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Pancreatic Neoplasms: HELP
Articles by William P. Steward
Based on 9 articles published since 2010
(Why 9 articles?)

Between 2010 and 2020, W. Steward wrote the following 9 articles about Pancreatic Neoplasms.
+ Citations + Abstracts
1 Guideline Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs). 2012

Ramage, John K / Ahmed, A / Ardill, J / Bax, N / Breen, D J / Caplin, M E / Corrie, P / Davar, J / Davies, A H / Lewington, V / Meyer, T / Newell-Price, J / Poston, G / Reed, N / Rockall, A / Steward, W / Thakker, R V / Toubanakis, C / Valle, J / Verbeke, C / Grossman, A B / Anonymous3020709. ·Basingstoke and North Hampshire Hospital, Aldermaston Road, Basingstoke RG24 9NA, UK. john.ramage@bnhft.nhs.uk ·Gut · Pubmed #22052063.

ABSTRACT: These guidelines update previous guidance published in 2005. They have been revised by a group who are members of the UK and Ireland Neuroendocrine Tumour Society with endorsement from the clinical committees of the British Society of Gastroenterology, the Society for Endocrinology, the Association of Surgeons of Great Britain and Ireland (and its Surgical Specialty Associations), the British Society of Gastrointestinal and Abdominal Radiology and others. The authorship represents leaders of the various groups in the UK and Ireland Neuroendocrine Tumour Society, but a large amount of work has been carried out by other specialists, many of whom attended a guidelines conference in May 2009. We have attempted to represent this work in the acknowledgements section. Over the past few years, there have been advances in the management of neuroendocrine tumours, which have included clearer characterisation, more specific and therapeutically relevant diagnosis, and improved treatments. However, there remain few randomised trials in the field and the disease is uncommon, hence all evidence must be considered weak in comparison with other more common cancers.

2 Review Pancreatic stellate cells and pancreas cancer: current perspectives and future strategies. 2014

Haqq, Jonathan / Howells, Lynne M / Garcea, Giuseppe / Metcalfe, Matthew S / Steward, Will P / Dennison, Ashley R. ·Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom. Electronic address: jh250@le.ac.uk. · Department of Hepatobiliary and Pancreatic Surgery & Cancer Studies and Molecular Medicine Group, University Hospitals of Leicester & University of Leicester, Leicester LE5 4PW, United Kingdom. ·Eur J Cancer · Pubmed #25091797.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly malignant disease with a very poor prognosis. To date patient outcomes have not improved principally due to the limited number of patients suitable for surgical resections and the radiation and chemotherapy resistance of these tumours. In the last decade, a failure of conventional therapies has forced researchers to re-examine the environment of PDAC. The tumour environment has been demonstrated to consist of an abundance of stroma containing many cells but predominantly pancreatic stellate cells (PSCs). Recent research has focused on understanding the interaction between PSCs and PDAC cells in vitro and in vivo. It is believed that the interaction between these cells is responsible for supporting tumour growth, invasion and metastasis and creating the barrier to delivery of chemotherapeutics. Novel approaches which focus on the interactions between PDAC and PSCs which sustain the tumour microenvironment may achieve significant patient benefits. This manuscript reviews the current evidence regarding PSCs, their interaction with PDAC cells and the potential implication this may have for future therapies. METHODS: A PubMed search was carried out for the terms 'pancreas cancer' OR 'pancreatic cancer', AND 'pancreatic stellate cells', NOT 'hepatic stellate cells'. All studies were screened and assessed for their eligibility and manuscripts exploring the relationship between PSCs and PDAC were included. The studies were subdivided into in vitro and in vivo groups. RESULTS: One hundred and sixty-six manuscripts were identified and reduced to seventy-three in vitro and in vivo studies for review. The manuscripts showed that PDAC cells and PSCs interact with each other to enhance proliferation, reduce apoptosis and increase migration and invasion of cancer cells. The pathways through which they facilitate these actions provide potential targets for future novel therapies. CONCLUSION: There is accumulating evidence supporting the multiple roles of PSCs in establishing the tumour microenvironment and supporting the survival of PDAC. To further validate these findings there is a need for greater use of physiologically relevant models of pancreatic cancer in vitro such as three dimensional co-cultures and the use of orthotopic and genetically engineered murine (GEM) models in vivo.

3 Review Pooled survival and response data from phase III randomized controlled trials for gemcitabine-based regimes in the treatment of advanced pancreatic cancer. 2013

Arshad, Ali / Al-Leswas, Dhya / Al-Taan, Omer / Stephenson, James / Metcalfe, Matthew / Steward, William P / Dennison, Ashley R. ·Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK. ali.arshad@doctors.org.uk ·Am J Clin Oncol · Pubmed #21436672.

