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Pancreatic Neoplasms: HELP
Articles by Fiona Campbell
Based on 25 articles published since 2009
(Why 25 articles?)
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Between 2009 and 2019, F. Campbell wrote the following 25 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Diagnosis and management of pancreatic cancer in adults: A summary of guidelines from the UK National Institute for Health and Care Excellence. 2018

O'Reilly, Derek / Fou, Linyun / Hasler, Elise / Hawkins, James / O'Connell, Susan / Pelone, Ferruccio / Callaway, Mark / Campbell, Fiona / Capel, Margred / Charnley, Richard / Corrie, Pippa / Elliot, Dawn / Goodburn, Lesley / Jewell, Anna / Joharchi, Suzanne / McGeeney, Laura / Mukherjee, Somnath / Oppong, Kofi / Whelan, Phil / Primrose, John / Neoptolemos, John. ·Manchester Royal Infirmary, Central Manchester NHS Foundation Trust and University of Manchester, United Kingdom. Electronic address: doreilly@doctors.org.uk. · National Institute for Health and Care Excellence, United Kingdom. · Bristol Royal Infirmary, University Hospitals Bristol NHS Foundation Trust, United Kingdom. · University of Liverpool, The Royal Liverpool & Broadgreen University Hospital NHS Trust, United Kingdom. · George Thomas Hospice, United Kingdom. · Freeman Hospital, Newcastle upon Tyne, United Kingdom. · Cambridge University Hospitals NHS Foundation Trust and University of Cambridge, United Kingdom. · Northumbria Healthcare Foundation Trust, United Kingdom. · Department of General, Visceral and Transplantation Surgery, University of Heidelberg, Germany. · CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford & Churchill Hospital, United Kingdom. · University of Southampton, Southampton General Hospital, United Kingdom. · University of Heidelberg, Germany. ·Pancreatology · Pubmed #30292643.

ABSTRACT: To enable standardisation of care of pancreatic cancer patients and facilitate improvement in outcome, the United Kingdom's National Institute for Health and Care Excellence (NICE) developed a clinical guideline for the diagnosis and management of pancreatic cancer in adults. Systematic literature searches, systematic review and meta-analyses were undertaken. Recommendations were drafted on the basis of the group's interpretation of the best available evidence of clinical and cost effectiveness. There was patient involvement and public consultation. Recommendations were made on: diagnosis; staging; monitoring of inherited high risk; psychological support; pain; nutrition management; and the specific management of people with resectable-, borderline-resectable- and unresectable-pancreatic cancer. The guideline committee also made recommendations for future research into neoadjuvant therapy, cachexia interventions, minimally invasive pancreatectomy, pain management and psychological support needs. These NICE guidelines aim to promote best current practice and support and stimulate research and innovation in pancreatic cancer.

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

Takaori, Kyoichi / Bassi, Claudio / Biankin, Andrew / Brunner, Thomas B / Cataldo, Ivana / Campbell, Fiona / Cunningham, David / Falconi, Massimo / Frampton, Adam E / Furuse, Junji / Giovannini, Marc / Jackson, Richard / Nakamura, Akira / Nealon, William / Neoptolemos, John P / Real, Francisco X / Scarpa, Aldo / Sclafani, Francesco / Windsor, John A / Yamaguchi, Koji / Wolfgang, Christopher / Johnson, Colin D / Anonymous480853. ·Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan. Electronic address: takaori@kuhp.kyoto-u.ac.jp. · Department of Surgery and Oncology, Pancreas Institute, University of Verona, Verona, Italy. · Academic Unit of Surgery, University of Glasgow, Glasgow, United Kingdom. · Department of Radiation Oncology, University Hospitals Freiburg, Germany. · Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Department of Medicine, The Royal Marsden NHS Foundation Trust, London and Surrey, United Kingdom. · Pancreatic Surgery Unit, Università Vita e Salute, Milano, Italy. · HPB Surgical Unit, Department of Surgery and Cancer, Imperial College, Hammersmith Hospital, London, United Kingdom. · Department of Medical Oncology, Kyorin University School of Medicine, Tokyo, Japan. · Endoscopic Unit, Paoli-Calmettes Institute, Marseille, France. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Radiation Oncology and Image-applied Therapy, Kyoto University Hospital, Kyoto, Japan. · Division of General Surgery, Yale University, New Haven, CT, United States of America. · Epithelial Carcinogenesis Group, CNIO-Spanish National Cancer Research Centre, Madrid, Spain. · Department of Surgery, University of Auckland, HBP/Upper GI Unit, Auckland City Hospital, Auckland, New Zealand. · Department of Advanced Treatment of Pancreatic Disease, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan. · Department of Surgery, The Johns Hopkins University, Baltimore, MD, United States of America. · University Surgical Unit, Southampton General Hospital, Southampton, United Kingdom. ·Pancreatology · Pubmed #26699808.

