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Pancreatic Neoplasms: HELP
Articles by Stephen P. Pereira
Based on 36 articles published since 2010
(Why 36 articles?)
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Between 2010 and 2020, S. P. Pereira wrote the following 36 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Conference report: improving outcomes for gastrointestinal cancer in the UK. 2018

Forgacs, Ian / Ashton, Rachel / Allum, William / Bowley, Terry / Brown, Hilary / Coleman, Michel P / Fitzgerald, Rebecca / Glynn, Michael / Hiom, Sara / Jones, Roger / Machesney, Michael / Maher, Jane / Pereira, Stephen P / Steele, Robert / Veitch, Andrew / Wyatt, Steve. ·Kings College Hospital, London, UK. · Ashton Editorial Consulting, London, UK. · Royal Marsden NHS Foundation Trust, London, UK. · The Elmhurst Practice, London, UK. · College of Social Sciences, University of Birmingham, Birmingham, UK. · London School of Hygiene and Tropical Medicine, London, UK. · MRC Cancer Unit, University of Cambridge, Cambridge, UK. · Royal London Hospital-Barts Health NHS Trust, London, UK. · Cancer Research UK, London, UK. · Royal College of General Practitioners, London, UK. · Barts Health NHS Trust, London, UK. · Macmillan Cancer Support, London, UK. · UCL Institute for Liver and Digestive Health, London, UK. · University of Dundee and Clinical Direction of Scottish Bowel Screening Programme. · New Cross Hospital, Wolverhampton, UK. ·Frontline Gastroenterol · Pubmed #29484161.

ABSTRACT: -- No abstract --

2 Review Imaging modalities for characterising focal pancreatic lesions. 2017

Best, Lawrence Mj / Rawji, Vishal / Pereira, Stephen P / Davidson, Brian R / Gurusamy, Kurinchi Selvan. ·Department of Surgery, Royal Free Campus, UCL Medical School, Rowland Hill Street, London, UK, NW32PF. · University College London Medical School, London, UK. · UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, Upper 3rd Floor, London, UK, NW3 2PF. ·Cochrane Database Syst Rev · Pubmed #28415140.

ABSTRACT: BACKGROUND: Increasing numbers of incidental pancreatic lesions are being detected each year. Accurate characterisation of pancreatic lesions into benign, precancerous, and cancer masses is crucial in deciding whether to use treatment or surveillance. Distinguishing benign lesions from precancerous and cancerous lesions can prevent patients from undergoing unnecessary major surgery. Despite the importance of accurately classifying pancreatic lesions, there is no clear algorithm for management of focal pancreatic lesions. OBJECTIVES: To determine and compare the diagnostic accuracy of various imaging modalities in detecting cancerous and precancerous lesions in people with focal pancreatic lesions. SEARCH METHODS: We searched the CENTRAL, MEDLINE, Embase, and Science Citation Index until 19 July 2016. We searched the references of included studies to identify further studies. We did not restrict studies based on language or publication status, or whether data were collected prospectively or retrospectively. SELECTION CRITERIA: We planned to include studies reporting cross-sectional information on the index test (CT (computed tomography), MRI (magnetic resonance imaging), PET (positron emission tomography), EUS (endoscopic ultrasound), EUS elastography, and EUS-guided biopsy or FNA (fine-needle aspiration)) and reference standard (confirmation of the nature of the lesion was obtained by histopathological examination of the entire lesion by surgical excision, or histopathological examination for confirmation of precancer or cancer by biopsy and clinical follow-up of at least six months in people with negative index tests) in people with pancreatic lesions irrespective of language or publication status or whether the data were collected prospectively or retrospectively. DATA COLLECTION AND ANALYSIS: Two review authors independently searched the references to identify relevant studies and extracted the data. We planned to use the bivariate analysis to calculate the summary sensitivity and specificity with their 95% confidence intervals and the hierarchical summary receiver operating characteristic (HSROC) to compare the tests and assess heterogeneity, but used simpler models (such as univariate random-effects model and univariate fixed-effect model) for combining studies when appropriate because of the sparse data. We were unable to compare the diagnostic performance of the tests using formal statistical methods because of sparse data. MAIN RESULTS: We included 54 studies involving a total of 3,196 participants evaluating the diagnostic accuracy of various index tests. In these 54 studies, eight different target conditions were identified with different final diagnoses constituting benign, precancerous, and cancerous lesions. None of the studies was of high methodological quality. None of the comparisons in which single studies were included was of sufficiently high methodological quality to warrant highlighting of the results. For differentiation of cancerous lesions from benign or precancerous lesions, we identified only one study per index test. The second analysis, of studies differentiating cancerous versus benign lesions, provided three tests in which meta-analysis could be performed. The sensitivities and specificities for diagnosing cancer were: EUS-FNA: sensitivity 0.79 (95% confidence interval (CI) 0.07 to 1.00), specificity 1.00 (95% CI 0.91 to 1.00); EUS: sensitivity 0.95 (95% CI 0.84 to 0.99), specificity 0.53 (95% CI 0.31 to 0.74); PET: sensitivity 0.92 (95% CI 0.80 to 0.97), specificity 0.65 (95% CI 0.39 to 0.84). The third analysis, of studies differentiating precancerous or cancerous lesions from benign lesions, only provided one test (EUS-FNA) in which meta-analysis was performed. EUS-FNA had moderate sensitivity for diagnosing precancerous or cancerous lesions (sensitivity 0.73 (95% CI 0.01 to 1.00) and high specificity 0.94 (95% CI 0.15 to 1.00), the extremely wide confidence intervals reflecting the heterogeneity between the studies). The fourth analysis, of studies differentiating cancerous (invasive carcinoma) from precancerous (dysplasia) provided three tests in which meta-analysis was performed. The sensitivities and specificities for diagnosing invasive carcinoma were: CT: sensitivity 0.72 (95% CI 0.50 to 0.87), specificity 0.92 (95% CI 0.81 to 0.97); EUS: sensitivity 0.78 (95% CI 0.44 to 0.94), specificity 0.91 (95% CI 0.61 to 0.98); EUS-FNA: sensitivity 0.66 (95% CI 0.03 to 0.99), specificity 0.92 (95% CI 0.73 to 0.98). The fifth analysis, of studies differentiating cancerous (high-grade dysplasia or invasive carcinoma) versus precancerous (low- or intermediate-grade dysplasia) provided six tests in which meta-analysis was performed. The sensitivities and specificities for diagnosing cancer (high-grade dysplasia or invasive carcinoma) were: CT: sensitivity 0.87 (95% CI 0.00 to 1.00), specificity 0.96 (95% CI 0.00 to 1.00); EUS: sensitivity 0.86 (95% CI 0.74 to 0.92), specificity 0.91 (95% CI 0.83 to 0.96); EUS-FNA: sensitivity 0.47 (95% CI 0.24 to 0.70), specificity 0.91 (95% CI 0.32 to 1.00); EUS-FNA carcinoembryonic antigen 200 ng/mL: sensitivity 0.58 (95% CI 0.28 to 0.83), specificity 0.51 (95% CI 0.19 to 0.81); MRI: sensitivity 0.69 (95% CI 0.44 to 0.86), specificity 0.93 (95% CI 0.43 to 1.00); PET: sensitivity 0.90 (95% CI 0.79 to 0.96), specificity 0.94 (95% CI 0.81 to 0.99). The sixth analysis, of studies differentiating cancerous (invasive carcinoma) from precancerous (low-grade dysplasia) provided no tests in which meta-analysis was performed. The seventh analysis, of studies differentiating precancerous or cancerous (intermediate- or high-grade dysplasia or invasive carcinoma) from precancerous (low-grade dysplasia) provided two tests in which meta-analysis was performed. The sensitivity and specificity for diagnosing cancer were: CT: sensitivity 0.83 (95% CI 0.68 to 0.92), specificity 0.83 (95% CI 0.64 to 0.93) and MRI: sensitivity 0.80 (95% CI 0.58 to 0.92), specificity 0.81 (95% CI 0.53 to 0.95), respectively. The eighth analysis, of studies differentiating precancerous or cancerous (intermediate- or high-grade dysplasia or invasive carcinoma) from precancerous (low-grade dysplasia) or benign lesions provided no test in which meta-analysis was performed.There were no major alterations in the subgroup analysis of cystic pancreatic focal lesions (42 studies; 2086 participants). None of the included studies evaluated EUS elastography or sequential testing. AUTHORS' CONCLUSIONS: We were unable to arrive at any firm conclusions because of the differences in the way that study authors classified focal pancreatic lesions into cancerous, precancerous, and benign lesions; the inclusion of few studies with wide confidence intervals for each comparison; poor methodological quality in the studies; and heterogeneity in the estimates within comparisons.

