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Pancreatic Neoplasms: HELP
Articles by Paula Ghaneh
Based on 35 articles published since 2010
(Why 35 articles?)
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Between 2010 and 2020, P. Ghaneh wrote the following 35 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline Guidelines for time-to-event end-point definitions in trials for pancreatic cancer. Results of the DATECAN initiative (Definition for the Assessment of Time-to-event End-points in CANcer trials). 2014

Bonnetain, Franck / Bonsing, Bert / Conroy, Thierry / Dousseau, Adelaide / Glimelius, Bengt / Haustermans, Karin / Lacaine, François / Van Laethem, Jean Luc / Aparicio, Thomas / Aust, Daniela / Bassi, Claudio / Berger, Virginie / Chamorey, Emmanuel / Chibaudel, Benoist / Dahan, Laeticia / De Gramont, Aimery / Delpero, Jean Robert / Dervenis, Christos / Ducreux, Michel / Gal, Jocelyn / Gerber, Erich / Ghaneh, Paula / Hammel, Pascal / Hendlisz, Alain / Jooste, Valérie / Labianca, Roberto / Latouche, Aurelien / Lutz, Manfred / Macarulla, Teresa / Malka, David / Mauer, Muriel / Mitry, Emmanuel / Neoptolemos, John / Pessaux, Patrick / Sauvanet, Alain / Tabernero, Josep / Taieb, Julien / van Tienhoven, Geertjan / Gourgou-Bourgade, Sophie / Bellera, Carine / Mathoulin-Pélissier, Simone / Collette, Laurence. ·Methodology and Quality of Life Unit in Cancer, EA 3181, University Hospital of Besançon and CTD-INCa Gercor, UNICNCER GERICO, Besançon, France. Electronic address: franck.bonnetain@univ-fcomte.fr. · Leiden University Medical Center, Leiden, Netherlands. · Department of Medical Oncology, Institut de Cancérologie de Lorraine, Vandoeuvre-les-Nancy, France. · Bordeaux Segalen University & CHRU, Bordeaux, France. · Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala, Sweden. · Department of Radiation Oncology, Leuven, Belgium. · Digestive Surgical Department, Tenon hospital, Paris, France. · Gastro Intestinal Cancer Unit Erasme Hospital Brussels, Belgium. · Gastroenterology Department, Avicenne Hospital, Paris 13, Bobigny, France. · Institute for Pathology, University Hospital Carl-Gustav-Carus, Dresden, Germany. · Surgical and Gastroenterological Department, Endocrine and Pancreatic Unit, Hospital of 'G.B.Rossi', University of Verona, Italy. · Institut de Cancérologie de l'Ouest - Centre Paul Papin Centre de Lutte Contre le Cancer (CLCC), Angers, France. · Biostatistics Unit, Centre Antoine Lacassagne, Nice, France. · Oncology Department, Hôpital Saint-Antoine & CTD-INCa GERCOR, Assistance Publique des Hôpitaux de Paris, UPMC Paris VI, Paris, France. · Gastroenterology Department, Hopital la Timone, Assitance publique des Hopitaux de Marseille, Marseille, France. · Department of Surgery, Institut Paoli Calmettes, Marseille, France. · Department of Surgery, Agia Olga Hospital, Athens, Greece. · Department of Gastroenterology, Institut Gustave Roussy, Villejuif, France. · Biostatistician, Biostatistics Unit, Centre Antoine Lacassagne, Nice, France. · Department of Radiotherapy, Institut fuer Radioonkologie, Vienna, Austria. · Department of Surgical Oncology, Royal Liverpool Hospital, United Kingdom. · Department of Gastroenterology, Beaujon Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. · Digestive Oncology and Gastro-enterology Department, Jules Bordet Institute, Brussels, Belgium. · Digestive Cancer Registry, INSERM U866, Dijon, France. · Medical Oncology Unit, Ospedali Riuniti di Bergamo, Bergame, Italy. · Inserm, Centre for Research in Epidemiology and Population Health, U1018, Biostatistics Team, Villejuif, France. · Gastroenterology Department, Caritas Hospital, Saarbrücken, Germany. · Department of the Gastrointestinal Tumors and Phase I Unit, Vall d'Hebron University Hospital, Barcelona, Spain. · Statistics Department, EORTC, Brussels, Belgium. · Department of Medical Oncology, Institut Curie, Hôpital René Huguenin, Saint-Cloud, France. · Division of Surgery and Oncology at the University of Liverpool and Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Digestive Surgery, Universitu Hospital Strasbourg, France. · Department of Hepato-pancreatic and Biliary Surgery, Beaujon Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France. · Department of Hepato-gastroenterology and Digestive Oncology, Georges Pompidou European hospital, Paris, France. · Department of Radiation Oncology, Academisch Medisch Centrum, Amsterdam, The Netherlands. · Institut Du Cancer de Montpellier, Comprehensive Cancer Centre, and Data Center for Cancer Clinical Trials, CTD-INCa, Montpellier, France. · Clinical and Epidemiological Research Unit, Institut Bergonie, Comprehensive Cancer Centre, Bordeaux, France; Data Center for Cancer Clinical Trials, CTD-INCa, Bordeaux, France; INSERM, Centre d'Investigation Clinique - Épidémiologie Clinique CIC-EC 7, F-33000 Bordeaux, France. ·Eur J Cancer · Pubmed #25256896.

ABSTRACT: BACKGROUND: Using potential surrogate end-points for overall survival (OS) such as Disease-Free- (DFS) or Progression-Free Survival (PFS) is increasingly common in randomised controlled trials (RCTs). However, end-points are too often imprecisely defined which largely contributes to a lack of homogeneity across trials, hampering comparison between them. The aim of the DATECAN (Definition for the Assessment of Time-to-event End-points in CANcer trials)-Pancreas project is to provide guidelines for standardised definition of time-to-event end-points in RCTs for pancreatic cancer. METHODS: Time-to-event end-points currently used were identified from a literature review of pancreatic RCT trials (2006-2009). Academic research groups were contacted for participation in order to select clinicians and methodologists to participate in the pilot and scoring groups (>30 experts). A consensus was built after 2 rounds of the modified Delphi formal consensus approach with the Rand scoring methodology (range: 1-9). RESULTS: For pancreatic cancer, 14 time to event end-points and 25 distinct event types applied to two settings (detectable disease and/or no detectable disease) were considered relevant and included in the questionnaire sent to 52 selected experts. Thirty experts answered both scoring rounds. A total of 204 events distributed over the 14 end-points were scored. After the first round, consensus was reached for 25 items; after the second consensus was reached for 156 items; and after the face-to-face meeting for 203 items. CONCLUSION: The formal consensus approach reached the elaboration of guidelines for standardised definitions of time-to-event end-points allowing cross-comparison of RCTs in pancreatic cancer.

