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Pancreatic Neoplasms: HELP
Articles by Sean P. Cleary
Based on 32 articles published since 2010
(Why 32 articles?)
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Between 2010 and 2020, S. Cleary wrote the following 32 articles about Pancreatic Neoplasms.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Article Trajectories of physical activity, from young adulthood to older adulthood, and pancreatic cancer risk; a population-based case-control study in Ontario, Canada. 2020

Sandhu, Jaspreet / De Rubeis, Vanessa / Cotterchio, Michelle / Smith, Brendan T / Griffith, Lauren E / Brenner, Darren R / Borgida, Ayelet / Gallinger, Steven / Cleary, Sean / Anderson, Laura N. ·Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. · Public Health Ontario, Toronto, ON, Canada. · Alberta Health Services, Cancer Control, Calgary, AB, Canada. · Department of Oncology and Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. · Division of General Surgery, Toronto General Hospital, Toronto, ON, Canada. · Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. · Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA. · Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada. ln.anderson@mcmaster.ca. ·BMC Cancer · Pubmed #32085738.

ABSTRACT: BACKGROUND: There is inconsistent evidence on the association between physical activity and pancreatic cancer risk and few studies have investigated early life or life-course physical activity. The objective of this study was to evaluate the association between trajectories of physical activity across the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) using cases (n = 315) from the Ontario Pancreas Cancer Study and controls (n = 1254) from the Ontario Cancer Risk Factor Study. Self-reported recall of moderate and vigorous physical activity was measured at three time points: young adulthood (20s-30s), mid-adulthood (40s-50s) and older-adulthood (1 year prior to questionnaire completion). Physical activity trajectories were identified using latent class analysis. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression adjusted for covariates: age, sex, race, alcohol, smoking, vegetable, fruit and meat consumption, and family history of pancreatic cancer. RESULTS: Six life-course physical activity trajectories were identified: inactive at all ages (41.2%), low activity at all ages (31.9%), increasingly active (3.6%), high activity in young adulthood with substantial decrease (13.0%), high activity in young adulthood with slight decrease (5.0%), and persistent high activity (5.3%). Compared to the inactive at all ages trajectory, the associations between each trajectory and pancreatic cancer after confounder adjustment were: low activity at all ages (OR: 1.11; 95% CI: 0.75, 1.66), increasingly active (OR: 1.11; 95% CI: 0.56, 2.21), high activity in young adulthood with substantial decrease in older adulthood (OR: 0.76; 95% CI: 0.47, 1.23), high activity in young adulthood with slight decrease in older adulthood (OR: 0.98; 95% CI: 0.62, 1.53), and persistently high activity (OR: 1.50; 95% CI: 0.86, 2.62). When time periods were evaluated separately, the OR for the association between high moderate activity in the 20s-30s and pancreatic cancer was 0.89 (95% CI: 0.64, 1.25) and some sex differences were observed. CONCLUSION: Distinct life-course physical activity trajectories were identified, but there was no evidence that any of the trajectories were associated with pancreatic cancer. Future studies with larger sample sizes are needed to understand the associations between physical activity trajectories over the life-course and pancreatic cancer risk.

2 Article Trajectories of body mass index, from adolescence to older adulthood, and pancreatic cancer risk; a population-based case-control study in Ontario, Canada. 2019

De Rubeis, Vanessa / Cotterchio, Michelle / Smith, Brendan T / Griffith, Lauren E / Borgida, Ayelet / Gallinger, Steven / Cleary, Sean / Anderson, Laura N. ·Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S4L8, Canada. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. · Public Health Ontario, Toronto, ON, Canada. · Division of General Surgery, Toronto General Hospital, Toronto, ON, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada. · Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. · Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA. · Department of Health Research Methods, Evidence, and Impact, McMaster University, 1280 Main Street West, Hamilton, ON, L8S4L8, Canada. ln.anderson@mcmaster.ca. · Child Health Evaluative Sciences, The Hospital for Sick Children Research Institute, Toronto, ON, Canada. ln.anderson@mcmaster.ca. ·Cancer Causes Control · Pubmed #31230151.

ABSTRACT: PURPOSE: Pancreatic cancer has the highest fatality rate of all cancers. Adulthood obesity is an established risk factor for pancreatic cancer; however, life-course obesity is not well understood. The aim of this study was to evaluate the association between body mass index (BMI) trajectories throughout the life-course and pancreatic cancer risk. METHODS: A population-based case-control study was conducted (2011-2013) in Ontario, Canada. Cases were recruited from the Ontario pancreas cancer study (n = 310) and controls from the Ontario cancer risk factor study (n = 1258). Questionnaires captured self-reported height and weight at four timepoints (adolescence, 20 s, 30-40 s, 50-60 s). BMI trajectories were identified using latent class growth mixture modeling. Odds ratios (OR) and 95% confidence intervals (CI) were estimated from multivariable logistic regression. RESULTS: Five BMI trajectories were identified: stable-normal weight (38.9%), progressively overweight (42.2%), persistent overweight (12.6%), progressive obesity (4.2%), and persistent obesity (2.1%). The persistent overweight (OR = 1.55; 95% CI 1.02, 2.39) and progressive obesity trajectories (OR = 1.49; 95% CI 0.77, 2.87) compared to stable-normal weight were associated with increased odds of pancreatic cancer. When BMI was evaluated separately the strongest associations with pancreatic cancer emerged in young and mid-adulthood. CONCLUSION: BMI trajectories characterized by overweight in early adulthood were associated with increased pancreatic cancer risk suggesting a life-course approach to disease risk.

3 Article Management and surveillance of non-functional pancreatic neuroendocrine tumours: Retrospective review. 2019

Yohanathan, Lavanya / Dossa, Fahima / St Germain, Amelie Tremblay / Golbafian, Faegheh / Moulton, Carol-Anne / McGilvray, Ian D / Greig, Paul D / Serra, Stefano / Wei, Alice C / Jhaveri, Kartik S / Gallinger, Steve / Cleary, Sean P. ·Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA. · Division of General Surgery, University of Toronto, Toronto, ON, Canada. · Department of Surgery, Hotel-Dieu De Levis, Levis, QC, Canada. · Department of Family Medicine, London, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Department of Pathology, University Health Network/University of Toronto, Canada. · Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. · Joint Department of Medical Imaging, University Health Network, Mount Sinai Hospital and Women's College Hospital, University of Toronto, Toronto, ON, Canada. · Division of General Surgery, University of Toronto, Toronto, ON, Canada; Division of Hepatobiliary and Pancreatic Surgery, Mayo Clinic, Rochester, MN, USA; Department of Surgery, University Health Network, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada. Electronic address: cleary.sean@mayo.edu. ·Pancreatology · Pubmed #30803874.

ABSTRACT: BACKGROUND: /Objective. To determine the outcomes of a non-operative management approach for sporadic, small, non-functional pancreatic neuroendocrine tumours. METHODS: A retrospective chart review of patients with non-functional pancreatic neuroendocrine tumours initially managed non-operatively at a single institution was performed. Patients were identified through a search of radiologic reports, and individuals with ≥2 cross-sectional imaging studies performed >6 months apart from Jan. 1, 2000 to Dec. 31, 2013 were included. Data on tumour size, radiologic characteristics at diagnosis, interval radiologic growth, and surgical outcomes were recorded. RESULTS: Over the thirteen-year study period, 95 patients met inclusion criteria and were followed radiologically for a median of 36 months (18-69 months). Median initial tumour size on first imaging was 14.0 mm (IQR 10-19 mm). Median overall tumour growth rate was 0.03 mm/month (IQR: 0.00-0.14 mm/month). There was no significant relationship between initial tumour size and growth rate for tumours ≤ 2 cm or for lesions between 2 and 4 cm. Thirteen (14%) patients initially managed non-operatively underwent resection during the follow-up period. Reasons for surgery included interval tumour growth, patient anxiety or preference, or diagnostic uncertainty. Median time to surgery was 14 months (IQR 8-19 months). No patients progressed beyond resectability or developed metastatic disease during the observation period. CONCLUSION: For patients with sporadic, small, non-functional pancreatic neuroendocrine tumours, radiologic surveillance appears to be a safe initial approach to management.

4 Article Integration of Genomic and Transcriptional Features in Pancreatic Cancer Reveals Increased Cell Cycle Progression in Metastases. 2019

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Lemire, Mathieu / Zhang, Amy / Chan-Seng-Yue, Michelle / Wilson, Gavin / Grant, Robert C / Merico, Daniele / Lungu, Ilinca / Bartlett, John M S / Chadwick, Dianne / Liang, Sheng-Ben / Eagles, Jenna / Mbabaali, Faridah / Miller, Jessica K / Krzyzanowski, Paul / Armstrong, Heather / Luo, Xuemei / Jorgensen, Lars G T / Romero, Joan M / Bavi, Prashant / Fischer, Sandra E / Serra, Stefano / Hafezi-Bakhtiari, Sara / Caglar, Derin / Roehrl, Michael H A / Cleary, Sean / Hollingsworth, Michael A / Petersen, Gloria M / Thayer, Sarah / Law, Calvin H L / Nanji, Sulaiman / Golan, Talia / Smith, Alyssa L / Borgida, Ayelet / Dodd, Anna / Hedley, David / Wouters, Bradly G / O'Kane, Grainne M / Wilson, Julie M / Zogopoulos, George / Notta, Faiyaz / Knox, Jennifer J / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Deep Genomics, Inc., Toronto, ON M5G 1L7, Canada; The Centre for Applied Genomics (TCAG), The Hospital for Sick Children, Toronto, ON M5G 0A4, Canada. · Diagnostic Development, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada. · Genomics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · Genome Sequence Informatics, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada. · Department of Pathology, McGill University Health Centre, Montreal, QC H4A 3J1, Canada. · UHN Biobank, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Pathology, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada; Department of Pathology, Memorial Sloan Kettering Cancer Centre, New York, NY 10065, USA. · Department of Surgery, Mayo Clinic, Rochester, MN 55905, USA. · University of Nebraska Medical Centre, Omaha, NE 68198, USA. · Mayo Clinic College of Medicine, Rochester, MN 55905, USA. · University of Nebraska Medical Centre, Omaha, NE 68198, USA; Massachusetts General Hospital, Boston, MA 02114, USA. · Department of Surgery, Sunnybrook Health Sciences Centre, Toronto, ON M4N 3M5, Canada. · Department of Surgery, Kingston General Hospital, Kingston, ON K7L 2V7, Canada. · Pancreatic Cancer Translational Research Laboratory, Oncology Institute, Sheba Medical Center, Tel Hashomer, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. · Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada. · Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. · Wallace McCain Centre for Pancreatic Cancer, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada. · Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada; Goodman Cancer Research Centre, Montreal, QC H3A 1A3, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Division of Research, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, ON M5G 0A3, Canada; Department of Surgery, University of Toronto, Toronto, ON M5T 1P5, Canada; Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, ON M5G 2M9, Canada; Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada. Electronic address: steven.gallinger@uhn.ca. ·Cancer Cell · Pubmed #30686769.

