hidalgo, M / Scarpa, A / Sharp, L / Furlong, L I / Real, F X / La Vecchia, C / Malats, N / Anonymous4870902. ·Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, and CIBERONC, Spain. · Branch of Medical Statistics, Biometry and Epidemiology "G.A. Maccacaro," Department of Clinical Sciences and Community Health, University of Milan, Milan. · Unit of Medical Statistics, Biometry and Bioinformatics, National Cancer Institute, IRCCS Foundation, Milan. · Department of Epidemiology, Mario Negri Institute for Pharmacological Research-IRCCS, Milan, Italy. · Research Programme on Biomedical Informatics (GRIB), Hospital del Mar Research Institute (IMIM), Pompeu Fabra Univeristy (UPF), Barcelona, Spain. · Department of Surgery, Technical University of Munich, Munich. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. · Department of Gastroenterology, Santa Creu i Sant Pau Hospital, Barcelona. · Exocrine Pancreas Research Unit and Vall d'Hebron Research Institute (VHIR), Vall d'Hebron University Hospital, Barcelona. · Department of Medicine, Universitat Autònoma de Barcelona, Barcelona. · Network of Biomedical Research Centres (CIBER), Hepatic and Digestive Diseases and Epidemiology and Public Health, Madrid, Spain. · Gastrocentrum, Karolinska Institutet and University Hospital, Stockholm, Sweden. · Department of Gastroenterology, Parc de Salut Mar University Hospital, Barcelona. · Department of Surgery, 12 de Octubre University Hospital, Madrid, Spain. · Department of Molecular and Clinical Cancer Medicine, The Royal Liverpool University Hospital, Liverpool. · Centre for Public Health, Queen's University Belfast, Belfast, UK. · Department of Medicine, University Institute of Oncology of Asturias, Oviedo, Spain. · Department of Gastroenterology, University Hospital of Giessen and Marburg, Marburg, Germany. · Molecular Genetics Laboratory, General University Hospital of Elche, Elche, Spain. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, John Vane Science Centre, London, UK. · General and Digestive Surgery Department, Salamanca University Hospital, Salamanca. · Department of Gastroenterology, Clinical University Hospital of Santiago de Compostela, Santiago de Compostela. · Department of Oncology, Ramón y Cajal Hospital, Madrid, and CIBERONC, Spain. · Research Programme, National Cancer Registry Ireland. · ARC-Net Centre for Applied Research on Cancer and Department of Pathology and Diagnostics, University and Hospital trust of Verona, Verona, Italy. · Clara Campal Integrated Oncological Centre, Sanchinarro Hospital, Madrid, Spain. · Institute of Health & Society, Newcastle University, UK. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid, and CIBERONC. · Department of Experimental and Health Sciences, Pompeu Fabra University, Barcelona, Spain. ·Ann Oncol · Pubmed #28383714.

ABSTRACT: Background: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. Methods: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. Results: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. Conclusions: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

21 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

22 Article Proteomic analysis of pancreatic cancer stem cells: Functional role of fatty acid synthesis and mevalonate pathways. 2017

Brandi, Jessica / Dando, Ilaria / Pozza, Elisa Dalla / Biondani, Giulia / Jenkins, Rosalind / Elliott, Victoria / Park, Kevin / Fanelli, Giuseppina / Zolla, Lello / Costello, Eithne / Scarpa, Aldo / Cecconi, Daniela / Palmieri, Marta. ·University of Verona, Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, Verona 37134, Italy. · University of Verona, Department of Neuroscience, Biomedicine and Movement, Verona 37134, Italy. · University of Liverpool, MRC Centre for Drug Safety Science, Department of Molecular & Clinical Pharmacology, Liverpool L69 3GE, United Kingdom. · NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Therapeutic Cancer Medicine, Royal Liverpool University Hospital, Liverpool L69 3GA, United Kingdom. · Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy. · University and Hospital Trust of Verona, Applied Research on Cancer Network (ARC-NET), Department of Pathology and Diagnostics, Verona 37134, Italy. · University of Verona, Department of Biotechnology, Proteomics and Mass Spectrometry Laboratory, Verona 37134, Italy. Electronic address: daniela.cecconi@univr.it. ·J Proteomics · Pubmed #27746256.