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

3 Review The yin and yang of vitamin D receptor (VDR) signaling in neoplastic progression: operational networks and tissue-specific growth control. 2010

Campbell, F C / Xu, Haibo / El-Tanani, M / Crowe, P / Bingham, V. ·Centre for Cancer Research and Cell Biology, Queen's University of Belfast, Lisburn Rd, Belfast BT9 7BL, Northern Ireland, UK. f.c.campbell@qub.ac.uk ·Biochem Pharmacol · Pubmed #19737544.

ABSTRACT: Substantive evidence implicates vitamin D receptor (VDR) or its natural ligand 1alpha,25-(OH)2 D3 in modulation of tumor growth. However, both human and animal studies indicate tissue-specificity of effect. Epidemiological studies show both inverse and direct relationships between serum 25(OH)D levels and common solid cancers. VDR ablation affects carcinogen-induced tumorigenesis in a tissue-specific manner in model systems. Better understanding of the tissue-specificity of vitamin D-dependent molecular networks may provide insight into selective growth control by the seco-steroid, 1alpha,25-(OH)2 D3. This commentary considers complex factors that may influence the cell- or tissue-specificity of 1alpha,25-(OH)2 D3/VDR growth effects, including local synthesis, metabolism and transport of vitamin D and its metabolites, vitamin D receptor (VDR) expression and ligand-interactions, 1alpha,25-(OH)2 D3 genomic and non-genomic actions, Ca2+ flux, kinase activation, VDR interactions with activating and inhibitory vitamin D responsive elements (VDREs) within target gene promoters, VDR coregulator recruitment and differential effects on key downstream growth regulatory genes. We highlight some differences of VDR growth control relevant to colonic, esophageal, prostate, pancreatic and other cancers and assess the potential for development of selective prevention or treatment strategies.

4 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.

5 Clinical Trial Effect of adjuvant chemotherapy with fluorouracil plus folinic acid or gemcitabine vs observation on survival in patients with resected periampullary adenocarcinoma: the ESPAC-3 periampullary cancer randomized trial. 2012

Neoptolemos, John P / Moore, Malcolm J / Cox, Trevor F / Valle, Juan W / Palmer, Daniel H / McDonald, Alexander C / Carter, Ross / Tebbutt, Niall C / Dervenis, Christos / Smith, David / Glimelius, Bengt / Charnley, Richard M / Lacaine, François / Scarfe, Andrew G / Middleton, Mark R / Anthoney, Alan / Ghaneh, Paula / Halloran, Christopher M / Lerch, Markus M / Oláh, Attila / Rawcliffe, Charlotte L / Verbeke, Caroline S / Campbell, Fiona / Büchler, Markus W / Anonymous1780731. ·Institute of Translational Medicine, Liverpool Cancer Trials Unit, Liverpool Cancer Research United Kingdom Centre, University of Liverpool, Liverpool, England, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #22782416.