ABSTRACT: We integrated clinical, genomic, and transcriptomic data from 224 primaries and 95 metastases from 289 patients to characterize progression of pancreatic ductal adenocarcinoma (PDAC). Driver gene alterations and mutational and expression-based signatures were preserved, with truncations, inversions, and translocations most conserved. Cell cycle progression (CCP) increased with sequential inactivation of tumor suppressors, yet remained higher in metastases, perhaps driven by cell cycle regulatory gene variants. Half of the cases were hypoxic by expression markers, overlapping with molecular subtypes. Paired tumor heterogeneity showed cancer cell migration by Halstedian progression. Multiple PDACs arising synchronously and metachronously in the same pancreas were actually intra-parenchymal metastases, not independent primary tumors. Established clinical co-variates dominated survival analyses, although CCP and hypoxia may inform clinical practice.

5 Article Agnostic Pathway/Gene Set Analysis of Genome-Wide Association Data Identifies Associations for Pancreatic Cancer. 2019

Walsh, Naomi / Zhang, Han / Hyland, Paula L / Yang, Qi / Mocci, Evelina / Zhang, Mingfeng / Childs, Erica J / Collins, Irene / Wang, Zhaoming / Arslan, Alan A / Beane-Freeman, Laura / Bracci, Paige M / Brennan, Paul / Canzian, Federico / Duell, Eric J / Gallinger, Steven / Giles, Graham G / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hung, Rayjean J / Kooperberg, Charles / Kurtz, Robert C / Malats, Núria / LeMarchand, Loic / Neale, Rachel E / Olson, Sara H / Scelo, Ghislaine / Shu, Xiao O / Van Den Eeden, Stephen K / Visvanathan, Kala / White, Emily / Zheng, Wei / Anonymous5331143 / Albanes, Demetrius / Andreotti, Gabriella / Babic, Ana / Bamlet, William R / Berndt, Sonja I / Borgida, Ayelet / Boutron-Ruault, Marie-Christine / Brais, Lauren / Brennan, Paul / Bueno-de-Mesquita, Bas / Buring, Julie / Chaffee, Kari G / Chanock, Stephen / Cleary, Sean / Cotterchio, Michelle / Foretova, Lenka / Fuchs, Charles / M Gaziano, J Michael / Giovannucci, Edward / Goggins, Michael / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Janout, Vladimir / Klein, Eric A / Kurtz, Robert C / Laheru, Daniel / Lee, I-Min / Lu, Lingeng / Malats, Núria / Mannisto, Satu / Milne, Roger L / Oberg, Ann L / Orlow, Irene / Patel, Alpa V / Peters, Ulrike / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Sesso, Howard D / Severi, Gianluca / Silverman, Debra / Strobel, Oliver / Sund, Malin / Thornquist, Mark D / Tobias, Geoffrey S / Wactawski-Wende, Jean / Wareham, Nick / Weiderpass, Elisabete / Wentzensen, Nicolas / Wheeler, William / Yu, Herbert / Zeleniuch-Jacquotte, Anne / Kraft, Peter / Li, Donghui / Jacobs, Eric J / Petersen, Gloria M / Wolpin, Brian M / Risch, Harvey A / Amundadottir, Laufey T / Yu, Kai / Klein, Alison P / Stolzenberg-Solomon, Rachael Z. ·National Institute for Cellular Biotechnology, Dublin City University, Glasnevin, Dublin, Ireland. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Division of Applied Regulatory Science, Office of Translational Science, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Division of Epidemiology II, Office of Surveillance and Epidemiology, Center for Drug Evaluation & Research, U.S. Food and Drug Administration, Silver Spring, MD. · Department of Computational Biology, St Jude Children's Research Hospital, Memphis, Tennessee. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY. · Department of Environmental Medicine, New York University School of Medicine, New York, NY. · Department of Population Health, New York University School of Medicine, New York, NY. · Department of Epidemiology and Biostatistics, University of California, San Francisco, CA. · International Agency for Research on Cancer (IARC), Lyon, France. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, Spain. · Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, Victoria, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Victoria, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Victoria, Australia. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, Spain. · CIBERONC, Madrid, Spain. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN. · Division of Research, Kaiser Permanente Northern California, Oakland, CA. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Department of Epidemiology, University of Washington, Seattle, WA. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, Villejuif, France. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · Department of Social & Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA. · Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN. · Cancer Care Ontario, University of Toronto, Toronto, ON, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, ON, Canada. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT. · Division of Aging, Brigham and Women's Hospital, Boston, MA. · Boston VA Healthcare System, Boston, MA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, Prague, Czech Republic. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, Olomouc, Czech Republic. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT. · Department of Public Health Solutions, National Institute for Health and Welfare, Helsinki, Finland. · Epidemiology Research Program, American Cancer Society, Atlanta, GA. · CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, Barcelona, Spain. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain. · Department of Surgical and Perioperative Sciences, Umeå University, Umeå, Sweden. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY. · MRC Epidemiology Unit, University of Cambridge, Cambridge, UK. · Department of Research, Cancer Registry of Norway, Institute of Population-Based Cancer Research, Oslo, Norway. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · Genetic Epidemiology Group, Folkhälsan Research Center and Faculty of Medicine, University of Helsinki, Helsinki, Finland. · Department of Community Medicine, Faculty of Health Sciences, University of Tromsø, The Arctic University of Norway, Tromsø, Norway. · Information Management Systems, Silver Spring, MD. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY. · Department of Biostatistics, Harvard School of Public Health, Boston, MA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX. ·J Natl Cancer Inst · Pubmed #30541042.

ABSTRACT: BACKGROUND: Genome-wide association studies (GWAS) identify associations of individual single-nucleotide polymorphisms (SNPs) with cancer risk but usually only explain a fraction of the inherited variability. Pathway analysis of genetic variants is a powerful tool to identify networks of susceptibility genes. METHODS: We conducted a large agnostic pathway-based meta-analysis of GWAS data using the summary-based adaptive rank truncated product method to identify gene sets and pathways associated with pancreatic ductal adenocarcinoma (PDAC) in 9040 cases and 12 496 controls. We performed expression quantitative trait loci (eQTL) analysis and functional annotation of the top SNPs in genes contributing to the top associated pathways and gene sets. All statistical tests were two-sided. RESULTS: We identified 14 pathways and gene sets associated with PDAC at a false discovery rate of less than 0.05. After Bonferroni correction (P ≤ 1.3 × 10-5), the strongest associations were detected in five pathways and gene sets, including maturity-onset diabetes of the young, regulation of beta-cell development, role of epidermal growth factor (EGF) receptor transactivation by G protein-coupled receptors in cardiac hypertrophy pathways, and the Nikolsky breast cancer chr17q11-q21 amplicon and Pujana ATM Pearson correlation coefficient (PCC) network gene sets. We identified and validated rs876493 and three correlating SNPs (PGAP3) and rs3124737 (CASP7) from the Pujana ATM PCC gene set as eQTLs in two normal derived pancreas tissue datasets. CONCLUSION: Our agnostic pathway and gene set analysis integrated with functional annotation and eQTL analysis provides insight into genes and pathways that may be biologically relevant for risk of PDAC, including those not previously identified.

6 Article Neoadjuvant therapy and major arterial resection for potentially reconstructable arterial involvement by stage 3 adenocarcinoma of the pancreas. 2019

Loveday, Benjamin P T / Zilbert, Nathan / Serrano, Pablo E / Tomiyama, Koji / Tremblay, Amélie / Fox, Adrian M / Segedi, Maja / O'Malley, Martin / Borgida, Ayelet / Bianco, Teresa / Creighton, Sean / Dodd, Anna / Fraser, Adriana / Moore, Malcolm / Kim, John / Cleary, Sean / Moulton, Carol-Anne / Greig, Paul / Wei, Alice C / Gallinger, Steven / Dhani, Neesha / McGilvray, Ian D. ·Department of Surgery, University Health Network, University of Toronto, Toronto, Canada; Department of Surgery, University of Auckland, Auckland, New Zealand. · Department of Surgery, University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada. · Department of Surgery, McMaster University, Hamilton, Canada. · Department of Surgery, University Health Network, University of Toronto, Toronto, Canada. · St-Vincent Hospital, University of Melbourne, Melbourne, Australia. · Department of Surgery, University of British Columbia, Vancouver, Canada. · Joint Department of Medical Imaging, University of Toronto, Toronto, Canada. · Ontario Pancreas Cancer Study, Mount Sinai Hospital, Toronto, Canada. · McCain Center for Pancreas Cancer, Princess Margaret Cancer Centre, Toronto, Canada. · University of Toronto, Toronto, Canada; BC Cancer Agency, Vancouver, Canada. · Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada. · Department of Surgery, University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada; Department of Surgery, Mayo Clinic, Rochester MN, USA. · University of Toronto, Toronto, Canada; Department of Medical Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, Canada. · Department of Surgery, University Health Network, University of Toronto, Toronto, Canada; University of Toronto, Toronto, Canada. Electronic address: ian.mcgilvray@uhn.ca. ·HPB (Oxford) · Pubmed #30471960.

ABSTRACT: BACKGROUND: Stage 3 pancreatic ductal adenocarcinoma (PDAC) is defined by arterial involvement. This study objective was to evaluate outcomes for patients with stage 3 PDAC with potentially reconstructable arterial involvement, considered for neoadjuvant therapy (NAT) and pancreatic resection, and to compare outcomes following arterial (AR) and non-arterial resection (NAR). METHODS: This study included patients from 2009 to 2016 with biopsy-proven stage 3 PDAC who were offered NAT before surgical exploration. AR was performed if required to achieve R0 resection. Time to event outcomes were analysed from diagnosis date. RESULTS: 87/89 patients (97.8%) received NAT (chemotherapy 41.6%, chemotherapy/radiotherapy 56.2%). 46/89 (51.7%) underwent exploration; 31 underwent resection (AR n = 20, NAR n = 11). AR patients had longer operative time (681 vs. 563 min, p = 0.006) and more blood loss (1600 vs. 575 mL, p = 0.0004), with no difference for blood transfusion, pancreatic fistula, length of stay, reoperation, or mortality. R0 rate was 30/31. Post-resection 90-day mortality was 3.2%. Median overall survival was statistically comparable between the AR and NAR groups (19.7 vs. 28.4 months, p = 0.41). CONCLUSIONS: AR had comparable clinical and oncologic outcomes to NAR. Following careful selection and non-progression after NAT, major AR may cautiously be considered if required to obtain a negative resection margin.