2 Review Immunohistochemical hENT1 expression as a prognostic biomarker in patients with resected pancreatic ductal adenocarcinoma undergoing adjuvant gemcitabine-based chemotherapy. 2017

Bird, N T E / Elmasry, M / Jones, R / Psarelli, E / Dodd, J / Malik, H / Greenhalf, W / Kitteringham, N / Ghaneh, P / Neoptolemos, J P / Palmer, D. ·Liverpool University Pharmacology Unit, Institute of Translational Medicine, University of Liverpool, Crown Street, Liverpool L69 3BX, UK. ·Br J Surg · Pubmed #28199010.

ABSTRACT: BACKGROUND: Human equilibrative nucleoside transporters (hENTs) are transmembranous proteins that facilitate the uptake of nucleosides and nucleoside analogues, such as gemcitabine, into the cell. The abundance of hENT1 transporters in resected pancreatic ductal adenocarcinoma (PDAC) might make hENT1 a potential biomarker of response to adjuvant chemotherapy. The aim of this study was to see whether hENT1 expression, as determined by immunohistochemistry, was a suitable predictive marker for subsequent treatment with gemcitabine-based adjuvant chemotherapy. METHODS: A systematic review was performed, searching databases from January 1997 to January 2016. Articles pertaining to hENT1 immunohistochemical analysis in resected PDAC specimens from patients who subsequently underwent adjuvant gemcitabine-based chemotherapy were identified. Eligible studies were required to contain survival data, reporting specifically overall survival (OS) and disease-free survival (DFS) with associated hazard ratios (HRs) stratified by hENT1 status. RESULTS: Of 42 articles reviewed, eight were suitable for review, with seven selected for quantitative meta-analysis. The total number of patients included in the meta-analysis was 770 (405 hENT1-negative, 365 hENT1-positive). Immunohistochemically detected hENT1 expression was significantly associated with both prolonged DFS (HR 0·58, 95 per cent c.i. 0·42 to 0·79) and OS (HR 0·52, 0·38 to 0·72) in patients receiving adjuvant gemcitabine but not those having fluoropyrimidine-based adjuvant therapy. CONCLUSION: Expression of hENT1 is a suitable prognostic biomarker in patients undergoing adjuvant gemcitabine-based chemotherapy.

3 Review Adjuvant therapy in pancreatic cancer. 2014

Jones, Owain Peris / Melling, James Daniel / Ghaneh, Paula. ·Owain Peris Jones, James Daniel Melling, Paula Ghaneh, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, 5 Floor UCD Building, Daulby Street, Liverpool L69 3GA, United Kingdom. ·World J Gastroenterol · Pubmed #25356036.

ABSTRACT: Pancreatic cancer remains one of the leading causes of cancer related death worldwide with an overall five-year survival of less than 5%. Potentially curative surgery, which alone can improve 5-year survival to 10%, is an option for only 10%-20% of patients at presentation owing to local invasion of the tumour or metastatic disease. Adjuvant chemotherapy has been shown to improve 5-year survival to 20%-25% but conflicting evidence remains with regards to chemoradiation. In this article we review the current evidence available from published randomised trials and discuss ongoing phase III trials in relation to adjuvant therapy in pancreatic cancer.

4 Review Meta-analysis of immunohistochemical prognostic markers in resected pancreatic cancer. 2011

Smith, R A / Tang, J / Tudur-Smith, C / Neoptolemos, J P / Ghaneh, P. ·Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK. ·Br J Cancer · Pubmed #21448172.

ABSTRACT: BACKGROUND: The potential prognostic value of several commonly investigated immunohistochemical markers in resected pancreatic cancer is variably reported. The objective of this study was to conduct a systematic review of literature evaluating p53, p16, smad4, bcl-2, bax, vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) expression as prognostic factors in resected pancreatic adenocarcinoma and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Relevant literature was identified using Medline, EMBASE and ISI Web of Science. The primary end point was overall survival assessed on univariate analysis. Only studies analysing resected pancreatic adenocarcinoma were eligible for inclusion and the summary log(e) hazard ratio (logHR) and variance were pooled using an inverse variance approach. Evidence of heterogeneity was evaluated using the χ(2) test for heterogeneity and its impact on the meta-analysis was assessed by the I(2) statisic. Hazard ratios greater than one reflect adverse survival associated with positive immunostaining. RESULTS: Vascular endothelial growth factor emerged as the most potentially informative prognostic marker (11 eligible studies, n=767, HR=1.51 (95% confidence interval, CI=1.18-1.92)) with no evidence of any significant publication bias (Egger's test, P=0.269). Bcl-2 (5 eligible studies, n=314, HR=0.51 (95% CI=0.38-0.68)), bax (5 studies, n=274, HR=0.63 (95% CI=0.48-0.83)) and p16 (3 studies, n=229, HR=0.63 (95% CI=0.43-0.92)) also returned significant overall survival differences, but in smaller patient series due to a lack of evaluable literature. Neither p53 (17 studies, n=925, HR=1.22 (95% CI=0.96-1.56)), smad4 (5 studies, n=540, HR=0.88 (95% CI=0.61-1.27)) nor EGFR (4 studies, n=250, HR=1.35 (95% CI=0.80-2.27)) was found to represent significant prognostic factors when analysing the pooled patient data. There was evidence of significant heterogeneity in four of the seven study groups. CONCLUSION: These results support the case for immunohistochemical expression of VEGF representing a significant and reproducible marker of adverse prognosis in resected pancreatic cancer.