3 Review Systematic review of novel ablative methods in locally advanced pancreatic cancer. 2014

Keane, Margaret G / Bramis, Konstantinos / Pereira, Stephen P / Fusai, Giuseppe K. ·Margaret G Keane, Stephen P Pereira, Institute for Liver and Digestive Health, University College London, Royal Free Campus, London NW3 2PF, United Kingdom. ·World J Gastroenterol · Pubmed #24605026.

ABSTRACT: Unresectable locally advanced pancreatic cancer with or without metastatic disease is associated with a very poor prognosis. Current standard therapy is limited to chemotherapy or chemoradiotherapy. Few regimens have been shown to have a substantial survival advantage and novel treatment strategies are urgently needed. Thermal and laser based ablative techniques are widely used in many solid organ malignancies. Initial studies in the pancreas were associated with significant morbidity and mortality, which limited widespread adoption. Modifications to the various applications, in particular combining the techniques with high quality imaging such as computed tomography and intraoperative or endoscopic ultrasound has enabled real time treatment monitoring and significant improvements in safety. We conducted a systematic review of the literature up to October 2013. Initial studies suggest that ablative therapies may confer an additional survival benefit over best supportive care but randomised studies are required to validate these findings.

4 Clinical Trial Diagnosis of pancreaticobiliary malignancy by detection of minichromosome maintenance protein 5 in biliary brush cytology. 2017

Keane, Margaret G / Huggett, Matthew T / Chapman, Michael H / Johnson, Gavin J / Webster, George J / Thorburn, Douglas / Mackay, James / Pereira, Stephen P. ·Institute for Liver and Digestive Health, University College London, Royal Free Campus, Pond St, London NW3 2PF, UK. · Department of Gastroenterology, University College London Hospitals NHS Foundation Trust, 235 Euston Road, London NW1 2BG, UK. · Department of Genetics, Evolution and Environment, University College London, Gower St, London WC1E 6BT, UK. ·Br J Cancer · Pubmed #28081547.

ABSTRACT: BACKGROUND: Biliary brush cytology is the standard method of evaluating biliary strictures, but is insensitive at detecting malignancy. In pancreaticobiliary cancer minichromosome maintenance replication proteins (MCM 2-7) are dysregulated in the biliary epithelium and MCM5 levels are elevated in bile samples. This study aimed to validate an immunocolorimetric ELISA assay for MCM5 as a pancreaticobiliary cancer biomarker in biliary brush samples. METHODS: Biliary brush specimens were collected prospectively at ERCP from patients with a biliary stricture. Collected samples were frozen at -80 °C. The supernatant was washed and lysed cells incubated with HRP-labelled anti-MCM5 mouse monoclonal antibody. Test positivity was determined by optical density absorbance. Patients underwent biliary brush cytology or additional investigations as per clinical routine. RESULTS: Ninety-seven patients were included in the study; 50 had malignant strictures. Median age was 65 years (range 21-94) and 51 were male. Compared with final diagnosis the MCM5 assay had a sensitivity for malignancy of 65.4% compared with 25.0% for cytology. In the 72 patients with paired MCM5 assay and biliary brush cytology, MCM5 demonstrated an improved sensitivity (55.6% vs 25.0%; P=0.0002) for the detection of malignancy. CONCLUSIONS: Minichromosome maintenance replication protein5 is a more sensitive indicator of pancreaticobiliary malignancy than standard biliary brush cytology.

5 Clinical Trial Phase I/II study of verteporfin photodynamic therapy in locally advanced pancreatic cancer. 2014

Huggett, M T / Jermyn, M / Gillams, A / Illing, R / Mosse, S / Novelli, M / Kent, E / Bown, S G / Hasan, T / Pogue, B W / Pereira, S P. ·UCL Institute for Liver and Digestive Health, University College London, UCL Medical School-Royal Free Hospital Campus, U3 Floor, Pond Street, London NW3 2QG, UK. · Thayer School of Engineering, Dartmouth College, Hanover, NH 03755, USA. · Department of Radiology, University College Hospital, London, UK. · National Medical Laser Centre, University College London, London, UK. · Department of Pathology, University College Hospital, London, UK. · UCLH Cancer Clinical Trials Unit, University College Hospital, London, UK. · Wellman Center for Photomedicine, Massachusetts General Hospital, Boston, MA 02114, USA. ·Br J Cancer · Pubmed #24569464.