7 Article Follow-up Recommendations for Completely Resected Gastroenteropancreatic Neuroendocrine Tumors. 2018

Singh, Simron / Moody, Lesley / Chan, David L / Metz, David C / Strosberg, Jonathan / Asmis, Timothy / Bailey, Dale L / Bergsland, Emily / Brendtro, Kari / Carroll, Richard / Cleary, Sean / Kim, Michelle / Kong, Grace / Law, Calvin / Lawrence, Ben / McEwan, Alexander / McGregor, Caitlin / Michael, Michael / Pasieka, Janice / Pavlakis, Nick / Pommier, Rodney / Soulen, Michael / Wyld, David / Segelov, Eva / Anonymous4510956. ·Department of Medical Oncology, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada. · Perelman School of Medicine, Department of Gastroenterology, University of Pennsylvania, Philadelphia. · Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Centre, Tampa, Florida. · Department of Internal Medicine, University of Ottawa, Ottawa, Ontario, Canada. · Department of Nuclear Medicine, Royal North Shore Hospital, Sydney, Australia. · Department of Medical Oncology, University of California San Francisco Helen Diller Family Comprehensive Cancer Center, San Francisco. · North American Neuroendocrine Tumor Society, Albany, New York. · Department of Endocrinology, Wellington Regional Hospital, Wellington, New Zealand. · Department of Surgery, Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Gastroenterology, Mount Sinai Hospital, New York, New York. · Department of Nuclear Medicine, Peter MacCullum Cancer Centre, Melbourne, Australia. · Department of Surgery, Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Department of Medical Oncology, Auckland Hospital, Auckland, New Zealand. · Department of Oncology, University of Alberta, Edmonton, Alberta, Canada. · Department of Medical Imaging, Sunnybrook Health Sciences Centre, Toronto, Ontario, Canada. · Department of Medical Oncology, Peter MacCullum Cancer Centre, Melbourne, Australia. · Department of Surgery, Tom Baker Cancer Centre, Calgary, Alberta, Canada. · Department of Medical Oncology, Royal North Shore Hospital, Sydney, Australia. · Department of Surgery, Oregon Health & Science University, Portland. · Perelman School of Medicine, Department of Medical Imaging, University of Pennsylvania, Philadelphia. · Department of Medical Oncology, Royal Brisbane and Women's Hospital, Queensland, Australia. · Department of Medical Oncology, Monash University, Clayton, Australia. ·JAMA Oncol · Pubmed #30054622.

ABSTRACT: There is no consensus on optimal follow-up for completely resected gastroenteropancreatic neuroendocrine tumors. Published guidelines for follow-up are complex and emphasize closer surveillance in the first 3 years after resection. Neuroendocrine tumors have a different pattern and timescale of recurrence, and thus require more practical and tailored follow-up. The Commonwealth Neuroendocrine Tumour Collaboration convened an international multidisciplinary expert panel, in collaboration with the North American Neuroendocrine Tumor Society, to create patient-centered follow-up recommendations for completely resected gastroenteropancreatic neuroendocrine tumors. This panel used the RAND/UCLA (University of California, Los Angeles) Appropriateness Method to generate recommendations. A large international survey was conducted outlining current the surveillance practice of neuroendocrine tumor practitioners and shortcomings of the current guidelines. A systematic review of available data to date was supplemented by recurrence data from 2 large patient series. The resultant guidelines suggest follow-up for at least 10 years for fully resected small-bowel and pancreatic neuroendocrine tumors and also identify clinical situations in which no follow-up is required. These recommendations stratify follow-up strategies based on evidence-based prognostic factors that allow for a more individualized patient-centered approach to this complex and heterogeneous malignant neoplasm.

8 Article Indications and Perioperative Outcomes for Pancreatectomy with Arterial Resection. 2018

Tee, May C / Krajewski, Adam C / Groeschl, Ryan T / Farnell, Michael B / Nagorney, David M / Kendrick, Michael L / Cleary, Sean P / Smoot, Rory L / Croome, Kristopher P / Truty, Mark J. ·Department of Surgery, Mayo Clinic, Rochester, MN. · Department of Surgery, Mayo Clinic, Rochester, MN. Electronic address: Truty.Mark@mayo.edu. ·J Am Coll Surg · Pubmed #29752997.

ABSTRACT: BACKGROUND: Pancreatectomy with arterial resection (AR) is performed infrequently. As indications evolve, we evaluated indications, outcomes, and predictors of mortality, morbidity, and survival after AR. STUDY DESIGN: We performed a single-institution review of elective pancreatectomies with AR (from July1990 to July 2017). Univariate and multivariate analyses were performed for predictors of outcomes and survival. RESULTS: A total of 111 patients underwent pancreatectomy with AR including any hepatic (54%), any celiac (44%), any superior mesenteric (14%), or multiple ARs (14%), with revascularization in 55%. The majority of cases were planned (77%) and performed post-2010 (78%). Overall 90-day major morbidity (≥grade III) and mortality were 54% and 13%, respectively, due to post-pancreatectomy hemorrhage (PPH), postoperative pancreatic fistula (POPF), or ischemia in the majority of cases. There was a significant decrease in mortality post-2010 (9% vs 29%, p = 0.02), and this was protective on multivariate analysis (odds ratio [OR] 0.1, p = 0.004); PPH increased mortality (OR 6.1, p < 0.001). Post-pancreatectomy hemorrhage was associated with major morbidity (OR 5.1, p = 0.005), reoperation (OR = 23.0, p = 0.004), ICU (OR 5.5, p < 0.001), and readmission (OR 2.6, p = 0.004). Other morbidity predictors were AR with graft (OR 4.0, p = 0.031) and POPF (OR 3.1, p = 0.003). Median survival was 28.5 months and improved for ductal adenocarcinoma after neoadjuvant chemotherapy (p = 0.038). There were no differences in survival based on AR type. CONCLUSIONS: Regardless of indication or type, pancreatectomy with AR is associated with risks greater than standard resections. Mortality has decreased in the modern era; however, morbidity remains high from hemorrhagic, fistula, or ischemia-related complications. Mitigation measures are needed if advanced resections are considered with increasing frequency given the potential oncologic benefit of AR in selected cases after modern chemotherapy.

9 Article Genome-wide meta-analysis identifies five new susceptibility loci for pancreatic cancer. 2018

Klein, Alison P / Wolpin, Brian M / Risch, Harvey A / Stolzenberg-Solomon, Rachael Z / Mocci, Evelina / Zhang, Mingfeng / Canzian, Federico / Childs, Erica J / Hoskins, Jason W / Jermusyk, Ashley / Zhong, Jun / Chen, Fei / Albanes, Demetrius / Andreotti, Gabriella / Arslan, Alan A / Babic, Ana / Bamlet, William R / Beane-Freeman, Laura / Berndt, Sonja I / Blackford, Amanda / Borges, Michael / Borgida, Ayelet / Bracci, Paige M / Brais, Lauren / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, Bas / Buring, Julie / Campa, Daniele / Capurso, Gabriele / Cavestro, Giulia Martina / Chaffee, Kari G / Chung, Charles C / Cleary, Sean / Cotterchio, Michelle / Dijk, Frederike / Duell, Eric J / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gallinger, Steven / M Gaziano, J Michael / Gazouli, Maria / Giles, Graham G / Giovannucci, Edward / Goggins, Michael / Goodman, Gary E / Goodman, Phyllis J / Hackert, Thilo / Haiman, Christopher / Hartge, Patricia / Hasan, Manal / Hegyi, Peter / Helzlsouer, Kathy J / Herman, Joseph / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert / Hung, Rayjean J / Jacobs, Eric J / Jamroziak, Krzysztof / Janout, Vladimir / Kaaks, Rudolf / Khaw, Kay-Tee / Klein, Eric A / Kogevinas, Manolis / Kooperberg, Charles / Kulke, Matthew H / Kupcinskas, Juozas / Kurtz, Robert J / Laheru, Daniel / Landi, Stefano / Lawlor, Rita T / Lee, I-Min / LeMarchand, Loic / Lu, Lingeng / Malats, Núria / Mambrini, Andrea / Mannisto, Satu / Milne, Roger L / Mohelníková-Duchoňová, Beatrice / Neale, Rachel E / Neoptolemos, John P / Oberg, Ann L / Olson, Sara H / Orlow, Irene / Pasquali, Claudio / Patel, Alpa V / Peters, Ulrike / Pezzilli, Raffaele / Porta, Miquel / Real, Francisco X / Rothman, Nathaniel / Scelo, Ghislaine / Sesso, Howard D / Severi, Gianluca / Shu, Xiao-Ou / Silverman, Debra / Smith, Jill P / Soucek, Pavel / Sund, Malin / Talar-Wojnarowska, Renata / Tavano, Francesca / Thornquist, Mark D / Tobias, Geoffrey S / Van Den Eeden, Stephen K / Vashist, Yogesh / Visvanathan, Kala / Vodicka, Pavel / Wactawski-Wende, Jean / Wang, Zhaoming / Wentzensen, Nicolas / White, Emily / Yu, Herbert / Yu, Kai / Zeleniuch-Jacquotte, Anne / Zheng, Wei / Kraft, Peter / Li, Donghui / Chanock, Stephen / Obazee, Ofure / Petersen, Gloria M / Amundadottir, Laufey T. ·Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. aklein1@jhmi.edu. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. aklein1@jhmi.edu. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, 06520, USA. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Department of Obstetrics and Gynecology, New York University School of Medicine, New York, NY, 10016, USA. · Department of Population Health, New York University School of Medicine, New York, NY, 10016, USA. · Department of Environmental Medicine, New York University School of Medicine, New York, NY, 10016, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN, 55905, USA. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, MD, 21287, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, M5G 1×5, Canada. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, 94158, USA. · International Agency for Research on Cancer (IARC), 69372, Lyon, France. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · Division of Preventive Oncology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · National Center for Tumor Diseases (NCT), 69120, Heidelberg, Germany. · Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), 3720 BA, Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, 3584 CX, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, SW7 2AZ, UK. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, 50603, Kuala Lumpur, Malaysia. · Division of Preventive Medicine, Brigham and Women's Hospital, Boston, MA, 02215, USA. · Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, 02115, USA. · Department of Biology, University of Pisa, 56126, Pisa, Italy. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, 00185, Rome, Italy. · Gastroenterology and Gastrointestinal Endoscopy Unit, Vita-Salute San Raffaele University, IRCCS San Raffaele Scientific Institute, 20132, Milan, Italy. · Cancer Genomics Research Laboratory, National Cancer Institute, Division of Cancer Epidemiology and Genetics, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD, 21702, USA. · Cancer Care Ontario, University of Toronto, Toronto, Ontario, M5G 2L7, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, M5T 3M7, Canada. · Department of Pathology, Academic Medical Center, University of Amsterdam, 1007 MB, Amsterdam, The Netherlands. · Unit of Nutrition and Cancer, Cancer Epidemiology Research Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), Barcelona, 08908, Spain. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, 65653, Brno, Czech Republic. · Yale Cancer Center, New Haven, CT, 06510, USA. · Department of Translational Research and The New Technologies in Medicine and Surgery, University of Pisa, 56126, Pisa, Italy. · Division of Aging, Brigham and Women's Hospital, Boston, MA, 02115, USA. · Boston VA Healthcare System, Boston, MA, 02132, USA. · Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, 106 79, Athens, Greece. · Cancer Epidemiology and Intelligence Division, Cancer Council Victoria, Melbourne, VIC, 3004, Australia. · Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC, 3010, Australia. · Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC, 3004, Australia. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · SWOG Statistical Center, Fred Hutchinson Cancer Research Center, Seattle, WA, 98109, USA. · Department of General Surgery, University Hospital Heidelberg, 69120, Heidelberg, Germany. · Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, 90032, USA. · Department of Epidemiology, University of Texas MD Anderson Cancer Center, Houston, TX, 77230, USA. · First Department of Medicine, University of Szeged, 6725, Szeged, Hungary. · Division of Cancer Control and Population Sciences, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. · Department of Radiation Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, 21231, USA. · Institute of Public Health and Preventive Medicine, Charles University, 2nd Faculty of Medicine, 150 06, Prague 5, Czech Republic. · Epidemiology Research Program, American Cancer Society, Atlanta, GA, 30303, USA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, 02-776, Warsaw, Poland. · Department of Epidemiology and Public Health, Faculty of Medicine, University of Ostrava, 701 03, Ostrava, Czech Republic. · Faculty of Medicine, University of Olomouc, 771 47, Olomouc, Czech Republic. · Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. · School of Clinical Medicine, University of Cambridge, Cambridge, CB2 0SP, UK. · Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, 44195, USA. · ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), 08003, Barcelona, Spain. · CIBER Epidemiología y Salud Pública (CIBERESP), 08003, Barcelona, Spain. · Hospital del Mar Institute of Medical Research (IMIM), Universitat Autònoma de Barcelona, 08003, Barcelona, Spain. · Universitat Pompeu Fabra (UPF), 08002, Barcelona, Spain. · Department of Gastroenterology, Lithuanian University of Health Sciences, 44307, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, 37134, Verona, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, MA, 02115, USA. · Cancer Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI, 96813, USA. · Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), 28029, Madrid, Spain. · CIBERONC, 28029, Madrid, Spain. · Oncology Department, ASL1 Massa Carrara, Carrara, 54033, Italy. · Department of Public Health Solutions, National Institute for Health and Welfare, 00271, Helsinki, Finland. · Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital, 775 20, Olomouc, Czech Republic. · Population Health Department, QIMR Berghofer Medical Research Institute, Brisbane, 4029, Australia. · Department of General Surgery, University of Heidelburg, Heidelberg, Germany. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA. · Department of Surgery, Oncology and Gastroenterology (DiSCOG), University of Padua, 35124, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, 40138, Bologna, Italy. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029, Madrid, Spain. · Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, 08002, Barcelona, Spain. · Centre de Recherche en Épidémiologie et Santé des Populations (CESP, Inserm U1018), Facultés de Medicine, Université Paris-Saclay, UPS, UVSQ, Gustave Roussy, 94800, Villejuif, France. · Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA. · Department of Medicine, Georgetown University, Washington, 20057, USA. · Laboratory for Pharmacogenomics, Biomedical Center, Faculty of Medicine in Pilsen, Charles University, 323 00, Pilsen, Czech Republic. · Department of Surgical and Perioperative Sciences, Umeå University, 901 85, Umeå, Sweden. · Department of Digestive Tract Diseases, Medical University of Łodz, 90-647, Łodz, Poland. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo della Sofferenza", 71013, San Giovanni Rotondo, FG, Italy. · Division of Research, Kaiser Permanente Northern California, Oakland, CA, 94612, USA. · Department of General, Visceral and Thoracic Surgery, University Hamburg-Eppendorf, 20246, Hamburg, Germany. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, 21205, USA. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, 142 20, Prague 4, Czech Republic. · Department of Epidemiology and Environmental Health, University at Buffalo, Buffalo, NY, 14214, USA. · Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN, 38105, USA. · Department of Epidemiology, University of Washington, Seattle, WA, 98195, USA. · Perlmutter Cancer Center, New York University School of Medicine, New York, NY, 10016, USA. · Department of Biostatistics, Harvard School of Public Health, Boston, MA, 02115, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA. · Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA. amundadottirl@mail.nih.gov. ·Nat Commun · Pubmed #29422604.

