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Pancreatic Neoplasms: HELP
Articles by Daniel H. Palmer
Based on 25 articles published since 2009
(Why 25 articles?)
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Between 2009 and 2019, D. Palmer wrote the following 25 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
1 Review Chemotherapy for pancreatic cancer. 2019

Springfeld, Christoph / Jäger, Dirk / Büchler, Markus W / Strobel, Oliver / Hackert, Thilo / Palmer, Daniel H / Neoptolemos, John P. ·Heidelberg University Hospital, National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg, Germany. Electronic address: christoph.springfeld@med.uni-heidelberg.de. · Heidelberg University Hospital, National Center for Tumor Diseases, Department of Medical Oncology, Heidelberg, Germany. · Heidelberg University Hospital, Department of Surgery, Heidelberg, Germany. · University of Liverpool, Department of Molecular and Clinical Cancer Medicine, Liverpool, UK. ·Presse Med · Pubmed #30879894.

ABSTRACT: Chemotherapy is an important part of multimodality pancreatic cancer treatment. After curative resection, adjuvant chemotherapy can significantly improve disease free survival and overall survival. The current standard of care is six months adjuvant chemotherapy with modified folinic acid, 5-fluorouracil, irinotecan and oxaliplatin (mFOLFIRINOX) in patients fit enough for this protocol, otherwise six months of gemcitabine and capecitabine based on the European Study Group for Pancreatic Cancer (ESPAC)-4 study. In patients with metastatic disease, combination chemotherapy according to the FOLFIRINOX protocol or with gemcitabine plus nab-paclitaxel is an important improvement to gemcitabine monotherapy that was the standard for many years. Patients not fit for combination chemotherapy however may still benefit from gemcitabine. Patients with good performance status may benefit from second-line chemotherapy. Chemoradiation has long been used in locally advanced pancreatic cancer but is now tempered following the LAP07 study. This trial showed no difference in overall survival in those patients with stable disease after four months of gemcitabine (with or without erlotinib) randomized to either continuation of gemcitabine therapy or chemoradiation (54Gy with capecitabine). As an alternative to radiation, other forms local therapies including radiofrequency ablation, irreversible electroporation, high-intensity focused ultrasound, microwave ablation and local anti-KRAS therapy (using siG12D-LODER) are currently under investigation. Given the systemic nature of pancreas cancer from an early stage, the success of any local approach other than complete surgical resection (with adjuvant systemic therapy) is likely to be very limited. In patients with locally advanced, irresectable cancer, chemotherapy may offer the chance for secondary resection with a survival similar to patients with primary resectable disease. Downstaging regimens need to be evaluated in prospective randomized trials in order to make firm recommendations. Selection of patient groups for specific therapy including cytotoxics is becoming a reality using assays based on drug cellular transport and metabolism, and molecular signatures. Going forward, high throughput screening of different chemotherapy agents using molecular signatures based on patients' derived organoids holds considerable promise.

2 Review Therapeutic developments in pancreatic cancer: current and future perspectives. 2018

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

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

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

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

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

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

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

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

5 Clinical Trial A phase I trial of the γ-secretase inhibitor MK-0752 in combination with gemcitabine in patients with pancreatic ductal adenocarcinoma. 2018