ABSTRACT: Recently, we have shown that the secretome of pancreatic cancer stem cells (CSCs) is characterized by proteins that participate in cancer differentiation, invasion, and metastasis. However, the differentially expressed intracellular proteins that lead to the specific characteristics of pancreatic CSCs have not yet been identified, and as a consequence the deranged metabolic pathways are yet to be elucidated. To identify the modulated proteins of pancreatic CSCs, iTRAQ-based proteomic analysis was performed to compare the proteome of Panc1 CSCs and Panc1 parental cells, identifying 230 modulated proteins. Pathway analysis revealed activation of glycolysis, the pentose phosphate pathway, the pyruvate-malate cycle, and lipid metabolism as well as downregulation of the Krebs cycle, the splicesome and non-homologous end joining. These findings were supported by metabolomics and immunoblotting analysis. It was also found that inhibition of fatty acid synthase by cerulenin and of mevalonate pathways by atorvastatin have a greater anti-proliferative effect on cancer stem cells than parental cells. Taken together, these results clarify some important aspects of the metabolic network signature of pancreatic cancer stem cells, shedding light on key and novel therapeutic targets and suggesting that fatty acid synthesis and mevalonate pathways play a key role in ensuring their viability. BIOLOGICAL SIGNIFICANCE: To better understand the altered metabolic pathways of pancreatic cancer stem cells (CSCs), a comprehensive proteomic analysis and metabolite profiling investigation of Panc1 and Panc1 CSCs were carried out. The findings obtained indicate that Panc1 CSCs are characterized by upregulation of glycolysis, pentose phosphate pathway, pyruvate-malate cycle, and lipid metabolism and by downregulation of Krebs cycle, spliceosome and non-homologous end joining. Moreover, fatty acid synthesis and mevalonate pathways are shown to play a critical contribution to the survival of pancreatic cancer stem cells. This study is helpful for broadening the knowledge of pancreatic cancer stem cells and could accelerate the development of novel therapeutic strategies.

23 Article GATA6 regulates EMT and tumour dissemination, and is a marker of response to adjuvant chemotherapy in pancreatic cancer. 2017

Martinelli, Paola / Carrillo-de Santa Pau, Enrique / Cox, Trevor / Sainz, Bruno / Dusetti, Nelson / Greenhalf, William / Rinaldi, Lorenzo / Costello, Eithne / Ghaneh, Paula / Malats, Núria / Büchler, Markus / Pajic, Marina / Biankin, Andrew V / Iovanna, Juan / Neoptolemos, John / Real, Francisco X. ·Epithelial Carcinogenesis Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Cancer Progression and Metastasis Group, Institute for Cancer Research, Medical University Wien, Vienna, Austria. · Cancer Research UK Liverpool Clinical Trials Unit, University of Liverpool, Liverpool, UK. · NIHR Liverpool Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Department of Preventive Medicine, Public Health and Microbiology, Universidad Autónoma de Madrid, Madrid, Spain. · Centre de Recherche en Cancérologie de Marseille (CRCM), INSERM U1068, CNRS UMR 7258, Aix-Marseille Université and Institut Paoli-Calmettes, Parc Scientifique et Technologique de Luminy, Marseille, France. · Institute for Research in Biomedicine (IRB), Barcelona, Spain. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center-CNIO, Madrid, Spain. · Department for General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Cancer Division, The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, Australia. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. ·Gut · Pubmed #27325420.

