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Pancreatic Neoplasms: HELP
Articles by Paula Ghaneh
Based on 28 articles published since 2009
(Why 28 articles?)
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Between 2009 and 2019, Paula Ghaneh wrote the following 28 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 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.

3 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.

4 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.

5 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.

6 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 / Anonymous2721324. ·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.

7 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.

8 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.

9 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 / Anonymous9620671. ·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.

10 Clinical Trial Randomised Phase I/II trial assessing the safety and efficacy of radiolabelled anti-carcinoembryonic antigen I(131) KAb201 antibodies given intra-arterially or intravenously in patients with unresectable pancreatic adenocarcinoma. 2009

Sultana, Asma / Shore, Susannah / Raraty, Michael Gt / Vinjamuri, Sobhan / Evans, Jonathan E / Smith, Catrin Tudur / Lane, Steven / Chauhan, Seema / Bosonnet, Lorraine / Garvey, Conall / Sutton, Robert / Neoptolemos, John P / Ghaneh, Paula. ·Division of Surgery and Oncology, University of Liverpool, Liverpool, UK. asmasul@liv.ac.uk ·BMC Cancer · Pubmed #19243606.

ABSTRACT: BACKGROUND: Advanced pancreatic cancer has a poor prognosis, and the current standard of care (gemcitabine based chemotherapy) provides a small survival advantage. However the drawback is the accompanying systemic toxicity, which targeted treatments may overcome. This study aimed to evaluate the safety and tolerability of KAb201, an anti-carcinoembryonic antigen monoclonal antibody, labelled with I(131) in pancreatic cancer (ISRCTN 16857581). METHODS: Patients with histological/cytological proven inoperable adenocarcinoma of the head of pancreas were randomised to receive KAb 201 via either the intra-arterial or intravenous delivery route. The dose limiting toxicities within each group were determined. Patients were assessed for safety and efficacy and followed up until death. RESULTS: Between February 2003 and July 2005, 25 patients were enrolled. Nineteen patients were randomised, 9 to the intravenous and 10 to the intra-arterial arms. In the intra-arterial arm, dose limiting toxicity was seen in 2/6 (33%) patients at 50 mCi whereas in the intravenous arm, dose limiting toxicity was noted in 1/6 patients at 50 mCi, but did not occur at 75 mCi (0/3).The overall response rate was 6% (1/18). Median overall survival was 5.2 months (95% confidence interval = 3.3 to 9 months), with no significant difference between the intravenous and intra-arterial arms (log rank test p = 0.79). One patient was still alive at the time of this analysis. CONCLUSION: Dose limiting toxicity for KAb201 with I(131) by the intra-arterial route was 50 mCi, while dose limiting toxicity was not reached in the intravenous arm.

11 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.

12 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.

13 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.

14 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.

15 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.

16 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.

17 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.

18 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.

19 Article Incidence of post-ERCP pancreatitis from direct pancreatic juice collection in hereditary pancreatitis and familial pancreatic cancer before and after the introduction of prophylactic pancreatic stents and rectal diclofenac. 2015

Nicholson, James A / Greenhalf, William / Jackson, Richard / Cox, Trevor F / Butler, Jane V / Hanna, Thomas / Harrison, Sara / Grocock, Christopher J / Halloran, Christopher M / Howes, Nathan R / Raraty, Michael G / Ghaneh, Paula / Johnstone, Marianne / Sarkar, Sanchoy / Smart, Howard L / Evans, Jonathan C / Aithal, Guruprasad P / Sutton, Robert / Neoptolemos, John P / Lombard, Martin G. ·From the *National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital; †Liverpool Clinical Trials Unit; Departments of ‡Gastroenterology, and §Radiology, Royal Liverpool University Hospital, Liverpool; and ║Digestive Diseases Biomedical Research Unit, National Institute for Health Research Nottingham, Queen's Medical Centre, Nottingham, United Kingdom. ·Pancreas · Pubmed #25438071.