ABSTRACT: BACKGROUND: Patients with pancreatic cancer have a poor prognosis apart from the few suitable for surgery. Photodynamic therapy (PDT) produces localised tissue necrosis but previous studies using the photosensitiser meso-tetrahydroxyphenylchlorin (mTHPC) caused prolonged skin photosensitivity. This study assessed a shorter acting photosensitiser, verteporfin. METHODS: Fifteen inoperable patients with locally advanced cancers were sensitised with 0.4 mg kg(-1) verteporfin. After 60-90 min, laser light (690 nm) was delivered via single (13 patients) or multiple (2 patients) fibres positioned percutaneously under computed tomography (CT) guidance, the light dose escalating (initially 5 J, doubling after each three patients) until 12 mm of necrosis was achieved consistently. RESULTS: In all, 12 mm lesions were seen consistently at 40 J, but with considerable variation in necrosis volume (mean volume 3.5 cm(3) at 40 J). Minor, self-limiting extrapancreatic effects were seen in multifibre patients. No adverse interactions were seen in patients given chemotherapy or radiotherapy before or after PDT. After PDT, one patient underwent an R0 Whipple's pancreaticoduodenectomy. CONCLUSIONS: Verteporfin PDT-induced tumour necrosis in locally advanced pancreatic cancer is feasible and safe. It can be delivered with a much shorter drug light interval and with less photosensitivity than with older compounds.

6 Clinical Trial Endoscopic retrograde pancreatography criteria to diagnose autoimmune pancreatitis: an international multicentre study. 2011

Sugumar, Aravind / Levy, Michael J / Kamisawa, Terumi / Webster, G J / Kim, Myung-Hwan / Enders, Felicity / Amin, Zahir / Baron, Todd H / Chapman, Mike H / Church, Nicholas I / Clain, Jonathan E / Egawa, Naoto / Johnson, Gavin J / Okazaki, Kazuichi / Pearson, Randall K / Pereira, Stephen P / Petersen, Bret T / Read, Samantha / Sah, Raghuwansh P / Sandanayake, Neomal S / Takahashi, Naoki / Topazian, Mark D / Uchida, Kazushige / Vege, Santhi Swaroop / Chari, Suresh T. ·Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MN 55905, USA. ·Gut · Pubmed #21131631.

ABSTRACT: BACKGROUND: Characteristic pancreatic duct changes on endoscopic retrograde pancreatography (ERP) have been described in autoimmune pancreatitis (AIP). The performance characteristics of ERP to diagnose AIP were determined. METHODS: The study was done in two phases. In phase I, 21 physicians from four centres in Asia, Europe and the USA, unaware of the clinical data or diagnoses, reviewed 40 preselected ERPs of patients with AIP (n=20), chronic pancreatitis (n=10) and pancreatic cancer (n=10). Physicians noted the presence or absence of key pancreatographic features and ranked the diagnostic possibilities. For phase II, a teaching module was created based on features found most useful in the diagnosis of AIP by the four best performing physicians in phase I. After a washout period of 3 months, all physicians reviewed the teaching module and reanalysed the same set of ERPs, unaware of their performance in phase I. RESULTS: In phase I the sensitivity, specificity and interobserver agreement of ERP alone to diagnose AIP were 44, 92 and 0.23, respectively. The four key features of AIP identified in phase I were (i) long (>1/3 the length of the pancreatic duct) stricture; (ii) lack of upstream dilatation from the stricture (<5 mm); (iii) multiple strictures; and (iv) side branches arising from a strictured segment. In phase II the sensitivity (71%) of ERP significantly improved (p<0.05) without a significant decline in specificity (83%) (p>0.05); the interobserver agreement was fair (0.40). CONCLUSIONS: The ability to diagnose AIP based on ERP features alone is limited but can be improved with knowledge of some key features.

7 Article Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer. 2019

Mohammad, Goran Hamid / Vassileva, Vessela / Acedo, Pilar / Olde Damink, Steven W M / Malago, Massimo / Dhar, Dipok Kumar / Pereira, Stephen P. ·Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London NW3 2QG, UK. · Komar Research Center, Komar University of Science and Technology, Sulaimani 46001, Iraq. · Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College London, London W12 0UQ, UK. · Department of Surgery, Maastricht University Medical Center & Nutrim School for Nutrition, Toxicology and Metabolism, Maastricht University, 6200 MD Maastricht, The Netherlands. · Hepato-pancreatic-biliary and Liver Transplantation Surgery, Royal Free Hospital Campus, University College London, London NW3 2QG, UK. · King Faisal Specialist Hospital and Research Center, Comparative Medicine Department and Organ Transplantation Center, Riyadh 11211, Saudi Arabia. · Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London NW3 2QG, UK. stephen.pereira@ucl.ac.uk. ·Cancers (Basel) · Pubmed #31527446.

ABSTRACT: Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.

8 Article Changes in tumor vascularity depicted by contrast-enhanced EUS as a predictor of prognosis and treatment efficacy in patients with unresectable pancreatic cancer (PEACE): A study protocol. 2019

Sãftoiu, Adrian / Bhutani, Manoop S / Itoi, Takao / Arcidiacono, Paolo G / Bories, Erwan / Cazacu, Irina M / Constantin, Alina / Coronel, Emmanuel / Dietrich, Christoph F / Duda, Dan G / Garcia, Julio Iglesias / Hocke, Michael / Ignee, Andre / Jenssen, Christian / Jinga, Mariana / Khor, Christopher / Oppong, Kofi W / Pereira, Stephen / Petrone, Maria Chiara / Santo, Erwin / Seicean, Andrada / Seo, Dong Wan / Siyu, Sun / Vilmann, Peter / Waxman, Irving / Yeaton, Paul. ·Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, Craiova, Romania. · Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, Texas, USA. · Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan. · Pancreato-Biliary Endoscopy and Endosonography Division, San Raffaele Scientific Institute, Vita Salute San Raffaele University Milan, Milan, Italy. · Endoscopy Unit, Paoli Calmettes Institute, Marseille, France. · Research Center of Gastroenterology and Hepatology Craiova, University of Medicine and Pharmacy Craiova, Craiova, Romania; Department of Gastroenterology, Hepatology and Nutrition, MD Anderson Cancer Center, Houston, Texas, USA, USA. · Department of Gastroenterology, Ponderas Academic Hospital, Bucharest, Romania. · Medical Department, Caritas-Krankenhaus, Uhlandstr 7, D-97980 Bad Mergentheim, Germany. · Department of Radiation Oncology, Harvard Medical School, Massachusetts General Hospital, Boston, Massachusetts, USA. · Department of Gastroenterology and Hepatology, University Hospital of Santiago de Compostella, Santiago, Spain. · Department of Gastroenterology, Helios Kliniken Meiningen, Meiningen, Germany. · Department of Internal Medicine, Krankenhaus Maerkisch-Oderland, D-15344 Strausberg and Brandenburg Institute of Clinical Ultrasound at Medical University Brandenburg, Germany. · Department of Gastroenterology, Central Clinical Emergency Military Hospital Dr. Carol Davila, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania. · Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore. · HPB Unit, Freeman Hospital, Newcastle upon Tyne, London, UK. · University College London Institute for Liver and Digestive Health, Royal Free Hospital Campus, London, UK. · Tel Aviv Souraski Medical Center, Invasive Endoscopy Unit, Gastroenterology Institute, Tel Aviv, Israel. · Regional Institute of Gastroenterology and Hepatology, University of Medicine and Pharmacy "Iuliu Hațieganu," Cluj-Napoca, Romania. · Asan Medical Center, Seoul, South Korea. · Endoscopy Center, Liaoning Engineering Technology Research Center of Diagnosis and Treatment of Digestive Endoscopy, Shengjing Hospital of China Medical University, Shenyang, China. · Gastrointestinal Unit, Copenhagen University Hospital Herlev, Herlev, Denmark. · Center for Endoscopic Research and Therapeutics, University of Chicago Medicine and Biological Sciences, Chicago, IL, USA. · Carilion Clinic Roanoke, Roanoke, USA. ·Endosc Ultrasound · Pubmed #31249159.