ABSTRACT: In 2020, 146,063 deaths due to pancreatic cancer are estimated to occur in Europe and the United States combined. To identify common susceptibility alleles, we performed the largest pancreatic cancer GWAS to date, including 9040 patients and 12,496 controls of European ancestry from the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4). Here, we find significant evidence of a novel association at rs78417682 (7p12/TNS3, P = 4.35 × 10

10 Article The Association of Recently Diagnosed Diabetes and Long-term Diabetes With Survival in Pancreatic Cancer Patients: A Pooled Analysis. 2018

Jeon, Christie Y / Li, Donghui / Cleary, Sean / Stolzenberg-Solomon, Rachael / Bosetti, Cristina / La Vecchia, Carlo / Porta, Miquel / Toriola, Adetunji T / Hung, Rayjean J / Kurtz, Robert C / Olson, Sara H. · ·Pancreas · Pubmed #29401167.

ABSTRACT: OBJECTIVES: It is unclear whether long-standing diabetes or new-onset pancreatogenic diabetes contributes to poor prognosis in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: We investigated the influence of diabetes diagnosed shortly before PDAC and long-term diabetes on overall survival in 2792 PDAC patients who had participated in 3 PDAC case-control studies in the Pancreatic Cancer Case-Control Consortium. There were 300 patients with long-term diabetes of more than 3 years' duration (11%) and 418 patients with recently diagnosed diabetes of 3-year duration or less (15%). We performed Cox regression to determine the association of long-term diabetes and recently diagnosed diabetes with overall survival, adjusting for study site, age, sex, race, stage of disease, surgery, chemotherapy, smoking history, and body mass index at diagnosis. RESULTS: In the overall population, neither long-term diabetes (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.97-1.26) nor recently diagnosed diabetes (HR, 1.06; 95% CI, 0.94-1.18) was associated with shorter survival. When stratified by stage of disease, long-term diabetes was associated with 42% increase in rate of death in persons with resectable PDAC (HR, 1.42; 95% CI, 1.13-1.78), whereas it was not associated with survival in PDAC patients with more advanced disease. CONCLUSION: Long-term diabetes was associated with increased rate of death in patients with resectable PDAC.

11 Article Exome-Wide Association Study of Pancreatic Cancer Risk. 2018

Grant, Robert C / Denroche, Robert E / Borgida, Ayelet / Virtanen, Carl / Cook, Natalie / Smith, Alyssa L / Connor, Ashton A / Wilson, Julie M / Peterson, Gloria / Roberts, Nicholas J / Klein, Alison P / Grimmond, Sean M / Biankin, Andrew / Cleary, Sean / Moore, Malcolm / Lemire, Mathieu / Zogopoulos, George / Stein, Lincoln / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Canada. · Ontario Pancreas Cancer Study, Toronto, Canada. · Princess Margaret Genomics Centre, Toronto, Canada. · Research Institute of the McGill University Health Centre, Montreal, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Pathology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, Maryland. · University of Melbourne Centre for Cancer Research, Victorian Comprehensive Cancer Centre, Melbourne, Australia. · Wohl Cancer Research Centre, Institute of, Cancer Sciences, University of Glasgow, Glasgow, United Kingdom; West of Scotland Pancreatic Unit, Glasgow Royal Infirmary, Glasgow, United Kingdom; South Western Sydney Clinical School, Faculty of Medicine, University of NSW, Liverpool, Australia. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. · Ontario Institute for Cancer Research, Toronto, Canada; Ontario Pancreas Cancer Study, Toronto, Canada. Electronic address: steven.gallinger@uhn.ca. ·Gastroenterology · Pubmed #29074453.

ABSTRACT: We conducted a case-control exome-wide association study to discover germline variants in coding regions that affect risk for pancreatic cancer, combining data from 5 studies. We analyzed exome and genome sequencing data from 437 patients with pancreatic cancer (cases) and 1922 individuals not known to have cancer (controls). In the primary analysis, BRCA2 had the strongest enrichment for rare inactivating variants (17/437 cases vs 3/1922 controls) (P = 3.27x10

12 Article Association of Distinct Mutational Signatures With Correlates of Increased Immune Activity in Pancreatic Ductal Adenocarcinoma. 2017

Connor, Ashton A / Denroche, Robert E / Jang, Gun Ho / Timms, Lee / Kalimuthu, Sangeetha N / Selander, Iris / McPherson, Treasa / Wilson, Gavin W / Chan-Seng-Yue, Michelle A / Borozan, Ivan / Ferretti, Vincent / Grant, Robert C / Lungu, Ilinca M / Costello, Eithne / Greenhalf, William / Palmer, Daniel / Ghaneh, Paula / Neoptolemos, John P / Buchler, Markus / Petersen, Gloria / Thayer, Sarah / Hollingsworth, Michael A / Sherker, Alana / Durocher, Daniel / Dhani, Neesha / Hedley, David / Serra, Stefano / Pollett, Aaron / Roehrl, Michael H A / Bavi, Prashant / Bartlett, John M S / Cleary, Sean / Wilson, Julie M / Alexandrov, Ludmil B / Moore, Malcolm / Wouters, Bradly G / McPherson, John D / Notta, Faiyaz / Stein, Lincoln D / Gallinger, Steven. ·PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada4Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada5Department of Statistical Science, University of Toronto, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada6Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada2Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. · Transformative Pathology, Ontario Institute for Cancer Research, Toronto, Ontario, Canada. · University of Liverpool, Liverpool, England. · Heidelberg University Hospital, Heidelberg, Germany. · Mayo Clinic, Rochester, Minnesota. · Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts. · University of Nebraska Medical Centre, Omaha, Nebraska. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. · Division of Medical Oncology, Princess Margaret Cancer Centre, Toronto, Ontario, Canada. · Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada15Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada16Department of Pathology, University Health Network, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada18BioSpecimen Sciences Program, University Health Network, Toronto, Ontario, Canada. · PanCuRx Translational Research Initiative, Ontario Institute for Cancer Research, Toronto, Ontario, Canada3Hepatobiliary/Pancreatic Surgical Oncology Program, University Health Network, Toronto, Ontario, Canada. · Theoretical Biology and Biophysics (T-6), Los Alamos National Laboratory, Los Alamos, New Mexico20Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. · Genome Technologies Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada17Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. · Informatics and Bio-computing Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada13Molecular Genetics Department, University of Toronto, Toronto, Ontario, Canada. ·JAMA Oncol · Pubmed #27768182.