ABSTRACT: OBJECTIVES: Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP). METHODS: A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008. RESULTS: There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035). CONCLUSIONS: Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

20 Article Biomarkers for early diagnosis of pancreatic cancer. 2015

Jenkinson, Claire / Earl, Julie / Ghaneh, Paula / Halloran, Christopher / Carrato, Alfredo / Greenhalf, William / Neoptolemos, John / Costello, Eithne. ·Department of Molecular and Clinical Cancer Medicine, National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK. ·Expert Rev Gastroenterol Hepatol · Pubmed #25373768.

ABSTRACT: Pancreatic ductal adenocarcinoma is an aggressive malignancy with a 5-year survival rate of approximately 5%. The lack of established strategies for early detection contributes to this poor prognosis. Although several novel candidate biomarkers have been proposed for earlier diagnosis, none have been adopted into routine clinical use. In this review, the authors examine the challenges associated with finding new pancreatic cancer diagnostic biomarkers and explore why translation of biomarker research for patient benefit has thus far failed. The authors also review recent progress and highlight advances in the understanding of the biology of pancreatic cancer that may lead to improvements in biomarker detection and implementation.

21 Article Pancreatic cancer hENT1 expression and survival from gemcitabine in patients from the ESPAC-3 trial. 2014

Greenhalf, William / Ghaneh, Paula / Neoptolemos, John P / Palmer, Daniel H / Cox, Trevor F / Lamb, Richard F / Garner, Elizabeth / Campbell, Fiona / Mackey, John R / Costello, Eithne / Moore, Malcolm J / Valle, Juan W / McDonald, Alexander C / Carter, Ross / Tebbutt, Niall C / Goldstein, David / Shannon, Jennifer / Dervenis, Christos / Glimelius, Bengt / Deakin, Mark / Charnley, Richard M / Lacaine, François / Scarfe, Andrew G / Middleton, Mark R / Anthoney, Alan / Halloran, Christopher M / Mayerle, Julia / Oláh, Attila / Jackson, Richard / Rawcliffe, Charlotte L / Scarpa, Aldo / Bassi, Claudio / Büchler, Markus W / Anonymous5150777. ·Affiliations of authors: Liverpool Cancer Research UK Cancer Trials Unit, Liverpool Cancer Research UK Centre, University of Liverpool, Liverpool, UK (WG, JPN, EG, TFC, PG, EC, CMH, CLR, FC, RJ) · the Princess Margaret Hospital, Toronto, Canada (MJM) · Manchester Academic Health Sciences Centre, Christie NHS Foundation Trust, School of Cancer and Enabling Sciences, University of Manchester, UK (JWV) · Queen Elizabeth Hospital, University Hospital Birmingham NHS Foundation Trust, Birmingham, UK (DHP) · Beatson West of Scotland Cancer Centre, Glasgow, UK (ACM) · Glasgow Royal Infirmary, Glasgow, UK (RC) · Hôpital Tenon, Université, Pierre et Marie Curie, Paris, France (FL) · Austin Health, Melbourne, Australia (NCT) · Prince of Wales Hospital and Clinical School University of New South Wales, New South Wales, Australia (DG) · Nepean Cancer Centre and University of Sydney, Sydney, Australia (JS) · Agia Olga Hospital, Athens, Greece (CD) · Medical Oncology, Clatterbridge Centre for Oncology, Bebington, Merseyside, UK (DS) · Department of Oncology, Akademiska Sjukhuset, Uppsala University, Uppsala, Sweden (BG) · University Hospital, North Staffordshire, UK (MD) · Freeman Hospital, Newcastle upon Tyne, UK (RMC) · Service de Chirurgie Digestive et Viscérale, Hôpital Tenon, Paris, France (FL) · Cross Cancer Institute and University of Alberta, Alberta, Canada (JRM, AGS) · Churchill Hospital, Oxford University Hospitals NHS Trust, Oxford, UK (MRM) · St James's University Hospital, Leeds, UK (AA) · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany (JM) · Petz Aladar Hospital, Gyor, Hungary (AO) · Departments of Surgery and Pathology and ARC-NET Research Center, University of Verona, Italy (AS, CB) · Department of Surgery, University of Heidelberg, Heidelberg, Germany (MWB). ·J Natl Cancer Inst · Pubmed #24301456.