ABSTRACT: Patients with unresectable pancreatic cancer have a poor prognosis. The analysis of prognostic factors before treatment may be helpful in determining the best therapeutic strategies. The aim of the PEACE study is to assess the vascularity of pancreatic malignant tumors using contrast-enhanced harmonic EUS (CEH-EUS) and to clarify the prognostic value of tumor vascularity in patients with locally advanced and metastatic pancreatic cancer. Hereby, we present the protocol of a prospective, nonrandomized, single-arm, multicenter study aiming to assess changes in tumor vascularity using CEH-EUS before and 2 months after treatment initiation in patients with unresectable, locally advanced/metastatic pancreatic cancer and to examine the correlation between vascular changes and treatment response, progression-free survival, and overall survival.

9 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.

10 Article Determination of optimal ultrasound planes for the initialisation of image registration during endoscopic ultrasound-guided procedures. 2018

Bonmati, Ester / Hu, Yipeng / Gibson, Eli / Uribarri, Laura / Keane, Geri / Gurusami, Kurinchi / Davidson, Brian / Pereira, Stephen P / Clarkson, Matthew J / Barratt, Dean C. ·UCL Centre for Medical Image Computing, University College London, London, UK. e.bonmati@ucl.ac.uk. · Wellcome/EPSRC Centre for Interventional and Surgical Science, University College London, London, UK. e.bonmati@ucl.ac.uk. · UCL Centre for Medical Image Computing, University College London, London, UK. · Wellcome/EPSRC Centre for Interventional and Surgical Science, University College London, London, UK. · Institute for Liver and Digestive Health, University College London, London, UK. · Division of Surgery and Interventional Science, University College London, London, UK. ·Int J Comput Assist Radiol Surg · Pubmed #29663274.

ABSTRACT: PURPOSE: Navigation of endoscopic ultrasound (EUS)-guided procedures of the upper gastrointestinal (GI) system can be technically challenging due to the small fields-of-view of ultrasound and optical devices, as well as the anatomical variability and limited number of orienting landmarks during navigation. Co-registration of an EUS device and a pre-procedure 3D image can enhance the ability to navigate. However, the fidelity of this contextual information depends on the accuracy of registration. The purpose of this study was to develop and test the feasibility of a simulation-based planning method for pre-selecting patient-specific EUS-visible anatomical landmark locations to maximise the accuracy and robustness of a feature-based multimodality registration method. METHODS: A registration approach was adopted in which landmarks are registered to anatomical structures segmented from the pre-procedure volume. The predicted target registration errors (TREs) of EUS-CT registration were estimated using simulated visible anatomical landmarks and a Monte Carlo simulation of landmark localisation error. The optimal planes were selected based on the 90th percentile of TREs, which provide a robust and more accurate EUS-CT registration initialisation. The method was evaluated by comparing the accuracy and robustness of registrations initialised using optimised planes versus non-optimised planes using manually segmented CT images and simulated ([Formula: see text]) or retrospective clinical ([Formula: see text]) EUS landmarks. RESULTS: The results show a lower 90th percentile TRE when registration is initialised using the optimised planes compared with a non-optimised initialisation approach (p value [Formula: see text]). CONCLUSIONS: The proposed simulation-based method to find optimised EUS planes and landmarks for EUS-guided procedures may have the potential to improve registration accuracy. Further work will investigate applying the technique in a clinical setting.

11 Article Risk of malignancy in resected pancreatic mucinous cystic neoplasms. 2018

Keane, M G / Shamali, A / Nilsson, L N / Antila, A / Millastre Bocos, J / Marijinissen Van Zanten, M / Verdejo Gil, C / Maisonneuve, P / Vaalavuo, Y / Hoskins, T / Robinson, S / Ceyhan, G O / Abu Hilal, M / Pereira, S P / Laukkarinen, J / Del Chiaro, M. ·Institute for Liver and Digestive Health, University College London, London. · Department of Surgery, Southampton University Hospital, Southampton, UK. · Department of Surgery, Karolinska University Hospital, Stockholm, Sweden. · Department of Gastroenterology and Alimentary Tract Surgery, Tampere University Hospital, Tampere, Finland. · Department of Gastroenterology, Miguel Servet University Hospital, Zaragoza, Spain. · Department of Pathology, Nijmegen University Hospital, Nijmegen, The Netherlands. · Department of Gastroenterology, Ciudad Real University Hospital, Ciudad Real, Spain. · European Institute of Oncology, Milan, Italy. · Department of Hepato-Pancreato-Biliary Surgery, Freeman Hospital, Newcastle upon Tyne, UK. · Surgical Clinic, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany. ·Br J Surg · Pubmed #29488646.

ABSTRACT: BACKGROUND: Pancreatic mucinous cystic neoplasms (MCNs) are rare mucin-producing cystic tumours defined by the presence of ovarian-type stroma. MCNs have a malignant potential and thus surgery is frequently performed. The aim of this cohort study was to define better the criteria for surgical resection in patients with MCN. METHODS: This multicentre retrospective study included all resected MCNs between 2003 and 2015 in participating centres. Lesions without ovarian-type stroma were excluded. Patient characteristics, preoperative findings, histopathology findings and follow-up data were recorded. RESULTS: The study included 211 patients; their median age was 53 (range 18-82) years, and 202 (95·7 per cent) were women. Median preoperative tumour size was 55 (range 12-230) mm. Thirty-four of the 211 (16·1 per cent) were malignant, and high-grade dysplasia (HGD) was found in a further 13 (6·2 per cent). One-third of MCNs in men were associated with invasive cancer, compared with 15·3 per cent in women. Five cases of malignant transformation occurred in MCNs smaller than 4 cm. All cases of malignancy or HGD were associated with symptoms or features of concern on preoperative cross-sectional imaging. In multivariable analysis, raised carbohydrate antigen 19-9 (odds ratio (OR) 10·54, 95 per cent c.i. 2·85 to 218·23; P < 0·001), tumour size (OR 4·23, 3·02 to 11·03; P = 0·001), mural nodules (OR 3·55, 1·31 to 20·55; P = 0·002) and weight loss (OR 3·40, 2·34 to 12·34; P = 0·034) were independent factors predictive of malignant transformation. CONCLUSIONS: Small indeterminate MCNs with no symptoms or features of concern may safely be observed as they have a low risk of malignant transformation.

