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Pancreatic Neoplasms: HELP
Articles by Colin J. McKay
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, C. Mckay wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Guideline European experts consensus statement on cystic tumours of the pancreas. 2013

Del Chiaro, Marco / Verbeke, Caroline / Salvia, Roberto / Klöppel, Gunter / Werner, Jens / McKay, Colin / Friess, Helmut / Manfredi, Riccardo / Van Cutsem, Eric / Löhr, Matthias / Segersvärd, Ralf / Anonymous3160750. ·Division of Surgery, CLINTEC, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden. Electronic address: marco.del-chiaro@karolinska.se. ·Dig Liver Dis · Pubmed #23415799.

ABSTRACT: Cystic lesions of the pancreas are increasingly recognized. While some lesions show benign behaviour (serous cystic neoplasm), others have an unequivocal malignant potential (mucinous cystic neoplasm, branch- and main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm). European expert pancreatologists provide updated recommendations: diagnostic computerized tomography and/or magnetic resonance imaging are indicated in all patients with cystic lesion of the pancreas. Endoscopic ultrasound with cyst fluid analysis may be used but there is no evidence to suggest this as a routine diagnostic method. The role of pancreatoscopy remains to be established. Resection should be considered in all symptomatic lesions, in mucinous cystic neoplasm, main duct intraductal papillary mucinous neoplasm and solid pseudo-papillary neoplasm as well as in branch duct intraductal papillary mucinous neoplasm with mural nodules, dilated main pancreatic duct >6mm and possibly if rapidly increasing in size. An oncological partial resection should be performed in main duct intraductal papillary mucinous neoplasm and in lesions with a suspicion of malignancy, otherwise organ preserving procedures may be considered. Frozen section of the transection margin in intraductal papillary mucinous neoplasm is suggested. Follow up after resection is recommended for intraductal papillary mucinous neoplasm, solid pseudo-papillary neoplasm and invasive cancer.

2 Review The role of endoscopic ultrasound in the management of intraductal papillary mucinous neoplasms: a systematic update. 2016

Smith, Lyn A / McKay, Colin J. ·West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, Scotland, UK - lyn.smith@ggc.scot.nhs.uk. ·Minerva Med · Pubmed #27627636.

ABSTRACT: The widespread use of cross-sectional imaging has led to an increased frequency of incidentally detected pancreatic cysts. Neoplastic cysts such as mucinous lesions and solid pseudo-papillary neoplasms have malignant potential and therefore the early detection of these lesions presents an opportunity for prevention or early detection and management of pancreatic adenocarcinoma. Serous neoplastic lesions and non-neoplastic pancreatic cysts such as pseudocysts or walled off pancreatic necrosis and are not associated with malignant potential. It is important to identify those mucinous lesions with the highest potential of malignancy in order to direct management either towards surveillance or resection. The preoperative diagnosis of these cysts is a challenge as cross-sectional imaging alone is often inadequate at making the diagnosis. Endoscopic ultrasound (EUS) with or without fine-needle aspiration (FNA) can assess the morphology of cysts including identification of high risk characteristics of cysts as well as allowing aspiration of cyst fluid, which can be analyzed for cytology, mucin, tumor markers, amylase and molecular markers. Intraductal papillary mucinous neoplasms (IPMN) have three main subtypes; main duct IPMNs (MD-IPMN), branch duct IPMNs (BD-IPMN) and mixed type IPMNs which have feature of both the aforementioned. MD-IPMNs have the highest malignant potential and are often easier to identify on cross-sectional imaging due to the involvement of the main pancreatic duct. Current guidelines suggest that these lesions should generally be considered for resection without further evaluation. Several guidelines exist for the investigation and management of BD-IPMNs, which have a lower malignant potential and there has been much interest in more clearly defining the role of EUS and EUS-FNA in this group of patients. In this review article we discuss the role of EUS in the diagnosis, risk stratification and management of these lesions.

3 Review Investigation and management of pancreatic tumours. 2014

Smith, Lyn A / Jamieson, Nigel B / McKay, Colin J. ·Department of Gastroenterology, Glasgow Royal Infirmary, Glasgow, UK. · Department of General Surgery, Glasgow Royal Infirmary, Glasgow, UK. ·Frontline Gastroenterol · Pubmed #28839761.

ABSTRACT: Pancreatic cancer is the 10th most commonly diagnosed cancer in the UK and the fifth most common cause of cancer death. It remains one of the most aggressive cancers with over 95% of patients affected dying of their disease. Often presenting at an advanced stage of disease progression, there is currently no simple screening test available. Therefore a high clinical suspicion and prompt appropriate investigation is required from physicians when dealing with patients with symptoms in keeping with pancreatic cancer. The gastroenterology 2010 curriculum states that trainees should learn the presentation and multidisciplinary management of patients with pancreatic tumours. In this article we discuss the typical clinical presentations of common and less common pancreatic tumours followed by the investigation, staging and management required.

4 Review The role of endoscopic ultrasound in the management of intraductal papillary mucinous neoplasms. 2014

Smith, L A / Mckay, C J. ·Department of Gastroenterology West of Scotland Pancreatic Unit Glasgow Royal Infirmary, Glasgow, UK - lynsmith1@nhs.net. ·Minerva Med · Pubmed #25000220.

ABSTRACT: As the use of cross-sectional imaging increases so does the incidence of asymptomatic pancreatic cysts. Pancreatic neoplastic cysts can be broadly grouped into mucinous lesions and solid pseudopapillary neoplasms, which have malignant potential and serous lesions, which have negligible malignant potential. Non-neoplastic pancreatic cysts such as pseudocysts are not associated with malignant potential. It is important to identify those mucinous lesions with the highest potential of malignancy as identifying these lesions may allow prevention or early treatment of pancreatic carcinoma. The preoperative diagnosis of these cysts remains challenging with imaging alone often proving inadequate at making the diagnosis. Endoscopic ultrasound (EUS) can assess the morphology of cysts including identification of malignant characteristics of cysts as well as allowing aspiration of cyst fluid, which can be analysed for cytology, mucin, tumour markers, amylase and DNA analysis. Intraductal papillary mucinous neoplasms (IPMNs) can be subdivided into main duct IPMNs (MD-IPMN), branch duct IPMNs (BD-IPMN) and mixed type IPMNs which have feature of both the aforementioned. MD-IPMNs have the highest malignant potential and are often easier to identify on cross-sectional imaging due to the involvement of the main pancreatic duct. BD-IPMNs however can be difficult to distinguish from non-mucinous lesions such as pseudocysts, serous cyst adenomas and other benign cysts such as duplication cysts and in this group of lesions EUS is a valuable tool both to aid diagnosis and to identify BD-IPMNs, which should be considered for surgical resection.