Cook, Natalie / Basu, Bristi / Smith, Donna-Michelle / Gopinathan, Aarthi / Evans, Jeffry / Steward, William P / Palmer, Daniel / Propper, David / Venugopal, Balaji / Hategan, Mirela / Anthoney, D Alan / Hampson, Lisa V / Nebozhyn, Michael / Tuveson, David / Farmer-Hall, Hayley / Turner, Helen / McLeod, Robert / Halford, Sarah / Jodrell, Duncan. ·Cancer Research UK, Cambridge Research Institute, University of Cambridge Robinson Way, Cambridge CB2 0RE, UK. · Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0RE, UK. · Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow G12 0YN, United Kingdom. · Department of Oncology, University of Leicester, Leicester LE2 7LX, UK. · Clatterbridge Cancer Centre, Clatterbridge Road, Bebington, Wirral CH63 4JY, UK. · Bart's Cancer Institute, Queen Mary University of London EC1M 6BQ, London, UK. · Cancer Research UK, Centre for Drug Development, Angel Building, 407 St. John Street, London EC1V 4AD, UK. · St James Institute of Oncology, University of Leeds & Leeds Teaching Hospitals Trust, Leeds LS9 7TF, UK. · Department of Mathematics and Statistics, Fylde College, Lancaster University, Lancaster LA1 4YF, UK. · Merck & Co., Inc., Kenilworth, NJ 07033, USA. · Cold Spring Harbor Laboratories, Cold Spring Harbor, NY 11724, USA. ·Br J Cancer · Pubmed #29438372.

ABSTRACT: BACKGROUND: The Notch pathway is frequently activated in cancer. Pathway inhibition by γ-secretase inhibitors has been shown to be effective in pre-clinical models of pancreatic cancer, in combination with gemcitabine. METHODS: A multi-centre, non-randomised Bayesian adaptive design study of MK-0752, administered per os weekly, in combination with gemcitabine administered intravenously on days 1, 8 and 15 (28 day cycle) at 800 or 1000 mg m RESULTS: Overall, 44 eligible patients (performance status 0 or 1 with adequate organ function) received gemcitabine and MK-0752 as first or second line treatment for pancreatic cancer. RP2Ds of MK-0752 and gemcitabine as single agents could be combined safely. The Bayesian algorithm allowed further dose escalation, but pharmacokinetic analysis showed no increase in MK-0752 AUC (area under the curve) beyond 1800 mg once weekly. Tumour response evaluation was available in 19 patients; 13 achieved stable disease and 1 patient achieved a confirmed partial response. CONCLUSIONS: Gemcitabine and a γ-secretase inhibitor (MK-0752) can be combined at their full, single-agent RP2Ds.

6 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.

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

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

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

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

Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Psarelli, Eftychia E / Valle, Juan W / Halloran, Christopher M / Faluyi, Olusola / O'Reilly, Derek A / Cunningham, David / Wadsley, Jonathan / Darby, Suzanne / Meyer, Tim / Gillmore, Roopinder / Anthoney, Alan / Lind, Pehr / Glimelius, Bengt / Falk, Stephen / Izbicki, Jakob R / Middleton, Gary William / Cummins, Sebastian / Ross, Paul J / Wasan, Harpreet / McDonald, Alec / Crosby, Tom / Ma, Yuk Ting / Patel, Kinnari / Sherriff, David / Soomal, Rubin / Borg, David / Sothi, Sharmila / Hammel, Pascal / Hackert, Thilo / Jackson, Richard / Büchler, Markus W / 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.

9 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.

10 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.

11 Clinical Trial A phase Ib/IIa trial to evaluate the CCK2 receptor antagonist Z-360 in combination with gemcitabine in patients with advanced pancreatic cancer. 2010

Meyer, T / Caplin, M E / Palmer, D H / Valle, J W / Larvin, M / Waters, J S / Coxon, F / Borbath, I / Peeters, M / Nagano, E / Kato, H. ·UCL, London, UK. t.meyer@ucl.ac.uk ·Eur J Cancer · Pubmed #20006921.