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 Agreement among Magnetic Resonance Imaging/Magnetic Resonance Cholangiopancreatography (MRI-MRCP) and Endoscopic Ultrasound (EUS) in the evaluation of morphological features of Branch Duct Intraductal Papillary Mucinous Neoplasm (BD-IPMN). 2018

Uribarri-Gonzalez, Laura / Keane, Margaret G / Pereira, Stephen P / Iglesias-García, Julio / Dominguez-Muñoz, J Enrique / Lariño-Noia, Jose. ·Gastroenterology Department, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: luribarrigonzalez@gmail.com. · Gastroenterology Department, University College London Hospital NHS Foundation Trust and the Royal Free Hospital NHS Foundation Trust, London, UK. Electronic address: geri.keane.09@ucl.ac.uk. · Gastroenterology Department, University College London Hospital NHS Foundation Trust and the Royal Free Hospital NHS Foundation Trust, London, UK. Electronic address: stephen.pereira@ucl.ac.uk. · Gastroenterology Department, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: julioiglesiasgarcia@gmail.com. · Gastroenterology Department, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: enriquedominguezmunoz@hotmail.com. · Gastroenterology Department, Complejo Hospitalario Universitario de Santiago de Compostela, Santiago de Compostela, Spain. Electronic address: joselarnoi@outlook.es. ·Pancreatology · Pubmed #29338919.

ABSTRACT: BACKGROUND/OBJECTIVES: To evaluate the agreement between the imaging modalities MRI-MRCP and EUS in cystic lesions of the pancreas which were thought to be a BD-IPMN. METHODS: Multicenter retrospective study included all patients between 2010 and 2015 with a suspected BD-IPMN who underwent an EUS and MRI-MRCP within 6 months or less of each other. Location, number, size, worrisome features and high-risk stigmata were evaluated. Interobserver agreement was evaluated by Kappa score. RESULTS: 173 patients were included (97 UHSC, 76 UCLH-RFH), mean age 65 (range 25-87 years), 66 males. When comparing both modalities there was good agreement for the location of the cyst. The median lesion size was larger by MRI-MRCP than EUS although it was not significant. With regards to worrisome features, there was moderate agreement for main PD of 5-9 mm and abrupt change (k = 0.45 and 0.52). Fair agreement was seen for the cyst wall thickening (k = 0.25). No agreement was seen between the presence of non-enhanced mural nodules or lymphadenopathy (k < 0). With regards to high-risk stigmata, poor agreement was obtained for the detection of an enhanced solid component (k = 0.12). No agreement was observed for main PD > 10 mm (k < 0). CONCLUSIONS: In this multicentre study of patients with a BD-IPMN under active surveillance, most disagreement between these modalities was seen in the proximal pancreas. There was generally only minimal concordance between the imaging findings of EUS and MRI-MRCP for the detection of high-risk stigmata and worrisome features.

14 Article Photodynamic Priming Mitigates Chemotherapeutic Selection Pressures and Improves Drug Delivery. 2018

Huang, Huang-Chiao / Rizvi, Imran / Liu, Joyce / Anbil, Sriram / Kalra, Ashish / Lee, Helen / Baglo, Yan / Paz, Nancy / Hayden, Douglas / Pereira, Steve / Pogue, Brian W / Fitzgerald, Jonathan / Hasan, Tayyaba. ·Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. · Department of Dermatology, Massachusetts General Hospital, Boston, Massachusetts. · The University of Texas School of Medicine at San Antonio, San Antonio, Texas. · Merrimack Pharmaceuticals, Inc., Cambridge, Massachusetts. · MGH Biostatistics Center, Massachusetts General Hospital, Boston, Massachusetts. · UCL Institute for Liver and Digestive Health, University College London, London, United Kingdom. · Thayer School of Engineering, Dartmouth College, Hanover, New Hampshire. · Wellman Center for Photomedicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts. thasan@mgh.harvard.edu. · Division of Health Sciences and Technology, Harvard University and Massachusetts Institute of Technology, Cambridge, Massachusetts. ·Cancer Res · Pubmed #29187403.

ABSTRACT: Physiologic barriers to drug delivery and selection for drug resistance limit survival outcomes in cancer patients. In this study, we present preclinical evidence that a subtumoricidal photodynamic priming (PDP) strategy can relieve drug delivery barriers in the tumor microenvironment to safely widen the therapeutic window of a nanoformulated cytotoxic drug. In orthotopic xenograft models of pancreatic cancer, combining PDP with nanoliposomal irinotecan (nal-IRI) prevented tumor relapse, reduced metastasis, and increased both progression-free survival and 1-year disease-free survival. PDP enabled these durable improvements by targeting multiple tumor compartments to (i) increase intratumoral drug accumulation by >10-fold, (ii) increase the duration of drug exposure above a critical therapeutic threshold, and (iii) attenuate surges in CD44 and CXCR4 expression, which mediate chemoresistance often observed after multicycle chemotherapy. Overall, our results offer preclinical proof of concept for the effectiveness of PDP to minimize risks of tumor relapse, progression, and drug resistance and to extend patient survival.

15 Article Evidence of Altered Glycosylation of Serum Proteins Prior to Pancreatic Cancer Diagnosis. 2017

Krishnan, Shibu / Whitwell, Harry J / Cuenco, Joy / Gentry-Maharaj, Aleksandra / Menon, Usha / Pereira, Stephen P / Gaspari, Marco / Timms, John F. ·Research Center for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, University of Catanzaro 'Magna Graecia', 88100 Catanzaro, Italy. shibu.krishnan@farmaci.uu.se. · Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK. h.whitwell@imperial.ac.uk. · Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK. joy.cuenco@gmail.com. · Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK. a.gentry-maharaj@ucl.ac.uk. · Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK. u.menon@ucl.ac.uk. · Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London NW3 2QG, UK. stephen.pereira@ucl.ac.uk. · Research Center for Advanced Biochemistry and Molecular Biology, Department of Experimental and Clinical Medicine, University of Catanzaro 'Magna Graecia', 88100 Catanzaro, Italy. marco.gaspari1@gmail.com. · Institute for Women's Health, University College London, Gower Street, London WC1E 6BT, UK. john.timms@ucl.ac.uk. ·Int J Mol Sci · Pubmed #29232830.