ABSTRACT: CONTEXT: Patients with periampullary adenocarcinomas undergo the same resectional surgery as that of patients with pancreatic ductal adenocarcinoma. Although adjuvant chemotherapy has been shown to have a survival benefit for pancreatic cancer, there have been no randomized trials for periampullary adenocarcinomas. OBJECTIVE: To determine whether adjuvant chemotherapy (fluorouracil or gemcitabine) provides improved overall survival following resection. DESIGN, SETTING, AND PATIENTS: The European Study Group for Pancreatic Cancer (ESPAC)-3 periampullary trial, an open-label, phase 3, randomized controlled trial (July 2000-May 2008) in 100 centers in Europe, Australia, Japan, and Canada. Of the 428 patients included in the primary analysis, 297 had ampullary, 96 had bile duct, and 35 had other cancers. INTERVENTIONS: One hundred forty-four patients were assigned to the observation group, 143 patients to receive 20 mg/m2 of folinic acid via intravenous bolus injection followed by 425 mg/m2 of fluorouracil via intravenous bolus injection administered 1 to 5 days every 28 days, and 141 patients to receive 1000 mg/m2 of intravenous infusion of gemcitabine once a week for 3 of every 4 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival with chemotherapy vs no chemotherapy; secondary measures were chemotherapy type, toxic effects, progression-free survival, and quality of life. RESULTS: Eighty-eight patients (61%) in the observation group, 83 (58%) in the fluorouracil plus folinic acid group, and 73 (52%) in the gemcitabine group died. In the observation group, the median survival was 35.2 months (95%% CI, 27.2-43.0 months) and was 43.1 (95%, CI, 34.0-56.0) in the 2 chemotherapy groups (hazard ratio, 0.86; (95% CI, 0.66-1.11; χ2 = 1.33; P = .25). After adjusting for independent prognostic variables of age, bile duct cancer, poor tumor differentiation, and positive lymph nodes and after conducting multiple regression analysis, the hazard ratio for chemotherapy compared with observation was 0.75 (95% CI, 0.57-0.98; Wald χ2 = 4.53, P = .03). CONCLUSIONS: Among patients with resected periampullary adenocarcinoma, adjuvant chemotherapy, compared with observation, was not associated with a significant survival benefit in the primary analysis; however, multivariable analysis adjusting for prognostic variables demonstrated a statistically significant survival benefit associated with adjuvant chemotherapy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00058201.

6 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.

7 Article Macrophage-Derived Granulin Drives Resistance to Immune Checkpoint Inhibition in Metastatic Pancreatic Cancer. 2018

Quaranta, Valeria / Rainer, Carolyn / Nielsen, Sebastian R / Raymant, Meirion L / Ahmed, Muhammad S / Engle, Dannielle D / Taylor, Arthur / Murray, Trish / Campbell, Fiona / Palmer, Daniel H / Tuveson, David A / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Department of Cellular and Molecular Physiology, University of Liverpool, Liverpool, United Kingdom. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. mschmid@liverpool.ac.uk. ·Cancer Res · Pubmed #29789416.

ABSTRACT: The ability of disseminated cancer cells to evade the immune response is a critical step for efficient metastatic progression. Protection against an immune attack is often provided by the tumor microenvironment that suppresses and excludes cytotoxic CD8

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

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

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

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

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

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

10 Article Zeb1 in Stromal Myofibroblasts Promotes 2018

Sangrador, Irene / Molero, Xavier / Campbell, Fiona / Franch-Expósito, Sebastià / Rovira-Rigau, Maria / Samper, Esther / Domínguez-Fraile, Manuel / Fillat, Cristina / Castells, Antoni / Vaquero, Eva C. ·Gastrointestinal and pancreatic oncology research group, Hospital Clinic, Barcelona, CiberEHD, Spain. · Exocrine Pancreas Research Unit, Hospital Universitari Vall d'Hebron, Autonomous University of Barcelona, CiberEHD, Barcelona, Spain. · Department of Pathology, Royal Liverpool and Broadgreen University Hospitals NHS Trust, Liverpool, United Kingdom. · Gastroenterology Department, Hospital Clinic, IDIBAPS, CiberEHD, University of Barcelona, Barcelona, Spain. · Gene Therapy and Cancer, IDIBAPS, CiberER, University of Barcelona, Barcelona, Spain. · Institut de Malalties Digestives i Metabòliques, Hospital Clínic, IDIBAPS, University of Barcelona, Barcelona, Spain. · Gastrointestinal and pancreatic oncology research group, Hospital Clinic, Barcelona, CiberEHD, Spain. evaquero@comb.cat. ·Cancer Res · Pubmed #29490942.

ABSTRACT: The transcription factor Zeb1 has been identified as a crucial player in Kras-dependent oncogenesis. In pancreatic ductal adenocarcinoma (PDAC), Zeb1 is highly expressed in myofibroblasts and correlates with poor prognosis. As Kras mutations are key drivers in PDAC, we aimed here to assess the necessity of Zeb1 for Kras-driven PDAC and to define the role of Zeb1-expressing myofibroblasts in PDAC development. Genetically engineered mice with conditional pancreatic

11 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.