5 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.

6 Clinical Trial Sample size re-estimation in paired comparative diagnostic accuracy studies with a binary response. 2017

McCray, Gareth P J / Titman, Andrew C / Ghaneh, Paula / Lancaster, Gillian A. ·Institute of Primary Care and Health Sciences, Keele University, David Weatherall Building, Stoke-on-Trent, ST5 5BG, UK. g.mccray@keele.ac.uk. · Department of Mathematics and Statistics, Lancaster University, Fylde College, Lancaster, LA14YF, UK. · Institute of Translational Medicine, University of Liverpool, Cedar House, L69 3GE, Ashton St, Liverpool, L3 5PS, UK. · Institute of Primary Care and Health Sciences, Keele University, David Weatherall Building, Stoke-on-Trent, ST5 5BG, UK. ·BMC Med Res Methodol · Pubmed #28705147.

ABSTRACT: BACKGROUND: The sample size required to power a study to a nominal level in a paired comparative diagnostic accuracy study, i.e. studies in which the diagnostic accuracy of two testing procedures is compared relative to a gold standard, depends on the conditional dependence between the two tests - the lower the dependence the greater the sample size required. A priori, we usually do not know the dependence between the two tests and thus cannot determine the exact sample size required. One option is to use the implied sample size for the maximal negative dependence, giving the largest possible sample size. However, this is potentially wasteful of resources and unnecessarily burdensome on study participants as the study is likely to be overpowered. A more accurate estimate of the sample size can be determined at a planned interim analysis point where the sample size is re-estimated. METHODS: This paper discusses a sample size estimation and re-estimation method based on the maximum likelihood estimates, under an implied multinomial model, of the observed values of conditional dependence between the two tests and, if required, prevalence, at a planned interim. The method is illustrated by comparing the accuracy of two procedures for the detection of pancreatic cancer, one procedure using the standard battery of tests, and the other using the standard battery with the addition of a PET/CT scan all relative to the gold standard of a cell biopsy. Simulation of the proposed method illustrates its robustness under various conditions. RESULTS: The results show that the type I error rate of the overall experiment is stable using our suggested method and that the type II error rate is close to or above nominal. Furthermore, the instances in which the type II error rate is above nominal are in the situations where the lowest sample size is required, meaning a lower impact on the actual number of participants recruited. CONCLUSION: We recommend multinomial model maximum likelihood estimation of the conditional dependence between paired diagnostic accuracy tests at an interim to reduce the number of participants required to power the study to at least the nominal level. TRIAL REGISTRATION: ISRCTN ISRCTN73852054 . Registered 9th of January 2015. Retrospectively registered.

7 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.

8 Clinical Trial Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial. 2017

Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Psarelli, Eftychia E / Valle, Juan W / Halloran, Christopher M / Faluyi, Olusola / O'Reilly, Derek A / Cunningham, David / Wadsley, Jonathan / Darby, Suzanne / Meyer, Tim / Gillmore, Roopinder / Anthoney, Alan / Lind, Pehr / Glimelius, Bengt / Falk, Stephen / Izbicki, Jakob R / Middleton, Gary William / Cummins, Sebastian / Ross, Paul J / Wasan, Harpreet / McDonald, Alec / Crosby, Tom / Ma, Yuk Ting / Patel, Kinnari / Sherriff, David / Soomal, Rubin / Borg, David / Sothi, Sharmila / Hammel, Pascal / Hackert, Thilo / Jackson, Richard / Büchler, Markus W / Anonymous3241111. ·University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. · University of Liverpool, Liverpool, UK; The Clatterbridge Cancer Centre, Wirral, UK. · The Royal Liverpool University Hospital, Liverpool, UK. · University of Liverpool, Liverpool, UK. · University of Manchester/The Christie NHS Foundation Trust, Manchester, UK. · University of Liverpool, Liverpool, UK; The Royal Liverpool University Hospital, Liverpool, UK. · The Clatterbridge Cancer Centre, Wirral, UK. · Manchester Royal Infirmary, Manchester, UK. · Royal Marsden Hospital, London, UK. · Weston Park Hospital, Sheffield, UK. · Royal Free Hospital, London, UK. · St James's University Hospital, Leeds, UK. · Karolinska Institute, Stockholm, Sweden; Clinical Research Sörmland, Eskilstuna, Sweden. · University of Uppsala, Uppsala, Sweden. · Bristol Haematology and Oncology Centre, Bristol, UK. · University of Hamburg Medical institutions UKE, Hamburg, Germany. · Royal Surrey County Hospital, Guildford, UK. · Guy's Hospital, London, UK. · Hammersmith Hospital, London, UK. · The Beatson West of Scotland Cancer Centre, Glasgow, UK. · Velindre Hospital, Cardiff, UK. · Queen Elizabeth Hospital, Birmingham, UK. · Churchill Hospital, Oxford, UK. · Derriford Hospital, Plymouth, UK. · Ipswich Hospital, Ipswich, UK. · Skåne University Hospital, Lund, Sweden. · University Hospital Coventry, Coventry, UK. · Hôpital Beaujon, Clichy, France. · University of Heidelberg, Germany. ·Lancet · Pubmed #28129987.