ABSTRACT: Importance: Outcomes for patients with pancreatic ductal adenocarcinoma (PDAC) remain poor. Advances in next-generation sequencing provide a route to therapeutic approaches, and integrating DNA and RNA analysis with clinicopathologic data may be a crucial step toward personalized treatment strategies for this disease. Objective: To classify PDAC according to distinct mutational processes, and explore their clinical significance. Design, Setting, and Participants: We performed a retrospective cohort study of resected PDAC, using cases collected between 2008 and 2015 as part of the International Cancer Genome Consortium. The discovery cohort comprised 160 PDAC cases from 154 patients (148 primary; 12 metastases) that underwent tumor enrichment prior to whole-genome and RNA sequencing. The replication cohort comprised 95 primary PDAC cases that underwent whole-genome sequencing and expression microarray on bulk biospecimens. Main Outcomes and Measures: Somatic mutations accumulate from sequence-specific processes creating signatures detectable by DNA sequencing. Using nonnegative matrix factorization, we measured the contribution of each signature to carcinogenesis, and used hierarchical clustering to subtype each cohort. We examined expression of antitumor immunity genes across subtypes to uncover biomarkers predictive of response to systemic therapies. Results: The discovery cohort was 53% male (n = 79) and had a median age of 67 (interquartile range, 58-74) years. The replication cohort was 50% male (n = 48) and had a median age of 68 (interquartile range, 60-75) years. Five predominant mutational subtypes were identified that clustered PDAC into 4 major subtypes: age related, double-strand break repair, mismatch repair, and 1 with unknown etiology (signature 8). These were replicated and validated. Signatures were faithfully propagated from primaries to matched metastases, implying their stability during carcinogenesis. Twelve of 27 (45%) double-strand break repair cases lacked germline or somatic events in canonical homologous recombination genes-BRCA1, BRCA2, or PALB2. Double-strand break repair and mismatch repair subtypes were associated with increased expression of antitumor immunity, including activation of CD8-positive T lymphocytes (GZMA and PRF1) and overexpression of regulatory molecules (cytotoxic T-lymphocyte antigen 4, programmed cell death 1, and indolamine 2,3-dioxygenase 1), corresponding to higher frequency of somatic mutations and tumor-specific neoantigens. Conclusions and Relevance: Signature-based subtyping may guide personalized therapy of PDAC in the context of biomarker-driven prospective trials.

13 Article Effect of Pancreatic Fistula on Recurrence and Long-Term Prognosis of Periampullary Adenocarcinomas after Pancreaticoduodenectomy. 2016

Serrano, Pablo E / Kim, Dowan / Kim, Peter T / Greig, Paul D / Moulton, Carol-Anne / Gallinger, Steven / Wei, Alice C / Cleary, Sean P. ·Department of Surgery, McMaster University, Hamilton, Canada. ·Am Surg · Pubmed #28234183.

ABSTRACT: Pancreatic fistula (PF) is common after pancreaticoduodenectomy (PD). Its effect on recurrence and survival is not known. Retrospective study of patients undergoing PD for periampullary adenocarcinomas (2000-2012). Standard statistical analyses were performed to determine the impact of PF on disease-free survival (DFS) and overall survival (OS). There were 634 PDs (pancreatic adenocarcinoma: 347, other periampullary adenocarcinomas: 287). Any-grade PF developed in 81/634 (13%). Perioperative mortality rate was 1.7 per cent (11/634), higher in patients with PF (10 vs 0.5%, P < 0.001). In multivariable analysis, PF significantly reduced DFS in pancreatic [hazard ratio (HR) = 1.6, 95% confidence-interval (CI): 1.1-2.6, P = 0.043] but not in other periampullary adenocarcinomas [HR = 1.3 (95% CI: 0.8-2.2), P = 0.45]. Positive lymph nodes, margins, and high-grade histology were associated with decreased DFS and OS. Adjuvant therapy was associated with improved OS in pancreatic [HR = 0.7 (95% CI: 0.5-0.9), P = 0.02] but not in other periampullary adenocarcinomas [HR = 1.14 (95% CI: 0.8-1.7), P = 0.49]. PF did not alter OS in either group. After PD, PF is associated with decreased DFS in pancreatic but not in other periampullary adenocarcinomas. This decrease DFS did not alter OS. Tumor grade, lymph nodes, and resection margin status are associated with DFS and OS.

14 Article Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016. 2016

Bossé, D / Ng, T / Ahmad, C / Alfakeeh, A / Alruzug, I / Biagi, J / Brierley, J / Chaudhury, P / Cleary, S / Colwell, B / Cripps, C / Dawson, L A / Dorreen, M / Ferland, E / Galiatsatos, P / Girard, S / Gray, S / Halwani, F / Kopek, N / Mahmud, A / Martel, G / Robillard, L / Samson, B / Seal, M / Siddiqui, J / Sideris, L / Snow, S / Thirwell, M / Vickers, M / Goodwin, R / Goel, R / Hsu, T / Tsvetkova, E / Ward, B / Asmis, T. ·Ontario: The Ottawa Hospital Cancer Centre, Ottawa (Asmis, Bossé, Cripps, Goel, Goodwin, Halwani, Hsu, Martel, Ng, Robillard, Vickers); Queen's University and Cancer Centre of Southeastern Ontario, Kingston (Biagi); Princess Margaret Cancer Centre, Toronto (Brierley, Cleary, Dawson); Juravinski Cancer Centre, Hamilton (Tsvetkova); Cancer Centre of Southeastern Ontario, Kingston (Mahmud). · Newfoundland and Labrador: Dr. H. Bliss Murphy Cancer Centre, St. John's (Ahmad, Seal, Siddiqui). · Quebec: Hôpital Charles-LeMoyne Cancer Centre, Greenfield Park (Samson); McGill University Health Centre, Montreal (Alfakeeh, Alruzug, Chaudhury, Kopek, Thirlwell, Ward); Sir Mortimer B. Davis Jewish General Hospital (Galiatsatos); Centre Hospitalier Pierre-Boucher (Ferland); Centre Hospitalier Universitaire de Montréal (Girard, Sideris). · Nova Scotia: QEII Health Sciences Centre, Halifax (Colwell, Dorreen, Snow). · New Brunswick: Saint John Regional Hospital, Saint John (Gray). ·Curr Oncol · Pubmed #28050151.

ABSTRACT: The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2016 was held in Montreal, Quebec, 5-7 February. Experts in radiation oncology, medical oncology, surgical oncology, and infectious diseases involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics: ■ Follow-up and survivorship of patients with resected colorectal cancer■ Indications for liver metastasectomy■ Treatment of oligometastases by stereotactic body radiation therapy■ Treatment of borderline resectable and unresectable pancreatic cancer■ Transarterial chemoembolization in hepatocellular carcinoma■ Infectious complications of antineoplastic agents.

15 Article A renewed model of pancreatic cancer evolution based on genomic rearrangement patterns. 2016

Notta, Faiyaz / Chan-Seng-Yue, Michelle / Lemire, Mathieu / Li, Yilong / Wilson, Gavin W / Connor, Ashton A / Denroche, Robert E / Liang, Sheng-Ben / Brown, Andrew M K / Kim, Jaeseung C / Wang, Tao / Simpson, Jared T / Beck, Timothy / Borgida, Ayelet / Buchner, Nicholas / Chadwick, Dianne / Hafezi-Bakhtiari, Sara / Dick, John E / Heisler, Lawrence / Hollingsworth, Michael A / Ibrahimov, Emin / Jang, Gun Ho / Johns, Jeremy / Jorgensen, Lars G T / Law, Calvin / Ludkovski, Olga / Lungu, Ilinca / Ng, Karen / Pasternack, Danielle / Petersen, Gloria M / Shlush, Liran I / Timms, Lee / Tsao, Ming-Sound / Wilson, Julie M / Yung, Christina K / Zogopoulos, George / Bartlett, John M S / Alexandrov, Ludmil B / Real, Francisco X / Cleary, Sean P / Roehrl, Michael H / McPherson, John D / Stein, Lincoln D / Hudson, Thomas J / Campbell, Peter J / Gallinger, Steven. ·Ontario Institute for Cancer Research, Toronto, Ontario M5G 0A3, Canada. · Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK. · UHN Program in BioSpecimen Sciences, Department of Pathology, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 1L7, Canada. · Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Department of Computer Science, University of Toronto, Toronto, Ontario M5S 3G4, Canada. · Eppley Institute for Research in Cancer, Nebraska Medical Center, Omaha, Nebraska 68198, USA. · Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A8, Canada. · Princess Margaret Cancer Centre, University Health Network (UHN), Toronto, Ontario M5G 2M9, Canada. · Division of Surgical Oncology, Sunnybrook Health Sciences Centre, Odette Cancer Centre, Toronto, Ontario M4N 3M5, Canada. · Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905, USA. · Research Institute of the McGill University Health Centre, Montreal, Québec, Canada, H3H 2L9. · Theoretical Biology and Biophysics (T-6) and Center for Nonlinear Studies, Los Alamos National Laboratory, Los Alamos, New Mexico, USA, 87545. · Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario M5G 1X5, Canada. · Department of Surgery, University Health Network, Toronto, Ontario M5G 2C4, Canada. · Department of Haematology, University of Cambridge, Cambridge CB2 0XY, UK. ·Nature · Pubmed #27732578.

ABSTRACT: Pancreatic cancer, a highly aggressive tumour type with uniformly poor prognosis, exemplifies the classically held view of stepwise cancer development. The current model of tumorigenesis, based on analyses of precursor lesions, termed pancreatic intraepithelial neoplasm (PanINs) lesions, makes two predictions: first, that pancreatic cancer develops through a particular sequence of genetic alterations (KRAS, followed by CDKN2A, then TP53 and SMAD4); and second, that the evolutionary trajectory of pancreatic cancer progression is gradual because each alteration is acquired independently. A shortcoming of this model is that clonally expanded precursor lesions do not always belong to the tumour lineage, indicating that the evolutionary trajectory of the tumour lineage and precursor lesions can be divergent. This prevailing model of tumorigenesis has contributed to the clinical notion that pancreatic cancer evolves slowly and presents at a late stage. However, the propensity for this disease to rapidly metastasize and the inability to improve patient outcomes, despite efforts aimed at early detection, suggest that pancreatic cancer progression is not gradual. Here, using newly developed informatics tools, we tracked changes in DNA copy number and their associated rearrangements in tumour-enriched genomes and found that pancreatic cancer tumorigenesis is neither gradual nor follows the accepted mutation order. Two-thirds of tumours harbour complex rearrangement patterns associated with mitotic errors, consistent with punctuated equilibrium as the principal evolutionary trajectory. In a subset of cases, the consequence of such errors is the simultaneous, rather than sequential, knockout of canonical preneoplastic genetic drivers that are likely to set-off invasive cancer growth. These findings challenge the current progression model of pancreatic cancer and provide insights into the mutational processes that give rise to these aggressive tumours.

16 Article BRM polymorphisms, pancreatic cancer risk and survival. 2016

Segedi, Maja / Anderson, Laura N / Espin-Garcia, Osvaldo / Borgida, Ayelet / Bianco, Teresa / Cheng, Dangxiao / Chen, Zhuo / Patel, Devalben / Brown, M Catherine / Xu, Wei / Reisman, David / Gallinger, Steven / Cotterchio, Michelle / Hung, Rayjean / Liu, Geoffrey / Cleary, Sean P. ·Department of Surgery, University of British Columbia, Vancouver, BC, Canada. · Princess Margaret Cancer Centre-University Health Network-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada. · Mount Sinai Hospital-Lunenfeld Research Institute, Toronto, ON, Canada. · Medical Oncology, University of Florida, Gainesville, FL. · Prevention and Cancer Control, Cancer Care Ontario, Toronto, ON, Canada. · Princess Margaret Cancer Centre-University Health Network-Ontario Cancer Institute, University of Toronto, Toronto, ON, Canada. Geoffrey.Liu@uhn.ca. ·Int J Cancer · Pubmed #27487558.