5 Review Exploiting inflammation for therapeutic gain in pancreatic cancer. 2013

Steele, C W / Jamieson, N B / Evans, T R J / McKay, C J / Sansom, O J / Morton, J P / Carter, C R. ·The Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. ·Br J Cancer · Pubmed #23385734.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy associated with <5% 5-year survival, in which standard chemotherapeutics have limited benefit. The disease is associated with significant intra- and peritumoral inflammation and failure of protective immunosurveillance. Indeed, inflammatory signals are implicated in both tumour initiation and tumour progression. The major pathways regulating PDAC-associated inflammation are now being explored. Activation of leukocytes, and upregulation of cytokine and chemokine signalling pathways, both have been shown to modulate PDAC progression. Therefore, targeting inflammatory pathways may be of benefit as part of a multi-target approach to PDAC therapy. This review explores the pathways known to modulate inflammation at different stages of tumour development, drawing conclusions on their potential as therapeutic targets in PDAC.

6 Review Clinical potential of microRNAs in pancreatic ductal adenocarcinoma. 2011

Steele, Colin W / Oien, Karin A / McKay, Colin J / Jamieson, Nigel B. ·Beatson Institute for Cancer Research, Glasgow, UK. ·Pancreas · Pubmed #22001830.

ABSTRACT: OBJECTIVES: Aggressive invasion and early metastases are characteristic features of pancreatic ductal adenocarcinoma (PDAC). More than 90% of patients have surgically nonresectable disease at presentation. Despite increasing knowledge of the genetics of this complex disease, systemic therapies, particularly gemcitabine, have modest clinical benefit and marginal survival advantage. MicroRNAs have been shown to have a role in oncogenesis, invasion, and metastases via epigenetic posttranscriptional gene regulation. Our objective was to discuss the clinical impact of microRNAs within PDAC. METHODS: This review details the understanding of microRNAs to date and explores the clinical utility of microRNAs in PDAC. RESULTS: Recent studies have focused on the impact of microRNA expression in PDAC, many of which have shown the diagnostic, predictive, and prognostic utility of microRNA profiling in PDAC identifying numerous potential targets including miR-21, miR-196a, and miR-217. CONCLUSIONS: MicroRNA stability in body fluid and tissue samples makes this area one of the most promising for earlier detection of PDAC. Indeed, microRNAs may in the future serve as a long-awaited screening tool for PDAC. Furthermore, microRNA expression profiling in PDAC may be incorporated into modern treatment algorithms to enhance therapeutic management. Equally as exciting is the potential for novel therapeutics directed against these important disease mediators.

7 Review Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. 2011

Jamieson, Nigel B / Carter, C Ross / McKay, Colin J / Oien, Karin A. ·West of Scotland Pancreatic Unit and Department of Pathology, Glasgow Royal Infirmary, Alexandra Parade, Glasgow, United Kingdom. ·Clin Cancer Res · Pubmed #21444679.

ABSTRACT: PURPOSE: The management of pancreatic ductal adenocarcinoma (PDAC) continues to present a great challenge particularly with regard to prediction of outcome following pancreaticoduodenectomy. Molecular markers have been extensively investigated by numerous groups with the aim of enhancing prognostication; however, despite hundreds of studies that have sought to assess the potential prognostic value of molecular markers in predicting the clinical course following resection of PDAC, at this time, no molecular marker assay forms part of recommended clinical practice. EXPERIMENTAL DESIGN: We conducted a systematic review and meta-analysis of the published literature for immunohistochemistry-based biomarkers of PDAC outcome. A dual search strategy was applied to the PubMed database on January 6, 2010, to identify cohort studies that reported associations between immunohistochemical biomarker expression and survival outcomes in PDAC, and conformed to the REMARK (REporting recommendations for tumor MARKer prognostic studies) criteria. RESULTS: A total of 103 distinct proteins met all inclusion criteria. Promising markers that emerged for the prediction of overall survival included BAX (HR = 0.31, 95% CI: 0.71-0.56), Bcl-2 (HR = 0.41, 95% CI: 0.27-0.63), survivin (HR = 0.46, 95% CI: 0.29-0.73), Ki-67: (HR = 2.42, 95% CI: 1.87-3.14), COX-2 (HR = 1.39, 95% CI: 1.13-1.71), E-cadherin (HR = 1.80, 95% CI: 1.33-2.42), and S100 calcium-binding proteins, in particular S100A2 (HR = 3.23, 95% CI: 1.58-6.62). CONCLUSIONS: We noted that that there was incomplete adherence to the REMARK guidelines with inadequate methodology reporting as well as failure to perform multivariate analysis. Addressing the persistent incomplete adoption of these criteria may eventually result in the incorporation of molecular marker assessment within PDAC management algorithms.

8 Clinical Trial Accuracy of endoscopic ultrasound elastography used for differential diagnosis of focal pancreatic masses: a multicenter study. 2011

Săftoiu, A / Vilmann, P / Gorunescu, F / Janssen, J / Hocke, M / Larsen, M / Iglesias-Garcia, J / Arcidiacono, P / Will, U / Giovannini, M / Dietrich, C / Havre, R / Gheorghe, C / McKay, C / Gheonea, D I / Ciurea, T / Anonymous2510690. ·Gastroenterology Department, University of Medicine and Pharmacy, Craiova, Romania. adry@umfcv.ro ·Endoscopy · Pubmed #21437851.