ABSTRACT: BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

9 Clinical Trial PANasta Trial; Cattell Warren versus Blumgart techniques of panreatico-jejunostomy following pancreato-duodenectomy: Study protocol for a randomized controlled trial. 2016

Halloran, Christopher M / Platt, Kellie / Gerard, Abbie / Polydoros, Fotis / O'Reilly, Derek A / Gomez, Dhanwant / Smith, Andrew / Neoptolemos, John P / Soonwalla, Zahir / Taylor, Mark / Blazeby, Jane M / Ghaneh, Paula. ·National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Clinical Directorate of General Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust and the University of Liverpool, Liverpool, L69 3GA, UK. halloran@liverpool.ac.uk. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, The Duncan Building, Daulby Street, Liverpool, L69 3GA, UK. halloran@liverpool.ac.uk. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. kplatt@liverpool.ac.uk. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. agerard@liverpool.ac.uk. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. polydorf@liverpool.ac.uk. · Department of Surgery, Manchester Royal Infirmary, Oxford Rd, Manchester, M13 9WL, UK. Derek.O'Reilly@cmft.nhs.uk. · Queen's Medical Center, Derby Road, Nottingham, NG7 2UH, UK. Dhanny.Gomez@nuh.nhs.uk. · Department of Pancreatic Surgery, Abdominal Medicine and Surgery CSU, St James's University Hospital, 3rd Floor Bexley Wing, Leeds, LS9 7TF, UK. AndrewM.Smith@leedsth.nhs.uk. · National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Clinical Directorate of General Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust and the University of Liverpool, Liverpool, L69 3GA, UK. johnyboy@liverpool.ac.uk. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. johnyboy@liverpool.ac.uk. · Churchill Hospital, Oxford University Hospitals NHS Trust, Headington, Oxford, OX3 7LJ, UK. Zahir.Soonawalla@ouh.nhs.uk. · Mater Hospital, Belfast Health and Social care Trust, Crumlin Rd, Belfast, BT12 6AB, UK. Mark.Taylor@belfasttrust.hscni.net. · Bristol Center for Surgical Research, School of Social and Community Medicine, University of Bristol, BS8 2PS and University Hospitals Bristol NHS Foundation Trust, Bristol, BS2 8HW, UK. J.M.Blazeby@bristol.ac.uk. · National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Clinical Directorate of General Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust and the University of Liverpool, Liverpool, L69 3GA, UK. paula@liverpool.ac.uk. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool, L69 3GL, UK. paula@liverpool.ac.uk. ·Trials · Pubmed #26772736.

ABSTRACT: BACKGROUND: Failure of the pancreatic remnant anastomosis to heal following pancreato-duodenectomy is a major cause of significant and life-threatening complications, notably a post-operative pancreatic fistula. Recently, non-randomized trials have shown superiority of a most intuitive anastomosis (Blumgart technique), which involves both a duct-to-mucosa and a full-thickness pancreatic "U" stitch, in effect a mattress stitch, over a standard duct-mucosa technique (Cattell-Warren). The aim of this study is to examine if these findings remain within a randomized setting. METHODS/DESIGN: The PANasta trial is a randomized, double-blinded multi-center study, whose primary aim is to assess whether a Blumgart pancreatic anastomosis (trial intervention) is superior to a Cattell-Warren pancreatic anastomosis (control intervention), in terms of pancreatic fistula rates. Patients with suspected malignancy of the pancreatic head, in whom a pancreato-duodenectomy is recommended, would be recruited from several UK specialist regional centers. The hypothesis to be tested is that a Blumgart anastomosis will reduce fistula rate from 20 to 10 %. Subjects will be stratified by research site, pancreatic consistency and diameter of pancreatic duct; giving a sample size of 253 per group. The primary outcome measure is fistula rate at the pancreatico-jejunostomy. Secondary outcome measures are: entry into adjuvant therapy, mortality, surgical complications, non-surgical complications, hospital stay, cancer-specific quality of life and health economic assessments. Enrolled patients will undergo pancreatic resection and be randomized immediately prior to pancreatic reconstruction. The operation note will only record "anastomosis constructed as per PANasta trial randomization," thus the other members of the trial team and patient are blinded. An inbuilt internal pilot study will assess the ability to randomize patients, while the construction of an operative manual and review of operative photographs will maintain standardization of techniques. DISCUSSION: The PANasta trial will be the first multi-center randomized controlled trial (RCT) comparing two types of duct-to-mucosa pancreatic anastomosis with surgical quality assurance. TRIAL REGISTRATION: ISRCTN52263879 . Date of registration 15 January 2015.

10 Clinical Trial Optimal duration and timing of adjuvant chemotherapy after definitive surgery for ductal adenocarcinoma of the pancreas: ongoing lessons from the ESPAC-3 study. 2014

Valle, Juan W / Palmer, Daniel / Jackson, Richard / Cox, Trevor / Neoptolemos, John P / Ghaneh, Paula / Rawcliffe, Charlotte L / Bassi, Claudio / Stocken, Deborah D / Cunningham, David / O'Reilly, Derek / Goldstein, David / Robinson, Bridget A / Karapetis, Christos / Scarfe, Andrew / Lacaine, Francois / Sand, Juhani / Izbicki, Jakob R / Mayerle, Julia / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Lind, Pehr A / Middleton, Mark R / Anthoney, Alan / Sumpter, Kate / Carter, Ross / Büchler, Markus W. ·Juan W. Valle, Derek O'Reilly, Manchester Academic Health Sciences Centre, Christie Hospital NHS Foundation Trust and University of Manchester, Manchester · Richard Jackson, Trevor Cox, John P. Neoptolemos, Paula Ghaneh, Charlotte L. Rawcliffe, Liverpool Cancer Research UK Centre and the National Institute for Health Research Pancreas Biomedical Research Unit, University of Liverpool, Liverpool · Daniel Palmer, the Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust · Deborah D. Stocken, the Cancer Research UK Clinical Trials Unit, University of Birmingham, Birmingham · David Cunningham, Royal Marsden Hospital Foundation Trust, Sutton · Mark R. Middleton, Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford · Alan Anthoney, The Leeds Teaching Hospital Trust, Leeds · Kate Sumpter, Freeman Hospital, Newcastle upon Tyne · Ross Carter, Glasgow Royal Infirmary, Glasgow, United Kingdom · Claudio Bassi, Giovanni Butturini, University of Verona, Verona, Italy · David Goldstein, Bridget A. Robinson, Christos Karapetis, the Australasian Gastro-Intestinal Trials Group, Camperdown, Australia · Andrew Scarfe, University of Alberta, Edmonton, Canada · Francois Lacaine, Hôpital TENON, Assistance Publique Hôpitaux de Paris, Universite Pierre Et Marie Curie, Paris, France · Juhani Sand, Tampere University Hospital, Tampere, Finland · Jakob R. Izbicki, University of Hamburg, Hamburg · Julia Mayerle, Ernst-Moritz-Arndt-Universität Greifswald, Greifswald · Markus W. Büchler, University of Heidelberg, Heidelberg, Germany · Christos Dervenis, the Agia Olga Hospital, Athens, Greece · Attila Oláh, the Petz Aladar Hospital, Gyor, Hungary · Pehr A. Lind, Karolinska-Stockholm Söder Hospital, Stockholm, Sweden. ·J Clin Oncol · Pubmed #24419109.