ABSTRACT: Variant alleles of two promoter polymorphisms in the BRM gene (BRM-741, BRM-1321), create MEF2D transcription binding sites that lead to epigenetic silencing of BRM, the key catalytic component of the SWI/SNF chromatin remodeling complex. BRM suppression can be reversed pharmacologically.(1) Our group and others have reported associations with lung, head and neck, hepatocellular cancer risk,(1-3) and with lung and esophageal cancer prognosis (ASCO 2013; abstract 11057 & 4077). Herein, we assessed risk and survival associations with pancreatic cancer. A provincial population-based case-control study was conducted with 623 histologically confirmed pancreatic adenocarcinoma cases and 1,192 age/gender distribution-matched controls.(4) Survival of cases was obtained through the Ontario Cancer Registry. Logistic and Cox proportional hazard regression models were fitted, adjusting for relevant covariates. Median age was 65 y; 52% were male; Stage I (8%), II (55%), III (14%), IV (23%); 53% after curative resection, 79% after chemotherapy; and 83% had died. In the risk analysis, adjusted odds ratios (aOR) were 1.01 (95% CI: 0.1-2.0) and 0.96 (95% CI: 0.7-1.3) for the homozygotes of BRM-741 and BRM-1321, respectively; aOR of double-homozygotes was 1.11 (95% CI: 0.80-1.53), compared to the double-wildtype. For the survival analysis, adjusted hazard ratios (aHR) were 2.19 (95% CI: 1.9-2.5) for BRM-741 and 1.94 (95% CI: 1.7-2.2) for BRM-1321, per unit increase in variant alleles. Compared with the double-wildtype, aHR for carrying no, one, and two double-homozygotes were 2.14 (95% CI: 1.6-2.8), 4.17 (95% CI: 3.0-5.7), 8.03 (95% CI: 5.7-11.4), respectively. In conclusion, two functional promoter BRM polymorphisms were not associated with pancreatic adenocarcinoma risk, but are strongly associated with survival.

17 Article Candidate DNA repair susceptibility genes identified by exome sequencing in high-risk pancreatic cancer. 2016

Smith, Alyssa L / Alirezaie, Najmeh / Connor, Ashton / Chan-Seng-Yue, Michelle / Grant, Robert / Selander, Iris / Bascuñana, Claire / Borgida, Ayelet / Hall, Anita / Whelan, Thomas / Holter, Spring / McPherson, Treasa / Cleary, Sean / Petersen, Gloria M / Omeroglu, Atilla / Saloustros, Emmanouil / McPherson, John / Stein, Lincoln D / Foulkes, William D / Majewski, Jacek / Gallinger, Steven / Zogopoulos, George. ·Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3. · McGill University and Genome Quebec Innovation Centre, 740 Dr. Penfield Avenue, Montreal, QC, Canada H3A 0G1. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3. · MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7. · Department of Health Sciences Research, Mayo Clinic College of Medicine, 200 First Street SW, Rochester, MN 55905, USA. · Department of Pathology, McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1. · Department of Medical Oncology, Hereditary Cancer Clinic, University Hospital of Heraklion, Voutes, Heraklion 71110, Greece. · Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Avenue, Toronto, ON, Canada M5G 1X5; MaRS Centre, Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON, Canada M5G 0A3; Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, 60 Murray Street, Toronto, ON, Canada M5T 3H7. Electronic address: steven.gallinger@uhn.ca. · Research Institute of the McGill University Health Centre, 1001 Décarie Boulevard, Montreal, QC, Canada H4A 3J1; Goodman Cancer Research Centre, McGill University, 1160 Pine Avenue West, Montreal, QC, Canada H3A 1A3; Program in Cancer Genetics, Departments of Oncology and Human Genetics, Sir Mortimer B. Davis-Jewish General Hospital, McGill University, 3755 Côte-Ste-Catherine Road, Montreal, QC, Canada H3T 1E2. Electronic address: george.zogopoulos@mcgill.ca. ·Cancer Lett · Pubmed #26546047.

ABSTRACT: The genetic basis underlying the majority of hereditary pancreatic adenocarcinoma (PC) is unknown. Since DNA repair genes are widely implicated in gastrointestinal malignancies, including PC, we hypothesized that there are novel DNA repair PC susceptibility genes. As germline DNA repair gene mutations may lead to PC subtypes with selective therapeutic responses, we also hypothesized that there is an overall survival (OS) difference in mutation carriers versus non-carriers. We therefore interrogated the germline exomes of 109 high-risk PC cases for rare protein-truncating variants (PTVs) in 513 putative DNA repair genes. We identified PTVs in 41 novel genes among 36 kindred. Additional genetic evidence for causality was obtained for 17 genes, with FAN1, NEK1 and RHNO1 emerging as the strongest candidates. An OS difference was observed for carriers versus non-carriers of PTVs with early stage (≤IIB) disease. This adverse survival trend in carriers with early stage disease was also observed in an independent series of 130 PC cases. We identified candidate DNA repair PC susceptibility genes and suggest that carriers of a germline PTV in a DNA repair gene with early stage disease have worse survival.

18 Article Ductal pancreatic cancer modeling and drug screening using human pluripotent stem cell- and patient-derived tumor organoids. 2015

Huang, Ling / Holtzinger, Audrey / Jagan, Ishaan / BeGora, Michael / Lohse, Ines / Ngai, Nicholas / Nostro, Cristina / Wang, Rennian / Muthuswamy, Lakshmi B / Crawford, Howard C / Arrowsmith, Cheryl / Kalloger, Steve E / Renouf, Daniel J / Connor, Ashton A / Cleary, Sean / Schaeffer, David F / Roehrl, Michael / Tsao, Ming-Sound / Gallinger, Steven / Keller, Gordon / Muthuswamy, Senthil K. ·Princess Margaret Cancer Center, University Health Network (UHN), University of Toronto, Toronto, Ontario, Canada. · McEwen Center for Regenerative Medicine, University Health Network, Toronto, Ontario, Canada. · Department of Physiology, Western University, London, Ontario, Canada. · Department of Pharmacology, Western University, London, Ontario, Canada. · Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan. · Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan. · Structural Genomics Consortium, Toronto, Ontario, Canada. · Division of Anatomic Pathology, Vancouver General Hospital, Vancouver, British Columbia, Canada. · Department of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada. · Pancreas Centre British Columbia, Vancouver, British Columbia, Canada. · Division of Medical Oncology, British Columbia Cancer Agency, Vancouver, British Columbia, Canada. · Division of General Surgery, University of Toronto, Toronto, Ontario, Canada. · Department of Pathology, University Health Network, Toronto, Ontario, Canada. ·Nat Med · Pubmed #26501191.

ABSTRACT: There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo. Expression of TP53(R175H) induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

19 Article Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer. 2015

Childs, Erica J / Mocci, Evelina / Campa, Daniele / Bracci, Paige M / Gallinger, Steven / Goggins, Michael / Li, Donghui / Neale, Rachel E / Olson, Sara H / Scelo, Ghislaine / Amundadottir, Laufey T / Bamlet, William R / Bijlsma, Maarten F / Blackford, Amanda / Borges, Michael / Brennan, Paul / Brenner, Hermann / Bueno-de-Mesquita, H Bas / Canzian, Federico / Capurso, Gabriele / Cavestro, Giulia M / Chaffee, Kari G / Chanock, Stephen J / Cleary, Sean P / Cotterchio, Michelle / Foretova, Lenka / Fuchs, Charles / Funel, Niccola / Gazouli, Maria / Hassan, Manal / Herman, Joseph M / Holcatova, Ivana / Holly, Elizabeth A / Hoover, Robert N / Hung, Rayjean J / Janout, Vladimir / Key, Timothy J / Kupcinskas, Juozas / Kurtz, Robert C / Landi, Stefano / Lu, Lingeng / Malecka-Panas, Ewa / Mambrini, Andrea / Mohelnikova-Duchonova, Beatrice / Neoptolemos, John P / Oberg, Ann L / Orlow, Irene / Pasquali, Claudio / Pezzilli, Raffaele / Rizzato, Cosmeri / Saldia, Amethyst / Scarpa, Aldo / Stolzenberg-Solomon, Rachael Z / Strobel, Oliver / Tavano, Francesca / Vashist, Yogesh K / Vodicka, Pavel / Wolpin, Brian M / Yu, Herbert / Petersen, Gloria M / Risch, Harvey A / Klein, Alison P. ·Department of Epidemiology, Johns Hopkins School of Public Health, Baltimore, Maryland, USA. · Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · 1] Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. [2] Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA. · Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, Ontario, Canada. · Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. · Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA. · Department of Population Health, QIMR Berghofer Medical Research Institute, Kelvin Grove,Queensland, Australia. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · International Agency for Research on Cancer (IARC), Lyon, France. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, US Department of Health and Human Services, Bethesda, Maryland, USA. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, Minnesota, USA. · Laboratory for Experimental Oncology and Radiobiology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), German Cancer Consortium (DKTK), Heidelberg, Germany. · 1] Department for Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, the Netherlands. [2] Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, the Netherlands. [3] Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. [4] Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Digestive and Liver Disease Unit, 'Sapienza' University of Rome, Rome, Italy. · Università Vita Salute San Raffaele and Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milan, Italy. · 1] Department of Surgery, University Health Network, University of Toronto, Toronto, Ontario, Canada. [2] Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada. · 1] Cancer Care Ontario, University of Toronto, Toronto, Ontario, Canada. [2] Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute and Medical Faculty Masaryk University, Brno, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · Department of Medical Sciences, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Department of Radiation Oncology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic. · Cancer Epidemiology Unit, University of Oxford, Oxford, UK. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA. · Department of Biology, Section of Genetics, University of Pisa, Pisa, Italy. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, Connecticut, USA. · Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland. · Department of Oncology, Azienda USL 1 Massa Carrara, Massa Carrara, Italy. · Laboratory of Toxicogenomics, Institute of Public Health, Prague, Czech Republic. · National Institute for Health Research (NIHR) Pancreas Biomedical Research Unit, Liverpool Clinical Trials Unit and Cancer Research UK Clinical Trials Unit, Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, UK. · Department of Surgery, Gastroenterology and Oncology, University of Padua, Padua, Italy. · Pancreas Unit, Department of Digestive Diseases, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · ARC-NET-Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Rockville, Maryland, USA. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital 'Casa Sollievo della Sofferenza', San Giovanni Rotondo, Italy. · Department of General, Visceral and Thoracic Surgery, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Sciences, Prague, Czech Republic. · 1] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. [2] Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA. · Epidemiology Program, University of Hawaii Cancer Center, Honolulu, Hawaii, USA. · 1] Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. [2] Department of Pathology, Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins School of Medicine, Baltimore, Maryland, USA. ·Nat Genet · Pubmed #26098869.

ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10(-14)), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10(-8)) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10(-8)). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10(-9)), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk.