ABSTRACT: BACKGROUND AND AIMS: The role of GATA factors in cancer has gained increasing attention recently, but the function of GATA6 in pancreatic ductal adenocarcinoma (PDAC) is controversial. GATA6 is amplified in a subset of tumours and was proposed to be oncogenic, but high GATA6 levels are found in well-differentiated tumours and are associated with better patient outcome. By contrast, a tumour-suppressive function of GATA6 was demonstrated using genetic mouse models. We aimed at clarifying GATA6 function in PDAC. DESIGN: We combined GATA6 silencing and overexpression in PDAC cell lines with GATA6 ChIP-Seq and RNA-Seq data, in order to understand the mechanism of GATA6 functions. We then confirmed some of our observations in primary patient samples, some of which were included in the ESPAC-3 randomised clinical trial for adjuvant therapy. RESULTS: GATA6 inhibits the epithelial-mesenchymal transition (EMT) in vitro and cell dissemination in vivo. GATA6 has a unique proepithelial and antimesenchymal function, and its transcriptional regulation is direct and implies, indirectly, the regulation of other transcription factors involved in EMT. GATA6 is lost in tumours, in association with altered differentiation and the acquisition of a basal-like molecular phenotype, consistent with an epithelial-to-epithelial (ET CONCLUSIONS: We provide mechanistic insight into GATA6 tumour-suppressive function, its role as a regulator of canonical epithelial differentiation, and propose that loss of GATA6 expression is both prognostic and predictive of response to adjuvant therapy.

24 Article The impact of diabetes mellitus on survival following resection and adjuvant chemotherapy for pancreatic cancer. 2016

Kleeff, Jörg / Costello, Eithne / Jackson, Richard / Halloran, Chris / Greenhalf, William / Ghaneh, Paula / Lamb, Richard F / Lerch, Markus M / Mayerle, Julia / Palmer, Daniel / Cox, Trevor / Rawcliffe, Charlotte L / Strobel, Oliver / Büchler, Markus W / Neoptolemos, John P. ·Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK. · NIHR Pancreas Biomedical Research Unit, University of Liverpool, Liverpool L69 3GA, UK. · Department of Medicine A, Ernst-Moritz-Arndt-University Greifswald, Greifswald, Germany. · Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Br J Cancer · Pubmed #27584663.

ABSTRACT: BACKGROUND: Diabetes mellitus is frequently observed in pancreatic cancer patients and is both a risk factor and an early manifestation of the disease. METHODS: We analysed the prognostic impact of diabetes on the outcome of pancreatic cancer following resection and adjuvant chemotherapy using individual patient data from three European Study Group for Pancreatic Cancer randomised controlled trials. Analyses were carried out to assess the association between clinical characteristics and the presence of preoperative diabetes, as well as the effect of diabetic status on overall survival. RESULTS: In total, 1105 patients were included in the analysis, of whom 257 (23%) had confirmed diabetes and 848 (77%) did not. Median (95% confidence interval (CI)) unadjusted overall survival in non-diabetic patients was 22.3 (20.8-24.1) months compared with 18.8 (16.9-22.1) months for diabetic patients (P=0.24). Diabetic patients were older, had increased weight and more co-morbidities. Following adjustment, multivariable analysis demonstrated that diabetic patients had an increased risk of death (hazard ratio: 1.19 (95% CI 1.01, 1.40), P=0.034). Maximum tumour size of diabetic patients was larger at randomisation (33.6 vs 29.7 mm, P=0.026). CONCLUSIONS: Diabetes mellitus was associated with increased tumour size and reduced survival following pancreatic cancer resection and adjuvant chemotherapy.