ABSTRACT: BACKGROUND AND STUDY AIMS: Endoscopic ultrasound (EUS) elastography represents a new imaging procedure that might characterize the differences of hardness and strain between diseased tissue and normal tissue. The aim of this study was to assess the efficiency of EUS elastography for the differentiation of focal masses in chronic pancreatitis and pancreatic cancer. PATIENTS AND METHODS: The study group comprised 258 patients with focal pancreatic masses included prospectively at 13 participating centers. Qualitative analysis of the diagnoses made by two expert doctors using all recorded video clips was performed in order to test the interobserver variability. A post-processing software analysis was used to examine the EUS elastography videos by calculating average-hue histograms of individual elastography images. The quantitative information was used to calculate intra-observer variability and the accuracy of the method. RESULTS: Qualitative analysis of the recorded videos revealed a kappa value of 0.72. Intra-observer variability analysis revealed that the single measure intraclass correlation ranged between 0.86 and 0.94. The average-hue histogram analysis of the data indicated a sensitivity of 93.4 %, a specificity of 66.0 %, a positive predictive value of 92.5 %, a negative predictive value of 68.9 %, and an overall accuracy of 85.4 %, based on a cut-off value of 175. Area under the receiver operating characteristic curve (AUROC) was 0.854 ( P < 0.0001) with a confidence interval of 0.804 - 0.894. CONCLUSION: The value of quantitative analysis of EUS elastography recordings was proven by good reproducibility of the videos, as well as good parameters of the AUROC analysis. (Clinical Trials.gov identifier: CT00909103).

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

Neoptolemos, John P / Stocken, Deborah D / Bassi, Claudio / Ghaneh, Paula / Cunningham, David / Goldstein, David / Padbury, Robert / Moore, Malcolm J / Gallinger, Steven / Mariette, Christophe / Wente, Moritz N / Izbicki, Jakob R / Friess, Helmut / Lerch, Markus M / Dervenis, Christos / Oláh, Attila / Butturini, Giovanni / Doi, Ryuichiro / Lind, Pehr A / Smith, David / Valle, Juan W / Palmer, Daniel H / Buckels, John A / Thompson, Joyce / McKay, Colin J / Rawcliffe, Charlotte L / Büchler, Markus W / Anonymous10060671. ·Liverpool Cancer Research UK Cancer Trials Unit, Cancer Research UK Centre, University of Liverpool, Fifth Floor, UCD Bldg, Daulby Street, Liverpool, L69 3GA, United Kingdom. j.p.neoptolemos@liverpool.ac.uk ·JAMA · Pubmed #20823433.

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

10 Article Feasibility and clinical utility of endoscopic ultrasound guided biopsy of pancreatic cancer for next-generation molecular profiling. 2019

Dreyer, Stephan B / Jamieson, Nigel B / Evers, Lisa / Duthie, Fraser / Cooke, Susie / Marshall, John / Beraldi, Dario / Knight, Stephen / Upstill-Goddard, Rosanna / Dickson, Euan J / Carter, C Ross / McKay, Colin J / Biankin, Andrew V / Chang, David K. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · Department of Clinical Surgery, University of Edinburgh, Edinburgh, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. david.chang@glasgow.ac.uk. ·Chin Clin Oncol · Pubmed #31070037.

ABSTRACT: Next-generation sequencing is enabling molecularly guided therapy for many cancer types, yet failure rates remain relatively high in pancreatic cancer (PC). The aim of this study is to investigate the feasibility of genomic profiling using endoscopic ultrasound (EUS) biopsy samples to facilitate personalised therapy for PC. Ninty-five patients underwent additional research biopsies at the time of diagnostic EUS. Diagnostic formalin-fixed (FFPE) and fresh frozen EUS samples underwent DNA extraction, quantification and targeted gene sequencing. Whole genome (WGS) and RNA sequencing was performed as proof of concept. Only 2 patients (2%) with a diagnosis of PC had insufficient material for targeted sequencing in both FFPE and frozen specimens. Targeted panel sequencing (n=54) revealed mutations in PC genes (KRAS, GNAS, TP53, CDKN2A, SMAD4) in patients with histological evidence of PC, including potentially actionable mutations (BRCA1, BRCA2, ATM, BRAF). WGS (n=5) of EUS samples revealed mutational signatures that are potential biomarkers of therapeutic responsiveness. RNA sequencing (n=35) segregated patients into clinically relevant molecular subtypes based on transcriptome. Integrated multi-omic analysis of PC using standard EUS guided biopsies offers clinical utility to guide personalized therapy and study the molecular pathology in all patients with PC.

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

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

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

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

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

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

13 Article Defining the molecular pathology of pancreatic body and tail adenocarcinoma. 2018

Dreyer, S B / Jamieson, N B / Upstill-Goddard, R / Bailey, P J / McKay, C J / Anonymous3830933 / Biankin, A V / Chang, D K. ·West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. ·Br J Surg · Pubmed #29341146.

ABSTRACT: BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) remains a dismal disease, with very little improvement in survival over the past 50 years. Recent large-scale genomic studies have improved understanding of the genomic and transcriptomic landscape of the disease, yet very little is known about molecular heterogeneity according to tumour location in the pancreas; body and tail PDACs especially tend to have a significantly worse prognosis. The aim was to investigate the molecular differences between PDAC of the head and those of the body and tail of the pancreas. METHODS: Detailed correlative analysis of clinicopathological variables, including tumour location, genomic and transcriptomic data, was performed using the Australian Pancreatic Cancer Genome Initiative (APGI) cohort, part of the International Cancer Genome Consortium study. RESULTS: Clinicopathological data were available for 518 patients recruited to the APGI, of whom 421 underwent genomic analyses; 179 of these patients underwent whole-genome and 96 RNA sequencing. Patients with tumours of the body and tail had significantly worse survival than those with pancreatic head tumours (12·1 versus 22·0 months; P = 0·001). Location in the body and tail was associated with the squamous subtype of PDAC. Body and tail PDACs enriched for gene programmes involved in tumour invasion and epithelial-to-mesenchymal transition, as well as features of poor antitumour immune response. Whether this is due to a molecular predisposition from the outset, or reflects a later time point on the tumour molecular clock, requires further investigation using well designed prospective studies in pancreatic cancer. CONCLUSION: PDACs of the body and tail demonstrate aggressive tumour biology that may explain worse clinical outcomes.