20 Article Vitamin D and pancreatic cancer: a pooled analysis from the Pancreatic Cancer Case-Control Consortium. 2015

Waterhouse, M / Risch, H A / Bosetti, C / Anderson, K E / Petersen, G M / Bamlet, W R / Cotterchio, M / Cleary, S P / Ibiebele, T I / La Vecchia, C / Skinner, H G / Strayer, L / Bracci, P M / Maisonneuve, P / Bueno-de-Mesquita, H B / Zaton Ski, W / Lu, L / Yu, H / Janik-Koncewicz, K / Polesel, J / Serraino, D / Neale, R E / Anonymous4011075. ·Division of Population Health, QIMR Berghofer Medical Research Institute, Herston Centre for Research Excellence in Sun and Health, Queensland University of Technology, Kelvin Grove, Australia. · Department of Chronic Disease Epidemiology, Yale School of Public Health, New Haven, USA. · Department of Epidemiology, IRCCS-Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy. · Division of Epidemiology and Community Health, University of Minnesota, Minneapolis. · Department of Health Sciences Research, Mayo Clinic, Rochester, USA. · Prevention and Cancer Control, Cancer Care Ontario, Toronto Dalla Lana School of Public Health, University of Toronto, Toronto. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto Department of Surgery, University of Toronto, Toronto, Canada. · Division of Population Health, QIMR Berghofer Medical Research Institute, Herston. · Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. · Truven Health Analytics, Durham. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · National Institute for Public Health and the Environment, Bilthoven Department of Gastroenterology and Hepatology, University Medical Centre Utrecht, Utrecht, The Netherlands Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK. · Department of Epidemiology, The Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland. · Epidemiology Program, University of Hawaii Cancer Center, Honolulu, USA. · Division of Population Health, QIMR Berghofer Medical Research Institute, Herston Centre for Research Excellence in Sun and Health, Queensland University of Technology, Kelvin Grove, Australia rachel.neale@qimrberghofer.edu.au. ·Ann Oncol · Pubmed #25977560.

ABSTRACT: BACKGROUND: The potential role of vitamin D in the aetiology of pancreatic cancer is unclear, with recent studies suggesting both positive and negative associations. PATIENTS AND METHODS: We used data from nine case-control studies from the International Pancreatic Cancer Case-Control Consortium (PanC4) to examine associations between pancreatic cancer risk and dietary vitamin D intake. Study-specific odds ratios (ORs) were estimated using multivariable logistic regression, and ORs were then pooled using a random-effects model. From a subset of four studies, we also calculated pooled estimates of association for supplementary and total vitamin D intake. RESULTS: Risk of pancreatic cancer increased with dietary intake of vitamin D [per 100 international units (IU)/day: OR = 1.13, 95% confidence interval (CI) 1.07-1.19, P = 7.4 × 10(-6), P-heterogeneity = 0.52; ≥230 versus <110 IU/day: OR = 1.31, 95% CI 1.10-1.55, P = 2.4 × 10(-3), P-heterogeneity = 0.81], with the association possibly stronger in people with low retinol/vitamin A intake. CONCLUSION: Increased risk of pancreatic cancer was observed with higher levels of dietary vitamin D intake. Additional studies are required to determine whether or not our finding has a causal basis.

21 Article TERT gene harbors multiple variants associated with pancreatic cancer susceptibility. 2015

Campa, Daniele / Rizzato, Cosmeri / Stolzenberg-Solomon, Rachael / Pacetti, Paola / Vodicka, Pavel / Cleary, Sean P / Capurso, Gabriele / Bueno-de-Mesquita, H B As / Werner, Jens / Gazouli, Maria / Butterbach, Katja / Ivanauskas, Audrius / Giese, Nathalia / Petersen, Gloria M / Fogar, Paola / Wang, Zhaoming / Bassi, Claudio / Ryska, Miroslav / Theodoropoulos, George E / Kooperberg, Charles / Li, Donghui / Greenhalf, William / Pasquali, Claudio / Hackert, Thilo / Fuchs, Charles S / Mohelnikova-Duchonova, Beatrice / Sperti, Cosimo / Funel, Niccola / Dieffenbach, Aida Karina / Wareham, Nicholas J / Buring, Julie / Holcátová, Ivana / Costello, Eithne / Zambon, Carlo-Federico / Kupcinskas, Juozas / Risch, Harvey A / Kraft, Peter / Bracci, Paige M / Pezzilli, Raffaele / Olson, Sara H / Sesso, Howard D / Hartge, Patricia / Strobel, Oliver / Małecka-Panas, Ewa / Visvanathan, Kala / Arslan, Alan A / Pedrazzoli, Sergio / Souček, Pavel / Gioffreda, Domenica / Key, Timothy J / Talar-Wojnarowska, Renata / Scarpa, Aldo / Mambrini, Andrea / Jacobs, Eric J / Jamroziak, Krzysztof / Klein, Alison / Tavano, Francesca / Bambi, Franco / Landi, Stefano / Austin, Melissa A / Vodickova, Ludmila / Brenner, Hermann / Chanock, Stephen J / Delle Fave, Gianfranco / Piepoli, Ada / Cantore, Maurizio / Zheng, Wei / Wolpin, Brian M / Amundadottir, Laufey T / Canzian, Federico. ·Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD. · Oncology Department, ASL1 Massa Carrara, Massa Carrara, Italy. · Department of Molecular Biology of Cancer, Institute of Experimental Medicine, Academy of Science of Czech Republic, Prague, Czech Republic. · Department of Surgery, University Health Network, University of Toronto, Toronto, ON, Canada. · Digestive and Liver Disease Unit, S. Andrea Hospital, 'Sapienza' University of Rome, Rome, Italy. · Department of Determinants of Chronic Diseases (DCD), National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands. · Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands. · Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, United Kingdom. · Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. · Department of General Surgery, University Hospital Heidelberg, Heidelberg, Germany. · Department of Basic Medical Science, Laboratory of Biology, School of Medicine, University of Athens, Athens, Greece. · Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany. · Department of Gastroenterology, Lithuanian University of Health Sciences, Kaunas, Lithuania. · Department of Health Sciences Research, Mayo Clinic College of Medicine, Rochester, MN. · Department of Laboratory Medicine, University Hospital of Padua, Padua, Italy. · Surgical and Oncological Department, Pancreas Institute - University and Hospital Trust of Verona, Verona, Italy. · Department of Surgery, Second Faculty of Medicine, Charles University in Prague and Central Military Hospital, Prague, Czech Republic. · 1st Department of Propaedeutic Surgery, School of Medicine, University of Athens, Athens, Greece. · Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, WA. · Department of Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, TX. · National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Liverpool, United Kingdom. · Department of Surgery, Gastroenterology and Oncology (DISCOG), University of Padua, Padua, Italy. · Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA. · Department of Oncology, Palacky University Medical School and Teaching Hospital in Olomouc, Olomouc, Czech Republic. · Department of Surgery, Unit of Experimental Surgical Pathology, University Hospital of Pisa, Pisa, Italy. · German Cancer Consortium (DKTK), Heidelberg, Germany. · MRC Epidemiology Unit, Institute of Metabolic Science, University of Cambridge, Cambridge, United Kingdom. · Divisions of Preventive Medicine and Aging, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA. · Institute of Hygiene and Epidemiology, First Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Medicine - DIMED, University of Padua, Padua, Italy. · Department of Epidemiology and Public Health, Yale School of Public Health, New Haven, CT. · Department of Epidemiology, Harvard School of Public Health, Boston, MA. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA. · Pancreas Unit, Department of Digestive Diseases and Internal Medicine, Sant'Orsola-Malpighi Hospital, Bologna, Italy. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY. · Department of Digestive Tract Diseases, Medical University of Łodz, Łodz, Poland. · Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD. · Division of Epidemiology, Departments of Obstetrics and Gynecology, Environmental Medicine, and Population Health, New York University School of Medicine, New York, NY. · Surgical Clinic 4, University of Padua, Padua, Italy. · Department of Toxicogenomics, National Institute of Public Health, Prague, Czech Republic. · Division of Gastroenterology and Research Laboratory, IRCCS Scientific Institute and Regional General Hospital "Casa Sollievo Della Sofferenza,", San Giovanni Rotondo, Italy. · Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, United Kingdom. · ARC-NET: Centre for Applied Research on Cancer, University and Hospital Trust of Verona, Verona, Italy. · Epidemiology Research Program, American Cancer Society, Atlanta, GA. · Department of Hematology, Institute of Hematology and Transfusion Medicine, Warsaw, Poland. · Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD. · Blood Transfusion Service, Azienda Ospedaliero Universitaria Meyer, Florence, Italy. · Department of Biology, University of Pisa, Pisa, Italy. · Department of Epidemiology, University of Washington, Seattle, WA. · Department of Medicine and Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN. ·Int J Cancer · Pubmed #25940397.

ABSTRACT: A small number of common susceptibility loci have been identified for pancreatic cancer, one of which is marked by rs401681 in the TERT-CLPTM1L gene region on chromosome 5p15.33. Because this region is characterized by low linkage disequilibrium, we sought to identify whether additional single nucleotide polymorphisms (SNPs) could be related to pancreatic cancer risk, independently of rs401681. We performed an in-depth analysis of genetic variability of the telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC) genes, in 5,550 subjects with pancreatic cancer and 7,585 controls from the PANcreatic Disease ReseArch (PANDoRA) and the PanScan consortia. We identified a significant association between a variant in TERT and pancreatic cancer risk (rs2853677, odds ratio = 0.85; 95% confidence interval = 0.80-0.90, p = 8.3 × 10(-8)). Additional analysis adjusting rs2853677 for rs401681 indicated that the two SNPs are independently associated with pancreatic cancer risk, as suggested by the low linkage disequilibrium between them (r(2) = 0.07, D' = 0.28). Three additional SNPs in TERT reached statistical significance after correction for multiple testing: rs2736100 (p = 3.0 × 10(-5) ), rs4583925 (p = 4.0 × 10(-5) ) and rs2735948 (p = 5.0 × 10(-5) ). In conclusion, we confirmed that the TERT locus is associated with pancreatic cancer risk, possibly through several independent variants.

22 Article Association between alcohol consumption and pancreatic cancer risk: a case-control study. 2015

Rahman, Farah / Cotterchio, Michelle / Cleary, Sean P / Gallinger, Steven. ·Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada. · Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada; Prevention and Cancer Control, Cancer Care Ontario, Toronto, Ontario, Canada. · Department of Surgery, University Health Network, Toronto, Ontario, Canada; Prosserman Centre for Health Research, Lunenfeld-Tanenbaum Research Institute, Toronto, Ontario, Canada. · Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada; Division of General Surgery, Toronto General Hospital, Toronto, Ontario, Canada. ·PLoS One · Pubmed #25856529.