ABSTRACT: Although gemcitabine remains current first-line chemotherapy for patients with advanced pancreatic cancer, median survival times have not improved significantly since its introduction 15 years ago. Of the phase III trials which have investigated alternative regimens to single-agent gemcitabine, most have used combination regimens as the investigational arm. Accurate data on median overall, progression-free survival and objective response rates is important, for two principle reasons: advising patients about their prognosis and when powering phase II trials and evaluating the results of single-armed trials. This study aims to pool results from published randomized trials to date. Twenty-one randomized phase III trials involving a total of 6348 patients were identified from 1997 to 2010. Only one trial investigating a novel agent in combination with gemcitabine showed a significantly prolonged median and progression-free survival compared with single-agent gemcitabine. Pooled median and progression-free survivals for the single-agent gemcitabine arm involving 3171 patients across all studies were 6.15 and 3.3 months, respectively. Length of survival for patients with advanced pancreatic cancer remains disappointing. Further trials of novel agents to complement or replace gemcitabine are indicated.

4 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.

5 Clinical Trial Intravenous ω-3 Fatty Acids Plus Gemcitabine. 2017

Arshad, Ali / Isherwood, John / Mann, Christopher / Cooke, Jill / Pollard, Cristina / Runau, Franscois / Morgan, Bruno / Steward, William / Metcalfe, Matthew / Dennison, Ashley. ·1 Department of Hepatobiliary and Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK. · 2 Department of Radiology, University Hospitals of Leicester, Leicester, UK. · 3 Department of Medical Oncology, University Hospitals of Leicester, Leicester, UK. ·JPEN J Parenter Enteral Nutr · Pubmed #26220200.

ABSTRACT: BACKGROUND: Marine-derived ω-3 fatty acids (ω-3FAs) have proven antitumor activity in vivo and in vitro and improve quality of life (QOL) in clinical cancer studies. These changes may be mediated by reduction in circulating proangiogenic and proinflammatory factors. In this first study of intravenous ω-3FAs as a therapy in cancer patients, we aimed to assess if it could augment the antitumor activity of gemcitabine in patients with advanced pancreatic cancer and improve QOL. MATERIALS AND METHODS: Patients were administered gemcitabine 1000 mg/m RESULTS: Fifty patients were recruited. Response rate was 14.3% and disease control rate was 85.7%. Overall and progression free survival were 5.9 and 4.8 months, respectively. Increase in global health of > 10% over baseline was seen in 47.2% of patients. More than 50% of patients had > 10% increase in QOL scores in generic symptom scores and both disease-specific domains. Grade 3/4 adverse events were thrombocytopenia (8%), neutropenia (12%), nausea or vomiting (4%), and chills (6%). CONCLUSION: Intravenous ω-3FAs in combination with gemcitabine shows evidence of improved activity and benefit to QOL in patients with advanced pancreas cancer and is worthy of investigation in a randomized phase III trial.

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

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

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

7 Clinical Trial Cellular and plasma uptake of parenteral omega-3 rich lipid emulsion fatty acids in patients with advanced pancreatic cancer. 2014

Arshad, A / Chung, W Y / Isherwood, J / Mann, C D / Al-Leswas, D / Steward, W P / Metcalfe, M S / Dennison, A R. ·Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. Electronic address: ali.arshad@doctors.org.uk. · Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Gwendolen Road, Leicester LE5 4PW, UK. · Department of Medical Oncology, University Hospitals of Leicester, Leicester, UK. ·Clin Nutr · Pubmed #24140233.

ABSTRACT: BACKGROUND & AIMS: Omega-3 rich fatty acids (n-3FA) have powerful anti-inflammatory and anti-neoplastic properties. Previous studies have investigated plasma and cellular uptake of oral and parenteral n-3FA regimens. These have shown that n-3FA undergo rapid uptake into cells which is sustained for the length of the treatment course. The aim of this study was to investigate long-term uptake of prolonged, regular treatment courses of parenteral n-3FA which has not been previously reported. METHODS: As part of a phase II single-arm trial, patients with advanced pancreatic cancer were treated with gemcitabine plus parenteral n-3FA rich lipid emulsion (up to 100 g) each week for three consecutive weeks with a subsequent rest week. This was repeated for up to six months in total for each patient. Pre-treatment serum and erythrocyte cell membrane (ECM) pellet samples were obtained each week for the entire treatment course of each patient. Post-treatment samples were obtained for the first two cycles only to assess rapid uptake. Fatty acid methyl esters (FAME) were produced and analysed using gas chromatography. FAME proportions as a total of sample lipid composition for each class were plotted and the results analysed using a linear regression coefficient model. RESULTS: There was rapid and significant uptake of EPA and DHA FAME into plasma Non-Esterified Fatty Acids (NEFA) and EPA into ECM pellets in post-treatment samples (median increase of 1.06%, 0.65% and 0.05% respectively). There was significant reduction in n-6 fatty acid FAMEs and DHA in ECM pellets (decrease of 0.31% and 0.8% respectively- p = 0.031 for all). There was significant sustained uptake of EPA and DHA FAME into ECM pellets over the cohort's pooled treatment course with corresponding reduction in the n-6:n-3 ratio. CONCLUSIONS: Prolonged regular parenteral n-3FA administration results in rapid and sustained cellular uptake. This regimen is appropriate for therapies aimed at increasing n-3FA content of cellular membranes and reduction of the n-6:n-3 ratio.