12 Article Gastrin Induces Nuclear Export and Proteasome Degradation of Menin in Enteric Glial Cells. 2017

Sundaresan, Sinju / Meininger, Cameron A / Kang, Anthony J / Photenhauer, Amanda L / Hayes, Michael M / Sahoo, Nirakar / Grembecka, Jolanta / Cierpicki, Tomasz / Ding, Lin / Giordano, Thomas J / Else, Tobias / Madrigal, David J / Low, Malcolm J / Campbell, Fiona / Baker, Ann-Marie / Xu, Haoxing / Wright, Nicholas A / Merchant, Juanita L. ·Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan. · Department of Molecular, Cellular, and Developmental Biology, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, University of Michigan, Ann Arbor, Michigan. · Division of Metabolism Endocrinology and Diabetes, University of Michigan, Ann Arbor, Michigan. · Endocrine Oncology Program, University of Michigan, Ann Arbor, Michigan. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. · Department of Pathology, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Center for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. · Department of Internal Medicine, Division of Gastroenterology, University of Michigan, Ann Arbor, Michigan; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. Electronic address: merchanj@med.umich.edu. ·Gastroenterology · Pubmed #28859856.

ABSTRACT: BACKGROUND & AIMS: The multiple endocrine neoplasia, type 1 (MEN1) locus encodes the nuclear protein and tumor suppressor menin. MEN1 mutations frequently cause neuroendocrine tumors such as gastrinomas, characterized by their predominant duodenal location and local metastasis at time of diagnosis. Diffuse gastrin cell hyperplasia precedes the appearance of MEN1 gastrinomas, which develop within submucosal Brunner's glands. We investigated how menin regulates expression of the gastrin gene and induces generation of submucosal gastrin-expressing cell hyperplasia. METHODS: Primary enteric glial cultures were generated from the VillinCre:Men1 RESULTS: Enteric glial cells that stained positive for glial fibrillary acidic protein (GFAP+) expressed gastrin de novo through a mechanism that required PKA. Gastrin-induced nuclear export of menin via cholecystokinin B receptor (CCKBR)-mediated activation of PKA. Once exported from the nucleus, menin was ubiquitinated and degraded by the proteasome. GFAP and other markers of enteric glial cells (eg, p75 and S100B), colocalized with gastrin in human duodenal gastrinomas. CONCLUSIONS: MEN1-associated gastrinomas, which develop in the submucosa, might arise from enteric glial cells through hormone-dependent PKA signaling. This pathway disrupts nuclear menin function, leading to hypergastrinemia and associated sequelae.

13 Article Chemoresistance in Pancreatic Cancer Is Driven by Stroma-Derived Insulin-Like Growth Factors. 2016

Ireland, Lucy / Santos, Almudena / Ahmed, Muhammad S / Rainer, Carolyn / Nielsen, Sebastian R / Quaranta, Valeria / Weyer-Czernilofsky, Ulrike / Engle, Danielle D / Perez-Mancera, Pedro A / Coupland, Sarah E / Taktak, Azzam / Bogenrieder, Thomas / Tuveson, David A / Campbell, Fiona / Schmid, Michael C / Mielgo, Ainhoa. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Pharmacology and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York. · Department of Medical Physics and Clinical Engineering, Royal Liverpool University Hospital, Liverpool, United Kingdom. · Medicine and Translational Research, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria. · Department of Urology, University Hospital Grosshadern, Ludwig-Maximilians-University, Munich, Germany. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York. ·Cancer Res · Pubmed #27742686.

ABSTRACT: Tumor-associated macrophages (TAM) and myofibroblasts are key drivers in cancer that are associated with drug resistance in many cancers, including pancreatic ductal adenocarcinoma (PDAC). However, our understanding of the molecular mechanisms by which TAM and fibroblasts contribute to chemoresistance is unclear. In this study, we found that TAM and myofibroblasts directly support chemoresistance of pancreatic cancer cells by secreting insulin-like growth factors (IGF) 1 and 2, which activate insulin/IGF receptors on pancreatic cancer cells. Immunohistochemical analysis of biopsies from patients with pancreatic cancer revealed that 72% of the patients expressed activated insulin/IGF receptors on tumor cells, and this positively correlates with increased CD163