25 Article Three new pancreatic cancer susceptibility signals identified on chromosomes 1q32.1, 5p15.33 and 8q24.21. 2016

Zhang, Mingfeng / Wang, Zhaoming / Obazee, Ofure / Jia, Jinping / Childs, Erica J / Hoskins, Jason / Figlioli, Gisella / Mocci, Evelina / Collins, Irene / Chung, Charles C / Hautman, Christopher / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Buring, Julie / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goodman, Gary E / Goodman, Phyllis J / Kamineni, Aruna / Kolonel, Laurence N / Kulke, Matthew H / Malats, Núria / Olson, Sara H / Sesso, Howard D / Visvanathan, Kala / White, Emily / Zheng, Wei / Abnet, Christian C / Albanes, Demetrius / Andreotti, Gabriella / Brais, Lauren / Bueno-de-Mesquita, H Bas / Basso, Daniela / Berndt, Sonja I / Boutron-Ruault, Marie-Christine / Bijlsma, Maarten F / Brenner, Hermann / Burdette, Laurie / Campa, Daniele / Caporaso, Neil E / Capurso, Gabriele / Cavestro, Giulia Martina / Cotterchio, Michelle / Costello, Eithne / Elena, Joanne / Boggi, Ugo / Gaziano, J Michael / Gazouli, Maria / Giovannucci, Edward L / Goggins, Michael / Gross, Myron / Haiman, Christopher A / Hassan, Manal / Helzlsouer, Kathy J / Hu, Nan / Hunter, David J / Iskierka-Jazdzewska, Elzbieta / Jenab, Mazda / Kaaks, Rudolf / Key, Timothy J / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Krogh, Vittorio / Kupcinskas, Juozas / Kurtz, Robert C / Landi, Maria T / Landi, Stefano / Le Marchand, Loic / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Neale, Rachel E / Oberg, Ann L / Panico, Salvatore / Patel, Alpa V / Peeters, Petra H M / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Purdue, Mark / Quiros, J Ramón / Riboli, Elio / Rothman, Nathaniel / Scarpa, Aldo / Scelo, Ghislaine / Shu, Xiao-Ou / Silverman, Debra T / Soucek, Pavel / Strobel, Oliver / Sund, Malin / Małecka-Panas, Ewa / Taylor, Philip R / Tavano, Francesca / Travis, Ruth C / Thornquist, Mark / Tjønneland, Anne / Tobias, Geoffrey S / Trichopoulos, Dimitrios / Vashist, Yogesh / Vodicka, Pavel / Wactawski-Wende, Jean / Wentzensen, Nicolas / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Kooperberg, Charles / Risch, Harvey A / Jacobs, Eric J / Li, Donghui / Fuchs, Charles / Hoover, Robert / Hartge, Patricia / Chanock, Stephen J / Petersen, Gloria M / Stolzenberg-Solomon, Rachael S / Wolpin, Brian M / Kraft, Peter / Klein, Alison P / Canzian, Federico / Amundadottir, Laufey T. ·Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Oncology, the Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, New York, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, New York, USA. · New York University Cancer Institute, New York, New York, USA,. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, California, USA. · Division of Preventive Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Division of Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Victoria, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Southwest Oncology Group Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA. · Group Health Research Institute, Seattle, Washington, USA,. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. · Genetic and Molecular Epidemiology Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Department of Epidemiology, Harvard School of Public Health, Boston, Massachusetts, USA. · Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA. · Department of Epidemiology, University of Washington, Seattle, Washington, USA. · Division of Epidemiology, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee, USA. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of Laboratory Medicine, University Hospital of Padova, Padua, Italy,. · Inserm, Centre for Research in Epidemiology and Population Health (CESP), U1018, Nutrition, Hormones and Women's Health Team, F-94805, Villejuif, France. · University Paris Sud, UMRS 1018, F-94805, Villejuif, France. · IGR, F-94805, Villejuif, France. · Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany. · German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Biology, University of Pisa, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · Massachusetts Veteran's Epidemiology, Research, and Information Center, Geriatric Research Education and Clinical Center, Veterans Affairs Boston Healthcare System, Boston, Massachusetts, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece. · Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA. · Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Pathology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Department of Medicine, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Department of Oncology, Sidney Kimmel Cancer Center and Johns Hopkins University, Baltimore, Maryland, USA. · Laboratory of Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota, USA. · Preventive Medicine, University of Southern California, Los Angeles, California, USA. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA. · Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Harvard School of Public Health, Boston, Massachusetts, USA. · Harvard Medical School, Boston, Massachusetts, USA. · Department of Hematology, Medical University of Łodz, Łodz, Poland. · International Agency for Research on Cancer (IARC), Lyon, France. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Cancer Epidemiology Unit, University of Oxford, Oxford, United Kingdom. · School of Clinical Medicine, University of Cambridge, Cambridge, United Kingdom. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, Ohio, USA. · Centre de Recerca en Epidemiologia Ambiental (CREAL), CIBER Epidemiología y Salud Pública (CIBERESP), Spain. · Hospital del Mar Institute of Medical Research (IMIM), Barcelona, Spain. · National School of Public Health, Athens, Greece. · Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, USA. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · National Institute for Health and Welfare, Department of Chronic Disease Prevention, Helsinki, Finland. · Department of Population Health, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Dipartimento di Medicina Clinica E Chirurgia, Federico II Univeristy, Naples, Italy. · Epidemiology Research Program, American Cancer Society, Atlanta, Georgia, USA. · Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · School of Medicine, Universitat Autònoma de Barcelona, Barcelona, Spain. · CIBER de Epidemiología y Salud Pública (CIBERESP), Madrid, Spain. · Public Health and Participation Directorate, Asturias, Spain. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Laboratory of Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Pilsen, Czech Republic. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Surgical and Peroperative Sciences, Umeå University, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy. · Institute of Cancer Epidemiology, Danish Cancer Society, Copenhagen, Denmark. · Bureau of Epidemiologic Research, Academy of Athens, Athens, Greece. · Hellenic Health Foundation, Athens, Greece. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, Hamburg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Prague, Czech Republic. · Department of Social and Preventive Medicine, University at Buffalo, Buffalo, New York, USA. · New York University Cancer Institute, New York, New York, USA. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA,. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts, USA. · Department of Epidemiology, the Bloomberg School of Public Health, Baltimore, Maryland, USA. ·Oncotarget · Pubmed #27579533.