14 Article The role of induction chemotherapy + chemoradiotherapy in localised pancreatic cancer: initial experience in Scotland. 2017

Grose, Derek / McIntosh, David / Jamieson, Nigel / Carter, Ross / Dickson, Euan / Chang, David / Marashi, Husam / Wilson, Christina / Alfayez, Mohammed / Kerr, Ashleigh / O'Donoghue, Roisin / Haskins, Lea / Duthie, Fraser / McKay, Colin J / Graham, Janet. ·Beatson West of Scotland Cancer Centre, Glasgow, UK. ·J Gastrointest Oncol · Pubmed #28890819.

ABSTRACT: BACKGROUND: Despite being relatively rare pancreatic cancer is one of the highest causes of death. Even within the potentially resectable group outcomes are poor. We present our initial experiences utilising a neoadjuvant approach to localised pancreatic cancer, evaluating survival, response rates and tolerability. METHODS: This was a retrospective analysis of a prospectively maintained database. Patients from 2012 to 2015 referred to a busy regional Hepato-Pancreatic Biliary (HPB) MDT were included. Patients were classified according to respectability criteria (utilising NCCN guidelines) and a treatment plan agreed. Systemic therapy with either FOLFIRINOX or Gem/Cap was delivered followed by chemoradiotherapy if disease remained localised. Toxicity, response, pathological outcomes and survival were all recorded. RESULTS: A total of 85 patients were included in the study: 45 had initially resectable disease; 19 required a response for resection and 21 had locally advanced inoperable disease; 34 patients underwent resection. The median survival for the potentially resectable group was 22.2 months while for those undergoing resection it was 37 months. CONCLUSIONS: We have demonstrated that a neoadjuvant approach is deliverable and tolerable. In addition we have demonstrated impressive survival results in patients undergoing resection with no detriment in outcome for those not proceeding to surgery.

15 Article Hypermutation In Pancreatic Cancer. 2017

Humphris, Jeremy L / Patch, Ann-Marie / Nones, Katia / Bailey, Peter J / Johns, Amber L / McKay, Skye / Chang, David K / Miller, David K / Pajic, Marina / Kassahn, Karin S / Quinn, Michael C J / Bruxner, Timothy J C / Christ, Angelika N / Harliwong, Ivon / Idrisoglu, Senel / Manning, Suzanne / Nourse, Craig / Nourbakhsh, Ehsan / Stone, Andrew / Wilson, Peter J / Anderson, Matthew / Fink, J Lynn / Holmes, Oliver / Kazakoff, Stephen / Leonard, Conrad / Newell, Felicity / Waddell, Nick / Wood, Scott / Mead, Ronald S / Xu, Qinying / Wu, Jianmin / Pinese, Mark / Cowley, Mark J / Jones, Marc D / Nagrial, Adnan M / Chin, Venessa T / Chantrill, Lorraine A / Mawson, Amanda / Chou, Angela / Scarlett, Christopher J / Pinho, Andreia V / Rooman, Ilse / Giry-Laterriere, Marc / Samra, Jaswinder S / Kench, James G / Merrett, Neil D / Toon, Christopher W / Epari, Krishna / Nguyen, Nam Q / Barbour, Andrew / Zeps, Nikolajs / Jamieson, Nigel B / McKay, Colin J / Carter, C Ross / Dickson, Euan J / Graham, Janet S / Duthie, Fraser / Oien, Karin / Hair, Jane / Morton, Jennifer P / Sansom, Owen J / Grützmann, Robert / Hruban, Ralph H / Maitra, Anirban / Iacobuzio-Donahue, Christine A / Schulick, Richard D / Wolfgang, Christopher L / Morgan, Richard A / Lawlor, Rita T / Rusev, Borislav / Corbo, Vincenzo / Salvia, Roberto / Cataldo, Ivana / Tortora, Giampaolo / Tempero, Margaret A / Anonymous5070887 / Hofmann, Oliver / Eshleman, James R / Pilarsky, Christian / Scarpa, Aldo / Musgrove, Elizabeth A / Gill, Anthony J / Pearson, John V / Grimmond, Sean M / Waddell, Nicola / Biankin, Andrew V. ·The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; Genetic and Molecular Pathology, Adelaide, South Australia, Australia; School of Biological Sciences, The University of Adelaide, Adelaide, South Australia, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; South Eastern Area Laboratory Services Pathology, Prince of Wales Hospital, Randwick, New South Wales, Australia; Sonic Genetics, Douglass Hanly Moir Pathology, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Macarthur Cancer Therapy Centre, Campbelltown Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Department of Anatomical Pathology, SydPath, St Vincent's Hospital, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; School of Environmental and Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · Department of Surgery, Royal North Shore Hospital, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Camperdown, New South Wales, Australia. · Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; School of Medicine, Western Sydney University, Penrith, New South Wales, Australia. · Department of Surgery, Fiona Stanley Hospital, Murdoch, Washington. · Department of Gastroenterology, Royal Adelaide Hospital, North Terrace, Adelaide, South Australia, Australia. · Department of Surgery, Princess Alexandra Hospital, Woollongabba, Queensland, Australia. · School of Surgery, University of Western Australia, Australia and St John of God Pathology, Subiaco, Washington. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde National Health Service, Glasgow, United Kingdom. · Greater Glasgow and Clyde Bio-repository, Pathology Department, Queen Elizabeth University Hospital, Glasgow, United Kingdom. · Cancer Research UK Beatson Institute, Glasgow, United Kingdom; Institute for Cancer Science, University of Glasgow, Glasgow, United Kingdom. · Universitätsklinikum Erlangen, Erlangen, Germany. · Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · Department of Surgery, The Sol Goldman Pancreatic Cancer Research Center, the Johns Hopkins University School of Medicine, Baltimore, Maryland. · ARC-NET Center for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy; Department of Pathology and Diagnostics, University of Verona, Verona, Italy. · Department of Medicine, University and Hospital Trust of Verona, Verona, Italy. · Division of Hematology and Oncology, University of California, San Francisco, California. · Australian Pancreatic Cancer Genome Initiative. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom. · Universitätsklinikum Erlangen, Department of Surgery, University of Erlangen-Nueremberg, Germany. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; St Vincent's Clinical School, Faculty of Medicine, University of New South Wales Australia, Darlinghurst, New South Wales, Australia. · The Kinghorn Cancer Centre, Darlinghurst, and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia; University of Sydney, Sydney, New South Wales, Australia; Department of Anatomical Pathology, Royal North Shore Hospital, Sydney, New South Wales, Australia. · Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia; University of Melbourne Centre for Cancer Research, The University of Melbourne, Melbourne, Victoria, Australia. · QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia; Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, Brisbane, Queensland, Australia. Electronic address: nic.waddell@qimrberghofer.edu.au. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, Scotland, United Kingdom; Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia; South Western Sydney Clinical School, Faculty of Medicine, University of New South Wales Australia, Liverpool, New South Wales, Australia; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. Electronic address: andrew.biankin@glasgow.ac.uk. ·Gastroenterology · Pubmed #27856273.