ABSTRACT: BACKGROUND: Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection. METHODS: Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients. CONCLUSIONS: Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

22 Article Adjuvant therapy for pancreatic cancer. 2012

Sultana, Asma / Cox, Trevor / Ghaneh, Paula / Neoptolemos, John P. ·Department of Molecular and Clinical Cancer Medicine Centre, University of Liverpool, Liverpool, L69 3GA, UK. ·Recent Results Cancer Res · Pubmed #23129367.

ABSTRACT: Pancreatic cancer is a challenging malignancy to treat, as less than one-fifth of diagnosed cases are resectable, surgery is complex and postoperative recovery slow, treated patients tend to relapse and overall survival rates are low. It is one of the leading causes of cancer-related mortality. Adjuvant therapy has been employed in resectable disease, to target micrometastases and improve prognosis. Chemotherapy, chemoradiotherapy (chemoRT) and chemoradiotherapy (chemoRT) followed on by chemotherapy have been evaluated in randomised controlled trials. The European Study Group for Pancreatic Cancer (ESPAC)-1 and CONKO-001 trials clearly established the survival advantage of adjuvant chemotherapy with 5 fluorouracil (5FU) plus folinic acid and gemcitabine respectively over no chemotherapy. The ESPAC-3 (version 2) trial demonstrated equivalence between 5FU plus folinic acid and gemcitabine in terms of survival parameters, though gemcitabine had a better toxicity profile. The results of these key studies, together with smaller ones have been subjected to meta-analyses, with confirmation of improved survival with adjuvant systemic chemotherapy. The EORTC-40891 and ESPAC-1 trials found no survival advantage with adjuvant chemoRT compared to observation, and this has been reflected in a subsequent meta-analysis. The popularisation of chemoRT, with follow on chemotherapy (versus observation) was based on the small underpowered GITSG trial. The ESPAC-1 trial was unable to find a survival benefit for chemoRT, with follow on chemotherapy compared to observation. The RTOG-9704 trial assessed chemoRT with follow on chemotherapy in both arms and found no difference between survival in the gemcitabine and 5FU arms. There has never been a published head-to-head randomised comparison of adjuvant chemotherapy to chemoRT, with follow on chemotherapy. Ongoing randomised trials are looking into adjuvant combination chemotherapy, chemotherapy with follow on chemoRT, and neoadjuvant therapy. Novel agents continue to be assessed in early phase trials with a major emphasis on predictive and prognostic biomarkers. Based on the available evidence, adjuvant chemotherapy with gemcitabine or 5FU/folinic acid is the current recommended gold standard in the management of resected pancreatic cancer.

23 Article Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study. 2011

Halloran, Christopher M / Cox, Trevor F / Chauhan, Seema / Raraty, Michael G T / Sutton, Robert / Neoptolemos, John P / Ghaneh, Paula. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, and National Institute for Pancreas Biomedical Research Unit, Liverpool, UK. ·Pancreatology · Pubmed #22094930.

ABSTRACT: OBJECTIVES: Pancreatic resection for cancer may produce pancreatic exocrine insufficiency (PEI), which is poorly understood. This study examined the coefficient of fat absorption (CFA), symptoms, quality of life (QoL) and the accuracy of faecal elastase-1 (FE-1) measurement to predict PEI. METHODS: Forty patients were analysed following resection for pancreatic malignancy. The primary endpoint was PEI diagnosis defined by CFA <93%; secondary endpoints were PEI diagnosis using FE-1 <200 μg/g, body mass index (BMI), and symptom and QoL analysis. Interventions were 3-day stool collection, EORTC QLQ-C30 (version 1) questionnaire and patient's diary, at 6 weeks and 3, 6 and 12 months after surgery. RESULTS: CFA <93% was present in 67% of patients at 6 weeks and in 55% at 12 months. PEI using FE-1 was present in 77 and 83% of patients, respectively. No significant changes between time-points were observed. Sensitivity, specificity, PPV, NPV and accuracy for FE-1 in detecting CFA <93% were 91, 35, 70, 71 and 70%, respectively. CFA and FE-1 levels were uncorrelated. Overall, QoL increased at 6 (p = 0.0212) and 12 (p < 0.0001) months after surgery, mainly driven by physical, role and social functioning, and by appetite. Importantly, however, BMI and symptoms were unaffected by PEI, which suggests a subclinical presentation; such patients had attributes indicating poorer QoL (notably insomnia, p = 0.0012). CONCLUSIONS: PEI was common and sustained following resection and not associated with significant symptoms. These patients had a tendency toward poorer QoL. FE-1 is a poor surrogate for diagnosing impaired fat absorption. Postoperative pancreatic enzyme replacement should be considered more routinely. and IAP.