14 Article Macrophage-secreted granulin supports pancreatic cancer metastasis by inducing liver fibrosis. 2016

Nielsen, Sebastian R / Quaranta, Valeria / Linford, Andrea / Emeagi, Perpetua / Rainer, Carolyn / Santos, Almudena / Ireland, Lucy / Sakai, Takao / Sakai, Keiko / Kim, Yong-Sam / Engle, Dannielle / Campbell, Fiona / Palmer, Daniel / Ko, Jeong Heon / Tuveson, David A / Hirsch, Emilio / Mielgo, Ainhoa / Schmid, Michael C. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Department of Molecular and Clinical Pharmacology, University of Liverpool, Ashton Street, Liverpool L69 3GE, UK. · Aging Intervention Research Center, KRIBB, 125 Gwahak-ro, Yuseong-gu, Deajeon 305-806, Korea. · Korea University of Science and Technology, 217 Gajeong-ro, Yuseong-gu, Daejeon 305-350, Korea. · Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA. · Lustgarten Pancreatic Cancer Research Laboratory, Cold Spring Harbor, New York 11724, USA. · Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA. · Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy. ·Nat Cell Biol · Pubmed #27088855.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is a devastating metastatic disease for which better therapies are urgently needed. Macrophages enhance metastasis in many cancer types; however, the role of macrophages in PDAC liver metastasis remains poorly understood. Here we found that PDAC liver metastasis critically depends on the early recruitment of granulin-secreting inflammatory monocytes to the liver. Mechanistically, we demonstrate that granulin secretion by metastasis-associated macrophages (MAMs) activates resident hepatic stellate cells (hStCs) into myofibroblasts that secrete periostin, resulting in a fibrotic microenvironment that sustains metastatic tumour growth. Disruption of MAM recruitment or genetic depletion of granulin reduced hStC activation and liver metastasis. Interestingly, we found that circulating monocytes and hepatic MAMs in PDAC patients express high levels of granulin. These findings suggest that recruitment of granulin-expressing inflammatory monocytes plays a key role in PDAC metastasis and may serve as a potential therapeutic target for PDAC liver metastasis.

15 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.

16 Article Decreased Serum Thrombospondin-1 Levels in Pancreatic Cancer Patients Up to 24 Months Prior to Clinical Diagnosis: Association with Diabetes Mellitus. 2016

Jenkinson, Claire / Elliott, Victoria L / Evans, Anthony / Oldfield, Lucy / Jenkins, Rosalind E / O'Brien, Darragh P / Apostolidou, Sophia / Gentry-Maharaj, Aleksandra / Fourkala, Evangelia-O / Jacobs, Ian J / Menon, Usha / Cox, Trevor / Campbell, Fiona / Pereira, Stephen P / Tuveson, David A / Park, B Kevin / Greenhalf, William / Sutton, Robert / Timms, John F / Neoptolemos, John P / Costello, Eithne. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, Royal Liverpool University Hospital, UK. · MRC Centre for Drug Safety Science, Department of Pharmacology and Therapeutics, University of Liverpool, UK. · Department of Women's Cancer, Institute for Women's Health, University College London, UK. · Faculty of Medical & Human Sciences, 1.018 Core Technology Facility, University of Manchester, UK. · Department of Pathology, University of Liverpool, UK. · Institute for Liver and Digestive Health, University College London. · Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. ·Clin Cancer Res · Pubmed #26573598.

ABSTRACT: PURPOSE: Identification of serum biomarkers enabling earlier diagnosis of pancreatic ductal adenocarcinoma (PDAC) could improve outcome. Serum protein profiles in patients with preclinical disease and at diagnosis were investigated. EXPERIMENTAL DESIGN: Serum from cases up to 4 years prior to PDAC diagnosis and controls (UKCTOCS,n= 174) were studied, alongside samples from patients diagnosed with PDAC, chronic pancreatitis, benign biliary disease, type 2 diabetes mellitus, and healthy subjects (n= 298). Isobaric tags for relative and absolute quantification (iTRAQ) enabled comparisons of pooled serum from a test set (n= 150). Validation was undertaken using multiple reaction monitoring (MRM) and/or Western blotting in all 472 human samples and samples from a KPC mouse model. RESULTS: iTRAQ identified thrombospondin-1 (TSP-1) as reduced preclinically and in diagnosed samples. MRM confirmed significant reduction in levels of TSP-1 up to 24 months prior to diagnosis. A combination of TSP-1 and CA19-9 gave an AUC of 0.86, significantly outperforming both markers alone (0.69 and 0.77, respectively;P< 0.01). TSP-1 was also decreased in PDAC patients compared with healthy controls (P< 0.05) and patients with benign biliary obstruction (P< 0.01). Low levels of TSP-1 correlated with poorer survival, preclinically (P< 0.05) and at clinical diagnosis (P< 0.02). In PDAC patients, reduced TSP-1 levels were more frequently observed in those with confirmed diabetes mellitus (P< 0.01). Significantly lower levels were also observed in PDAC patients with diabetes compared with individuals with type 2 diabetes mellitus (P= 0.01). CONCLUSIONS: Circulating TSP-1 levels decrease up to 24 months prior to diagnosis of PDAC and significantly enhance the diagnostic performance of CA19-9. The influence of diabetes mellitus on biomarker behavior should be considered in future studies.