ABSTRACT: Biomarkers for the early detection of pancreatic cancer are urgently needed. The aim of this pilot study was to evaluate changes in serum

16 Article None 2017

Chen, Yuan / Xue, Shao-An / Behboudi, Shahriar / Mohammad, Goran H / Pereira, Stephen P / Morris, Emma C. ·Institute of Immunity and Transplantation, University College London, London, United Kingdom. · Genetic Engineering Laboratory, School of Biological and Environmental Engineering, Xi'An University, Xi'An, P. R. China. · The Pirbright Institute, Woking, Pirbright, United Kingdom. · Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, United Kingdom. · Chemistry Department, College of Science, University of Sulaimani, Sulaimanyah, Kurdistan Region, Iraq. · Institute for Liver and Digestive Health, University College London, London, United Kingdom. · Institute of Immunity and Transplantation, University College London, London, United Kingdom. e.morris@ucl.ac.uk. ·Clin Cancer Res · Pubmed #28710313.

ABSTRACT:

17 Article Separation of Solid Stress From Interstitial Fluid Pressure in Pancreas Cancer Correlates With Collagen Area Fraction. 2017

Nieskoski, Michael D / Marra, Kayla / Gunn, Jason R / Kanick, Stephen C / Doyley, Marvin M / Hasan, Tayyaba / Pereira, Stephen P / Stuart Trembly, B / Pogue, Brian W. ·Thayer School of Engineering, Dartmouth College, Hanover, NH 03755. · Thayer School of Engineering, Dartmouth College, Hanover, NH 03755;Department of Electrical and Computer Engineering, University of Rochester, Rochester, NY 14627. · Wellman Center for Photomedicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114. · Institute for Liver and Digestive Health, University College London, London NW3 2QG, UK. · Thayer School of Engineering, Dartmouth College, Hanover, NH 03755 e-mail: Brian.W.Pogue@Dartmouth.edu. ·J Biomech Eng · Pubmed #28388715.

ABSTRACT: Elevated total tissue pressure (TTP) in pancreatic adenocarcinoma is often associated with stress applied by cellular proliferation and hydrated hyaluronic acid osmotic swelling; however, the causal roles of collagen in total tissue pressure have yet to be clearly measured. This study illustrates one direct correlation between total tissue pressure and increased deposition of collagen within the tissue matrix. This observation comes from a new modification to a conventional piezoelectric pressure catheter, used to independently separate and quantify total tissue pressure, solid stress (SS), and interstitial fluid pressure (IFP) within the same tumor location, thereby clarifying the relationship between these parameters. Additionally, total tissue pressure shows a direct correlation with verteporfin uptake, demonstrating the impediment of systemically delivered molecules with increased tissue hypertension.

18 Article Successful management of a sporadic pancreatic insulinoma by endoscopic ultrasound-guided radiofrequency ablation. 2016

Waung, Julian A / Todd, Jeannie F / Keane, Margaret G / Pereira, Stephen P. ·Imperial Centre for Endocrinology, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, UK. · UCL Institute for Liver and Digestive Health, University College London, London, UK. ·Endoscopy · Pubmed #27081874.

ABSTRACT: -- No abstract --

19 Article Pyruvate Kinase M2 and Lactate Dehydrogenase A Are Overexpressed in Pancreatic Cancer and Correlate with Poor Outcome. 2016

Mohammad, Goran Hamid / Olde Damink, S W M / Malago, Massimo / Dhar, Dipok Kumar / Pereira, Stephen P. ·UCL Institute for Liver and Digestive Health, Royal Free Hospital Campus, University College London, London, United Kingdom. · Chemistry Department, School of Science, University of Sulaimani, Sulaimanyah, Kurdistan Region, Iraq. · Department of Surgery, Maastricht University Medical Centre, Maastricht, the Netherlands. · King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia. ·PLoS One · Pubmed #26989901.

ABSTRACT: Pancreatic cancer has a 5-year survival rate of less than 4%. Despite advances in diagnostic technology, pancreatic cancer continues to be diagnosed at a late and incurable stage. Accurate biomarkers for early diagnosis and to predict treatment response are urgently needed. Since alteration of glucose metabolism is one of the hallmarks of cancer cells, we proposed that pyruvate kinase type M2 (M2PK) and lactate dehydrogenase A (LDHA) enzymes could represent novel diagnostic markers and potential therapeutic targets in pancreatic cancer. In 266 tissue sections from normal pancreas, pancreatic cystic neoplasms, pancreatic intraepithelial neoplasia (PanIN) and cancer, we evaluated the expression of PKM2, LDHA, Ki-67 and CD8+ by immunohistochemistry and correlated these markers with clinicopathological characteristics and patient survival. PKM2 and LDHA expression was also assessed by Western blot in 10 human pancreatic cancer cell lines. PKM2 expression increased progressively from cyst through PanIN to cancer, whereas LDHA was overexpressed throughout the carcinogenic process. All but one cell line showed high expression of both proteins. Patients with strong PKM2 and LDHA expression had significantly worse survival than those with weak PKM2 and/or LDHA expression (7.0 months vs. 27.9 months, respectively, p = 0.003, log rank test). The expression of both PKM2 and LDHA correlated directly with Ki-67 expression, and inversely with intratumoral CD8+ cell count. PKM2 was significantly overexpressed in poorly differentiated tumours and both PKM2 and LDHA were overexpressed in larger tumours. Multivariable analysis showed that combined expression of PKM2 and LDHA was an independent poor prognostic marker for survival. In conclusion, our results demonstrate a high expression pattern of two major glycolytic enzymes during pancreatic carcinogenesis, with increased expression in aggressive tumours and a significant adverse effect on survival.

20 Article Cdc7 is a potent anti-cancer target in pancreatic cancer due to abrogation of the DNA origin activation checkpoint. 2016

Huggett, Matthew T / Tudzarova, Slavica / Proctor, Ian / Loddo, Marco / Keane, Margaret G / Stoeber, Kai / Williams, Gareth H / Pereira, Stephen P. ·UCL Institute for Liver and Digestive Health and UCL Cancer Institute, University College London, London, UK. · The Research Department of Pathology, UCL Cancer Institute, University College London, London, UK. · Oncologica Ltd, The Science Village, Chesterford Research Park, Cambridge, UK. ·Oncotarget · Pubmed #26921250.