8 Clinical Trial Restoration of mannose-binding lectin complement activity is associated with improved outcome in patients with advanced pancreatic cancer treated with gemcitabine and intravenous ω-3 fish oil. 2014

Arshad, Ali / Chung, Wen / Isherwood, John / Steward, William / Metcalfe, Matthew / Dennison, Ashley. ·Department of Hepatobiliary and Pancreatic Surgery, Leicester General Hospital, Leicester, UK. ·JPEN J Parenter Enteral Nutr · Pubmed #23423329.

ABSTRACT: BACKGROUND: Pancreatic cancer has an extremely poor clinical outcome. Surrogate biomarkers for outcome are scarce. There is mixed evidence for the association of high mannose-binding lectin (MBL) complement activity with cancer outcomes, including reduced survival and increased infectious complications. ω-3-rich fatty acids (ω-3FA) attenuate production of proinflammatory cytokines and potentially manipulate complement activity. MATERIALS AND METHODS: As part of a single-arm phase II trial in a university hospital, patients with advanced pancreatic adenocarcinoma were treated with weekly ω-3FA-rich intravenous infusion (Lipidem [B. Braun Melsungen AG, Melsungen, Germany]: up to 100 g/wk) plus gemcitabine chemotherapy until withdrawal or tumor progression. Primary outcome measure was objective response rate. Changes in complement activity, which were a secondary outcome measure, were analyzed and relation to clinical outcome determined. RESULTS: Twenty-three patients were assessable for time to progression (TTP), overall survival (OS), and complement activity. No hypoactivity in alternative and classical pathways was demonstrated. Baseline MBL was low in 10 of 23 patients (43.5%). There was no difference in OS or TTP between low- and high-baseline MBL patients. Of these 10 patients, 5 were classified as MBL responders. MBL responders had a tendency toward improved OS over nonresponders (8.9 vs 4.4 months, P = .07). MBL responders had significantly improved ttp over nonresponders (10.6 VS 5.3 MONTHS, P = .03). CONCLUSION: MBL restoration had an association with improved outcome in the cohort of patients with low MBL activity at baseline. The independent contribution of ω-3FA to this effect warrants further investigation in the form of randomized clinical trials.

9 Clinical Trial Reduction in circulating pro-angiogenic and pro-inflammatory factors is related to improved outcomes in patients with advanced pancreatic cancer treated with gemcitabine and intravenous omega-3 fish oil. 2013

Arshad, Ali / Chung, Wen Y / Steward, William / Metcalfe, Matthew S / Dennison, Ashley R. ·Department of Hepatobiliary and Department of Pancreatic Surgery, University Hospitals of Leicester, Leicester, UK. ali.arshad@doctors.org.uk ·HPB (Oxford) · Pubmed #23458624.

ABSTRACT: BACKGROUND: Pancreatic cancer is a rapidly progressive disease which is often only amenable to palliative treatment. Few patients respond to palliative chemotherapy, so surrogate markers indicating which patients are likely to respond to treatment are required. There is a well-established link between pro-inflammatory circulating cytokines and growth factors (CAF), and the development of neoplasia. Agents that may modulate these factors are of interest in developing potential novel therapeutic applications. METHODS: As part of a single-arm phase II trial in patients with advanced pancreatic cancer (APC) treated with gemcitabine and intravenous (i.v.) omega-3 rich lipid emulsion (n-3FA), serum samples were analysed for 14 CAF using a multiplex cytokine array. Baseline serum concentrations were correlated with overall (OS) and progression-free survival (PFS), and changes in concentration correlated with time and outcomes for CAF responders were analysed. RESULTS: Platelet-derived growth factor (PDGF) and fibroblast growth factor (FGF) concentrations reduced significantly with treatment over time. Low baseline interleukin (IL)-6 and -8 were correlated with improved OS. PDGF responders showed a tendency towards improved OS and FGF responders a significantly improved PFS. DISCUSSION: Treatment with gemcitabine plus i.v. n-3FA may reduce concentrations of CAF which may be associated with an improved outcome. Baseline IL-6 and -8 may be surrogate markers for outcome in patients with APC treated with this regimen.