ABSTRACT: PURPOSE: Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. PATIENTS AND METHODS: Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer-3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. RESULTS: There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P < .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P < .001). CONCLUSION: Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

11 Clinical Trial Adjuvant chemotherapy with fluorouracil plus folinic acid vs gemcitabine following pancreatic cancer resection: a randomized controlled trial. 2010

Neoptolemos, John P / Stocken, Deborah D / Bassi, Claudio / Ghaneh, Paula / Cunningham, David / Goldstein, David / Padbury, Robert / Moore, Malcolm J / Gallinger, Steven / Mariette, Christophe / Wente, Moritz N / Izbicki, Jakob R / Friess, Helmut / Lerch, Markus M / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Doi, Ryuichiro / Lind, Pehr A / Smith, David / Valle, Juan W / Palmer, Daniel H / Buckels, John A / Thompson, Joyce / McKay, Colin J / Rawcliffe, Charlotte L / Büchler, Markus W / Anonymous5551105. ·Liverpool Cancer Research UK Cancer Trials Unit, Cancer Research UK Centre, University of Liverpool, Fifth Floor, UCD Bldg, Daulby Street, Liverpool, L69 3GA, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #20823433.

ABSTRACT: CONTEXT: Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer. OBJECTIVE: To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up. INTERVENTIONS: Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m(2), intravenous bolus injection, followed by fluorouracil, 425 mg/m(2) intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m(2) intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months. MAIN OUTCOME MEASURES: Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life. RESULTS: Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (chi(1)(2) = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P < .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups. CONCLUSION: Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

12 Article Prognostic value of 2020

Mohamed, Eyas / Needham, Alexander / Psarelli, Eftychia / Carroll, Melvyn / Vinjamuri, Sobhan / Sanghera, Bal / Wong, Wai Lup / Halloran, Christopher / Ghaneh, Paula. ·Department of Pancreaticobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK. · Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK. · Department of Nuclear Medicine, Royal Liverpool University Hospital, Liverpool, UK. · Paul Strickland Scanner Centre, Mount Vernon Hospital, Middlesex, UK. · Department of Pancreaticobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK; Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK. · Department of Pancreaticobiliary Surgery, Royal Liverpool University Hospital, Liverpool, UK; Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK. Electronic address: p.ghaneh@liverpool.ac.uk. ·Eur J Surg Oncol · Pubmed #32070641.

ABSTRACT: PURPOSE: To investigate the value of METHODS: We conducted a retrospective analysis of patients with a confirmed diagnosis of pancreatic cancer who underwent RESULTS: A sum of 89 patients were analysed in this study. Median survival for patients categorised as having high TLG (≥55) and low TLG (<55) was 18 vs 5 months (p < 0.001). Similarly, the respective high vs low SUV

13 Article Differentiation of Autoimmune Pancreatitis from Pancreatic Cancer Remains Challenging. 2019

Dickerson, L D / Farooq, A / Bano, F / Kleeff, J / Baron, R / Raraty, M / Ghaneh, P / Sutton, R / Whelan, P / Campbell, F / Healey, P / Neoptolemos, J P / Yip, V S. ·Pancreas Unit, Department of General Surgery, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. · Department of Radiology, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. · Department of Visceral, Vascular and Endocrine Surgery, Martin-Luther-University Halle-Wittenberg, 06120, Halle (Saale), Germany. · Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK. · Department of Pathology, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Im Neuenheimer Feld 110, 69120, Heidelberg, Germany. · Pancreas Unit, Department of General Surgery, Royal Liverpool University Hospital, Prescot Street, Liverpool, L7 8XP, UK. vincent.yip@nhs.net. · Department of Hepatobiliary and Pancreas Surgery, 13C Royal London Hospital, Whitechapel Road, London, E1 1BB, UK. vincent.yip@nhs.net. ·World J Surg · Pubmed #30815742.

ABSTRACT: BACKGROUND: Autoimmune pancreatitis (AIP) is an uncommon form of chronic pancreatitis. Whilst being corticosteroid responsive, AIP often masquerades radiologically as pancreatic neoplasia. Our aim is to appraise demographic, radiological and histological features in our cohort in order to differentiate AIP from pancreatic malignancy. METHODS: Clinical, biochemical, histological and radiological details of all AIP patients 1997-2016 were analysed. The initial imaging was re-reviewed according to international guidelines by three blinded independent radiologists to evaluate features associated with autoimmune pancreatitis and pancreatic cancer. RESULTS: There were a total of 45 patients: 25 in type 1 (55.5%), 14 type 2 (31.1%) and 6 AIP otherwise not specified (13.3%). The median (IQR) age was 57 (51-70) years. Thirty patients (66.6%) were male. Twenty-six patients (57.8%) had resection for suspected malignancy and one for symptomatic chronic pancreatitis. Three had histologically proven malignancy with concurrent AIP. Two patients died from recurrent pancreatic cancer following resection. Multidisciplinary team review based on radiology and clinical history dictated management. Resected patients (vs. non-resected group) were older (64 vs. 53, p = 0.003) and more frequently had co-existing autoimmune pathologies (22.2 vs. 55.6%, p = 0.022). Resected patients also presented with less classical radiological features of AIP, which are halo sign (0/25 vs. 3/17, p = 0.029) and loss of pancreatic clefts (18/25 vs. 17/17, p = 0.017). There were no differences in demographic features other than age. CONCLUSION: Despite international guidelines for diagnosing AIP, differentiation from pancreatic cancer remains challenging. Resection remains an important treatment option in suspected cancer or where conservative treatment fails.