ABSTRACT: AIM: To evaluate the combination of the gastrin antagonist Z-360 and gemcitabine for advanced pancreatic cancer. METHODS: Previously untreated patients with PC were randomly allocated to Z-360 120 mg, 240 mg or placebo. Z-360/placebo was given on day -3 and gemcitabine 1000 mg/m(2) commenced on day 1 followed by Z-360 on day 2. Thereafter Z-360/placebo was given twice daily concurrently with standard dose of gemcitabine. Pharmacokinetics for both drugs was measured alone and in combination. Toxicity, response and quality of life were also recorded. RESULTS: Thirty-three patients with a median age of 62 years were randomised of which six had locally advanced disease and 26 had metastatic disease. Analysis of the area under the plasma concentration versus time curve (AUC), the maximum observed concentration (Cmax(obs)) and the time of the maximum observed concentration (Tmax(obs)) for Z-360, gemcitabine and 2,2-difluorodeoxyuridine (dFdU), could not exclude an effect on the systemic exposure to Z-360, gemcitabine and dFdU when co-administration of Z-360 and gemcitabine was compared with single agent administration. The most commonly reported adverse events were nausea, abdominal pain, vomiting and fatigue. At the end of the study, 62.5%, 25% and 60% had stable disease in the 120 mg, 240 mg and placebo group, respectively. A higher proportion of patients in Z-360 groups reported improvement in pain. CONCLUSIONS: Z-360 is safe and well tolerated when combined with gemcitabine. A Phase III trial is needed to determine whether the combination of Z-360 and gemcitabine is superior to gemcitabine alone in advanced PC.

12 Article Impact of intensified chemotherapy in metastatic pancreatic ductal adenocarcinoma (PDAC) in clinical routine in Europe. 2019

Javed, Muhammad Ahsan / Beyer, Georg / Le, Nha / Vinci, Alessio / Wong, Helen / Palmer, Daniel / Morgan, Robert D / Lamarca, Angela / Hubner, Richard A / Valle, Juan W / Alam, Salma / Chowdhury, Sumsur / Ma, Yuk Ting / Archibugi, Livia / Capurso, Gabriele / Maisonneuve, Patrick / Neesse, Albrecht / Sund, Malin / Schober, Marvin / Krug, Sebastian. ·NIHR Liverpool Pancreas Biomedical Research Unit, Institute of Translational Medicine, Royal Liverpool University Hospital, United Kingdom. · Department of Medicine A, University Medicine Greifswald, Greifswald, Germany; Medical Department II, University Hospital, LMU, Munich, Germany. · Gastroenterology Division, Second Internal Medicine Department, Semmelweis University, Budapest, Hungary. · University of Pavia, Department of Surgery, S. Matteo University Hospital Foundation, Pavia, Italy. · Department of Quality and Information Intelligence, The Clatterbridge Cancer Centre NHS Foundation Trust, Wirral, United Kingdom. · Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom. · Department of Medical Oncology, The Christie NHS Foundation Trust, Manchester, United Kingdom; Institute of Cancer Sciences, University of Manchester, Manchester, United Kingdom. · Department of Hepatobiliary Oncology, New Queen Elizabeth Hospital Birmingham, Birmingham, United Kingdom. · Digestive and Liver Disease Unit, S. Andrea Hospital, University Sapienza, Rome, Italy. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · University Medical Centre Göttingen, Department of Gastroenterology and Gastrointestinal Oncology, Göttingen, Germany. · University of Umea, Department of Surgical and Perioperative Sciences, Umea, Sweden. Electronic address: malin.sund@surgery.umu.se. · Department of Gastroenterology and Hepatology, Martin-Luther-University Halle-Wittenberg, Halle, Germany. ·Pancreatology · Pubmed #30529068.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis. Gemcitabine is the standard chemotherapy for patients with metastatic pancreatic adenocarcinoma (MPA). Randomized clinical trials evaluating intensified chemotherapies including FOLFIRINOX and nab-paclitaxel plus gemcitabine (NAB+GEM) have shown improvement in survival. Here, we have evaluated the efficacy of intensified chemotherapy versus gemcitabine monotherapy in real-life settings across Europe. METHODS: A retrospective multi-center study including 1056 MPA patients, between 2012 and 2015, from nine centers in UK, Germany, Italy, Hungary and the Swedish registry was performed. Follow-up was at least 12 months. Cox proportional Harzards regression was used for uni- and multivariable evaluation of prognostic factors. RESULTS: Of 1056 MPA patients, 1030 (98.7%) were assessable for survival analysis. Gemcitabine monotherapy was the most commonly used regimen (41.3%), compared to FOLFIRINOX (n = 204, 19.3%), NAB+GEM (n = 81, 7.7%) and other gemcitabine- or 5-FU-based regimens (n = 335, 31.7%). The median overall survival (OS) was: FOLFIRINOX 9.9 months (95%CI 8.4-12.6), NAB+GEM 7.9 months (95%CI 6.2-10.0), other combinations 8.5 months (95%CI 7.7-9.3) and gemcitabine monotherapy 4.9 months (95%CI 4.4-5.6). Compared to gemcitabine monotherapy, any combination of chemotherapeutics improved the survival with no significant difference between the intensified regimens. Multivariable analysis showed an association between treatment center, male gender, inoperability at diagnosis and performance status (ECOG 1-3) with poor prognosis. CONCLUSION: Gemcitabine monotherapy was predominantly used in 2012-2015. Intensified chemotherapy improved OS in comparison to gemcitabine monotherapy. In real-life settings, the OS rates of different treatment approaches are lower than shown in randomized phase III trials.