ABSTRACT: Pancreatic cancer is molecularly diverse, with few effective therapies. Increased mutation burden and defective DNA repair are associated with response to immune checkpoint inhibitors in several other cancer types. We interrogated 385 pancreatic cancer genomes to define hypermutation and its causes. Mutational signatures inferring defects in DNA repair were enriched in those with the highest mutation burdens. Mismatch repair deficiency was identified in 1% of tumors harboring different mechanisms of somatic inactivation of MLH1 and MSH2. Defining mutation load in individual pancreatic cancers and the optimal assay for patient selection may inform clinical trial design for immunotherapy in pancreatic cancer.

16 Article Investigating Various Thresholds as Immunohistochemistry Cutoffs for Observer Agreement. 2017

Ali, Asif / Bell, Sarah / Bilsland, Alan / Slavin, Jill / Lynch, Victoria / Elgoweini, Maha / Derakhshan, Mohammad H / Jamieson, Nigel B / Chang, David / Brown, Victoria / Denley, Simon / Orange, Clare / McKay, Colin / Carter, Ross / Oien, Karin A / Duthie, Fraser R. ·*Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow §Institute of Cardiovascular and Medical Sciences, University of Glasgow, Western Infirmary ¶Academic Unit of Surgery, School of Medicine, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow Royal Infirmary ‡Department of Pathology, Laboratory Medicine Building, Queen Elizabeth University Hospital, Greater Glasgow & Clyde NHS ∥West of Scotland Pancreatic Unit and Glasgow Royal Infirmary, Alexandra Parade, Glasgow #Pathology Laboratory, Forth Valley Royal Hospital, Larbert, UK †Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan. ·Appl Immunohistochem Mol Morphol · Pubmed #27093449.

ABSTRACT: BACKGROUND: Clinical translation of immunohistochemistry (IHC) biomarkers requires reliable and reproducible cutoffs or thresholds for interpretation of immunostaining. Most IHC biomarker research focuses on the clinical relevance (diagnostic, prognostic, or predictive utility) of cutoffs, with less emphasis on observer agreement using these cutoffs. From the literature, we identified 3 commonly used cutoffs of 10% positive epithelial cells, 20% positive epithelial cells, and moderate to strong staining intensity (+2/+3 hereafter) to use for investigating observer agreement. MATERIALS AND METHODS: A series of 36 images of microarray cores stained for 4 different IHC biomarkers, with variable staining intensity and percentage of positive cells, was used for investigating interobserver and intraobserver agreement. Seven pathologists scored the immunostaining in each image using the 3 cutoffs for positive and negative staining. Kappa (κ) statistic was used to assess the strength of agreement for each cutoff. RESULTS: The interobserver agreement between all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.64, 0.59, and 0.62, respectively, for 10%, 20%, and +2/+3 cutoffs. A good agreement was observed for experienced pathologists using the 10% cutoff, and their agreement was statistically higher than for junior pathologists (P=0.02). In addition, the mean intraobserver agreement for all 7 pathologists using the 3 cutoffs was reasonably good, with mean κ scores of 0.71, 0.60, and 0.73, respectively, for 10%, 20%, and +2/+3 cutoffs. For all 3 cutoffs, a positive correlation was observed with perceived ease of interpretation (P<0.003). Finally, cytoplasmic-only staining achieved higher agreement using all 3 cutoffs than mixed staining patterns. CONCLUSIONS: All 3 cutoffs investigated achieve reasonable strength of agreement, modestly decreasing interobserver and intraobserver variability in IHC interpretation. These cutoffs have previously been used in cancer pathology, and this study provides evidence that these cutoffs can be reproducible between practicing pathologists.

17 Article Prospective cohort study comparing transient EUS guided elastography to EUS-FNA for the diagnosis of solid pancreatic mass lesions. 2016

Mayerle, J / Beyer, G / Simon, P / Dickson, E J / Carter, R C / Duthie, F / Lerch, M M / McKay, C J. ·Department of Medicine A, University Medicine Greifswald, Ernst-Moritz-Arndt-University Greifswald, Germany. Electronic address: mayerle@uni-greifswald.de. · Department of Medicine A, University Medicine Greifswald, Ernst-Moritz-Arndt-University Greifswald, Germany. · Lister Department of Surgery, Glasgow Royal Infirmary, Glasgow, United Kingdom. · Department of Pathology, Southern General Hospital, Glasgow, United Kingdom. ·Pancreatology · Pubmed #26602088.

ABSTRACT: BACKGROUND: Semiquantitative EUS-elastography has been introduced to distinguish between malignant and benign pancreatic lesions. This study investigated whether semiquantitative EUS-guided transient real time elastography increases the diagnostic accuracy for solid pancreatic lesions compared to EUS-FNA. PATIENTS AND METHODS: This single centre prospective cohort study included all patients with solitary pancreatic lesions on EUS during one year. Patients underwent EUS-FNA and semiquantitative EUS-elastography during the same session. EUS and elastography results were compared with final diagnosis which was made on the basis of tissue samples and long-term outcome. RESULTS: 91 patients were recruited of which 68 had pancreatic malignancy, 17 showed benign disease and 6 had cystic lesions and were excluded from further analysis. Strain ratios from malignant lesions were significantly higher (24.00; 8.01-43.94 95% CI vs 44.00; 32.42-55.00 95% CI) and ROC analysis indicated optimal cut-off of 24.82 with resulting sensitivity, specificity and accuracy of 77%, 65% and 73% respectively. B-mode EUS and EUS-FNA had an accuracy for the correct diagnosis of malignant lesions of 87% and 85%. When lowering the cut-off strain ratio for elastography to 10 the sensitivity rose to 96% with specificity of 43% and accuracy of 84%, resulting in the least accurate EUS-based method. This was confirmed by pairwise comparison. CONCLUSION: Semiquantitative EUS-elastography does not add substantial value to the EUS-based assessment of solid pancreatic lesions when compared to B-mode imaging.