17 Article UHRF1 regulation of the Keap1-Nrf2 pathway in pancreatic cancer contributes to oncogenesis. 2016

Abu-Alainin, Wafa / Gana, Thompson / Liloglou, Triantafillos / Olayanju, Adedamola / Barrera, Lawrence N / Ferguson, Robert / Campbell, Fiona / Andrews, Timothy / Goldring, Christopher / Kitteringham, Neil / Park, Brian K / Nedjadi, Taoufik / Schmid, Michael C / Slupsky, Joseph R / Greenhalf, William / Neoptolemos, John P / Costello, Eithne. ·Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · Roy Castle Lung Cancer Research Programme, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, UK. · Department of Pharmacology and Therapeutics, University of Liverpool, UK. · Department of Pathology, Royal Liverpool University Hospital, UK. ·J Pathol · Pubmed #26497117.

ABSTRACT: The cellular defence protein Nrf2 is a mediator of oncogenesis in pancreatic ductal adenocarcinoma (PDAC) and other cancers. However, the control of Nrf2 expression and activity in cancer is not fully understood. We previously reported the absence of Keap1, a pivotal regulator of Nrf2, in ∼70% of PDAC cases. Here we describe a novel mechanism whereby the epigenetic regulator UHRF1 suppresses Keap1 protein levels. UHRF1 expression was observed in 20% (5 of 25) of benign pancreatic ducts compared to 86% (114 of 132) of pancreatic tumours, and an inverse relationship between UHRF1 and Keap1 levels in PDAC tumours (n = 124) was apparent (p = 0.002). We also provide evidence that UHRF1-mediated regulation of the Nrf2 pathway contributes to the aggressive behaviour of PDAC. Depletion of UHRF1 from PDAC cells decreased growth and enhanced apoptosis and cell cycle arrest. UHRF1 depletion also led to reduced levels of Nrf2-regulated downstream proteins and was accompanied by heightened oxidative stress, in the form of lower glutathione levels and increased reactive oxygen species. Concomitant depletion of Keap1 and UHRF1 restored Nrf2 levels and reversed cell cycle arrest and the increase in reactive oxygen species. Mechanistically, depletion of UHRF1 reduced global and tumour suppressor promoter methylation in pancreatic cancer cell lines, and KEAP1 gene promoter methylation was reduced in one of three cell lines examined. Thus, methylation of the KEAP1 gene promoter may contribute to the suppression of Keap1 protein levels by UHRF1, although our data suggest that additional mechanisms need to be explored. Finally, we demonstrate that K-Ras drives UHRF1 expression, establishing a novel link between this oncogene and Nrf2-mediated cellular protection. Since UHRF1 over-expression occurs in other cancers, its ability to regulate the Keap1-Nrf2 pathway may be critically important to the malignant behaviour of these cancers.

18 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.

19 Article Survey of UK histopathologists' approach to the reporting of resection specimens for carcinomas of the pancreatic head. 2013

Feakins, Roger / Campbell, Fiona / Verbeke, Caroline S. ·Department of Histopathology, Barts Health NHS Trust, Pathology and Pharmacy Building, Royal London Hospital, London, UK. ·J Clin Pathol · Pubmed #23580659.

ABSTRACT: To assess UK histopathologists' approach to reporting resection specimens for carcinomas of the pancreatic head. Questions were asked using an online survey service. The responses revealed considerable variation in dissection and sampling procedures, interpretation of histology, and the structure of services in the UK. Assessment of resection margins was a notable area of inconsistency. Information in guidelines and better support for some centres could help reduce the observed differences in practice.

20 Article Nrf2 is overexpressed in pancreatic cancer: implications for cell proliferation and therapy. 2011

Lister, Adam / Nedjadi, Taoufik / Kitteringham, Neil R / Campbell, Fiona / Costello, Eithne / Lloyd, Bryony / Copple, Ian M / Williams, Samantha / Owen, Andrew / Neoptolemos, John P / Goldring, Chris E / Park, B Kevin. ·MRC Centre for Drug Safety Science, Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, UK. ·Mol Cancer · Pubmed #21489257.