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

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

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

14 Article 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

15 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.

16 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.

17 Article Advanced pancreatic adenocarcinoma outcomes with transition from devolved to centralised care in a regional Cancer Centre. 2017

Faluyi, Olusola O / Connor, Joanna L / Chatterjee, Madhuchanda / Ikin, Carl / Wong, Helen / Palmer, Daniel H. ·Department of Medical Oncology, Clatterbridge Cancer Centre, Bebington, Wirral CH63 4JY, UK. · Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 3BX, UK. · Clinical Effectiveness Team, Clinical Governance Department, Clatterbridge Cancer Centre, Bebington CH63 4JY, UK. ·Br J Cancer · Pubmed #28081546.

ABSTRACT: BACKGROUND: Previous observations suggest suboptimal 'real world' survival outcomes for advanced pancreatic adenocarcinoma. We hypothesized that centralisation of advanced pancreatic adenocarcinoma management would improve chemotherapy treatment and survival from the disease. METHODS: The data was prospectively collected on all cases of advanced pancreatic adenocarcinoma reviewed through Clatterbridge Cancer Centre according to two groups; 1 October 2009-31st Dec 2010 (devolved care) or 1 January 2013-31 March 2014 (centralised care). Analysis included treatment received, 30-day chemotherapy mortality rate and overall survival (OS). RESULTS: More patients received chemotherapy with central care (67.0% (n=115) vs 43.0% (n=121); P=2.2 × 10 CONCLUSIONS: A centralised clinic model for advanced pancreatic cancer management resulted in prompt, safe and higher use of chemotherapy compared with devolved care. This was associated with a modest survival benefit. Prospective studies are required to validate the findings reported and the basis for improved survival with centralised care.

18 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.

19 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.

20 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.

21 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.

22 Article Evolution in functionality of a metastatic pancreatic neuroendocrine tumour (pNET) causing Cushing's syndrome: treatment response with chemotherapy. 2014

Rajeev, Surya Panicker / McDougall, Steffan / Terlizzo, Monica / Palmer, Daniel / Daousi, Christina / Cuthbertson, Daniel J. ·Department of Obesity and Endocrinology, University Hospital Aintree, Liverpool L9 7AL, UK. daniel.cuthbertson@liverpool.ac.uk. ·BMC Endocr Disord · Pubmed #25151270.