18 Article SIRT3 & SIRT7: Potential Novel Biomarkers for Determining Outcome in Pancreatic Cancer Patients. 2015

McGlynn, Liane M / McCluney, Simon / Jamieson, Nigel B / Thomson, Jackie / MacDonald, Alasdair I / Oien, Karin / Dickson, Euan J / Carter, C Ross / McKay, Colin J / Shiels, Paul G. ·Institute of Cancer Sciences, University of Glasgow, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; Academic Department of Surgery, University of Glasgow, Glasgow, United Kingdom. · Institute of Cancer Sciences, Pathology, Wolfson Building, Beatson Labs, Glasgow, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom. ·PLoS One · Pubmed #26121130.

ABSTRACT: PURPOSE: The sirtuin gene family has been linked with tumourigenesis, in both a tumour promoter and suppressor capacity. Information regarding the function of sirtuins in pancreatic cancer is sparse and equivocal. We undertook a novel study investigating SIRT1-7 protein expression in a cohort of pancreatic tumours. The aim of this study was to establish a protein expression profile for SIRT1-7 in pancreatic ductal adenocarcinomas (PDAC) and to determine if there were associations between SIRT1-7 expression, clinico-pathological parameters and patient outcome. MATERIAL AND METHODS: Immunohistochemical analysis of SIRT1-7 protein levels was undertaken in a tissue micro-array comprising 77 resected PDACs. Statistical analyses determined if SIRT1-7 protein expression was associated with clinical parameters or outcome. RESULTS: Two sirtuin family members demonstrated significant associations with clinico-pathological parameters and patient outcome. Low level SIRT3 expression in the tumour cytoplasm correlated with more aggressive tumours, and a shorter time to relapse and death, in the absence of chemotherapeutic intervention. Low levels of nuclear SIRT7 expression were also associated with an aggressive tumour phenotype and poorer outcome, as measured by disease-free and disease-specific survival time, 12 months post-diagnosis. CONCLUSIONS: Our data suggests that SIRT3 and SIRT7 possess tumour suppressor properties in the context of pancreatic cancer. SIRT3 may also represent a novel predictive biomarker to determine which patients may or may not respond to chemotherapy. This study opens up an interesting avenue of investigation to potentially identify predictive biomarkers and novel therapeutic targets for pancreatic cancer, a disease that has seen no significant improvement in survival over the past 40 years.

19 Article Targeting the LOX/hypoxia axis reverses many of the features that make pancreatic cancer deadly: inhibition of LOX abrogates metastasis and enhances drug efficacy. 2015

Miller, Bryan W / Morton, Jennifer P / Pinese, Mark / Saturno, Grazia / Jamieson, Nigel B / McGhee, Ewan / Timpson, Paul / Leach, Joshua / McGarry, Lynn / Shanks, Emma / Bailey, Peter / Chang, David / Oien, Karin / Karim, Saadia / Au, Amy / Steele, Colin / Carter, Christopher Ross / McKay, Colin / Anderson, Kurt / Evans, Thomas R Jeffry / Marais, Richard / Springer, Caroline / Biankin, Andrew / Erler, Janine T / Sansom, Owen J. ·Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK. · The Garvan Institute of Medical Research, Sydney, NSW, Australia. · Cancer Research UK Manchester Institute, Withington Manchester, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK. · Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK Institute of Cancer Sciences University of Glasgow Garscube Estate, Glasgow, UK. · Institute of Cancer Research, London, UK. · Biotech Research & Innovation Centre (BRIC), University of Copenhagen, Copenhagen (UCPH), Denmark janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk. · Cancer Research UK Beatson Institute Garscube Estate, Glasgow, UK janine.erler@bric.ku.dk o.sansom@beatson.gla.ac.uk. ·EMBO Mol Med · Pubmed #26077591.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer-related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1-Cre Kras(G12D/+) Trp53(R172H/+) (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor-free survival in KPC mice with early-stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.

20 Article IP-10/CXCL10 induction in human pancreatic cancer stroma influences lymphocytes recruitment and correlates with poor survival. 2014

Lunardi, Serena / Jamieson, Nigel B / Lim, Su Yin / Griffiths, Kristin L / Carvalho-Gaspar, Manuela / Al-Assar, Osama / Yameen, Sabira / Carter, Ross C / McKay, Colin J / Spoletini, Gabriele / D'Ugo, Stefano / Silva, Michael A / Sansom, Owen J / Janssen, Klaus-Peter / Muschel, Ruth J / Brunner, Thomas B. ·Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, United Kingdom. · Jenner Institute, University of Oxford, Old Road Campus, OX2 7BN, Oxford, United Kingdom. · Hepatobiliary and Pancreatic Surgery, Churchill Hospital, Oxford, United Kingdom. · Beatson Institute of Cancer Research, Garscube Estate, Glasgow, G61 1BD, United Kingdom. · Department of Surgery, Technische Universitaet Muenchen, 81675 Muenchen, Germany. · Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, Oxford, OX3 7DQ, United Kingdom. Department of Radiation Oncology, University Hospitals Freiburg, 79106 Freiburg, Germany. ·Oncotarget · Pubmed #25415223.

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is characterized by an abundant desmoplastic reaction driven by pancreatic stellate cells (PSCs) that contributes to tumor progression. Here we sought to characterize the interactions between pancreatic cancer cells (PCCs) and PSCs that affect the inflammatory and immune response in pancreatic tumors. Conditioned media from mono- and cocultures of PSCs and PCCs were assayed for expression of cytokines and growth factors. IP-10/CXCL10 was the most highly induced chemokine in coculture of PSCs and PCCs. Its expression was induced in the PSCs by PCCs. IP-10 was elevated in human PDAC specimens, and positively correlated with high stroma content. Furthermore, gene expression of IP-10 and its receptor CXCR3 were significantly associated with the intratumoral presence of regulatory T cells (Tregs). In an independent cohort of 48 patients with resectable pancreatic ductal adenocarcinoma, high IP-10 expression levels correlated with decreased median overall survival. Finally, IP-10 stimulated the ex vivo recruitment of CXCR3+ effector T cells as well as CXCR3+ Tregs derived from patients with PDAC. Our findings suggest that, in pancreatic cancer, CXCR3+ Tregs can be recruited by IP-10 expressed by PSCs in the tumor stroma, leading to immunosuppressive and tumor-promoting effects.