ABSTRACT: BACKGROUND: Nrf2 is a key transcriptional regulator of a battery of genes that facilitate phase II/III drug metabolism and defence against oxidative stress. Nrf2 is largely regulated by Keap1, which directs Nrf2 for proteasomal degradation. The Nrf2/Keap1 system is dysregulated in lung, head and neck, and breast cancers and this affects cellular proliferation and response to therapy. Here, we have investigated the integrity of the Nrf2/Keap1 system in pancreatic cancer. RESULTS: Keap1, Nrf2 and the Nrf2 target genes AKR1c1 and GCLC were detected in a panel of five pancreatic cancer cell lines. Mutation analysis of NRF2 exon 2 and KEAP1 exons 2-6 in these cell lines identified no mutations in NRF2 and only synonomous mutations in KEAP1. RNAi depletion of Nrf2 caused a decrease in the proliferation of Suit-2, MiaPaca-2 and FAMPAC cells and enhanced sensitivity to gemcitabine (Suit-2), 5-flurouracil (FAMPAC), cisplatin (Suit-2 and FAMPAC) and gamma radiation (Suit-2). The expression of Nrf2 and Keap1 was also analysed in pancreatic ductal adenocarcinomas (n = 66 and 57, respectively) and matching normal benign epithelium (n = 21 cases). Whilst no significant correlation was seen between the expression levels of Keap1 and Nrf2 in the tumors, interestingly, Nrf2 staining was significantly greater in the cytoplasm of tumors compared to benign ducts (P < 0.001). CONCLUSIONS: Expression of Nrf2 is up-regulated in pancreatic cancer cell lines and ductal adenocarcinomas. This may reflect a greater intrinsic capacity of these cells to respond to stress signals and resist chemotherapeutic interventions. Nrf2 also appears to support proliferation in certain pancreatic adenocarinomas. Therefore, strategies to pharmacologically manipulate the levels and/or activity of Nrf2 may have the potential to reduce pancreatic tumor growth, and increase sensitivity to therapeutics.

21 Article Considerations for the use of plasma cytokeratin 18 as a biomarker in pancreatic cancer. 2010

Dive, C / Smith, R A / Garner, E / Ward, T / George-Smith, S St / Campbell, F / Greenhalf, W / Ghaneh, P / Neoptolemos, J P. ·Clinical and Experimental Pharmacology Group, Paterson Institute for Cancer Research, University of Manchester, Manchester, UK. ·Br J Cancer · Pubmed #20051949.

ABSTRACT: BACKGROUND: Enzyme-linked immunoassays of full-length (M65) and/or caspase-cleaved (M30) cytokeratin 18 (CK18) released from epithelial cells undergoing necrosis and/or apoptosis, respectively, may have prognostic or predictive biomarker utility in a range of solid tumour types. Characterisation of baseline levels of circulating full length and cleaved CK18 specifically in patients with pancreatic cancer. METHODS: Plasma samples from 103 patients with pancreatic cancer stored at -80 degrees C were assayed for M65 and M30 levels. The median (inter-quartile range (IQR)) duration of plasma storage was 34 (23-57) months. Patients with metastatic disease (n=19) were found to have greater median (IQR) M65 levels (1145 (739-1698) U l(-1)) compared with the locally advanced (n=20; 748 (406-1150) U l(-1)) and resected (n=64; 612 (331-987) U l(-1)) patients (P=0.002). Elevated M65 levels were associated with poorer overall survival on univariate (P<0.001) but not multivariate (P=0.202) analysis. M65 concentrations also exhibited significant associations with concurrent serum-bilirubin levels (P<0.001) and the duration of plasma storage (P<0.001). CONCLUSIONS: Baseline plasma CK18 levels in pancreatic cancer are affected by the presence of obstructive jaundice and prolonged plasma storage. Clinical biomarker studies utilising serial CK18 levels are warranted in pancreatic cancer, provided consideration is given to these potentially confounding factors.

22 Article S100A6 binds to annexin 2 in pancreatic cancer cells and promotes pancreatic cancer cell motility. 2009

Nedjadi, T / Kitteringham, N / Campbell, F / Jenkins, R E / Park, B K / Navarro, P / Ashcroft, F / Tepikin, A / Neoptolemos, J P / Costello, E. ·Division of Surgery and Oncology, University of Liverpool, Liverpool, UK. ·Br J Cancer · Pubmed #19724273.