24 Article Adjuvant therapy in pancreatic cancer. 2010

Thomas, Amy / Dajani, Khaled / Neoptolemos, John P / Ghaneh, Paula. ·Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Liverpool, UK. ·Dig Dis · Pubmed #21088421.

ABSTRACT: Pancreatic cancer is one of the major causes of cancer death in Europe with a 5-year survival rate of less than 5%. Although surgery cannot guarantee a cure, the 5-year survival does improve to around 10% following resection and increases to 20-30% with adjuvant chemotherapy. The European Study Group for Pancreatic Cancer (ESPAC) 1 trial was the first adequately powered, randomized study to assess chemoradiotherapy (CRT), concurrent with 5-fluorouracil (5-FU) and chemotherapy [5-FU/folinic acid (FA)] in resected pancreatic cancer. There was a survival benefit for adjuvant chemotherapy, but not for adjuvant CRT. Adjuvant CRT also did not improve survival in the EORTC multicenter prospective randomized trial by Klinkenbijl et al. (1999). The phase 3 RTOG 9704 trial compared pre- and postchemoradiation gemcitabine to pre- and postchemoradiation 5-FU. Overall there was no difference in overall survival between the 2 arms. Adjuvant gemcitabine significantly improved disease-free survival and later overall survival compared to surgery alone in the CONKO-001 randomized trial. The ESPAC-3(v2) trial compared adjuvant gemcitabine versus 5-FU/FA. The final 2-year analysis demonstrated median survival from resection of patients treated with 5-FU/FA was 23.0 months (95% CI: 21.1, 25.0) and 23.6 months (95% CI: 21.4, 26.4) for patients treated with gemcitabine. Further randomized studies will assess the role of adjuvant combination chemotherapy (ESPAC-4). The key to the future of adjuvant therapy in pancreatic cancer will be the identification of novel and effective agents, and better biomarker technology underpinned by translational research which will inform the design of future trials.

25 Article Classification of R1 resections for pancreatic cancer: the prognostic relevance of tumour involvement within 1 mm of a resection margin. 2009

Campbell, Fiona / Smith, Richard A / Whelan, Philip / Sutton, Robert / Raraty, Michael / Neoptolemos, John P / Ghaneh, Paula. ·Department of Pathology, School of Cancer Studies, University of Liverpool, Royal Liverpool University Hospital, , 5th Floor Duncan Building, Daulby Street, Liverpool L69 3GA, UK. f.campbell@liv.ac.uk ·Histopathology · Pubmed #19723142.

ABSTRACT: AIMS: The current Royal College of Pathologists guidelines for pancreatoduodenectomy specimen reporting recommend that microscopic evidence of tumour within 1 mm of a resection margin (RM) should be classified as R1. No clinical evidence exists to justify this classification. The aim of this study was to identify the proportion of pancreatoduodenectomy specimens in which 'equivocal' RMs are present (tumour involvement within 1 mm of, but not directly reaching, one or more resection margins) and whether the survival of these patients was similar to that of patients with 'unequivocal' RM involvement. METHODS AND RESULTS: Patients with histologically confirmed pancreatic ductal adenocarcinoma undergoing pancreatoduodenectomy between 1997 and 2007 (n = 163) were identified from a prospective database. One hundred and twenty-eight cases (79%) were classified as R1. Of these, 57 (45% of all R1 cases) were based on 'equivocal' margin involvement. There was no significant difference in overall survival between equivocal and unequivocal R1 resections (log rank, P = 0.102). All R1 resections had a poorer survival on univariate (log rank, P = 0.013), but not multivariate, analysis (Cox, P = 0.132). CONCLUSIONS: Our results indicate that cases with microscopic tumour involvement within 1 mm of a resection margin should be considered synonymous with incomplete excision for resected pancreatic cancer.

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