14 Article Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer. 2019

Sheel, A R G / Harrison, S / Sarantitis, I / Nicholson, J A / Hanna, T / Grocock, C / Raraty, M / Ramesh, J / Farooq, A / Costello, E / Jackson, R / Chapman, M / Smith, A / Carter, R / Mckay, C / Hamady, Z / Aithal, G P / Mountford, R / Ghaneh, P / Hammel, P / Lerch, M M / Halloran, C / Pereira, S P / Greenhalf, W. ·Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK. · Department of Gastroenterology, The Royal Liverpool University Hospital, London, UK. · Department of Radiology, The Royal Liverpool University Hospital, London, UK. · Institute for Liver & Digestive Health, University College London, London, UK. · Department of Pancreatico-Biliary Surgery, Leeds Teaching Hospital Trust, Leeds, UK. · West of Scotland Pancreatic unit, Glasgow Royal Infirmary, Glasgow, UK. · Department of Hepatobiliary and Pancreatic Diseases, University Hospital Southampton, Southampton, UK. · NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2UH, UK. · Mersey Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK. · Service de Gastroentérologie-Pancréatologie, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, 92118, Clichy Cedex, France. · Department of Medicine A, University Medicine Greifswald, Sauerbruch-Strasse, 17475, Greifswald, Germany. ·Am J Gastroenterol · Pubmed #30353057.

ABSTRACT: OBJECTIVES: Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS: This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS: There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS: The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.

15 Article The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma. 2019

Ghaneh, Paula / Kleeff, Jorg / Halloran, Christopher M / Raraty, Michael / Jackson, Richard / Melling, James / Jones, Owain / Palmer, Daniel H / Cox, Trevor F / Smith, Chloe J / O'Reilly, Derek A / Izbicki, Jakob R / Scarfe, Andrew G / Valle, Juan W / McDonald, Alexander C / Carter, Ross / Tebbutt, Niall C / Goldstein, David / Padbury, Robert / Shannon, Jennifer / Dervenis, Christos / Glimelius, Bengt / Deakin, Mark / Anthoney, Alan / Lerch, Markus M / Mayerle, Julia / Oláh, Attila / Rawcliffe, Charlotte L / Campbell, Fiona / Strobel, Oliver / Büchler, Markus W / Neoptolemos, John P / Anonymous11311124. ·Liverpool Cancer Research U.K. Cancer Trials Unit, University of Liverpool, Liverpool, United Kingdom University of Liverpool, Liverpool, UK. · The Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Department of Surgery, Manchester Royal Infirmary, Manchester, UK. · Department of Surgery, University of Hamburg Medical institutions UKE, Hamburg, Germany. · Department of Oncology Division of Medical Oncology 2228 Cross Cancer Institute and University of Alberta, Canada. · Department of Medical Oncology , The Christie, Manchester, UK. · Department of Medical Oncology, The Beatson West of Scotland Cancer Centre, Glasgow, Scotland, UK. · Department of Surgery, Glasgow Royal Infirmary, Glasgow, Scotland, UK. · Department of Medical Oncology, Austin Health, Melbourne, Australia. · Department of Medical Oncology, Prince of Wales hospital and Clinical School University of New South Wales, Australia. · Department of Surgery, Flinders Medical Centre, Adelaide, South Australia. · Department of Medical Oncology, Nepean Cancer Centre and University of Sydney, Australia. · Department of Surgery, The Agia Olga Hospital, Athens, Greece. · Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology, Uppsala Clinical Research Center, Uppsala, Sweden. · Department of Surgery, University Hospital, North Staffordshire, UK. · Division of Oncology at the University of Leeds, St James's University Hospital, Leeds, UK. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany. · Department of Surgery, The Petz Aladar Hospital, Gyor, Hungary. · Department of Pathology, The Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · The Department of Surgery, University of Heidelberg, Heidelberg, Germany. ·Ann Surg · Pubmed #29068800.

ABSTRACT: OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

16 Article Role of Radiological Imaging in the Diagnosis and Characterization of Pancreatic Cystic Lesions: A Systematic Review. 2018

Mohamed, Eyas / Jackson, Richard / Halloran, Christopher M / Ghaneh, Paula. ·From the Department of Molecular and Clinical Cancer Medicine and. · Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, United Kingdom. ·Pancreas · Pubmed #30199486.

ABSTRACT: The evidence on the ability of radiological tests to predict a specific diagnosis and also their aptitude in identifying pathological markers indicative of malignancy in cystic lesions of the pancreas remains inconclusive. We conducted a systematic review on MEDLINE for the use of computed tomography (CT), magnetic resonance imaging, and positron emission tomography/CT (PET/CT) in the diagnosis and characterization of these cysts. The accuracy of CT scan for reaching a specific diagnosis was 39% to 61.4%, whereas its accuracy for differentiating benign from malignant lesions was 61.9% to 80%. Magnetic resonance imaging showed a better accuracy in identifying a specific diagnosis of 50% to 86%, whereas its accuracy in differentiating benign from malignant lesions was 55.6% to 87%. The use of magnetic resonance imaging was superior to CT scan in identifying septations, mural nodules, and ductal communication. The sensitivity of PET/CT in diagnosing malignancy was 85.7% to 100% with a reported accuracy of 88% to 95%. The evidence gathered from this review suggests that the adequacy of CT imaging in full characterization of pancreatic cysts is suboptimal, and therefore a low threshold for supplementary imaging is advised. The use of PET/CT should be considered in high-risk patients with equivocal findings.

17 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 / Anonymous2171112. ·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.

18 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 / Anonymous2111112. ·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.