ABSTRACT: BACKGROUND: High levels of S100A6 have been associated with poor outcome in pancreatic cancer patients. The functional role of S100A6 is, however, poorly understood. METHODS: Immunoprecipitation followed by two-dimensional gel electrophoresis and mass spectrometry were undertaken to identify S100A6 interacting proteins in pancreatic cancer cells. Immunohistochemistry and coimmunofluorescence were performed to examine expression or colocalisation of proteins. siRNA was used to deplete specific proteins and effects on motility were measured using Boyden Chamber and wound healing assays. RESULTS: Our proteomic screen to identify S100A6 interacting proteins revealed annexin 11, annexin 2, tropomyosin beta and a candidate novel interactor lamin B1. Of these, annexin 2 was considered particularly interesting, as, like S100A6, it is expressed early in the development of pancreatic cancer and overexpression occurs with high frequency in invasive cancer. Reciprocal immunoprecipitation confirmed the interaction between annexin 2 and S100A6 and the proteins colocalised, particularly in the plasma membrane of cultured pancreatic cancer cells and primary pancreatic tumour tissue. Analysis of primary pancreatic cancer specimens (n=55) revealed a strong association between high levels of cytoplasmic S100A6 and the presence of annexin 2 in the plasma membrane of cancer cells (P=0.009). Depletion of S100A6 was accompanied by diminished levels of membrane annexin 2 and caused a pronounced reduction in the motility of pancreatic cancer cells. CONCLUSION: These findings point towards a functional role for S100A6 that may help explain the link between S100A6 expression in pancreatic cancer and aggressive disease.

23 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.

24 Article A preoperative prognostic score for resected pancreatic and periampullary neuroendocrine tumours. 2009

Sakka, Nicole / Smith, Richard A / Whelan, Philip / Ghaneh, Paula / Sutton, Robert / Raraty, Michael / Campbell, Fiona / Neoptolemos, John P. ·Division of Surgery and Oncology, School of Cancer Studies, University of Liverpool, Liverpool, UK. ·Pancreatology · Pubmed #19684431.

ABSTRACT: BACKGROUND/AIMS: To identify potential preoperative prognostic factors in resected pancreatic and periampullary neuroendocrine tumours. METHODS: Clinico-pathological data for 54 consecutive patients with pancreatic or periampullary neuroendocrine tumours referred to our institution over a 10-year period were identified from a prospective database. RESULTS: 34 patients underwent pancreatic resection (12 males, 22 females; median age 54 (IQR 44-71) years). There was a single 30-day mortality (3%). Nodal status (log rank, p = 0.652), microscopic resection margin involvement (p = 0.549) and tumour size (p = 0.122) failed to exhibit any prognostic value. Only the presence of malignant tumour characteristics was associated with poorer overall survival (p = 0.008). Analysis of preoperative parameters showed that age >60 years (p = 0.056), platelet-lymphocyte ratio >300 (p = 0.008), alkaline phosphatase levels >125 U/l (p = 0.042) and alanine aminotransferase >35 U/l (p = 0.016) were adverse prognostic factors. A risk stratification score was generated where each adverse preoperative parameter was allocated a score of 1. A cumulative score of < or =1 was defined as low risk, while a score of > or =2 was defined as high risk. Median overall survival in the high-risk group was 10.4 months, while the median survival in the low-risk group was >60 months (p < 0.001). CONCLUSION: Significant prognostic information can be gained from routine preoperative biochemistry and haematology results in resected pancreatic and periampullary neuroendocrine tumours. These findings merit further evaluation in a larger patient cohort.

25 Minor Application of Ga(68) -DOTA-exendin-4 PET/CT to localize an occult insulinoma. 2016

Cuthbertson, D J / Banks, M / Khoo, B / Antwi, K / Christ, E / Campbell, F / Raraty, M / Wild, D. ·Neuroendocrine Tumour Group, University Hospital Aintree, Liverpool, UK. daniel.cuthbertson@liverpool.ac.uk. · Neuroendocrine Tumour Group, University Hospital Aintree, Liverpool, UK. · ENETS Centre of Excellence, Royal Free London NHS Foundation Trust, London, UK. · Clinic of Radiology and Nuclear Medicine, University of Basel, Basel, Switzerland. · Division of Endocrinology, Diabetology and Clinical Nutrition, University Hospital of Bern, Bern, Switzerland. · LCL Department of Cellular Pathology, Royal Liverpool University Hospital, Liverpool, UK. · Department of Pancreatic Surgery, Royal Liverpool University Hospital, Liverpool, UK. ·Clin Endocrinol (Oxf) · Pubmed #26562613.

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