ABSTRACT: PURPOSE: Cdc7 is a serine/threonine kinase which is responsible for the 'firing' of replication origins leading to initiation of DNA replication. Inhibition or depletion of Cdc7 in normal cells triggers a DNA origin activation checkpoint causing a reversible G1 arrest. Here we investigate Cdc7 as a novel therapeutic target in pancreatic cancer. EXPERIMENTAL DESIGN: Cdc7 target validation was performed by immunoexpression profiling in a cohort of 73 patients with pancreatic adenocarcinoma including 24 controls. Secondly Cdc7 kinase was targeted in Capan-1 and PANC-1 pancreatic cancer cell line models using either an siRNA against Cdc7 or alternatively a small molecule inhibitor (SMI) of Cdc7 (PHA-767491). RESULTS: Cdc7 was significantly overexpressed in pancreatic adenocarcinoma compared to benign pancreatic tissue (median LI 34.3% vs. 1.3%; P<0.0001). Cdc7 knockdown using siRNA in Capan-1 and PANC-1 cells resulted in marked apoptotic cell death when compared with control cells. A prominent sub-G1 peak was seen on flow cytometry (sub-G1 51% vs. 3% and 45% vs. 0.7% in Capan-1 and PANC-1 cells, respectively). Annexin V labelling confirmed apoptosis in 64% vs. 11% and 75% vs. 8%, respectively. Western blotting showed cleavage of PARP-1 and caspase-3 and presence of γH2A.X. TUNEL assay showed strong staining in treated cells. These results were mirrored following Cdc7 kinase inhibition with PHA-767491. CONCLUSIONS: Our findings show that Cdc7 is a potent anti-cancer target in pancreatic adenocarcinoma and that Cdc7 immunoexpression levels might be used as a companion diagnostic to predict response to therapeutic siRNAs or SMIs directed against this kinase.

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

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

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

22 Article Serous cystic neoplasm of the pancreas: a multinational study of 2622 patients under the auspices of the International Association of Pancreatology and European Pancreatic Club (European Study Group on Cystic Tumors of the Pancreas). 2016

Jais, B / Rebours, V / Malleo, G / Salvia, R / Fontana, M / Maggino, L / Bassi, C / Manfredi, R / Moran, R / Lennon, A M / Zaheer, A / Wolfgang, C / Hruban, R / Marchegiani, G / Fernández Del Castillo, C / Brugge, W / Ha, Y / Kim, M H / Oh, D / Hirai, I / Kimura, W / Jang, J Y / Kim, S W / Jung, W / Kang, H / Song, S Y / Kang, C M / Lee, W J / Crippa, S / Falconi, M / Gomatos, I / Neoptolemos, J / Milanetto, A C / Sperti, C / Ricci, C / Casadei, R / Bissolati, M / Balzano, G / Frigerio, I / Girelli, R / Delhaye, M / Bernier, B / Wang, H / Jang, K T / Song, D H / Huggett, M T / Oppong, K W / Pererva, L / Kopchak, K V / Del Chiaro, M / Segersvard, R / Lee, L S / Conwell, D / Osvaldt, A / Campos, V / Aguero Garcete, G / Napoleon, B / Matsumoto, I / Shinzeki, M / Bolado, F / Fernandez, J M Urman / Keane, M G / Pereira, S P / Acuna, I Araujo / Vaquero, E C / Angiolini, M R / Zerbi, A / Tang, J / Leong, R W / Faccinetto, A / Morana, G / Petrone, M C / Arcidiacono, P G / Moon, J H / Choi, H J / Gill, R S / Pavey, D / Ouaïssi, M / Sastre, B / Spandre, M / De Angelis, C G / Rios-Vives, M A / Concepcion-Martin, M / Ikeura, T / Okazaki, K / Frulloni, L / Messina, O / Lévy, P. ·Department of Gastroenterology and Pancreatology, Beaujon Hospital, AP-HP, Clichy, France. · The Pancreas Institute, G.B. Rossi Hospital, University of Verona Hospital Trust, Verona, Italy. · Division of Gastroenterology and Hepatology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Division of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA Department of Pathology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Departments of Surgery and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA. · Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. · First Department of Surgery, Yamagata University Faculty of Medicine, Yamagata, Japan. · Department of Surgery, Seoul National University College of Medicine, Seoul, Korea. · Division of Gastroenterology, Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea. · Department of Surgery, Yonsei University College of Medicine, Pancreaticobiliary Cancer Clinic, Yonsei Cancer Center, Severance Hospital, Seoul, Korea. · Pancreatic Surgery Unit, Department of Surgery, Polytechnic University of Marche Region, Ancona-Torrette, Italy. · NIHR Pancreas Biomedical Research Unit, Department of Molecular and Clinical Cancer Medicine, Royal Liverpool University Hospital, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Surgery, Oncology and Gastroenterology, 3rd Surgical Clinic, University of Padua, Padua, Italy. · Department of Medical and Surgical Sciences (DIMEC), Alma Mater Studiorum-University of Bologna, S. Orsola-Malpighi Hospital, Bologna, Italy. · Pancreatic Surgery Unit, IRCCS San Raffaele Scientific Institute, Milan, Italy. · Hepato-Pancreato-Biliary Unit, Pederzoli Hospital, Peschiera del Garda, Italy. · Department of Gastroenterology, Hepatopancreatology and GI Oncology, Erasme University Hospital, Université Libre de Bruxelles, Brussels, Belgium. · Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, China. · Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea. · Department of Pathology, Gyeongsang National University School of Medicine, Jinju, Korea. · Hepato-Pancreato-Biliary Unit, Freeman Hospital, Newcastle upon Tyne, UK. · National Institute of Surgery and Transplantology named after Shalimov, Kiev, Ukraine. · Division of Surgery, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet at Center for Digestive Diseases, Karolinska University Hospital, Stockholm, Sweden. · Division of Gastroenterology, Brigham and Women's Hospital, Boston, Massachusetts, USA. · Hospital de Clínicas de Porto Alegre, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil. · Hôpital Privé Mermoz, Gastroentérologie, Lyon, France. · Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, Kobe University Graduate School of Medicine, Kobe, Japan. · Gastroenterology Department, Hospital de Navarra, Pamplona, Spain. · Department of Gastroenterology and Hepatology, University College Hospital, London, UK. · Department of Gastroenterology, Hospital Clinic, CIBEREHD, IDIBAPS, University of Barcelona, Barcelona, Spain. · Department of Pancreatic Surgery, Humanitas Research Hospital, Rozzano, Milan, Italy. · Gastroenterology and Liver Services, Concord Hospital, Sydney, New South Wales, Australia. · Radiological Department, General Hospital Cá Foncello, Treviso, Italy. · Division of Gastroenterology and Gastrointestinal Endoscopy, San Raffaele Scientific Institute, Milan, Italy. · Department of Internal Medicine, Digestive Disease Center and Research Institute, SoonChunHyang University School of Medicine, Bucheon, Korea. · Department of Gastroenterology, Bankstown-Lidcombe Hospital, Bankstown, New South Wales, Australia. · Department of Digestive Surgery, Timone Hospital, Marseille, France. · Gastrohepatology Department, San Giovanni Battista Molinette Hospital, University of Turin, Turin, Italy. · Gastroenterology Department, Hospital de la Santa Creu i Sant Pau, Institut de Reçerca-IIB Sant Pau, Universitat Autònoma de Barcelona, Barcelona, Spain. · The Third Department of Internal Medicine, Division of Gastroenterology and Hepatology, Kansai Medical University, Osaka, Japan. · Department of Medicine, Pancreas Center, University of Verona, Verona, Italy. ·Gut · Pubmed #26045140.