19 Article PET-PANC: multicentre prospective diagnostic accuracy and health economic analysis study of the impact of combined modality 18fluorine-2-fluoro-2-deoxy-d-glucose positron emission tomography with computed tomography scanning in the diagnosis and management of pancreatic cancer. 2018

Ghaneh, Paula / Hanson, Robert / Titman, Andrew / Lancaster, Gill / Plumpton, Catrin / Lloyd-Williams, Huw / Yeo, Seow Tien / Edwards, Rhiannon Tudor / Johnson, Colin / Abu Hilal, Mohammed / Higginson, Antony P / Armstrong, Tom / Smith, Andrew / Scarsbrook, Andrew / McKay, Colin / Carter, Ross / Sutcliffe, Robert P / Bramhall, Simon / Kocher, Hemant M / Cunningham, David / Pereira, Stephen P / Davidson, Brian / Chang, David / Khan, Saboor / Zealley, Ian / Sarker, Debashis / Al Sarireh, Bilal / Charnley, Richard / Lobo, Dileep / Nicolson, Marianne / Halloran, Christopher / Raraty, Michael / Sutton, Robert / Vinjamuri, Sobhan / Evans, Jonathan / Campbell, Fiona / Deeks, Jon / Sanghera, Bal / Wong, Wai-Lup / Neoptolemos, John P. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK. · Liverpool Cancer Research UK Cancer Trials Unit, University of Liverpool, Liverpool, UK. · Department of Mathematics and Statistics, Lancaster University, Lancaster, UK. · Centre for Health Economics and Medicines Evaluation, Bangor University, Bangor, UK. · Faculty of Medicine, University of Southampton, Southampton, UK. · Department of Surgery, University Hospital Southampton NHS Foundation Trust, Southampton, UK. · Department of Radiology, Portsmouth Hospitals NHS Trust, Portsmouth, UK. · Department of Gastrointestinal Surgery, Leeds Teaching Hospitals NHS Trust, Leeds, UK. · Department of Radiology, Leeds Teaching Hospitals NHS Trust, Leeds, UK. · Department of Surgery, Glasgow Royal Infirmary, NHS Greater Glasgow and Clyde, Glasgow, UK. · Department of Surgery, University Hospitals Birmingham NHS Foundation Trust, Birmingham, UK. · Department of General Surgery, Wye Valley NHS Trust, Hereford, UK. · Barts Cancer Institute, Barts and the London School of Medicine and Dentistry, London, UK. · Gastrointestinal and Lymphoma Unit, Royal Marsden NHS Foundation Trust, London, UK. · Institute for Liver and Digestive Health, University College London Hospitals NHS Foundation Trust, London, UK. · Department of Surgery, Royal Free London NHS Foundation Trust, London, UK. · Department of Surgery, Royal Blackburn Hospital, East Lancashire Hospitals NHS Trust, Blackburn, UK. · Department of Surgery, University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK. · Department of Surgery, Ninewells Hospital and Medical School, NHS Tayside, Dundee, UK. · Department of Oncology, King's College Hospital NHS Foundation Trust, London, UK. · Department of Surgery, Morriston Hospital, Abertawe Bro Morgannwg University Health Board, Swansea, UK. · Department of Surgery, Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. · Faculty of Medicine and Life Sciences, University of Nottingham, Nottingham, UK. · Department of Oncology, Aberdeen Royal Infirmary, NHS Grampian, Aberdeen, UK. · Department of Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Department of Nuclear Medicine, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Department of Radiology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Department of Pathology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, UK. · Institute of Applied Health Research, University of Birmingham, Birmingham, UK. · Paul Strickland Scanner Centre, Mount Vernon Hospital, Middlesex, UK. ·Health Technol Assess · Pubmed #29402376.

ABSTRACT: BACKGROUND: Pancreatic cancer diagnosis and staging can be difficult in 10-20% of patients. Positron emission tomography (PET)/computed tomography (CT) adds precise anatomical localisation to functional data. The use of PET/CT may add further value to the diagnosis and staging of pancreatic cancer. OBJECTIVE: To determine the incremental diagnostic accuracy and impact of PET/CT in addition to standard diagnostic work-up in patients with suspected pancreatic cancer. DESIGN: A multicentre prospective diagnostic accuracy and clinical value study of PET/CT in suspected pancreatic malignancy. PARTICIPANTS: Patients with suspected pancreatic malignancy. INTERVENTIONS: All patients to undergo PET/CT following standard diagnostic work-up. MAIN OUTCOME MEASURES: The primary outcome was the incremental diagnostic value of PET/CT in addition to standard diagnostic work-up with multidetector computed tomography (MDCT). Secondary outcomes were (1) changes in patients' diagnosis, staging and management as a result of PET/CT; (2) changes in the costs and effectiveness of patient management as a result of PET/CT; (3) the incremental diagnostic value of PET/CT in chronic pancreatitis; (4) the identification of groups of patients who would benefit most from PET/CT; and (5) the incremental diagnostic value of PET/CT in other pancreatic tumours. RESULTS: Between 2011 and 2013, 589 patients with suspected pancreatic cancer underwent MDCT and PET/CT, with 550 patients having complete data and in-range PET/CT. Sensitivity and specificity for the diagnosis of pancreatic cancer were 88.5% and 70.6%, respectively, for MDCT and 92.7% and 75.8%, respectively, for PET/CT. The maximum standardised uptake value (SUV CONCLUSION: PET/CT provided a significant incremental diagnostic benefit in the diagnosis of pancreatic cancer and significantly influenced the staging and management of patients. PET/CT had limited utility in chronic pancreatitis and other pancreatic tumours. PET/CT is likely to be cost-effective at current reimbursement rates for PET/CT to the UK NHS. This was not a randomised controlled trial and therefore we do not have any information from patients who would have undergone MDCT only for comparison. In addition, there were issues in estimating costs for PET/CT. Future work should evaluate the role of PET/CT in intraductal papillary mucinous neoplasm and prognosis and response to therapy in patients with pancreatic cancer. STUDY REGISTRATION: Current Controlled Trials ISRCTN73852054 and UKCRN 8166. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

20 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.

21 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.

22 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.