21 Article Expression of KOC, S100P, mesothelin and MUC1 in pancreatico-biliary adenocarcinomas: development and utility of a potential diagnostic immunohistochemistry panel. 2014

Ali, Asif / Brown, Victoria / Denley, Simon / Jamieson, Nigel B / Morton, Jennifer P / Nixon, Colin / Graham, Janet S / Sansom, Owen J / Carter, C Ross / McKay, Colin J / Duthie, Fraser R / Oien, Karin A. ·Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden G61 1QH, UK. · Pathology Laboratory, Forth Valley Royal Hospital, Stirling Road, Larbert FK5 4WR, UK. · West of Scotland Pancreatic Unit and Glasgow Royal Infirmary, Alexandra Parade, Glasgow G31 2ER, UK. · Beatson Institute for Cancer Research, Glasgow G61 1BD, UK. · Medical Oncology, Beatson West of Scotland Cancer Centre, Glasgow G12 0YN, UK. · Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK. · Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, College of Medical Veterinary and Life Sciences, University of Glasgow, Garscube Estate, Switchback Road, Bearsden G61 1QH, UK ; Department of Pathology, Southern General Hospital, Greater Glasgow & Clyde NHS, Glasgow G51 4TF, UK. ·BMC Clin Pathol · Pubmed #25071419.

ABSTRACT: BACKGROUND: Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens. METHODS: Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0-300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve. RESULTS: The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off. CONCLUSION: A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.

22 Article AKT regulates NPM dependent ARF localization and p53mut stability in tumors. 2014

Hamilton, Garth / Abraham, Aswin G / Morton, Jennifer / Sampson, Oliver / Pefani, Dafni E / Khoronenkova, Svetlana / Grawenda, Anna / Papaspyropoulos, Angelos / Jamieson, Nigel / McKay, Colin / Sansom, Owen / Dianov, Grigory L / O'Neill, Eric. ·Cancer Research UK/MRC Oxford Institute, Department of Oncology, University of Oxford, Old Road Campus, Roosevelt Drive, UK; These authors contributed equally to this work. · Beatson Institute for Cancer Research, Garscube Estate, Switchback Road, Glasgow, UK. · Cancer Research UK/MRC Oxford Institute, Department of Oncology, University of Oxford, Old Road Campus, Roosevelt Drive, UK. · West of Scotland Pancreatic Unit and University Department of Surgery, Glasgow Royal Infirmary, Alexandra Parade. Glasgow. ·Oncotarget · Pubmed #25071014.

ABSTRACT: Nucleophosmin (NPM) is known to regulate ARF subcellular localization and MDM2 activity in response to oncogenic stress, though the precise mechanism has remained elusive. Here we describe how NPM and ARF associate in the nucleoplasm to form a MDM2 inhibitory complex. We find that oligomerization of NPM drives nucleolar accumulation of ARF. Moreover, the formation of NPM and ARF oligomers antagonizes MDM2 association with the inhibitory complex, leading to activation of MDM2 E3-ligase activity and targeting of p53. We find that AKT phosphorylation of NPM-Ser48 prevents oligomerization that results in nucleoplasmic localization of ARF, constitutive MDM2 inhibition and stabilization of p53. We also show that ARF promotes p53 mutant stability in tumors and suppresses p73 mediated p21 expression and senescence. We demonstrate that AKT and PI3K inhibitors may be effective in treatment of therapeutically resistant tumors with elevated AKT and carrying gain of function mutations in p53. Our results show that the clinical candidate AKT inhibitor MK-2206 promotes ARF nucleolar localization, reduced p53(mut) stability and increased sensitivity to ionizing radiation in a xenograft model of pancreatic cancer. Analysis of human tumors indicates that phospho-S48-NPM may be a useful biomarker for monitoring AKT activity and in vivo efficacy of AKT inhibitor treatment. Critically, we propose that combination therapy involving PI3K-AKT inhibitors would benefit from a patient stratification rationale based on ARF and p53(mut) status.

23 Article Targeting mTOR dependency in pancreatic cancer. 2014

Morran, Douglas C / Wu, Jianmin / Jamieson, Nigel B / Mrowinska, Agata / Kalna, Gabriela / Karim, Saadia A / Au, Amy Y M / Scarlett, Christopher J / Chang, David K / Pajak, Malgorzata Z / Anonymous6310790 / Oien, Karin A / McKay, Colin J / Carter, C Ross / Gillen, Gerry / Champion, Sue / Pimlott, Sally L / Anderson, Kurt I / Evans, T R Jeffry / Grimmond, Sean M / Biankin, Andrew V / Sansom, Owen J / Morton, Jennifer P. ·CRUK Beatson Institute, Glasgow, UK. · The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. · School of Environmental & Life Sciences, University of Newcastle, Ourimbah, New South Wales, Australia. · The Kinghorn Cancer Centre and the Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, Sydney, New South Wales, Australia West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK Department of Surgery, Bankstown Hospital, Bankstown, Sydney, New South Wales, Australia Faculty of Medicine, South Western Sydney Clinical School, University of NSW, Liverpool, New South Wales, Australia The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK. · CRUK Beatson Institute, Glasgow, UK Institute of Cancer Sciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK. · West of Scotland PET Centre, Gartnavel General Hospital, Glasgow, UK. · West of Scotland Radionuclide Dispensary, NHS Greater Glasgow and Clyde, Glasgow, UK. · The Wolfson Wohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, University of Queensland, St Lucia, Brisbane, Queensland, Australia. ·Gut · Pubmed #24717934.