ABSTRACT: OBJECTIVES: Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. DESIGN: Retrospective multinational study including SCN diagnosed between 1990 and 2014. RESULTS: 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16-99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2-200)), 9% had resection beyond 1 year of follow-up (3 years (1-20), size at diagnosis: 25 mm (4-140)) and 39% had no surgery (3.6 years (1-23), 25.5 mm (1-200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN's related mortality was 0.1% (n=1). CONCLUSIONS: After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. TRIAL REGISTRATION NUMBER: IRB 00006477.

23 Article Needle-based confocal laser endomicroscopy in pancreatic cystic tumors assessment. 2015

Ştefănescu, Daniela / Pereira, Stephen P / Keane, Margaret / Săftoiu, Adrian. ·Research Center of Gastroenterology and Hepatology, University of Medicine and Pharmacy of Craiova, Romania; adrian.saftoiu@umfcv.ro. ·Rom J Morphol Embryol · Pubmed #26743270.

ABSTRACT: Pancreatic cystic tumors (PCT) are relatively common findings in general population due to the widespread use of cross-sectional imaging. PCT can be benign, with premalignant potential or malignant, a different management being applied for each type: benign cysts are usually referred for follow-up (based on imaging), while premalignant or malignant lesions should be surgically resected. The aim of this review is to describe the latest imaging technique that could be used for PCT diagnosis and to establish its clinical impact. Endoscopic ultrasound (EUS) is generally used to evaluate a pancreatic mass and to identify its characteristics. It offers a good visualization of the lesion. When combined with fine needle aspiration and cystic fluid analysis, the diagnosis potential is increased, although its accuracy for differentiating benign and malign tumors remains modest. EUS-guided needle-based confocal laser endomicroscopy (nCLE) is a new imaging technique that uses a miniprobe thin enough to be passed through a 19G needle. It provides in vivo images of the pancreas at a cellular level, offering the possibility to assess any changes that might have occurred. Several studies have shown that nCLE is feasible to use for PCT evaluation, imaging criteria being established with 100% specificity for intraductal papillary mucinous neoplasms (IPMN) and serous cystadenoma (SCA). Regarding the safety, more studies are needed. EUS-guided nCLE appears to be a new imaging technique that provides encouraging results for differential diagnosis between mucinous/non-mucinous cysts.

24 Article Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. 2015

Radon, Tomasz P / Massat, Nathalie J / Jones, Richard / Alrawashdeh, Wasfi / Dumartin, Laurent / Ennis, Darren / Duffy, Stephen W / Kocher, Hemant M / Pereira, Stephen P / Guarner posthumous, Luisa / Murta-Nascimento, Cristiane / Real, Francisco X / Malats, Núria / Neoptolemos, John / Costello, Eithne / Greenhalf, William / Lemoine, Nick R / Crnogorac-Jurcevic, Tatjana. ·Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. · Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom. · MS Bioworks, LLC, Ann Arbor, Michigan. · Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. · Institute for Liver and Digestive Health, University College London, London, United Kingdom. · Hospital General Universitari Vall Hebron, Barcelona, Spain. · Hospital del Mar - Parc de Salut Mar, Barcelona, Spain. · Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain. · The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom. · Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom. t.c.jurcevic@qmul.ac.uk. ·Clin Cancer Res · Pubmed #26240291.

ABSTRACT: PURPOSE: Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals. EXPERIMENTAL DESIGN: Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. RESULTS: LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84-0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84-0.96) and 0.93 (95% CI, 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94-0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81-0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94-0.99) to 0.99 (95% CI, 0.97-1.00, P = 0.04), but did not improve the comparison of stage I-IIA PDAC (n = 17) with healthy urine. CONCLUSIONS: We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens.

25 Article Fasting cycles potentiate the efficacy of gemcitabine treatment in in vitro and in vivo pancreatic cancer models. 2015

D'Aronzo, Martina / Vinciguerra, Manlio / Mazza, Tommaso / Panebianco, Concetta / Saracino, Chiara / Pereira, Stephen P / Graziano, Paolo / Pazienza, Valerio. ·Gastroenterology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy. · Institute for Liver and Digestive Health, Division of Medicine, University College London (UCL), London, United Kingdom. · School of Science and Technology, Nottingham Trent University, Nottingham, United Kingdom. · Bioinformatics Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza", Istituto Mendel, Italy. · Pathology Unit, I.R.C.C.S. "Casa Sollievo della Sofferenza" Hospital San Giovanni Rotondo (FG), Italy. ·Oncotarget · Pubmed #26176887.

ABSTRACT: BACKGROUND/AIMS: Pancreatic cancer (PC) is ranked as the fourth leading cause of cancer-related deaths worldwide. Despite recent advances in treatment options, a modest impact on the outcome of the disease is observed so far. Short-term fasting cycles have been shown to potentiate the efficacy of chemotherapy against glioma. The aim of this study was to assess the effect of fasting cycles on the efficacy of gemcitabine, a standard treatment for PC patients, in vitro and in an in vivo pancreatic cancer mouse xenograft model. MATERIALS AND METHODS: BxPC-3, MiaPaca-2 and Panc-1 cells were cultured in standard and fasting mimicking culturing condition to evaluate the effects of gemcitabine. Pancreatic cancer xenograft mice were subjected to 24h starvation prior to gemcitabine injection to assess the tumor volume and weight as compared to mice fed ad libitum. RESULTS: Fasted pancreatic cancer cells showed increased levels of equilibrative nucleoside transporter (hENT1), the transporter of gemcitabine across the cell membrane, and decreased ribonucleotide reductase M1 (RRM1) levels as compared to those cultured in standard medium. Gemcitabine was more effective in inducing cell death on fasted cells as compared to controls. Consistently, xenograft pancreatic cancer mice subjected to fasting cycles prior to gemcitabine injection displayed a decrease of more than 40% in tumor growth. CONCLUSIONS: Fasting cycles enhance gemcitabine effect in vitro and in the in vivo PC xenograft mouse model. These results suggest that restrictive dietary interventions could enhance the efficacy of existing cancer treatments in pancreatic cancer patients.

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