ABSTRACT: Genome-wide association studies (GWAS) have identified common pancreatic cancer susceptibility variants at 13 chromosomal loci in individuals of European descent. To identify new susceptibility variants, we performed imputation based on 1000 Genomes (1000G) Project data and association analysis using 5,107 case and 8,845 control subjects from 27 cohort and case-control studies that participated in the PanScan I-III GWAS. This analysis, in combination with a two-staged replication in an additional 6,076 case and 7,555 control subjects from the PANcreatic Disease ReseArch (PANDoRA) and Pancreatic Cancer Case-Control (PanC4) Consortia uncovered 3 new pancreatic cancer risk signals marked by single nucleotide polymorphisms (SNPs) rs2816938 at chromosome 1q32.1 (per allele odds ratio (OR) = 1.20, P = 4.88x10 -15), rs10094872 at 8q24.21 (OR = 1.15, P = 3.22x10 -9) and rs35226131 at 5p15.33 (OR = 0.71, P = 1.70x10 -8). These SNPs represent independent risk variants at previously identified pancreatic cancer risk loci on chr1q32.1 ( NR5A2), chr8q24.21 ( MYC) and chr5p15.33 ( CLPTM1L- TERT) as per analyses conditioned on previously reported susceptibility variants. We assessed expression of candidate genes at the three risk loci in histologically normal ( n = 10) and tumor ( n = 8) derived pancreatic tissue samples and observed a marked reduction of NR5A2 expression (chr1q32.1) in the tumors (fold change -7.6, P = 5.7x10 -8). This finding was validated in a second set of paired ( n = 20) histologically normal and tumor derived pancreatic tissue samples (average fold change for three NR5A2 isoforms -31.3 to -95.7, P = 7.5x10 -4-2.0x10 -3). Our study has identified new susceptibility variants independently conferring pancreatic cancer risk that merit functional follow-up to identify target genes and explain the underlying biology.

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