ABSTRACT: PURPOSE: Evidence is inconsistent regarding alcohol and pancreatic cancer risk, although heavy drinking may increase risk. METHODS: A population-based case-control study was conducted using 345 pancreas cancer cases diagnosed 2011-2012 and 1,285 frequency-matched controls from Ontario, Canada. Logistic regression was used to evaluate alcohol consumption and pancreatic cancer risk; data was also stratified by sex and smoking status to assess interaction. RESULTS: Alcohol consumption was not associated with pancreatic cancer risk (age-adjusted odds ratio=0.78, 95% CI: 0.58, 1.05 for 1 - 3 drinks/week; age-adjusted odds ratio=0.86, 95% CI: 0.63, 1.17 for 4 - 20 drinks/week), however there was a non-significant increased risk for heavy drinkers consuming ≥ 21 drinks/week (age-adjusted odds ratio=1.35, 95% CI: 0.81, 2.27). Cigarette smoking modified the alcohol-cancer relationship; among current smokers, heavy alcohol consumption was associated with a significantly increased pancreatic cancer risk (age-adjusted odds ratio=4.04, 95% CI: 1.58, 10.37), whereas this significant association with heavy drinking was not observed among non-smokers (age-adjusted odds ratio=2.01, 95% CI: 0.50, 8.18). Furthermore, light - moderate alcohol intake was associated with increased pancreas cancer risk among current smokers. CONCLUSIONS: While alcohol was not significantly associated with pancreatic cancer risk, smoking status modified this relationship such that among current smokers, alcohol intake was associated with a greater than two-fold increased risk of pancreatic cancer. The results should be interpreted with caution due to small sample sizes within subgroups and correction for multiple comparisons should be considered. These findings should be replicated in larger studies where more precise estimates of risk can be obtained.

23 Article Improved long-term outcomes after resection of pancreatic adenocarcinoma: a comparison between two time periods. 2015

Serrano, Pablo E / Cleary, Sean P / Dhani, Neesha / Kim, Peter T W / Greig, Paul D / Leung, Kenneth / Moulton, Carol-Anne / Gallinger, Steven / Wei, Alice C. ·Department of Surgery, McMaster University, Hamilton, ON, Canada. ·Ann Surg Oncol · Pubmed #25348784.

ABSTRACT: BACKGROUND: Despite reduced perioperative mortality and routine use of adjuvant therapy following pancreatectomy for pancreatic ductal adenocarcinoma (PDAC), improvement in long-term outcome has been difficult to ascertain. This study compares outcomes in patients undergoing resection for PDAC within a single, high-volume academic institution over two sequential time periods. METHODS: Retrospective review of patients with resected PDAC, in two cohorts: period 1 (P1), 1991-2000; and period 2 (P2), 2001-2010. Univariate and multivariate analyses using the Cox proportional hazards model were performed to determine prognostic factors associated with long-term survival. Survival was evaluated using Kaplan-Meier analyses. RESULTS: A total of 179 pancreatectomies were performed during P1 and 310 during P2. Perioperative mortality was 6.7 % (12/179) in P1 and 1.6 % (5/310) in P2 (p = 0.003). P2 had a greater number of lymph nodes resected (17 [0-50] vs. 7 [0-31]; p < 0.001), and a higher lymph node positivity rate (69 % [215/310] vs. 58 % [104/179]; p = 0.021) compared with P1. The adjuvant therapy rate was 30 % (53/179) in P1 and 63 % (195/310) in P2 (p < 0.001). By multivariate analysis, node and margin status, tumor grade, adjuvant therapy, and time period of resection were independently associated with overall survival (OS) for both time periods. Median OS was 16 months (95 % confidence interval [CI] 14-20) in P1 and 27 months (95 % CI 24-30) in P2 (p < 0.001). CONCLUSIONS: Factors associated with improved long-term survival remain comparable over time. Short- and long-term survival for patients with resected PDAC has improved over time due to decreased perioperative mortality and increased use of adjuvant therapy, although the proportion of 5-year survivors remains small.

24 Article Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium. 2014

Bosetti, C / Rosato, V / Li, D / Silverman, D / Petersen, G M / Bracci, P M / Neale, R E / Muscat, J / Anderson, K / Gallinger, S / Olson, S H / Miller, A B / Bas Bueno-de-Mesquita, H / Scelo, G / Janout, V / Holcatova, I / Lagiou, P / Serraino, D / Lucenteforte, E / Fabianova, E / Ghadirian, P / Baghurst, P A / Zatonski, W / Foretova, L / Fontham, E / Bamlet, W R / Holly, E A / Negri, E / Hassan, M / Prizment, A / Cotterchio, M / Cleary, S / Kurtz, R C / Maisonneuve, P / Trichopoulos, D / Polesel, J / Duell, E J / Boffetta, P / La Vecchia, C. ·Department of Epidemiology, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy cristina.bosetti@marionegri.it. · Department of Epidemiology, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy. · M.D. Anderson Cancer Center, University of Texas, Houston. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda. · Department of Health Sciences Research, Medicine and Medical Genetics, Mayo Clinic, Rochester. · Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA. · Queensland Institute of Medical Research, Brisbane, Australia. · Department of Public Health Sciences, Penn State University, Penn State. · Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, USA. · University Health Network, Department of Surgery, University of Toronto, Toronto, Canada. · Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada. · National Institute for Public Health and the Environment (RIVM), Bilthoven Department of Gastroenterology and Hepatology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK. · International Agency for Research on Cancer (IARC), Lyon, France. · Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc. · Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic. · Department of Epidemiology, Harvard School of Public Health, Boston, USA Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Athens, Greece. · Unit of Epidemiology and Biostatistics, CRO Aviano National Cancer Institute, IRCCS, Aviano. · Department of Preclinical and Clinical Pharmacology Mario Aiazzi Mancini, Università degli Studi di Firenze, Florence, Italy. · Regional Authority of Public Health in Banská Bystrica, Banská Bystrica, Slovakia. · Department of Epidemiology, IRCCS - Istituto di Ricerche Farmacologiche 'Mario Negri', Milan, Italy M.D. Anderson Cancer Center, University of Texas, Houston Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda Department of Health Sciences Research, Medicine and Medical Genetics, Mayo Clinic, Rochester Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, USA Queensland Institute of Medical Research, Brisbane, Australia Department of Public Health Sciences, Penn State University, Penn State Division of Epidemiology and Community Health, University of Minnesota, Minneapolis, USA University Health Network, Department of Surgery, University of Toronto, Toronto, Canada Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, USA Dalla Lana School of Public Health, University of Toronto, Toronto, Canada National Institute for Public Health and the Environment (RIVM), Bilthoven Department of Gastroenterology and Hepatology, University Medical Center Utrecht (UMCU), Utrecht, The Netherlands Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, London, UK International Agency for Research on Cancer (IARC), Lyon, France Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc Institute of Hygiene and Epidemiology, 1st Faculty of Medicine, Charles University in Prague, Prague, Czech Republic Department of Epidemiology, Harvard School of Public Health, Boston, USA Department of Hygiene, Epidemiology and Medical Statistics, School of Medicine, University of Athens, Athens, Greece Unit of Epidemiology and Biostatistics, CRO Aviano National Cancer Institute, IRCCS, Aviano Department of Preclinical and Clinical Pharmacology Mario Aiazzi Mancini, Università degli Studi di Firenze, Florence, Italy Regional Authority of Public Health in Banská Bystrica, Banská Bystrica, Slovakia Public Health, Women · Public Health, Women's and Children's Hospital, Adelaide, SA, Australia. · Cancer Center and Institute of Oncology, Warsaw, Poland. · Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Institute and MF MU, Brno, Czech Republic. · Louisiana State University School of Public Health, New Orleans, USA. · Dalla Lana School of Public Health, University of Toronto, Toronto, Canada Cancer Care Ontario, Toronto, Canada. · Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, USA. · Division of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy. · Department of Epidemiology, Harvard School of Public Health, Boston, USA. · Unit of Nutrition, Environment and Cancer, Catalan Institute of Oncology (ICO-IDIBELL), L'Hospitalet de Llobregat, Barcelona, Spain. · The Tisch Cancer Institute and Institute for Translational Epidemiology, Icahn School of Medicine at Mount Sinai, New York, USA. · Department of Clinical Sciences and Community Health, Università degli Studi di Milano, Milan, Italy. ·Ann Oncol · Pubmed #25057164.

ABSTRACT: BACKGROUND: Type 2 diabetes mellitus has been associated with an excess risk of pancreatic cancer, but the magnitude of the risk and the time-risk relationship are unclear, and there is limited information on the role of antidiabetic medications. PATIENTS AND METHODS: We analyzed individual-level data from 15 case-control studies within the Pancreatic Cancer Case-Control Consortium, including 8305 cases and 13 987 controls. Pooled odds ratios (ORs) were estimated from multiple logistic regression models, adjusted for relevant covariates. RESULTS: Overall, 1155 (15%) cases and 1087 (8%) controls reported a diagnosis of diabetes 2 or more years before cancer diagnosis (or interview, for controls), corresponding to an OR of 1.90 (95% confidence interval, CI, 1.72-2.09). Consistent risk estimates were observed across strata of selected covariates, including body mass index and tobacco smoking. Pancreatic cancer risk decreased with duration of diabetes, but a significant excess risk was still evident 20 or more years after diabetes diagnosis (OR 1.30, 95% CI 1.03-1.63). Among diabetics, long duration of oral antidiabetic use was associated with a decreased pancreatic cancer risk (OR 0.31, 95% CI 0.14-0.69, for ≥15 years). Conversely, insulin use was associated with a pancreatic cancer risk in the short term (OR 5.60, 95% CI 3.75-8.35, for <5 years), but not for longer duration of use (OR 0.95, 95% CI 0.53-1.70, for ≥15 years). CONCLUSION: This study provides the most definitive quantification to date of an excess risk of pancreatic cancer among diabetics. It also shows that a 30% excess risk persists for more than two decades after diabetes diagnosis, thus supporting a causal role of diabetes in pancreatic cancer. Oral antidiabetics may decrease the risk of pancreatic cancer, whereas insulin showed an inconsistent duration-risk relationship.

25 Article Aberrant right hepatic artery in pancreaticoduodenectomy for adenocarcinoma: impact on resectability and postoperative outcomes. 2014

Kim, Peter T W / Temple, Sara / Atenafu, Eshetu G / Cleary, Sean P / Moulton, Carol-Anne / McGilvray, Ian D / Gallinger, Steven / Greig, Paul D / Wei, Alice C. ·Department of Surgical Oncology, University Health Network, Toronto, ON, Canada; Department of Surgery, University of Toronto, Toronto, ON, Canada. ·HPB (Oxford) · Pubmed #23782313.

ABSTRACT: OBJECTIVES: An aberrant right hepatic artery (aRHA) may pose technical and oncologic challenges during pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA) as a result of its proximity to the head of the pancreas. The aim of this study was to assess the impact of an aRHA on resectability, and perioperative and oncologic outcomes after PD for PA. METHODS: An 11-year retrospective cohort study was conducted. A total of 289 patients with PA scheduled for PD with intent for resection were included in the study. RESULTS: Of 289 patients, 249 underwent PD and 40 were found to have unresectable tumours. Incidences of aRHA in the resectable (14.9%) and unresectable (7.5%) groups were similar (P = 0.2); the main reasons for aborting PD were not directly related to the presence of an aRHA. In patients who underwent resection, complications occurred more frequently in the standard PD group (41.5% versus 24.3%; P = 0.04), but there was no difference in rates of positive margin (R1) resection (10.8% versus 16.0%; P = 0.4) or median overall survival (17 months versus 23 months; P = 0.1) between patients with and without an aRHA. CONCLUSIONS: The presence of an aRHA in patients with PA does not affect resectability. In patients with resectable tumours, the presence of an aRHA does not increase morbidity or R1 resection rates and does not impact on overall survival.

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