ABSTRACT: OBJECTIVE: Pancreatic cancer is a leading cause of cancer-related death in the Western world. Current chemotherapy regimens have modest survival benefit. Thus, novel, effective therapies are required for treatment of this disease. DESIGN: Activating KRAS mutation almost always drives pancreatic tumour initiation, however, deregulation of other potentially druggable pathways promotes tumour progression. PTEN loss leads to acceleration of Kras(G12D)-driven pancreatic ductal adenocarcinoma (PDAC) in mice and these tumours have high levels of mammalian target of rapamycin (mTOR) signalling. To test whether these KRAS PTEN pancreatic tumours show mTOR dependence, we compared response to mTOR inhibition in this model, to the response in another established model of pancreatic cancer, KRAS P53. We also assessed whether there was a subset of pancreatic cancer patients who may respond to mTOR inhibition. RESULTS: We found that tumours in KRAS PTEN mice exhibit a remarkable dependence on mTOR signalling. In these tumours, mTOR inhibition leads to proliferative arrest and even tumour regression. Further, we could measure response using clinically applicable positron emission tomography imaging. Importantly, pancreatic tumours driven by activated KRAS and mutant p53 did not respond to treatment. In human tumours, approximately 20% of cases demonstrated low PTEN expression and a gene expression signature that overlaps with murine KRAS PTEN tumours. CONCLUSIONS: KRAS PTEN tumours are uniquely responsive to mTOR inhibition. Targeted anti-mTOR therapies may offer clinical benefit in subsets of human PDAC selected based on genotype, that are dependent on mTOR signalling. Thus, the genetic signatures of human tumours could be used to direct pancreatic cancer treatment in the future.

24 Article Pre-operative cardiopulmonary exercise testing predicts adverse post-operative events and non-progression to adjuvant therapy after major pancreatic surgery. 2013

Chandrabalan, Vishnu V / McMillan, Donald C / Carter, Roger / Kinsella, John / McKay, Colin J / Carter, C Ross / Dickson, Euan J. ·Academic Department of Surgery, University of Glasgow, Glasgow, UK. · Department of Respiratory Medicine, Glasgow Royal Infirmary, Glasgow, UK. · Section of Anaesthesia, Glasgow Royal Infirmary, Glasgow, UK. · West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, UK. ·HPB (Oxford) · Pubmed #23458160.

ABSTRACT: BACKGROUND: Surgery followed by chemotherapy is the primary modality of cure for patients with resectable pancreatic cancer but is associated with significant morbidity. The aim of the present study was to evaluate the role of cardiopulmonary exercise testing (CPET) in predicting post-operative adverse events and fitness for chemotherapy after major pancreatic surgery. METHODS: Patients who underwent a pancreaticoduodenectomy or total pancreatectomy for pancreatic head lesions and had undergone pre-operative CPET were included in this retrospective study. Data on patient demographics, comorbidity and results of pre-operative evaluation were collected. Post-operative adverse events, hospital stay and receipt of adjuvant therapy were outcome measures. RESULTS: One hundred patients were included. Patients with an anaerobic threshold less than 10 ml/kg/min had a significantly greater incidence of a post-operative pancreatic fistula [International Study Group for Pancreatic Surgery (ISGPS) Grades A-C, 35.4% versus 16%, P = 0.028] and major intra-abdominal abscesses [Clavien-Dindo (CD) Grades III-V, 22.4% versus 7.8%, P = 0.042] and were less likely to receive adjuvant therapy [hazard ratio (HR) 6.30, 95% confidence interval (CI) 1.25-31.75, P = 0.026]. A low anaerobic threshold was also associated with a prolonged hospital stay (median 20 versus 14 days, P = 0.005) but not with other adverse events. DISCUSSION: CPET predicts a post-operative pancreatic fistula, major intra-abdominal abscesses as well as length of hospital stay after major pancreatic surgery. Patients with a low anaerobic threshold are less likely to receive adjuvant therapy.

25 Article Activation of the IL-6R/Jak/stat pathway is associated with a poor outcome in resected pancreatic ductal adenocarcinoma. 2013

Denley, Simon M / Jamieson, Nigel B / McCall, Pamela / Oien, Karin A / Morton, Jennifer P / Carter, C Ross / Edwards, Joanne / McKay, Colin J. ·West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, G31 2ER, UK. ·J Gastrointest Surg · Pubmed #23435739.

ABSTRACT: BACKGROUND AND OBJECTIVE: Chronic localized pancreatic inflammation in the form of chronic pancreatitis is an established risk factor for human pancreatic ductal adenocarcinoma (PDAC) development. Constitutive activation of inflammation-related signal transducer and activator of transcription (Stat)3 signaling has been implicated in the development and progression a number of malignancies, including PDAC. Although, the Janus Kinase (Jak)/Stat pathway is a potential drug target, clinicopathological, molecular, and prognostic features of Stat3-activated PDAC remain uncertain. Our aim was to determine the clinicopathological impact of this inflammatory pathway in resectable PDAC. METHODS: Using a tissue microarray-based cohort of PDAC from 86 patients undergoing pancreaticoduodenectomy with curative intent and complete clinicopathological data available, we evaluated expression of the interleukin-6 receptor (IL-6R)/Jak/Stat pathway by immunohistochemistry. IL-6R, Jak, phospho (p)-Jak, Stat3, pStat3(Tyr705), and pStat3(Ser727) were assessed in PDAC and pancreatic intraepithelial neoplasia. A Cox regression multivariate analysis model was used to determine factors influencing survival. Activation of the IL-6R/Jak/Stat3 pathway was compared with the systemic inflammatory response as measured by serum C-reactive protein levels. RESULTS: High pJak was associated with reduced overall survival in multivariate analysis when compared with those with moderate or low expression (p = 0.036; hazard ratio (HR) = 1.68) as was pStat3(Tyr705) (p < 0.001; HR = 2.66) independent of lymph node status and tumor grade. Patients with a combination of pJakhigh/pStat3(Tyr705) high expression had an especially poor prognosis (median survival of 8.8 months; 95 % CI, 4.4-13.2). While the IL-6R/Jak/Stat pathway did not correlate with serum C-reactive protein levels, high pStat3 expression was associated with a reduction in the density of the local tumoral immune response. CONCLUSION: Activation of the Jak/Stat3 pathway via phosphorylation was associated with adverse outcome following resection of PDAC with curative intent supporting potential roles for pJak and pStat3 as prognostic biomarkers markers and therapeutic targets.

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