ABSTRACT: BACKGROUND: We report the case of a patient who had a non-functional metastatic pancreatic neuroendocrine tumour (pNET), which changed in functionality during the course of the disease. This case demonstrates the effectiveness of conventional cytotoxic chemotherapy in the management of select group of patients with this rare, challenging condition. CASE PRESENTATION: Our patient was a 34 year old man under oncology follow up, diagnosed with a non-functional metastatic pancreatic neuroendocrine tumour treated with a Whipple's procedure two years ago. Despite treatment with somatostatin analogues and sunitinib, a tyrosine kinase inhibitor, he had demonstrated radiological progression of his metastatic disease. He now presented with a short history of Cushing's syndrome. A presumptive diagnosis of a rapidly progressive, metastatic, functional pNET with ectopic ACTH production was made, confirmed biochemically and with liver biopsy. The proliferative index, Ki-67 of 20% of the liver biopsy prompted us to treat him with conventional cytotoxic chemotherapy using streptozocin, 5-fluorouracil and doxorubicin. Prior to its administration clinical and biochemical control of the hypercortisolemic state was achieved with metyrapone. However the clinical, biochemical and radiological response to chemotherapy was so dramatic obviating the need for metyrapone therapy. CONCLUSIONS: Non-functional pNETs may evolve in their clinical and biologic behaviour producing functional hormonal syndromes. Chemotherapy may be an effective therapeutic modality in such circumstances.

23 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.

24 Article Peptide receptor radionuclide therapy with (90)Y-DOTATATE/(90)Y-DOTATOC in patients with progressive metastatic neuroendocrine tumours: assessment of response, survival and toxicity. 2013

Vinjamuri, S / Gilbert, T M / Banks, M / McKane, G / Maltby, P / Poston, G / Weissman, H / Palmer, D H / Vora, J / Pritchard, D M / Cuthbertson, D J. ·Department of Nuclear Medicine, Royal Liverpool University Hospital, Liverpool, UK, L7 8XP. ·Br J Cancer · Pubmed #23492685.

ABSTRACT: BACKGROUND: Peptide receptor radionuclide therapy (PRRT) is an established treatment for patients with metastatic neuroendocrine tumours (NETs), although which factors are associated with an improved overall survival (OS) remains unclear. The primary aim of this study is to determine to what extent a radiological response to (90)Y-DOTATOC/(90)Y-DOTATATE PRRT is associated with an improved OS. The association of biochemical and clinical response to OS were assessed as secondary outcome measures. METHODS: A retrospective analysis was conducted on 57 patients: radiological response was classified using RECIST criteria, biochemical response was classified using WHO criteria and clinical response was assessed subjectively. Responses were recorded as positive response (PR), stable disease (SD) or progressive disease (PD), and survival analysed. RESULTS: Radiological response was achieved in 71.5% (24.5% PR, 47% SD) and was associated with a greater OS (51 and 56 months, respectively), compared with PD (18 months). A biochemical or clinical response post PRRT were not associated with a statistically significant improvement in OS. However, when combined with radiological response a survival benefit was observed according to the number of outcomes (radiological, biochemical, clinical), in which a response was observed. Mild haematological toxicity was common, renal toxicity was rare. CONCLUSION: In patients with progressive metastatic NETs receiving (90)Y-DOTATOC/(90)Y-DOTATATE PRRT, a radiological response with either a PR or a SD post therapy confers a significant OS benefit.

25 Minor Beyond ESPAC-4: better surgery and systemic therapy. 2017

Psarelli, Eftychia E / Jackson, Richard / Neoptolemos, John P / Palmer, Daniel H / Ghaneh, Paula / Halloran, Christopher M / Büchler, Markus W. ·Liverpool Clinical and Cancer Research UK Trials Unit, University of Liverpool, Liverpool L69 3GL, UK. · Liverpool Clinical and Cancer Research UK Trials Unit, University of Liverpool, Liverpool L69 3GL, UK; Royal Liverpool University Hospital, Liverpool, UK. Electronic address: j.p.neoptolemos@liverpool.ac.uk. · Liverpool Clinical and Cancer Research UK Trials Unit, University of Liverpool, Liverpool L69 3GL, UK; Clatterbridge Cancer Centre, Wirral, UK. · Liverpool Clinical and Cancer Research UK Trials Unit, University of Liverpool, Liverpool L69 3GL, UK; Royal Liverpool University Hospital, Liverpool, UK. · Department of General, Abdominal and Transplant Surgery, University of Heidelberg, Heidelberg, Germany. ·Lancet · Pubmed #28422026.

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