23 Article Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients. 2016

Rizzato, Cosmeri / Campa, Daniele / Talar-Wojnarowska, Renata / Halloran, Christopher / Kupcinskas, Juozas / Butturini, Giovanni / Mohelníková-Duchoňová, Beatrice / Sperti, Cosimo / Tjaden, Christine / Ghaneh, Paula / Hackert, Thilo / Funel, Niccola / Giese, Nathalia / Tavano, Francesca / Pezzilli, Raffaele / Pedata, Mariangela / Pasquali, Claudio / Gazouli, Maria / Mambrini, Andrea / Souček, Pavel / di Sebastiano, Pierluigi / Capurso, Gabriele / Cantore, Maurizio / Oliverius, Martin / Offringa, Rienk / Małecka-Panas, Ewa / Strobel, Oliver / Scarpa, Aldo / Canzian, Federico. ·Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Translational Research and New Technologies in Medicine and Surgery and. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, Department of Biology, University of Pisa, Pisa, Italy. · Department of Digestive Tract Diseases, Medical University of Łódź, Łódź, Poland. · Department of Molecular and Clinical Cancer Medicine, NIHR Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Unit of Surgery B, The Pancreas Institute, Department of Surgery and Oncology, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy. · Department of Oncology, Palacky University Medical School and Teaching Hospital, Olomouc, Czech Republic. · Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy. · Department of General, Visceral and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Translational Research and New Technologies in Medicine and Surgery and. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", S. Giovanni Rotondo (FG), Italy. · Pancreas Unit, Department of Digestive Disease, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Oncological Department, ASL 1 Massa Carrara, Massa Carrara, Italy. · Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Surgery, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", San Giovanni Rotondo (FG), Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Transplant Surgery Department, Institute for Clinical and Experimental Medicine, Prague, Czech Republic. · Division of Molecular Oncology of Gastrointestinal Tumors, German Cancer Research Center (DKFZ), Heidelberg, Germany and. · ARC-NET, Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany, f.canzian@dkfz.de. ·Carcinogenesis · Pubmed #27497070.

ABSTRACT: Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

24 Article Immunobiological effects of gemcitabine and capecitabine combination chemotherapy in advanced pancreatic ductal adenocarcinoma. 2016

Middleton, Gary / Greenhalf, William / Costello, Eithne / Shaw, Victoria / Cox, Trevor / Ghaneh, Paula / Palmer, Daniel H / Neoptolemos, John P. ·Institute of Immunology and Immunotherapy, University of Birmingham B15 2TT and University Hospital Birmingham NHS Foundation Trust, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. · National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Clinical Directorate of General Surgery, Royal Liverpool and Broadgreen University Hospitals NHS Trust and the University of Liverpool, Liverpool L69 3GA, UK. · Cancer Research UK Liverpool Cancer Trials Unit, University of Liverpool, Block C Waterhouse Building, 1-3 Brownlow Street, Liverpool L69 3GA, UK. ·Br J Cancer · Pubmed #26931369.

ABSTRACT: BACKGROUND: Preclinical studies suggest that chemotherapy may enhance the immune response against pancreatic cancer. METHODS: The levels of granulocyte macrophage-colony-stimulating factor (GM-CSF) and interleukin-6 (IL-6) and the associated inflammatory marker C-reactive protein (CRP) were assessed in 38 patients receiving gemcitabine and capecitabine combination chemotherapy for advanced pancreatic cancer within the TeloVac trial. Apoptosis (M30) and total immune response (delayed-type hypersensitivity and/or T-cell response) were also assessed and levels of apoptosis induction correlated with immune response. The telomerase GV1001 vaccine was given either sequentially (n=18) or concomitantly (n=24) with the combination chemotherapy. RESULTS: There were no differences between baseline and post-treatment levels of CRP (P=0.19), IL-6 (P=0.19) and GM-CSF (P=0.71). There was a positive correlation between post-chemotherapy CRP and IL-6 levels (r=0.45, P=0.005) and between CRP with carbohydrate antigen-19-9 (CA19-9) levels at baseline (r=0.45, P=0.015) and post treatment (r=0.40, P=0.015). The change in CRP and IL-6 levels was positively correlated (r=0.40, P=0.012). Hazard ratios (95% CI) for baseline CA19-9 (1.30 (1.07-1.59), P=0.009) and CRP (1.55 (1.00-2.39), P=0.049) levels were each independently predictive of survival. The M30 mean matched differences between pre- and post-chemotherapy showed evidence of apoptosis in both the sequential (P=0.058) and concurrent (P=0.0018) chemoimmunotherapy arms. Respectively, 5 of 10 and 9 of 20 patients had a positive immune response but there was no association with apoptosis. CONCLUSIONS: Combination gemcitabine and capecitabine chemotherapy did not affect circulating levels of GM-CSF, IL-6 and CRP. Chemotherapy-induced apoptosis was not associated with the immunogenicity induced by the GV1001 vaccine in advanced pancreatic cancer.

25 Article Management and Outcome of 64 Patients with Pancreatic Serous Cystic Neoplasms. 2016

Gomatos, Ilias P / Halloran, Christopher / Ghaneh, Paula / Raraty, Michael / Polydoros, Fotis / Campbell, Fiona / Evans, Jonathan / Sutton, Robert / Garry, Jo / Whelan, Philip / Neoptolemos, John P. ·National Institutes of Health Research Liverpool Pancreas Biomedical Research Unit and Clinical Directorate of General Surgery, University of Liverpool, Liverpool, UK. ·Dig Surg · Pubmed #26918360.

ABSTRACT: BACKGROUND: The optimal management approach to pancreatic serous cystic neoplasms (SCNs) is still evolving. METHODS: Consecutive patients with SCN managed at the Liverpool Pancreas Cancer Centre between 2000 and 2013 were retrospectively reviewed. RESULTS: There were 64 patients consisting of 39 women (60.9%) and 25 men (39.1%). Forty-seven patients (73.4%) had surgical removal and 17 (26.6%) were observed. The possibility of a non-SCN malignancy was the predominant indication for resection in 27 (57.4%) patients. Postoperative morbidity occurred in 26 (55.3%) patients with 2 (4.3%) deaths. An increased risk of resection was associated with patient's age (p = 0.011), diagnosis before 2009 (p < 0.001), pain (p = 0.043), possibility of cancer (p = 0.009) and a solid SCN component on imaging (p = 0.002). Independent factors associated with resection were a diagnosis before 2009 (p = 0.005) and a solid SCN component (p < 0.001). Independent factors associated with shorter time to surgical resection were persistent pain (p = 0.003) and a solid SCN component (p = 0.007). CONCLUSION: There was a reduction in the proportion of resections with the application of an observe-only policy for asymptomatic patients with more definite features of SCN. Improved criteria are still required in the remainder of patients with uncertain features of SCN in deciding for intervention or surveillance.

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